Postoperative nausea and vomiting (PONV) are major adverse consequences following laparoscopic cholecystectomy. Several drugs have been used to combat its occurrence. This study aimed to show the efficacy of the intraperitoneal route and compare different antiemetic effects of dexamethasone, dexmedetomidine, and their combination on PONV after laparoscopic cholecystectomy under general anesthesia in a tertiary care hospital. Prospective randomized triple-blind study. The trial was conducted at Benha University Hospitals. The trial was done from August 2023 to April 2024. Two hundred and forty patients aged 20-50 years, Apfel Score 1, the American Society of Anesthesiologists (ASA) physical status Classification I or II who underwent laparoscopic cholecystectomy. Exclusion criteria were a history of psychotic illnesses, Parkinson's disease, motion disorder, and a history of chemotherapy. Patients were randomized equally into four groups. Group I (control group) received 20 mL normal saline, Group II (dexamethasone group) received 8 mg dexamethasone, Group III (dexmedetomidine group) received dexmedetomidine 1mic/kg, and Group IV (combination group) received the combination of both dexamethasone (8 mg) + dexmedetomidine (1mic/kg). The medications were diluted in 20 mL normal saline. The incidence of PONV encountered by patients in the first 24 h following surgery was recorded. Nausea was reported in 26 (43.33%), 10 (16.67%), 11 (18.33%), and 6 (10%) in Groups I, II, III, and IV, respectively. Vomiting was observed in 25 (41.67%), 11 (18.33%), 10 (16.67%), and five (8.33%) in Groups I, II, III, and IV, respectively. Antiemetic medication was required for 24 (40%), 11 (18.33%), 12 (20%), and eight (13.33%) in Groups I, II, III, and IV, respectively. Nausea, vomiting, and antiemetics requirements differed significantly among the four groups ( value < 0.05). Intraperitoneal administration of dexamethasone and dexmedetomidine either alone or in combination decreased the incidence of PONV among patients scheduled for laparoscopic cholecystectomy. ClinicalTrials.gov identifier: NCT05988671.

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