Preconditioning and novel treatments for stroke
Stroke is a serious cardiovascular event associated with significant morbidity and mortality. Hypoxic preconditioning has been proposed as a mechanism to reduce stroke severity, thereby enhancing patient recovery. By creating a hypoxic state, the subsequent acclimation occurs via increased vascular density, glycolytic capacity and erythropoiesis. Dunn and colleagues (2012) hypothesized that ischemic preconditioning would contribute to improved outcomes in a rodent model of stroke. To test this hypothesis, researchers used chronic implants with fiber optic dissolved oxygen sensors placed into the cortex of Wistar rats. These implants had a protruding portion that could be connected via fiber optic lead to an OxyLite system to record data. Using fluorescence quenching technology, the system enabled researchers to determine the concentration of dissolved oxygen available in the brain tissue. Following implantation, rats were maintained in hypoxic conditions for 21 days, and cortical partial pressure of oxygen pO2 was assessed before and after hypoxic preconditioning. The pO2 significantly increased following the 21-day bout of preconditioning. Further, to examine the effect of hypoxic preconditioning on stroke outcomes, investigators occluded the middle cerebral artery. Ischemic damage was significantly reduced in rats that underwent hypoxic acclimation. This effect is thought to be mediated, in part, by hypoxia-induced increases in capillary density and reduced inflammation.
The work by Dunn et al. (2012) demonstrates hypoxia acclimation may reduce stroke severity, however, this approach has not yet been developed for the clinic. Currently, when a stroke occurs, it is essential to rapidly restore cerebral blood flow. These treatments can be effective however they must be initiated within a few hours of the thrombotic event. Thus, a treatment that can be administered within longer window following stroke is currently being sought. Stimulation of the sphenopalatine ganglion (SPG) has been proposed as a novel treatment modality for stroke, and such studies have now progressed into the pre-clinical space. However, to elucidate the mechanistic effects of SPG stimulation, pre-clinical models are essential. Using a rat model of photothrombotic stroke, Levi et al. (2012) investigated the efficacy of SPG stimulation for restoration of cerebral blood flow. Following craniotomy in Sprague-Dawley rats, a bipolar hook stimulating electrode was implanted in nerve bundles to stimulate the SPG. Treatment was administered either 15 minutes or 24 hours following photothrombotic stroke. To assess cerebral blood flow, a laser Doppler probe was mounted above the cortical surface for continuous measurements. SPG stimulation led to vasodilation and subsequently increased cerebral blood flow, as well as partial reperfusion of occluded vessels. Further, treatment was associated with reduced necrotic core lesion size and fewer seizure-like events even when administered 24 hours after the thrombotic event. These results indicate the development of an SPG stimulation treatment protocol may provide a novel solution for stroke patients.
Oxygen delivery and preventing microcirculatory dysfunction in hemorrhagic shock
Hemorrhagic shock often accompanies and exacerbates traumatic brain energy. Emerging evidence suggests that the standard treatment, rapid restoration of blood volume and pressure with crystalloids, can have negative consequences. Teranishi et al. (2012) propose the need for a resuscitation strategy to reduce hemorrhage volume and reduce the risk of ischemic brain injury. To identify the optimal treatment, they used a swine model of combined traumatic brain injury and uncontrolled hemorrhage, followed by administration of a hemoglobin-based oxygen carrier (HBOC). Briefly, a craniotomy was performed on Yorkshire pigs and a pO2 sensor connected to the OxyLite system was placed in the brain. A fluid-percussion device was used to induce brain injury, and a liver lobectomy was used to induce free bleeding to mimic hemorrhagic shock. A thirty minute-window followed, to simulate a hospital arrival time, and animals received a bolus of either HBOC, lactate ringer solution or no treatment (control). Animals receiving the HBOC bolus demonstrated improved tissue oxygenation, cerebral blood flow, and mean arterial pressure. Oxygen supply to the brain during traumatic brain injury is essential to minimize progression, and this study demonstrates administration of a hemoglobin-based oxygen carrier is an effective strategy to improve brain tissue oxygen availability.
Restoring and maintaining oxygenation and blood flow in other organs is also essential when treating shock. Letson et al. (2017) examined the effects of a small-volume 3% sodium chloride adenosine, lidocaine and magnesium (ALM) bolus and 0.9% NaCl/ALM drip in a rat model of hemorrhagic shock. As in the Teranishi et al. (2012) experiment, liver injury was used to induce uncontrolled hemorrhage. Fifteen minutes after injury, animals received no treatment, saline bolus, Hextend (a blood plasma volume expander) or ALM. Sixty minutes following bolus administration, animals received subsequent treatment as follows: no treatment + no drip, saline treatment + 0.9% NaCl, Hextend treatment + 0.9% NaCl, ALM treatment + 0.9% NaCl ALM. To assess tissue oxygen and blood flow in organs, investigators implanted OxyLite and OxyFlo sensors. Flow and pO2 sensors were implanted in the jejunum of the small intestine, kidney corticomedullary junction and vastus intermedius muscle. The ALM-treated group showed improved cardiac function as well as increased blood flow and pO2 in the gut and kidney during the first phase of resuscitation. ALM treatment also protected the gut and kidney during secondary resuscitation phase (drip treatment), as it was associated with delayed microcirculatory dysfunction mediated by decreased pO2 and increased blood flow. Conversely, the Hextend treatment was associated with reduce survival and greater microvascular injury. These findings suggest further work is required to ensure the use of appropriate emergency treatment for hemorrhagic shock.
The ability to assess microvascular blood flow and tissue oxygen concentrations is especially useful when investigating stroke and shock models, among a variety of other cardiovascular research applications. Microvascular flow data can indicate occlusion, as observed in stroke models, or microcirculatory health of individual organs, as demonstrated in shock studies. Further, measuring dissolved oxygen can provide more meaningful data than blood oxygen saturation. Dissolved oxygen in the brain, for example, indicates unbound oxygen available to the tissue. In contrast, there are a variety of factors that influence oxygen-hemoglobin dissociation and quantifying the percent of hemoglobin bound to oxygen may not be indicative of what is immediately available to the tissue. Using the OxyFlo and OxyLite probes, researchers can quantify tissue blood flow and dissolved oxygen with a wide range of probe sizes appropriate for multiple applications.
For more information on Oxford Optronix OxyFlo blood perfusion monitors or OxyLite tissue oxygen monitors, click here.
Keywords: Dissolved oxygen measurement, cerebral oximetry, blood flow sensor, blood perfusion, laser doppler
Dunn, J. F., Wu, Y., Zhao, Z., Srinivasan, S., & Natah, S. S. (2012). Training the Brain to Survive Stroke. PLoS ONE, 7(9), 1–9.
Letson, H. L., & Dobson, G. P. (2017). 3% NaCl adenosine, lidocaine, Mg2+(ALM) bolus and 4 hours drip infusion reduces noncompressible hemorrhage by 60% in a rat model. Journal of Trauma and Acute Care Surgery, 82(6), 1063–1072.
Levi, H., Schoknecht, K., Prager, O., Chassidim, Y., Weissberg, I., Serlin, Y., & Friedman, A. (2012). Stimulation of the sphenopalatine Ganglion induces reperfusion and blood-brain barrier protection in the Photothrombotic stroke model. PLoS ONE, 7(6).
Teranishi, K., Scultetus, A., Haque, A., Stern, S., Philbin, N., Rice, J., … Arnaud, F. (2012). Traumatic brain injury and severe uncontrolled haemorrhage with short delay pre-hospital resuscitation in a swine model. Injury, 43(5), 585–593.