Robert L. Goodale

Effect of decreasing afferent vagal activity with ondansetron on symptoms of bulimia nervosa: a randomised, double-blind trial

BACKGROUND Several lines of evidence have led us to postulate that afferent vagal hyperactivity could be an important factor in the pathophysiology of the eating disorder bulimia nervosa. Ondansetron is a peripherally active antagonist of the serotonin receptor 5-HT3, and is marketed for prevention of vagally-mediated emesis caused by cancer chemotherapeutic agents. We investigated the effects of ondansetron on bulimic behaviours in patients with severe and chronic bulimia nervosa in a randomised, double-blind, placebo-controlled study. METHODS We enrolled patients with severe bulimia nervosa (at least seven coupled binge/vomit episodes per week). The patients were otherwise healthy, their weight was normal, and they were not receiving medical or psychiatric treatment. During the first week of the study, patients recorded all eating-behaviour events to establish a baseline. In the second week, all patients received placebo, but were told that they were receiving either placebo or active drug. At the end of this single-blind phase, patients were randomly assigned placebo or ondansetron (24 mg daily) for a further 4 weeks. The primary outcome measure was the number of binge/vomit episodes per week. Data were analysed by intention to treat. FINDINGS 29 patients met the inclusion criteria, of whom 28 completed the baseline study, and 26 completed the single-blind placebo week. 12 patients were assigned placebo, and 14 ondansetron; one patient in the ondansetron group dropped out owing to accidental injury. During the 4th week of double-blind treatment, mean binge/vomit frequencies were 13.2 per week (SD 11.6) in the placebo group, versus 6.5 per week (3.9) in the ondansetron group (estimated difference 6.8 [95% CI 4.0-9.5]; p<0.0001). The ondansetron group also showed significant improvement, compared with the placebo group, in two secondary indicators of disease severity. The amount of time spent engaging in bulimic behaviours was decreased on average by 7.6 h per week in the ondansetron group, compared with 2.3 h in the placebo group (estimated difference 5.1 [0.6-9.7]). Similarly, the number of normal meals and snacks increased on average by 4.3 normal eating episodes without vomiting per week in the ondansetron group, compared with 0.2 in the placebo group (estimated difference 4.1 [1.0-7.2]). INTERPRETATION The decrease in binge-eating and vomiting under ondansetron treatment was not achieved by compensatory changes in eating behaviour such as by a smaller number of binges of longer duration, or by not eating, or by binge-eating without vomiting. Instead, our findings indicate a normalisation of the physiological mechanism(s) controlling meal termination and satiation. Since meal termination and satiety are mainly vagally mediated functions, since binge-eating and vomiting produce intense stimulation of vagal afferent fibres, and since ondansetron and other 5-HT3 antagonists decrease afferent vagal activity, the symptom improvement may result from a pharmacological correction of abnormal vagal neurotransmission.

Hemodynamic, respiratory, and metabolic effects of laparoscopic cholecystectomy

In 10 patients undergoing laparoscopic cholecystectomy, creation of pneumoperitoneum caused immediate venous hypertension and stasis in the lower extremities as measured by percutaneous catheter and duplex scanning. These changes disappeared after deflation. As measured by spirometry, significant reductions in forced vital capacity of 23% and forced expiratory volume in 1 second of 22% were present 24 hours after surgery, and plasma interleukin-6 levels rose to 18 pg/mL. The visual analogue scale of resting pain increased to a median value of 2.5 postoperatively. When compared with other studies of open cholecystectomy, our results showed fewer restrictions of ventilation, lower cytokine levels, and lower pain scores. The minimal soft tissue trauma and early ambulation after laparoscopic cholecystectomy may decrease the risk of thrombosis despite an acute episode of venous stasis.

Pancreatitis as a complication of anticholinesterase insecticide intoxication.

