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Pancreatitis
- 1. Pancreatitis
- 2. Definición • Inflamación aguda del tejido pancreático de etiología variable con participación regional del páncreas y/o de tejidos a distancia. DiMarino A. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th edition.
- 3. Fisiología • Tres fases de estimulación pancreática: – Cefálica – Gástrica – Intestinal DiMarino A. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th edition.
- 4. Fases de la pancreatitis Fase inflamatoria Necrosante DiMarino A. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th edition.
- 5. • El curso natural de la pancreatitis aguda Grave es bifásica. Primera Fase ; se caracteriza por El Síndrome de Respuesta Inflamatoria Sistémica Resultado de la acción de los Mediadores inflamatorios ( 14 días) La segunda fase; se caracteriza por complicaciones Sépticas derivadas de la infección de necrosis pancreática Mayor de 14 dias DiMarino A. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th edition.
- 6. Amilasa • Prueba rápida y barata. • Se eleva de 6 a 12 horas de inicio y declina alrededor de 48 de instaurado el cuadro. • El 25% de la amilasa sérica es eliminado por los riñones. DiMarino A. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th edition.
- 7. Amilasa • Una limitación de la amilasa sérica es que no es 100% sensible y específico. • Con respecto a la sensibilidad, que es superior al 85% y su especificidad es muy baja. • . DiMarino A. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th edition.
- 8. Lipasa: La sensibilidad de la lipasa sérica para el diagnóstico de la pancreatitis aguda es similar a la de la amilasa sérica y se sitúa entre 85% y 100%. La lipasa perdura mas tiempo elevada que la amilasa. DiMarino A. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th edition.
- 9. Criterios de Atlanta para pancreatitis aguda severa. Falla organica a. Choque: TAS < 90 mmhg b. Insuficiencia respiratoria: Pao2 ≤60 mm Hg c. Falla renal: creatinina sérica >2 mg/dL d. Sangrado gastrointestinal: >500 mL/24 hr Complicaciones locales a. Necrosis b. Absceso c. Pseudoquiste Pronostico temprano desfavorable a. Ranson's b. APACHE-II DiMarino A. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th edition.
- 10. Marcadores Útiles de Gravedad DiMarino A. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th edition.
- 11. CRITERIOS CLÍNICOS Debe prestarse especial atención a las primeras 12-24 horas de estancia del paciente en el hospital, incluyendo esas críticas primeras horas en las que el enfermo permanece en el área de urgencia.Todo paciente con PA que en esta primera fase tenga hipoxia con PaO2 < 60 mmHg no controlable con oxigenoterapia convencional, o que presente oliguria de menos de 20 ml/h durante más de 4 h, a pesar de una adecuada reposición intravenosa de fluidos, debe ser considerado firme candidato a la vigilancia intensiva. DiMarino A. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th edition.
- 12. www.sfar.org/scores2/apache22.html Sistema de valoración de la gravedad APACHE II
- 14. Criterios de Ranson y Glasgow NON-GALLSTONE PANCREATITIS (1974) GALLSTONE PANCREATITIS (1982) Al ingreso edad >55 años >70 años GB >16,000/mm3 >18,000/mm3 Glucosa sérica >200 mg/dL >220 mg/dL LDH sérica >350 IU/L >400 IU/L AST >250 IU/L >250 IU/L A las 48 hr de ingreso Descenso del hematocrito >10 % >10% Incremento del nitrogeno ureico >5 mg/dL >2 mg/dL Calcio sérico <8 mg/dL <8 mg/dL po2 <60 mm Hg NA Déficit de base >4 mEq/L >5 mEq/L Secuestro de liquido >6 L >4 L DiMarino A. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th edition.
- 16. Índice SOFA
- 17. Mortalidad según SOFA Ferreira F. Serial Evaluation of the SOFA Score to Predict Outcome in Critically Ill Patients JAMA 2001;286(14):1754-1758 (doi:10.1001/jama.286.14.1754)
- 18. Criterios Radiológicos Precoces de Gravedad • La TC con contraste intravenoso completa la clasificación radiológica y la extensión de la necrosis . • Debe someterse a esta prueba a todos los pacientes con criterios de gravedad entre los 3 y 10 días tras el comienzo de los síntomas. • La TC simple (TC sin contraste radiológico intravenoso) identifica las lesiones morfológicas del páncreas en Grados A, B, C, D y E. • Las dos últimas categorías son sinónimo de gravedad .
