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MANAGEMENT OF SEVERE ACUTE PANCREATITIS : Standards and Future Perspectives

Xin Shi, Ketan R Vagholkar, Helmut Friess,Waldemar Uhl, Markus W Buechler
Department of Visceral and Transplantation Surgery, University of Bern, Inselspital, Switzerland

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Severe acute pancreatitis is an inflammatory disease that often takes a complicated and life-threatening course. There is still much controversial debate over treatment of severe acute pancreatitis. Conservative management comprises early diagnosis, prompt and aggressive fluid replenishment, adequate nutritional support, management of pain, and optimal antibiotic therapy. Administration of such extensive conservative treatment is best undertaken in an intensive care unit (ICU), where the response of the patient to the treatment can be closely monitored and judged. Surgical intervention is warranted when there is supervening infection of the necrotic pancreas. Among all the surgical approaches, necrosectomy and continuous local lavage allow debridement of devitalized and infected tissue with preservation of vital pancreatic tissue, and yield good results if performed at the right time. Clinical and experimental studies aim to target the maintenance of the integrity of the intestinal barrier and function, to preserve pancreatic microcirculation, and to balanced and modulate the inflammatory response. However, whether these new approaches will be of major clinical benefit has to be evaluated in randomized clinical trials in the future.

Severe acute pancreatitis (SAP) has a complicated and ill-defined pathophysiology. It is associated with a high complication rate and unpredictable outcome. The choice of therapy depends mainly on the judgement of the attending clinician, and presently no specific drug to treat the disease is available. Due to variability of the pathophysiological events in SAP, it is associated with a mortality rate of 10-45%. [1], [2] Therefore the management of SAP, which still remains a contentious issue, poses a significant clinical challenge to the attending clinicians.

The various approaches to the conservative and surgical management of SAP are reviewed in this paper, and an attempt is made to give future perspectives on the management of this disease.

Principles of Conservative Therapy in Sap

Upon confrontation with a patient suffering from suspected SAP, three facts need to be determined:
a) is it SAP?
b) what is the aetiology of SAP? and
c) what outcome and future course can be expected for the disease? The solutions to these questions will direct the further management of the patient. [3]

The diagnosis of acute pancreatitis (AP) is established by a detailed history and clinical examination supported by laboratory (measurement of pancreatic enzymes in blood or urine) and radiological investigations. Once the diagnosis of AP is established, the disease has to be staged as mild or severe acute pancreatitis. Serum markers such as C-reactive protein (CRP), [4] polymorphonuclear granulocytes-elastase, [5] and LDH, and procedures such as contrast-enhanced computed tomography (CT), [6] are helpful in this differentiation. The most difficult decisions during management concern whether surgery is indicated, and the timing and approach of surgical intervention. [7] The dilemma regarding the indication for surgical intervention remains throughout the course of conservative management, and needs careful assessment of the clinical course and results of radiological and laboratory investigations. Role of fluid replenishment

It is essential to provide adequate replacement of intravascular volume in patients with SAP. The rapid restoration and maintenance of intravascular fluid volume remains one of the important therapeutic measures generally accepted as effective in the management of SAP. [8] Fluid resuscitation corrects hypotension and renal insufficiency. During the initial period, fluid requirements may exceed 5-6 liters per day, and at times more than 10 liters may be needed to maintain an adequate intravascular volume. Careful charting of the intake, output and vital parameters provide information regarding the adequacy of fluid replenishment.

When fluid needs are enormous and the patient is seriously ill, it is essential to measure the central venous pressure (CVP) by means of a CVP catheter or Swan-Ganz catheter in order to gauge the adequacy of fluid replenishment and to ensure that large volumes of intravenous fluid do not lead to congestive heart failure.[8] The use of a Swan-Ganz catheter is particularly advisable when fluid requirements are substantial, while the cardiovascular status is unstable, or when respiratory function is deteriorating. Patients undergoing vigorous replenishment are prone to electrolyte imbalances, and careful monitoring of sodium, potassium, calcium, and magnesium is therefore essential.

