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Objective: To examine factors influencing conversion from a laparoscopic to an open procedure in patients requiring surgery for Crohn's disease., Summary Background Data: Laparoscopic management of patients with complications of Crohn's produces better outcomes than traditional open approaches, but it is difficult to determine before surgery who will be amenable to laparoscopic management. In this series, a laparoscopic approach was offered to virtually all patients to determine reasons for laparoscopic failure., Methods: Data regarding patients who underwent attempted laparoscopic procedures for Crohn's (January 1993 to June 2000) were collected prospectively. The bowel was mobilized laparoscopically and extracorporeal anastomoses were performed. Conversion to open surgery was defined as creation of an incision of more than 5 cm., Results: One hundred ten patients (age 37 +/- 1.1 years, 58% female) underwent 113 attempted laparoscopic interventions. Indications for surgery included obstruction (77%), failure of medical management (35%), fistula (27%), and perineal sepsis (4%). Sixty-eight procedures (60%) were completed laparoscopically. Procedures completed laparoscopically included ileocecectomy (n = 46), small bowel resection (n = 22), fecal diversion (n = 7), intestinal stricturoplasty (n = 7), resection of prior ileocolonic anastomosis (n = 5), segmental colectomy (n = 1), and lysis of adhesions (n = 1). Forty-five procedures (40%) were converted as a result of adhesions (n = 21), extent of inflammation or disease (n = 9), size of the inflammatory mass (n = 7), inability to dissect a fistula (n = 5), or inability to assess anatomy (n = 3). Factors associated with conversion were internal fistula as an indication for surgery, smoking, steroid administration, extracecal colonic disease, and preoperative malnutrition. In laparoscopic patients, mean times to passage of flatus and first bowel movement were 3.6 +/- 0.2 days and 4.4 +/- 0.2 days, respectively. Mean time to discharge was 6 +/- 0.2 days., Conclusions: Attempted laparoscopic management is safe and effective if there is an appropriate threshold for conversion to an open procedure. Conversion factors identified in this study largely reflect technical challenge and severity of disease. Patients taking steroids and those with known fistulas or colonic involvement threaten laparoscopic failure, but many of these patients can be managed laparoscopically and have better outcomes. By understanding the reasons for conversion, it is hoped that the chances of laparoscopic success can be improved by modifying standard preoperative medical management or using additional technological capabilities (e.g., robotics).

Objective: To describe the management and outcome after surgical reconstruction of 156 patients with postoperative bile duct strictures managed in the 1990s., Summary Background Data: The management of postoperative bile duct strictures and major bile duct injuries remains a challenge for even the most skilled biliary tract surgeon. The 1990s saw a dramatic increase in the incidence of bile duct strictures and injuries from the introduction and widespread use of laparoscopic cholecystectomy. Although the management of these injuries and short-term outcome have been reported, long-term follow-up is limited., Methods: Data were collected prospectively on 156 patients treated at the Johns Hopkins Hospital with major bile duct injuries or postoperative bile duct strictures between January 1990 and December 1999. With the exception of bile duct injuries discovered and repaired during surgery, all patients underwent preoperative percutaneous transhepatic cholangiography and placement of transhepatic biliary catheters before surgical repair. Follow-up was conducted by medical record review or telephone interview during January 2000., Results: Of the 156 patients undergoing surgical reconstruction, 142 had completed treatment with a mean follow-up of 57.5 months. Two patients died of reasons unrelated to biliary tract disease before the completion of treatment. Twelve patients (7.9%) had not completed treatment and still had biliary stents in place at the time of this report. Of patients who had completed treatment, 90. 8% were considered to have a successful outcome without the need for follow-up invasive, diagnos tic, or therapeutic interventional procedures. Patients with reconstruction after injury or stricture after laparoscopic cholecystectomy had a better overall outcome than patients whose postoperative stricture developed after other types of surgery. Presenting symptoms, number of stents, interval to referral, prior repair, and length of postoperative stenting were not significant predictors of outcome. Overall, a successful outcome, without the need for biliary stents, was obtained in 98% of patients, including those requiring a secondary procedure for recurrent stricture., Conclusions: Major bile duct injuries and postoperative bile duct strictures remain a considerable surgical challenge. Management with preoperative cholangiography to delineate the anatomy and placement of percutaneous biliary catheters, followed by surgical reconstruction with a Roux-en-Y hepaticojejunostomy, is associated with a successful outcome in up to 98% of patients.

The purpose of this study was to assess the usefulness of a cauterizing laparoscopic linear stapler for intestinal anastomosis. In a porcine model, intestinal anastomoses performed with a standard laparoscopic linear stapler, a cauterizing laparoscopic linear stapler (RF stapler), and a two-layer, hand-sewn technique were compared by measuring bursting pressures at 4 and 7 days after surgery. During surgery, the RF stapler provided better hemostasis than the regular stapler for mesenteric transection. At 4 days, one leak occurred in the RF stapler group, and the bursting pressure in the RF stapler group was significantly lower than the bursting pressures in the regular stapler group and the hand-sewn group. In addition, the bursting pressure was significantly greater in the hand-sewn group than in the regular stapler group at 4 days. By 7 days, there were no differences in bursting pressure among the groups. We recommend that the RF stapler not be used for intestinal anastomosis. However, the device may be beneficial for controlling vasculature.

Purpose: This phase II trial evaluated continuous-infusion cisplatin and fluorouracil (5-FU) with radiotherapy followed by esophagectomy. The objectives of this trial were to determine the complete pathologic response rate, survival rate, toxicity, pattern of failure, and feasibility of administering adjuvant chemotherapy in patients with resectable cancer of the esophagus treated with preoperative chemoradiation., Patients and Methods: Patients were staged using computed tomography, endoscopic ultrasound, and laparoscopy. The preoperative treatment plan consisted of continuous intravenous infusion of cisplatin and 5-FU and a total dose of 44 Gy of radiation. Esophagogastrectomy was planned for approximately 4 weeks after the completion of chemoradiotherapy. Paclitaxel and cisplatin were administered as postoperative adjuvant therapy., Results: Forty-two patients were enrolled onto the trial. Of the 39 patients who proceeded to surgery, 29 responded to preoperative treatment: 11 achieved pathologic complete response (CR) and 18 achieved a lower posttreatment stage. Five patients had no change in stage, whereas eight had progressive disease (four with distant metastases and four with increases in the T and N stages). At a median follow-up of 30.2 months, the median survival time has not been reached and the 2-year survival rate is 62%. The median survival of pathologic complete responders has not been reached, whereas the 2-year survival rate of this group is 91% compared with 51% in patients with complete tumor resection with residual tumor (P =.03)., Conclusion: An excellent survival rate, comparable to that of our prior preoperative trial, was achieved with lower doses of preoperative cisplatin and 5-FU concurrent with radiotherapy.