Severe pancreatitis and a pseudocyst occurred in a patient following accidental ingestion of an anticholinesterase insecticide, a substance not previously known to produce pancreatitis. Experiments were done to elucidate the mechanism. In one group of dogs the pancreatic duct was perfused and intraductal pressures were measured. The cholinesterase inhibitor 0,0-diethyl-0-(2-isopropyl-6-methyl-4-pyriinidinyl)phospborothioate (25 mg/kg) caused a significant increase in the mean intraductal pressure from 12 ± 2.4 to 27.8 ± 5.9 cm saline. In a second group of dogs pancreatic secretory rates were measured. Anticholinesterase (75 mg/kg) in combination with secretin infusion (1 U/kg/hr) caused a significant increase in the secretin stimulated flow rate from 0.13 to 0.56 cc/min. Atropine (75 μg/kg) abolished the anticholinesterase induced pressure and secretory rate increases. In a third group of dogs administration of cholinesterase inhibitor 75 mg/kg and secretin infusion 2 U/kg/hr resulted in acute pancreatic interstitial edema, acinar cell vacuolization, hyperamylasemia and hyperlipasemia. These results suggest that occurrence of pancreatitis as a complication of anticholinesterase insecticide intoxication is the result of hypersecretion and pharmacologie ductal obstruction.

Functional neuroimaging of gastric distention.

This study aimed to measure brain activation during gastric distention as a way to investigate short-term satiety. We estimated regional cerebral blood flow with positron emission tomography (15O-water) during gastric balloon inflation and deflation in 18 healthy young women. The contrast between inflated minus deflated conditions showed activation in the following four key regions that were identified a priori: dorsal brain stem; left inferior frontal gyrus; bilateral insula; and right subgenual, anterior cingulate cortex. Extant neuroimaging literature provides context for these areas as follows: the brain stem represents vagal projection zones for visceral afferent processing; the inferior frontal gyrus serves as a convergence zone for processing food-related stimuli; and both the insula and subgenual anterior cingulate cortex respond to emotional stimulation. The identification of neural correlates of gastric distention is a key step in the discovery of new treatments for obesity. New therapies could intervene by modifying the perception of gastric distention, an important contributor to meal termination and short-term satiety. This first study of brain activation during nonpainful, proximal gastric distention provides the groundwork for future research to discover novel treatments for obesity.

Laparoscopic drainage of lymphoceles after kidney transplantation: Indications and limitations

BACKGROUND Symptomatic lymphoceles are not uncommon after kidney transplantations. Surgical marsupialization with internal drainage is the treatment of choice. However, laparoscopic drainage is reportedly as effective, with only minimal trauma. METHODS We attempted 14 laparoscopic lymphocele drainages during a 3-year period and studied the indications and limitations, using intraoperative ultrasonography in all cases. RESULTS Laparoscopic drainage was successful in only 9 (64%) of 14 patients. A conversion to open laparotomy was necessary in five patients; their lymphoceles were lateral and either posterior or inferior to the kidney. Two patients with initially successful laparoscopic drainage required conversion to open laparotomy 21 and 83 days later; their lymphoceles were inferior to the kidney. Laparoscopic drainage shortened the median hospital stay by 4 days versus open surgical drainage and by 7 days versus conversion. Hospital costs for laparoscopic drainage averaged

High levels of carbon monoxide are produced by electro-cautery of tissue during laparoscopic cholecystectomy.

7400 less versus open drainage and

Hypercalcemia associated with pancreatitis and hyperamylasemia in renal transplant recipients: Data from the Minnesota randomized trial of cyclosporine versus antilymphoblast azathioprine

10,300 less versus conversion. CONCLUSIONS In patients with symptomatic lymphoceles medial and either superior or anterior to the kidney, laparoscopic drainage under intraoperative ultrasonographic guidance is easy, safe, and effective. It decreases hospitalization, convalescence, and costs. In patients with symptomatic lymphoceles lateral and either posterior or inferior to the kidney, laparoscopic drainage may fail because of anatomic inaccessibility and technical impracticability.

Effect of ondansetron, a 5-HT3 receptor antagonist, on the dynamic association between bulimic behaviors and pain thresholds.

