Clinical Pancreatology for Practising Gastroenterologists and Surgeons - part 3 doc

PART I 90 or only weakly active metabolites. Thus it may be used safely in cases of renal failure. It does not cause seizures. Nevertheless, it has an important emetic effect that is sometimes difficult to manage. When used sublingually the dose is 0.2–0.4 mg every 6–8 hours. The usual parenteral dose is 0.3–0.6 mg intramuscularly or intravenously every 6 hours or 0.002 mg/kg per hour as an intravenous perfusion. 4 Tramadol: although it has agonist effects on opioid receptors, it also shows analgesic activity due to other mechanisms. It is a weaker analgesic than morphine (about eight times). Since its half-life is slightly longer, it is used parenterally at a dose of 100–150 mg every 6–8 hours (0.17 mg/kg per hour in perfusion). In cases of renal failure the drug accumulates in the bloodstream and it is advisable to increase the interval between doses. It favors the development of seizures in the con- ditions described for meperidine. Unlike most opiates it does not cause addiction. 5 Hydromorphone is eight times more potent as an analgesic than morphine. The recommended dose is 0.5 mg every 3 hours intravenously or 1–2 mg intramuscularly or subcutaneously. A dose of 0.2–1 mg/ hour may be given as a perfusion. 6 Fentanyl is 80 times more potent than morphine. It is hardly used parenterally in pancreatitis but the transdermal route, which allows slow drug release, is used especially to treat chronic pain. Recently, this treatment has also been used successfully in acute pancreatitis (see below). Effect on the sphincter of Oddi Traditionally, several opioids, including morphine, have been rejected as treatments for pain in acute pancreatitis on the assump- tion that they increase biliary pressure. This was based on the findings of preliminary studies that indirectly measured biliary pressure after the use of these drugs. However, opioids such as meperidine did not cause pressure changes and consequently it has become the narcotic of choice in acute pancreatitis. However, as commented before, morphine has several advantages over meperidine in the management of this disorder: it is more potent, its management is more widely known, and it is safer in cases of renal failure with less risk of seizures. Direct manometric studies of the sphincter of Oddi have not fully confirmed the initial hypothesis (Table 9.2). In these studies both morphine and meperidine significantly increased the frequency of the phasic waves of the sphincter, whereas buprenorphine and tramadol did not seem to have any effect. The increase in frequency of the phasic waves causes a reduction in pas- sive filling of the sphincter segment and results in an increase in biliary pressure (confirming the result of the preliminary studies). However, only high cumulative doses of morphine cause a significant increase in the basal pressure of the sphincter of Oddi. Furthermore, no study has yet shown that the increased basal pressure of the sphincter caused by this dose of morphine has a deleterious effect on patients with acute pancreatitis. Therefore it is possible to use morphine (or any Table 9.2 Effect of opioids on sphincter of Oddi dynamics (direct measurement). Drug Study Dose Results Morphine Helm et al. (1988) Successive dose: 2.5, 2.5, 5, 2.5–5 mg/kg: increased frequency 10 mg/kg every 5 min i.v. 10–20 mg/kg: increased basal pressure, frequency and amplitude Thune et al. (1990) Cumulative dose: 2.5, 5, Increased frequency of phasic waves 10 mg/kg every 2 min i.v. Meperidine Elta & Barnett (1994) 1 mg/kg i.v. Increased frequency of phasic waves Thune et al. (1990) Cumulative dose: 25, 25, Decreased frequency of phasic waves 50 mg/kg every 2 min i.v. Sherman & Lehman (1996) 1 mg/kg to 75 mg i.v. Increased frequency of phasic waves Buprenorphine Staritz et al. (1986) 0.3 mg i.v. No changes Cuer et al. (1989) 0.3 mg i.v. No changes Tramadol Staritz et al. (1986) 50 mg i.v. No changes i.v., intravenous. CHAPTER 9 91 other opioid) in the management of pain in acute pancreatitis, although more studies are still necessary to confirm this hypothesis. Controlled studies Despite the number of therapeutic drugs used to treat pain in acute pancreatitis, there are few published controlled studies that compare these drugs with each other or with a placebo (Table 9.3). In 1984, Blamey and colleagues compared the use of intramuscular buprenorphine with intramuscular meperidine in 32 patients with acute pancreatitis. These authors found similar analgesic responses to these drugs in both the intensity and duration of pain relief. Adverse effects were minimal (nausea and vomiting) and occurred in the same proportion in both types of treatment. A year later, Ebbehoj et al. studied the analgesic effect of rectal indomethacin (indometacin) compared with a placebo in 30 patients with acute pancreatitis. In this study, treatment with indomethacin significantly reduced the number of days with pain and the amount of other analgesics (opiates) given. In 1995 Patankar et al. reported another controlled study com- paring the use of pancreatic enzymes with a placebo in 23 patients with acute pancreatitis. No difference was found in the analgesia obtained by these patients. The main adverse effect seen was nausea, which occurred in approximately half the patients in both groups. Re- cently, Jakobs and colleagues compared the analgesic effects of intravenous buprenorphine and procaine. In 40 patients with acute pancreatitis or acute bouts of chronic pancreatitis, buprenorphine produced higher pain relief and reduced the need for additional analgesics. Apart from slight sedation of the buprenorphine-treated