Background: This study compares the effects of carbon dioxide pneumoperitoneum versus laparotomy on cellular-mediated immune response in a murine model., Methods: Sixty-eight female C3H/He mice were sensitized to keyhole limpet hemocyanin (KLH) and to a mouse mammary carcinoma cell line (MC2) before surgery. Animals were randomized into 4 groups: group I, anesthesia (control); group II, pneumoperitoneum with carbon dioxide; group III, extraperitoneal wound; group IV, laparotomy. All animals were challenged subsequently with KLH and MC2 tumor cells. Delayed-type hypersensitivity skin reaction (DTH) to KLH was measured on postoperative days (PODs) 1, 2, 4, and 5. Tumor growth was assessed weekly as an indicator of postoperative cellular immune response., Results: Compared with preoperative values, postoperative DTH skin reactions were significantly less for all PODs in groups III and IV (P < .05), on POD 1 and 4 in group II (P < .05) and POD 4 for group I (P < .05). Group IV showed significantly fewer DTH skin reactions for all PODs compared with groups I and II (P < .05) and all PODs except on day 2 compared with group III (P < .05). Tumor growth was significantly increased at postoperative week 2 (n = 3/17 mice) and 3 (n = 4/17 mice) in group IV, when compared with groups I and II (P < .05)., Conclusions: Cellular immunity is preserved after carbon dioxide pneumoperitoneum compared with extraperitoneal incisions and laparotomy as measured by DTH and the ability to reject an immunogenictumor.

The behavior of pancreatic mucinous cystic neoplasms has long been debated. Some authors contend that histologically benign neoplasms can recur and metastasize. We reviewed the gross and microscopic findings and outcomes of 61 mucinous cystic neoplasms diagnosed at The Johns Hopkins Hospital from March 20, 1984 to July 8, 1998. Each neoplasm was placed into one of four categories based on complete histologic examination: invasive mucinous cystadenocarcinoma, mucinous cystic neoplasm with in situ carcinoma, borderline mucinous cystic neoplasm, and mucinous cystadenoma. Neoplasms in the latter three categories were included only if they were entirely resected and completely examined. Patient outcomes were obtained from hospital records and patient and physician follow-up. Twenty (33%) of the patients had invasive mucinous cystadenocarcinomas, and they had 2- and 5-year disease-specific survival rates of 67% and 33% (mean follow-up of survivors, 4.2 years), respectively. Nine (15%) patients had mucinous cystic neoplasms with in situ carcinoma (mean follow-up of survivors, 4.1 years). Five (8.2%) patients had borderline mucinous cystic neoplasms (mean follow-up of survivors, 5.6 years). Twenty-seven (44%) patients had mucinous cystadenomas (mean follow-up of survivors, 5.1 years). No mucinous cystadenoma, borderline mucinous cystic neoplasm, or mucinous cystic neoplasm with in situ carcinoma recurred or metastasized. No patient with the diagnosis of mucinous cystadenoma, borderline mucinous cystic neoplasm, or mucinous cystic neoplasm with in situ carcinoma died of disease. The difference in disease-specific survival rates between patients with invasive mucinous cystadenocarcinomas and those with noninvasive tumors was significant (p < 0.0001, log-rank test). One case, originally showing only benign histology on incisional biopsy, contained foci of invasive carcinoma on complete resection. Completely resected and entirely examined mucinous cystadenomas, borderline mucinous cystic neoplasms, and mucinous cystic neoplasms with in situ carcinoma follow benign courses. Because invasive carcinoma can be focal, failure to study an entire mucinous cystic neoplasm may result in the miscategorization of a malignant neoplasm as benign.

Background: Cystic pancreatic neoplasms may be benign, premalignant, or malignant. These lesions may remain asymptomatic for long periods and can be quite large at the time of presentation., Methods: A retrospective analysis was used to determine whether preoperative evaluation can predict pathology and determine resectability and outcome., Results: Over 12 years, 145 cystic pancreatic neoplasms, of which 24 (17%) were larger than 10 cm, were managed at the Johns Hopkins Hospital. Those 24 large tumors included 9 of 73 cystadenomas (12%), 7 of 27 cystadenocarcinomas (26%), 2 of 35 adenocarcinomas producing mucin or associated with a cyst (6%), 5 of 9 Hamoudi tumors (55%), and 1 dermoid cyst. Clinical symptoms, liver function tests, and computed tomographic scans did not distinguish benign from malignant pathology. On 18 angiograms, 2 malignant and 4 benign neoplasms demonstrated encasement or occlusion; however, 3 of these 6 tumors were resectable. Twenty of 22 patients (91%) who were explored underwent resection with no hospital mortality. For the entire series, 5-year survival for those with cystadenomas, cystadenocarcinomas, and cystic adenocarcinomas was 97%, 38%, and 9%, respectively. Three-year survival for those 7 with cystadenocarcinomas larger than 10 cm was 54%, compared with 51% for those 20 with smaller cystadenocarcinomas., Conclusions: Preoperative evaluation usually does not predict pathology, resectability, or outcome. Moreover, resectability is high and morbidity is low, irrespective of size. Large cystic pancreatic tumors should be explored to determine pathology, attempt resection, and provide an opportunity for long-term survival.

Outpatient laparoscopic cholecystectomy has become nearly mandatory in the current health care economic environment. This study determined the opinions of patients and their nurses regarding disability and pain after laparoscopic cholecystectomy. Using a 14-point questionnaire, 32 consecutive patients who underwent inpatient LC were surveyed. The nurses caring for these patients were surveyed with a nine-point questionnaire. Seventy-one percent of patients believed that they could not have been discharged the day of surgery; the nurses reported that 81% of the patients could not have gone home. Nausea and vomiting were common. Pain was rated as 9 or 10 in 19% of patients. Nurses reported that 56% of postoperative patients were not receptive to discharge teaching. Morning (16) versus afternoon (16) procedures were not different. Successful programs of outpatient LC must: 1) ensure adequate home support because patient capability will be limited, 2) optimize pain control, 3) minimize nausea and vomiting, and 4) deliver patient education preoperatively.

Gastrointestinal involvement in scleroderma is almost universal. We describe a patient with a benign stricture and volvulus of transverse colon, a life threatening but treatable complication of scleroderma bowel disease. We review the literature on colon volvulus in scleroderma and discuss the importance of recognizing this rare complication.

