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NON-SURGICAL MANAGEMENT OF ACUTE PANCREATITIS
Rakesh K Tandon
Professor and Head, Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi - 110 029.
Acute pancreatitis (AP) is a potentially lethal condition resulting from an acute inflammatory process in the pancreas usually manifested by upper abdominal pain and raised concentrations of pancreatic enzymes in blood, urine and peritoneal fluid. Fortunately, it is a self limiting, benign disease in 90% of the patients, but in the remaining 10% of patients, the disease is severe and is associated with major morbidity and mortality in upto 50%.1 The challenge to clinicians therefore is to recognize and treat effectively this latter subgroup of severe necrotizing form of acute pancreatitis.
As is implied in the title, acute pancreatitis has been traditionally considered a surgical disease and surgery does indeed play a significant role in treating complications of severe acute pancreatitis. However, it is early recognition of the 10% of severe necrotizing acute pancreatitis patients and their aggressive medical (non surgical) management in an intensive care set-up that has perhaps had the maximum impact on the outcome of these patients during the last few years. In this chapter, I propose to outline these non surgical elements of management of AP.
Diagnosis : A classical presentation of AP with severe upper abdominal pain radiating to the back, associated with vomiting and accompanied by a rise in serum amylase is not difficult to diagnose. But that is often not the case; either the pain is not typical or is absent (15% of cases) or the associated features raise a serious possibility of other causes of acute abdomen. If the patient with AP presents after 48-72 hours the serum amylase may have come down to normal levels. In such a situation raised serum lipase or urinary diastase help in making the diagnosis. [2] A plain radiograph of the abdomen may demonstrate the "colon cut off" sign or the typical "sentinel loop". Ultrasound and CT scan of the abdomen demonstrate the enlargement of the pancreas as well as peripancreatic fluid collections. Indeed, a contrast enhanced CT scan of the abdomen is being considered almost the gold standard for diagnosing acute pancreatitis. However, in most cases the ideal time to perform it is 4th or 5th day of acute pancreatitis as by then the extent of necrosis is fairly well demarcated and, if necessary, a decision may be made regarding an intervention.
ASSESSMENT OF SEVERITY OF AP
Clinical assessment
The presence of one or more extra pancreatic organ failure is the most important and clinically relevant indicator of severity. Organ failure is defined in terms of shock (BP < 90 mm Hg, tachycardia > 130/min), respiratory failure (p02 < 60 mm of Hg), renal failure (serum creatinine > 2 mg/dl, urinary output < 50 ml/hr) or gastrointestinal bleeding (> 500 ml/24 hrs). As prognostic markers, these organ failures compare well when tested against the multiple prognostic criteria. [3] Such a clinical assessment has an excellent specificity but poor sensitivity and good positive and negative predictive values.
Multiple clinical criteria
Ranson and colleagues developed a list of 11 factors to predict severe disease (five on admission and six within the first 48 hours after admission (Table 1). If the patient exhibited three or more risk factors, the chances of an aggressive disease increased (Fig. 1). These studies were based on alcoholic patients. The disadvantage of Ranson’s criteria is that you have to wait upto 48 hours to assess the severity of AP and that is a precious time lost for starting aggressive treatment measures. Secondly, the prediction of severity and mortality is too wide ranging and variable in patients with Ranson’s scores [3-5] .
TABLE 1 :
Ranson’s criteria of severityAt admission
Age > 55 year
WBC > 16,000/mm3
Glucose > 200 mg/dl
LDH > 350 IU/L
AST > 250 U/LDuring initial 48 h Haematocrit decrease of > 10
BUN increase of > 5 mg/dl
Ca++ < 8 mg/dl
PaO2 < 60 mmHg
Base deficit > 4 mEq/L
Fluid sequestration > 6 L
Fig 1 : Mortality increases with increasing Ranson's scores. The modified Glasgow or the Imrie criteria consist of eight parameters and require 48 hour period of observation and data accrual (Table 2). These help to grade the severity of disease in gallstone pancreatitis.
