Review article: enzyme supplementation in cystic fibrosis, chronic pancreatitis, pancreatic and periampullary cancer.

BACKGROUND: Over 11000 UK patients each year develop pancreatic exocrine insufficiency--the major causes are not rare: cystic fibrosis (>300 new cases/year), pancreatic cancer (>7000 new cases/year) and chronic pancreatitis (>4000 new cases/year). Affected patients present in diverse ways, and for chronic pancreatitis, diagnosis is frequently made rather late in the course of the disease. AIM: To raise awareness of key clinical issues specific to patients with pancreatic exocrine insufficiency through experience from UK clinicians, and to offer advice regarding appropriate treatment with pancreatic enzymes. METHODS: Three case studies describe clinical issues relating to pancreatic enzyme supplementation that may lead to underuse in patients with cystic fibrosis, pancreatic and periampullary cancer or chronic pancreatitis. RESULTS: The efficacy of the treatment of exocrine pancreatic insufficiency is dependent on adequate meal-time enzyme replacement therapy. Improvements in patients' weight and nutritional status are what is aimed for - an important reason for all doctors, nurses and dieticians to give this therapy close attention. CONCLUSIONS: Pancreatic exocrine insufficiency may result in malnutrition, but enzyme supplementation can greatly improve quality of life in these patients.

An open randomized comparison of clinical effectiveness of protocol-driven opioid analgesia, celiac plexus block or thoracoscopic splanchnicectomy for pain management in patients with pancreatic and other abdominal malignancies.

UNLABELLED: In inoperable malignancy, pain relief with opioids is often inadequate. Nerve block procedures may improve symptom control. Our aim was to assess celiac plexus block (CPB) and thoracoscopic splanchnicectomy (TS) in patients receiving appropriate medical management (MM). METHODS: Patients with confirmed irresectable malignancy of the pancreas or upper abdominal viscera who required opioid analgesia were randomized to MM alone, MM+CPB, or MM+TS. Randomization was stratified by treatment centre, tumour type and previous opioid medication. The primary endpoint was pain relief at 2 months. RESULTS: 65 patients (58 pancreas cancer) were randomized, 18 withdrew or died within 2 months. Effective pain relief was achieved in only one third of subjects at 2 weeks, and just under half at 2 months (MM: 6/19 and 5/12 evaluable patients; CPB: 5/14 and 5/9; TS 4/14 and 4/11). There were no significant differences between the groups in pain scores or opioid consumption, and there was no correlation between continued use of opioids and effective pain relief. DISCUSSION: Previous randomized studies have shown small differences in pain scores, but no difference in opioid consumption and quality of life. The absence of any benefit from interventions in the present study questions their value.

Acute renal cortical necrosis in a series of young men with severe acute pancreatitis.

Diffuse renal cortical necrosis from any cause is rare in the Western World. Over the last 5 decades, there have been isolated case reports of acute cortical necrosis as a consequence of acute pancreatitis, but the long-term outcome of these patients has not previously been reported. Here, we report 3 young men, aged 16-21 years, who have presented over the past 19 years with severe acute pancreatitis associated with oliguric acute renal failure. They were all found to have diffuse renal cortical necrosis and consequently made no renal recovery. Despite the appreciable mortality associated with acute pancreatitis complicated by acute renal failure, they all survived the initial illness and all have successfully undergone renal transplantation. We present a detailed account of each patient including diagnostic strategies and discuss the possible factors contributing to a favorable outcome in these patients.

Severe acute pancreatitis and pregnancy.

For most patients with pregnancy-associated pancreatitis there is little maternal survival threat and only occasionally are there foetal deaths. We describe 4 young women with pregnancy-associated severe acute pancreatitis who each had gallstones. Their ages were 17, 18, 20 and 24 years. Each was a tertiary referral to our unit in Glasgow and each pursued a life-threatening course with hospital stays ranging from 37 to 90 days. One patient required pancreatic necrosectomy for infected necrosis, another had percutaneous management of a pancreatic abscess and 2 had cystogastrostomy as treatment for pancreatic pseudocyst. All underwent early endoscopic sphincterotomy and later cholecystectomy. It is important to be aware that pregnancy-associated acute pancreatitis may be severe, posing a survival threat even in the youngest patients. Gallstones, as we reported almost 20 years ago, are the most common aetiological factor in such patients.