group, the secondary effects were few and comparable. Another recent German controlled trial confirmed the lower analgesic effects Table 9.3 Controlled studies with analgesics in acute pancreatitis. No. of Pain Adverse Study patients Drugs assessment Outcome effects Blamey et al. 32 Buprenorphine 0.3 mg i.m. Standard Similar relief Similar (nausea, (1984) lineal scale Similar duration of vomiting) Meperidine 100 mg i.m. Categories pain relief scale Ebbehoj et al. 30 Indomethacin 50 mg twice Visual analog Indomethacin group: None (1985) (rectal) scale less number of days Placebo with pain and opiate administration Patankar et al. 23 Oral pancreatic enzymes Visual analog Similar pain relief and Similar (nausea) (1995) (7800 U protease daily) scale analgesic requirements Placebo Jakobs et al. 40 Buprenorphine 0.3 mg Visual analog Buprenorphine group: Buprenorphine (2000) (bolus i.v.) + 2.4 mg scale higher pain relief and group: higher (infusion i.v.) per 24 hours less additional analgesic sedation rate Procaine 2 g (infusion i.v.) requirements per 24 hours Stevens et al. 32 TTS fentanyl + meperidine Self-reported Fentanyl group: less None reported (2002) Placebo + meperidine pain intensity pain intensity at 36, 45, and 60 hours from admission Kahl et al. 107 Pentazocine 30 mg (bolus Visual analog Pentazocine group: lower None (2004) i.v.) per 6 hours scale pain scores over 72 Procaine 2 g (infusion i.v.) hours per 24 hours i.m., intramuscular; i.v., intravenous; TTS, transdermal therapeutic system. PART I 92 of procaine. Finally, Stevens et al. reported that transdermal fentanyl (plus meperidine for further relief) failed as compared with placebo (plus meperidine) in obtaining significant pain relief during the first 24 hours in hospital in 32 patients with acute pancreatitis. However, fentanyl was more effective for pain relief after the first 36 hours in hospital. Thus although there is scanty evidence, we must con- clude that the use of certain opioids such as meperidine and buprenorphine is safe and effective for pain control in patients with acute pancreatitis. Further controlled studies are needed to confirm whether opioids in general are more effective than theoretically less potent but more widely used drugs such as NSAIDs and to clarify the role of morphine (more potent and safer than meperidine) in pain management in this condition. Epidural analgesia Epidural analgesia is becoming widely used in delivery and in the immediate postoperative period after abdominal or gynecologic surgery. When this route of administration is used, the drug is concentrated where the painful impulses enter the spinal cord (i.e., on the spinal nerve roots). This permits the use of doses substantially lower than those required for oral or parenteral administration. Systemic adverse effects are thus decreased. The procedure involves the insertion of a catheter 3 cm into the epidural space between T5 and T9 (usually T8) and analgesia is instituted by injection of an analgesic drug through the catheter. Because dural puncture is not intended, the site of entry may be at any vertebral level that permits a segmental blockade approximately limited to the chosen region. Usually local anesthetics such as bupivacaine or opioids such as fentanyl or morphine, or a combination of both types of drugs, are used. The association of both agents permits the use of lower doses, minimizing local anesthetic-induced complications of motor blockade and opioid-induced complications. The dose of local anesthetic used can produce high concentrations in blood following ab- sorption from the epidural space, which is rich in ve- nous plexuses. On the other hand, since conduction in autonomic, sensory, and motor nerves is not affected by opioids, blood pressure, motor function, and nocicep- tive sensory perception typically are not influenced by epidural opioids. Pruritus, nausea, vomiting, and urinary retention may appear. Delayed respiratory depres- sion and sedation, presumably from cephalad spread of opioid within the cerebrospinal fluid, occurs infre- quently with the doses of opioids currently used. The technique may involve a single dose but to achieve analgesia over a prolonged period a catheter should be placed for either intermittent dosage or continuous perfusion. As previously mentioned, PCA pumps can be applied. If continuous perfusion is administered, stable analgesic levels are obtained. Therefore, early patient mobilization, improvement in muscular tone, and fewer episodes of hypotension are expected. After correct placing of the epidural catheter, it is necessary to administer a single dose; if adverse effects do not develop, a continuous perfusion should be programmed with variable rate according to the analgesic level obtained. Table 9.4 shows some examples of epidural administration of analgesic drugs. This type of analgesia has reduced postoperative morbidity and mortality. Recently, a systematic review reported that in patients undergoing laparotomy epidural administration of local anesthetics and opioids provided higher postoperative analgesia than the use of local anesthetics alone. However, local anesthetics were found to be associated with less gastrointestinal Table 9.4 Epidural administration of opioids and local anesthesics. Loading dose Infusion (per hour) Bolus Morphine 1–2 mg 0.2–0.4 mg 0.1–0.2mg/hour Meperidine 25–50 mg 10–15 mg 20–25 mg/hour Fentanyl 100 mg 50–75 mg 25–50 mg/hour Fentanyl + bupivacaine (0.0625%) 75 mg + 3.75 mg 50 mg + 2.5 mg 12.5 mg + 0.0625 mg/30 min (6 mL) (4 mL/hour) (1 mL) Morphine + bupivacaine (0.0625%) 1mg + 5 mg 0.15 mg + 1.8mg 0.15mg +1.8mg/30 min (3 mL) (3 mL) CHAPTER 9 93 paralysis than when systemic or epidural