Effects of inhalation of low dose nitrite or carbon monoxide on post reperfusion mitochondrial function and tissue injury in hemorrhagic shock swine (original) (raw)
Related papers
Nitric Oxide, 2015
Objective: The cellular injury that occurs in the setting of hemorrhagic shock and resuscitation (HS/R) affects all tissue types and can drive altered inflammatory responses. Resuscitative adjuncts hold the promise of decreasing such injury. Here we test the hypothesis that sodium nitrite (NaNO 2), delivered as a nebulized solution via an inhalational route, protects against injury and inflammation from HS/R. Methods: Mice underwent HS/R to a mean arterial pressure (MAP) of 20 or 25 mmHg. Mice were resuscitated with Lactated Ringers after 90-120 minutes of hypotension. Mice were randomized to receive nebulized NaNO 2 via a flow through chamber (30mg in 5mL PBS). Pigs (30-35 kg) were anesthetized and bled to a MAP of 30-40 mmHg for 90 minutes, randomized to receive NaNO 2 (11 mg in 2.5 mL PBS) nebulized into the ventilator circuit starting 60 minutes into the hypotensive period, followed by initial resuscitation with Hextend. Pigs had ongoing resuscitation and support for up to four hours. Hemodynamic data were collected continuously. Results: NaNO 2 limited organ injury and inflammation in murine hemorrhagic shock. A nitrate/nitrite depleted diet exacerbated organ injury, as well as mortality, and inhaled NaNO 2 significantly reversed this effect. Furthermore, NaNO 2 limited mitochondrial oxidant injury. In porcine HS/R, NaNO 2 had no significant influence on shock induced hemodynamics. NaNO 2 limited hypoxia/reoxia or HS/R-induced mitochondrial injury and promoted mitochondrial fusion. Conclusion: NaNO 2 may be a useful adjunct to shock resuscitation based on its limitation of mitochondrial injury.
Asian Journal of Transfusion Science, 2015
Background: Transfusion of blood remains the gold standard for fluid resuscitation from hemorrhagic shock. Hemoglobin (Hb) within the red blood cell transports oxygen and modulates nitric oxide (NO) through NO scavenging and nitrite reductase. Aims: This study was designed to examine the effects of incorporating a novel NO modulator, RRx-001, on systemic and microvascular hemodynamic response after blood transfusion for resuscitation from hemorrhagic shock in a hamster window chamber model. In addition, to RRx-001 the role of low dose of nitrite (1 × 10 −9 moles per animal) supplementation after resuscitation was studied. Materials and Methods: Severe hemorrhage was induced by arterial controlled bleeding of 50% of the blood volume (BV) and the hypovolemic state was maintained for 1 h. The animals received volume resuscitation by an infusion of 25% of BV using fresh blood alone or with added nitrite, or fresh blood treated with RRx-001 (140 mg/kg) or RRx-001 (140 mg/kg) with added nitrite. Systemic and microvascular hemodynamics were followed at baseline and at different time points during the entire study. Tissue apoptosis and necrosis were measured 8 h after resuscitation to correlate hemodynamic changes with tissue viability. Results: Compared to resuscitation with blood alone, blood treated with RRx-001 decreased vascular resistance, increased blood flow and functional capillary density immediately after resuscitation and preserved tissue viability. Furthermore, in RRx-001 treated animals, both mean arterial pressure (MAP) and met Hb were maintained within normal levels after resuscitation (MAP >90 mmHg and metHb <2%). The addition of nitrite to RRx-001 did not significantly improve the effects of RRx-001, as it increased methemoglobinemia and lower MAP. Conclusion: RRx-001 alone enhanced perfusion and reduced tissue damage as compared to blood; it may serve as an adjunct therapy to the current gold standard treatment for resuscitation from hemorrhagic shock.
Circulation, 2009
gladwinmt@upmc.edu. Clinical Summary Cardiac arrest results in significant morbidity and mortality driven mainly by the cardiac and neurological injury resulting from global ischemia and reperfusion injury. Although resuscitation rates can exceed 65% for some rhythms, between 50-75% of these patients will die before hospital discharge and up to a third of survivors will suffer significant brain injury. Only hypothermia has shown clinical benefit as a post-resuscitation therapy in a subset of patients. Clearly additional therapies are needed. The recent finding that nitrite acts as an ischemic reservoir for enzyme independent nitric oxide generation has resulted in numerous animal studies where it has proven beneficial in reducing focal ischemic organ injury. Based on promising results in focal heart and brain ischemia, Dezfulian et al. have adapted a mouse model of cardiac arrest to model the high clinical mortality and myocardial and neurological dysfunction associated with cardiac arrest. Within this model, nitrite therapy given at the start of resuscitation resulted in significant improvements in survival and myocardial and neurological function in survivors. The authors further investigate the potential mechanism for cardioprotection which involves nitrite's role as a mitochondrial antioxidant early in resuscitation. The significant benefits attributed to nitrite, along with its ease of delivery and known primate and human safety data make this a promising therapy for a condition with few current therapeutic options.
