title: Resuscitation with Na+/H+ exchanger inhibitor in traumatic haemorrhagic shock: cardiopulmonary performance, oxygen transport and tissue inflammation.
abstract: 1. The aim of the present study was to examine the effects of inhibition of the Na(+)/H(+) exchanger (NHE-1) on cardiopulmonary performance, oxygen carrying capacity and tissue inflammation in a pig model of traumatic haemorrhage-resuscitation. 2. In 12 instrumented anaesthetized pigs, traumatic haemorrhage was modelled by producing tibia fractures, followed by haemorrhage of 25 mL/kg for 20 min, and then a 4 mm hepatic arterial tear with surgical repair after 20 min. Animals then underwent low-volume fluid resuscitation with either Hextend (vehicle; n = 6; Hospira, Lake Forest, IL, USA) or 3 mg/kg BIIB513 (an NHE-1 inhibitor) + Hextend (n = 6). The experiment was terminated 6 h after the beginning of resuscitation. 3. Compared with vehicle-treated controls, the addition of NHE-1 inhibition with BIIB513 significantly improved the left ventricle stroke work index and attenuated increases in pulmonary arterial pressure and pulmonary vascular resistance. Furthermore, BIIB513 treatment significantly increased the oxygenated haemoglobin ratio, blood oxygen content and mixed venous blood oxygen saturation and improved blood oxygen delivery. In addition, BIIB513 treatment reduced lung tissue levels of interleukin-6 by 80%, tumour necrosis factor-alpha by 37% and myeloperoxidase activity by 38%. Nuclear factor-kappaB DNA binding activity in the lung was also slightly and significantly attenuated following BIIB513 treatment. 4. In conclusion, the present study shows that NHE-1 inhibition facilitates the response to fluid resuscitation after traumatic haemorrhage by improving cardiac function, pulmonary vascular function and oxygen carrying capacity, which results in reduced tissue inflammatory injury.
authors.affiliation: Department of Research, Division of Neonatology, Mount Sinai Medical Center, Miami Beach, FL, USA. dwu@msmc.com
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wu
authors.forename: Jiansong
authors.initials: J
authors.lastname: Qi
authors.forename: Hui
authors.initials: H
authors.lastname: Dai
authors.forename: Henri
authors.initials: H
authors.lastname: Doods
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
mesh_terms: D000818:Animals; D016887:Cardiopulmonary Resuscitation / Q000379:methods*; D018836:Inflammation Mediators / Q000494:pharmacology / Q000502:physiology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008698:Mesylates / Q000494:pharmacology / Q000627:therapeutic use; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D012151:Resuscitation / Q000379:methods; D012771:Shock, Hemorrhagic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013552:Swine
chemical_list: D018836:Inflammation Mediators; D008698:Mesylates; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; C402725:BIIB 513; D010100:Oxygen