Small bowel obstruction and toxicity of a new model of adhesion prevention

University dissertation from Surgery (Lund)

Abstract: Abstract Background: Small bowel obstruction (SBO) is a common surgical diagnosis. If no signs of strangulation are evident, the majority of the patients can be conservatively managed. Approximately one third of the patients need surgical treatment and there is a need for early parameters that can predict operative intervention. The etiology of SBO in most cases is postoperative abdominal adhesions. Laparoscopic surgery generates less surgical trauma and thereby possibly less adhesion formation and subsequent decreased risk of SBO. The burden of postoperative adhesions is substantial and there is a need for an adhesion preventive agent that can be used in different clinical situations and reduce the clinical complications caused by adhesions, ie SBO, infertility and chronic abdominal pain. Previous experimental studies have reported promising anti adhesive effect of intraabdominally installed differently charged polypeptides in different clinical settings. However, there was observed toxicity of the cationic polypeptide when administered alone. Aims/methods: The aims of the retrospective clinical studies were to identify early parameters predicting surgical intervention in patients with SBO (I) and to determine whether there is a difference in the incidence of SBO after open versus laparoscopic surgery for suspected appendicitis (II). In the experimental studies the aims were to establish the lowest anti adhesive dose of α-polylysine (PL) in combination with polyglutamate (PG) and determine the toxic dose of α-PL (III), to investigate the possible anti adhesive effect of another four cationic polypeptides in combination with PG (IV). Furthermore, explore the mechanism of toxicity as well as the biodistribution of α-PL, alone or in combination with PG, after intravenous and intraperitoneal administration (V). Results/conclusions: 109 patients were included, 65 were conservatively managed and 44 were surgically treated. We identified five parameters, possible to retrieve within 4 hours from hospital admission, that were more frequent in the patients that were surgically treated for SBO. These parameters can possibly be used to advance the selection of patients for operation (I). The incidence of SBO after open and laparoscopic surgery for suspected appendicitis was low in both groups, 1% (24/2333) and 0,4% (10/2372) respectively. The difference was minor but significant, favoring the laparoscopic approach (II). We could show that the anti adhesive effect of α-PL/PG was dose dependent and the lowest effective dose for α-PL was established. The toxic dose of α-PL was determined and the gap between the lowest effective dose and the toxic dose is probably too narrow (III). All four alternative cationic polypeptides (polyarginine, lactoferrin, lysozyme,ε-PL) investigated in the fourth study showed anti adhesive effect. ε-PL, another isoform of PL, was superior to the other three and showed less toxicity than α-PL (IV). High doses of intravenous α-PL caused a damage to endothelial cells with subsequent edema and extravasation of blood in lung and liver. The biodistribution and accumulation of α-PL and α-PL/PG in blood and organs is lower and slower after intraperitoneal than intravenous administration (V).