Bench-to-bedside review: Latest results in hemorrhagic shock

Hemorrhagic shock is a leading cause of death in trauma patients worldwide. Bleeding control, maintenance of tissue oxygenation with fluid resuscitation, coagulation support, and maintenance of normothermia remain mainstays of therapy for patients with hemorrhagic shock. Although now widely practised as standard in the USA and Europe, shock resuscitation strategies involving blood replacement and fluid volume loading to regain tissue perfusion and oxygenation vary between trauma centers; the primary cause of this is the scarcity of published evidence and lack of randomized controlled clinical trials. Despite enormous efforts to improve outcomes after severe hemorrhage, novel strategies based on experimental data have not resulted in profound changes in treatment philosophy. Recent clinical and experimental studies indicated the important influences of sex and genetics on pathophysiological mechanisms after hemorrhage. Those findings might provide one explanation why several promising experimental approaches have failed in the clinical arena. In this respect, more clinically relevant animal models should be used to investigate pathophysiology and novel treatment approaches. This review points out new therapeutic strategies, namely immunomodulation, cardiovascular maintenance, small volume resuscitation, and so on, that have been introduced in clinics or are in the process of being transferred from bench to bedside. Control of hemorrhage in the earliest phases of care, recognition and monitoring of individual risk factors, and therapeutic modulation of the inflammatory immune response will probably constitute the next generation of therapy in hemorrhagic shock. Further randomized controlled multicenter clinical trials are needed that utilize standardized criteria for enrolling patients, but existing ethical requirements must be maintained

A Hemoglobin-Based Multifunctional Therapeutic: Polynitroxylated Pegylated Hemoglobin

Polynitroxylated pegylated hemoglobin (PNPH) as a multifunctional therapeutic takes advantage of the ability of hemoglobin (Hb) to transport oxygen, the antioxidative stress activities from the redox coupling of nitroxide and heme iron, and the hypercolloid properties of pegylation. The published preclinical data demonstrating that PNPH acts as a neurovascular protective multifunctional therapeutic in an animal model simulating prehospital resuscitation of traumatic brain injury (TBI) with hemorrhagic shock (HS) are reviewed. Preliminary results on the potential utility of PNPH for neurovascular protection in thrombolytic stroke therapy and for correction of vascular dysfunction through transfusion in sickle-cell disease (SCD) are also discussed. We hypothesize that with PNPH, Hb has more than been tamed--it has become a therapeutic and not just a nontoxic extracellular oxygen carrier--and that successful PNPH development as a multifunctional therapeutic that protects the neurovasculature and reduces oxidative stress may represent a paradigm shift in transfusion and critical care medicine, which may meet a number of unmet medical needs resulting from oxidative stress and inadequate blood flow, such as HS, TBI, SCD, and stroke

Haemoglobin, oxygen carriers and perioperative organ perfusion

Under normal conditions, only 20-30% of the delivered oxygen is metabolised. In normovolaemic anaemia, the organism reacts with increases in cardiac output and oxygen extraction. Once these mechanisms are exceeded, allogeneic blood transfusions may be administered. However, such transfusions are associated with serious adverse effects and alternatives such as artificial oxygen carriers are being sought. The main groups of artificial oxygen carriers are extracellular haemoglobin solutions and perfluorocarbons. Preparations undergoing experimental and clinical assessment include Human Polymerized Haemoglobin (Polyheme), Polymerized Bovine Haemoglobin-based Oxygen Carrier (HBOC-201, Hemopure), Haemoglobin Raffimer (HemoLink), Diaspirin Cross-linked Haemoglobin (HemAssist), Human Recombinant Haemoglobin (rHb), Enzyme Cross-linked Poly-haemoglobin, Maleimide-activated Polyethylene-glycol Modified Haemoglobin (MP4, Hemospan), Zero-linked Haemoglobin (ZL-HbBv) and Recombinant Hybrid of Human-alpha-chains and Bovine-beta-chains and Perflubron (Oxygent). Research into some of these compounds has been discontinued, while others have advanced into clinical phase III trials, but none has achieved market approval for Europe, US or Canada so far

Arterial pulmonary hypertension in noncardiac intensive care unit

Pulmonary artery pressure elevation complicates the course of many complex disorders treated in a noncardiac intensive care unit. Acute pulmonary hypertension, however, remains underdiagnosed and its treatment frequently begins only after serious complications have developed. Significant pathophysiologic differences between acute and chronic pulmonary hypertension make current classification and treatment recommendations for chronic pulmonary hypertension barely applicable to acute pulmonary hypertension. In order to clarify the terminology of acute pulmonary hypertension and distinguish it from chronic pulmonary hypertension, we provide a classification of acute pulmonary hypertension according to underlying pathophysiologic mechanisms, clinical features, natural history, and response to treatment. Based on available data, therapy of acute arterial pulmonary hypertension should generally be aimed at acutely relieving right ventricular (RV) pressure overload and preventing RV dysfunction. Cases of severe acute pulmonary hypertension complicated by RV failure and systemic arterial hypotension are real clinical challenges requiring tight hemodynamic monitoring and aggressive treatment including combinations of pulmonary vasodilators, inotropic agents and systemic arterial vasoconstrictors. The choice of vasopressor and inotropes in patients with acute pulmonary hypertension should take into consideration their effects on vascular resistance and cardiac output when used alone or in combinations with other agents, and must be individualized based on patient response

