RESUMO
BACKGROUND: Hypertonic saline (23.4%, HTS) bolus administration is common practice for refractory intracranial hypertension, but its effects on coagulation are unknown. We hypothesize that 23.4% HTS in whole blood results in progressive impairment of coagulation in vitro and in vivo in a murine model of traumatic brain injury (TBI). STUDY DESIGN: For the in vitro study, whole blood was collected from 10 healthy volunteers, and citrated native thrombelastography was performed with normal saline (0.9%, NS) and 23.4% HTS in serial dilutions (2.5%, 5%, and 10%). For the in vivo experiment, we assessed the effects of 23.4% HTS bolus vs NS on serial thrombelastography and tail-bleeding times in a TBI murine model (n = 10 rats with TBI and 10 controls). RESULTS: For the in vitro work, clinically relevant concentrations of HTS (2.5% dilution) shortened time to clot formation and increased clot strength (maximum amplitude) compared with control and NS. With higher HTS dosing (5% and 10% blood dilution), there was progressive prolongation of time to clot formation, decreased angle, and decreased maximum amplitude. In the in vivo study, there was no significant difference in thrombelastography measurements or tail-bleeding times after bolus administration of 23.4% HTS compared with NS at 2.5% blood volume. CONCLUSIONS: At clinically relevant dilutions of HTS, there is a paradoxical shortening of time to clot formation and increase in clot strength in vitro and no significant effects in a murine TBI model. However, with excess dilution, caution should be exercised when using serial HTS boluses in TBI patients at risk for trauma-induced coagulopathy.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Hipertensão Intracraniana/sangue , Hipertensão Intracraniana/tratamento farmacológico , Solução Salina Hipertônica/farmacologia , Solução Salina Hipertônica/uso terapêutico , Animais , Lesões Encefálicas Traumáticas/complicações , Modelos Animais de Doenças , Feminino , Humanos , Hipertensão Intracraniana/etiologia , Masculino , Ratos Sprague-Dawley , Autorrelato , Tromboelastografia , Fatores de TempoRESUMO
BACKGROUND: Understanding the molecular mechanisms in perturbation of the metabolome following ischaemia and reperfusion is critical in developing novel therapeutic strategies to prevent the sequelae of post-injury shock. While the metabolic substrates fueling these alterations have been defined, the relative contribution of specific organs to the systemic metabolic reprogramming secondary to ischaemic or haemorrhagic hypoxia remains unclear. MATERIALS AND METHODS: A porcine model of selected organ ischaemia was employed to investigate the relative contribution of liver, kidney, spleen and small bowel ischaemia/reperfusion to the plasma metabolic phenotype, as gleaned through ultra-high performance liquid chromatography-mass spectrometry-based metabolomics. RESULTS: Liver ischaemia/reperfusion promotes glycaemia, with increases in circulating carboxylic acid anions and purine oxidation metabolites, suggesting that this organ is the dominant contributor to the accumulation of these metabolites in response to ischaemic hypoxia. Succinate, in particular, accumulates selectively in response to the hepatic ischemia, with levels 6.5 times spleen, 8.2 times small bowel, and 6 times renal levels. Similar trends, but lower fold-change increase in comparison to baseline values, were observed upon ischaemia/reperfusion of kidney, spleen and small bowel. DISCUSSION: These observations suggest that the liver may play a critical role in mediating the accumulation of the same metabolites in response to haemorrhagic hypoxia, especially with respect to succinate, a metabolite that has been increasingly implicated in the coagulopathy and pro-inflammatory sequelae of ischaemic and haemorrhagic shock.