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Intensive care management of acute pancreatitis
Current Anaesthesia and Critical Care
(1998) 9, 20-24
© 1998HarcourtBrace & Co_Ltd
Focus on: Scoring systems in the intensive care unit
Intensive care management of acute pancreatitis
A. R. De Gaudio and R. Moretti
Acute pancreatitis is characterized by an intense inflammatory process which leads to early widespread organ dysfunction and late local complications. Currently, for the 80% of patients who suffer a moderate attack, management is largely supportive. The remaining 20% who develop severe pancreatitis have an increased risk of major complications which m a y require intensive care management. In these patients both general supportive and some specific therapeutic measures m a y be necessary. General measures include restoration and maintenance of plasma volume, respiratory, renal and nutritional support, analgesia and antibiotics. Specific measures, such as inhibition of pancreatic secretion or pancreatic enzyme activation, have not been successful in clinical trials. However, most of these studies have included small numbers of patients with moderate pancreatitis. Further evaluation of this approach is required with larger numbers and sicker patients. When bacterial infection of pancreatic necrosis becomes evident, surgical intervention should be considered. This includes percutaneous drainage, endoscopic removal of impacted gallstones and aggressive surgery for necrosis. bed (pancreatic necrosis, infection, fluid collections or pseudocysts, or haemorrhage from erosion of local vessels). Systemic complications of the inflammatory response to acute pancreatitis include hypovolaemic shock, acute renal failure and the adult respiratory distress syndrome; the condition of such patients may be further complicated by the development of sepsis. Death within the first week is usually due to development of one or more of these systemic complications?
Introduction
The clinical spectrum of acute pancreatitis ranges from a mild self-limiting disease to a condition that may lead rapidly to multiple organ dysfunction and death. About 80% of patients who suffer an attack of acute pancreatitis recover without major morbidity, and medical care is generally supportive (nil by mouth, adequate intravenous hydration and pain control with analgesics). The remaining 20% of patients develop one or more complications and require intensive care. The overall mortality rate for acute pancreatitis is about 10%; however, in those who develop complications this can rise to 50%. 1 Complications, caused by the release of activated pancreatic enzymes, may be local, affecting the pancreatic
Pathophysiology
In about 20% of patients, pancreatitis may be caused by the following factors: 1. Direct injury to the pancreas or ductal hypertension secondary to endoscopic retrograde pancreatography 2. Metabolic: hypertriglyceridaemia, hypercalcaemia and pharmacological agents such as corticosteroids 3. Following hypovolaemic shock or cardiopulmonary bypass 4. Infectious: mumps and coxsackie virus.
A. RaffaeleDe GaudioMD, Instituteof Anesthesiologyand Intensive Care, Universityof Florence,Ospedaledi Careggi,VialeMorgani85, 50134 Florence,Italy_RenatoMorettiMD, Director,Departmentof Surgery,OspedaleSS. Armunziata,Florence~Italy. Correspondenceto: A. R. D. 20
MANAGEMENTOF ACUTE PANCREATITIS 21 Table 1 Localand systemiccomplicationsof acute pancreatitis Local complications
Pancreatic necrosis and haemorrhage Pancreatic abscess Pancreatic fluid collectionor pseudocysts Systemic complications
Cardiovascularfailure (loss of intravascularvolumeand hypovolaemic shock) Respiratoryfailure (hypoxia,atelectasis,pneumonia, adult respiratory distress syndrome) Renal failure (oliguria, azotaemia,acute tubularnecrosis) Metabolic (hyperglycaemia,hypocalcaemia) Gastrointestinalbleeding Disseminatedintravascularcoagulation Although the agent initiating acute pancreatitis is often unknown, several factors have been associated with development of acute pancreatitis. 2 These include biliarypancreatic reflux, precipitation of protein plugs in the pancreatic ductules and direct toxic effect on the pancreas itself. Common bile duct stones are seen in about 50% of patients with acute pancreatitis. Stones may obstruct the pancreatic duct and cause a reflux of biliary secretions. In a high percentage of patients (previously classified as idiopathic pancreatitis), biliary sludge or occult microlithiasis is now recognized as a cause of acute pancreatitis. 3,4 Clinical pancreatitis is seen in about 10% of alcoholic patients. Regardless of the cause, activated pancreatic enzymes are implicated in the pathogenesis of local and multiple systemic complications (Table 1).
Local complications Pancreatic enzymes released within the gland and into the pancreatic bed provoke an inflammatory response with interstitial oedema and neutrophil infiltration which may lead to haemorrhage, pancreatic necrosis and abscess formation. These complications are the most difficult to treat. Haemorrhage usually occurs from the retroperitoneal vessels and/or the splenic, middle colic and pancreaticoduodenal vessels_ 5 Pancreatic necrosis following severe inflammation may become infected and lead to local abscess formation. This is probably due to bacterial translocation. Pancreatic pseudocysts are localized collections of pancreatic secretions which may became infected by enteric microorganisms or increase in diameter over the ensuing weeks. They may be responsible for obstructive complications or persisting fevers. 2,5 Pseudocysts are best identified by ultrasound or computed tomography (CT). Intra-abdominal complications include paralytic ileus and biliary or duodenal obstruction due to pancreatic enlargement and peripanereatic inflammation. The release of enzymes from the pancreas may cause peripancreatic collections, forming chronic pseudocysts.