Background: There is increasing pressure to perform traditional inpatient surgical procedures in an outpatient setting. The aim of the current trial was to determine the safety and cost savings of performing laparoscopic cholecystectomy in an outpatient setting using a "mock" outpatient setting., Methods: Patients who were scheduled for laparoscopic cholecystectomy by four attending surgeons and for whom operating time was available in the outpatient center were studied. All patients received a standardized anesthetic, including ondansetron, and were discharged from the outpatient postanesthesia care unit if appropriate. At discharge, all patients were admitted to a clinical research center where they were observed in a "mock home" setting and monitored for complications that would have necessitated readmission. A decision analysis was created assuming all patients underwent outpatient surgery with either direct admission or discharge to home and readmission if complications developed., Results: Of 99 patients who were enrolled in this study, 96 patients would have met the discharge criteria for home. No major complications were observed in these 96 patients. Eleven patients experienced postoperative nausea and vomiting, 3 of whom required an additional 24 h of hospital observation. In the decision model, the optimal strategy would be to perform the procedure on an outpatient basis and readmit patients only for complications, with an average baseline cost savings of $742/patient., Conclusions: The results show that outpatient laparoscopic cholecystectomy is safe and cost-effective in selected patients, and that the mock home setting provides a means of studying the safety of transition of care.

Incisional hernias and abdominal wall defects are frequently iatrogenic problems that have been found to complicate as many as 11% of all abdominal operations. Current techniques for closure of large, chronic abdominal wall defects have limitations. The use of local musculofascial flaps rather than fascial patches (i.e., the tensor fascia lata) or synthetic material for the repair of chronic abdominal wall defects is preferable. The superiority of innervated muscle flaps that provide dynamic abdominal support has been demonstrated. This report focuses on patients with chronic abdominal wall defects in whom previous techniques have failed. An algorithmic approach to planned reconstruction is presented utilizing the "components separation" technique as its foundation. Thirty-seven patients who underwent abdominal reconstruction following this algorithm are reviewed and their clinical course is outlined. The components separation technique provides a compound innervated and vascularized muscle flap for dynamic support of the reconstructed abdominal wall. The experience documented here and by others suggests that this technique is a safe and effective method for reconstructing the abdominal wall in patients with recurrent herniation. Enterocutaneous fistulas, however, continue to present a challenge to the surgeon.

Laparoscopic cholecystectomy has received nearly universal acceptance and is currently considered the "gold standard" for the treatment of cholelithiasis. Many centers have employed "short-stay" units or "23-hour admissions" for postoperative observation following laparoscopic cholecystectomy. The practice of early discharge as "true" outpatients following this procedure has not been well defined. A retrospective analysis of 130 consecutive patients undergoing laparoscopic cholecystectomy in an outpatient surgery unit was performed. A follow-up telephone survey was carried out of patients who successfully completed the procedure as outpatients. One hundred thirty patients underwent outpatient laparoscopic cholecystectomy. The patient population consisted of 78% women, with an age range of 17 to 76 years (mean age 47.1 years). Symptomatic gallstone disease was the indication for laparoscopic cholecystectomy in 92% of the patients. All patients underwent successful completion of laparoscopic cholecystectomy with no conversions to an open procedure. The mean length of operation was 75 +/- 23 minutes (range 25 to 147 minutes). The mean length of stay in the postanesthesia care unit (PACU) ranged from 95 to 460 minutes with a mean length of stay of 200 +/- 79 minutes. A total of eight patients (6.2%) were admitted to the hospital directly from the PACU in the immediate postoperative period. Six of these eight patients were discharged on the first postoperative day. Following discharge from the PACU, an additional six patients (4.6%) required hospital admission. Three of these six patients were discharged after a single day of hospitalization. Ninety-eight of 116 eligible patients were available for follow-up telephone evaluation. The outpatient experience was rated as good by 75.5% of the patients, fair by 22.5%, and poor by 2%. In retrospect, 20.4% of the patients stated that they would have preferred an inpatient to an outpatient procedure. Laparoscopic cholecystectomy can be performed as a true outpatient procedure with patients discharged to home within hours of completion of the procedure. Less than 10% of patients will fail this protocol and another 5% of the patients may require hospitalization after returning to their homes.

Purpose: Cytomegaloviral enterocolitis is an uncommon disorder that can complicate inflammatory bowel disease. It is more common in patients with acquired immunodeficiency syndrome and can occur in patients on immunosuppressive therapy for autoimmune or inflammatory diseases and in allograft recipients. Mortality rates of up to 71 percent have been reported for cytomegaloviral enterocolitis. The aims of this study were 1) to identify the presentation, underlying medical conditions, treatment, and outcome of patients with cytomegaloviral enterocolitis and 2) to determine the prevalence of this infection in patients undergoing intestinal resection for inflammatory bowel disease., Methods: A retrospective chart review of patients with pathologic evidence of cytomegaloviral enterocolitis from 1985 through 1996 was performed. To determine the prevalence of this condition, the hospital discharge database was searched for the diagnoses of ulcerative colitis and Crohn's disease in patients who underwent bowel resection., Results: 93 patients (mean age, 44 years; 66 percent males) had cytomegaloviral infection in the small intestine (n = 6), large intestine (n = 86), or appendix (n = 1). Patients with acquired immunodeficiency syndrome (n = 42), with ulcerative colitis (n = 11), with Crohn's disease (n = 11), receiving organ transplant (n = 12), receiving bone marrow transplant (n = 8), and in other immunosuppressed states (n = 11) comprised this study. Seventeen patients (18 percent) underwent intestinal resection, and the remaining 76 patients were treated medically. Abdominal pain (77 vs. 37 percent; P < 0.01) and gastrointestinal bleeding (65 vs. 34 percent; P < 0.05) were more common presenting symptoms in patients who required resection than patients in the medically managed group. Mortality was 17.6 percent in the surgically managed group and 14.5 percent in the patients who were managed medically. The median duration of ulcerative colitis in patients with coexisting cytomegaloviral infection was 12 months. The prevalence of cytomegaloviral enterocolitis was 4.6 percent in patients with ulcerative colitis and 0.8 percent in patients with Crohn's disease., Conclusions: These data suggest that cytomegaloviral infection more frequently complicates ulcerative colitis than Crohn's disease. Furthermore, a short and fulminant course of ulcerative colitis may indicate coexisting cytomegaloviral infection. The overall low mortality in this retrospective study suggests that aggressive medical and surgical treatment improves survival in patients with cytomegaloviral enterocolitis.

The interaction between distinct cell types within the liver seems to be important in regulating hepatic function. However, these interactions have not been well characterized because of difficulty in reproducing the hepatic environment in an ex vivo model. In the present study a coculture system of hepatocytes and endothelial cells was established to investigate the communication between parenchymal and nonparenchymal cells. Freshly isolated rat hepatocytes were placed onto a monolayer of primary aortic rat endothelial cells. Analysis of the proteins secreted into the extracellular medium after pulse labeling with radioactive amino acids revealed the presence of a 180,000-apparent molecular weight glycoprotein, BBB-180, which was not detected in the extracellular medium of hepatocytes or endothelial cells when they were cultured separately. This glycoprotein was identified as alpha2-macroglobulin after sequencing of the proteolytic peptides derived from the purified protein. This finding was confirmed by Northern and Western blotting, immunoprecipitation, and RT-PCR. The expression of alpha2-macroglobulin required direct contact between hepatocytes and viable endothelial cells. These findings suggest that endothelial cells modulate hepatocyte gene expression by direct cellular interactions.

