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Resuscitation after hemorrhage using recombinant human hemoglobin (rHb1.1) in rats

Effects on nitric oxide and prostanoid systems

Loeb, Alex L. PhD; McIntosh, Laura J. BS; Raj, Nichelle R. BS; Longnecker, David E. MD

Laboratory Investigations

Objectives Hemoglobin-based oxygen carriers are designed to replace blood volume and to increase oxygen delivery to tissues after blood loss. The goals of the present study were two-fold: a) to determine the systemic and regional vascular effects of resuscitation with recombinant human hemoglobin (rHb1.1) in rats during controlled hemorrhage; and b) to determine whether nitric oxide (NO) or prostaglandins were involved in the observed responses.

Design Paralyzed, ventilated rats were hemorrhaged (18 mL blood/kg body weight) during halothane anesthesia and allowed to stabilize for 30 mins. Systemic and regional hemodynamics and oxygen delivery were monitored at three time points, using the radioactive microsphere method. Microspheres were first infused at the end of the hemorrhage stabilization period (t = 0 min). rHb1.1 (1 g/kg body weight) or rHb1.1 diluent (phosphate buffered saline, 36 mL/kg body weight) were infused over 20 mins and microspheres were administered again, 30 mins later (t = 50 mins). Saline (0.5 mL), indomethacin (5 mg/kg to inhibit cyclooxygenase), or NG-monomethyl-L-arginine (L-NMMA, 100 mg/kg, to inhibit NO synthase) were then infused in rHb1.1-treated rats and microspheres injected once more (t = 80 mins).

Setting Research laboratory.

Subjects Male Wistar rats (n = 37).

Interventions Recombinant human hemoglobin (rHb1.1), rHb1.1 diluent (phosphate buffered saline) resuscitation of hemorrhaged rats. Saline, L-NMMA, or indomethacin treatment after resuscitation.

Measurements and Main Results Resuscitation with rHb1.1 increased mean arterial pressure (MAP), cardiac output, and systemic oxygen delivery significantly when compared with diluent. After rHb1.1 resuscitation, regional blood flows were significantly increased in skin, kidney, spleen, and heart compared with diluent resuscitation. Compared with saline treatment after rHb1.1 resuscitation, L-NMMA increased MAP and regional resistances in virtually all tissues; indomethacin did not alter MAP, but increased resistance in the brain.

Conclusions These data indicate that rHb1.1 resuscitation was more effective than diluent in improving systemic and regional hemodynamics and oxygen delivery, suggesting that rHb1.1 may be of benefit in the treatment of acute blood loss. Increased resistance after L-NMMA in the presence of rHb1.1 indicated that rHb1.1 resuscitation did not eliminate NO dependent circulatory control. Increased resistance after indomethacin in brain indicated that vasodilator prostanoids were important in regulating vascular resistance in these tissues after rHb1.1 resuscitation. (Crit Care Med 1998; 26:1071-1080)

From the Departments of Anesthesia (Drs. Loeb and Longnecker, Ms. Mclntosh, and Ms. Raj) and Pharmacology (Dr. Loeb), University of Pennsylvania, Philadelphia, PA.

Supported, in part, by Somatogen. A grant from Somatogen was awarded to Dr. Loeb. Dr. Longnecker serves on the Clinical Advisory Board of Somatogen, for which he receives compensation.

Address requests for reprints to: Dr. Alex L. Loeb, Department of Anesthesia, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104-4283.

© Williams & Wilkins 1998. All Rights Reserved.