Extracellular phospholipases A2 in relation to systemic inflammatory response syndrome (SIRS) and systemic complications in severe acute pancreatitis.

The pathophysiology of severe acute pancreatitis (AP) resembles other conditions with systemic inflammatory response syndrome (SIRS) such as sepsis predisposing to remote organ failure. Because extracellular phospholipases A2 (PLA2) have been implicated in AP, their serum concentrations were analyzed with respect to SIRS and systemic complications in patients with severe AP. The serum samples were collected daily for 12 days in 57 patients with severe AP. SIRS, early organ complications, local complications, and outcome of AP were recorded. Time-resolved fluoroimmunoassays were used for group I and group II PLA2 measurements. Thirty-nine (68.4%) patients fulfilled the criteria of SIRS within 12 days from admission. Pancreatic necrosis was detected in 43 (75.4%) patients. Infected necrosis was found preoperatively or at operation in five (8.8%) patients. Twenty-six (45.6%) and eight (14.0%) patients had respiratory or renal failure, respectively. Seven (12.3%) patients died of their disease. All patients with systemic complications fulfilled the criteria of SIRS. The increasing number of positive SIRS criteria was associated with increased frequency of systemic complications. Pancreatic necrosis was not significantly associated with SIRS. The serum concentration of group II PLA2 was significantly higher in patients with SIRS (p < 0.05) compared with patients without from day 7 onward. The concentration of group II PLA2 increased (p < 0.01) in patients with SIRS but decreased in patients without. The serum concentration of group II PLA2 did not differ significantly with respect to systemic complications. The concentration of group I PLA2 decreased (p < 0.05) similarly in patients with and without SIRS or systemic complications during follow-up, respectively. Early systemic complications of severe AP are associated with SIRS with increasing frequency as the number of positive SIRS criteria increases. Group II PLA2 but not group I PLA2 may have pathophysiologic importance in severe AP-associated SIRS. Increasing serum concentration of group II PLA2 seems to reflect the ongoing systemic inflammation in severe AP-associated SIRS.

Bactericidal/permeability-increasing protein and group I and II phospholipase A2 during the induction phase of human acute pancreatitis.

Activated endogenous mediators of inflammation have important roles in the pathogenesis and complications of acute pancreatitis (AP). These mediators include bactericidal/ permeability-increasing protein (BPI) and phospholipase A2 (PLA2). The time course of their activation during human AP is not known. The aim of this study was to evaluate the kinetics of BPI, group I (pancreatic) and group II (synovial type) PLA2 during human AP with temporally defined onset, as being induced by endoscopic retrograde cholangiopancreatography (ERCP). Serum samples of 273 consecutive patients undergoing ERCP were collected before and at 3, 6, and 24 h after ERCP. Twenty-four (8.7%) patients developed ERCP-induced pancreatitis. Seven of them were graded to have a severe disease. Forty randomly selected patients undergoing ERCP without evidence of pancreatitis served as controls. The serum concentrations of BPI and groups I and II PLA2 were measured by specific immunoassays. The mean concentration of BPI increased from 14 to 26 microg/L at 24 h after ERCP in patients with AP. In the control group, BPI values remained unchanged, and the difference was statistically significant (p<0.001). The increase of BPI was seen in 22 of 28 patients with AP at 3 h after the onset of the disease. BPI values were higher in severe post-ERCP pancreatitis than in mild disease (p = 0.07; NS). The serum concentrations of group II PLA2 before ERCP were consistently higher in the control patients than in the patients with pancreatitis, 65.8 and 14.2 microg/L, respectively. High baseline values in the control group were associated with preexisting infectious diseases. Thereafter, the mean concentration decreased in the control group to 44 microg/L and increased in the pancreatitis group up to 27.5 microg/L. The difference was statistically significant (p = 0.007). Increased group II PLA2 values were seen in 10 of 17 patients with mild AP and in five of seven patients with severe disease. There were no significant differences in group I or II PLA2 values in patients with mild or severe AP. The serum concentration of group I PLA2 increased in the patients with post-ERCP pancreatitis from 5.4 to 37.5 microg/L at 24 h. The difference was statistically significant, (p< 0.001) as compared with controls. In conclusion, in acute pancreatitis, the increase of BPI in serum starts at 3 h after the onset of the disease, and the concentration seems to correlate with the severity of the disease. Increased group II PLA2 concentrations also were seen in patients with mild AP. The kinetics of group I PLA2 resembles that of other pancreatic enzymes.