PLOS ONE, 2015
Aims Currently, there is no effective resuscitative adjunct to fluid and blood products to limit tissue injury for traumatic hemorrhagic shock. The objective of this study was to investigate the role of inhaled carbon monoxide (CO) to limit inflammation and tissue injury, and specifically mitochondrial damage, in experimental models of hemorrhage and resuscitation. Results Inhaled CO (250 ppm for 30 minutes) protected against mortality in severe murine hemorrhagic shock and resuscitation (HS/R) (20% vs. 80%; P<0.01). Additionally, CO limited the development of shock as determined by arterial blood pH (7.25±0.06 vs. 7.05±0.05; P<0.05), lactate levels (7.2±5.1 vs 13.3±6.0; P<0.05), and base deficit (13±3.0 vs 24±3.1; P<0.05). A dose response of CO (25-500 ppm) demonstrated protection against HS/R lung and liver injury as determined by MPO activity and serum ALT, respectively. CO limited HS/ R-induced increases in serum tumor necrosis factor-α and interleukin-6 levels as determined by ELISA (P<0.05 for doses of 100-500ppm). Furthermore, inhaled CO limited HS/R induced oxidative stress as determined by hepatic oxidized glutathione:reduced glutathione levels and lipid peroxidation. In porcine HS/R, CO did not influence hemodynamics. However, CO limited HS/R-induced skeletal muscle and platelet mitochondrial injury as determined by respiratory control ratio (muscle) and ATP-linked respiration and mitochondrial reserve capacity (platelets).
PLoS ONE, 2012
Purpose: Hemorrhagic shock and resuscitation is frequently associated with liver ischemia-reperfusion injury. The aim of the study was to investigate whether hypoxemic resuscitation attenuates liver injury. Methods: Anesthetized, mechanically ventilated New Zealand white rabbits were exsanguinated to a mean arterial pressure of 30 mmHg for 60 minutes. Resuscitation under normoxemia (Normox-Res group, n = 16, PaO 2 = 95-105 mmHg) or hypoxemia (Hypox-Res group, n = 15, PaO 2 = 35-40 mmHg) followed, modifying the FiO 2. Animals not subjected to shock constituted the sham group (n = 11, PaO 2 = 95-105 mmHg). Indices of the inflammatory, oxidative and nitrosative response were measured and histopathological and immunohistochemical studies of the liver were performed. Results: Normox-Res group animals exhibited increased serum alanine aminotransferase, tumor necrosis factor-alpha, interleukin (IL)-1b and IL-6 levels compared with Hypox-Res and sham groups. Reactive oxygen species generation, malondialdehyde formation and myeloperoxidase activity were all elevated in Normox-Res rabbits compared with Hypox-Res and sham groups. Similarly, endothelial NO synthase and inducible NO synthase mRNA expression was up-regulated and nitrotyrosine immunostaining increased in animals resuscitated normoxemically, indicating a more intense nitrosative stress. Hypox-Res animals demonstrated a less prominent histopathologic injury which was similar to sham animals. Conclusions: Hypoxemic resuscitation prevents liver reperfusion injury through attenuation of the inflammatory response and oxidative and nitrosative stresses.
Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences, 2011
Hypertensive patients have higher morbidity and mortality from hemorrhage. In this study, we investigated hemodynamic responses and serum nitrite concentrations during graded hemorrhagic shock and resuscitation in hypertensive (HT) and normotensive (NT) rats. Thirteen male rats were divided into two groups, namely HT (n = 6) and NT (n = 7). Hypertension was induced by deoxycorticosterone acetate (DOCA)-salt method in uninephrectomized rats. After 8 weeks, graded hemorrhagic shock was induced during 34 minutes in four steps separated by 8-minute intervals (totally 16 ml/kg). The animals were kept in this condition for 120 minutes (shock period). Then, they were resuscitated with blood withdrawal. Mean arterial pressure (MAP) and heart rate (HR) were measured throughout the experiment. Blood samples were taken before and after shock induction and at the end of the shock period. HT rats experienced more MAP and HR reduction during the shock period and less improvement of hemodynamic re...
