Future Developments in Resuscitation

Because resuscitation from hemorrhagic shock begins with control of bleeding, improvements in the ability to diagnose and treat hemorrhage are likely to prove beneficial in improving patient outcomes after trauma. The past decade has seen the development and widespread use of focused assessment by sonography for trauma (FAST)^[104] and high-resolution CT to improve the diagnosis of hemorrhage and the use of damage control surgery and angiography to correct it. Modalities to promote hemostasis that will become prominent in the next decade include two different classes of pharmaceutical drugs. The first are for topical use during emergency surgery, whereas the latter are intended for systemic administration.

Topical preparations of thrombin and fibrinogen can be directly applied to open wound surfaces at the time of surgical exploration to facilitate immediate clot formation. This "fibrin glue" will not work in the presence of brisk hemorrhage because it is rapidly washed away, but it is advantageous in the management of oozing surfaces and organs that are difficult to suture or cauterize, such as the lung or liver.^[105] Fibrin glue is assembled from recombinant or highly purified thrombin and the patient's own plasma, which means that it carries no risk of viral disease transmission. Systemic uptake is also limited, so inappropriate coagulation remote from the site of application is unlikely. Future formulations of thrombin and fibrinogen will come layered on collagen-based dressings for rapid control of large injuries to solid visceral organs or the musculoskeletal system.^[106] Trials of these "hemostatic dressings" are under way at the present time.

Recombinant activated human coagulation factor VII (rFVIIa) is licensed for the treatment of hemophiliacs with active or anticipated hemorrhage and known antibodies to factor VIII. The observation of rapid hemostasis in this population led to the anecdotal use of rFVIIa in other congenital and acquired coagulopathies, including the dilutional coagulopathy of traumatic hemorrhage. Factor VIIa in supraphysiologic doses works by triggering a thrombin burst on the surface of platelets activated by exposed tissue factor; immediate clot formation is produced that is thought to depend on no other coagulation factors except factors II (thrombinogen) and I (fibrinogen). Because tissue factor is required, coagulation is limited to the site of vascular injury, and inappropriate clotting of uninjured organs or vessels has not been demonstrated. Prospective trials of rFVIIa have demonstrated decreased blood loss in patients undergoing elective open prostate surgery^[107] and rapid reversal of coagulopathy in patients taking warfarin (Coumadin).^[108] Retrospective reports have suggested a role for rFVIIa in the management of acute traumatic hemorrhage,^[109] gastrointestinal hemorrhage from cirrhosis,^[110] hemorrhage after cardiovascular surgery^[111] and liver transplantation,^[112] and intracranial hemorrhage in both neonates^[113] and the elderly.^[114] A controlled trial of rFVIIa in hemorrhaging trauma patients is under way now in Europe; an American trial is likely.

Other anticipated developments in the field of resuscitation include more specific management strategies for the consequences of shock and reperfusion. Hemorrhagic shock followed by resuscitation can be viewed as an ischemia-reperfusion injury involving the entire body. Prevention of organ ischemia or damage may be possible in the future through the administration of agents that regulate cellular function and humoral signaling. Possibilities include manipulation of shock-related pathophysiologic alterations such as complement and granulocyte activation, endothelial activation, leukostasis, and edema formation with resultant organ injury.^[115] Modification may be possible through the use of oxygen carriers (fluorocarbons and modified hemoglobins), antioxidants, nitric oxide scavengers, and antiendotoxin compounds. Inhibition of selectin receptors (selectins control the early steps in neutrophil activation) has resulted in decreased leukocyte migration and tissue damage in a laboratory model of hemorrhagic shock.^[116] Rats subjected to controlled and uncontrolled hemorrhagic shock and subsequent fluid resuscitation that received P-selectin monoclonal antibody had a 70% survival rate versus only 30% in the untreated group. Neutrophil infiltration and hepatocellular injury were also significantly decreased in the treated animals.