Systemic complications Severe hypovolaemia is due to a loss of intravascular volume through transcapillary leakage of fluids in the
peritoneum, retroperitoneum and lumen of the gut. Such losses are comparable to a 40% body surface area burn. The peritoneal surfaces are equal to about 40% of body surface area and some authors have defined pancreatitis as a 'peritoneal burn'.5 In addition, vomiting and nasogastric suctioning increase the fluid deficit. In addition to fluid losses, there may be an accompanying electrolyte imbalance, particularly of calcium and magnesium (hypocalcaernia and hypomagnesaemia). The severe hypovolaemia normally manifests through hypotension tachycardia and decreased cardiac output, and poor perfusion may be further complicated by the development of a systemic inflammatory response. Once these patients are volume resuscitated they demonstrate a high cardiac output and low peripheral vascular resistance state. A similar change is observed with severe sepsis, where resuscitation leads from a low to a high output state. These changes are due to the circulation of vasoactive substances (e.g. cytokines, platelet activating factor) whose presence is more manifest in a full circulation. 6 A common complication of hypovolaemia is renal failure, which has been associated with a higher mortality in these patients. 2 Respiratory complications are characterized by hypoxaemia and mild metabolic acidosis. However, 30% of patients may develop progressive pulmonary insufficiency, which is usually due to a combination of pleural effusions, pulmonary infiltrates and major atelectasis. 2 Hepatic dysfunction is characterized by an increase of serum bilirubin, alkaline phosphatase and transaminase levels. These changes are due to biliary obstruction, hepatic parenchymal necrosis and pericholangitis. Coagulation disorders are also common in acute pancreatitis. Typically these are thrombocytopenia and hypofibrinogenaemia associated with increased circulating levels of fibrin-fibrinogen degradation products due to development of disseminated intravascular coagulation. 2 Clinical assessment
Physicalfindings Patients usually present with mid-epigastric pain which may radiate to the back and into both flanks, associated with nausea and profuse vomiting. Examination of the abdomen reveals anything from diffuse abdominal tenderness to board-like rigidity and an ileus. Patients are hypovolaemic manifest through tachycardia, poor perfusion, hypotension and tachypnoea. They may have many of the 'SIRS' criteria such as alterations of temperature, heart rate, respiratory rate, white blood cell count and evidence of organ dysfunction]
Laboratory findings At admission, 95% of patients have markedly increased amylase levels in the blood and urine, particularly in gallstone pancreatitis. 2 Other pancreatic enzymes may also have elevated concentrations in blood and urine; these include leukocyte elastase, trypsinogen activation peptide
22 CURRENTANAESTHESIA AND CRITICAL CARE and trypsinogen. There may also be non-specific increases in lipase 8-~°and C-reactive protein concentrations.
Occasionally it may be necessary to undertake a laparotomy or laparoscopy when the diagnosis is not clear and conditions with similar presentations need to be excluded. These include conditions such as acute gangrenous cholecystitis and mesenteric infarction.
colleagues 12 reported 43 early laboratory and clinical measurements in patients with acute pancreatitis. Ranson suggested that five measures on admission (age, white blood cells, glucose, LDH, SGOT) and six more within 48 h of admission (Hct, urea, serum calcium, PaO~, base deficit and estimated fluid sequestration) could be related to prognosis when exceeding certain critical values. The criteria were refined and modified for alcoholic pancreatitis and gallstone pancreatitis. The risk of life-threatening complications increases when more than four criteria are present. In 1984, Blamey and colleagues t3 developed a Glasgow Scoring System based on eight criteria. This was a less complicated method of assessment based on a study of patients with gallstone pancreatitis. Both classification systems have a high rate of false-positive and false-negative predictions. Consequently they may fail to indicate consistently either the severity of pancreatitis or the likely patient outcome. Other scoring systems, such as APACHE II, do not appear to be substantially more accurate. 14 Recently, computed tomography findings have been quantified and used as a method for assessing severity of disease. The CT prognostic index of acute pancreatitis identifies five different grades based on CT morphology (normal pancreas, focal or diffuse enhancement, peripancreatic inflammation, single fluid collection, two or more fluid collections) and in addition, points are allocated based on the degree of pancreatic necrosis (no necrosis, necrosis of one-third of the pancreas, necrosis of half of the pancreas, necrosis of over half of the pancreas). A score of 7-10 points is associated with a high rate of complications (92%) and mortality (17%). 15'16 Recently, C-reactive protein, leukocyte elastase and trypsinogen activation peptide have shown promise as markers of disease severity? However, in spite of these objective measures of prognosis, clinical observation remains an essential guide to assessment of disease severity.
Prognostic assessment
Treatment
The more severe attacks of acute pancreatitis are associated with a higher risk of developing complications. Table 2 indicates some of the measures currently used to estimate the severity of the disease. In 1974, Ranson and
Intensive care treatment is mainly directed to general supportive measures, with some specific measures targeted at limiting the severity of pancreatic inflammation and interrupting the pathogenesis of complications (Table 3).