Objective: The objective was to determine whether surgical enucleation of mucinous cystadenoma of the pancreas is a safe and adequate operation., Summary Background Data: Mucinous cystadenomas of the pancreas are premalignant cystic lesions. Resection is the preferred treatment but often requires a pancreatoduodenectomy or a distal pancreatectomy with or without a splenectomy. Although these procedures can now be performed with a low mortality rate, substantial morbidity still occurs, especially in patients who have an otherwise normal pancreas., Methods: Between January 1990 and June 1997, 36 mucinous cystadenomas of the pancreas were resected at The Johns Hopkins Hospital. Most of these patients underwent pancreatoduodenectomy or distal pancreatectomy. However, 10 patients (28%) underwent enucleation of their cystic tumor. These 10 patients had a mean age of 63 years, and 6 were men. The cystic lesion was demonstrated by computed tomography in all patients. Enucleation of the cyst was performed in each patient, and four underwent another concomitant abdominal procedure. These 10 patients were followed with periodic computed tomographic scans and clinical examinations., Results: Enucleation took less time and was associated with less blood loss than resection. Pancreatic fistulas occurred more frequently after enucleation, but the incidence of major complications was similar between the two groups. Follow-up after enucleation averaged 43 months, and none of the patients developed late sequelae or recurrence., Conclusions: This experience suggests that enucleation of mucinous cystadenomas of the pancreas can be performed safely and that the recurrence rate is low after this procedure. The authors conclude that enucleation is an adequate procedure for benign cystic neoplasms of the pancreas.

As the population in the United States ages, an increasing number of elderly patients may be considered for pancreaticoduodenal resection. This high-volume, single-institution experience examines the morbidity, mortality, and long-term survival of 727 patients undergoing pancreaticoduodenectomy between December 1986 and June 1996. Outcomes of patients 80 years of age and older (n = 46) were compared to those of patients younger than 80 years. In these older patients, pancreaticoduodenectomy was performed for pancreatic adenocarcinoma (n = 25; 54%), ampullary adenocarcinoma (n = 9; 20%) distal bile duct adenocarcinoma (n = 5; 11%), duodenal adenocarcinoma (n = 2; 4%), cystadenocarcinoma; (n = 2; 4%), cystadenoma (n = 1; 2%), and chronic pancreatitis (n = 2; 4%). When compared to the 681 concurrent patients younger than 80 years who were undergoing pancreaticoduodenectomy, the two groups were statistically similar with respect to sex, race, intraoperative blood loss, and type of pancreaticoduodenectomy performed. Patients 80 years of age or older had a shorter median operative time (6.4 hours vs. 7.0 hours; P = 0.02) but a longer postoperative length of stay (median = 15 days vs. 13 days; P = 0.01) and a higher complication rate (57% vs. 41%; P = 0.05) when compared to their younger counterparts. Pancreaticoduodenectomy in the older group resulted in a 4.3% perioperative mortality rate compared to 1.6% in the younger group (P = NS). In the subset of patients undergoing pancreaticoduodenectomy for periampullary adenocarcinoma (n = 495), patients 80 years of age or older (n = 41) had a median survival of 32 months and a 5-year survival rate of 19%, compared to 20 months and 27%, respectively, in patients younger than 80 years (n = 454; P = 0.77). These data demonstrate that pancreaticoduodenectomy can be performed safely in selected patients 80 years of age or older, with morbidity and mortality rates approaching those observed in younger patients. Based on these data, age alone should not be a contraindication to pancreaticoduodenectomy.

Purpose: The purpose of this study is to delineate the effect of different operative procedures on the cell-mediated immune response in a pediatric animal model using the delayed type hypersensitivity (DTH) skin test., Methods: Sprague Dawley rats (1 week old) were sensitized against keyhole limpet hemocyanin (KLH). Animals were challenged 2 weeks later by an intradermal injection of KLH (0.3 mg) in sterile saline. Rats with positive DTH skin reactions at 24 and 48 hours after challenge (baseline) were divided randomly into five groups (n = 10 each): group I, unmanipulated control; group II, anesthesia; group III, anesthesia and midline extraperitoneal incision; Group IV, anesthesia and laparoscopy (pneumoperitoneum with carbon dioxide); Group V, anesthesia and midline laparotomy. Before each procedure (day 0) and on postoperative days 3 and 6, animals were again challenged intradermally with KLH (0.3 mg). DTH skin reaction was evaluated 24 and 48 hours later., Results: A statistically significant difference (P < .05) in DTH skin reaction at 24 and 48 hours was observed between postoperative days 1 to 5 in the extraperitoneal and laparotomy groups with respect to baseline and the control group. Statistically significant differences were found in postoperative days 1, 4, and 5 between laparoscopy and laparotomy. The laparoscopy group showed a statistically significant decrease in DTH skin induration on postoperative day 2 when compared with the control group. At postoperative day 7 and 8 there was no statistical difference in DTH skin response comparing baseline values or between groups., Conclusions: These results suggest that in a pediatric animal model, abdominal surgical procedures accompanied by extensive tissue dissection produce a cellular immunosuppression, lasting up to 7 days, which is not observed in less invasive procedures. Observations concerning lesser immunosuppressive effects of laparoscopy when compared with laparotomy in adult models, as previously described by our laboratory, were also found in this pediatric model.

Objective: The authors reviewed the pathology, complications, and outcomes in a consecutive group of 650 patients undergoing pancreaticoduodenectomy in the 1990s., Summary Background Data: Pancreaticoduodenectomy has been used increasingly in recent years to resect a variety of malignant and benign diseases of the pancreas and periampullary region., Methods: Between January 1990 and July 1996, inclusive, 650 patients underwent pancreaticoduodenal resection at The Johns Hopkins Hospital. Data were recorded prospectively on all patients. All pathology specimens were reviewed and categorized. Statistical analyses were performed using both univariate and multivariate models., Results: The patients had a mean age of 63 +/- 12.8 years, with 54% male and 91% white. The number of resections per year rose from 60 in 1990 to 161 in 1995. Pathologic examination results showed pancreatic cancer (n = 282; 43%), ampullary cancer (n = 70; 11%), distal common bile duct cancer (n = 65; 10%), duodenal cancer (n = 26; 4%), chronic pancreatitis (n = 71; 11%), neuroendocrine tumor (n = 31; 5%), periampullary adenoma (n = 21; 3%), cystadenocarcinoma (n = 14; 2%), cystadenoma (n = 25; 4%), and other (n = 45; 7%). The surgical procedure involved pylorus preservation in 82%, partial pancreatectomy in 95%, and portal or superior mesenteric venous resection in 4%. Pancreatic-enteric reconstruction, when appropriate, was via pancreaticojejunostomy in 71% and pancreaticogastrostomy in 29%. The median intraoperative blood loss was 625 mL, median units of red cells transfused was zero, and the median operative time was 7 hours. During this period, 190 consecutive pancreaticoduodenectomies were performed without a mortality. Nine deaths occurred in-hospital or within 30 days of operation (1.4% operative mortality). The postoperative complication rate was 41%, with the most common complications being early delayed gastric emptying (19%), pancreatic fistula (14%), and wound infection (10%). Twenty-three patients required reoperation in the immediate postoperative period (3.5%), most commonly for bleeding, abscess, or dehiscence. The median postoperative length of stay was 13 days. A multivariate analysis of the 443 patients with periampullary adenocarcinoma indicated that the most powerful independent predictors favoring long-term survival included a pathologic diagnosis of duodenal adenocarcinoma, tumor diameter <3 cm, negative resection margins, absence of lymph node metastases, well-differentiated histology, and no reoperation., Conclusions: This single institution, high-volume experience indicates that pancreaticoduodenectomy can be performed safely for a variety of malignant and benign disorders of the pancreas and periampullary region. Overall survival is determined largely by the pathology within the resection specimen.

