Effect of transcutaneous vagus nerve stimulation on muscle activity in the gastrointestinal tract (transVaGa): a prospective clinical trial.

PURPOSE: Postoperative ileus (POI) is a common complication after abdominal surgery. Invasive stimulation of the cervical vagus nerve is known to reduce inflammatory response and ameliorated POI after surgery in a mouse model. However, the transcutaneous vagus nerve stimulation (tVNS) is a possible non-invasive approach. In this clinical study, we aimed to investigate the effect of tVNS on the activation of the stomach muscle in humans. METHODS: Patients requiring open laparotomy were screened for this prospective proof of concept clinical study. After open laparotomy, muscle activity of the stomach was measured by a free running electromyography (EMG) before and during tVNS on the ear. Frequency and amplitude of compound gastric action potentials were the electrophysiological parameters we assessed to reveal the changes in electro motor gastric activity. Gastrin levels as a surrogate marker for vagus nerve activation was analyzed before, 1 and 3 h after tVNS. RESULTS: Fourteen patients were included, no severe adverse events and no medical device related adverse events occurred. tVNS led to significant reduction of action potential frequency and significant elevation of action potential amplitude in the stomach compared to control. Gastrin levels were significantly elevated 3 h after tVNS compared to levels before tVNS. CONCLUSION: Application of tVNS is a safe and feasible procedure during surgical intervention. Our results provide evidence that tVNS activates efferent visceral vagal fibers. Therefore, this low risk and easy to perform method could be useful to prevent postoperative ileus. CLINICAL TRIAL REGISTER NUMBER: DRKS00013340.

Non-invasive transcutaneous auricular vagus nerve stimulation prevents postoperative ileus and endotoxemia in mice.

BACKGROUND: The cholinergic anti-inflammatory pathway comprises the perception of peripheral inflammation by afferent sensory neurons and reflex activation of efferent vagus nerve activity to regulate inflammation. Activation of this pathway was shown to reduce the inflammatory response and improve outcome of postoperative ileus (POI) and sepsis in rodents. Herein, we tested if a non-invasive auricular electrical transcutaneous vagus nerve stimulation (tVNS) affects inflammation in models of POI or endotoxemia. METHODS: Mice underwent tVNS or sham stimulation before and after induction of either POI by intestinal manipulation (IM) or endotoxemia by lipopolysaccharide administration. Some animals underwent a preoperative right cervical vagotomy. Neuronal activation of the solitary tract nucleus (NTS) and the dorsal motor nucleus of the vagus nerve (DMV) were analyzed by immunohistological detection of c-fos+ cells. Gene and protein expression of IL-6, MCP-1, IL-1ß as well as leukocyte infiltration and gastrointestinal transit were analyzed at different time points after IM. IL-6, TNFα, and IL-1ß serum levels were analyzed 3 hours after lipopolysaccharide administration. RESULTS: tVNS activated the NTS and DMV and reduced intestinal cytokine expression, reduced leukocyte recruitment to the manipulated intestine segment, and improved gastrointestinal transit after IM. Endotoxemia-induced IL-6 and TNF-α release was also reduced by tVNS. The protective effects of tVNS on POI and endotoxemia were abrogated by vagotomy. CONCLUSION: tVNS prevents intestinal and systemic inflammation. Activation of the DMV indicates an afferent to efferent central circuitry of the tVNS stimulation and the beneficial effects of tVNS depend on an intact vagus nerve. tVNS may become a non-invasive approach for treatment of POI.

HIPEC ROC I: a phase I study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum-based chemotherapy in patients with platinum-sensitive recurrent epithelial ovarian cancer.

This phase I study tested the safety, feasibility, pharmacokinetics and pharmacodynamics of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion (HIPEC) in patients with platinum-sensitive recurrent epithelial ovarian cancer (EOC) undergoing secondary cytoreductive surgery followed by postoperative platinum-based intravenous chemotherapy. Twelve patients with operable, recurrent platinum-sensitive EOC (recurrence ≥6 months after first-line therapy) were included according to the classical 3+3 dose-escalation design at three dose levels-60, 80 and 100 mg/m(2). After surgical cytoreduction, a single dose of cisplatin was administered via HIPEC for 90 min at 41-43°C. Postoperatively, all patients were treated with standard intravenous platinum-based combination chemotherapy. One of six patients experienced a dose-limiting toxicity (grade 3 renal toxicity) at a dose of 100 mg/m(2). The remaining five patients treated with 100 mg/m(2) tolerated their treatment well. The recommended phase II dose was established at 100 mg/m(2). The mean peritoneal-to-plasma AUC ratio was 19·5 at the highest dose level. Cisplatin-induced DNA adducts were confirmed in tumor samples. Common postoperative grade 1-3 toxicities included fatigue, postoperative pain, nausea, and surgical site infection. The ability to administer standard intravenous platinum-based chemotherapy after HIPEC was uncompromised. Cisplatin administered as HIPEC at a dose of 100 mg/m(2) has an acceptable safety profile in selected patients undergoing secondary cytoreductive surgery for platinum-sensitive recurrent EOC. Favorable pharmacokinetic and pharmacodynamic properties of HIPEC with cisplatin were confirmed at all dose levels, especially at 100 mg/m(2). The results are encouraging to determine the efficacy of HIPEC as a complementary treatment in patients with EOC.

Preoperative short-term parenteral administration of polyunsaturated fatty acids ameliorates intestinal inflammation and postoperative ileus in rodents.

PURPOSE: Abdominal surgery results in an inflammation of the intestinal muscularis externa (ME), subsequently leading to postoperative ileus (POI). Polyunsaturated fatty acids (PUFA) are known to modulate inflammation. The aim of this study was to analyze the effect of preoperative parenteral administration of marine (n-3) or soybean (n-6) PUFA lipid emulsions (PUFA-LE) on POI and tissue fatty acid profiles. METHODS: Rodents underwent intestinal manipulation (IM) after 5 days of parenteral administration of 10-mL/kg body weight saline, (n-3), or (n-6) PUFA-LE. Sham animals received saline treatment without IM. In rats, postoperative inflammation was quantified by ME neutrophil levels and NO production in organ culture, and ME function was determined by an in vitro contractility measurement. Additionally, in vivo gastrointestinal transit (GIT) was analyzed in mice. Lipopolysaccharide-induced IL-6 expression of rat bone marrow-derived mononuclear cells and ME was analyzed. Fatty acids were measured by gas chromatography in rat blood, bone marrow cells, and ME. RESULTS: The (n-3) PUFA-LE reduced neutrophil levels and NO production after IM and improved in vitro jejunal contractility and GIT time. The (n-6) PUFA-LE significantly reduced postoperative inflammation and tended to improve intestinal motility (P < 0.06). Interestingly, (n-6) PUFA-LE significantly reduced the levels of arachidonic acid in ME (-63%), while (n-3) PUFA-LE reduced arachidonic acid (-20%) and additionally raised EPA (+550%). CONCLUSION: Short-term preoperative parenteral administration of (n-3) or (n-6) PUFA-LE significantly alters tissue-specific fatty acid profiles. Preoperative parenteral PUFA-LE supplementation, preferably by marine (n-3) PUFA, ameliorates postoperative intestinal inflammation and dysmotility and could be a promising therapeutic option in POI prophylaxis.