Effect of PGG-glucan on the rate of serious postoperative infection or death observed after high-risk gastrointestinal operations. Betafectin Gastrointestinal Study Group.

BACKGROUND: Postoperative infections remain common after high-risk gastrointestinal procedures. PGG-glucan (Betafectin; Alpha Beta Technology Inc, Worcester, Mass), derived from yeast cell walls, promotes phagocytosis and intracellular killing of bacterial pathogens by leukocytes, prevents infection in an animal model of wound infection, and acts synergistically with antibiotics to reduce mortality in rat peritonitis. HYPOTHESIS: We hypothesized that infectious complications in these patients might be reduced by the administration of a nonspecific immune-enhancing agent. DESIGN: Multicenter, prospective, randomized, double-blind, placebo-controlled trial of 1249 patients prospectively stratified into colorectal or noncolorectal strata. SETTING: Thirty-nine medical centers throughout the United States. PATIENTS: Aged 18 years or older, scheduled for gastrointestinal procedure lasting 2 to 8 hours, with 2 or more defined risk factors. INTERVENTIONS: PGG-glucan, 0.5 mg/kg or 1.0 mg/kg, or placebo once preoperatively and 3 times postoperatively. All patients received standardized antibiotic prophylaxis. MAIN OUTCOME MEASURES: Serious infection or death within 30 days. RESULTS: All randomized patients revealed no difference in serious infections and deaths in the treated groups compared with placebo groups (15% vs 14%, P>.90). In the prospectively defined noncolorectal stratum (n = 391), PGG-glucan administration was associated with a statistically significant relative reduction (39%) in serious infections and death (placebo, 46 [36%] of 129 vs either PGG-glucan group, 29 [21%] of 132 and 28 [22%] of 130, P<.02). PGG-glucan reduced postoperative infection or death in malnourished patients having noncolorectal procedures (31 [44%] of 70, placebo group; 16 [24%] of 68, 0.5-mg/kg PGG-glucan group; 12 [17%] of 72, 1.0-mg/kg PGG-glucan group; P<.001). Study drug was stopped owing to adverse effects more frequently for patients receiving PGG-glucan than placebo (2%, 4%, and 7% for the placebo group, 0.5-mg/kg PGG-glucan group, and 1.0-mg/kg PGG-glucan group, respectively, P<.003). CONCLUSION: Perioperative administration of PGG-glucan reduced serious postoperative infections or death by 39% after high-risk noncolorectal operations.

Microbiology in intraabdominal infections: what is the message for clinical studies? (Opinion paper).

Bacterial flora participating in intraabdominal infections are well known. Data are reviewed here documenting the constant antibiotic susceptibility of this flora despite many years of widespread use of antibiotics. The flaws inherent in the concept of "microbiologic efficacy" in evaluating antibiotic efficacy are examined. Among the possible results of a clinical trial, outcomes not in accord with antibiotic sensitivity data occur regularly. Factors such as host defense responses, source control and inoculum density also influence the outcome in a clinical trial but are not currently being measured. Recommendations for improved conduct of trails are made.

Management of intrathoracic stomach with polypropylene mesh prosthesis reinforced transabdominal hiatus hernia repair.

BACKGROUND: Posterior cruroplasty repair of a large paraesophageal hiatus hernia has a higher than desirable rate of recurrence attributable to the inexorable cyclic negative intrathoracic pressure of respiration and positive intraabdominal pressure produced by straining, physical exertion, and coughing. To reduce the risk of recurrence after repair of a large hiatus hernia and intrathoracic stomach, we have used posterior cruroplasty reinforced with an onlay polypropylene mesh prosthesis. This paper reviews the feasibility of this technique. STUDY DESIGN: We did a retrospective review of 44 patients with large hiatus hernia and intrathoracic stomach who had posterior cruroplasty and onlay of polypropylene mesh prosthesis applied to the crura and adjacent diaphragm to repair the hiatal defect. RESULTS: Preoperative symptoms (mean duration, 26 months) included pain (33 patients), vomiting (21), dysphagia (19) and anemia (8). The typical patient (28 men and 16 women, mean age, 60) had two-thirds or more of the stomach above the diaphragm. Organoaxial gastric volvulus and herniated large or small bowel were present in 10 and 9 patients, respectively. A gastrostomy was performed for temporary drainage in 38 patients in addition to the hernia repair; 11 patients underwent a concomitant Nissen fundoplication. Postoperative complications included pleural effusion (four patients), atrial dysrhythmia (three patients), and superficial wound infection (two patients). Mean followup for 43 patients was 52 months. There have been no clinical recurrences. CONCLUSIONS: Mesh prosthesis reinforced hiatus hernia repair is effective, appears to have a low clinical recurrence rate, and should be an option in the treatment of a large hiatus hernia with intrathoracic stomach.