opioids were used. In patients with acute pancreatitis, this type of analgesia has many theoretical advantages. Firstly, it permits a reduction in high doses of opioids when these are excessive and/or associated with adverse effects (as previously mentioned, opioids facilitate the occurrence or aggravation of respiratory failure and some show increased neurotoxicity in the presence of renal failure). Also, it allows severely ill patients to achieve a sitting or semi-sitting position readily and therefore improves gas exchange and reduces the incidence of respiratory infections. Intestinal blood flow and motility is also said to improve. Finally, in postoperative patients, epidural analgesia reduces the metabolic response and improves catabolism. All these beneficial effects favor mobilization, reduce the incidence of complications, and permit early resumption of oral feeding. Unfortu- nately, there are still no controlled studies of patients with acute pancreatitis which confirm the theoretical benefits of this type of analgesia. Nevertheless, this type of analgesia may have adverse effects, such as hypotension (due to involvement of the sympathetic nervous system when the catheter is in- serted or medication administered), headache, urinary retention, radicular damage, or catheter migration. The most serious, though infrequent, complication is the development of epidural hematoma or abscess. Epidural analgesia is contraindicated in hypovolemic shock, severe coagulopathy, infection, or radiculopa- thy at the level of catheter insertion. As previously mentioned, since variable amounts of the drugs reach the peripheral blood, systemic adverse effects of local anesthetics or opioids might develop. Large series of patients with acute pancreatitis treated by epidural anesthesia have been reported to have had excellent pain control, with no neurologic or septic complications. Finally, there have been sporadic Patient with acute pancreatitis Without organ failure Metamizol i.v. or tramadol i.v.* (+ meperidine s.c. between dose if necessary) Adequate pain relief No pain relief Metamizol or tramadol if necessary Adequate pain relief Meperidine s.c.* or buprenorphine i.v. i.m.* No pain relief Epidural analgesia* (+ parenteral opioids) With organ failure Figure 9.1 Guidelines for the treatment of pain in acute pancreatitis. *, Patient-controlled analgesia, if possible; i.m., intramuscular; i.v., intravenous; s.c., subcutaneous. domethacin treatment of acute pancreatitis. A controlled double-blind trial. Scand J Gastroenterol 1985;20: 788–800. Elta GH, Barnett JL. Meperidine need not be proscribed during sphincter of Oddi manometry. Gastrointest Endosc 1994;40:7–9. Helm JF, Venu RP, Geenen JE et al. Effects of morphine on the human sphincter of Oddi. Gut 1988;29:1402–1407. Holte K, Kehlet H. Epidural anaesthesia and analgesia: effects on surgical stress responses and implications for postoperative nutrition. Clin Nutr 2002;21:199–206. Isenhower HI, Mueller BA. Selection of narcotic analgesics for pain associated with pancreatitis. Am J Health Syst Pharm 1998;55:480–486. Jakobs R, Adamek MU, von Bubnoff AC, Riemann JF. Buprenorphine or procaine for pain relief in acute pancreatitis. A prospective randomized study. Scand J Gastroenterol 2000;35:1319–1323. Jorgesen H, Wetterslev J, Moiniche S, Dahl JB. Epidural local anaesthesics versus opioid-based analgesic regimens for postoperative gastrointestinal paralysis, PONV and pain after abdominal surgery. Cochrane Database Syst Rev 2003;4:CD001893. Kahl S, Zimmerman S, Pross M et al. Procaine hydrochloride fails to relieve pain in patients with acute pancreatitis. Digestion 2004;69:5–9. Patankar BV, Chand R, Johnson CD. Pancreatic enzyme supplementation in acute pancreatitis. HPB Surg 1995;8: 159–162. Rodgers A, Walker N, Schung S et al. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ 2000;321:1–12. Sherman S, Lehman G. Opioids and the sphincter of Oddi. Gastrointest Endosc 1996;44 :239–242. Staritz M, Poralla T, Manns M et al. Effect of modern analgesic drugs (tramadol, pentazocine and buprenorphine) on the bile duct sphincter in man. Gut 1986;27:567–569. Stevens M, Esler R, Asher G. Transdermal fentanyl for the management of acute pancreatitis pain. Appl Nurs Res 2002;15:102–110. Thompson DR. Narcotic analgesic effects on the sphincter of Oddi: a review of the data and therapeutic implications in treating pancreatitis. Am J Gastroenterol 2001;96:1266– 1272. Thune A, Baker RA, Saccone GT et al. Differing effects of pethidine and morphine on human sphincter of Oddi motility. Br J Surg 1990;77:992–995. PART I 94 reports of good pain relief following percutaneous pharmacologic blockade of the celiac plexus. Guidelines for the management of pain in acute pancreatitis Pain due to acute pancreatitis should be treated from the very onset of the disease by regular analgesic administration. In general terms, PCA pumps are recommended (see Table 9.1). Staged treatment should be given (Fig. 9.1). Thus we may use metamizol (2000 mg every 6–8 hours intravenously) or tramadol (100 mg every 8 hours intravenously), with meperidine (50–100 mg subcutaneously as a single dose) for rescue between doses. When pain control is satisfactory or the pain disappears, the same dosage may be used on demand by the patient. However, if the pain is not controlled, opioids become necessary. Until studies confirm the safety of morphine and its derivatives, the use of meperidine (50–100 mg every 4 hours subcutaneously) or buprenorphine (0.3–0.6 mg every 6 hours parenterally; 0.2–0.4 mg every 6 hours sublingually; 0.002 mg/kg per hour as intravenous continuous perfusion) is recommended. Patients who require high doses of