Diagnostic imaging Most abdomen radiographs are non-specific. The bestknown finding is segmental dilatation of a small bowel loop in the left upper abdominal quadrant called the 'sentinel l o o p ' ) Chest X-ray may show no changes. However, left-sided pleural effusions are common. There may also be progressive changes suggestive of noncardiogenic pulmonary oedema, i.e. diffuse bilateral ground glass shadowing. This is associated with hypoxaemia. Occasionally there may be unilateral changes suggesting aspiration pneumonitis which may have occurred during the period of profuse vomiting. Ultrasonography has an established role in the diagnosis of gallstones and pancreatic cysts, but gaseous distension of the bowel loops often precludes an adequate evaluation of the pancreas. The use of high-resolution dynamic CT provides excellent imaging of the pancreas and the peripancreatic retroperitoneum, in particular the dynamic CT, which uses contrast and demonstrates areas of poor enhancement, indicating areas of pancreatic necrosis. Recently, it has been demonstrated that magnetic resonance (MR) provides similar information to CT scanning but has the advantage of not needing contrast infusion. This has significant advantages for those patients in whom renal function is still preserved and thereby allows risk for this complication to be kept at a minimum. 1 Diagnostic surgical procedures
Table 2 Prognosticassessmentof acute pancreatitis Score systems
Eleven Ranson's criteria Eight criteria GlasgowScore System Apache II Biochemical tests
C-reactiveprotein Leukocyteelastase Trypsinogenactivationpeptide Diagnostic imaging techniques
Computedtomographyprognosticindex Magnetic resonance Clinical observation
General supportive measures In the absence of significant specific measures for acute pancreatitis, general supportive measures acquire significant importance as they buy time for the patient while spontaneous resolution is allowed to occur. The first supportive measure should be restoration and maintenance of intravascular volume as soon as possible in order to avoid complications such as acute renal failure. Fluid requirements may be several litres to compensate for the degree of vomiting, gastrointestinal and
MANAGEMENTOF ACUTE PANCREATITIS 23 Table 3 Intensivecare managementof acute pancreatitis: general and specific supportivemeasures General supportive measures
Restoration of intravascularvolume Electrolyteleplacement Respiratorysupport Renal support Analgesia Nutritional support Antibiotics Antacids, H2 antagonists Peritoneal lavage Specific measures
Inhibition of pancreatic secretion Inhibition of pancreatic enzymes Non-invasive/invasivesurgicalprocedures
retroperitoneal sequestration_ Assessment of optimal fluid therapy requires a close clinical monitoring of vital signs (heart rate, blood pressure and peripheral perfusion) as well as measures such as central venous pressure, urine output mad base deficit. In patients with cardiovascular or respiratory failure, pulmonary artery catheterization might facilitate monitoring. Inadequate resuscitation may promote a mild uncomplicated acute pancreatitis to a more severe disease, 56 Electrolyte replacement may be necessary for low magnesium and calcium (ionized) concentrations. However, since hypercalcaemia may initiate pancreatifis, administration of calcium based on total calcium concentrations should be cautious_ 2 Respiratory support may be necessary for patients in whom arterial hypoxaemia may lead to hypoxic insult. Although it is generally preferable that patients are not intubated in order to avoid later nosocomial complications, intubafion and ventilation may become inevitable in exhausted or hypoxic patients. 17'18 Renal support with continuous haemofiltration may become necessary, but it has also been suggested that continuous veno-venous haemofiltration in patients with multisystem failure may benefit outcome by eliminating mediators. 19 Achievement of adequate analgesia is an important part of management, particularly in those patients who are not yet intubated and ventilated. Opioid derivatives are still the drugs of choice (morphine only provokes contraction of the sphincter of Oddi when given in high doses). Direct interruption of afferent nocicepfive visceral stimulation by continuous epidural anaesthesia or continuous coeliac plexus block are both effective alternatives, especially in patients with alcoholic pancreatitis or with a history of opioid addiction. -~° There remains some controversy over the timing of parenteral nutritional support. Total parenteral nutrition is assumed to 'rest' the pancreas, thereby limiting enzyme release and autodigestion. Consequently, it has been proposed that earlier nutrition might improve outcome. A randomized prospective clinical trial demonstrated no benefits with respect to mortality, morbidity, length of stay or days to oral intake when parenteral nutrition was started very early. 2~ However, in one retrospective study,
a significant decrease in morbidity and mortality was demonstrated. 22 Another point of view is that early enteral nutrition, particularly when delivered distal to the ligament of Treitz, is preferable, since it might reduce the risk of bacterial translocation across the bowel wall. 5 The use of prophylactic antibiotics in uncomplicated pancreatitis until recently was considered of little value. New studies suggest that there is a decrease of the frequency of infection and sepsis complicating acute pancreatitis when early antibiotic treatment is started with imipenem or cefuroxime. 23'24 However, there has been no clinical benefit following the use of selective decontamination of the digestive tract. 25 The use of agents to protect the gastrointestinal mucosa from bleeding is relatively non-controversial. Antacids, H 2 receptor antagonists or sucralfate are thought to offer significant protection against erosive gastritis.