Role of intensive care

The intensive care unit (ICU) is pivotal in providing specific organ support for patients with severe pancreatitis. These patients are resource-intensive9 and frequently develop single or multiple organ failure which has to be treated further.

The principles of ICU therapy in SAP include eliminating the cause of the primary insult if possible. [7] , [8] Secondary causes of organ failure such as hypovolaemia and tissue hypoperfusion, hypoxaemia, and pancreatic nosocomial infections must be identified and promptly treated. Although there is no specific therapy available, experimental and preliminary clinical studies indicate that early isovolaemic haemodilution with dextran may have distinct beneficial effects. [10] In addition, maintaining high generalized oxygen transport may also be advantageous. [11]

Role of nutritional support

The provision of nutritional support for the patient with SAP is an essential component of supportive therapy, especially since some patients with pancreatitis are nutritionally depleted prior to their illness and face increasing metabolic demands throughout the course of SAP. [12] Failure to reverse or prevent malnutrition, and a prolonged negative nitrogen balance, increases mortality rates.

The route by which nutrition is administered is still controversial, however, and remains a subject for debate. In the last decade there has been a trend away from the use of total parenteral nutrition (TPN) in favour of enteral nutrition (EN) in the support of the critically ill patient in general. Studies suggest that early EN started within 24 hours of admission to the ICU, compared with TPN or delayed EN, is associated with improved wound healing and decreased septic complications. [13] When EN is given it has been suggested that it should be delivered distal to the ligament of Treiz (below the area of the cholecystokinin (CCK) cells distal to the third part of the duodenum), as CCK stimulation may worsen the course of the disease. [14] It has long been known that intragastric delivery of nutrients results in an increased volume of pancreatic secretion, with increased protein and bicarbonate secretion. By contrast, jejunal nutrient delivery is not associated with any increase in pancreatic exocrine secretory volume, protein or bicarbonate secretion. On the other hand, there is increasing evidence of negative effects of TPN, such as increased gut permeability, increased central vein catheter-related sepsis, an immunosuppressive effect, [15] increased incidenceof septic complications [16] and greatly increased costs. Presently a controlled randomized clinical study has evaluated the role of EN in SAP. [17] The findings indicate that EN has benefits with regard to reducing the total and septic complications.

Role of prophylactic antibiotics in SAP

Pancreatic infection is an early and frequent finding in experimental models of SAP. However, in humans with necrotizing pancreatitis, infection of pancreatic necrosis normally occurs in the second or third week after onset [18] with a frequency of 40-70%.

In the past, three controlled, randomized clinical trials failed to show any benefit of antibiotics to improve the outcome of AP. [19-21] However, these studies had severe flaws, and careful analysis of the data clearly reveals why antibiotic treatment was without any effect. First, the studies included patients with mild AP (no necrosis), in whom an infection of the pancreas is a rarity. Second, these studies used antibiotics which we now know do not penetrate into the pancreas. Third, the antibiotics used do not adequately cover the spectrum of bacteria (Gram negative bacteria and anaerobes) which are normally found in SAP. Newer clinical trials taking into account the flaws of these previous studies indicate a benefit of antibiotic therapy in the prevention of infection in acute necrotizing pancreatitis. [22-27] The results are shown in Table 1. A meta-analysis of these studies showed a benefit of antibiotics in reducing mortality. [28] Sensitivity analysis showed that the advantage was limited to patients with SAP who received broad-spectrum antibiotics that achieve therapeutic pancreatic tissue levels. It is therefore recommended to commence a course of prophylactic imipenem or a broad-spectrum third-generation cephalosporin or broad-spectrum penicillin in patients with SAP. [23] These antibiotics should penetrate into the pancreatic gland/adjacent fatty tissue and should cover the bacterial spectrum commonly found in infected pancreatic necrosis. [29]

