Pain Management

Pain is the cardinal symptom of acute pancreatitis, and its relief is a clinical priority. The strategy in patients with acute pancreatitis, as for all acute pain, is the staged use of analgesics. Although some debate still surrounds step-up and step-down approaches, it is best practice to use NSAIDs for the management of mild pain (Pezzilli et al, 2007). The potential risk of bleeding as a result of the antiplatelet effect of NSAIDS has not been an issue in practice. For patients with moderate and severe pain, and for those for whom NSAIDs are inadequate, the second step is to use a weak opioid; the third step is to use a strong opioid.

Although experimental findings show that morphine can induce spasm of the sphincter of Oddi and exacerbate the severity of acute pancreatitis, it is worth noting that the avoidance of morphine as an analgesic has not been supported by clinical studies (Economou & Ward-McQuaid, 1971). A comprehensive review of the literature shows that all opiates increase the pressure in the sphincter of Oddi but that physiologic effect is of marginal clinical relevance (Thompson, 2001).

In practice, patients with severe acute pancreatitis require intravenous analgesia, and patient-controlled analgesia should be considered. Epidural analgesia can be considered for patients with severe and critical acute pancreatitis who require high doses of opioids for an extended period. Oral analgesics can be introduced but are less helpful in the acute setting because of the longer onset of action and concerns about variable absorption. Because the pain in acute pancreatitis is continuous, oral analgesics should be prescribed at regular intervals that are at least equal to the half-life of the drug. Although it has been reported that analgesics can also be given transdermally or rectally, no RCTs have compared the different routes of administration of the same analgesic in patients with acute pancreatitis.

Different analgesics have been compared in patients with acute pancreatitis, and the six published RCTs are summarized in Table 54.2 (Blamey et al, 1984; Ebbehoj et al, 1985; Jakobs et al, 2000; Kahl et al, 2004; Peiro et al, 2008; Stevens et al, 2002). These trials had a different study design, evaluated different analgesics, and had small sample sizes; only three of the trials were double-blinded. From these studies it can be said that no credible clinical evidence supports avoiding the use of morphine in treating the pain associated with acute pancreatitis; however, the NSAID of choice is metamizole (2 g/8 h IV), and the opioid of choice is buprenorphine (0.3 g/4 h IV). There is no evidence to support the use of parenterally administered local anesthetics such as procaine in the management of pain associated with acute pancreatitis. However, the lack of high-quality evidence means that the choice of analgesic and the strategy for administration remain uncertain. No recent guidelines relating to the management of acute pancreatitis provide a specific recommendation regarding pain management (Loveday et al, 2010).

Table 54.2 Randomized Controlled Trials of Analgesics in Patients with Acute Pancreatitis

Fluid Resuscitation

Acute pancreatitis can be associated with substantial third-space fluid losses, and the resultant hypovolemia that impairs the microcirculation of the pancreas is a major determinant of pancreatic necrosis. The reflex splanchnic vasoconstriction in response to hypovolemia may compound pancreatic hypoperfusion and further predispose to ischemia. Fluid resuscitation is one of the most important aspects of the early management of acute pancreatitis (Gardner et al, 2008; Talukdar & Vege, 2009) and is the intervention most likely to improve outcome. No high-level evidence describes the optimal resuscitation fluid, required fluid rate, or best marker to guide resuscitation and indicate its adequacy (Banks & Freeman, 2006; Pandol et al, 2007). It is not even known whether colloids or crystalloids are more effective in improving pancreatic microcirculation and outcome. The initial goal of fluid resuscitation is to restore circulating blood volume (euvolemia), with the aim of normalizing heart rate, blood pressure, central venous pressure, and urine output, even though these do not reflect the adequacy of pancreatic and splanchnic perfusion (Flint & Windsor, 2003). In general, urine output should be restored at greater than 0.5 mL/h/kg body weight, and the central venous pressure should be restored to between 8 and 12 cm H₂O. Swan-Ganz monitoring can be helpful in hemodynamically unstable patients, and some evidence shows that as an independent risk factor of pancreatitis severity and a marker of hydrations status, hematocrit might be useful with fluid resuscitation (Pitchumoni et al, 2005; Wu et al, 2009). Adequate fluid resuscitation is likely when the hematocrit is restored to between 30% and 35%. A number of other approaches to guide resuscitation offer promise but have not become established in clinical practice. An example is the use of intramucosal pH (pHi) derived by nasogastric tonometry (Juvonen et al, 2000a; van Haren et al, 2007), which is predictive of severity and reflects the adequacy of perfusion in the splanchnic circulation.