S p e c i mf eiacs u r e s Specific measures are primarily directed at reducing the provoking agents or the inflammatory response that ensues. Peritoneal lavage has been used in an attempt to remove digestive enzymes and inflammatory mediators from the peritoneum. This procedure has been shown to reduce mortality in those with pancreatic infection treated by lavage for at least 1 week. 26 Continued pancreatic secretion of digestive enzymes maintains and augments the autodigestive process. Simple procedures such as nasogastric suction might be expected to reduce pancreatic secretion, but several controlled trials have failed to show an effect on the clinical course other than relief from nausea, vomiting and ileus] '2 Inhibition of pancreatic secretion with agents such as anticholinergics, cimetidine, fluorouracil and glucagon, have shown benefits in animal models, but not in human. 1 Somatostatin and its analogue octreotide inhibit many physiological regulatory functions in the gastrointestinal tract and the exocrine/endocrine activity of the pancreas. These agents might be of benefit in disorders where the pancreatic duct flow is compromised. Unfortunately, in four placebo-controlled trials involving nearly 400 patients neither somatostatin nor octreotide improved the clinical course of acute pancreatitis. 27 Agents that inhibit pancreatic enzymes such as proteases would seem ideal for reducing the severity of pancreatitis.' Aprotinin and gabexate mesilate have shown some benefits in animal models, but as yet no demonstrable effects in clinical trials. ~ Other specific treatments include surgical procedures such as percutaneous drainage for pancreatic abscesses, which is not particularly successful, and similar drainage of infected pseudocysts, in which some benefits have been reported. Early surgical intervention is indicated in biliary obstruction, necrotizing infected pancreatitis, pancreatic abscesses and bleeding. Relative indications include sterile necrosis of more than 50% of the pancreas, pancreatic duct disruption and/or chemical peritonitis. Surgical treatment of biliary obstruction has evolved in recent years with the
24
CURRENT ANAESTHESIA AND CRITICAL CARE
advent of endoscopic sphincterotomy, which might be considered during the acute phase (in the first 72 h). Other surgical procedures that may be undertaken in the acute phase include necrotic tissue debridement and drainage of the pancreatic bed. Conclusions • The cause of idiopathic acute pancreatitis now appears to be related to biliary dysfunction leading to biliary sludge and microlithiasis • The presence and extent of pancreatic necrosis and infection are the main determinants of clinical evolution and prognosis • Prognostic assessment based on specific parameters and their scores is controversial. Clinical observations continue to be the best estimates of severity of disease • The major aspects of treatment remain symptomatic relief and general supportive therapy • Methods to reduce pancreatic secretion or inhibit proteases have not shown a clear clinical efficacy • Early endoscopic treatment is gaining favour for biliary stone-induced pancreatitis • Surgery is indicated when infected or extensive sterile necrosis is detected • Further studies are necessary to identify effective methods for inhibiting the local and general inflammatory response.
References 1. Forsmark C E, Toskes P T. Acute pancreatitis, medical management. Crit Care Clin 1995; 11: 295-309. 2. Ranson J H C. Pancreatitis. In: Prough D S, Traystman R J, eds. Critical care, state of the art. Society of Critical Care Medicine 1993; 14: 375-392. 3. Ros E, Navarro S, Bru C, Garcia-Puges A, Valderrama R. Occult microlithiasis in idiopathic acute pancreatitis: prevention of relapses by cholecystectomy or ursodeoxycolic acid therapy. Gastroenterology 1991; 101: 1701-1709. 4_ Lee S P, Nicholls J F, Park H Z. Biliary sludge as a cause of acute pancreatitis. New Engl J Med 1992; 326: 589-593. 5. Baker C C, Huynh T. Acute pancreatitis, surgical management. Crit Care Clin 1995; 11: 311-322. 6. Beget H G, Bittner R, Buchler M et al. Hemodynamic data pattern in patients with acute pancreatitis_ Gastroenterology 1986; 90: 74-79. 7. Vincent J I, Thijs L G, Reinhart K et al. Guidelines for the problem of sepsis (ESICM). Intensive Care Med 1994; 20: 300-304.