Total dorsal pancreatectomy for intraductal papillary mucinous neoplasm in a patient with pancreas divisum.

We report a case of intraductal papillary mucinous neoplasm confined to the dorsal (Santorini) pancreatic duct. A 51-year-old woman presented with a cystic lesion in the head of her pancreas and pancreas divisum. A biopsy taken during cyst-enteric drainage revealed dysplastic epithelium so the patient was scheduled for resection. At operation, excision of the entire dorsal pancreas was performed with preservation of the unaffected ventral pancreas and the spleen and its vessels. Over 6 years later she remains well with stable weight and a good quality of life. This case illustrates the benefits of anatomical preservation in pancreatic resection, and was performed some years prior to the only other reported similar case.

A randomized study of early nasogastric versus nasojejunal feeding in severe acute pancreatitis.

BACKGROUND: After 50 yr in which nasoenteric feeding was considered contraindicated in acute pancreatitis (AP), several clinical studies have shown that early nasojejunal (NJ) feeding can be achieved in most patients. A pilot study of early nasogastric (NG) feeding in patients with objectively graded severe AP proved that this approach was also feasible. A randomized study comparing NG versus NJ feeding has been performed. METHODS: A total of 50 consecutive patients with objectively graded severe AP were randomized to receive either NG or NJ feeding via a fine bore feeding tube. The end points were markers of the acute phase response APACHE II scores and C-reactive protein (CRP) measurements, and pain patterns by visual analogue score (VAS) and analgesic requirements. Complications were monitored and comparisons made of both total hospital and intensive-care stays. RESULTS: A total of 27 patients were randomized to NG feeding and 23 to NJ. One of those in the NJ group had a false diagnosis, thereby reducing the number to 22. Demographics were similar between the groups and no significant differences were found between the groups in APACHE II score, CRP measurement, VAS, or analgesic requirement. Clinical differences between the two groups were not significant. Overall mortality was 24.5% with five deaths in the NG group and seven in the NJ group. CONCLUSIONS: The simpler, cheaper, and more easily used NG feeding is as good as NJ feeding in patients with objectively graded severe AP. This appears to be a useful and practical therapeutic approach to enteral feeding in the early management of patients with severe AP.

Systemic inflammatory response predicts outcome in patients undergoing resection for ductal adenocarcinoma head of pancreas.

The aim of the present study was to examine the relationship between the clinicopathological status, the pre- and postoperative systemic inflammatory response and survival in patients undergoing potentially curative resection for ductal adenocarcinoma of the head of the pancreas. Patients (n = 65) who underwent resection of ductal adenocarcinoma of the head of pancreas between 1993 and 2001, and had pre- and postoperative measurements of C-reactive protein, were included in the study. The majority of patients had stage III disease (International Union Against Cancer Criteria, IUCC), positive circumferential margin involvement (R1), tumour size greater than 25 mm with perineural and lymph node invasion and died within the follow-up period. On multivariate analysis, tumour size (hazard ratio (HR) 2.10, 95% confidence interval (CI) 1.20-3.68, P = 0.009), vascular invasion (HR 2.58, 95% CI 1.48-4.50, P < 0.001) and postoperative C-reactive protein (HR 2.00, 95% CI 1.14-3.52, P = 0.015) retained independent significance. Those patients with a postoperative C-reactive protein < or = 10 mg l(-1) had a median survival of 21.5 months compared with 8.4 months in those patients with a C-reactive protein >10 mg l(-1) (P < 0.001). The results of the present study indicate that, in patients who have undergone potentially curative resection for ductal adenocarcinoma of the head of pancreas, the presence of a systemic inflammatory response predicts poor outcome.

Urinary trypsinogen activation peptide as a marker of severe acute pancreatitis.