TABLE 1 Prospective, randomized studies of prophylactic antibiotic treatment in severe acute pancreatitis
Author	Year	Antibiotic Drug	Controls	Mortality of AB#	Infection rate of AB#
Pederzoli P22	1993	Imipenem	Placebo	7%	12%*
Sainio V23	1995	Cefuroxin	Placebo	3%	30%
Luiten EJT24	1995	SDD	Placebo	22%	18%++
Delcenserie R25	1996	Ceftazidin/Amileacin/Metronidazole	Placebo	9%	0%++
Schwarz M26	1997	Ofloxacin/Metronidazole	Placebo	0%	61%
Bassi C27	1998	Imipenem	Pefloxacin	10%$	10%++ $
# AB, antibiotic treatment; * p; �p=0.028; ++p=0.03; $Imipenem

 

Role of selective decontamination of digestive tract (SDD)

The hypothesis that AP promotes bacterial translocation, leading to infection in the inflamed pancreas and peripancreatic tissue, has been tested in rats fed with fluorescent beads, sensitive inert markers of translocation. [30] The results suggest a transperitoneal route of translocated bacteria for pancreatic infection.

A controlled trial of SDD under these circumstances was performed in 102 patients with SAP. [24] Patients were randomized to receive SDD (oral colistin, amphotericin and norfloxacin with addition of a daily dose of the three drugs given as a rectal enema and systemic cefotaxime until Gram-negative bacteria were successfully eliminated from the oral cavity and rectum) or were randomized to a control group. The incidence of Gram-negative pancreatic infection was significantly reduced in patients treated with SDD. Furthermore, the mortality was also lower in the treatment group (22%) compared with the control group (35%). However, the use of SDD is associated with the emergence of resistant Staphylococcus aureus. It is likely that this aspect and the inconvenience of administering SDD are the reasons why this therapy is not enthusiastically employed.

Role of somatostatin and octreotide

Somatostatin and its long-acting analogue octreotide are potent inhibitors of exocrine pancreatic secretion. They also stimulate the activity of the reticuloendothelial system and play a regulatory role, mostly inhibitory, in the modulation of the immune response via autocrine and neuroendocrine pathways. Both are cytoprotective with respect to the pancreas. [31] Both agents are effective in acute experimental pancreatitis [32] and in the prevention of complications in patients undergoing surgery for chronic pancreatitis and pancreatic tumours. [33] , [34]

Somatostatin and its analogue octreotide have been studied in a number of animal experiments, with differing results. [35-37] In humans, a case-matched study using historical controls which examined the effect of octreotide in patients with SAP and pulmonary failure showed potentially beneficial results of octreotide treatment. [38] However, a randomized, placebo-controlled, multicentre trial of octreotide in 58 patients with moderate to severe pancreatitis could not confirm these promising findings. [39] Mortality was similar in octreotide and control patients. Complications such as respiratory failure, acute renal failure, MOF and pancreatic necrosis were higher in the octreotide treatment group than in the control patients.

The largest completed study on this approach is a randomized, placebo-controlled trial in which 31 centres in Germany and one in Switzerland enrolled a total of 302 patients with moderate to severe acute pancreatitis. [40] There was no difference in the development of complications between controls (71%) and octreotide-treated patients (76%). Furthermore, mortality was unchanged (16% in the control group and 15% in the treatment group).

Taken together, these data show insufficient evidence at present to support the use of octreotide or somatostatin in the treatment of patients with moderate to severe acute pancreatitis. Additionally, the therapeutic effect of octreotide and somatostatin, if present at all, is probably very small and therefore unlikely to have any significant impact on the management of patients with SAP.

