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The brain metabolic activity after resuscitation with liposome-encapsulated hemoglobin in a rat model of hypovolemic shock.

ABSTRACT: We examined the effect of resuscitation with liposome-encapsulated hemoglobin (LEH) on cerebral bioenergetics in a rat model of 45% hypovolemia. The rats were resuscitated with isovolemic LEH or saline after 15?minutes of shock and followed up to 6?hours. Untreated hypovolemic rats received no fluid. The cerebral uptake of F-18-fluorodeoxyglucose (FDG) was measured by PET, and at 6?hours, the brain was collected for various assays. Hypovolemia decreased cellular adenosine triphosphate (ATP), phosphocreatine, nicotinamide adenine dinucleotide (NAD)/NADH ratio, citrate synthase activity, glucose-6-phosphate, and nerve growth factor (NGF), even when FDG uptake remained unchanged. The FDG uptake was reduced by saline, but not by LEH infusion. The reduced FDG uptake in saline group was associated with a decrease in hexokinase I expression. The LEH infusion effectively restored ATP content, NAD/NADH ratio, and NGF expression, and reduced the hypovolemia-induced accumulation of pyruvate and ubiquitinated proteins; in comparison, saline was significantly less effective. The LEH infusion was associated with low pH and high anion gap, indicating anionic gap acidosis. The results suggest that hypovolemic shock perturbs glucose metabolism at the level of pyruvate utilization, resulting in deranged cerebral energy stores. The correction of volume and oxygen deficits by LEH recovers the cerebral metabolism and creates a prosurvival phenotype.

SUBMITTER: Rao G

PROVIDER: S-EPMC4640343 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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The brain metabolic activity after resuscitation with liposome-encapsulated hemoglobin in a rat model of hypovolemic shock.

Rao Geeta G Hedrick Andria F AF Yadav Vivek R VR Xie Jun J Hussain Alamdar A Awasthi Vibhudutta V

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20150506 9

We examined the effect of resuscitation with liposome-encapsulated hemoglobin (LEH) on cerebral bioenergetics in a rat model of 45% hypovolemia. The rats were resuscitated with isovolemic LEH or saline after 15 minutes of shock and followed up to 6 hours. Untreated hypovolemic rats received no fluid. The cerebral uptake of F-18-fluorodeoxyglucose (FDG) was measured by PET, and at 6 hours, the brain was collected for various assays. Hypovolemia decreased cellular adenosine triphosphate (ATP), pho ...[more]

PMID: 25944591

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Project description:Traumatic brain injury (TBI) is often accompanied by hemorrhage, and treatment of hemorrhagic shock (HS) after TBI is particularly challenging because the two therapeutic treatment strategies for TBI and HS often conflict. Ischemia/reperfusion injury from HS resuscitation can be exaggerated by TBI-induced loss of autoregulation. In HS resuscitation, the goal is to restore lost blood volume, while in the treatment of TBI the priority is focused on maintenance of adequate cerebral perfusion pressure and avoidance of secondary bleeding. In this study, we investigate the responses to resuscitation from severe HS after TBI in rats, using fresh blood, polymerized human hemoglobin (PolyhHb), and lactated Ringer's (LR). Rats were subjected to TBI by pneumatic controlled cortical impact. Shortly after TBI, HS was induced by blood withdrawal to reduce mean arterial pressure (MAP) to 35-40 mmHg for 90 min before resuscitation. Resuscitation fluids were delivered to restore MAP to ~ 65 mmHg and animals were monitored for 120 min. Increased systolic blood pressure variability (SBPV) confirmed TBI-induced loss of autoregulation. MAP after resuscitation was significantly higher in the blood and PolyhHb groups compared to the LR group. Furthermore, blood and PolyhHb restored diastolic pressure, while this remained depressed for the LR group, indicating a loss of vascular tone. Lactate increased in all groups during HS, and only returned to baseline level in the blood reperfused group. The PolyhHb group possessed lower SBPV compared to LR and blood groups. Finally, sympathetic nervous system (SNS) modulation was higher for the LR group and lower for the PolyhHb group compared to the blood group after reperfusion. In conclusion, our results suggest that PolyhHb could be an alternative to blood for resuscitation from HS after TBI when blood is not available, assuming additional testing demonstrate similar favorable results. PolyhHb restored hemodynamics and oxygen delivery, without the logistical constraints of refrigerated blood.

