Dexamethasone for the Treatment of Established Postoperative Nausea and Vomiting - a Randomised, Placebo-controlled, Dose-finding Study

This study is divided into a main study and three adjunct protocols:

Main study:

Postoperative nausea and vomiting (PONV) are frequent adverse effects of surgery and anesthesia. Dexamethasone is well established for the prophylaxis of PONV, but the efficacy of dexamethasone for the treatment of established PONV symptoms remains unknown. The primary objective of the main study is to test the antiemetic efficacy of dexamethasone for the treatment of established PONV in adults undergoing surgery under general anaesthesia, and to test for dose-responsiveness. The secondary objective is the evaluation of the potential adverse effect profile of dexamethasone, No prophylactic antiemetics are allowed. Premedication, conduct of anesthesia and postoperative analgesia will be at the discretion of the responsible anesthesiologist. Patients who have received their assigned study drug and who continue to experience PONV will receive antiemetic rescue treatment (ondansetron, droperidol). The minimum delay between administration of the study drug and rescue is 60 min (to ensure that dexamethasone has the scope to show antiemetic efficacy). Primary efficacy endpoint: Complete absence of any nausea and/or vomiting (including retching) in a previously nauseated or vomiting patient within 24 hours after administration of the study treatment. Secondary endpoints: Time to treatment failure; quality of sleep during the first postoperative night (numerical rating scale ranging from 0 = no sleep at all to 10 = excellent sleep); blood glucose (in the morning after administration of study drug); any minor or major adverse effects during 24h.

Adjunct protocol 1:

In therapeutic PONV trials, efficacy is usually quantified using a dichotomous outcome, i.e. a previously nauseous or vomiting patient stays totally PONV-free over a given period of time (for instance, 24 hours). This outcome is valid for the endpoint vomiting (including retching): a previously vomiting patient stays completely vomiting-free after treatment. For nausea, the situation is different. A patient may suffer from severe nausea, and, after treatment, the degree of nausea may significantly decrease although nausea may not disappear completely. Nevertheless, such a treatment may be regarded as efficacious. A very similar context can be found in the postoperative pain setting where an efficacious analgesic may decrease the degree of pain to a significant extent although the pain does not disappear completely. In analgesic trials, efficacy is therefore not expressed as a dichotomous outcome (pain - no pain) but as a continuum on a 0 to 100 mm visual analogue scale. Patients with moderate to severe postoperative pain (VAS ≥3/10) would be randomised to receive an experimental or a control (placebo) intervention and relief would be then recorded over time. Outcomes are expressed as maximum pain relief, area under the time-analgesic effect curve for pain intensity (i.e. summed pain intensity difference, or SPID), or summed pain relief (TOTPAR). AIM: To apply the methodology acute pain trials to the measurement of the anti-nausea efficacy of antiemetic drugs. To investigate the variability of responses based on measurement of nausea intensity using a visual analogue scale compared with a 4-point categorical scale. METHODS: Patients of the main study protocol will be asked to rate their degree of "baseline" nausea on a 100 mm visually analogue scale ranging from 0 mm = no nausea at all to 100 mm = worst possible nausea, and on a 4-point categorical scale (none, moderate, severe, intolerable). Subsequently, after having received the assigned study drug, patients will be asked to score their degree of nausea on VAS every 15 minutes until 60 minutes after administration of the study drug (i.e. until they would receive the rescue medication).