Pharmacoeconomic analysis of ampicillin-sulbactam versus cefoxitin in the treatment of intraabdominal infections.

We conducted a retrospective pharmacoeconomic analysis of a prospective, multicenter, double-blind, randomized, controlled trial comparing the beta-lactamase inhibitor combination ampicillin-sulbactam (96 patients) and the cephalosporin cefoxitin (101) in the treatment of intraabdominal infections. An institutional perspective was adopted for the analysis. The primary outcomes of interest were cure and failure rates, development of new infection, and antibiotic-related adverse events. Epidemiologic data pertaining to outcomes was retrieved primarily from the trial, although results of other published studies were taken into consideration through extensive sensitivity analyses. Data pertaining to potential resource use and economic impact were retrieved mainly from the University Health Consortium and hospital-specific sources. When considering only costs associated with drug acquisition through cost-minimization analysis, a potential savings of $37.24/patient may be realized with ampicillin-sulbactam relative to cefoxitin based on an average 7-day regimen. Outcome data collected for the entire hospitalization during the trial revealed an approximately 9% greater frequency of failure with cefoxitin relative to ampicillin-sulbactam. When considering all outcomes of interest in the initial base-case analysis, a potential cost savings of approximately $890/patient may be realized with ampicillin-sulbactam relative to cefoxitin. In assessing the impact of the significant variability in probability and cost estimates, Monte Carlo analysis revealed a savings of $425/patient for ampicillin-sulbactam over cefoxitin (95% CI -$618 to $1516 [corrected]). Given the model assumptions, our analysis suggests a 78% certainty level that savings will be experienced when ampicillin-sulbactam is chosen over cefoxitin.

A novel motility effect of tachykinins in normal and inflamed colon.

The role of tachykinins in stimulating phasic and giant migrating contractions (GMCs) in the normal and inflamed colon in conscious dogs was investigated by close-intra-arterial infusions of test substances. At low doses (0.1 nmol), substance P and neurokinin (NK1) receptor agonist ([Sar9,Met(O2)11]substance P] stimulated phasic contractions only. At higher doses (2.0 nmol), they stimulated phasic contractions and GMCs. The phasic contractions were blocked partially but significantly by prior close-intra-arterial infusions of tetrodotoxin and atropine but not by hexamethonium. NK1 receptor antagonist partially but significantly inhibited the phasic contractile response to substance P, whereas NK2 and NK3 receptor antagonists had no significant effect. The contractile response to NK2 receptor agonist was less than one-half of the response to substance P; NK3 receptor agonist did not stimulate any contractile activity. The stimulation of GMCs by higher doses of substance P was not blocked by prior infusions of atropine, tetrodotoxin, or NK1, NK2, and NK3 receptor antagonists, nor was the contractile response to substance P blocked by H1 and H2 receptor antagonists. Inflammation depressed the phasic contractile response but enhanced the stimulation of GMCs by substance P. The ability of substance P to stimulate GMCs is novel and suggests its potential role in increasing the frequency of these contractions during colonic inflammation.

Central inhibition of nitric oxide synthase modulates upper gastrointestinal motor activity.