opioids for adequate pain control, and especially those with organ failure (mainly renal and/or respiratory failure), should be treated with epidural anesthesia using either local anesthesics alone or, better, local anesthesics plus opioids (see Table 9.4). This kind of analgesia may be administered in addition to systemic opioids, the dose of which can then be reduced, or can be used as the sole treatment. Recommended reading Blamey SL, Finlay IG, Carter DC, Imrie CW. Analgesia in acute pancreatitis: comparison of buprenorphine and pethidine. BMJ 1984;288:1494–1495. Cuer JC, Dapoigny M, Ajmi S et al. Effects of buprenorphine on motor activity of the sphincter of Oddi in man. Eur J Clin Pharmacol 1989;36:203–204. Ebbehoj N, Friis J, Svendsen B, Bülow S, Madsen P. In- 95 Acute pancreatitis is a disease with a wide spectrum of clinical courses, ranging from the mild form with mini- mum morbidity and almost zero mortality, to the severe form with a high percentage of complications and high risk for a lethal outcome. In about 80% of patients, the inflammatory process is self-limited, involving only the pancreas and immediate pancreatic tissues, and resolves spontaneously within less than a week. These mild cases require only a short period of fasting, intravenous hydration, elec- trolytes, and analgesia. Patients can usually start an oral low-fat diet within 3–7 days of the onset of their pain, resulting in minor and usually easily reversible nutritional defects. This is not the case in severe acute pancreatitis, which is characterized by various degrees of necrosis of pancreatic parenchyma as well as local and systemic complications such as systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF). This form of the disease represents a typical hypermeta- bolic septic model, with increased resting energy requirements and considerable protein catabolism that leads to severe malnutrition. As a result nutritional support in acute pancreatitis should be one of the main therapeutic aims and nutritional management should depend on the underlying pancreatic disease. Malnutrition and metabolic changes in acute pancreatitis: why? Regardless of the etiology, all cases of acute pancreatitis share a common pathogenetic pathway that involves the premature activation of trypsinogen to trypsin, after which a cascade of pancreatic enzyme activation begins that leads to autodigestion of the pancreas and peripancreatic tissues. At the same time, a number of powerful inflammatory mediators are produced locally and systemically, with cytokines being the most important because they initiate or amplify an inflammatory cascade and induce the development of SIRS and re- mote organ failure. Later in the course of the disease, infective complications may occur, particularly infected pancreatic necrosis, consequent sepsis, and sepsis- related MOF, that further increase energy requirements. The release of inflammatory mediators, particularly tumor necrosis factor (TNF)-a and interleukin (IL)-6, and in cases of sepsis the release of catabolic hormones (catecholamines, cortisol, glucagon), change protein and energy metabolism in ways that increase both energy demands and urinary nitrogen excretion, which, in parallel with the reduction of food intake, result in the development of protein–energy malnutrition. Clinical studies have shown that patients with acute pancreatitis have a resting energy expenditure (REE) that is 1.2–1.5 times that predicted by the Harris– Benedict equation, depending on the severity of the disease. Septic patients are the ones with the greater protein–energy needs, since they are in marked metabolic stress. These patients exhibit accelerated catabolism and protein breakdown and have a decreased blood supply to vital organs due to hypovolemia or decreased cardiac performance during the inflammatory process. As already mentioned, nitrogen loss during severe disease is increased. While a healthy adult loses approximately 12 g of nitrogen daily in the urine in the 10 Nutrition in the acute phase of pancreatitis: why, when, how, and how long? Konstantina Paraskeva, Costas Avgerinos, and Christos Dervenis fasting state, patients with acute pancreatitis complicated by sepsis commonly lose up to 40 g of nitrogen daily, with most of this loss coming from the skeletal muscle. Negative nitrogen adversely affects host de- fenses and immune competence balance and is associated with increased morbidity and mortality. Another metabolic response to severe inflammation and energy deprivation is endogenous gluconeogenesis from protein degradation, which can only partially be inhibited by exogenous glucose. Intravenous administration of high doses of glucose carries the risk of hyperglycemia as the insulin response is often impaired. Furthermore, insulin release is also frequently impaired as a result of the inflamed pancreas, rendering the patient susceptible to hyperglycemia in 40–90% of cases. It has been suggested that transient hyperglycemia may impair complement fixation, evoking an immunosuppressive state. Parenteral nutrition is associated with an additional risk for hyperglycemia and careful monitor- ing of blood glucose levels is necessary in these patients. Finally, lipid metabolism is also altered in acute pancreatitis via a mechanism that is not entirely clear. In- creased serum triglycerides may either be the cause or the result of acute pancreatitis. Increase in cholesterol and free fatty acids in serum have also been reported. After the acute phase subsides, serum lipids tend to return to normal. Infusion of exogenous fat does not seem to interfere with the development or the course of acute pancreatitis and is therefore not contraindicated, provided