Current principles of treatment in acute pancreatitis.

The treatment of mild acute pancreatitis (AP) with fluid replacement and other conservative measures is adequate and sufficient in the majority of patients. The corner-stones of the treatment of patients with severe acute pancreatitis include early aggressive fluid resuscitation, intensive care with close monitoring and support of organ function, antibiotic prophylaxis, early supportive treatment of organ failure, and surgery in selected cases with infected pancreatic necrosis or deterioration of patient's condition in spite of maximal conservative therapy. Early endoscopic removal of common bile duct stones should be considered in cases with biliary AP. Altogether, increased accuracy in early diagnosis and development of intensive care have resulted in a significant decrease in mortality of patients with severe pancreatitis. In this paper, we review the current principles and methods of treatment in acute pancreatitis at Helsinki University Central Hospital.

Rapid measurement of urinary trypsinogen-2 as a screening test for acute pancreatitis.

BACKGROUND: Acute pancreatitis can be difficult to diagnose. We developed a rapid dipstick screening test for pancreatitis, based on the immunochromatographic measurement of urinary trypsinogen-2. METHODS: We prospectively compared the urinary trypsinogen-2 dipstick test with a quantitative urinary trypsinogen-2 assay, a urinary dipstick test for amylase, and serum and urinary amylase assays in 500 consecutive patients with acute abdominal pain at two emergency departments. Acute pancreatitis was diagnosed according to standardized criteria. RESULTS: The urinary trypsinogen-2 dipstick test was positive in 50 of the 53 patients with acute pancreatitis (sensitivity, 94 percent), including all 7 with severe pancreatitis. Two patients with urinary trypsinogen-2 concentrations below the sensitivity threshold of the test (50 ng per milliliter) and one with a very high concentration had false negative results. The test was also positive in 21 of the 447 patients without pancreatitis (specificity, 95 percent), including 7 with abdominal cancers, 3 with cholangitis, and 2 with chronic pancreatitis. The sensitivity and specificity of the dipstick test were similar to those of the quantitative urinary trypsinogen-2 assay and higher than those of the urinary amylase dipstick test. The serum amylase assay had a sensitivity of 85 percent (with a cutoff value of 300 U per liter for the upper reference limit) and a specificity of 91 percent. The sensitivity and specificity of the urinary amylase assay (cutoff value, 2000 U per liter) were 83 and 88 percent, respectively. CONCLUSIONS: In patients with acute abdominal pain seen in the emergency department, a negative dipstick test for urinary trypsinogen-2 rules out acute pancreatitis with a high degree of probability. A positive test usually identifies patients in need of further evaluation.

Urinary trypsinogen-2 test strip in detecting ERCP-induced pancreatitis.

