Experimental paperHemorrhagic shock resuscitation with carbon monoxide saturated blood☆
Introduction
Treatment of blood loss and hemorrhagic shock begins with the infusion of plasma expanders to restitute vascular volume and, upon continued exsanguination, is followed by the restitution of oxygen carrying capacity with blood transfusions. The decision to transfuse blood depends on a variety of factors including the estimated magnitude of the blood loss, measurements of tissue and the concern that the progressing anemia will lead to a condition where oxygen carrying capacity may be insufficient to supply the metabolic demand. Trauma and hemorrhage can lead to the development of end-organ damage, a deregulated systemic inflammatory response, and ultimately result in multiple organ dysfunction syndromes.1 At the cellular level, these inflammatory responses involve the initiation of signaling cascades and the activation of many prototypical molecular pathways, resulting in the generation of multiple stressor products, including cytoprotective responses.
Several studies have demonstrated that the expression of cytoprotective reaction in the setting of hemorrhagic shock can determine the outcome.2 Final tissue injury after hemorrhage can be exacerbated by pharmacological inhibition of heme-oxygenase-1 (HO-1) enzymatic activity and nitric oxide (NO).2 Conversely, induction of HO-1 before hemorrhage can ameliorate the resultant organ injury. HO-1 is the rate-limiting enzyme in catalyzing the breakdown of heme into its by-products of free iron, biliverdin and carbon monoxide (CO), and is induced by multiple stressors, including cytokines, lipopolysaccharide, oxidative stress, and NO.3 CO, in particular, has been demonstrated to possess anti-inflammatory and antiapoptotic properties.4, 5, 6 Different studies have previously shown that CO can decrease inflammatory response to cytokines in a model of endotoxic shock while simultaneously increasing anti-inflammatory cytokines levels.3, 4, 5, 6
Volume restitution with plasma expanders and autotransfusion as a response to hemorrhage, dilute the blood components. In particular, the dilution of red blood cells (RBCs) lowers blood viscosity, and therefore the viscosity dependant component of peripheral vascular resistance. Experimental studies in hemorrhagic shock showed the threshold for blood/plasma viscosity required to maintain microvascular perfusion and particularly functional capillary density (FCD).7, 8, 9, 10 According to these findings, maintenance of FCD differentiates between survival and non-survival in conditions of prolonged hemorrhagic shock even though oxygen carrying capacity and tissue oxygen are the same.7
Blood transfusions have immediate subjective as well as physiological beneficial effects which are not fully explained by the restoration of oxygen carrying capacity since this occurs as much as several hours later, depending on the storage period. Recent studies have shown that an increase in hematocrit (Hct) after blood transfusion in a normal organism led to a rapid increase in NO production via restored shear stress.11 Similar effects were obtained when Hct was decreased via hemodilution and plasma viscosity was increased, raising shear stress and consequently augmenting the levels of perivascular NO at the microcirculation, producing a stable and homogeneously perfused microcirculation.12 Therefore, the beneficial effect of blood transfusions may be, in part, linked to the increase or restoration of shear stress and mechanotransduction by blood viscosity.
This study analyzes systemic, microcirculatory and tissue cellular effects in the hamster window chamber model after subjected to acute hemorrhagic shock and resuscitation. Resuscitation was performed infusing CO saturated or unsaturated RBCs suspended in 10% human serum albumin (HSA) to obtain the necessary colloidal osmotic pressure (COP) for resuscitation. The concentration of RBCs in the resuscitation blood matched the hamster Hct before resuscitation. However, the objective was not to increase or restore to baseline blood viscosity, but only to maintain blood rheological properties, change oxygen carrying capacity and establish CO effects.
Section snippets
Animal preparation
Investigations were performed in male Golden Syrian Hamsters fitted with a dorsal chamber window.13 This model has been extensively used for investigation of the intact microvasculature of adipose, subcutaneous tissue and skeletal muscle in conscious animals for extended periods.10, 14 A complete description of the preparation is given in references.10, 14 Pentobarbital sodium (50 mg/kg, i.p.) is used for window implantation and for carotid artery and jugular vein catheterization. Four to five
Results
A total of 18 animals (60.9 ± 4.2 g) were studied. Animals were assigned randomly to the experimental groups: CORBC (n = 6; 59.2 ± 5.0 g); O2RBC (n = 6; 61.6 ± 4.1 g); and, NR (n = 6; 60.2 ± 3.9 g).
Discussion
The principal finding of this study is that resuscitation with CORBC and O2RBC provides an identical recovery of systemic and microvascular conditions. Both resuscitated groups achieved and sustained similar level of recovery. This is remarkable because, O2RBC group had increased oxygen carrying capacity by 25% after resuscitation compared to CORB group, which did not receive the RBC's functional oxygen capacity. Identical amounts of RBCs were infused in CORBC and O2RBC groups, but oxygen
Acknowledgments
This work has been supported by grants R01-HL76182 to AGT, R24-64395, R01-62354 and R01-62318 to MI.
References (32)
- et al.
Hemorrhagic shock
Curr Probl Surg
(1995) - et al.
Carbon monoxide from heme catabolism protects against hepatobiliary dysfunction in endotoxin-treated rat liver
Gastroenterology
(2001) - et al.
Application of the “two-slit” photometric technique to the measurement of microvascular volumetric flow rates
Microvasc Res
(1978) - et al.
Current controversies in shock and resuscitation
Surg Clin North Am
(2001) - et al.
Differential expression pattern of heme oxygenase-1/heat shock protein 32 and nitric oxide synthase-II and their impact on liver injury in a rat model of hemorrhage and resuscitation
Crit Care Med
(1999) - et al.
Heme oxygenase: colors of defense against cellular stress
Am J Physiol Lung Cell Mol Physiol
(2000) - et al.
Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis
J Exp Med
(2000) - et al.
Carbon monoxide inhibits apoptosis in vascular smooth muscle cells
Cardiovasc Res
(2002) - et al.
Systemic and subcutaneous microvascular pO2 dissociation during 4-h hemorrhagic shock in conscious hamsters
Am J Physiol
(1996) - et al.
Oxygen delivery at high blood viscosity and decreased arterial oxygen content to brains of conscious rats
Am J Physiol Heart Circ Physiol
(2001)
Increase plasma viscosity sustains microcirculation after resuscitation from hemorrhagic shock and continuous bleeding
Shock
Hyperosmotic-hyperoncotic vs. hyperosmotic-hyperviscous small volume resuscitation in hemorrhagic shock
Shock
Paradoxical hypotension following increased hematocrit and blood viscosity
Am J Physiol Heart Circ Physiol
Elevated plasma viscosity in extreme hemodilution increases perivascular nitric oxide concentration and microvascular perfusion
Am J Physiol Heart Circ Physiol
Technical report: a new chamber technique for microvascular studies in unanaesthetized hamsters
Res Exp Med
Improving microcirculation is more effective than substitution of red blood cells to correct metabolic disorder in experimental hemorrhagic shock
Shock
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A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2006.06.021.