We investigated the role of central nitric oxide (NO) synthase inhibition in the modulation of fasting gastrointestinal motor activity and gastric emptying rate of solid nutrient meals in conscious dogs. N(omega)-nitro-L-arginine methyl ester and N(omega)-nitro-L-arginine were infused intracerebroventricularly. Circular muscle contractions were recorded with surgically implanted strain gauge transducers. Gastric emptying was measured by a radiolabeled meal. The inhibition of NO synthase in the brain suppressed phase III activity in the stomach and the duodenum but not in the jejunum or the ileum. However, the central inhibition of NO synthase had no significant effect on the rate of gastric emptying of solid nutrient meals or the duration of postprandial disruption of migrating motor complex cycling. The central actions of NO synthase inhibition were blocked by bilateral truncal vagotomy but not by intravenous administration of propranolol or phentolamine. We conclude that the inhibition of NO synthase in the brain generates a stimulus that selectively inhibits gastric and duodenal phase III activities. This stimulus, however, may not affect the postprandial gastroduodenal motor activity or the rate of gastric emptying of solid nutrient meals.

Urinary adenosine excretion in patients receiving amphotericin B.

BACKGROUND: Intravenous amphotericin B (AMB) administration in animals causes renal vasoconstriction, ischemia, and oliguria that may result in irreversible renal injury; the mechanism of AMB nephrotoxicity may be similar in human beings. Adenosine is excreted in urine by the ischemic kidney. We hypothesized that adenosine excretion and oliguria would be a marker for patients who later would manifest AMB-associated renal insufficiency and that pre-AMB saline administration (which ameliorates AMB nephrotoxicity) would negate the change in adenosine excretion and urine output. METHODS: Twenty hospitalized patients being treated at the direction of their attending physician and who were receiving AMB (15 to 75 mg intravenously) had urine collected for 1 hour before and for 2 hours during AMB infusion. Eleven patients received normal saline solution (500 ml intravenously) before the AMB infusion; the other nine formed the comparator group. An aliquot of each urine collection was precipitated with perchloric acid to remove protein and cellular elements and centrifuged, and the supernatant was assayed for adenosine by using high-pressure liquid chromatography. RESULTS: Infusion of AMB was associated with a decrease in mean urine output both in patients who received saline solution (245 before versus 149 ml/hr during AMB infusion, p = 0.04) and in patients in comparator group (139 versus 89 ml/hr, p = 0.027). The mean urinary adenosine excretion was unchanged in the saline-loaded group (0.1354 before versus 0.1255 mmol/hr during drug infusion, p = 0.25) and was decreased in the comparator group (0.2276 versus 0.1127 mmol/hr, p = 0.01). Development of renal insufficiency did not correlate with the change in urine output or adenosine excretion. CONCLUSIONS: AMB infusion in human beings results in decreased urine output and decreased adenosine excretion. The latter effect is prevented by a pre-AMB saline load. The changes in urine output and adenosine excretion are not predictive of the development of renal insufficiency.

Penetration of meropenem in plasma and abdominal tissues from patients undergoing intraabdominal surgery.

We assessed the penetration of a new carbapenem antibiotic, meropenem, into abdominal tissues. A single 1,000-mg intravenous dose was administered to 66 patients undergoing elective intraabdominal surgery. Plasma, body fluid (peritoneal fluid and bile), and tissue samples (colon, gallbladder, omentum, stomach, fascia, muscle, and skin) were taken at various times up to 8 hours after administration of the dose. Meropenem concentrations were determined by means of validated bioassay techniques. Peak meropenem concentrations in most tissue specimens and one body fluid occurred within approximately 1 hour; the exceptions were bile and muscle specimens, in which peak concentrations were present in approximately 2 to approximately 4 hours. The bile concentration increased with time, thus indicating active excretion of drug into bile. Only one adverse event (mild nausea) was attributable to meropenem. Our results show that meropenem achieves adequate tissue concentrations for the treatment of intraabdominal infections due to susceptible bacteria.

Management of secondary peritonitis.