BACKGROUND AND STUDY AIMS: We have evaluated a new urinary trypsinogen-2 test strip, based on the principle of immunochromatography, in the diagnosis of acute pancreatitis induced by endoscopic retrograde cholangiopancreatography (ERCP). PATIENTS AND METHODS: One hundred six consecutive patients undergoing ERCP (with opacification of the pancreatic duct) at the Helsinki University Central Hospital were included in the study. Patients were tested with a urinary trypsinogen-2 test strip six hours after ERCP. Quantitative trypsinogen-2 as well as serum and urine amylase values were measured before the procedure and six hours after it. RESULTS: In patients developing pancreatitis after ERCP, the median urinary trypsinogen-2 concentration six hours after the endoscopic procedure was 1780 micrograms/l (range 29-10,700 micrograms/l), and in patients without pancreatitis the median concentration was 3.6 micrograms/l (range 0.1-3390 micrograms/l; P < 0.0001). The sensitivity and specificity figures for the urinary trypsinogen-2 test strip results in diagnosing post-ERCP pancreatitis were comparable (81% and 97%, respectively) to those for serum amylase (91% and 96%) and urine amylase measurements (81% and 95%). The test strip showed a good correlation (kappa = 0.75) with the quantitative trypsinogen-2 assay. CONCLUSIONS: The increase in urinary trypsinogen-2 concentration after ERCP reflects pancreatic injury, and can be detected by the test strip. Patients should be tested before the ERCP procedure as well, since elevated baseline values occur. The test is reliable and easy to perform even on an outpatient basis. However, its clinical usefulness requires evaluation in further trials.

Incorrect estimation of severity of acute pancreatitis by contrast-enhanced computed tomography.

BACKGROUND AND AIMS: In acute pancreatitis, contrast-enhanced CT is widely accepted to give reliable information in the early assessment of severity. This study critically evaluates the clinical data, outcome, and CE-CT findings in patients with incorrect radiological estimation of the severity of the condition. MATERIAL AND METHODS: All patients suspected of having severe pancreatitis underwent contrast-enhanced CT. Clinical data and CE-CT findings of 341 patients were re-examined. RESULTS AND CONCLUSIONS: In 28 patients (8.2%) the radiological diagnosis was inconsistent with the clinical findings. The most common reason--in 20 of the 28 patients (71.4%)--for failure to estimate the severity of pancreatitis was partial necrosis of the gland. In severe cases the partial necrosis was overlooked in nine patients (32.1%). In mild cases clinical significance of partial necrosis--overestimated as representative for the whole gland and technical failure both explained the incorrect interpretation in six (21.4%) patients; and in five patients (17.9%) intermediate patchy enhancement was incorrectly regarded as low. The misleading estimation remained inexplicable in only two (7.1%) patients. These results emphasize adequate assessment of CE-CT and inclusion of all areas of the pancreas in the estimation of enhancement.

Increased serum trypsinogen 2 and trypsin 2-alpha 1 antitrypsin complex values identify endoscopic retrograde cholangiopancreatography induced pancreatitis with high accuracy.

AIMS: To evaluate the clinical utility of two new tests for serum trypsinogen 2 and trypsin 2-alpha 1 antitrypsin complex (trypsin 2-AAT) in diagnosing and assessing the severity of acute pancreatitis (AP) induced by endoscopic retrograde cholangiopancreatography (ERCP). PATIENTS: Three hundred and eight consecutive patients undergoing ERCP at Helsinki University Central Hospital in 1994 and 1995. METHODS: Patients were followed prospectively for pancreatitis and clinical outcome. They were tested for serum trypsinogen 2, trypsin 2-AAT, and amylase in samples obtained before and one, six, and 24 hours after ERCP. RESULTS: Pancreatitis developed in 31 patients (10%). Their median serum trypsinogen 2 increased 26-fold to 1401 micrograms/l at six hours after the procedure and trypsin 2-AAT showed an 11-fold increase to 88 micrograms/l at 24 hours. The increase in both markers was stronger in severe than in mild pancreatitis, and in patients without pancreatitis there was no significant increase. Baseline trypsinogen 2 and trypsin 2-AAT concentrations were elevated in 29% and 32% of patients, respectively. The diagnostic accuracy of a threefold elevation over the baseline value was therefore analysed. The sensitivity and specificity of these parameters in the diagnosis of post-ERCP pancreatitis was 93% and 91%, respectively, for serum trypsinogen 2 at six hours after the examination, and 93% and 90%, for trypsin 2-AAT at 24 hours. CONCLUSIONS: Serum trypsinogen 2 and trypsin 2-AAT reflect pancreatic injury after ERCP. High concentrations are associated with severe pancreatic damage. The delayed increase in trypsin 2-AAT compared with trypsinogen 2 appears to reflect the pathophysiology of AP. A greater than threefold increase in trypsinogen 2 six hours after ERCP is an accurate indicator of pancreatitis.