BACKGROUND: Trypsinogen activation peptide (TAP) may be an early marker of severe pancreatitis. Previous studies have included all patients with organ failure in the group with severe pancreatitis, although patients with transient organ failure may have a good prognosis. The aim of this study was to determine the value of urinary TAP estimation for prediction of severity of acute pancreatitis, and to validate use of several markers of prediction of severity against a new, stringent definition of severity. METHODS: Patients with acute pancreatitis were recruited within 24 h of onset of symptoms. Urine and blood samples were collected for 24 h, and Acute Physiology And Chronic Health Evaluation (APACHE) II (24 h), Ranson (48 h) and Glasgow (48 h) scores were calculated. Severe acute pancreatitis was defined by the presence of a local complication or the presence of organ failure for more than 48 h. RESULTS: Urinary TAP levels were significantly greater in patients with severe pancreatitis than in those with mild disease during the first 36 h of admission. The highest of three estimations of TAP in the first 24 h was as effective as APACHE II at 24 h in predicting severity. At 24 h after admission, urinary TAP was better than C-reactive protein (CRP) in predicting severity. The combination of TAP and CRP at 24 h allowed identification of high- and low-risk groups. The new definition of severity excluded 24 of 190 patients with transient organ failure; none of these patients died. CONCLUSION: Use of TAP improved early prediction of the severity of acute pancreatitis. Organ failure that resolves within 48 h does not signify a severe attack of acute pancreatitis.

A novel application of ultrasound contrast: demonstration of splenic arterial bleeding.

Recent research in the use of ultrasound contrast agents has found they are able to increase the diagnostic power of ultrasound, to a level that may exceed other imaging modalities, in the diagnosis of liver lesions. Their application in the assessment of haemorrhage following angiographic embolisation has not previously been described. We report on a case where metal coil embolisation of a bleeding splenic artery aneurysm was completed to angiographic satisfaction, but on injection of ultrasound contrast medium, the aneurysm, distal to the embolisation, showed the presence of ultrasound contrast medium within it. We suggest that contrast enhanced ultrasound may be more sensitive than conventional angiography in the assessment of blood flow through intra-abdominal small vessel aneurysms or solid organs.

The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease.

BACKGROUND: Mutations in the PRSS1 gene explain most occurrences of hereditary pancreatitis (HP) but many HP families have no PRSS1 mutation. Recently, an association between the mutation N34S in the pancreatic secretory trypsin inhibitor (SPINK1 or PSTI) gene and idiopathic chronic pancreatitis (ICP) was reported. It is unclear whether the N34S mutation is a cause of pancreatitis per se, whether it modifies the disease, or whether it is a marker of the disease. PATIENTS AND METHODS: A total of 327 individuals from 217 families affected by pancreatitis were tested: 152 from families with HP, 108 from families with ICP, and 67 with alcohol related CP (ACP). Seven patients with ICP had a family history of pancreatitis but no evidence of autosomal dominant disease (f-ICP) compared with 87 patients with true ICP (t-ICP). Two hundred controls were also tested for the N34S mutation. The findings were related to clinical outcome. RESULTS: The N34S mutation was carried by five controls (2.5%; allele frequency 1.25%), 11/87 (13%) t-ICP patients (p=0.0013 v controls), and 6/7 (86%) affected (p<0.0001 v controls) and 1/9 (11%) unaffected f-ICP cases. N34S was found in 4/108 affected HP patients (p=0.724 v controls), in 3/27 (11%) with wild-type and in 1/81 (1%) with mutant PRSS1, and 4/67 ACP patients (all p>0.05 v controls). The presence of the N34S mutation was not associated with early disease onset or disease severity. CONCLUSIONS: The prevalence of the N34S mutation was increased in patients with ICP and was greatest in f-ICP cases. Segregation of the N34S mutation in families with pancreatitis is unexplained and points to a complex association between N34S and another putative pancreatitis related gene.

Dynamic nature of early organ dysfunction determines outcome in acute pancreatitis.