Role of endoscopy

The early identification of patients with severe gallstone-associated pancreatitis is essential to allow a prompt referral for early endoscopic retrograde cholangiography (ERCP). A study conducted in the United Kingdom revealed that patients with predicted severe gallstone pancreatitis had a significant reduction in morbidity when ERCP was undertaken within 72 hours of admission, but there was no significant difference in mortality. [41] Data from Poland showed a significant reduction in both the complication rate (13% versus 34%, p) and mortality (0.6% versus 11%, p) in patients endoscopically sphincterotomized within 72 hours after admission, compared to patients who did not undergo this procedure. [42] A study from Hong Kong randomized 195 patients with gallstone pancreatitis to receive ERCP/endoscopic sphincterotomy (ES) within 24 hours (n=97), or conservative treatment (n=98) unless they had signs of cholangitis or sepsis.43 Overall there was a reduction in biliary sepsis in the urgent ERCP/ES group compared with the conservativegroup, but no significant reduction in either systemic or local complications.

However, controversial results were reported in a multicentre trial conducted in Germany. [44] The overall rate of complications was similar in patients with and without ERCP/ES, but patients in the urgent ERCP/ES group had more severe complications. Complications occurred in 46% of patients assigned to early ERCP and in 51% of those assigned to conservative treatment. However, respiratory failure was more frequent in the ERCP treatment group (p=0.03) and jaundice was more frequent in the conservative treatment group (p=0.02).

Thus the exact role of ERCP/ES in SAP still remains to be clearly defined. However, there is little doubt regarding the urgent need for ERCP/EC within 24 hours of admission in patients suffering from gallstone-associated SAP with marked cholestasis leading to progressive jaundice, associated with signs of cholangiosepsis.

Operative management of SAP

The role of surgery remains controversial in the management of SAP. Earlier in this century, most patients with AP of even moderate severity underwent operative intervention. The results were poor, with mortality rates up to 50%. Conservative approaches in SAP persisted for many years as well. However, over the past ten years it has become clear that certain patients with SAP do benefit significantly from operative intervention. Nevertheless, the decision regarding whether and when to operate is often difficult and requires careful clinical judgement.

Indications for Surgery in SAP

With the availability of modern, sophisticated ICU services, the outcome of conservative treatment in SAP patients is improving, with a significant reduction in mortality. [8], [45] More and more specialized centers treat patients with SAP conservatively as long as there is no infection of the pancreatic necrosis.[8], [45], [47] In this respect, surgical treatment of SAP is usually only recommended in cases with infected pancreatic necrosis.48 There are a few exceptions, such as persistent and severe biliary pancreatitis when an obstructing gallstone that cannot be managed endoscopically is lodged at the ampulla of Vater, [49] but they are extremely rare.

The other contentious issues regarding surgical management of SAP which need to be addressed are timing of surgical intervention and whether patients with sterile necrosis in SAP should be operated.

Early Versus Late Surgical Intervention

In recent years, the timing of surgery for SAP has changed remarkably. Formerly, early surgical management was favoured, [50] especially if systemic organ complications arose. The most recently completed prospective, randomized-controlled study addressing this aspect of treatment randomly allocated patients with unequivocal SAP to two treatment arms. [51] Group A included early necrosectomy (within 48 to 72 hours of onset) and Group B, late necrosectomy (at least 12 days after onset). Both groups continued with open packing and staged necrosectomies. Although difference in the mortality rate (58% versus 27%) was not statistically significant, the odds ratio for mortality was much higher in the early operation group, which led the authors to discontinue the study. A possible reason for the poor results, especially in patients with early surgery, might be that demarcation of pancreatic necrosis did not occur, therefore removal of necrosis was difficult and was perhaps associated with bleeding. When this is the case, surgical treatment should be performed at the earliest within two to three weeks after onset of SAP. [2] , [52] Early surgery in SAP is only required in cases with proven early infection of the pancreatic necrosis if these patients do not respond to optimal ICU therapy. [7] , [52]

SURGICAL INTERVENTION IN STERILE SAP: DO PATIENTS BENEFIT FROM IT?

The observation that some patients with SAP survive without becoming infected, thus avoiding surgery, is well known. Moreover, operating upon patients who have sterile SAP may increase the risk of subsequent infection and of the associated mortality. This is the basis of justification for the critical decision as to whether patients with sterile SAP should undergo surgical intervention.