Pancreatitis associated protein as an early marker of acute pancreatitis.

BACKGROUND: Measuring serum pancreatitis associated protein (PAP) in acute pancreatitis has proved valuable to monitoring the course of the disease and the recovery of the patient. AIMS: The aim was to analyze the utility of PAP on admission as a diagnostic and prognostic marker of acute pancreatitis. PATIENTS: Values of PAP were prospectively analyzed in 80 healthy volunteers, 164 patients with abdominal pain but without pancreatitis, 109 patients with mild acute pancreatitis, and 38 patients with severe acute pancreatitis. METHODS: The diagnosis of acute pancreatitis was verified with clinical, laboratory, radiological, and in some cases findings at operation or necropsy. RESULTS: Mean (95% confidence intervals) serum PAP values were 27 (24 to 29) micrograms/l in healthy volunteers, 78 (59 to 96) micrograms/l in patients with abdominal pain, 191 (134 to 247) micrograms/l, in patients with mild acute pancreatitis, and 599 (284 to 914) micrograms/l in patients with severe acute pancreatitis. Differences between the groups were significant (p = 0.04 - 0.01). Despite the differences in means, the ranges overlapped between the groups. The sensitivity of PAP on admission to detect acute pancreatitis was 38%-53% and the respective specificity 89%-77% depending on the cut off level. The sensitivity of PAP to detect severe acute pancreatitis was 45%-68% and the specificity 74%-59% depending on the cut off level. CONCLUSIONS: Admission PAP did not distinguish severe from mild acute pancreatitis better than C reactive protein. Measurement of PAP does not give appreciable diagnostic advantages in the early phase of acute pancreatitis.

Serum complex of trypsin 2 and alpha 1 antitrypsin as diagnostic and prognostic marker of acute pancreatitis: clinical study in consecutive patients.

OBJECTIVE: To estimate the usefulness of serum concentrations of the complex of trypsin 2 and alpha 1 antitrypsin in diagnosing and assessing the severity of acute pancreatitis in comparison with serum C reactive protein, amylase, and trypsinogen 2 concentrations (reference markers). DESIGN: Markers were measured in consecutive patients admitted with acute abdominal pain that was either due to pancreatitis or to other disease unrelated to the pancreas (controls). SETTING: Department of surgery of a teaching hospital in Helsinki. SUBJECTS: 110 patients with acute pancreatitis and 66 with acute abdominal diseases of extrapancreatic origin. On the basis of the clinical course, acute pancreatitis was classified as mild (82 patients) or severe (28 patients). MAIN OUTCOME MEASURES: Clinical diagnosis of acute pancreatitis and severity of the disease. RESULTS: At admission all patients with acute pancreatitis had clearly raised concentrations of trypsin 2-alpha 1 antitrypsin complex (32 micrograms/l), whereas only three of the controls had such values. Of the markers studied, trypsin 2-alpha 1 antitrypsin complex had the largest area under the receiver operating curve, both in differentiating acute pancreatitis from extrapancreatic disease and in differentiating mild from severe disease. CONCLUSIONS: Of the markers studied, trypsin 2-alpha 1 antitrypsin complex was the most accurate in differentiating between acute pancreatitis and extrapancreatic disease and in predicting a severe course for acute pancreatitis.

Serum trypsinogen-2 in the prediction of outcome in acute necrotizing pancreatitis.

