I did not have the occasion to blog about my own research to date. Well, let’s do it ! This post will also serve as background information for future discussion.
During my postdoc, I had the possibility of studying cerebrovascular physiology. My lab was interested in cerebral blood flow and metabolism in humans. When I arrived in Copenhagen, the Journal of Applied Physiology’s Point:Counterpoint: Sympathetic activity does/does not influence cerebral blood flow was “in press”. I found that issue really fascinating… I did not know: A) that I was about to be involved in that debate, and B) that story would form the background for my first grant proposal to CIHR and my first research scholar application to FRSQ ! Let’s take a look at the main results of 3 studies conducted during my postdoc.
But first, some background. In clinical situations such as during general anesthesia, a reduction in arterial pressure, e.g. hypotension, may appear following a reduction in cardiac output, peripheral vascular resistance, or both. Evidence suggests that under a mean arterial pressure of ~60 mmHg, autoregulation in the cerebral vascular beds is impaired. As a consequence, blood flow in the brain becomes pressure passive and it will decrease with a further lowering in arterial pressure.
Since the presence of arterial hypotension has the potential to challenge the perfusion of vital organs such as the brain, it is clinically relevant to restore arterial pressure within the range of autoregulation in order to secure cerebral perfusion pressure. However, the means by which arterial pressure increases is important. For example, if peripheral vasoconstriction is the mean by which arterial pressure is increased, this approach will not be necessarily associated with a parallel increase in blood flow to vital organs such as the brain (arterial pressure does not always represent efficient blood flow, which is the variable that needs to be influenced in order to restore systemic oxygen delivery and improve tissue oxygenation). Depending on their specific target, some vasopressor agents will exclusively influence vascular resistance (such as phenylephrine), others will have a predominant influence on vascular resistance with a minor chronotropic and/or inotropic influence on the heart (such as norepinephrine) while others will have chronotropic and/or inotropic properties (such as ephedrine).
Before the beginning of my postdoc, existing literature suggested that increasing arterial pressure with vasopressors (phenylephrine, norepinephrine) was not associated with a reduction in cerebral blood flow/oxygenation. However, intrigued by a clinical observation where the frontal lobe oxygenation, measured by near-infrared spectroscopy, in one of our subjects was notably reduced following a bolus of phenylephrine, we decided to document this clinical observation by looking at the frontal lobe oxygenation changes in response to an elevation in mean arterial pressure by routine use of phenylephrine in patients who underwent elective surgery and experienced anesthesia-induced hypotension (1). Correction of anesthesia-induced hypotension was then changed to the administration of ephedrine to evaluate whether that vasopressor would similarly affect frontal lobe oxygenation while increasing mean arterial pressure by elevating cardiac output. The main results are presented in the figure below:
Although mean arterial pressure increased to a similar extent with both phenylephrine and ephedrine (see administration of drug vs. high MAP), we observed a 14% reduction in frontal lobe oxygenation following the administration of phenylephrine. On the other hand, frontal lobe oxygenation was maintained following the administration of ephedrine. These results suggest that while vasopressors are administered to increase or maintain cerebral blood flow and oxygenation, drugs which increase arterial pressure via total peripheral vasoconstriction may lead to a reduction in cerebral oxygenation. In addition, cardiac output may be an important variable to manipulate to increase arterial pressure as frontal lobe oxygenation seemed to be maintained following administration of ephedrine. A recent study presents interesting results in that sense and I will discuss that study in an upcoming post.
Then, we decided to test in the laboratory, the influence of phenylephrine and norepinephrine on cerebral blood flow velocity and cerebral oxygenation in normotensive healthy young subjects. In the first study (2), young healthy subjects received norepinephrine in three concentrations (0.05, 0.1, and 0.15 mg kg-1min-1 for 20 min separated by 5 min between each infusion). Mean arterial pressure (MAP), cerebral oxygenation characterized by frontal lobe oxygenation (ScO2) and internal jugular venous oxygen saturation (SjvO2) (yes dear! You have to remember that I was in Denmark!), middle cerebral artery mean flow velocity (MCAVmean) measured by transcranial doppler, cardiac output, heart rate and arterial pressure of carbon dioxide were evaluated during the control period of saline infusion and the three doses of norepinephrine. The figure below presents the main results:
We observed that although the infusion of norepinephrine increased mean arterial pressure by peripheral vasoconstriction in a dose-response manner, it negatively affected cerebral oxygenation, characterized by a reduction in both frontal lobe oxygenation and internal jugular venous oxygen saturation.
Another study performed in similar healthy subjects (3) was undertaken with the utilization of phenylephrine to support our initial clinical observations. Subjects received an intravenous bolus injection of saline and three 5-ml doses of phenylephrine (0.1, 0.25, and 0.4 mg) separated by 20 min, and the variables described for the norepinephrine study (see Figure above) were monitored for 15 min. Mean arterial pressure increased ~20% with augmenting doses of phenylephrine while cardiac output (CO) was reduced. Then, following the maximal impact of the drug, frontal lobe oxygenation (ScO2) was decreased by 7% .
Thus, the elevation in arterial pressure by an augmentation in total peripheral vasoconstriction is associated with a reduction in cerebral oxygenation in healthy subjects and patients undergoing elective surgery. This could partly be explained by a lowered cardiac output. Further research is needed to support these results that could eventually influence actions in the operating room. Of course, there are some limitations to these results. I will address some limitations related to transcranial doppler and near-infrared spectroscopy in another post.
Finally, several exciting studies related to that issue have recently been published and I will discuss the results of these studies pretty soon !
(1) Nissen P, Brassard P, Jørgensen TB, Secher NH. Phenylephrine but not ephedrine reduces frontal lobe oxygenation following anesthesia-induced hypotension Neurocrit Care 12(1):17-23, 2010
(2) Brassard P, Larsen TS, Secher NH. Is cerebral oxygenation negatively affected by infusion of norepinephrine in healthy subjects? Br J Anaesth 102(6): 800-805, 2009
(3) Brassard P, Seifert T, Wissenberg M, Jensen PM, Hansen CK, Secher NH. Phenylephrine decreases frontal lobe oxygenation at rest but not during moderately intense exercise J Appl Physiol 108(6):1472-1478, 2010