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Total joint arthroplasty and deformity surgery of the spine can require complex reconstructive procedures accompanied by the potential for major blood loss. In an attempt to minimize the perioperative blood loss associated with these procedures, recent focus has concentrated on the efficacy of pharmacologic agents. Antifibrinolytics such as ε-aminocaproic acid, tranexamic acid, and aprotinin have been shown to reduce perioperative blood loss, autologous blood donation, transfusions, and associated costs in cardiac as well as major orthopaedic surgery. These agents reduce perioperative blood loss by inhibition of clot breakdown. Prospective, randomized studies have shown that the use of these agents can be effective in reducing the perioperative blood loss and transfusion requirements in total joint arthroplasty, pediatric scoliosis surgery, and adult reconstructive surgery of the spine. Aprotinin, however, is currently under suspension from use pending further evaluation of a trial. Although concerns exist about increased thrombotic events with the use of these agents, large meta-analyses suggest that antifibrinolytics can be safely and efficaciously employed to decrease perioperative blood loss and transfusion requirements.