that patients are monitored for hypertriglyceridemia. Energy supply in acute pancreatitis Patients with severe acute pancreatitis manifest increased basal energy requirements, accentuated protein catabolism, and endogenous gluconeogenesis. The goals of nutritional support in this setting are (i) to lessen nitrogen wasting, (ii) to support organ structure and function, and (iii) to positively affect the clinical course of the disease if possible. Individual protein–calorie needs vary widely depending mostly on the severity of the disease, as well as the age, body size (height and weight), and sex of the patient. The most accurate method of measuring caloric requirement is indirect calorimetry, which is also useful for determining the fuel mix being oxidized and for assessing the metabolic stress level. Unfortu- nately, it is not often available, and therefore the most commonly used method for estimation of REE is the equation devised by Harris and Benedict. The formulas for calculating REE (in kcal/day), using the four vari- ables age, height, weight, and sex, are as follows: BMR women = 655 + 9.5W + 1.8H - 4.7A BMR men = 66 + 13.7W + 5H - 6.8A where W is the actual or usual weight (kg), H is height (cm), and A is age (years). In patients with acute pancreatitis, REE as determined by indirect calorimetry varies from 77 to 158% of the energy expenditure predicted by the Harris–Benedict equation, being higher in patients with pancreatitis complicated by sepsis or MOF. These results make the Harris–Benedict equation a very rough method for estimating the energy demands of these patients. Even simpler REE equations are often used in clinical practice and it should be remembered that these may overestimate or underestimate the measured values by 20 or even 30% for any individual. In severely ill patients, REE is usually about 25–35 kcal/kg daily and 1.2–1.5 g of protein per kilogram dry body weight, ad- justing for obesity. With increasing metabolic stress, calories and protein should be increased, except in critically ill patients. During the early catabolic stage, 15–25 kcal/kg and 1.5 g/kg of protein are more suitable in nonsurgical patients with MOF. During artificial nutrition, energy should be provided in the form of mixed fuel, with 60–70% given as glucose and 30–40% as lipid emulsion. Patients with severe disease and MOF often have high serum glucose and triglyceride levels. Intravenous infusion of glucose and fat does not suppress endogenous production and may therefore result in further elevations of blood glucose and triglycerides. Hyperglycemia predisposes to fluid retention (due to increased insulin requirements) and immunosuppression. High-dose lipid emulsion is also immunosuppressive and hypertriglyceridemia may exacerbate pancreatitis; therefore blood glucose levels should be monitored and should not exceed 10 mmol/L, while serum triglyceride concentrations should not exceed 1.5–2 times normal. Requirements for protein can be adjusted by performance of a nitrogen balance study. Hypocalcemia is the most frequent mineral aber- ration seen in patients with acute pancreatitis, and a marked reduction of serum calcium is associated with a poor prognosis. Systemic endotoxin exposure appears to play a significant role in the development of PART I 96 hypocalcemia in severe attacks. In cases where ionized calcium is low and this is not a false reduction due to hypoalbuminemia, an attempt to correct this reduction should be made. Excessive calcium infusion may induce pancreatitis. Patients with pancreatitis may also benefit from glutamine supplementation, as it is an important fuel for the gastrointestinal tract (pancreatic islets, acinar cells, and enterocytes). The oxidation of one molecule of glutamine produces 30 mmol of ATP, which makes this amino acid a very rich energy source. It appears that although enterocytes are rich in glutamine and may even synthesize it endogenously, this amino acid is an essential nutrient in stressed patients. Attempts to favorably modulate the immune and inflammatory responses of severely ill patients led to efforts to enrich nutrition with various immune- enhancing nutrients. This has become known as im- munonutrition. Of the various nutrients that have been suggested as beneficial, glutamine, arginine, w-3 fatty acids, and nucleotides have been introduced into clinical use in the form of several standard formulas, often in combination preparations. There are a number of reports, mainly in severely injured patients, dealing with the role of immune-enhanced enteral diets in these cases. A metaanalysis of 1009 patients from 11 trials showed that immune-modulated regimens resulted in a significant reduction of infective complications and length of hospital stay, but with no effect on survival. Only one study dealt with the use of glutamine in acute pancreatitis, as a supplement in standard total parenteral nutrition (TPN). This investigation found that glutamine improved leukocyte activity and reduced proinflammatory cytokine release in acute pancreatitis. No conclusions can be drawn from these studies and although it seems possible that immune-enriched diets could play a role, further studies are needed to clarify this issue. In the light of the emerging evidence regarding the primary role of the intestine in the pathophysiology of acute pancreatitis, enteral feeding is now considered the preferred mode of nutritional support in these patients. Enteral feeding has proved to be safe and in the majority of patients may cover caloric needs. Due to its beneficial effect on gut integrity, it should be started very early in the course of the disease (during the first 24 hours) and should