8. Gross V, Scholmerich J, Leser H G e t al. Granulocyte elastase in assessment of severity of acute pancreatitis. Comparison with acute-phase proteins, C-reactive protein, al-antitripsin and protease inhibitor alpha 2-macroglobulin. Dig Dis Sci 1990; 35: 97-105. 9. Gudgeon A M, Heath D I, Hurley P e t al. Trypsinogen activation peptides essay in the early prediction of severity of acute pancreatitis. Lancet 1990; 335: 4-8. 10. Kemppainen E A, Hedstrom J I, Puolakkainen Sainio S V. Rapid measurement of urinary trypsinogen-2 as a screening test for acute pancreatitis. N Engl J Med 1997: 1788-1793. 11. Saifuddin A, Wars J, Pddgway J, Chalmers A G. Comparison of MR and CT scanning in severe acute pancreatitis: initial experiences. Clin Radiol 1993; 48:111-116. 12. Ranson J H, Rifldnd K M, Roses D F, Fink S D, Eng K, Localio S A. Objective early identification of severe acute pancreatitis. Am J Gastrenterol 1974; 61: 443-451. 13. Blamey S L, Imrie C W, O'Neil J, Gilmour W H, Carter D C_ Prognostic factors in acute pancreatitis. Gut 1984; 25: 1340-1346. 14. Wilson C, Heath D I, lmrie C W. Prediction of outcome in acute pancreatitis: a comparative study of APACHE II, a clinical assessment and multiple factor scoring systems. Br J Surg 1990; 77: 1260-1264. 15. Balthazar E J, Robinson D L, Megibow A J, Ranson H J. Acute pancreatitis: value of CT in establishing prognosis. Radiology 1990; 174: 331-336. 16_ Patel A G, Horn E M, Karetzky M. Acute pancreatitis: current concepts of risk stratification and management. Intensive Care World 1996; 13: 164-167. 17. Cobo J C, Abraham E, Bland R D, Shoemaker W C. Sequential hemodynamic and oxygen transport abnormalities in patients with acute pancreatitis. Surgery 1984; 95: 324-330. 18. Interiano B, Stuard D, Hyde R W. Acute respiratory distress syndrome in pancreatitis. Ann Intern Med 1972; 77: 923-926. 19. Gebhardt C, Bodeker H, Blinzler L, Kraus D, Hergdt G. Wandel in der Therapie der schweren akuten Pankreatitis Chimrg 1994; 65: 33-40. 20. Rykowski J J, Hilgier M. Continuous celiac plexus block in acute pancreatitis. Reg Anaesth 1995; 20: 528-532. 21. Sax H C, Warner B W, Talamini M A e t al. Early total parenteral nutrition in acute pancreatitis: lack of beneficial effects. Am J Surg 1987; 153: 117-124. 22. Kalfarentzos F E, Karavia D, Karatzas T_ Total parenteral nutrition in severe acute pancreatitis. J Am Coll Nutr 1991; 10: 156-162. 23. Pederzoli P, Bassi C, Visentini S, Campedelli A. A randomized multicenter clinical trial of antibiotic therapy prophylaxis of septic complications in acute necrotizmg pancreatitis with imipenem. Surg Gynecol Obstet 1993; 176: 480--483. 24. Sainio V, Kemppainen E, Puolakkainen P e t al. Early antibiotic treatment in acute necrotising pancreatitis. Lancet 1995; 346: 663-667_ 25. McClelland P, Murray A, Yaqoob M. Prevention of bacterial infection and sepsis in acute severe pancreatitis. Ann R Coll Surg Engl 1992, 74: 329-334. 26. Mayer A D, McMahon M J, Corfield A P et al. Controlled clinical trial of peritoneal lavage for the treatment of severe acute pancreatitis. N Engl J Med 1985; 312: 399-404. 27. Lamberts S W J, Van der Lely A J, Herder W W, Hofland L J. Drug therapy: octreotide. N Engl J Med 1996; 334: 246-254.
(1998) 9, 20-24
© 1998HarcourtBrace & Co_Ltd
Focus on: Scoring systems in the intensive care unit
Intensive care management of acute pancreatitis
A. R. De Gaudio and R. Moretti
Acute pancreatitis is characterized by an intense inflammatory process which leads to early widespread organ dysfunction and late local complications. Currently, for the 80% of patients who suffer a moderate attack, management is largely supportive. The remaining 20% who develop severe pancreatitis have an increased risk of major complications which m a y require intensive care management. In these patients both general supportive and some specific therapeutic measures m a y be necessary. General measures include restoration and maintenance of plasma volume, respiratory, renal and nutritional support, analgesia and antibiotics. Specific measures, such as inhibition of pancreatic secretion or pancreatic enzyme activation, have not been successful in clinical trials. However, most of these studies have included small numbers of patients with moderate pancreatitis. Further evaluation of this approach is required with larger numbers and sicker patients. When bacterial infection of pancreatic necrosis becomes evident, surgical intervention should be considered. This includes percutaneous drainage, endoscopic removal of impacted gallstones and aggressive surgery for necrosis. bed (pancreatic necrosis, infection, fluid collections or pseudocysts, or haemorrhage from erosion of local vessels). Systemic complications of the inflammatory response to acute pancreatitis include hypovolaemic shock, acute renal failure and the adult respiratory distress syndrome; the condition of such patients may be further complicated by the development of sepsis. Death within the first week is usually due to development of one or more of these systemic complications?
Introduction
The clinical spectrum of acute pancreatitis ranges from a mild self-limiting disease to a condition that may lead rapidly to multiple organ dysfunction and death. About 80% of patients who suffer an attack of acute pancreatitis recover without major morbidity, and medical care is generally supportive (nil by mouth, adequate intravenous hydration and pain control with analgesics). The remaining 20% of patients develop one or more complications and require intensive care. The overall mortality rate for acute pancreatitis is about 10%; however, in those who develop complications this can rise to 50%. 1 Complications, caused by the release of activated pancreatic enzymes, may be local, affecting the pancreatic
Pathophysiology
In about 20% of patients, pancreatitis may be caused by the following factors: 1. Direct injury to the pancreas or ductal hypertension secondary to endoscopic retrograde pancreatography 2. Metabolic: hypertriglyceridaemia, hypercalcaemia and pharmacological agents such as corticosteroids 3. Following hypovolaemic shock or cardiopulmonary bypass 4. Infectious: mumps and coxsackie virus.