Objective: The aim of this study were to review the experience with adenocarcinoma of the ampulla of Vater at The Johns Hopkins Hospital and to determine what factors influenced the long-term outcome in these patients., Summary Background Data: Adenocarcinoma of the ampulla of Vater is the second most common periampullary malignancy. However, most series have relatively small numbers. As a result, analysis of factors influencing outcome has been limited., Methods: From 1969 to 1996, 120 patients with adenocarcinoma of the ampulla of Vater were managed at The Johns Hopkins Hospital. Clinical, operative, and pathologic factors were correlated with morbidity and long-term survival. Factors influencing outcome were evaluated by univariate and multivariate analyses., Results: Resection was performed in 106 patients (88%), and 105 of these patients (99%) underwent either pancreatoduodenal resection (n = 103) or total pancreatectomy (n = 2). Resection rate increased from 62% in the 1970s to 82% in the 1980s to 96% in the 1990s (p < 0.05). Overall mortality after resection was 3.8% with no mortality in the 45 consecutive patients resected in the past 5 years. Morbidity also decreased significantly (p < 0.05) from 70% before to 38% after December 1992. Five-year survival for resected patient was 38%. Factors favorably influencing long-term outcome were resection (p < 0.001), no perioperative blood transfusions (p < 0.05), negative lymph node status (p = 0.05), and moderate or well-differentiated tumors (p < 0.05). In a multivariate analysis, the best predictor of prolonged survival was absence of intraoperative transfusion (p = 0.06, relative risk = 1.90, 95% confidence limits = 0.95-3.78)., Conclusions: Compared to carcinoma of the pancreas, carcinoma of the ampulla of Vater has a higher resectability rate and a better prognosis. Early diagnosis is important because lymph node status influences survival. Careful operative dissection and avoidance of transfusions also improves long-term survival.

Objective: The authors provide the results of follow-up evaluation after combined surgical and radiologic management of 89 patients with major bile duct injuries during laparoscopic cholecystectomy., Summary Background Data: The incidence and mechanism of injury of major bile duct injuries during laparoscopic cholecystectomy has been clearly defined. Furthermore, a number of series have described the management of these injuries by surgical, endoscopic, and radiologic techniques with excellent short-term results. Long-term follow-up data, however, are lacking in the management of these injuries., Methods: Data were collected prospectively on 89 patients treated at a single institution with major bile duct injuries after laparoscopic cholecystectomy managed between July 1, 1990, and July 1, 1996. Patients referred with injuries underwent early percutaneous transhepatic cholangiography and biliary drainage. Based on the cholangiographic appearance and clinical situation, patients were managed by either percutaneous balloon dilatation or surgical reconstruction with a Roux-en-Y hepaticojejunostomy with transanastomotic stenting. Follow-up was obtained by personal interview during October 1996., Results: Two patients died without an attempt at definitive therapy. Both deaths were caused by sepsis and multisystem organ failure present at the time of transfer to the authors' institution. The remaining 87 patients were managed initially by either balloon dilatation (N = 28) or surgical reconstruction (N = 59). Ten patients have not completed treatment and still have biliary stents in place. Evaluation of 25 patients completing treatment after balloon dilatation (mean follow-up, 27.8 months) showed a success rate of 64%. Evaluation of 52 patients completing treatment after surgical reconstruction (mean follow-up, 33.4 months) showed a success rate of 92%. All failures were managed successfully by either surgical reconstruction or balloon dilatation., Conclusions: Major bile duct injuries can be managed successfully by combined surgical and radiologic techniques. This series provides, for the first time, significant follow-up on a large number of patients with overall success rates of 64% after balloon dilatation and 92% after surgical reconstruction. The combination of surgery and balloon dilatation resulted in a successful outcome in 100% of patients treated.

Background: Surgeons are often called upon to perform pancreaticoduodenectomy for either suspicion of malignancy or symptoms due to benign disease. Perioperative morbidity and mortality following pancreaticoduodenectomy have decreased markedly over the last 2 decades. In response, many surgical centers advocate expanding the indications for pancreaticoduodenectomy to include lesions other than periampullary carcinoma., Patients and Methods: A retrospective review of medical records for 108 patients undergoing pancreaticoduodenectomy for benign disease at The Johns Hopkins Medical Institutions over 100 months was completed. The subset of patients with a histopathologic diagnosis of chronic pancreatitis was identified and compared with patients undergoing pancreaticoduodenectomy for other benign conditions., Results: The mortality rate for the present series was less than 1%. Perioperative complications, the majority of which were self-limited, occurred in 51% of patients. The most common complication was delayed gastric emptying. Pancreatic anastamotic leak occurred in 18% of patients and developed significantly more frequently in patients with benign diseases other than chronic pancreatitis (31% versus 8%, P < 0.05)., Conclusion: Among appropriately selected patients, the rates of perioperative mortality and serious morbidity are low, and concerns about mortality and morbidity should not prevent an aggressive approach to surgical resection in patients with benign disease.