TABLE 2 :
Modified glasgow criteria for severity of acute pancreatitis (1984)Age (Yr) > 55
WBC > 15,000 Glucose (mg/dl) > 180 BUN (mg/dl) > 96 PO2 (mg/Hg) < 60 Calcium (g/dl) < 8 Albumin (g/dl) < 3.2 LDH (IU/L) > 600 More recently a newer, more sophisticated but more complex prognostic index called the acute physiology and chronic health enquiry score (APACHE-II) has been devised. It is based on 12 physiologic variables, age of the patient and history of major organ disease. A score of < 7 predicts a mild attack whereas a score of eight and more predicts a severe attack with likely organ failures. It is more sensitive and specific and unlike the previous scores, can be calculated upon admission and hence result in a more rapid prognostic classification.
Single prognostic markers
Besides the above mentioned scoring systems, individual laboratory tests have been proposed to establish severity. The various laboratory parameters that can predict severity are methemalbumin, Alpha 2-macroglobulin, Alfa 1-antitrypsin, C3 and C4 levels, phospholipase A2, C-reactive protein, trypsinogen activated peptide (TAP) and granulocytic elastase. The C-reactive protein has at least as good a predictive value as the multiple criteria of Ranson or Glasgow. Its level however, rises on the second day of hospitalisation. Some preliminary reports suggest that markers such as TAP and granulocytic elastase may be able to predict severity on the day of admission to the hospital. [4], [5] Interest is growing also in the possibility of IL-6 and IL-8 levels in blood as prognostic indicators. [6] Thus, we may have simple, cheap and accurate ways of establishing the severity. Obesity is an independant risk factor for severity in acute pancreatitis. Severity studies have shown that obese patients have a higher chance of developing organ failure specially respiratory failure and of having a higher fatality as compared with non-obese patients. [3]
Computerised tomography of the abdomen
Computerised tomography is the most reliable method of diagnosing acute pancreatitis. Pancreatic swelling, reduced tissue attenuation, andincreased peripancreatic and perirenal fluid collections are the typical changes seen. Contrast enhanced computerized tomography (CECT) (now termed incremental dynamic bolus computed tomography) brings out well the areas of poor perfusion in the pancreas and hence has become an essential tool for determining the presence of necrosis and even the extent of necrosis. Utilizing these changes, Balthazar has developed a scoring system as shown in Table 3. With increasing score of pancreatic injury there is a proportionate increase in morbidity and mortality (Fig. 2)
Fig 2 : CT in acute pacreatitis Balthazar's scoring
TABLE 3
CT in acute pancreatitis : Balthazar’s scoringCT findings Score A = Normal 0 B = Pancreatic enlargement 1 C = Peripancreatic inflammation 2 D = 1 peripancreatic fluid collection 3 E = > 1 peripancreatic fluid collection 4 No necrosis 0 1/3rd necrosis
2 1/2 necrosis
4 > 1/2 necrosis
6
GENERAL SUPPORTIVE MEASURES
Irrespective of the severity of AP all patients require the following supportive measures:
Maintenance of normal intravascular volume
It is of paramount importance in averting early death due to hypovolumic shock and cardiovascular failure. This has to be done carefully by assessing the fluid deficit using clinical criteria as well as intravascular pressure measurements. Adequate volume replacement will also prevent renal dysfunction. Dehydration has been shown to be a major modulator of cellular dysfunction and inhibits protein catabolism in a severe disease like acute pancreatitis. Furthermore, dehydration will result in a decrease in secretory capacity of the pancreatic acinar cells, a feature characteristic of early acute pancreatitis. Adequate hydration will thus prevent this cellular dysfunction. [8]
After the initial resuscitation, the fluid deficit should be reassessed at regular intervals by charting pulse rate, postural drop in blood pressure, urine output, skin turgor, haematocrit and plasma urea nitrogen level and by measuring the central venous pressure. Optimal fluid requirements maybe as high as 6-10 litres in 24 hours. A central venous pressure catheter is necessary to monitor such a large fluid replacement. When the estimated volume deficit exceeds three to four litres, one unit of human serum albumin (12.5 gm) should be given per litre of crystalloids infused.