A. RaffaeleDe GaudioMD, Instituteof Anesthesiologyand Intensive Care, Universityof Florence,Ospedaledi Careggi,VialeMorgani85, 50134 Florence,Italy_RenatoMorettiMD, Director,Departmentof Surgery,OspedaleSS. Armunziata,Florence~Italy. Correspondenceto: A. R. D. 20
MANAGEMENTOF ACUTE PANCREATITIS 21 Table 1 Localand systemiccomplicationsof acute pancreatitis Local complications
Pancreatic necrosis and haemorrhage Pancreatic abscess Pancreatic fluid collectionor pseudocysts Systemic complications
Cardiovascularfailure (loss of intravascularvolumeand hypovolaemic shock) Respiratoryfailure (hypoxia,atelectasis,pneumonia, adult respiratory distress syndrome) Renal failure (oliguria, azotaemia,acute tubularnecrosis) Metabolic (hyperglycaemia,hypocalcaemia) Gastrointestinalbleeding Disseminatedintravascularcoagulation Although the agent initiating acute pancreatitis is often unknown, several factors have been associated with development of acute pancreatitis. 2 These include biliarypancreatic reflux, precipitation of protein plugs in the pancreatic ductules and direct toxic effect on the pancreas itself. Common bile duct stones are seen in about 50% of patients with acute pancreatitis. Stones may obstruct the pancreatic duct and cause a reflux of biliary secretions. In a high percentage of patients (previously classified as idiopathic pancreatitis), biliary sludge or occult microlithiasis is now recognized as a cause of acute pancreatitis. 3,4 Clinical pancreatitis is seen in about 10% of alcoholic patients. Regardless of the cause, activated pancreatic enzymes are implicated in the pathogenesis of local and multiple systemic complications (Table 1).
Local complications Pancreatic enzymes released within the gland and into the pancreatic bed provoke an inflammatory response with interstitial oedema and neutrophil infiltration which may lead to haemorrhage, pancreatic necrosis and abscess formation. These complications are the most difficult to treat. Haemorrhage usually occurs from the retroperitoneal vessels and/or the splenic, middle colic and pancreaticoduodenal vessels_ 5 Pancreatic necrosis following severe inflammation may become infected and lead to local abscess formation. This is probably due to bacterial translocation. Pancreatic pseudocysts are localized collections of pancreatic secretions which may became infected by enteric microorganisms or increase in diameter over the ensuing weeks. They may be responsible for obstructive complications or persisting fevers. 2,5 Pseudocysts are best identified by ultrasound or computed tomography (CT). Intra-abdominal complications include paralytic ileus and biliary or duodenal obstruction due to pancreatic enlargement and peripanereatic inflammation. The release of enzymes from the pancreas may cause peripancreatic collections, forming chronic pseudocysts.
Systemic complications Severe hypovolaemia is due to a loss of intravascular volume through transcapillary leakage of fluids in the
peritoneum, retroperitoneum and lumen of the gut. Such losses are comparable to a 40% body surface area burn. The peritoneal surfaces are equal to about 40% of body surface area and some authors have defined pancreatitis as a 'peritoneal burn'.5 In addition, vomiting and nasogastric suctioning increase the fluid deficit. In addition to fluid losses, there may be an accompanying electrolyte imbalance, particularly of calcium and magnesium (hypocalcaernia and hypomagnesaemia). The severe hypovolaemia normally manifests through hypotension tachycardia and decreased cardiac output, and poor perfusion may be further complicated by the development of a systemic inflammatory response. Once these patients are volume resuscitated they demonstrate a high cardiac output and low peripheral vascular resistance state. A similar change is observed with severe sepsis, where resuscitation leads from a low to a high output state. These changes are due to the circulation of vasoactive substances (e.g. cytokines, platelet activating factor) whose presence is more manifest in a full circulation. 6 A common complication of hypovolaemia is renal failure, which has been associated with a higher mortality in these patients. 2 Respiratory complications are characterized by hypoxaemia and mild metabolic acidosis. However, 30% of patients may develop progressive pulmonary insufficiency, which is usually due to a combination of pleural effusions, pulmonary infiltrates and major atelectasis. 2 Hepatic dysfunction is characterized by an increase of serum bilirubin, alkaline phosphatase and transaminase levels. These changes are due to biliary obstruction, hepatic parenchymal necrosis and pericholangitis. Coagulation disorders are also common in acute pancreatitis. Typically these are thrombocytopenia and hypofibrinogenaemia associated with increased circulating levels of fibrin-fibrinogen degradation products due to development of disseminated intravascular coagulation. 2 Clinical assessment
Physicalfindings Patients usually present with mid-epigastric pain which may radiate to the back and into both flanks, associated with nausea and profuse vomiting. Examination of the abdomen reveals anything from diffuse abdominal tenderness to board-like rigidity and an ileus. Patients are hypovolaemic manifest through tachycardia, poor perfusion, hypotension and tachypnoea. They may have many of the 'SIRS' criteria such as alterations of temperature, heart rate, respiratory rate, white blood cell count and evidence of organ dysfunction]
Laboratory findings At admission, 95% of patients have markedly increased amylase levels in the blood and urine, particularly in gallstone pancreatitis. 2 Other pancreatic enzymes may also have elevated concentrations in blood and urine; these include leukocyte elastase, trypsinogen activation peptide
22 CURRENTANAESTHESIA AND CRITICAL CARE and trypsinogen. There may also be non-specific increases in lipase 8-~°and C-reactive protein concentrations.