be continued until the patient toler- ates oral feeding. In cases where the caloric goal cannot be achieved by enteral nutrition, combined parenteral nutrition should be used. Even a low volume of low- residue enteral diet given in cases where TPN is used is sufficient to protect the intestinal mucosa. Recently, it was suggested that gastric feeding may be feasible in patients with severe pancreatitis. The optimal feeding formula has yet to be determined, but an elemental or immune-enhancing diet (10–30 mL/hour) con- tinuously perfused to the jejunum is suggested. Total parenteral nutrition in acute pancreatitis Traditionally, TPN has been the only nutrient-provid- ing treatment in patients with acute pancreatitis and prolonged starvation. TPN achieves energy and protein provision without stimulating pancreatic exocrine secretion. Although Feller et al. in 1974, in an uncontrolled retrospective study, showed a decrease in the mortality rate of patients with acute pancreatitis who received intravenous hyperalimentation, several other similar retrospective uncontrolled clinical trials have failed to reproduce these results. On the contrary, other authors observed a higher incidence of catheter-related sepsis among TPN groups but no difference in total mortality. Two prospective nonrandomized trials have been published on this subject. In 1989, Sitzmann et al. divided 73 patients with acute pancreatitis into three groups depending on their ability to tolerate glucose- free, lipid-based, and lipid-free nutrition. Within 15 days most patients in all groups achieved improvement in nutritional status. A higher mortality was observed in the fat-free group as well as among patients with persistent negative nitrogen balance. A high incidence of catheter sepsis was also documented. In 1991, Kalfaretzos et al. divided 67 patients with severe acute pancreatitis (more than three Ranson criteria) into two groups of early (within 72 hours after admission) and late (after 72 hours) onset of TPN. They noted a significantly lower incidence of complications and mortality in the early group but a high incidence of catheter- related sepsis as well. The only prospective randomized controlled trial on the effects of early parenteral nutrition versus no nutritional support in patients with acute pancreatitis was published by Sax et al. in 1987. During this study, 54 patients were randomized to receive either supporting treatment alone or supportive treatment with early CHAPTER 10 97 TPN (within 24 hours of admission). TPN had no significant effect on clinical outcome, duration, and pancreatitis-related complications, but patients in the TPN group had a ninefold increase in the incidence of catheter sepsis. A significant drawback of this study is the fact that all patients studied had mild pancreatitis (mean Ranson score 1) and hence had low complication and mortality rates with conventional treatment. In conclusion, it can be stated that there is no strong information regarding the role of TPN in acute pancreatitis and more trials are needed in order to establish any benefit. The use of TPN does not seem to interfere with the progress of the disease but indicates a trend in improvement of morbidity and mortality in patients with severe pancreatitis who achieve a state of positive nitrogen balance and in those who require prolonged starvation (i.e., persistent pancreatic inflammation, abscess, and pancreatic fistula). TPN is associated with certain disadvantages, such as an increased rate of catheter-related infections, metabolic disturbances such as hyperglycemia, effects on gut permeability, and increased cost. Role of the gut in acute pancreatitis Contamination of pancreatic necrosis and consequent sepsis is the main cause of death in severe pancreatitis, although in the early period of the disease SIRS remains the main fatal cause. The organisms responsible for secondary pancreatic infection are usually Gram-negative bacteria of the same type that colonize the gastrointestinal tract. This suggests gut barrier dysfunction, increased intestinal permeability, and subsequent bacterial translocation through the gut wall. Indeed, changes in intestinal permeability have been proven to occur in acute pancreatitis and are directly related to the severity of the disease. Patients with severe acute pancreatitis have increased intestinal permeability compared with healthy controls or those with mild attacks, and patients who develop MOF have even greater changes compared with those with severe disease and more favorable outcome. Intestinal permeability changes occur within 72 hours of the onset of pancreatitis and normalize during recovery. It has been proposed that intestinal permeability may allow bacteria and bacterial components to migrate from the intestinal lumen to extraintestinal sites. In fact, bacterial translocation from the lumen to the pancreas and mesenteric lymph nodes is well documented in animal models but has not been convincingly demonstrated in humans. Nevertheless there are some data that support the hypothesis. Firstly, it has been demonstrated that 50% of patients with pancreatic necrosis have gut-origin bacteria colonizing the pancreas, and that colonization is maximal during the second to third week after the onset of the disease. Secondly, intestinal colonization with Gram-negative organisms precedes pancreatic infection and represents an early risk factor for developing a pancreatic infection. Thirdly, clinical studies indicate an association between gut dysfunction and infection, acute respiratory distress syndrome, and MOF. However, studies in patients with acute pancreatitis have demonstrated that the changes in gut permeability