Biomedical Papers, 2012
Background. We evaluated the effect of hypertension on hemodynamic responses and serum nitrite concentrations in normotensive (NT) and deoxycorticosteron acetate (DOCA)-Salt hypertensive (HT) rats. Methods. Uncontrolled hemorrhagic shock was induced in NT and HT rats (n=7 each) by preliminary bleed of 25 ml/ kg followed by a 75% tail amputation. The mean arterial pressure (MAP), heart rate and serum nitrite were measured pre-hemorrhage and during hemorrhage. Results. Changes in time-averaged MAP after hemorrhage were significantly greater in HT group than NT. After resuscitation, the HT rats failed to restore MAP to baseline level. Serum nitrite level in both groups was significantly increased during shock period. Survival rate of HT animals was lower than NT group, although it was not statistically significant. Conclusions. Marked reduction of MAP and less improvement after resuscitation suggested the less adaptation of cardiovascular system in HT animals which may interfere with management of these subjects during uncontrolled hemorrhagic shock.
Cardiovascular Research, 2011
Severe sepsis and septic shock, which are among the most common causes of death in intensive care units worldwide, cause high morbidity, mortality, and social and economic costs. Therefore, developing successful therapies against sepsis is one of the most important challenges in critical care medicine. Death from septic shock is caused by refractory hypotension and multiple organ failure (MOF). Although excessive systemic vasodilation triggered by nitric oxide (NO) is believed to mediate the hypotension, several endogenous factors and phenomena are responsible for MOF, including tissue hypoperfusion and ischaemia, mitochondrial dysfunction, and other cytotoxic effects, all of which might be directly or indirectly antagonized by local NO. Hence, selective inhibition of the production of hypotension-causing NO in the macrocirculation and/or selective treatment with microvasculature-specific NO donors could theoretically constitute a successful therapy. Recently, the NO metabolite nitrite was recognized as an NO donor specifically in hypoxic/acidic conditions, which can be expected in the septic microvasculature. We recently showed that treatment with nitrite can protect mice against progressive hypothermia, mitochondrial dysfunction, organ damage, and even death induced by tumour necrosis factor or lipopolysaccharide. In this review, we discuss the rationale for using nitrite for the treatment of shock, the possible mechanisms of nitrite-mediated protection, and the lessons that can be drawn for possible future translation of the results from mouse models to the clinic.
Acta Anaesthesiologica Scandinavica, 1999
Background: Inhibition of nitric oxide synthase (NOS) has been claimed to be beneficial in septic shock. We investigated the overall and regional effects of a NOS-inhibitor on perfusion and metabolism during severe endotoxic shock. Methods: Nineteen anaesthetised pigs were catheterised and ultrasonic flow-probes were placed around the portal vein, the hepatic artery, and the superior mesenteric artery. Thirteen animals were given a 3-h infusion of endotoxin; in 6 of these an infusion of N G -nitro-L-arginine-methyl-ester (L-NAME) was started an hour after the start of endotoxin while 7 animals served as controls and received endotoxin only. Six animals were sham operated with no further intervention. Results: Endotoxin produced a hypodynamic shock with pulmonary hypertension. L-NAME did not increase arterial blood pressure, but deepened the fall in cardiac output and enhanced the increase in systemic and pulmonary vascular resistance. The infusion of endotoxin caused a decrease in flows in all regions. The addition of L-NAME induced a further decrease in the mesenteric artery flow only. L-NAME had no additional effect on hepatic artery flow ratio, while a transient decrease was seen in
Nitrite therapy is neuroprotective and safe in cardiac arrest survivors
Nitric Oxide, 2012
Cardiac arrest results in significant mortality after initial resuscitation due in most cases to ischemiareperfusion induced brain injury and to a lesser degree myocardial dysfunction. Nitrite has previously been shown to protect against reperfusion injury in animal models of focal cerebral and heart ischemia. Nitrite therapy after murine cardiac arrest improved 22 h survival through improvements in myocardial contractility. These improvements accompanied transient mitochondrial inhibition which reduced oxidative injury to the heart. Based on preliminary evidence that nitrite may also protect against ischemic brain injury, we sought to test this hypothesis in a rat model of asphyxia cardiac arrest with prolonged survival (7 d). Cardiac arrest resulted in hippocampal CA1 delayed neuronal death well characterized in this and other cardiac arrest models. Nitrite therapy did not alter post-arrest hemodynamics but did result in significant (75%) increases in CA1 neuron survival. This was associated with increases in hippocampal nitrite and S-nitrosothiol levels but not cGMP shortly after therapy. Mitochondrial function 1 h after resuscitation trended towards improvement with nitrite therapy. Based on promising preclinical data, the first ever phase I trial of nitrite infusions in human cardiac arrest survivors has been undertaken. We present preliminary data showing low dose nitrite infusion did not result in hypotension or cause methemoglobinemia. Nitrite thus appears safe and effective for clinical translation as a promising therapy against cardiac arrest mediated heart and brain injury.