Reducing pancreatic secretion
a) The patient is kept nil orally.
b) Continuous gastric suction is recommended only if the patient has severe vomiting and/or complete paralytic ileus. In others, nasogastric tubes have neither been shown to aid pain relief nor to shorten hospital stay [9-11] (Table 4).
c) H2 receptor antagonist therapy : Fifty mg ranitidine or 20 mg famotidine twice daily is advisable only when there is evidence of upper GI bleeding. Three randomized trials have failed to show any benefit in other patients with AP11-13 (Table 4).
d) Anticholinergic agents14 and other measures aimed at reducing the pancreatic secretion have similarly been found useless when tested by controlled studies [15-24] (Table 4).
TABLE 4
Results of randomized control trials (RCTs) of measures meant to decrease pancreatic secretionTreatment Studies showing improved
outcome/total number of studiesReference No. Nasogastric suction 0/3 9-11 H2 blockers 0/3 11-13 Atropine 0/1 14 Glucagon 0/4 15-18 Fluorouracil 0/1 19 Somatostatin 0/2 20,21 Calcitonin 0/1 22 Parenteral nutrition 0/1 24 Measures to reduce the pancreatic enzyme secretion
They have been used in the treatment of AP because of the present understanding that it is the activation and release of pancreatic enzymes that result in most of the damage to pancreas and the neighbouring organs in AP. Unfortunately, most of them have also not shown any beneficial effect in controlled trials [25-35] (Table 5). The only possible procedure that may benefit by removing the toxic products may be a prolonged (seven days) rather than short duration (2-4 days) peritoneal lavage 36 but it needs to be tested at a few other centres.
TABLE 5
Results of RCTs of measures aimed at reducing enzymes or removing the toxic factorsTreatment Presumed mechanism of action Studies showing improved outcome/ total number of studies
Reference no. Aprotinin
Intravenous
Decrease
Protease0/5 15,25-28 Intraperitoneal
0/1 29,3 Gabexate Decrease
Protease0/2 30,3 Fresh frozen Decrease 0/1 32 Plasma (FFP) Protease Peritoneal lavage Removes toxic factors 2-4 days
0/3 33-35 7 days
1/1 36
Prophylactic antibiotics [37-39]
Early trials with ampicillin failed to show any benefit but at least two recent controlled trial using imipenem or a cephalosporin have shown a reduction in the rate of sepsis. [40] , [41] There is a general agreement that patients with large areas of necrosis should certainly be treated prophylactically with antibiotics.
Endoscopic papillotomy in acute biliary pancreatitis
Since the study in 1988 from Leister [42] the impression has been that patients with severe acute pancreatitis benefit from endoscopic papillotomy if performed within the initial 72 hours. Subsequent studies, [43] , [44] particularly the latest multicentre European study, [45] have clarified that it is those patients with acute pancreatitis who have some evidence of biliary obstruction and/or cholangitis who only benefit from common bile duct clearance in acute stage (Table 6).
TABLE 6
Acute biliary pancreatitis : role of ERCP and EPTInvestigators Number of patients EPT studied Period within which EPT performed EPT No Neoptolemos et al [42] 121 Morbidity
72 hrs 12% 24%* Mortality
2% 8% Fan et al [43] 195 24 hrs 0% 12%* Morbidity
5% 9% Mortality
Nowak et al [44] 188 24 hrs Morbidity
14% 34% Mortality
1% 11% Folsch et al [45] 238 72 hrs 46% 51% Morbidity
11% 6% Mortality
* Statistically significant difference.
42 (Neoptolemos et al) If data pertaining to only the severe patients were analysed the differences in the morbidity and mortality were much greater in EPT and No. EPT groups, ie 21 vs 61% and 2 vs 18% respectively. Thus the benefit was best seen in severe pancreatitis. [43] (Fan et al) Although no difference in mortality, a significant reduction in biliary sepsis (morbidity) was noted. [45] of 339 consecutive patients with biliary pancreatitis, 101 were excluded as they had evidence of biliary obstruction.