Objective: The authors hypothesized that pancreaticogastrostomy is safer than pancreaticojejunostomy after pancreaticoduodenectomy and less likely to be associated with a postoperative pancreatic fistula., Summary Background Data: Pancreatic fistula is a leading cause of morbidity and mortality after pancreaticoduodenectomy, occurring in 10% to 20% of patients. Nonrandomized reports have suggested that pancreaticogastrostomy is less likely than pancreaticojejunostomy to be associated with postoperative complications., Methods: Between May 1993 and January 1995, the findings for 145 patients were analyzed in this prospective trial at The Johns Hopkins Hospital. After giving their appropriate preoperative informed consent, patients were randomly assigned to pancreaticogastrostomy or pancreaticojejunostomy after completion of the pancreaticoduodenal resection. All pancreatic anastomoses were performed in two layers without pancreatic duct stents and with closed suction drainage. Pancreatic fistula was defined as drainage of greater than 50 mL of amylase-rich fluid on or after postoperative day 10., Results: The pancreaticogastrostomy (n = 73) and pancreaticojejunostomy (n = 72) groups were comparable with regard to multiple parameters, including demographics, medical history, preoperative laboratory values, and intraoperative factors, such as operative time, blood transfusions, pancreatic texture, length of pancreatic remnant mobilized, and pancreatic duct diameter. The overall incidence of pancreatic fistula after pancreaticoduodenectomy was 11.7% (17/145). The incidence of pancreatic fistula was similar for the pancreaticogastrostomy (12.3%) and pancreaticojejunostomy (11.1%) groups. Pancreatic fistula was associated with a significant prolongation of postoperative hospital stay (36 +/- 5 vs. 15 +/- 1 days) (p < 0.001). Factors significantly increasing the risk of pancreatic fistula by univariate logistic regression analysis included ampullary or duodenal disease, soft pancreatic texture, longer operative time, greater intraoperative red blood cell transfusions, and lower surgical volume (p < 0.05). A multivariate logistic regression analysis revealed the factors most highly associated with pancreatic fistula to be lower surgical volume and ampullary or duodenal disease in the resected specimen., Conclusions: Pancreatic fistula is a common complication after pancreaticoduodenectomy, with an incidence most strongly associated with surgical volume and underlying disease. These data do not support the hypothesis that pancreaticogastrostomy is safer than pancreaticojejunostomy or is associated with a lower incidence of pancreatic fistula.

Background: Since 1989, laparoscopic cholecystectomy has been widely adopted as a treatment for gallstone disease. We analyzed the association between the introduction of this procedure and three variables: the rate at which cholecystectomy was performed in Maryland, the characteristics of patients undergoing cholecystectomy in routine clinical practice, and operative mortality., Methods and Results: We used 1985-1992 hospital-discharge data from all 54 acute care hospitals in Maryland, to identify open and laparoscopic cholecystectomies, characteristics of patients undergoing these procedures, and deaths occurring during hospitalizations in which these procedures were performed. The annual rate of cholecystectomy, adjusted for age, rose from 1.69 per 1000 state residents in 1987-1989 to 2.17 per 1000 residents in 1992, an increase of 28 percent (P < 0.001). As compared with patients undergoing open cholecystectomy, patients undergoing laparoscopic cholecystectomy tended to be younger, less likely to have acute cholecystitis or a common-duct stone, and more likely to be white and have private health insurance or belong to a health maintenance organization (P < 0.001). Although the operative mortality associated with laparoscopic cholecystectomy was less than that with open cholecystectomy (adjusted odds ratio, 0.22; 95 percent confidence interval, 0.13 to 0.37) and the overall mortality rate for all cholecystectomies declined from 0.84 percent in 1989 to 0.56 percent in 1992, there was no significant change in the total number of cholecystectomy-related operative deaths because of the increase in the cholecystectomy rate., Conclusions: In Maryland, although the adoption of laparoscopic cholecystectomy has been accompanied by a 33 percent decrease in overall operative mortality per procedure, the total number of cholecystectomy-related deaths has not fallen because of a 28 percent increase in the total rate of cholecystectomy.

The rapid adoption of laparoscopic cholecystectomy by the world of general surgery is remarkable. The experience of the first five years has done much to promote the safety and efficacy of this important procedure. As experience continues to accumulate, there will be more data to establish the contraindications, the proper role of cholangiography and the best means of avoiding complications. Improved tools and technical aids will also improve surgeons' ability to safely perform this procedure for their patients.

The initial 22-month experience with laparoscopic cholecystectomy in 400 patients employing an algorithm of selective cholangiographic evaluation is reported. Preoperative or postoperative endoscopic retrograde cholangiography was performed whenever stones were suspected clinically. Preoperative endoscopic retrograde cholangiography was performed in 44 patients (11%), in whom 14 (3.5%) had an endoscopic sphincterotomy with extraction of common bile duct stones. Intraoperative cholangiography was performed in only eight patients (2%) almost exclusively to acquire experience with the technique, and all cholangiograms were normal. Laparoscopic cholecystectomy was successfully completed in 96% of the patients. There were no deaths in this series, and major complications occurred in only 5% of patients. Two patients (0.5%) had a significant common bile duct injury that was recognized and successfully repaired at the initial operation. No late common bile duct strictures have been recognized. Six patients (1.5%) underwent postoperative endoscopic retrograde cholangiography for suspected common bile duct stones, with three patients requiring endoscopic sphincterotomy and stone extraction. This experience suggests that the use of preoperative and postoperative endoscopic retrograde cholangiography can be based on clinical presentation and laboratory evaluation and does not need to be performed routinely. Routine intraoperative cholangiography is not necessary in most patients undergoing laparoscopic cholecystectomy. The authors conclude that laparoscopic cholecystectomy can be performed safely with the selective use of cholangiography.

The pathologic and clinical classification, as well as the behavior, of cystic tumors of the pancreas has been the subject of controversy. We retrospectively reviewed 50 patients with a diagnosis of cystic tumor of the pancreas observed at The Johns Hopkins Hospital from 1984 to 1991. These tumors were classified into three broad groups: I, cystadenoma; II, cystadenocarcinoma; and III, adenocarcinoma with mucin production or an associated cyst. The three groups did not differ with respect to age or sex. The most common clinical presentation was abdominal pain. Symptoms and signs among the three groups were similar except that patients with cystadenomas were less likely (p less than 0.05) to be jaundiced and more likely (p less than 0.05) to be asymptomatic. Radiologic findings on computerized tomography, cholangiography, and arteriography also overlapped, making precise preoperative determination of tumor type difficult. Operative classification was also often not possible. The resectability rate (Group I, 91%; Group II, 67%; Group III, 53%) and 5-year survival rate (Group I, 90%; Group II, 72%; Group III, 14%) correlated with careful pathologic determination. Cystic tumors of the pancreas represent a spectrum of disease ranging from benign cystadenoma to adenocarcinoma masquerading as cystadenocarcinoma. We recommend resection whenever possible, even when preoperative evaluation suggests benign disease.

Laparoscopic cholecystectomy is a combined endoscopic-operative technique for removal of the gallbladder. Patients with symptomatic gallstones are candidates for this procedure. Current absolute contraindications include pregnancy, acute cholangitis, peritonitis or abdominal sepsis, and a major bleeding disorder. Safe use of the procedure requires specific training and subsequent animal and proctored clinical experience. The technique is guided by video-endoscopy, and is performed through four cannulas/ports. Potential complications include bleeding, injury to the common bile duct, trocar injury to the bowel, and spillage of bile and/or stones. The length of hospital stay and postoperative recovery are significantly shortened compared to standard cholecystectomy. Patients appear to prefer this procedure over lithotripsy or dissolution because the gallbladder and stones are removed and additional or continued treatment is not necessary. This procedure offers notable advantages to the patient, and is becoming a standard procedure for qualified general surgeons.