Occasionally it may be necessary to undertake a laparotomy or laparoscopy when the diagnosis is not clear and conditions with similar presentations need to be excluded. These include conditions such as acute gangrenous cholecystitis and mesenteric infarction.
colleagues 12 reported 43 early laboratory and clinical measurements in patients with acute pancreatitis. Ranson suggested that five measures on admission (age, white blood cells, glucose, LDH, SGOT) and six more within 48 h of admission (Hct, urea, serum calcium, PaO~, base deficit and estimated fluid sequestration) could be related to prognosis when exceeding certain critical values. The criteria were refined and modified for alcoholic pancreatitis and gallstone pancreatitis. The risk of life-threatening complications increases when more than four criteria are present. In 1984, Blamey and colleagues t3 developed a Glasgow Scoring System based on eight criteria. This was a less complicated method of assessment based on a study of patients with gallstone pancreatitis. Both classification systems have a high rate of false-positive and false-negative predictions. Consequently they may fail to indicate consistently either the severity of pancreatitis or the likely patient outcome. Other scoring systems, such as APACHE II, do not appear to be substantially more accurate. 14 Recently, computed tomography findings have been quantified and used as a method for assessing severity of disease. The CT prognostic index of acute pancreatitis identifies five different grades based on CT morphology (normal pancreas, focal or diffuse enhancement, peripancreatic inflammation, single fluid collection, two or more fluid collections) and in addition, points are allocated based on the degree of pancreatic necrosis (no necrosis, necrosis of one-third of the pancreas, necrosis of half of the pancreas, necrosis of over half of the pancreas). A score of 7-10 points is associated with a high rate of complications (92%) and mortality (17%). 15'16 Recently, C-reactive protein, leukocyte elastase and trypsinogen activation peptide have shown promise as markers of disease severity? However, in spite of these objective measures of prognosis, clinical observation remains an essential guide to assessment of disease severity.
Prognostic assessment
Treatment
The more severe attacks of acute pancreatitis are associated with a higher risk of developing complications. Table 2 indicates some of the measures currently used to estimate the severity of the disease. In 1974, Ranson and
Intensive care treatment is mainly directed to general supportive measures, with some specific measures targeted at limiting the severity of pancreatic inflammation and interrupting the pathogenesis of complications (Table 3).
Diagnostic imaging Most abdomen radiographs are non-specific. The bestknown finding is segmental dilatation of a small bowel loop in the left upper abdominal quadrant called the 'sentinel l o o p ' ) Chest X-ray may show no changes. However, left-sided pleural effusions are common. There may also be progressive changes suggestive of noncardiogenic pulmonary oedema, i.e. diffuse bilateral ground glass shadowing. This is associated with hypoxaemia. Occasionally there may be unilateral changes suggesting aspiration pneumonitis which may have occurred during the period of profuse vomiting. Ultrasonography has an established role in the diagnosis of gallstones and pancreatic cysts, but gaseous distension of the bowel loops often precludes an adequate evaluation of the pancreas. The use of high-resolution dynamic CT provides excellent imaging of the pancreas and the peripancreatic retroperitoneum, in particular the dynamic CT, which uses contrast and demonstrates areas of poor enhancement, indicating areas of pancreatic necrosis. Recently, it has been demonstrated that magnetic resonance (MR) provides similar information to CT scanning but has the advantage of not needing contrast infusion. This has significant advantages for those patients in whom renal function is still preserved and thereby allows risk for this complication to be kept at a minimum. 1 Diagnostic surgical procedures
Table 2 Prognosticassessmentof acute pancreatitis Score systems
Eleven Ranson's criteria Eight criteria GlasgowScore System Apache II Biochemical tests
C-reactiveprotein Leukocyteelastase Trypsinogenactivationpeptide Diagnostic imaging techniques
Computedtomographyprognosticindex Magnetic resonance Clinical observation
General supportive measures In the absence of significant specific measures for acute pancreatitis, general supportive measures acquire significant importance as they buy time for the patient while spontaneous resolution is allowed to occur. The first supportive measure should be restoration and maintenance of intravascular volume as soon as possible in order to avoid complications such as acute renal failure. Fluid requirements may be several litres to compensate for the degree of vomiting, gastrointestinal and
MANAGEMENTOF ACUTE PANCREATITIS 23 Table 3 Intensivecare managementof acute pancreatitis: general and specific supportivemeasures General supportive measures
Restoration of intravascularvolume Electrolyteleplacement Respiratorysupport Renal support Analgesia Nutritional support Antibiotics Antacids, H2 antagonists Peritoneal lavage Specific measures
Inhibition of pancreatic secretion Inhibition of pancreatic enzymes Non-invasive/invasivesurgicalprocedures