Antibiotics

Although the use of broad-spectrum antibiotics to treat the established infection in acute pancreatitis is a well-established practice, the use of prophylactic antibiotics has been controversial for decades. Three RCTs in the 1970s failed to demonstrate a beneficial effect of antibiotic prophylaxis, probably because of a small sample size, inappropriate selection of antibiotics—such as ampicillin, which does not sufficiently penetrate the pancreas—and inclusion of patients with mild pancreatitis (Table 54.3; Craig et al, 1975; Finch et al, 1976; Howes et al, 1975). Between 1993 and 2009, several randomized, controlled, open-label trials were published evaluating the efficacy of prophylactic antibiotic treatment in patients with severe acute pancreatitis (Delcenserie et al, 1996; Pederzoli et al, 1993; Rokke et al, 2007; Sainio et al, 1995; Schwarz et al, 1997; Spicak et al, 2003; Xue et al, 2009). The results of these trials were conflicting. Although some RCTs demonstrated a significant reduction of infectious complications and mortality with the use of prophylactic antibiotics, others failed to do so (see Table 54.3). Only three double-blind, placebo-controlled RCTs were published between 2004 and 2009, and all of them were unable to show a beneficial effect of antibiotic prophylaxis regarding infectious pancreatic complications, the need for surgery, and mortality (Dellinger et al, 2007; Garcia-Barrasa et al, 2009; Isenmann et al, 2004). This is in line with the findings of a meta-analysis that showed an inverse relationship between methodologic quality of the studies and impact of antibiotic prophylaxis on mortality (de Vries et al, 2007).

Table 54.3 Randomized Controlled Trials of Intravenous Antibiotic Prophylaxis vs. No Antibiotics in Patients with Acute Pancreatitis

On the other hand, it is worth noting that the three double-blind RCTs mentioned were not without flaws. These include a large crossover to open-label antibiotics in the control group (i.e., a high percentage of patients in the placebo group were treated with intravenous antibiotics) and the inclusion of patients on the basis of predicted severity of acute pancreatitis rather than proven necrotizing pancreatitis. All the studies were underpowered because the power calculation was based on an infection rate of 40%, whereas the actual infection rates in the placebo groups of the trials were only 12% to 17%.

Several attempts have been made to statistically aggregate data on the use of prophylactic antibiotics in acute pancreatitis. Although only two new RCTs were published from 2006 through 2007, it is notable that seven of the 10 meta-analyses were published within this period (Petrov, 2008). Thirteen RCTs were included in these seven meta-analyses. Because of different inclusion criteria and various meta-analysis techniques used, concordance is lacking, and they provide contradictory recommendations regarding the role of prophylactic antibiotics in reducing the risk of pancreatic infectious complications. Overall, it appears that the most recent studies do not support the use of prophylactic antibiotics to reduce the frequency of pancreatic infectious complications, surgical intervention, and death in patients with acute pancreatitis. Therefore routine broad-spectrum prophylactic antibiotics in patients with severe acute pancreatitis cannot be recommended on the basis of current evidence.

Nutritional Management

Severe acute pancreatitis is associated with a cytokine-mediated systematic inflammatory response and a hypercatabolic state (Windsor & Hammodat, 2000; see Chapter 10). The adverse consequences of this include protein-calorie malnutrition, expansion of the extracellular fluid compartment, and immune suppression. A meta-analysis of RCTs showed that nutritional support, both enteral and parenteral, significantly reduced risk of mortality in patients with acute pancreatitis compared with no nutritional support (Petrov et al, 2008c). Nutritional support is thus an essential part of the management of patients with severe acute pancreatitis (Banks & Freeman, 2006; Pandol et al, 2007).

Type of Feeding

The feasibility of providing nutritional support in patients with acute pancreatitis has been known for more than 3 decades. Parenteral nutrition (PN), rather than enteral nutrition (EN), became the standard of care because of the concept of “resting” the pancreas. The rationale for this was to prevent stimulating increased secretion of pancreatic proteolytic enzymes and exacerbating pancreatitis severity. But the use of PN has decreased in the face of well-recognized problems, such as catheter-related sepsis, the high cost of treatment, electrolyte and metabolic disturbances, villous atrophy and gut barrier failure with promotion of bacterial translocation, systemic sepsis, and multiple organ failure.

