In this webinar, Fiona McBryde, PhD discusses the cerebral blood flow-pressure relationship, how cerebral autoregulation may vary in disease and clinically-relevant states, and the importance of performing measurements in awake, freely-moving laboratory animals.
- Importance of blood flow in maintaining brain perfusion in ischemic stroke
- Understanding the cerebral pressure-flow relationship
- Cerebral autoregulation and how it may vary during stroke and anesthesia
- Mechanisms regulating the venous reservoir
- Importance of conducting untethered measurements in conscious animals
Dr. McBryde begins this webinar with a discussion of pressure, flow, and perfusion to the “selfish” brain. Although the brain accounts for only 2% of human body weight, it receives approximately 15% of cardiac output and consumes approximately 20% of available blood oxygen at rest. Due to the brain’s high metabolic activity and lack of energy reserves, it may induce systemic hypertension to protect cerebral blood flow.
Although 70% of strokes occur against the clinical background of hypertension, there are no clinical guidelines that discriminate between hyper- and normotensive patients in terms of how blood pressure (BP) should be targeted. To address this knowledge gap, Dr. McBryde and colleagues characterized cardiovascular stroke responses in rats using telemetry devices. Following surgery recovery and baseline recording, ischemic stroke was induced in these animals via transient middle cerebral artery occlusion. At the time of stroke, an abrupt decrease in penumbra oxygen was observed, which surged following occlusion suture removal.
Dr. McBryde and colleagues also performed interventional studies with a focus on preventing this surge in BP. Data from these studies were consistent with many clinical trial results in stroke patients wherein treating to prevent post-stroke hypertension appears neither harmful nor beneficial overall. While the pre-stroke BP baseline is known in preclinical studies, it is not always practical to check general practitioner records for BP or medication compliance history when treating a stroke. Furthermore, a disproportionate amount of clinical patients have undiagnosed or poorly controlled hypertension, and so pre-stroke baseline BP is uncertain.
“As a thought experiment, what would happen in the real world if we applied a standard fixed blood pressure target to all stroke patients?”
Patients with unknown hypertension prior to stroke likely inadvertently experience a decrease in BP to a lower level than their pre-stroke baseline following treatment. Dr. McBryde and colleagues therefore performed the previous experiment with an additional group of hypertensive rats that were treated down to normotensive levels. Results from this study indicated that overtreating BP may compromise blood flow to the stroke penumbra. There was also a significant survival disadvantage in overtreated rats compared to treated and untreated rats which was associated with a larger infarct volume.
Dr. McBryde next explains cerebral autoregulation in ischemic stroke and addresses one of the most commonly misunderstood concepts in the brain pressure-flow relationship. Most undergraduate textbooks imply that cerebral autoregulation alone is powerful and sufficient to protect brain blood flow against all but the most extreme deviations in BP. However, the study on which this assumption is based was referring to a steady state between individuals and does not necessarily predict what will happen with dynamic BP fluctuations.
“This is an area where many of us in the field are advocating for increased awareness and understanding, and certainly I hope that the teaching in the medical schools of the upcoming clinical staff is starting to reflect our current understanding a little better.”
Dr. McBryde next describes a novel methodology for exploring pressure-flow interactions during induced BP decreases in conscious rats. Beat-to-beat arterial pressure was monitored via telemetry, and transient reductions in BP were induced by inflating silicone balloons after insertion into the abdominal vena cava. Resting cerebral blood flow was lower and vascular resistance was higher in hypertensive animals compared to normotensive controls.
Current clinical stroke treatments involve general anesthesia (GA), which generally causes a decrease in BP, and was therefore studied in these animals. Inducing GA during stroke led to a steeper BP drop in animals with controlled and uncontrolled hypertension compared to normotensive animals, indicating that GA likely compromises collateral blood flow to the penumbra. Additional experiments with two common anesthetic agents also revealed that there is less or no cerebral autoregulation during anesthesia.
“This is just emphasizing that anesthetizing stroke patients really is likely to require special care and perhaps that blood pressure might be a simple tool that could be used to prop up cerebral perfusion.”
In the last portion of this webinar, Dr. McBryde focuses on pressure and flow in the venous reservoir. At rest, human veins hold approximately 60% of total blood volume with a large proportion contained in the mesenteric circulation. Unlike in the brain, the pressure-flow relationship in the mesentery is not determined solely on the metabolic needs of the organ itself.
Research has suggested that there is an increase in venous pressure in hypertension, which is associated with heightened sympathetic nervous system (SNS) activity. Disrupting sympathetic input can ameliorate the development of hypertension, but not much is known about the dynamic blood flow-pressure interactions within these venous reservoirs, especially without the confounds of anesthesia. To address these questions, Dr. McBryde and colleagues chronically implanted rats with dual pressure telemeters to measure arterial and venous pressures.
“This particular approach is one of the most sophisticated and challenging chronic instrumentation that our team has attempted to date.”
For this talk, Dr. McBryde focuses solely on the effects of 20% volume reduction and expansion on blood flow, mean arterial pressure (MAP), and mean central filling pressure (MCFP), with and without SNS blocking by hexamethonium. Despite sizable volume depletion, MAP remained steady in both normotensive and hypertensive rats, but treatment with the SNS blocker resulted in BP crashes during volume depletion. Volume withdrawal also reduced MCFP in all four rat groups. A net outflow of blood from the mesenteric bed was observed in all rats, suggesting that the blood influx from the mesenteric bed buffers the reduced blood volume even when the SNS is blocked.
While SNS blockage lowers baseline MAP in both normotensive and hypertensive rats, little or no change was observed in all groups during volume expansion. Consistent with what was observed during volume depletion, MFCP increased during volume expansion in all rat strains. A net movement of blood into the mesenteric bed was observed in normotensive rats to accommodate almost all of the extra infused volume, but surprisingly, a small net blood outflow was observed in hypertensive rats. Dr. McBryde suggests that the mesenteric bed in hypertensive rats has a reduced capacity to accommodate blood volume increases.
Dr. McBryde concludes this webinar by listing some future directions, which include making these types of intricate, real-time pressure-flow recordings over much larger time periods than the previous studies presented. Long-term recordings will allow Dr. McBryde to evaluate causality and disease pathology over time, assess the impact of chronic interventions on organ blood flow, and perform circadian analyses, which can only be accomplished with wireless recordings.
- If flow is so sensitive to pressure, why are vasoregulatory mechanisms not tuned to match supply to demand?
- Why is resistance to the brain higher if it’s trying to selfishly maintain its own perfusion?
- Is there an imbalance between mesenteric inflow and outflow such that the sympathetic blockade does not compromise the volume shift out?
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University of Auckland