OBJECTIVE: The authors review current definition, classification, scoring, microbiology, inflammatory response, and goals of management of secondary peritonitis. SUMMARY BACKGROUND DATA: Despite improved diagnostic modalities, potent antibiotics, modern intensive care, and aggressive surgical treatment, up to one third of patients still die of severe secondary peritonitis. Against the background of current understanding of the local and systemic inflammatory response associated with peritonitis, there is growing controversy concerning the optimal antibiotic and operative therapy, intensified by lack of properly conducted randomized studies. In this overview the authors attempt to outline controversies, suggest a practical clinical approach, and highlight issues necessitating further research. METHODS: The authors review the literature and report their experience. RESULTS: The emerging concepts concerning antibiotic treatment suggest that less-in terms of the number of drugs and the duration of treatment-is better. The classical single operation for peritonitis, which obliterates the source of infection and purges the peritoneal cavity, may be inadequate for severe forms of peritonitis; for the latter, more aggressive surgical techniques are necessary to decompress increased intra-abdominal pressure and prevent or treat persistent and recurrent infection. The widespread acceptance of the more aggressive and demanding surgical methods has been hampered by the lack of randomized trials and reportedly high associated morbidity rates. CONCLUSIONS: Sepsis represents the host's systemic inflammatory response to bacterial peritonitis. To improve results, both the initiator and the biologic consequences of the peritoneal infective-inflammatory process should be addressed. The initiator may be better controlled in severe forms of peritonitis by aggressive surgical methods, whereas the search for methods to abort its systemic consequences is continuing.

Reassessment of groin anatomy during the evolution of preperitoneal hernia repair.

BACKGROUND: Need to define accurately groin anatomy as visualized by the preperitoneal approach. METHODS: Dissections of the right groin in 135 fresh male cadavers carried out during autopsy examination. Documentation by photographs and notes. RESULTS: Classic descriptions of groin anatomy confirmed for the most part. Errors concerning the lacunar ligament and conjoined tendon identified. Accurate descriptions, applicable to groin hernia repair, provided of the iliopubic tract, transversus abdominis arch and aponeurosis, femoral canal, and related structures. CONCLUSIONS: Improved communication and understanding by and among surgeons regarding groin anatomy is needed.

Hypothesis: compartmentalization of cytokines in intraabdominal infection.

BACKGROUND: Although the proximal role of systemic cytokines in the infectious-inflammatory cascades is well recognized, the magnitude and meaning of its intraperitoneal levels in peritonitis have received little attention. We hypothesized that in peritonitis a significant and clinically relevant cytokine-mediated inflammatory response is compartmentalized in the peritoneal cavity. METHODS: MEDLINE was used to search the literature for all articles dealing with experimental, primary, and secondary bacterial peritonitis and cytokines. RESULTS: Bacterial peritonitis is associated with an immense intraperitoneally compartmentalized cytokine response, with plasma levels of cytokines representing only the tip of the iceberg. Although certain amount of cytokines may be beneficial to the peritoneal defense mechanisms, higher levels correlate with adverse outcome. Thus it is plausible to look at acute peritonitis as initially a combined infective (microorganism) and inflammatory (cytokines) process. The clinical significance of the distinction between peritoneal inflammation and infection and the relevance of our findings to the stratification and treatment of peritonitis are discussed. CONCLUSIONS: Current surgical and antibiotic therapy for peritonitis is able to clear the peritoneal cavity of infective concentration of bacteria, but many patients continue to die of an uncontrolled activation of the inflammatory cascade. We suggest that one potential venue for therapeutic progress is the modulation of the compartmentalized peritoneal inflammatory response.

Inhibition of nitric oxide synthase in the brain suppresses colonic motor activity.

The effects of inhibition of nitric oxide (NO) synthase in the brain on colonic motor activity were investigated in conscious dogs. Intracerebroventricular (ICV) infusion of N omega-nitro-L-arginine methyl ester (L-NAME) and N omega-nitro-L-arginine (L-NNA) significantly suppressed colonic motor activity. The inhibitory effects occurred 1 h after the end of the infusion and lasted for at least 4 h. This suppression was blocked by a concurrent infusion of L-arginine but not D-arginine. The suppression of colonic motor activity was not blocked by bilateral truncal vagotomy or intravenous administration of phentolamine, an alpha-receptor antagonist, and propranolol, a beta-receptor antagonist. ICV infusion of L-NAME had no significant effect on the occurrence of giant migrating contractions in the colon. By contrast, intravenous administration of L-NAME at higher doses significantly enhanced colonic motor activity. We conclude that the inhibition of NO synthesis in the brain suppresses, whereas the inhibition of NO synthesis in peripheral neurons stimulates, colonic motor activity. The central effect may be mediated by a decrease in cerebral blood flow due to the inhibition of NO synthesis in cerebral arteries.

Prospective evaluation of abdominal sonography for the diagnosis of bowel obstruction.