In a study conducted by Bradley et al., 194 medically treated patients with AP were summarized. [53] Thirty-eight patients (20%) developed pancreatic necrosis. In this subgroup of patients, 27 (74%) developed pancreatic infection. This was treated by open drainage, yielding in a mortality rate of 15% (4/27). Those patients (n=11) with documented sterile SAP were all successfully treated without surgical intervention. These observations clearly suggest that sterile SAP can successfully be treated by medical means alone, and surgical intervention is not needed.

In contrast, another study [54] promotes the view that persisting or increasing multiple organ failure (MOF), despite adequate intensive care treatment, should be an indication for surgery even if necrosis is sterile. In this study, patients admitted with a diagnosis of SAP were reviewed, of whom 172 (69%) were found to have sterile necrosis either at operation or by fine needle aspiration. All were initially treated conservatively, but 107 developed abdominal or organ complications and subsequently underwent operation. The remaining patients were treated conservatively throughout their illness. In the surgically treated group there was a trend towards a higher incidence of pulmonary insufficiency, renal insufficiency and shock, and their APACHE II scores increased postoperatively. The mortality rate of the patients treated surgically was 14/107 (13%) compared with 4/65 (6.2%) for those treated conservatively. Although there is no significant difference between the mortality rates, the increased incidence of complications in the surgical group may indirectly also favour the conservative treatment strategy in sterile SAP.

Today, more and more clinicians believe that surgery to debride sterile necrosis is contraindicated. [51] , [55] , [56] Not infrequently, some patients with sterile necrosis will remain in critical condition in the ICU for several weeks,56 yet most survive. Moreover, even if the patient remains critically ill after 72 hours of ICU management, continued non-operative ICU treatment is still recommended. [56]

SURGICAL APPROACH IN SAP

The rationale for the surgical management of infected pancreatic necrosis is based on two major aspects. First is the removal of necrotic intra- and extrapancreatic tissue, as well as infected pancreatogenic ascites from the lesser sac and the peritoneal cavity. [57] In the later phase of necrotizing pancreatitis, septic multi-organ failure as a consequence of infected pancreatic necrosis or pancreatic abscess is the most important determinant of outcome. The only way to address this problem is with a thorough necrosectomy and evacuation of the septic foci to prevent further local and systemic bacterial spread. The second goal is the preservation of viable pancreatic tissue. Experience has shown that the necrotizing process is usually represented by fatty tissue necrosis in and around the gland but sparing the pancreatic parenchyma. [58] The amount of the remaining pancreatic parenchyma strongly influences the quality of long-term results regarding endocrine and exocrine pancreatic function. [59]

A variety of different approaches have been advocated in the operative management of SAP during the past decades, ranging from conservative, nonresecting, organ-preserving methods to aggressive, extensive resections. Unfortunately, neither non-debriding, conservative strategies, like peritoneal dialysis [60] or percutaneous drainage, [61] nor aggressive pancreatic resections such as partialor total anatomic pancreatectomy [62] reduced the overall mortality rate of SAP. The reason for these disappointing results is that none of these procedures took the pathophysiological background of the disease into account. Although triple tube drainage was aimed at two important factors-the retroperitoneal drainage of toxic exudate and the inhibition of exocrine pancreatic secretion-necrosectomy was not performed. In the few small series of selected patients with infected necrosis, percutaneous drainage failed to be of any benefit because the small-bore catheters were soon occluded by necrotic debris, resulting in inadequate drainage.

The appropriate procedure in the operative management of necrotizing pancreatitis is the careful removal of all necrosis and the preservation of viable pancreatic tissue. [57] This simple change in the intraoperative management decreases the mortality rate to 13%. [2], [63] Despite initial necrosectomy and simple drainage of the peripancreatic bed, recurrent intra-abdominal sepsis continues to be a major problem in some patients. [64] The cause of recurrent sepsis is probably multi-factorial, but most commonly due to either inadequate peripancreatic drainage or incomplete necrosectomy. Therefore, continuous evacuation of infected peripancreatic exudates and further debridement are mandatory.