retroperitoneal sequestration_ Assessment of optimal fluid therapy requires a close clinical monitoring of vital signs (heart rate, blood pressure and peripheral perfusion) as well as measures such as central venous pressure, urine output mad base deficit. In patients with cardiovascular or respiratory failure, pulmonary artery catheterization might facilitate monitoring. Inadequate resuscitation may promote a mild uncomplicated acute pancreatitis to a more severe disease, 56 Electrolyte replacement may be necessary for low magnesium and calcium (ionized) concentrations. However, since hypercalcaemia may initiate pancreatifis, administration of calcium based on total calcium concentrations should be cautious_ 2 Respiratory support may be necessary for patients in whom arterial hypoxaemia may lead to hypoxic insult. Although it is generally preferable that patients are not intubated in order to avoid later nosocomial complications, intubafion and ventilation may become inevitable in exhausted or hypoxic patients. 17'18 Renal support with continuous haemofiltration may become necessary, but it has also been suggested that continuous veno-venous haemofiltration in patients with multisystem failure may benefit outcome by eliminating mediators. 19 Achievement of adequate analgesia is an important part of management, particularly in those patients who are not yet intubated and ventilated. Opioid derivatives are still the drugs of choice (morphine only provokes contraction of the sphincter of Oddi when given in high doses). Direct interruption of afferent nocicepfive visceral stimulation by continuous epidural anaesthesia or continuous coeliac plexus block are both effective alternatives, especially in patients with alcoholic pancreatitis or with a history of opioid addiction. -~° There remains some controversy over the timing of parenteral nutritional support. Total parenteral nutrition is assumed to 'rest' the pancreas, thereby limiting enzyme release and autodigestion. Consequently, it has been proposed that earlier nutrition might improve outcome. A randomized prospective clinical trial demonstrated no benefits with respect to mortality, morbidity, length of stay or days to oral intake when parenteral nutrition was started very early. 2~ However, in one retrospective study,
a significant decrease in morbidity and mortality was demonstrated. 22 Another point of view is that early enteral nutrition, particularly when delivered distal to the ligament of Treitz, is preferable, since it might reduce the risk of bacterial translocation across the bowel wall. 5 The use of prophylactic antibiotics in uncomplicated pancreatitis until recently was considered of little value. New studies suggest that there is a decrease of the frequency of infection and sepsis complicating acute pancreatitis when early antibiotic treatment is started with imipenem or cefuroxime. 23'24 However, there has been no clinical benefit following the use of selective decontamination of the digestive tract. 25 The use of agents to protect the gastrointestinal mucosa from bleeding is relatively non-controversial. Antacids, H 2 receptor antagonists or sucralfate are thought to offer significant protection against erosive gastritis.
S p e c i mf eiacs u r e s Specific measures are primarily directed at reducing the provoking agents or the inflammatory response that ensues. Peritoneal lavage has been used in an attempt to remove digestive enzymes and inflammatory mediators from the peritoneum. This procedure has been shown to reduce mortality in those with pancreatic infection treated by lavage for at least 1 week. 26 Continued pancreatic secretion of digestive enzymes maintains and augments the autodigestive process. Simple procedures such as nasogastric suction might be expected to reduce pancreatic secretion, but several controlled trials have failed to show an effect on the clinical course other than relief from nausea, vomiting and ileus] '2 Inhibition of pancreatic secretion with agents such as anticholinergics, cimetidine, fluorouracil and glucagon, have shown benefits in animal models, but not in human. 1 Somatostatin and its analogue octreotide inhibit many physiological regulatory functions in the gastrointestinal tract and the exocrine/endocrine activity of the pancreas. These agents might be of benefit in disorders where the pancreatic duct flow is compromised. Unfortunately, in four placebo-controlled trials involving nearly 400 patients neither somatostatin nor octreotide improved the clinical course of acute pancreatitis. 27 Agents that inhibit pancreatic enzymes such as proteases would seem ideal for reducing the severity of pancreatitis.' Aprotinin and gabexate mesilate have shown some benefits in animal models, but as yet no demonstrable effects in clinical trials. ~ Other specific treatments include surgical procedures such as percutaneous drainage for pancreatic abscesses, which is not particularly successful, and similar drainage of infected pseudocysts, in which some benefits have been reported. Early surgical intervention is indicated in biliary obstruction, necrotizing infected pancreatitis, pancreatic abscesses and bleeding. Relative indications include sterile necrosis of more than 50% of the pancreas, pancreatic duct disruption and/or chemical peritonitis. Surgical treatment of biliary obstruction has evolved in recent years with the
24
CURRENT ANAESTHESIA AND CRITICAL CARE
advent of endoscopic sphincterotomy, which might be considered during the acute phase (in the first 72 h). Other surgical procedures that may be undertaken in the acute phase include necrotic tissue debridement and drainage of the pancreatic bed. Conclusions • The cause of idiopathic acute pancreatitis now appears to be related to biliary dysfunction leading to biliary sludge and microlithiasis • The presence and extent of pancreatic necrosis and infection are the main determinants of clinical evolution and prognosis • Prognostic assessment based on specific parameters and their scores is controversial. Clinical observations continue to be the best estimates of severity of disease • The major aspects of treatment remain symptomatic relief and general supportive therapy • Methods to reduce pancreatic secretion or inhibit proteases have not shown a clear clinical efficacy • Early endoscopic treatment is gaining favour for biliary stone-induced pancreatitis • Surgery is indicated when infected or extensive sterile necrosis is detected • Further studies are necessary to identify effective methods for inhibiting the local and general inflammatory response.
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