Project description:Background and purposeSystemic glucocorticoid therapy may effectively attenuate lung inflammation but also induce severe side-effects. Delivery of glucocorticoids by liposomes could therefore be beneficial. We investigated if liposome-encapsulated dexamethasone inhibited ventilator-induced lung inflammation. Furthermore, we evaluated whether targeting of cellular Fcγ-receptors (FcγRs) by conjugating immunoglobulin G (IgG) to liposomes, would improve the efficacy of dexamethasone-liposomes in attenuating granulocyte infiltration, one of the hallmarks of lung inflammation.Experimental approachMice were anaesthetized, tracheotomized and mechanically ventilated for 5 h with either 'low' tidal volumes ∼7.5 mL·kg(-1) (LV(T) ) or 'high' tidal volumes ∼15 mL·kg(-1) (HV(T) ). At initiation of ventilation, we intravenously administered dexamethasone encapsulated in liposomes (Dex-liposomes), dexamethasone encapsulated in IgG-modified liposomes (IgG-Dex-liposomes) or free dexamethasone. Non-ventilated mice served as controls.Key resultsDex-liposomes attenuated granulocyte infiltration and IL-6 mRNA expression after LV(T) -ventilation, but not after HV(T) -ventilation. Dex-liposomes also down-regulated mRNA expression of IL-1β and KC, but not of CCL2 (MCP-1) in lungs of LV(T) and HV(T) -ventilated mice. Importantly, IgG-Dex-liposomes inhibited granulocyte influx caused by either LV(T) or HV(T) -ventilation. IgG-Dex-liposomes diminished IL-1β and KC mRNA expression in both ventilation groups, and IL-6 and CCL2 mRNA expression in the LV(T) -ventilated group. Free dexamethasone prevented granulocyte influx and inflammatory mediator expression induced by LV(T) or HV(T) -ventilation.Conclusions and implicationsFcγR-targeted IgG-Dex-liposomes are pharmacologically more effective than Dex-liposomes particularly in inhibiting pulmonary granulocyte infiltration. IgG-Dex-liposomes inhibited most parameters of ventilator-induced lung inflammation as effectively as free dexamethasone, with the advantage that liposome-encapsulated dexamethasone will be released locally in the lung thereby preventing systemic side-effects.

Project description:BackgroundFast and effective treatment of hemorrhagic shock is one of the most important preclinical trauma care tasks e.g., in combat casualties in avoiding severe end-organ damage or death. In scenarios without immediate availability of blood products, alternate regimens of fluid resuscitation represent the only possibility of maintaining sufficient circulation and regaining adequate end-organ oxygen supply. However, the fluid choice alone may affect the extent of the bleeding by interfering with coagulation pathways. This study investigates the impact of hydroxyethyl starch (HES), gelatine-polysuccinate (GP) and balanced electrolyte solution (BES) as commonly used agents for fluid resuscitation on coagulation using a porcine hemorrhagic shock model.MethodsFollowing approval by the State and Institutional Animal Care Committee, life-threatening hemorrhagic shock was induced via arterial blood withdrawal in 24 anesthetized pigs. Isovolumetric fluid resuscitation with either HES, GP or BES (n = 3 × 8) was performed to compensate for the blood loss. Over four hours, hemodynamics, laboratory parameters and rotational thromboelastometry-derived coagulation were analyzed. As secondary endpoint the porcine values were compared to human blood.ResultsAll the agents used for fluid resuscitation significantly affected coagulation. We measured a restriction of laboratory parameters, clot development and clot firmness, particularly in HES- and GP-treated animals. Hemoglobin content dropped in all groups but showed a more pronounced decline in colloid-treated pigs. This effect was not maintained over the four-hour monitoring period.ConclusionHES, GP, and BEL sufficiently stabilized the macrocirculation, but significantly affected coagulation. These effects were most pronounced after colloid and particularly HES administration. Despite suitability for rapid hemodynamic stabilization, colloids have to be chosen with caution, because their molecular properties may affect coagulation directly and as a consequence of pronounced hemodilution. Our comparison of porcine and human coagulation showed increased coagulation activity in pig blood.

Dataset Information

The brain metabolic activity after resuscitation with liposome-encapsulated hemoglobin in a rat model of hypovolemic shock.

Publications

The brain metabolic activity after resuscitation with liposome-encapsulated hemoglobin in a rat model of hypovolemic shock.

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