After surgical debridement (necrosectomy), intraoperative and postoperative closed local lavage of the lesser sac and the necrotic cavities for the ongoing treatment of SAP can be given. [65] The combination of necrosectomy and postoperative local lavage of the lesser sac provides continuous evacuation of necrotic and infected debris as well as biologically active compounds. When this mechanical flow-through technique is used in the postoperative period, there is no need for routine reoperations, and viable pancreatic tissue with intact perfusion is spared. [66] Any tissue that becomes necrotic or demarcated after initial necrosectomy is rinsed out by the lavage fluid in the postoperative period. After operative debridement, an extensive intra- and postoperative lavage is performed using 24-48L of isotonic or slightly hyperosmotic potassium-free dialysis solution to clear the surface of the pancreatic bed. [67] For postoperative continuous local lavage, large-bore single (Charr 24-32) and double-lumen (Charr 16-24) catheters are positioned in the lesser sac and exteriorized through the right and left upper lateral abdominal wall at the level of the retroperitoneal spaces. At the end of the procedure, the gastrocolic and duodencolic ligaments are sutured to create a closed compartment for a regionally restricted lavage. [2], [64]

THE BERNESE APPROACH TO TREATING SAP2,52

Conservative management of AP has made great progress, and most patients with AP can be managed conservatively. However, severe local complications or MOF may develop in SAP, requiring grade the severity of the disease. In necrotizing pancreatitis patients, the APACHE II was an average 12.6 and the Ranson score a 3.9. Patients with proven necrotizing pancreatitis were treated with maximum intensive care measures and received imipenem/cilastatin(3-4 x 0.5 g/day) early (d 4h) and over a period of at least 14 days. The median duration of stay in the ICU for patients with necrotizing pancreatitis was 15 days (range 1-152). Out of the 103 patients suffering from necrotizing pancreatitis, most of them (n=70, 68%) could be treated successfully with conservative measures, and surgery was not needed.

In case of clinical signs of bacterial infection of pancreatic necrosis, CT-guided fine needle aspiration (FNA) with consecutive Gram stain and bacteriologic culture was performed. Once infected pancreatic necrosis was proven, patients underwent surgical intervention. In our clinic only infected pancreatic necrosis is still an indication for surgery. Operations were performed a median 21.7 days (range 10-49 days) after initial presentation of clinical symptoms of the disease. An operation consisted of debridement of infected pancreatic and peripancreatic necrosis (necrosectomy) supplemented by intra- and postoperative closed continuous lavage of the lesser sac and the involved retroperitoneum by means of double-lumen drainage tubes.

The death rate was 2.9% (2/70) in patients with sterile necrosis managed without surgery versus 21% (7/33) in patients with infected necrosis (p). These results support nonsurgical management in patients with sterile pancreatic necrosis, including early antibiotic treatment. While patients with infected necrosis still represent a high risk group, surgical treatment seems preferable for them.

FUTURE PERSPECTIVES IN THE MANAGEMENT OF SAP69

The development of a specific intervention in SAP awaits more precise characterization of the initiating events and the common pathways which are activated during the course of AP. The earliest metabolic events, those relating to the initiation of pancreatitis, may have little relevance to clinical treatment because the events are historic by the time the patient presents for medical care. However, the pathophysiological events responsible for the progression from mild to severe pancreatitis might be more accessible for medical intervention.

For the future, three approaches hold particular promise in the search for effective and specific interventions in SAP.