BACKGROUND: The accuracy of serum trypsinogen-2 in predicting the severity of acute necrotizing pancreatitis (ANP) was prospectively evaluated in 52 consecutive patients. METHODS: A new sensitive immunofluorometric assay was used for serum trypsinogen-2, RESULTS: Mean values during the first 24 h were 42.1 micrograms/l in control patients, 1435 micrograms/l in uncomplicated cases, and 4090 micrograms/l in complicated or fatal cases. There was a significant difference in serum trypsinogen-2 values between patients with uncomplicated and complicated disease (p = 0.002) already on admission. When a cutoff level of 1000 micrograms/l was used, patients with uncomplicated ANP were differentiated from patients with complicated ANP with a sensitivity of 91% and with a specificity of 71%. CONCLUSIONS: The immunofluorometric assay of serum trypsinogen-2 is a sensitive and specific method for prediction of the severity of the disease in necrotizing pancreatitis.

Early localization of necrosis by contrast-enhanced computed tomography can predict outcome in severe acute pancreatitis.

A total of 161 primary contrast-enhanced computed tomography (CT) scans of patients with acute necrotizing pancreatitis taken between 1982 and 1994 were analysed retrospectively. The aim was to assess the prognostic significance of the extent and anatomical site of pancreatic tissue necrosis in the first contrast-enhanced CT scan. The scans were obtained a mean of 2.9 days after the onset of symptoms. The pancreatic head was affected in 107 patients, the body in 119 and the tail in 138. Pancreatic tissue necrosis, when divided into four groups according to anatomical site, correlated with overall clinical outcome. The anatomical site of necrosis was clearly better than its crude extent in predicting the risk of complications. For patients with necrosis in the head of the pancreas, the outcome was as severe as when the entire pancreas was affected. In contrast, for patients with necrosis only in the distal part of the pancreas, the outcome was favourable with few complications. The exact site of pancreatic tissue necrosis should be known when early contrast-enhanced CT is used in prognostic scoring.

Urine trypsinogen-2 as marker of acute pancreatitis.

We examined the clinical utility of urine trypsinogen-2 as a marker of acute pancreatitis (AP). Fifty-nine patients with AP, 42 with acute abdominal diseases of extrapancreatic origin, and 63 without evidence of acute abdominal disease were studied. Urine trypsinogen-2 was determined by a time-resolved immunofluorometric assay. As reference methods we used serum trypsinogen-2, urine amylase, and serum amylase. The diagnostic accuracy of the markers was evaluated by receiver-operating characteristic (ROC) analysis. At admission, urine trypsinogen-2 differentiated patients with AP from controls with high accuracy. The area under the ROC curve (AUC) was 0.978, which was equal to that of serum trypsinogen-2 (0.998) and serum amylase (0.969) and significantly larger than that of urine amylase. For differentiation between severe and mild AP, urine trypsinogen-2 (0.730) was equal to serum trypsinogen-2 (0.721), and clearly better than amylase in serum and urine. These results suggest that determination of urine trypsinogen-2 is a useful test to detect AP and to evaluate disease severity.

Early antibiotic treatment in acute necrotising pancreatitis.

Despite improvements in surgical treatment and intensive care, mortality from severe acute pancreatitis remains high. We have carried out a randomised study of 60 consecutive patients with alcohol-induced necrotising pancreatitis to find out whether early antibiotic treatment can improve outcome. 30 patients were assigned cefuroxime (4.5 g/day intravenously) from admission. In the second group, no antibiotic treatment was given until clinical or microbiologically verified infection or after a secondary rise in C-reactive protein. The inclusion criteria were C-reactive protein concentration above 120 mg/L within 48 h of admission and low enhancement (< 30 Hounsfield units) on contrast-enhanced computed tomography. There were more infectious complications in the non-antibiotic than in the antibiotic group (mean per patient 1.8 vs 1.0, p = 0.01). The most common cause of sepsis was Staphylococcus epidermidis; positive cultures were obtained from pancreatic necrosis or the central venous line in 14 of 18 patients with suspected but blood-culture-negative sepsis. Mortality was higher in the non-antibiotic group (seven vs one in the antibiotic group; p = 0.03). Four of the eight patients who died had cultures from pancreatic necrosis positive for Staph epidermidis. We conclude that cefuroxime given early in necrotising pancreatitis is beneficial and may reduce mortality, probably by decreasing the frequency of sepsis.