A number of RCTs compared total PN and total EN in the management of predicted severe AP (Table 54.4; Casas et al, 2007; Doley et al, 2009; Eckerwall et al, 2006; Gupta et al, 2003; Kalfarentzos et al, 1997; Louie et al, 2005; Petrov et al, 2006; Wu et al, 2010). A meta-analysis of high-quality RCTs has shown a significant twofold reduction in the risk of total and pancreatic infectious complications and a 2.5-fold reduction in the risk of death in patients receiving total EN (Petrov et al, 2008f). The basis for the clinical benefits of EN over PN remain unclear, although EN may prevent or attenuate mucosal barrier failure and bacterial translocation (Windsor & Hammodat, 2000). Intestinal permeability studies are a surrogate marker for clinically relevant events and provide conflicting results. Three clinical studies showed increased intestinal permeability to both micromolecules and macromolecules in patients with severe acute pancreatitis when compared with mild acute pancreatitis and healthy volunteers (Ammori et al, 1999; Juvonen et al, 2000b; Nagpal et al, 2006). But an early RCT from the United Kingdom (Powell et al, 2000) in which patients with predicted severe AP were randomized to receive either EN or no artificial nutritional support showed significantly increased intestinal permeability by day 4 in patients allocated to the EN group. Similarly, a recent RCT from Sweden comparing nasogastric EN and PN in patients with predicted severe acute pancreatitis demonstrated impaired gut permeability on day 3 in the EN group (Eckerwall et al, 2006). This difference might be explained by the inclusion of a considerable number of patients with mild AP in whom intestinal permeability is unlikely to change (Petrov et al, 2008f).

Table 54.4 Randomized Controlled Trials of Total Enteral vs. Total Parenteral Nutrition in Patients with Predicted Severe Acute Pancreatitis

Therapeutic Endoscopic Retrograde Cholangiopancreatography

Endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy (ES) has been promoted as a proven intervention in patients with acute biliary pancreatitis since the early 1990s (see Chapters 18 and 27). This was based on the findings of two RCTs, from the United Kingdom and Hong Kong, of early ERCP (within 24 to 48 hours of admission) with or without ES versus conservative treatment (Neoptolemos et al, 1988; Fan et al, 1993). Both trials demonstrated that early ERCP was associated with a reduction in complications, but not in mortality, and only in patients with predicted severe acute pancreatitis.

Some evidence suggests that the duration of biliary obstruction, rather than the predicted severity of acute pancreatitis, is the most important determinant of outcome (Acosta et al, 1997, 2006). This is probably due to concomitant cholangitis secondary to the obstruction and probably best explains the usefulness of ERCP in the context of acute biliary pancreatitis (Petrov, 2009). The first multicenter RCT to examine the role of ERCP in acute pancreatitis was designed to include only patients without evidence of biliary obstruction (Folsch & Neoptolemos, 2002). This German study did not find any benefit of early ERCP (within 72 h after onset of symptoms) over conservative treatment. The most recent RCT, from Argentina, found that early ERCP in patients with biliary obstruction, defined by laboratory and radiologic criteria, and without evidence of acute cholangitis conferred no benefit (Oria et al, 2007).

Two important meta-analyses were published in 2008. The first found that compared with conservative treatment, early ERCP in patients with both predicted mild and predicted severe acute pancreatitis did not decrease the incidence of local pancreatic complications or mortality rate (Petrov et al, 2008d). The second meta-analysis was designed to negate the confounding effect of acute cholangitis and demonstrated no benefit of early ERCP over conservative treatment in terms of complications and mortality in patients with predicted mild and predicted severe acute pancreatitis (Petrov et al, 2008e). The conclusion to be drawn from these studies is that early ERCP is indicated in patients with acute pancreatitis if acute cholangitis is evident (see Chapter 43) but not for those with just cholestasis (Petrov, 2009). Although cholestasis can reflect a persisting main bile duct stone, it might also be due to edema of the ampulla secondary to stone passage to the duodenum and may thus be expected to improve over the first few days of admission. Persistent cholestasis without cholangitis may require an ERCP but not usually in the acute setting.

Cholecystectomy

Recurrent attacks of gallstone pancreatitis carry a morbidity rate of up to 40% (Banks & Freeman, 2006), and an early laparoscopic cholecystectomy is widely advocated within the same hospital admission (see Chapter 30). The optimal timing of cholecystectomy has been controversial. The U.K. guidelines for the management of acute pancreatitis recommend that all patients with biliary pancreatitis undergo definitive management of gallstones during the same hospital admission (index cholecystectomy; Working Group, 2005). However, some surgeons have concerns that early surgery may be associated with an increase in operative difficulty and hence morbidity and conversion rate; therefore they advocate cholecystectomy after a period of 4 to 6 weeks to allow resolution of the inflammatory process (interval cholecystectomy; Green, 2008; Larson et al, 2006). These two approaches have been compared in several RCTs, which demonstrated no difference in complication rates between index and interval cholecystectomy; however, index cholecystectomy resulted in a significantly shorter length of hospital stay (Siddiqui et al, 2008). It is worth mentioning that patients with acute biliary pancreatitis were excluded from these trials. An adequately powered RCT of index versus interval cholecystectomy is needed to draw a firm conclusion about the optimal timing of cholecystectomy in patients with acute biliary pancreatitis.