- 19. Tomografía computarizada Criterios tomográficos clásicos de Balthazar
- 20. Tratamiento: • Medidas generales: • Fluidoterapia: 250-300 ml/hr por 48 hr al menos. • Objetivo: Evitar la hipotensión por hipovolemia, así como la hemoconcentración, oliguria, uremia y taquicardia. • Los pacientes que recibieron un tercio de los líquidos perdidos en las primeras 72 horas tienen mas riesgo de mortalidad que aquellos que tuvieron fluidoterapia agresiva. DiMarino A. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th edition.
Notas del editor
- Acute pancreatitis appears to have two distinct stages. The first stage is related to the pathophysiology of the inflammatory cascade. This first phase usually lasts a week. During this phase, the severity of acute pancreatitis is related to extrapancreatic organ failure secondary to the patient's systemic inflammatory response elicited by acinar cell injury. Infectious complications are uncommon at this time. Fever, tachycardia, hypotension, respiratory distress, and leukocytosis are typically related to the systemic inflammatory response syndrome (SIRS). Multiple cytokines are involved, including platelet activating factor, tumor necrosis factor-α (TNF-α) and various interleukins (ILs) (see Chapter 2). During the first week the initial state of inflammation evolves dynamically with variable degrees of pancreatic and peripancreatic ischemia or edema to either resolution or to irreversible necrosis and liquefaction, or the development of fluid collections in and around the pancreas. The extent of the pancreatic and peripancreatic changes is usually proportional to the severity of extrapancreatic organ failure. However, organ failure may develop independent of pancreatic necrosis.[17] Approximately 75% to 80%, of patients with acute pancreatitis have a resolution of the disease process (interstitial pancreatitis) and do not enter the second phase. However, in 25% of patients, a more protracted course develops, often related to the necrotizing process (necrotizing pancreatitis) lasting weeks to months. The mortality peak in the second phase is related to a combination of factors, including organ failure secondary to sterile necrosis, infected necrosis, or complications from surgical intervention.[11,12,18-20] There are two peaks for mortality. Most studies in the United States and Europe reveal that about half the deaths occur within the first week or two, usually of multiorgan failure.[19-21] Death can be very rapid. About one quarter of all deaths in Scotland occurred within 24 hours of admission and one third within 48 hours.[21] After the second week of illness, patients succumb to pancreatic infection associated with multiorgan failure. Some studies in Europe report a very high late mortality rate from infection.[22] Patients who are older and have comorbid illnesses have a substantially higher mortality rate than younger healthier patients. In those who survive their illness, severe pancreatic necrosis can scar the pancreas, resulting in a stricture of the main pancreatic duct with subsequent obstructive chronic pancreatitis and permanent diabetes and malabsorption.[
- Two other features of experimental acute pancreatitis are early blockade of the secretion of pancreatic enzymes while enzyme synthesis continues and disruption of the paracellular barrier of acinar cells and intralobular pancreatic duct cells. The disruption facilitates the extravasation of pancreatic enzymes from acinar cells and from the duct lumen into interstitial spaces. This phenomenon may explain the rapid development of interstitial edema and the increase of pancreatic enzymes in the serum.[31]
- GENERAL CONSIDERATIONS Patients with acute pancreatitis require adequate intravenous hydration and adequate analgesia to eliminate or markedly reduce pain. The patient is usually on nothing per mouth until any nausea and vomiting have subsided. Abdominal pain can be treated with opiate analgesics, often by a patient-controlled anesthesia pump. Opiate dosing is monitored carefully and adjusted on a daily basis according to ongoing needs. Although morphine has been reported to increase sphincter of Oddi tone and increase serum amylase,[237] its use to treat the pain of pancreatitis has not been shown to adversely effect outcome. Nasogastric intubation is not used routinely because it is not beneficial in mild pancreatitis. It is used only to treat gastric or intestinal ileus or intractable nausea and vomiting. Similarly, proton pump inhibitors or H2-receptor blocking agents[69] are not beneficial and not used. Figure 58-5. Algorithm for the management of acute pancreatitis at various stages in its course. CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; ETOH, ethyl alcohol; FNA, fine-needle aspiration; GS, gallstones; ICU, intensive care