Antioxidant therapy in acute pancreatitis
Current research indicates that a sudden overwhelming release of free radicals is the common pathogenic mechanism in AP irrespective of its aetiology. Exogenous free radical scavengers (FRS) such as superoxide dismutase, catalase, peroxidase and dimethyl sulphoxide have been studied in experimental animals suffering from AP. Sanfey et al [46] reported significant amelioration by the FRS in a canine preparation. Uden et al47 have assessed the efficacy of micronutrient antioxidant therapy with selenium, methionine, beta-carotine, vitamin C and vitamin E. They suggested that it reduced the frequency of recurrent acute episodes of pancreatitis. Till date however, no clinical study has been effective in ameliorating the acute attack of pancreatitis and hence substances such as superoxide dismutase, catalase, vitamin E, vitamin C and selenium have no role for clinical therapy of acute pancreatitis.
Monitoring the progress
Daily charting of fluid balance and vital signs is imperative. Daily determination of haematocrit, white blood cell count, BUN, creatinine, serum electrolytes and glucose is helpful. Once the patient is pain free, serum amylase and lipase should be repeated and feeding started cautiously.
Nutrition support
Once pain has subsided, small feeds rich in carbohydrates but low in protein and fat are begun. A few days later, regular meals are given but large meals are avoided. There is no evidence that pancreatic juice flow is lower with elemental diet than with regular food.
Intervention in hyperlipidaemic acute pancreatitis
The routine supportive care will decrease both the abdominal pain and the triglyceride level. Occassionally marked hypertriglyceridaemia is refractory to these measures and plasma exchange is required.
ADDITIONAL THEREPEUTIC MEASURES IN SEVERE ACUTE PANCREATITIS WITH MULTISYSTEM ORGAN FAILURE
1. Refractory shock : After placing a Swan-Ganz catheter, a trial of intravenous vasopressors such as dopamine or isoproterenol is essential.
2. Hypocalcaemic tetany and severe hyperglycaemia : Intravenous calcium, correction of magnesium deficiency and administration of small doses of regular insulin are essential.
3. Adult respiratory distress syndrome (ARDS) : Manifested by pulmonary oedema and hypoxaemia, it requires intubation with application of positive end expiratory pressure (PEEP).
4. Acute renal failure (ARF) : It carries a mortality of 50%. This may be due to acute tubular necrosis in a setting of prolonged shock or sepsis, bilateral renal vein thrombosis or renal cortical necrosis. The treatment is the same as in any other setting of ARF. Haemodialysis or peritoneal dialysis may become necessary.
DEFINITION OF LOCAL COMPLICATIONS AND THEIR MANAGEMENT
Precise definitions of the complications are essential for their proper management. Infectious complications are currently responsible for 80% of deaths in AP. [48] Hence if mortality rates are to be reduced, attention must be devoted to the management of sepsis in these patients.
Sterile pancreatic necrosis
CECT shows local or diffuse areas of non enhancement. Needle aspiration under US or CT guidance will not yield bacteria on Gram stain or culture.49 Systemic pancreatic resection is not recommended for such patients.
Infected pancreatic necrosis
Sterile pancreatic necrosis precedes infected necrosis. This sequence is suggested by guided needle aspiration studies. Infection occurs after the first 7-10 days in about 40% of cases. The more extensive the necrosis, the higher and earlier are the chances of it getting infected. Infected necrosis is fatal without prompt surgical drainage. Classical purulence is absent. The necrosis predominates. Needle aspiration reveals infected thin grey turbid fluid.
Antibiotic therapy in infected pancreatic necrosisCurrently, eight antibiotics are known to cross the blood pancreas barrier and achieve therapeutic concentrations against the most common pathogens in such a setting. Ciprofloxacin achieves an MIC-90 against all except B fragilis. Of the remaining seven, cefotaxime, ceftazidime, netilmicin, rifampicin and co-trimoxazole achieve MIC-90 against five of the nine common pathogens; clindamycin against three and metronidazole against B fragilis. Thus, intravenous ciprofloxacin along with metronidazole would represent the most effective antibiotic combination in such a setting. [50]
Surgical management of infected pancreatic necrosis
There are three modalities in current practices :
i) Conventional treatment : This includes resection of involved pancreatic tissue or necrosectomy followed by drainage. Reoperation is done on demand as dictated by the appearance of clinical or radiological evidence of residual necrosis or infection.
ii) Lavage treatment : Necrosectomy is followed by lavage of the involved retroperitoneal area by using two drains. The average amount of fluid used is 6 litres/day. Lavage is stopped when the effluent is clear and there are no signs of active disease.
iii) Open management : Necrosectomy is followed by open wound packing and planned re-explorations which are undertaken irrespective of patient’s general condition and stopped when peritoneal cavity is clean. Fistulae and bleeding occur commonly during this type of management.