BACKGROUND: All patients with organ dysfunction are currently classified as having severe acute pancreatitis. The aim of this study was to characterize the systemic inflammatory response syndrome (SIRS) and early organ dysfunction in patients with acute pancreatitis and the relationship with overall mortality. METHODS: Patients with predicted severe acute pancreatitis of less than 48 h duration had daily organ dysfunction scores and SIRS criteria calculated. These features were then correlated with outcome. RESULTS: Of 121 patients, 68 (56 per cent) did not develop organ dysfunction; only two of these patients died (mortality rate 3 per cent). Fifty-three (44 per cent) had early organ dysfunction, of whom 11 died (21 per cent). Organ dysfunction and persistent SIRS were both associated with an increased mortality rate, but on multivariate analysis only deteriorating organ dysfunction was an independent determinant of survival. CONCLUSION: Early organ dysfunction in acute pancreatitis usually resolves and in itself has no significant influence on mortality. In contrast, worsening organ dysfunction was associated with death in more than half of the patients (11 of 20); it is this group of patients who should be classified as having severe acute pancreatitis.

A phase II trial of marimastat in advanced pancreatic cancer.

Pancreatic cancer has a poor response to conventional chemotherapy and radiotherapy. Inhibition of matrix metalloproteinase activity involved in tumour invasion and metastases is a novel biological approach for cancer treatment. This multicentre phase II clinical trial assessed marimastat, an oral matrix metalloproteinase inhibitor, in patients with advanced pancreatic cancer. A total of 113 patients received marimastat for 28 days at 100 mg b.d. (n = 9), 25 mg o.d. (n = 90) or 10 mg b.d. (n = 14). Patients with a response to treatment could continue marimastat beyond 28 days. Of 113 patients, 90 (80%) completed the 28-day study and 83 (73%) continued treatment. The principal side effect was arthralgia in 14 (12%) patients at 28 days and 33 (29%) patients over the whole study. There were 31 patients (27%) who required dose modification. Of 76 patients with evaluable CA19-9 levels, 23 (30%) showed no increase or fall in CA19-9. Of 83 patients with radiologically assessable disease, 41 (49%) had stable disease. The median survival was 245 days for those with a stable or falling CA19-9 level 128 days in those with rising CA19-9. The overall survival was 3.8 months. 5.9 months for stage II, 4.7 months for stage III and 3 months for stage IV disease. Of 90 patients, 46 (51%) had stabilization or reduction in pain, mobility and analgesia scores. Further development and clinical evaluation of matrix metalloproteinase inhibitors for the treatment of pancreatic cancer is warranted.

Brush cytology in the assessment of pancreatico-biliary strictures: a review of 406 cases.

AIMS: To assess the accuracy of brush cytology in patients investigated for pancreatico-biliary strictures. METHODS: All pancreatico-biliary brush cytology specimens submitted from two major teaching hospitals over a 6.5 year period were reviewed. Four hundred and forty eight satisfactory specimens from 406 patients with adequate clinical and/or pathological follow up data were examined in the study period. RESULTS: Two hundred and forty six patients (60.6%) were shown to have neoplastic strictures. One hundred and forty seven tumours were identified cytologically, including 87 of 146 pancreatic carcinomas, 29 of 47 cholangiocarcinomas, one of one bile duct adenoma, four of seven carcinomas of the gallbladder, eight of 13 ampullary carcinomas, two of three ampullary adenomas, 10 of 16 malignancies of undetermined origin, none of two islet cell tumours, one of three hepatocellular carcinomas, and five of eight metastatic tumours. The three adenomas identified on brush cytology could not be distinguished from adenocarcinoma morphologically. One hundred and sixty patients (39.4%) had benign strictures, most often as a result of chronic pancreatitis and bile duct stones. There were three false positive cytological diagnoses mainly as a result of the misinterpretation of cases with relatively scant and/or degenerative atypical epithelial cells. Forty one cases were reported as atypical or suspicious of malignancy on brush cytology, of which 29 were ultimately shown to have carcinoma. The overall diagnostic sensitivity and specificity were 59.8% and 98.1%, respectively. The sensitivity increased from 44.3% in the initial third of cases to 70.7% in the final third of cases examined in the series. CONCLUSIONS: Brush cytology, in conjunction with other clinical and radiological investigations, is a useful technique in the assessment of patients with suspected pancreatico-biliary neoplasia.

Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis.

BACKGROUND: Platelet activating factor (PAF) is believed to amplify the activity of key mediators of the systemic inflammatory response syndrome (SIRS) in acute pancreatitis, resulting in multiorgan dysfunction syndrome. We tested the hypothesis that a potent PAF antagonist, lexipafant, could dampen SIRS and reduce organ failure in severe acute pancreatitis. METHODS: We conducted a randomised, double blind, placebo controlled, multicentre trial of lexipafant (100 mg/24 hours intravenously for seven days commenced within 72 hours of the onset of symptoms) involving 290 patients with an APACHE II score >6. Power calculations assumed that complications would be reduced from 40% to 24%. Secondary end points studied included severity of organ failure, markers of the inflammatory response, and mortality rate. FINDINGS: Overall, 80/138 (58%) patients in the placebo group and 85/148 (57%) in the lexipafant group developed one or more organ failures. The primary hypothesis was invalidated by the unexpected finding that 44% of patients had organ failure on entry into the study; only 39 (14%) developed new organ failure. Organ failure scores were reduced in the lexipafant group only on day 3: median change -1 (range -4 to +8) versus 0 (-4 to +10) in the placebo group (p=0.04). Systemic sepsis affected fewer patients in the lexipafant group (13/138 v 4/148; p=0.023). Local complications occurred in 41/138 (30%) patients in the placebo group and in 30/148 (20%) in the lexipafant group (20%; p=0.065); pseudocysts developed in 19 (14%) and eight (5%) patients, respectively (p=0.025). Deaths attributable to acute pancreatitis were not significantly different. Interleukin 8, a marker of neutrophil activation, and E-selectin, a marker of endothelial damage, decreased more rapidly in the lexipafant group (both p<0.05); however, absolute values were not different between the two groups. INTERPRETATION: The high incidence of organ failure within 72 hours of the onset of symptoms undermined the primary hypothesis, and power calculations for future studies in severe acute pancreatitis will need to allow for this. Lexipafant had no effect on new organ failure during treatment. This adequately powered study has shown that antagonism of PAF activity on its own is not sufficient to ameliorate SIRS in severe acute pancreatitis

Percutaneous necrosectomy and sinus tract endoscopy in the management of infected pancreatic necrosis: an initial experience.

OBJECTIVE: To describe the development of a minimally invasive technique aimed at surgical debridement in addition to simple drainage of the abscess cavity. SUMMARY BACKGROUND DATA: Surgical intervention for secondary infection of pancreatic necrosis is associated with a death rate of 25% to 40%. Although percutaneous approaches may drain the abscess, they have often failed in the long term as a result of inability to remove the necrotic material adequately. METHODS: Fourteen consecutive patients with infected necrosis secondary to acute pancreatitis were studied. The initial four patients underwent sinus tract endoscopy along a drainage tract for secondary sepsis after prior open necrosectomy. This technique was then modified to allow primary debridement for proven sepsis to be carried out percutaneously in a further 10 patients. The techniques and initial results are described. RESULTS: Additional surgery for sepsis was successfully avoided in the initial four patients managed by sinus tract endoscopy, and none died. Of the following 10 patients managed by percutaneous necrosectomy, 2 died. The median inpatient stay was 42 days. There was one conversion for intraoperative bleeding. Eight patients recovered and were discharged from the hospital after a median of three percutaneous explorations. Only 40% of patients required intensive care management after surgery. CONCLUSIONS: These initial results in an unselected group of patients are encouraging and show that unlike with percutaneous or endoscopic techniques, both resolution of sepsis and adequate necrosectomy can be achieved. The authors' initial impression of a reduction in postoperative organ dysfunction is particularly interesting; however, the technique requires further evaluation in a larger prospective series.

Relationship of carotenoid and vitamins A and E with the acute inflammatory response in acute pancreatitis.