&NA; Pyrolysis of tissue in a hypoxic environment can produce carbon monoxide. The atmosphere of the peritoneal cavity is rendered hypoxic during laparoscopic cholecystectomy by insufflation with 100% carbon dioxide. To determine whether carbon monoxide is produced by electrocautery of tissue during laparoscopic cholecystectomy, nine patients undergoing this procedure had the insufflation gas after use of electrocautery analyzed for carbon monoxide. Blood was analyzed for carboxyhemoglobin in these same patients to determine whether carbon monoxide was being absorbed in dangerous amounts. Carbon monoxide was present in the peritoneal cavity 5 min after use of electrocautery was initiated at a median concentration of 345 ppm (range 25‐1600 ppm), and at the end of surgery at a concentration of 475 ppm (range 100‐1900 ppm). This was well in excess of the 35 ppm upper limit for a 1‐h exposure set by the Environmental Protection Agency. The carboxyhemoglobin concentrations (mean ± SD) were the same at the beginning (1.3% ± 0.7%), end (1.2% ± 0.7%), and the day after surgery (1.1% ± 0.6%). Although there was no evidence of significant absorption of carbon monoxide in these patients, care should be taken to scavenge the gases produced by cautery of tissues to avoid operating room contamination during laparoscopic surgery. (Anesth Analg 1993;77:338‐41)

Acute hypercalcemia induces acinar cell necrosis and intraductal protein precipitates in the pancreas of cats and guinea pigs.

The incidence and possible etiologic factors of acute pancreatitis and hyperamylasemia were statistically evaluated in renal transplant recipients. Two hundred twenty-four patients were randomized in a prospective trial of cyclosporine and antilymphoblast azathioprine immunosuppressive regimens. They had a median follow-up of 20 months. Pancreatitis developed in 8 patients and hyperamyl asemia developed in 20 patients. There were no statistical relationships between the incidences of pancreatitis and hyperamylasemia and the immunosuppressive drugs or viral infections. However, pancreatitis developed in 11 percent of the transplant patients with repeatedly elevated serum calcium levels (37 patients, p less than 0.01) and hyperamylasemia developed in 19 percent (p less than 0.025). Other etiologic factors, such as gallstones, alcoholism, and corticosteroids, played a minor role in this patient population. These results suggest that hypercalcemia is a major etiologic factor for pancreatitis in renal transplant recipients.

The effect of atropine and duct decompression on the evolution of Diazinon-induced acute canine pancreatitis.

Abstract Thresholds for detection of both pressure and thermal pain are elevated in patients with bulimia nervosa. The present study was aimed at determining (1) if pressure pain detection thresholds (PDT) varied dynamically with the primary disease symptoms of binge eating and vomiting and (2) if the elevation in PDT was effected by treatment with ondansetron (ONDAN), a 5‐HT3 receptor antagonist. PDT was defined as the mean of the minimal amount of pressure (measured in g) perceived as painful when exerted by a 1 mm2 blunted point onto the center of the ventral surface of the ungual phalanx of digits 2‐5 of the non‐dominant hand. Fourteen female patients with severe bulimia nervosa (currently >seven binge/vomit episodes per week;>2 years illness duration) served as participants. PDT were evaluated at weekly intervals during the course of ongoing treatment studies (double‐blind and ‘open’ label) investigating the therapeutic effects of ONDAN. Data were analyzed by random regression analyses, allowing for the repeated‐measures and non‐orthogonal design. Data collected from 14 patients under the no‐drug condition indicated that PDT increased over the interval between binge/vomit episodes, with significant elevations occurring at times when patients had naturally exceeded their average inter‐binge interval. Eleven of these 14 patients underwent 4 weeks of ONDAN treatment. Under this drug condition, the time since the last binge/vomit episode was no longer a significant predictor of PDT. These patients also experienced a significant reduction in the frequency of bulimic behaviors, a finding reported in detail elsewhere. The above finding from untreated patients support the involvement of a common underlying mechanism driving both the increase in pain detection thresholds and the occurrence of the next bulimic episode. This possibility is further supported by the findings that ONDAN treatment is associated with a significant moderation of both variables. The effect of ONDAN may be mediated by blockade of afferent vagal neurotransmission, although other mechanisms must be considered.