Letters to the Editor: Letter to the Editor
To the Editor
In a recent paper investigating the dose-dependent effects of nebivolol (1.25 and 2.5 mg/kg) on the changes in regional cerebral blood flow (rCBF) after an isovolemic exchange of blood for 10% pentastarch in isoflurane-anesthetized rats (hemoglobin reduced to approximately 60 g/L), Hu et al.1 found that hemodilution caused marked increases in rCBF, which were not affected by pretreatment with low-dose nebivolol, but were completely abolished with high-dose nebivolol. The authors theorized that high-dose nebivolol abolished the increase in rCBF during hemodilution because the plasma drug levels were sufficient to block the cerebral β2-adrenergic receptors. This theory is based on the assumption that the β2-adrenergic receptors mediate cerebral vasodilation during hemodilution. In support of this mechanism, Hu et al. cited results from a previous study in their laboratory using the same rat model, which demonstrated that the selective β2-adrenergic antagonist, ICI 118,551, caused marked attenuation of the increases in rCBF during hemodilution.2
We have demonstrated in pentobarbital-anesthetized dogs that hemodilution of a similar degree to that studied by Hu et al.1 caused increases in blood flow to regions of the brain (cerebral cortex, cerebellum, pons, medulla, and spinal cord), as evaluated with the radioactive microsphere technique, which were well preserved after high-grade, nonselective β-adrenergic blockade with propranolol (1 mg/kg IV).3 The completeness of the β-adrenergic blockade was confirmed by its ability to completely abolish the inotropic and depressor responses to isoproterenol (5 µg, IV), and to cause pronounced decreases in heart rate (−27%), dP/dtmax (−40%), and aortic blood flow (−28%). Since propranolol has been demonstrated to freely cross the blood–brain barrier,4 our findings suggest that neither the β1- nor the β2-adrenergic receptors play an important role in mediating vasodilation in the regional circulations of the brain during hemodilution.
In addition to vasomotor tone, arterial blood pressure and blood viscosity are determinants of cerebral blood flow during hemodilution.5 β-Adrenergic blockade markedly attenuated the increase in cardiac output accompanying hemodilution in our study and that of Hu et al.,1 but, in both studies, arterial blood pressure was well maintained (>90% of control value), reflecting an increase in systemic vascular resistance presumably via the arterial baroreceptor reflex.6 Thus, a difference in arterial blood pressure cannot explain the different cerebral blood flow findings in the 2 studies. Furthermore, the decrease in hematocrit, and therefore in blood viscosity, was similar in the absence and presence of β-adrenergic blockade in both studies, which also excludes this factor.
Possible explanations for the discrepancy in the cerebral blood flow findings in our study and that of Hu et al.1 include differences in species, method used to measure cerebral blood flow, and anesthetic technique. In any case, a balanced review of the literature indicates that the role of the β-adrenergic receptors in the increased cerebral blood flow during hemodilution remains a matter of debate. Further studies are required to resolve this issue.
George J. Crystal, PhD, FAHA
M. Ramez Salem, MD
Department of Anesthesiology
Advocate Illinois Masonic Medical Center
1. Hu T, Beattie WS, Mazer CD, Leong-Poi H, Fujii H, Wilson DF, Tsui AK, Liu E, Muhammad M, Baker AJ, Hare GM. Treatment with a highly selective β1
antagonist causes dose-dependent impairment of cerebral perfusion after hemodilution in rats. Anesth Analg. 2013;116:649–62
2. Hare GM, Worrall JM, Baker AJ, Liu E, Sikich N, Mazer CD. Beta2 adrenergic antagonist inhibits cerebral cortical oxygen delivery after severe haemodilution in rats. Br J Anaesth. 2006;97:617–23
3. Crystal GJ, Ruiz JR, Rooney MW, Salem MR. Regional hemodynamics and oxygen supply during isovolemic hemodilution in the absence and presence of high-grade beta-adrenergic blockade. J Cardiothorac Anesth. 1988;2:772–9
4. Olesen J, Hougård K, Hertz M. Isoproterenol and propranolol: ability to cross the blood-brain barrier and effects on cerebral circulation in man. Stroke. 1978;9:344–9
5. Fan FC, Chen RY, Schuessler GB, Chien S. Effects of hematocrit variations on regional hemodynamics and oxygen transport in the dog. Am J Physiol. 1980;238:H545–22
6. Crystal GJ, Salem MR. The Bainbridge and the “reverse” Bainbridge reflexes: history, physiology, and clinical relevance. Anesth Analg. 2012;114:520–32