occur early, whereas pancreatic infection usually occurs during the second to third week after the onset of the disease, and patients with increased permeability do not necessarily have more septic complications. The early changes in intestinal permeability have been also correlated with corresponding levels of endotoxemia. Endotoxins derive from Gram-negative bacteria and have systemic toxic effects, such as tachycardia, hypotension, and pyrexia, and also de- range the immune system. Endotoxemia appears to correlate with the severity, incidence of systemic complications, and mortality of patients with acute pancreatitis. Patients with severe attacks have higher serum concentrations of endotoxin compared with those with mild disease, and the same was found in nonsurvivors compared with survivors and in patients with MOF as opposed to those without it. Nevertheless, in a study conducted by Moore et al. on severely injured trauma patients, it was not possible to document bacteria or endotoxin in the portal blood, even in patients with MOF. Selective gut decontamination seems to reduce infection complications, but it does not increase patients’ survival. Overall, the maintenance of intestinal structure and function is a complicated and multifactorial process that requires the adequate delivery of energy and oxy- gen. Enterocytes use glutamine and short-chain fatty acids as primary fuel. The presence of these nutrients in the lumen stimulates the proliferation of mucosal cells and enhances gut integrity. Fasting leads to mucosal atrophy, increased rate of enterocyte apoptosis, decreased glutamine and arginine transport, and altered mucin composition of goblet cells. These changes may PART I 98 develop as early as the first week and intestinal permeability changes occur within 48–72 hours of the disease onset. Furthermore, the impairment of gut motility that occurs within 12 hours of the onset of acute pancreatitis favors bacterial overgrowth and contributes to endotoxemia and bacterial translocation. Enteral feeding repairs the mucosal damage caused by fasting and, if given very early, preserves epithelial integrity and bacterial ecology, therefore helping to maintain gut barrier function. The intestinal barrier is particularly susceptible to ischemia and therefore an adequate blood supply is of great importance for its function. Severe acute pancreatitis produces hypovolemia and third-space fluid losses that induce splanchnic vasoconstriction and subsequent intestinal ischemia. The hypoxia that occurs early in patients with acute pancreatitis may further contribute to mucosal ischemia. The ischemic effect is also enhanced by the local production of various inflammatory mediators. Intestinal reperfusion causes further damage through the production of oxy- gen free radicals and inflammatory mediators. Severe acute pancreatitis is associated with priming and subsequent overactivation of leukocytes, which may be the main cause of intestinal injury, by inducing gut ischemia, amplifying inflammation, and releasing oxy- gen free radicals. Fluid replacement and resuscitation is essential in order to maintain microcirculation and prevent ischemia and reperfusion injury. Recently, the role of the gut in acute pancreatitis has expanded beyond the bacterial translocation and endotoxin phenomenon, as emerging evidence has indicated that the gut may be a source of cytokines and a site of neutrophil priming. It appears that intestinal ischemia and reperfusion injury results in the overactivation of gut macrophages and gut-associated lymphoid tissue, which in turn release excessive cytokines and other mediators. The release of cytokines contributes to SIRS and MOF. Enteral nutrition Based on the above, efforts have been made to find a more natural way of delivering nutrients in patients with pancreatitis. Despite concerns for the possible stimulatory effect of oral feeding on pancreatic secretion and for disease exacerbation, several experimental and clinical trials have shown that delivery of nutrients to the jejunum does not increase pancreatic secretion and is well tolerated with no increase in complications. More specifically, although administration of lipid into the duodenum is a strong stimulatory factor for pancreatic exocrine secretion, jejunal delivery of the same amount of lipid causes minimal pancreatic reaction. Similar minor effects of intravenous lipid infusion have been shown in human studies. Gastric or duodenal protein or carbohydrate administration is also a strong stimulus for pancreatic secretion, whereas jejunal delivery of the same nutrients is harmless to the pancreas. Additionally, it has been confirmed that enteral feeding is technically feasible and clinically safe even in critically ill patients with severe disease, and provides efficient nutrition support. Severe paralytic ileus is not a contraindication to nasojejunal feeding, but in rare cases it may prevent adequate calorie intake. From the practical point of view, enteral feeding is achieved by the insertion of a nasojejunal feeding tube, usually placed endoscopically or under radiologic screening, distal to the ligament of Treitz. Occasionally, correct feeding tube location and maintenance of its patency may be troublesome. Five randomized controlled studies have been published that compare enteral nutrition (EN) with TPN. Kalfaretzos et al. randomized 38 patients, all with severe acute pancreatitis, in two groups (EN vs. TPN). They found a significant reduction in total, including septic, complications in the EN group. The cost was three times lower in the EN than the TPN group, and the authors suggested that the use of EN is preferable in all patients with severe