The present day recommendation would be that rigid adherence to any of the three modalities should not be practised; rather the surgical approach be tailored to the clinical setting.
Acute pancreatic pseudocyst
CECT scan shows fluid collection of low attenuation which is non enhancing. Needle aspiration returns fluid high in amylase that is sterile.
Close sonographic monitoring is done. Half of them resolve in six weeks. Early drainage is required if the cyst is > 5 cm in size or is enlarging resulting in worsening of symptoms. Percutaneous catheter drainage of both infected and sterile pseudocysts allows successful drainage and resolution in 67% to 91%. The mean duration of drainage was 19-28 days in patients where there was a communication between the main pancreatic duct (MPD) and the pseudocyst. Recurrence is less than 4%, Bacterial superinfection of sterile pseudocyst can occur in 52% of cases. Somatostatin can be used to decrease drainage in such cases.
Endoscopic cystoduodenostomy and cystogastrostomy
This is advocated if the pseudocyst is abetting the gastric or duodenal wall i.e. the distance between the pseudocyst and the latter is less than 1 cm. Furthermore, there must be a clear impression of the pseudocyst on the wall of the stomach or duodenum. Several workers [51-53] have demonstrated successful drainage in > 90% of patients with a relapse rate of 10-20%.
Endoscopic transpapillary drainage [54]
This is another approach which reduces the morbidity associated with cutting the gastroduodenal wall. If these methods fail, surgical open drainage is the only option left.
Pancreatic abscess
This is a later complication occurring in the 3rd-5th week after the onset of AP. It results from liquefaction of infected pancreatic necrosis or secondary infection of a pancreatic pseudocyst. CT scan shows it as a discrete abscess cavity. Percutaneous needle aspiration with gram stain and culture is the preferred method of establishing the diagnosis. Initially, percutaneous catheter drainage should be attempted. [55] If successful, as it is in about 50% of cases, it will obviate the need for surgical management. The patient should be given antibiotics and monitored closely as this technique results in cure in less than half of the patients. If clinical symptoms or radiologic abnormalities persist, surgical debridement with open packing should be done with further debridement as the packing is changed.
GI bleeding
This can be due to several causes and management has to be individualised.
i) Gastroduodenal erosions : This is a self limiting bleed which responds to antacids, ranitidine etc.
ii) Haemosuccus pancreaticus : It manifests as an ooze or brisk bleeding due to erosion of splenic or gastroduodenal arteries. Endoscopy shows a gush of blood from the papilla of Vater. Selective mesenteric angiography can be used to identify and embolize the bleeder.
iii) Fistulisation of abscess or pseudocysts in stomach, duodenun and colon : This presents with a major bleed and requires surgical intervention.
Prevention of Recurrence of Acute Biliary Pancreatitis
Cholecystectomy is generally recommended to be performed in patients with acute biliary pancreatitis within four weeks of the acute attack and this happens often within the same hospitalization as the acute attack. [56] , [57] A question has been raised of prevention if recurrence of acute biliary pancreatitis can be achieved as effectively or more effectively by doing on endoscopic papillotomy. To answer this question; Sanchez - Antolin et al [58] reviewed the hospital records of 108 consecutive patients who had suffered an attack of acute pancreatitis and were followed for a mean duration of 12 months (range 1-37 months). Those patients were classified into four groups : Group I received no treatment (n=36, 11 of these had normal ERCP and no ES), Group II underwent cholecystetomy (n=16); Group III underwent endoscopic papillotomy (n=37); and Group IV had both cholecystectomy and endoscopic papillotomy or surgical sphincteroplasty (n=10). Recurrences of acute pancreatitis occurred in 36% in Group I and nil in Group IV. An obvious inference from the study was that endoscopic papillotomy alone was effective in preventing recurrence of acute pancreatitis. A greater use of endoscopic papillotomy as an alternative to cholecystectomy for this indication appears to be emerging even in the average surgical risk patients. [59]
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