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We sought in this prospective study to use a multimodal approach to reduce stress and improve recovery in patients undergoing major surgery. During an initial study period, 30 patients were randomly allocated to receive general anesthesia (GA; Group 1) or a combination of GA and intraoperative thoracic epidural analgesia (TEA; Group 2) when undergoing radical cystectomy. Parenteral nutrition was provided for 5 days after surgery. During the second period, 15 patients were treated with a multimodal approach (Group 3) consisting of intraoperative GA and TEA, postoperative patient-controlled TEA, early oral nutrition, and enforced mobilization. Data for plasma and urine catecholamines, plasma cortisol, the nitrogen balance, the postoperative inflammatory nutrition index, pain relief, fatigue, sleep, overnight recovery, recovery of bowel function, and mobilization were recorded up to the fifth postoperative day. Plasma concentrations of catecholamines and cortisol were comparable in all patients, but those in Group 3 had lower levels of urinary catecholamine excretion. Protein intake was more effective with parenteral nutrition. Nitrogen balances were less negative, and the postoperative inflammatory nutrition index score increased significantly in the traditional groups but not in Group 3. Multimodally treated patients reported less fatigue and better overnight recovery. Along with improved pain relief, recovery of bowel function, and ambulation, there were no differences in the postoperative complication rates among the three groups. The multimodal approach reduced stress and improved metabolism and recovery after radical cystectomy.