Laparoscopic cholecystectomy is a minimally invasive procedure whereby the gallbladder is removed using laparoscopic techniques. The indications are similar to those for elective traditional cholecystectomy, but selection of patients is important for success. Contraindications are currently evolving. Patients with advanced cholecystitis, abdominal sepsis, ileus, bleeding disorders, pregnancy, and morbid obesity should not undergo this procedure. The procedure requires good traditional surgical skills, as well as additional laparoscopic (and laser) skills. Operative time is slightly longer than for traditional cholecystectomy, but decreases with experience. Morbidity is low, but there is a concern about bile duct injuries. Mortality is very low (0%) and is comparable to traditional cholecystectomy (0.4%). The major advantages of laparoscopic cholecystectomy are the short hospital stay (average: 2 days) and early return to normal activity (7 days). This results in a reduction in hospital costs. Adequate training and credentialing are important processes to foster good patient outcomes.

Many methods are available for gallstone dissolution, including oral bile salts; cholesterol solvents such as mono-octanoin or methyl tert-butyl either; and calcium or pigment solvents such as EDTA and polysorbate. Which of these approaches will be appropriate for an individual patient depends on the type of stones; whether they are in the gallbladder or the bile ducts; whether access to the biliary tree is available; the patient's age and general medical condition; and the availability of necessary expertise. In the US, both chenodeoxycholate and ursodeoxycholate are now available. Ursodeoxycholate is more expensive but appears to produce fewer side effects and may be more efficacious. These agents are most effective in thin women with small floating, radiolucent cholesterol stones in a functioning gallbladder. Only about half of the small subset of patients will experience partial or complete dissolution of stones within a year. Stone recurrence and the potential toxicity of long-term therapy are problems with this approach. Therefore, for most patients, cholecystectomy, either in the traditional fashion or using a laparoscopic approach (see article later in this issue by Gadacz et al), is the most cost-effective and perhaps the safest option. Intragallbladder instillation of methyl tert-butyl ether probably will be applicable only to a small subset of patients, and treatment is likely to be followed by a high recurrence rate. In patients with retained common duct cholesterol stones and access to the biliary tree, mono-octanoin therapy is advantageous in that it can be initiated as soon as cholangiography demonstrates no extravasation. In properly selected patients, a 90% success rate with this technique can be expected within 7 days.

Laparoscopic cholecystectomy is a combined endoscopic-operative technique for removing the gallbladder. Patients with symptomatic gallstones are eligible for this procedure. Contraindications include pregnancy, acute cholangitis, advanced cholecystitis, acute pancreatitis, peritonitis, significant bleeding disorder, portal hypertension, and a prior major upper abdominal operation. The procedure does require experience and specialized training. It is guided by an endoscope, camera, and video monitor, and is performed through four cannulas. The gallbladder is dissected from the hepatic bed under observation on a monitor. The possible complications are bleeding, injury to the common bile duct, and technical problems, such as perforation of the gallbladder. The length of the hospital stay and the postoperative recovery time are markedly shortened compared with standard cholecystectomy. The procedure has an advantage over stone dissolution and biliary lithotripsy in that the gallbladder is removed, and additional or continued treatment is not necessary. This procedure offers sufficient advantages to the patient that it will likely become a standard for qualified abdominal surgeons.

A primary small cell carcinoma of the esophagus in a 61-year-old woman was treated by transhiatal esophagectomy. The clinical data were correlated with data obtained from a review of the 129 cases reported in the world literature, thereby providing a clinical profile and suggested management strategy for this rare type of esophageal malignancy. Presenting symptoms of esophageal small cell carcinoma include dysphagia (75.3%), weight loss (38.4%), and chest pain (23.3%). Treatment regimens have included surgical intervention in 58%, radiotherapy in 10%, chemotherapy in 6%, or some combination of these in 26%. Overall survival is only 20.7 weeks after diagnosis. The fact that three fourths of affected patients had metastatic disease at the time of diagnosis leads us to recommend surgical intervention plus systemic chemotherapy in these patients.

Sixteen patients with urinary fistulas complicating Crohn's disease are reported upon. Fifteen of the fistulas were diagnosed by a history of pneumaturia. Roentgenologic procedures used to confirm the diagnosis were of little value. Specific surgical therapy varied with the locality of the fistula but, generally, consisted of division of the fistula, resection of the involved intestine with primary anastomosis and closure of the bladder. Long term follow-up showed excellent results.

To study the effect of intraabdominal sepsis on hepatic protein synthesis, male Sprague-Dawley rats underwent celiotomy with either cecal ligation and puncture (CLP) or sham operation. Eight and sixteen hours later total hepatic protein synthesis was measured by flooding dose technique. Specific synthetic rates of structural or secreted hepatic proteins were further studied 16 hr after CLP in an isolated perfused liver model. Total hepatic protein synthesis was significantly elevated at 16 hr (59 +/- 6%/day vs 37 +/- 6%/day, P less than 0.05), but not 8 hr post-CLP. Structural hepatic protein synthesis was unchanged after CLP; however, the synthetic rates of the acute-phase secretory proteins alpha 1-acid glycoprotein, transferrin and complement component C3 were significantly increased 16 hr after CLP. However, the albumin synthetic rate was not increased during sepsis. We conclude that sepsis causes augmentation of hepatic protein synthesis primarily to increase acute-phase proteins for host defense.

Protein synthesis and degradation rates were measured in incubated soleus (SOL) and extensor digitorum longus (EDL) muscles 4, 8, and 16 hours following cecal ligation and puncture (CLP) in rats. No significant differences in protein synthesis between septic and control rats were found. The proteolytic rate in SOL muscle was increased by 36% eight hours after CLP and by 42% 16 hours after CLP. In EDL muscle, protein breakdown was not significantly increased until 16 hours after CLP, at which time it was 53% above the control value. The plasma amino acid pattern became increasingly deranged during the course of the study, and at 16 hours almost all individual amino acid levels were significantly different in septic rats compared with control rats. There was a significant positive correlation between plasma concentrations of phenylalanine, histidine, and ornithine and the proteolytic rate in EDL and SOL muscles, with the best correlation being found between phenylalanine concentration and proteolytic rate in SOL muscle. These results suggest that muscle wasting during sepsis is caused by increased protein breakdown, not by decreased protein synthesis, and that accelerated muscle proteolysis is an early phenomenon in sepsis.