Effects of Ubiquinol with Fluid Resuscitation following Hemorrhagic Shock

Abstract Hemorrhagic shock (HS) and fluid resuscitation triggers ischemia-reperfusion injury in cells and increases the production of reactive oxygen species (ROS) which are known to activate the intrinsic pathway of apoptosis and contribute to organ dysfunction.1 Ubiquinol is a potent free radical scavenger which is produced endogenously and functions as part of the mitochondrial respiratory chain.2 No study has been conducted to investigate the effects of ubiquinol related to HS. The overall aim of this study was to examine the effects of ubiquinol on leukocyte mitochondria and in the lungs, diaphragm, heart and kidneys as a supplemental treatment for HS. A randomized experimental design was used for this study. Adult male Sprague-Dawley rats (n = 20) were anesthetized and HS was induced by withdrawing 40% of the rat's blood volume to maintain a mean arterial pressure of 45-55 mmHg for 60 minutes. Following HS the rats were resuscitated with blood and lactated Ringer's (LR) with or without ubiquinol (1 mg per 100 g of body weight). The rats were monitored for 120 minutes, the animals were euthanized and the organs harvested. Leukocyte mitochondria superoxide (O2*⁻) was measured by flow cytometry using MitoSOX Red, a mitochondrial-targeted variant of the fluorescent probe hydroethidine. Superoxide levels were measured at baseline, end of HS and 120 minutes following fluid resuscitation. Arterial blood values were also recorded at these times. At the end of experiment, diaphragms were evaluated for hydrogen peroxide (H2O2) using the fluorescent probe dihydrofluorescein-diacetate (Hfluor). The lungs, diaphragm, heart, and kidneys were examined for percent of apoptotic nuclear membrane damage using a differential dye uptake method with acridine orange and ethidium bromide. No significant differences were found between groups with regard to the volume of blood removed, hemodynamic status or arterial blood values (p 0.05). Ubiquinol decreased leukocyte mitochondrial production of O2*⁻ at the end of the experiment by 35% compared to the control group (4687.2 ± 265.4 versus 7227.9 ± 534.5, p ˂ 0.001). Similarly, the mean fluorescence intensity (MFI) of diaphragm H2O2 was significantly lower in the ubiquinol group compared to control (4193 ± 333 versus 23513 ± 5098, p ˂ 0.001). The percent of apoptosis in the lungs, diaphragm, heart, and kidneys was significantly reduced in the animals treated with ubiquinol compared to the control group (6.0 ± 0.7% versus 39.2 ± 1.1%, 4.7 ± 0.5% versus 30.6 ± 2.4%, 2.9 ± 0.6% versus 23.6 ± 1.2%, 2.4 ± 0.3% versus 42.1± 1.9%, respectively, p ˂ 0.001). Ubiquinol was effective in decreasing leukocyte mitochondrial O2*⁻ formation, which suggests that ubiquinol scavenged O2*⁻ within the mitochondria. Since ubiquinol is a potent antioxidant, it also probably scavenged other free radicals outside the mitochondria. The increased concentration of ubiquinol within the mitochondria would assist in maintaining the activities within the electron transport chain during HS. In addition, the decreased mitochondrial O2*⁻ would result in lower H2O2 production. The significant reduction in the percent of apoptosis in lungs, diaphragm, heart and kidneys between the control and treatment rats, suggests that decreased ROS production attenuated the activation of the intrinsic (mitochondrial) apoptosis pathway.3 The findings could also be attributed to the stabilization of the mitochondrial membrane by ubiquinol, which has been demonstrated in a previous study.4 In conclusion, ubiquinol may have application as a supplemental treatment to reduce free radical damage and apoptosis- related injury following HS and fluid resuscitation

Bench to bedside review: therapeutic modulation of nitric oxide in sepsis-an update.

Nitric oxide is a signalling molecule with an extensive range of functions in both health and disease. Discovered in the 1980s through work that earned the Nobel prize, nitric oxide is an essential factor in regulating cardiovascular, immune, neurological and haematological function in normal homeostasis and in response to infection. Early work implicated exaggerated nitric oxide synthesis as a potentially important driver of septic shock; however, attempts to modulate production through global inhibition of nitric oxide synthase were associated with increased mortality. Subsequent work has shown that regulation of nitric oxide production is determined by numerous factors including substrate and co-factor availability and expression of endogenous regulators. In sepsis, nitric oxide synthesis is dysregulated with exaggerated production leading to cardiovascular dysfunction, bioenergetic failure and cellular toxicity whilst at the same time impaired microvascular function may be driven in part by reduced nitric oxide synthesis by the endothelium. This bench to bedside review summarises our current understanding of the ways in which nitric oxide production is regulated on a tissue and cellular level before discussing progress in translating these observations into novel therapeutic strategies for patients with sepsis

Renal endothelial dysfunction in acute kidney ischemia reperfusion injury

Acute kidney injury is associated with alterations in vascular tone that contribute to an overall reduction in GFR. Studies in animal models indicate that ischemia triggers alterations in endothelial function that contribute significantly to the overall degree and severity of a kidney injury. Putative mediators of vasoconstriction that may contribute to the initial loss of renal blood flow and GFR are highlighted. In addition, there is discussion of how intrinsic damage to the endothelium impairs homeostatic responses in vascular tone as well as promotes leukocyte adhesion and exacerbating the reduction in renal blood flow. The timing of potential therapies in animal models as they relate to the evolution of AKI, as well as the limitations of such approaches in the clinical setting are discussed. Finally, we discuss how acute kidney injury induces permanent alterations in renal vascular structure. We posit that the cause of the sustained impairment in kidney capillary density results from impaired endothelial growth responses and suggest that this limitation is a primary contributing feature underlying progression of chronic kidney disease