Time-resolved immunofluorometric assay of trypsin-2 complexed with alpha 1-antitrypsin in serum.

We developed a sensitive time-resolved immunofluorometric assay (IFMA) for trypsin-2 complexed with alpha 1-antitrypsin (AAT). We used a trypsin-2-specific monoclonal antibody on the solid phase and a europium-labeled polyclonal antibody to AAT as tracer. The detection limit is 0.05 microgram/L and the range of linearity extends to 100 micrograms/L. We compared the clinical utility of the trypsin-2-AAT assay with that of free trypsinogen-2 and amylase in serum by studying 120 healthy subjects, 29 patients with acute pancreatitis, 11 with extrahepatic biliary obstruction, and 34 with acute abdominal disorders of extrapancreatic origin. In patients with acute pancreatitis the median concentration of trypsin-2-AAT in serum was 59-fold that in healthy controls, 42-fold that in patients with biliary obstruction, and 33-fold that in patients with acute abdominal disorders of extrapancreatic origin. These differences are greater than those for trypsinogen-2 (19-, 20-, and 28-fold, respectively) and amylase (5.4-, 6.5-, and 5.4-fold, respectively). Compared with the assays of free trypsinogen-2 and amylase, our assay of trypsin-2-AAT improved the clinical specificity for acute pancreatitis by eliminating false-positive results in our control groups. Increased concentrations of trypsin-2-AAT and trypsinogen-2 were also observed in patients with chronic renal failure undergoing dialysis.

Pancreatic resection versus peritoneal lavage in acute necrotizing pancreatitis. A prospective randomized trial.

Twenty-one patients with acute fulminant alcoholic pancreatitis were randomly allocated to either pancreatic resection group (11 patients) or nonoperative peritoneal lavage group (10 patients). Only patients under 50 years were included in the study to minimize the role of other severe disease. These patients represented the most severe cases of acute pancreatitis at our Department, constituting only 2% of all patients with acute pancreatitis during this period. The diagnosis was based on clinical symptoms and on signs indicating severely impaired systemic organ functions. All patients underwent contrast-enhanced computed tomography (CT), which showed contrast enhancement below 30 Hounsfield units. In the operated cases, the diagnosis of necrotizing pancreatitis was verified histologically. All patients with conservative treatment had dark brown fluid at peritoneal puncture. There was a difference (nonsignificant) in mortality (3/11 and 1/10, respectively), complication rate, or in the need of reoperations between the groups. Nonoperative peritoneal lavage was followed with shorter treatment at the intensive care unit (16.2 versus 25.9 days, respectively). The hospital stay also was significantly shorter in the nonoperative group (44.3 versus 56.1 days). The results indicate that intensive conservative treatment is justified as an initial therapy even in the most severe cases of acute pancreatitis.

CT evaluation of acute pancreatitis: 8 years clinical experience and experimental evidence.

One hundred sixty eight patients with suspected serious pancreatitis were examined by dynamic CT. According to clinical data 103 of the patients had an oedematous pancreatitis (OP) and 65 a haemorrhagic-necrotizing pancreatitis (HP). Contrast enhancement (CE) of the pancreas was measured by dynamic CT during the first 24 hours after admission to the hospital. A control study was performed in 48 hours, if the finding on the primary CT was not definite or there was a discrepancy between CT and the clinical finding. Patients with HP showed significantly lower CE during the first minute after bolus injection of contrast material than patients with either normal pancreas or those who had OP. Only 4 out of 65 patients with HP showed normal (over 40 HU) and 8 out of 103 patients with OP showed low (less than 30 HU) CE. The method seems to be the most reliable method available to differentiate HP from OP. Before giving contrast material to the patients severe hypovolemia and respiratory distress should be excluded and treated.