disease. In another other study, by Windsor et al., 34 patients were randomized in EN and TPN groups. In this study patients with moderate and severe disease were included. Patients who received EN fared better after 7 days with respect to APACHE II score and C-reactive protein (CRP) levels compared with the TPN group. The authors also reported an increase in serum IgM anti-endotoxin antibodies in the TPN group, levels of which remained unchanged in the EN group. The total antioxidant capacity was less in the former group. They concluded that patients on EN were exposed to less endotoxin levels. This was proba- bly related to preserved host defense. More recently, Abou-Assi and O’Keefe demonstrated earlier recovery, shorter hospital stay and shorter duration of nutritional support, better tolerance to restarting oral feeding, and much cheaper cost for nutrition in a group of 17 enterally fed patients with acute CHAPTER 10 99 [...]... (5) 34 34 84 53 34 35 76 65 All 53 ( 23) 65 (30 ) 2 (0) 4 (2) 232 220 Note: 32 patients from the German study were excluded from analysis due to inability to stratify pancreatitis severity; 75 patients from the Polish study were excluded because they underwent immediate nonrandomized endoscopic sphincterotomy (ES) for an ampullary stone ERCP, endoscopic retrograde cholangiopancreatography Table 13. 3 Outcomes... Timing of endoscopic sphincterotomy for acute biliary pancreatitis Gastrointest Endosc 1996; 43: 391 1 23 PART I Ranson JHC Etiological and prognostic factors in human acute pancreatitis: a review Am J Gastroenterol 1982;77: 633 – 638 Sharma VK, Howden CW Meta-analysis of randomized controlled trials of endoscopic retrograde cholangiography and endoscopic sphincterotomy for the treatment of acute biliary... pancreatitis in four randomized controlled trials (Modified from Soetikno et al 1998.) Morbidity, n (%) Mortality, n (%) Total number of cases Study ERCP ± ES Conventional ERCP ± ES Conventional ERCP ± ES Conventional UK Hong Kong Germany Poland 6 (24) 4 ( 13) 17 (65) 9 (39 ) 17 (61) 15 (54) 14 (70) 20 (74) 1 (4) 1 (3) 6 ( 23) 1 (4) 5 (18) 5 (18) 2 (10) 9 (33 ) 25 30 26 23 28 28 20 27 All 36 (35 ) 66 (64) 9 (9)... morbidity and mortality were higher after a 72-hour delay The authors followed 30 7 patients who had urgent ERCP for ABP For those treated within 24 hours of symptom onset there were no deaths and a 7% complication rate For patients treated between 24 and 72 hours, there was 2% mortality and a 16% complication rate Patients treated with ERCP after 72 hours did worst, with 13% mortality and a 32 % complication... responsible for the induction of TNF and IL-1 release in the lungs and other systemic organs are unknown The release of TNF and IL-1 is normally tightly controlled, although the mechanisms are at present only partly understood Soluble TNF receptors are released and may serve to regulate the local and systemic effects of TNF Similarly, soluble IL-1 receptor antagonist (IL1ra) is released in tandem with IL-1... response and improves disease severity in acute pancreatitis Gut 1998;42: 431 – 435 101 11 Antibiotic prophylaxis for acute pancreatitis in clinical practice: rationale, indications, and protocols for clinical practice Giovanni Butturini, Roberto Salvia, Nora Sartori, and Claudio Bassi Introduction Acute pancreatitis is characterized by a wide range of clinical manifestations, ranging from mild self-limiting... responsible for the cleavage of IL-1 into its biologically active form and its inhibition has been reported to improve outcome if given before or after induction of experimental acute pancreatitis Although none has been tested in the clinical setting of acute pancreatitis, large-scale trials of anti-TNF antibody, TNF receptor, and IL-1ra have been carried out in patients with sepsis Unfortunately,... et al (19 93) Luiten et al (1995) Sainio et al (1995) Delcenserie et al (1996) Schwarz et al (1997) Bassi et al (1998) No of patients Antimicrobial agents 74 102 60 23 Imipenem SDD and i.v cefotaxime Cefuroxime Ceftazidime, amikacin, metronidazole Ofloxacin, metronidazole Pefloxacin vs imipenem 26 60 Mortality (%) Control Case Control Case 30 38 40 58 12* 18** 30 0** 12 35 23 25 7 22 3* ** 9 53 34 61 0**... target for therapeutic intervention and the PAF antagonist lexipafant has been studied in several large clinical trials Interleukin-10 IL-10 is a potent antiinflammatory cytokine produced by monocytes and macrophages and inhibits the transcription of proinflammatory cytokines such as TNF and IL-1 Higher levels of IL-10 are seen in patients with severe acute pancreatitis and sustained high levels are associated... plus ES versus control (25% vs 38 .2%; P < 0.001) Although the data for mortality reached statistical significance only in the Polish study, the pooled data did show a significant decrease in mortality for the early ERCP group compared with control (5.2% vs 9.1%; P < 0.05) The authors report relative and absolute risk reduction of 34 .6 and 13. 2 in complications and 42.9 and 3. 9 in death with early ERCP . Case Pederzoli et al. (19 93) 74 Imipenem 30 12* 12 7 Luiten et al. (1995) 102 SDD and i.v. cefotaxime 38 18** 35 22 Sainio et al. (1995) 60 Cefuroxime 40 30 23 3*** Delcenserie et al. 23 Ceftazidime, amikacin,. arginine, w -3 fatty acids, and nucleotides have been introduced into clinical use in the form of several standard formulas, often in combination preparations. There are a number of reports,. severe pancreatitis and should stratify them for disease severity, nutritional status, and etiology of pancreatitis before randomization. PART I 100 Recommended reading Abou-Assi S, O’Keefe SJD.

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