unit; IV, intravenous; NG, nasogastric; NJ, nasojejunal; NPO, nil per os (nothing by mouth); TGs, triglycerides. The patient should be carefully monitored for any signs of early organ failure such as hypotension, pulmonary, or renal insufficiency by closely following vital signs and urinary output. Tachypnea should not be assumed to be due to abdominal pain; monitoring oxygen saturation and, if needed, blood gases is advised and oxygen supplementation is mandatory if there is hypoxemia. It cannot be overemphasized that any patient who exhibits signs of early organ dysfunction should be immediately transferred to intensive care monitoring as deterioration can be rapid and fatal. FLUID RESUSCITATION As the inflammatory process progresses early in the course of the disease, there is an extravasation of protein-rich intravascular fluid into the peritoneal cavity resulting in hemoconcentration. The decreased perfusion pressure into the pancreas leads to microcirculatory changes that lead to pancreatic necrosis. An admission hematocrit of more than 47% and a failure of the admission hematocrit to decrease at 24 hours have been shown to be predictors of necrotizing pancreatitis.[238] The relationship of hematocrit to severity of pancreatitis implies that the opposite is also true. Early vigorous intravenous hydration for the purpose of intravascular resuscitation is of foremost importance. The goal is to decrease the hematocrit. Laboratory and clinical studies with intravenous dextran to promote hemodilution have suggested efficacy in preventing severe disease.[239] Too often patients with acute pancreatitis are given suboptimal intravenous hydration. One of the markers of severity of pancreatitis defined by Ranson and colleagues is intravascular losses (“fluid sequestration”). Ranson and colleagues found that a sequestration of more than 6 L of fluids during the first 48 hours was an independent predictor of disease severity in non-gallstone pancreatitis.[14] If this amount of fluid (6 L) is added to the minimal intravenous fluid requirements of a 70-kg person during the first 48 hours, intravenous hydration should be at least 250 to 300 mL/hour for 48 hours. The rate of volume replacement is likely to be more important during the first 24 hours, when a rising hematocrit has been shown to correlate closely with severe disease. A study from the Mayo Clinic showed that patients with severe acute pancreatitis who do not receive at least one third of their initial 72-hour cumulative intravenous fluid volume during the first 24 hours after emergency department presentation are at risk for greater mortality than those who are initially resuscitated more aggressively.[240] Maintaining adequate intravascular volume in patients with severe disease may require 5 to 10 L of fluid such as isotonic saline daily for the first several days (200 to 400 mL/hour). Respiratory distress often suggests development of ARDS independent of intravascular volume status. However, in a patient with unclear cardiac output, a Swan-Ganz catheter can be useful to gauge fluid resuscitation and to avoid congestive heart failure. RESPIRATORY CARE Hypoxemia (oxygen saturation <90%) requires supplemental oxygen, ideally by nasal prongs or by face mask if needed. If nasal oxygen fails to correct hypoxemia or if there is fatigue and borderline respiratory reserve, endotracheal intubation and assisted ventilation are required early. It is important to use a Swan-Ganz catheter to determine whether hypoxemia is due to congestive heart failure (increased pulmonary artery wedge pressure) or to primary pulmonary damage (normal or low pulmonary artery wedge pressure). Due to the common and indolent nature of hypoxemia affecting patients with acute pancreatitis, current guidelines recommend the initial routine use of nasal cannula oxygen to all patients with acute pancreatitis.[12] ARDS is the most serious respiratory complication of acute pancreatitis; it is associated with severe dyspnea, progressive hypoxemia, and increased mortality. It generally occurs between the second and seventh day of illness (but can be present on admission) and consists of increased alveolar capillary permeability causing interstitial edema. Chest radiography may show multilobar alveolar infiltrates. Treatment is endotracheal intubation with positive end-expiratory pressure ventilation, often with low tidal volumes to protect the lungs from volutrauma. No specific treatment will prevent or resolve ARDS. After recovery, pulmonary structure and function usually return to normal. CARDIOVASCULAR CARE Cardiac complications of severe acute pancreatitis include congestive heart failure, myocardial infarction, cardiac dysrhythmia, and cardiogenic shock. An increase in cardiac index and a decrease in total peripheral resistance may be present and respond to infusion