BACKGROUND: Inflammation and oxidative stress are believed to be important in the development of the systemic complications of acute pancreatitis. The fat-soluble vitamins A and E, and the carotenoids have antioxidant properties. The aim of this study was to assess the effect of acute pancreatitis on serum concentrations of vitamin antioxidants and to relate such changes to the degree of the inflammatory response. METHODS: Thirteen consecutive patients with predicted severe acute pancreatitis were compared with 26 matched healthy controls. Five patients developed severe acute pancreatitis and three of these died. Vitamin antioxidant and C-reactive protein (CRP) levels were measured daily for up to 7 days. RESULTS: Patients had significantly lower levels of antioxidants throughout the course of the study (P < 0.017). In patients there was a significant correlation between peak CRP and trough antioxidant levels (P < 0. 01). In patients with mild acute pancreatitis, the concentrations of retinol and beta-carotene at final review were significantly higher than those in patients with severe acute pancreatitis (P < 0.05). This coincided with a reduction in CRP level. CONCLUSION: In acute pancreatitis, circulating concentrations of vitamin antioxidants are reduced and are inversely related to the rise in CRP level.

Nasogastric feeding in severe acute pancreatitis may be practical and safe.

BACKGROUND: Severe acute pancreatitis may be protracted and some form of nutritional support is frequently required to maintain the patient's nutritional status. Recent work has suggested that enteral feeding via a jejunal route of delivery may reduce the magnitude of the inflammatory response. Insertion of nasojejunal (NJ) tubes in the patient with severe acute pancreatitis involves both delay and inconvenience. We undertook a prospective, feasibility study to assess the safety and practicability of nasogastric (NG) feeding in patients with severe acute pancreatitis. PATIENTS AND METHODS: Twenty-six patients with objective evidence of severe acute pancreatitis received nasogastric feeding within 48 h of admission to our unit. RESULTS: Etiology was identified as cholelithiasis (18 patients), ethanol (5), and miscellaneous (3). The median Glasgow score was 4 (range 2-7), APACHE II score 10 (4-28), and C-reactive protein concentration 286 mg/L (79-469). Fifteen patients had pancreatic and/or peripancreatic necrosis. Eleven patients developed severe organ failure, necessitating ventilatory support. Six developed multiple organ system failure, requiring inotropic support and/or renal dialysis. There were four deaths (15.3%). Nine patients underwent early, and nine late, ERCP, respectively; six necrosectomy (5 proven infected necrosis, 1 continued deterioration despite maximal support) and 4 patients internal drainage of a pseudocyst. The feed was well-tolerated in 22 patients. In 3 patients gastric stasis proved troublesome. There was no evidence of clinical or biochemical deterioration on commencing nasogastric feeding. CONCLUSION: It would appear that early NG feeding is usually possible in severe acute pancreatitis. In most patients it appears safe, well-tolerated, and worthy of further study.

High early mortality rate from acute pancreatitis in Scotland, 1984-1995.

BACKGROUND: Death from acute pancreatitis within the first week after admission is usually a consequence of multiple organ dysfunction. Reports from specialist centres suggest that, with improvements in resuscitation and supportive care, such deaths are becoming uncommon but it is unclear if this is reflected in a decrease in early mortality rate from acute pancreatitis in the general population. METHODS: Data concerning patients discharged with a diagnosis of acute pancreatitis (International Classification of Disease-9 code 577.0) between 1984 and 1995 were obtained from the Information and Statistics Division, National Health Service in Scotland, and analysed on a computer database. RESULTS: The incidence of acute pancreatitis in Scotland continues to increase in both sexes. The in-hospital mortality rate (death from all causes) was 7.5 per cent and showed a slight but significant downward trend over the period of study. Death within 7 days of hospital admission accounted for 53.7 per cent of all deaths and the proportion of early deaths did not decline over the study interval. CONCLUSION: These results suggest that scope remains for considerable improvement in the early management of acute pancreatitis. There is an urgent need to improve the early recognition of severe pancreatitis coupled to a willingness on behalf of clinicians to transfer these patients at an early stage to a centre with high-dependency and intensive care facilities supervised by a multidisciplinary team with expertise in the endoscopic, radiological and surgical management of these patients.