Combined administration of nitric oxide gas and iloprost during cardiopulmonary bypass reduces platelet dysfunction: a pilot clinical study.
BACKGROUND
Thrombocytopenia and platelet dysfunction are major mechanisms of cardiopulmonary bypass-induced postoperative hemorrhage. This study evaluated the effects of low amounts of nitric oxide, iloprost (prostacyclin analog), and their combination administered directly into the oxygenator on platelet function, platelet-leukocyte interactions, and postoperative blood loss in patients undergoing coronary artery bypass grafting.


METHODS
Blood samples from 41 patients randomized to the control, nitric oxide (20 ppm), iloprost (2 ng x kg -1 x min -1 ), or nitric oxide plus iloprost groups were collected during cardiopulmonary bypass. Platelets and leukocytes were enumerated. Platelet membrane glycoprotein Ib and glycoprotein IIb/IIIa, P-selectin, platelet-derived microparticles, leukocyte CD11b/CD18 (Mac-1), and platelet-leukocyte aggregate were quantified by means of flow cytometry. Collagen and thrombin receptor-activating peptide-induced platelet aggregation in whole blood was analyzed by means of aggregometry.


RESULTS
Both nitric oxide or iloprost attenuated cardiopulmonary bypass-induced thrombocytopenia, reduction of glycoprotein Ib and glycoprotein IIb levels, translocation of P-selectin, microparticle formation, Mac-1 upregulation, and suppression of collagen-induced aggregation. Nitric oxide plus iloprost was significantly more effective in preventing thrombocytopenia, microparticle formation, and P-selectin translocation. Moreover, this treatment preserved thrombin receptor-activating peptide-induced aggregation, which was not rescued by single treatments. Both nitric oxide and nitric oxide plus iloprost attenuated postoperative blood loss.


CONCLUSIONS
Nitric oxide plus iloprost reduced the deleterious effects of cardiopulmonary bypass, such as thrombocytopenia, platelet activation, platelet-leukocyte aggregate formation, and suppression of platelet aggregative responses. The reduced postoperative bleeding observed with this treatment suggests that this is a new and clinically feasible therapeutic option for patients subjected to cardiopulmonary bypass.
Chung
Ada
A
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
Wildhirt
Stephen M
SM
Wang
Shoa
S
Koshal
Arvind
A
Radomski
Marek W
MW
D000368:Aged; D001792:Blood Platelets / Q000187:drug effects*; D002315:Cardiopulmonary Bypass; D001026:Coronary Artery Bypass; D004338:Drug Combinations; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D016285:Iloprost / Q000008:administration & dosage / Q000627:therapeutic use*; D007962:Leukocytes / Q000187:drug effects; D016177:Macrophage-1 Antigen / Q000032:analysis; D008875:Middle Aged; D009569:Nitric Oxide / Q000008:administration & dosage / Q000627:therapeutic use*; D010106:Oxygenators; D019007:P-Selectin / Q000032:analysis; D010446:Peptide Fragments / Q000187:drug effects; D010865:Pilot Projects; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000032:analysis; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000032:analysis; D019106:Postoperative Hemorrhage / Q000517:prevention & control; D011956:Receptors, Cell Surface / Q000187:drug effects; D013921:Thrombocytopenia / Q000517:prevention & control
D004338:Drug Combinations; D016166:Free Radical Scavengers; D016177:Macrophage-1 Antigen; D019007:P-Selectin; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D011956:Receptors, Cell Surface; C086309:thrombin receptor peptide SFLLRNP; D009569:Nitric Oxide; D016285:Iloprost