of crystalloids. If hypotension persists even with appropriate fluid resuscitation, intravenous dopamine may help maintain the systemic blood pressure. Dopamine does not impair the microcirculation of the pancreas as do other vasoconstrictors. METABOLIC COMPLICATIONS Hyperglycemia may present during the first several days of severe pancreatitis but usually normalizes as the inflammatory process subsides. Blood sugars fluctuate, and insulin should be administered cautiously. Hypocalcemia due to low serum albumin causes no symptoms and requires no specific therapy. However, reduced serum ionized calcium may occur and cause neuromuscular irritability. If hypomagnesemia coexists, magnesium replacement should restore serum calcium to normal. Causes of magnesium depletion include vomiting, loss of magnesium in the urine, or deposition of magnesium in areas of fat necrosis. Once the serum magnesium is normal, signs or symptoms of neuromuscular irritability may require administering intravenous calcium gluconate as long as the serum potassium is normal and digitalis is not being given. Intravenous calcium increases calcium binding to myocardial receptors, which displaces potassium and may induce a serious dysrhythmia. ANTIBIOTICS Antibiotics are not indicated in mild pancreatitis. However, pancreatic sepsis (infected necrosis and, less often, abscess) and nonpancreatic sepsis (line sepsis, urosepsis, or pneumonia) are major sources of morbidity and mortality in severe acute pancreatitis. Thus, it would seem logical to consider antibiotic prophylaxis to improve the outcome. The use of prophylactic antibiotics in acute pancreatitis to prevent complications is controversial. In the 1970s, controlled studies compared intravenous antibiotics to no therapy in the treatment of mild acute alcoholic pancreatitis,[241] with negative results. However, low-risk patients were studied (mild alcoholic disease with no mortality) and the wrong antibiotic (ampicillin) was used.[242] In the 1980s, the bacteriology of infected pancreatic tissue was elucidated by analyzing either surgical specimens[243] or fine-needle aspirations of the pancreas.[242] The majority of organisms detected were gram-negative aerobic or anaerobic species (Escherichia coli, Enterobacter aerogenes, Pseudomonas aeruginosa, Proteus species, Klebsiella pneumoniae, Citrobacter freundii, and Bacteroides species), with occasional gram positives (Streptococcus faecalis, Staphylococcus aureus, Streptococcus viridans, Staphylococcus epidermidis) and rare fungi (Candida species). Studies in the early 1990s elucidated the appropriate antibiotics to use given these organisms and the level of penetration of antibiotics into necrotic pancreatic tissue.[244] Imipenem, fluoroquinolones (ciprofloxacin, ofloxacin, pefloxacin), and metronidazole emerged as the drugs that achieved the highest inhibitory concentrations in pancreatic tissue, whereas aminoglycosides did not. Several randomized controlled (no placebo given), nonblinded clinical trials of prophylactic intravenous antibiotics in patients with severe pancreatitis were performed in Europe in the 1990s.[245-248] One study added oral nonabsorbable antibiotics to the intravenous antibiotic regimen.[249] Meta-analyses of the intravenous antibiotic trials showed that mortality of necrotizing pancreatitis was significantly reduced by antibiotics.[250,251] Very little comparative information is known as to which antibiotic is the most effective. One study compared pefloxacin to imipenem in severe disease, showing imipenem to be significantly more effective in reducing pancreatic and extrapancreatic infection; however, mortality was unaffected.[252] Likewise, little information is available on the length of treatment. One investigation compared one week of ciprofloxacin to three weeks and showed that longer treatment reduced the rates of pancreatic and nonpancreatic infection.[253] The aforementioned studies have been criticized because they were not placebo-controlled, double-blinded studies. Furthermore, the use of prophylactic antibiotics in all patients with severe pancreatitis raises the concern that some patients will become superinfected with resistant organisms or fungi, which might lead to greater mortality in the future. Two studies have used double-blind randomized protocols to study this question. The first randomized 114 patients with severe acute pancreatitis to prophylactic ciprofloxacin plus metronidazole or to placebo. Patients suspected of having an infection were allowed open-label antibiotics. There were no differences in rates of infected necrosis or mortality. The only difference noted was that the group randomized to receive placebo eventually received more open-label antibiotics than the group randomized to receive the original antibiotics (46% vs. 28%).