Perioperative β-Blockade and Stroke: A Cyclical Story of Translational Research
Gregory M.T. Hare, MD PhD FRCPC
Enthusiasm for the potential benefit of perioperative β-antagonists evolved from the exciting
improvement in survival associated with early treatment with beta antagonists in patients who
had suffered a myocardial infarction in the 1980’s (ISIS, MIAMI).1-3 With a predicted ~25%
reduction in post MI mortality,3 the strong impetus to find additional clinical indications for this
therapy is understandable. These efforts resulted in the early application of this class of drugs to
treat hypertension and studies were initiated to assess the efficacy of perioperative beta blockade
to reduce the risk of myocardial ischemia and cardiac mortality.4;5 The evolution of history has
demonstrated that these approaches were not as successful as had been hoped and the desired
clinical outcome of improved event free survival were not necessarily realized.6 The complexity
of our patient’s medical conditions, their associated co-morbidities and the complex
pathophysiology of cardiovascular diseases have defied the success of mono-therapy to improve
outcome. The realization that β-antagonists may not be appropriate first line antihypertensive
medications7;8 and that liberal treatment with perioperative beta blockers may cause adverse
clinical outcomes9 highlights this reality.
The current presentation outlines a translational approach to understanding the interaction
between acute β-antagonism, surgical blood loss (anemia) and stroke. This translational process
involved ongoing cross-talk and hypothesis derivation between clinical epidemiologists (Dr. W.
S. Beattie and colleagues) and integrative whole animal physiologists (Dr. G.M.T. Hare and
colleagues) who shared the goal of better understating the impact of acute β-blockade on critical
brain oxygen delivery, and stroke risk, in patients undergoing non-cardiac surgical procedures.
Although the publication of the POISE trial focused our attention on this problem in 2008,6 early
“danger signals” were already being assessed as early as 2005.
Our involvement began by completing translational animal studies to determine the risk of tissue
hypoxia in the brain following acute hemodilutional anemia. We identified that tissue hypoxia
(reduced brain tissue PO2) and increased expression of hypoxic signaling molecules (nNOS,
HIF) occurs early and progressively with decreasing hemoglobin levels.10-13 This suggested that
the well characterized anemia-induced increase in cerebral blood flow associated with acute
anemia did not result in “luxury perfusion” and increased brain oxygen delivery.14 In direct
contrast, it suggested that the increase in CBF was an adaptive mechanism directed at
maintaining adequate brain tissue perfusion to maintain adequate oxygen homeostasis. As β2mediated vasodilation was thought to contribute, we assessed the impact of a specific β2antagonist on cerebral tissuePO2 during acute anemia. We observed a decrease in cerebral
cortical blood flow and PO2 associated with β2-antagonism.15 After presenting our preliminary
data at the CAS annual meeting (Richard Knill Competition 2005); Dr. Scott Beattie approached
us with concerns about a potential “stroke signal” in β-blocked patients within his clinical
database. As a result, we undertook a number of studies to test the hypothesis that acute β-
blockade interrupts the adaptive cardiovascular responses to acute anemia leading to increased
cerebral hypoxia and stroke.
The first clinical correlate to our animal research was that pre-preoperative anemia was an
independent risk factor associated with increased mortality in patients undergoing non cardiac
surgery.16 This finding was in agreement with experimental animal findings those both acute and
chronic anemia are associated with increased tissue hypoxia and hypoxic cellular signaling, and
mortality.13;17-19
The second step in the mechanistic animal experimental approach was to demonstrate that acute
β-blockade with metoprolol worsened anemia included-cerebral hypoxia and increased
expression of hypoxia cell signaling as suggested by the increases risk of stroke observed in
patients who experienced acute blood loss in the treatment arm of the POISE trial.6 We observed
a sever worsening of cerebral perfusion and a dramatic decrease in brain tissue PO2 after acute
hemodilution in rats treated with metoprolol. This study was paralleled by the retrospective
observational finding that acute anemia accentuated adverse clinical outcomes associated with
perioperative β-blockade –including MACE20- however, an association with stroke incidence
was yet to be determined.
The primarily attributed to impairment in the cardiac output response to acute anemia; however,
the magnitude of the change in brain tissue PO2 suggested that an additional mechanism may be
involved. As the cardio selectivity of metoprolol is not very high, we formulated a secondary
hypothesis that acute interaction of metoprolol with the β-2 receptor may impair the cerebral
vasodilatation and tissue oxygen delivery during acute anemia. In vitro mouse studies
demonstrated that metoprolol inhabited β-2 mediated vasodilatation in a dose dependent manner
in both cerebral and mesenteric arteries.21 In addition, acute administration of metorprolol
impaired cerebral perfusion at rest in whole mouse experiments, in association with an increase
in systemic vascular resistance.21 This lead to a third experimental study in which we assessed
the impact of the highly selective β-blocker nebivolol on cerebral perfusion during anemia. We
assessed 2 doses of nebivolol: a low dose which would predominantly impact β-1 receptors on
the heart and a high dose which would be expected to interact with both the β-1 (heart) and β-2
(cerebral vasculature) receptor, based on the pharmacokinetic profiles of these chosen drug
doses.22 The data demonstrate that while both drug doses equally impaired cardiac output during
acute anemia, only the higher drug dose further attenuated cerebral perfusion and increased
expression hypoxic cell signaling molecules. Thus, the higher dose of nebivolol may have
impacted both the cardiac and cerebral vascular responses to acute anemia. This collective
experimental data led to the design of a final targeted retrospective database analysis directed at
testing the hypothesis that stroke risk in perioperative β-blocked patients would be increased in
those patients treated with a relatively non-selective β-antagonist (metoprolol).
These data were used to re-interrogate the clinical database with a high fidelity approach to
determining the impact of β-blockade and perioperative strokes. As the incidence of
perioperative stroke is low (<1%); this approach necessitating data collection form a very large
cohort of patients. Once completed the result from a propensity matched comparison of patients
treated with metoprolol (less cardioselective) vs. bisoprolol (more cardioselective) demonstrated
a higher stroke incidence in those patients treated with metoprolol.23 While the retrospective
nature of this trial do not allow us to suggest a causal relationship, corroborative findings from
other retrospective analysis are in agreement with the finding that perioperative treatment with
metoprolol is associated with a higher stroke rate, relative to other less, selective β-antagonists.24
While these translational studies in animal and humans are supportive of the hypothesis that the
appropriate use of more cardioselective β-blockers may reduce the risk of cardiac ischemia,
without increase sing stroke risk, the results are not as-of yet- causal. However, a strong basis
for a prospective randomized prospective trial to test the hypothesis has been established.
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