Total parenteral nutrition (TPN) is associated with hepatic biochemical and morphologic changes. Suggested causes include excessive glucose calories, fatty acid deficiency, and enterically derived hepatotoxins escaping atrophied bowel. Male Sprague-Dawley rats were cannulated or sham operated with internal jugular ligation. The cannulated groups received TPN with a 25% dextrose base, or TPN 12.5% dextrose and given nothing by mouth, or saline solution and allowed to eat ad lib. Sham animals ate ad lib. After 6 days the animals were killed and portal blood was assayed for endotoxin and cultured. Cultures were also taken of the liver. Serum hepatic enzyme concentration and hepatic fat were determined. All cultures and endotoxin assays were negative. Microscopy revealed nonlipid vacuolization in both TPN groups, a finding reproduced by direct portal infusion of endotoxin. There was significant hepatic steatosis in the 25% dextrose base TPN versus all other groups (28.6% liver weight versus 6.3% liver weight; p less than 0.05). This was correlated with caloric intake (28.7 calories/100 gm/day versus 21.2 calories/100 gm/day; p less than 0.05). Liver enzymes were not significantly different among groups. We conclude that hepatic steatosis in TPN is a result of overfeeding a glucose only substrate and that fatty infiltration is independent of changes in blood hepatic enzyme concentrations. Although other morphologic changes of hepatotoxin-induced injury were seen in the TPN group, portal endotoxemia to the level of 1 ng/ml could not be documented.

To determine the effect of early aggressive parenteral support in pancreatitis, 54 patients with acute pancreatitis were randomized to receive either conventional therapy (control group) or conventional therapy plus the institution of total parenteral nutrition within 24 hours. The two groups were similar demographically. The total parenteral nutrition group had a significantly higher rate of catheter-related sepsis than did an additional group of contemporaneous patients without pancreatitis who received total parental nutrition (10.5 percent and 1.47 percent, respectively; p less than 0.01). There was no advantage to the use of early total parenteral nutrition; that is, there was no difference in the number of days to oral intake, total hospital stay, or number of complications of pancreatitis. Patients with zero or one Ranson's criterion on admission were more likely to be eating by the seventh hospital day than were those with two or more Ranson's criteria (80 percent and 54 percent, respectively; p less than 0.05). The early institution of total parenteral nutrition in patients with acute pancreatitis did not appear to improve the outcome. Its use should be limited to prolonged periods of no oral intake or treatment of a specific complication, such as a pseudocyst.

Twenty patients undergoing major upper-gastrointestinal-tract or pancreaticobiliary surgery were randomized to receive postoperative nutritional support by total parenteral nutrition (TPN) or elemental diet administered by needle-catheter jejunostomy (NCJ). Both routes of administration provided adequate nutritional support. No unexpected complications were encountered. The NCJ group compared favorably with the TPN group at the end of the seven-day trial. The NCJ group provided significant cost efficiency while maintaining adequate nutritional support.

The effect of indomethacin on protein degradation in skeletal muscle from septic rats was investigated. Sepsis was induced by cecal ligation and puncture (CLP). Control rats were sham-operated. Protein degradation rate was estimated by measuring release of tyrosine from incubated soleus (SOL) and extensor digitorum longus (EDL) muscles. Three experiments were performed. In the first experiment, indomethacin was administered subcutaneously (3 mg/kg) at the time of CLP and again after 3 hours. Control rats received corresponding volumes of solvent. Groups of rats were studied after 8 hours (early sepsis) or 16 hours (late sepsis). In the second experiment, the animals were pretreated 45 minutes before induction of sepsis with indomethacin (3 mg/kg) and again 3 hours after CLP and were studied during early sepsis. In the third experiment, indomethacin was added in vitro (3 microM) to incubated normal or septic muscle or to normal muscle incubated in the presence of plasma from septic animals, and release of prostaglandin E2 (PGE2) by incubated muscle was measured in addition to protein degradation. There was no mortality in early sepsis. Survival rate 16 hours after CLP was 8/16 (50%) in rats receiving control injections and 7/15 (47%) in indomethacin-treated rats (NS). Proteolytic rate in incubated EDL and SOL was increased by 20-25% during early sepsis and by 30-50% during late sepsis. The increased proteolytic rate was not affected by administration of indomethacin, neither in the first nor in the second experiment. When indomethacin was added in vitro, release of PGE2 by septic muscles and by normal muscles incubated in the presence of septic plasma was reduced by about 50%, but the increased proteolytic rate in these muscles was not affected. In normal muscle, neither release of PGE2 nor protein degradation was affected by indomethacin in vitro. The present results do not support a role for prostaglandins in the enhancement of muscle proteolysis during sepsis. Since neither survival rate nor protein breakdown was affected by indomethacin, recent suggestions to use this substance in the treatment of septic patients might be questioned.

To examine alterations in amino acid metabolism after trauma and sepsis, male Sprague-Dawley rats underwent no operation (control, CON), celiotomy (trauma, TRA), or cecal ligation and puncture (sepsis, CLP). After 16 hr, plasma amino acid concentrations were determined. A second group of similarly prepared animals underwent isolated liver perfusion, and net amino acid uptake or release was determined over 30 min. Sepsis significantly decreased total amino acid concentration in portal plasma (CON, 3486 +/- 156 nmole/ml; TRA, 3407 +/- 150 nmole/ml; CLP, 2738 +/- 148 nmole/ml). Glutamine concentrations were uniformly lower in portal plasma than in arterial plasma in all states. There were depressed concentrations of the branched chain amino acids (BCAA) in portal plasma after trauma but not sepsis. In the isolated liver perfusion model, a marked increase in amino acid uptake was induced by sepsis (CON, 39.9 +/- 7.9 mumol/g liver protein; TRA, 49.5 +/- 17.3 mumol/g liver protein; CLP, 124 +/- 11 mumol/g liver protein). In addition, there was significantly greater uptake of threonine, asparagine, proline, methionine, tyrosine, and arginine. Although the BCAA isoleucine and valine were taken up to a greater extent in sepsis, the overall BCAA uptake was not significantly greater in sepsis than in control (CON 6.92 +/- 2.15 mumol/g liver protein vs CLP 15.8 +/- 1.9 mumol/g liver protein). The greatest increase in uptake following sepsis was among the gluconeogenic precursor amino acids alanine, glycine, threonine, and serine (CON, 27.0 +/- 4.2 mumol/g liver protein, TRA, 38.8 +/- 8.9 mumol/g liver protein; CLP, 62.8 +/- 6.0 mumol/g liver protein).(ABSTRACT TRUNCATED AT 250 WORDS)

The branched-chain amino acids (BCAAs)--leucine, isoleucine, and valine--share unique biochemical properties that may make them useful in altered physiologic states. They can be metabolized independently of liver function to provide energy, other amino acids, or small nitrogenous compounds. This unique ability makes the BCAAs a desirable supplement in liver disease with encephalopathy and, to a lesser extent, in sepsis with hepatic dysfunction. Furthermore, the BCAAs play a role in the regulation of protein synthesis, suggesting beneficial effects in catabolic states such as postoperative stress, trauma, renal failure, and burns. However, initial studies in these areas have presented equivocal results.