[254] Dellinger and colleagues[255] performed a multicenter, double-blind placebo-controlled randomized study in 32 centers in North America and Europe. One hundred patients were equally randomized to two groups, meropenem (1 g intravenously every eight hours) or placebo within 5 days of the onset of symptoms. Meropenem was continued for 7 to 21 days. This study demonstrated no significant difference between the treatment groups for pancreatic or peripancreatic infection, mortality, or requirement for surgical intervention. Based on these last two placebo-controlled studies, routine use of antibiotics is questionable in the absence of biliary sepsis or obvious pancreatic or peripancreatic infection. Although practice guidelines published prior to this latest paper recommended the use of prophylactic antibiotics in patients with severe necrotizing pancreatitis,[256] more recent guidelines[12] state that prophylactic antibiotics should not be used for the purpose of preventing infection in patients with necrotizing pancreatitis. ENDOSCOPIC The question of early removal of a possibly impacted gallstone in improving the outcome of gallstone pancreatitis remains a controversial issue. There have been three randomized fully published studies comparing urgent ERCP plus sphincterotomy (for any retained stones) versus conventional treatment in the management of gallstone pancreatitis.[257-259] The earliest study,[257] a single-center investigation from England, found that urgent ERCP within 72 hours of admission improved the outcome (complications and mortality) of patients with severe, but not mild, acute gallstone-induced pancreatitis. The second,[258] another single-center study from Hong Kong, found that the urgent intervention group had a reduction in biliary sepsis and a trend toward lower mortality compared with the control group. The third and largest study from Germany[259] included 22 centers and came to an opposite conclusion, namely, that there was a higher complication rate and a trend toward higher mortality in the urgently treated ERCP group compared with standard nonurgent therapy. Differences in the designs of these studies do not allow direct comparisons. However, there is consensus that severe acute gallstone pancreatitis with ascending cholangitis (jaundice and fever) is an indication for urgent ERCP (see Chapter 61). In a prospective study of biliary pancreatitis using ERCP, Uomo and colleagues[51] noted a 30.5% incidence of main pancreatic duct leakage. It has been proposed that early endoscopic stenting of the main pancreatic duct in patients with this problem may shorten hospital stay and the need for subsequent necrosectomy. Lau and colleagues[260] evaluated 144 patients with severe acute pancreatitis and found that the presence of a PD leak was significantly associated with the development of necrosis. Patients with a PD leak had a longer length of stay compared with the patients with acute pancreatitis with no PD leak. In this retrospective study, patients who underwent early ERCP and had a PD stent placed were less likely to have other more invasive interventions performed, such as placement of external drains. Although PD stents have been shown to be helpful in the management of late complications related to pancreatic duct disruption, such as fistulas and pseudocysts, it remains unclear that routine use of these stents will prevent late complications. Kozarek and associates found that PD stent placement was associated with polymicrobial contamination of the pancreas.[261] Although the contamination was largely asymptomatic, the benefit of placing a stent in the PD early in the course of acute pancreatitis to treat a duct disruption must be weighed against the possibility of seeding sterile necrosis with organisms that could lead to infected necrosis. Until randomized studies are performed, it is not clear whether potential advantages of early pancreatic duct stenting outweigh the risks. NUTRITIONAL In general, intravenous feedings are continued until patients are able to tolerate liquids or solids. The timing of early feedings is unclear. One report suggested that early refeeding improved outcome and allowed early discharge.[262] However, a meta-analysis of three studies showed that early refeeding prolonged hospitalization.[263] The question of whether an elevated serum amylase or lipase should influence the clinician to prolong the time to refeeding has been addressed. One hundred sixteen patients with acute pancreatitis were fed at the clinician's discretion; 21% developed pain on refeeding 250 kcal/day.[264] If the serum lipase was more than three-fold elevated, refeeding increased the clinical relapse rate compared with the group in which the lipase was less than three-fold elevated (39% vs. 16%). However, the corollary of this finding is that most patients with three-fold elevated serum lipase levels do not have a recrudescence of their pain on refeeding. Once refeeding is begun, a low-fat diet appears to be comparable to a clear liquid diet as the initial meal.