OBJECTIVE: The authors determined the utility of sonography compared with plain x-rays in the diagnosis of bowel obstruction. In a contemporaneous group of patients, they compared the cost of operative versus nonoperative management of small bowel obstruction. SUMMARY BACKGROUND DATA: Nonoperative treatment of simple bowel obstruction usually succeeds. However, because of the difficulty in assured diagnosis and the possibility of strangulation or other complication, exploration of suspected bowel obstruction is recommended. Most of these explorations could be avoided if diagnostic accuracy were better, yielding a desirable decrease in the overall cost of managing bowel obstruction. METHODS: Fifty patients whose clinical or plain x-ray findings suggested bowel obstruction underwent prospective evaluation by abdominal sonography and by flat and upright abdominal x-rays. Presence or absence of bowel obstruction was determined at laparotomy and by clinical evolution of the abdominal episode. Direct costs of care were determined from the hospital and physician bills of 54 patients treated contemporaneously with the sonography study. RESULTS: Sonography demonstrated bowel obstruction by showing fluid-filled dilated bowel loops proximal to collapsed bowel in 22 patients with one false-positive and three false-negative examinations. X-rays demonstrated bowel obstruction in 32 patients with nine false-positive and one false-negative examination. Cost data showed that operative treatment of simple bowel obstruction increased costs nearly eightfold. CONCLUSIONS: Sonography is as sensitive but more specific than plain x-rays in the diagnosis of bowel obstruction. Management based on sonographic findings has the potential to reduce costs of surgical care.

Obturator hernia: current diagnosis and treatment.

BACKGROUND: Obturator hernia is a rare pelvic hernia for which both diagnosis and therapy are difficult. Because symptoms are nonspecific and specific physical findings are often obscure, diagnosis of obturator hernia is often delayed until laparotomy for bowel obstruction. Strangulation is frequent, and mortality remains high (25%). Primary closure of the hernia defect is difficult because adjacent tissues are not easily mobilized. Although a variety of techniques have been described, surgical repair has not been standardized. METHODS: We report a case of bilateral obturator hernia with incarceration in association with bilateral femoral hernia in which these problems were satisfactorily addressed. RESULTS: The hernias were diagnosed by computed tomography (CT) scan and repaired with synthetic mesh placed in the preperioneal space. This technique is well suited to unilateral and bilateral combinations of obturator, inguinal, and femoral hernias. CT scan in the work-up of severe gastrointestinal symptoms with weight loss may lead to a diagnosis of occult hernia, thereby allowing elective repair and, hopefully, a reduction in mortality risk. CONCLUSIONS: We recommend CT scan for suspected obturator hernia and preperitoneal mesh repair of noninfected cases.

Microbiology of intraabdominal infection and contamination.

The processes involved in the genesis of an intraabdominal infection include bacterial contamination, selection, growth, invasion, localisation, and cure or failure. The four flora of abdominal infection (exogenous, gastric, biliary and faecal) are detailed. The author's choice of antibiotic agents for prophylaxis and treatment, and recommendations concerning the duration of treatment are outlined.

Nonopioid analgesics shorten the duration of postoperative ileus.

Morphine inhibits propagating and stimulates nonpropagating colon contractions in monkeys and humans. The use of morphine or other opioids that inhibit propulsive contractions prolongs postoperative ileus. In contrast, ketorolac tromethamine, a nonsteroidal analgesic, has no effect on colon contractions in monkeys. In 14 patients having elective abdominal operations, bipolar electrodes were implanted on the right (n = 13) and left (n = 10) colon. Group A (n = 8) received ketorolac, 30 mg IM q6h, for pain relief. Group B (n = 6) needed supplemental morphine, 2-10 mg IV or IM, plus ketorolac to control their pain. Myoelectric activity was recorded from each subject on postop Days 1-5 and analyzed by computer for electrical control activity (ECA), short and long electrical response activity (ERA), and propagation of long ERA. There was a difference between the two groups in return of propagated long ERA bursts that correlated with clinical recovery from postoperative ileus. Postoperative analgesia with ketorolac resulted in faster resolution of ileus compared to morphine plus ketorolac because opioid-induced motor abnormalities in the colon were avoided.