Maintaining Intestinal integrity and Function

Newer approaches in dehydration aiming to preserve optimal splanchnic mucosal blood flow and oxygen delivery, must be further evaluated for the treatment of SAP.70 A more relevant endpoint is needed to ensure optimal dehydration -one that reflects adequacy of oxygen delivery. An interventional study directed toward the normalization of splanchnic intramucosal pH in patients with pancreatitis has not yet been reported, although studies in septic and trauma patients demonstrate that this approach has real promise. [70] , [71]

Future clinical trials should include strategies to decrease splanchnic hypoperfusion, attenuate ischaemia/reperfusion injury, and avoid priming of neutrophils. [72] There are also new potential pharmacologic approaches in treating intestinal and pancreatic ischaemia/reperfusion injury. [73] Augmenting endogenous aqueous antioxidant defenses by using supplemental ascorbic acid has been suggested, and the results of trials are awaited. A synthetic analogue of ascorbic acid (CV3611) that penetrates cell walls and accumulates in pancreatic tissue has been reported to increase the survival rate significantly and to reduce the serum levels of pancreatic enzymes in diet-induced pancreatitis in mice. [74] The preferential action of dopexamine to increase oxygen delivery during AP as it increases splanchnic blood flow without increasing myocardial oxygen consumption is promising. [11] The nextmultidisciplinary management in the ICU.8 Systemic inflammatory response syndrome (SIRS), occurring in the early phase of SAP, may be treated in the ICU alone, without any specific drugs.

On the other hand, despite all advances in ICU therapy, infected pancreatic necrosis and consecutive septic MOF increase the mortality rate. In this respect, several surgical approaches have been advocated to improve outcome in SAP. [48] Although surgical treatment still remains controversial, it has been shown that in patients with SAP and sepsis, surgical intervention can lead to an amelioration of symptoms and has a clear advantage over conservative treatment alone. [66] , [68]

During the last 7 years, 254 patients with AP were treated in our clinic and were prospectively recorded. In each patient a contrast-enhanced CT scan was performed and C-reactive protein was measured in order to differentiate between oedematous pancreatitis and necrotizing pancreatitis. 103 patients (41%) had necrotizing pancreatitis. The APACHE II and Ranson scores were used to generation of enteral nutrients will likely contain specific supplements (e.g., prostaglandin E1 analogue and various growth factors) maintaining gut barrier function.

Improving Pancreatic Microcirculation

Some of the measures that maintain adequate splanchnic circulation and limit ischaemia/reperfusion injury should also benefit pancreatic microcirculation (e.g., tonometry-guided fluid replenishment and antioxidant therapy). Isovolaemic haemodilution to a haematocrit of 30% significantly decreased parenchymal necrosis in experimental pancreatitis. [75] Haemodilution with dextran improves pancreatic capillary perfusion and decreases cell vacuolization and interstitial oedema in acute biliary pancreatitis. [75] This approach has been shown to be clinically practicable in patients with AP and has yielded promising preliminary results. [76] The administration of high-molecular-weight dextran reduces the extent of trypsinogen activation, prevents acinar necrosis, and decreases mortality in rats. [77] Preliminary work with hypertonic saline-dextran as a fluid replenishment fluid suggests a lower fluid requirement and reduced pancreatic oedema compared with lactated Ringer’s solution. [78]

Modulating the Inflammatory Response

Attempts to use a magic bullet to modulate the inflammatory response have largely failed in the past. It might be naive to expect that a single agent would be capable of restoring homeostasis in the face of the complex activated cytokine cascades. Furthermore, our concept of the inflammatory response has been one-sided and now needs to recognize the importance of the compensatory anti-inflammatory response. The balance of opposing responses determines the systemic manifestations of the inflammatory response, and it is likely that multiple agents are necessary to beneficially modulate it.

Nevertheless, some single agents continue to show promise. Cytokine blockade with IL-1 receptor antagonists significantly decreases mortality in a mouse model of severe pancreatitis. [79] Platelet-activating factor antagonist (lexipafant) was shown to reduce organ dysfunction and suppress some aspects of the inflammatory response in a phased clinical trial, but it did not show improvement in mortality and pancreatitis-related complications. [80] The results from a large multicentric lexipafant phased study were disappointing and did not reveal any benefit in patients with moderate to severe acute pancreatitis. [81]

Intestinal ischaemia/reperfusion events may provide the site for the second hit of neutrophils, which leads to the exaggerated SIRS response in AP. There is some hope that receptor-mediated control of the primed state may allow modulation of the inflammatory response in the future. [82]

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