[265] Formerly, total parenteral nutrition (TPN) was the standard of care for refeeding patients with severe acute pancreatitis. Sax and coworkers[266] randomized 54 patients with mild pancreatitis to intravenous nutrition or to TPN. The TPN group had a greater number of septic complications and longer hospitalizations. McClave[267] randomized 30 patients with mild to moderate pancreatitis to receive TPN or enteral feedings administered through a nasoenteric tube, beginning 48 hours after admission. The Ranson and APACHE scores and blood glucose levels normalized more quickly in the enteral group, and the length of hospitalization showed a trend toward a shorter stay in the enteral group. Windsor[268] randomized 34 patients with either mild to moderate pancreatitis to either oral feedings or TPN or with severe pancreatitis to either enteral feedings via a nasoenteric tube or TPN. The group receiving oral or enteral feedings had shorter intensive care unit (ICU) stays and improved acute phase response markers and disease severity scores compared with the TPN group. Kalfarentzos[269] randomized 38 patients with severe necrotizing pancreatitis to TPN versus nasoenteric feedings. The enteral group had fewer septic complications and fewer total complications, although hospital stay, ICU stay, and days until resumption of a regular diet were similar in the two groups. Thus, these studies demonstrate that enteral nutrition is cheaper and safer and is preferable in patients with severe acute pancreatitis. It is still unclear, however, when nutrition should be initiated and for how long it needs to be continued. Furthermore it is unclear if nasoenteric feedings are needed or if nasogastric or even oral feedings are similarly effective if the patient tolerates this modality. Along those lines, a UK group randomized 50 patients with severe pancreatitis to nasogastric versus nasoenteric tube feedings. No difference was seen in the ability to tolerate feedings, in markers of inflammation, or in morbidity or mortality between the groups.[270] They also noted no differences in the length of hospital stay or complications in patients with severe acute pancreatitis. SURGICAL THERAPY Cholecystectomy is routinely performed in patients with gallstone pancreatitis, and a consensus conference suggested that in mild or severe gallstone pancreatitis, cholecystectomy should be performed as soon as the patient has recovered and the acute inflammatory process has subsided.[271] A second potential role for surgery in pancreatitis is to debride pancreatic necrosis (necrosectomy) or drain a pancreatic abscess. With regard to pancreatic necrosectomy, the data are more complicated and evolving. Studies in the 1980s suggested that early necrosectomy (within the first week of hospitalization for severe disease) reduced mortality. However, in the only randomized study comparing early (within 72 hours of admission) to late necrosectomy (12 days or more after admission), the mortality with early operation was greater than with later d?bridement (56% vs. 27%).[272] Some investigators have reported that it is important to differentiate sterile necrosis from infected necrosis by fine-needle aspiration of the pancreas. Sterile necrosis can be managed nonoperatively because the mortality of this condition without surgery is less than 5%.[273,274] Infected necrosis (as documented by fine-needle aspiration of the pancreas with Gram stain and cultures), on the other hand, has been historically regarded as an indication for surgical d?bridement because of the previous belief that infected necrosis treated medically has a nearly uniform fatal outcome.[275,276] This has led to the recommendation that patients who are not improving on maximal medical therapy or who develop organ failure should have a fine-needle aspiration of the pancreas (Fig. 58-6). The finding of infection should then lead to a consideration of surgical intervention. Figure 58-6. Walled-off pancreatic necrosis. Non–contrast-enhanced computed tomography reveals a 5.4-cm pus-filled fluid collection (arrows) with the tip of an aspirating needle in its lumen. The abscess is anterior to the pancreas (P) and medial to the stomach (S). A right subhepatic fluid collection (F) is present. However, surgical therapy of infected pancreatic necrosis carries a substantial mortality of 15% to 73%,[275-278] especially when it is carried out early within the first few weeks of the disease. Thus, it is unclear if the higher mortality rates that have been reported in patients with infected necrosis are the result of the underlying disease or the early surgical intervention. It has been shown that delaying surgical d?bridement beyond the fourth week in patients with pancreatic necrosis is associated with a lower mortality rate.[277] The concept that infected pancreatic necrosis requires prompt surgical d?bridement has been challenged by several reports of patients who have been treated by antibiotic therapy alone.[278-280] A series of 28 patients with infected pancreatic necrosis was treated prospectively with antibiotics rather than urgent surgical d?bridement.[281] Among 12 patients who eventually required elective surgical intervention, there were two deaths. Among the other 16 patients who were treated with long-term antibiotic therapy, there were also two deaths. Thus, 14 of 28 patients with infected necrosis were successfully treated with no surgical, endoscopic, or radiologic drainage. The types of necrosectomy operations that have been recommended include necrosectomy with closed continuous irrigation via indwelling catheters, necrosectomy with closed drainage without irrigation, or necrosectomy and open packing. There have been no randomized prospective trials comparing these various procedures. All are generally considered to provide equal benefit in skilled surgical centers. Several additional procedures have been introduced that are less invasive than standard open surgical d?bridement of infected necrosis. These techniques have generally been reserved for patients with infected pancreatic necrosis who are too ill to undergo prompt surgical d?bridement (such as those with organ failure or serious comorbid disease) and include laparoscopic necrosectomy with placement of large-caliber drains under direct surgical inspection and percutaneous catheter drainage of infected necrosis (see Chapter 26). Other minimally invasive approaches, including endoscopic (see Chapter 61) or a combined endoscopic and laparoscopic approach may become more commonly used as skill and technology advance. OTHER THERAPEUTIC AGENTS OF POSSIBLE OR QUESTIONABLE EFFICACY Pancreatic protease inhibitors have been used to treat established severe acute pancreatitis and to prevent post-ERCP pancreatitis (see earlier section). Gabexate mesylate is the most widely studied pancreatic protease inhibitor. A meta-analysis of five clinical trials of gabexate mesylate in acute pancreatitis found no effect on the 90-day mortality rate, but a reduced incidence of complications.[282] This agent is not available in the United States. Multiple trials of the antisecretory hormone somatostatin or its synthetic analog octreotide have failed to show convincing evidence of efficacy in the treatment of acute pancreatitis.[283] The use of anti-inflammatory cytokines has so far not shown efficacy. The largest experience has been with lexipafant, a PAF inhibitor. After initial promising reports,[284] subsequent studies have not shown clear efficacy.[285] Japanese investigators have suggested that pancreatic protease inhibitors and antibiotics can be better targeted to the affected regions in the pancreas with continuous regional arterial infusion (CRAI) into the celiac, splenic, inferior pancreaticoduodenal, and common hepatic arteries. Using CT, Anai and colleagues[286] showed that with CRAI the contrast was distributed to the entire pancreas in six of nine patients with inflammation of the entire pancreas; in the remaining three patients, contrast material did not penetrate the entire area of pancreatic inflammation. Two later studies suggested that intra-arterial infusion of the protease inhibitor nafamostat mesylate plus imipenem reduces mortality when compared with intravenous infusion of the same agents.[287,288] These studies warrant further investigation. Many other measures have been shown to be ineffective in randomized trials, including anticholinergics, glucagon, fresh frozen plasma, and peritoneal lavage.[60,289] Infectious complications and associated mortality are major concerns in acute pancreatitis. Enteral administration of probiotics might prevent infectious complications, but convincing evidence is scarce. Although an early study suggested that probiotics might decrease infectious complications,[290] other studies have suggested an increase in morbidity and mortality.[291] In this more recent study, infectious complications occurred in 46 patients in the probiotics group (30%) and in 41 of those in the placebo group (28%). Twenty four patients in the probiotics group died (16%), compared with 9 (6%) in the placebo group (relative risk of death, 2.53; 95% confidence interval, 1.22 to 5.25). Nine patients in the probiotics group developed bowel ischemia (8 with fatal outcome), compared with none in the placebo group (P = 0.004). At the present time, probiotic prophylaxis should therefore not be administered in this category of patients.