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Cardiac Output: The Neglected Stepchild of the Cerebral Blood Flow Physiology Family

Drummond, John C. MD, FRCPC*,†

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Journal of Neurosurgical Anesthesiology: April 2020 - Volume 32 - Issue 2 - p 93-94
doi: 10.1097/ANA.0000000000000677
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The notion that cardiac output (CO) might influence cerebral blood flow (CBF) is not new.1,2 Yet, despite substantial evidence that some relationship exists, the concept is not widely acknowledged. During the most recent meeting of the Society for Neuroscience in Anesthesiology and Critical Care, CBF autoregulation was the subject of numerous presentations and not once was CO mentioned. A suggestion once made by coauthors and me,3 that epinephrine used to support the circulation during hypotension might have enhanced CBF via an effect on CO was met with reviewer derision and passed through the review process only in a much diluted form. Why has such a frequently described phenomenon not achieved credibility among anesthesiologists?

I suspect that there are several elements to the explanation for the nonacceptance of this concept: (1) there is no tidy, unifying mechanism to explain the phenomenon in all of the situations in which it has been observed; and (2) the relationship between CO and CBF is not always evident, and may exist only in specific situations of physiological stress. The problem of acceptance has been compounded by some attempts to explain the phenomenon that have yielded physiological gobbledygook that has done more to discredit the idea than to support it.

MECHANISMS

There are likely to be at least 2 separate mechanisms that are operative in different situations and which may sometimes be simultaneously in play: (1) a sympathetic nervous system (SNS)-mediated vasoconstriction of extracranial and proximal intracranial vessels; and (2) a vasodilatory effect of pulsatility on more distal cerebral arterioles.

SNS-mediated Vasoconstriction

There is extensive SNS innervation, via the cervical sympathetic chain, of extracranial cerebral vessels and proximal intracranial vessels to at least the circle of Willis.4 Teleologically, it seems likely that Mother Nature provided this innervation to protect the cerebrum from sympathetically mediated increases in systemic blood pressure. But the unintended consequence may be that sympathetic stimulation from other causes, for example, the SNS response to decreased tissue perfusion/shock, may mean that low CO causes a decrease in CBF that is additive to the simultaneous effects of reduced mean arterial pressure (MAP) per se. As thoroughly reviewed by ter Laan et al,5 numerous studies have demonstrated an increase in CBF after extirpation or pharmacologic blockade of the cervical sympathetic chain. The evidence is clear, but acceptance of it has been limited. Perhaps it is because, while we are all aware at an anatomic level of the existence of “baro-stats,” there is no recognized “flow-stat.” But from the body’s ability to maintain MAP in the face of a decreasing intravascular volume and the associated reduction of CO, we know that a vigorous SNS response occurs, either in reaction to changes in input from baroreceptors or, perhaps, as a nonspecific response to tissue hypoperfusion. I suspect that the most important clinical implication of this phenomenon resides in the use of α1 agonists to support MAP. It is often asserted, erroneously I have argued,6 that α1 agonists cause direct cerebral vasoconstriction in humans. But, they are not direct cerebral vasoconstrictors.6 However, if they are used in a manner that further decreases an already reduced CO, it seems likely that they will have the potential to reduce CBF. I will further suggest, speculatively, that the once alleged association between α1 agonists and ischemic optic neuropathy7 is precisely this phenomenon at work. I have also wondered whether the difficulty in defining clear MAP thresholds for central nervous system ischemic injury arises in part because CO is an unmeasured variable that has muddled the MAP-CBF connection in the retrospective analyses that have sought to define that relationship.8 Is a normal CO also one of the reasons why relative hypotension seems so remarkably well tolerated during cardiopulmonary bypass? Further complicating the situation is that the extent to which the many agents used as components of general anesthesia might blunt the CO-SNS-CBF relationship, and thereby increase its variability, is unstudied.

Increased Arterial Pulsatility

The potential role of increased arterial pulsatility is a more difficult case to make with physiological certainty. Central to the argument is the observation that CO augmentation by dobutamine administration has been associated with increased CBF in several pathophysiologic states, including subarachnoid hemorrhage,9 sepsis,10 traumatic brain injury,11 and stroke.12 But there are flies in this physiological ointment. First, the number and size of the supportive clinical studies are limited (although I am unaware of studies with contrary observations). Second, and more importantly, while an independent association between CO and CBF was reported in all of these studies, in some10,12 there were simultaneous, albeit modest, increases in MAP. The important exceptions were the studies in subarachnoid hemorrhage and traumatic brain injury, in which CO increased without a simultaneous increase in MAP.9,11 If CO or MAP were initially at subnormal levels, reduction of the SNS-mediated vasoconstriction described above might have contributed to these observations. But in the studies of subarachnoid hemorrhage, stroke, and traumatic brain injury, both CO and MAP were initially normal.9,11,12 To many, dobutamine in the absence of an increase in MAP would seem intuitively unlikely to result in an increase in CBF. Herein, we are the prisoners of Ohm’s law: flow=pressure/resistance. For the cerebral circulation, CBF=MAP/cerebral vascular resistance (CVR). We do not recognize direct effects of dobutamine on CVR. Ergo, if MAP is constant, CBF should not change. But are we sure that CVR is unchanged? Typically, dobutamine, while leaving MAP little changed, is associated with an increase in pulse pressure. The literature, largely related to cardiopulmonary bypass, that compares pulsatile and nonpulsatile flow is replete with data demonstrating better microcirculatory flow with the former.13 The differences have been attributed to both nitric oxide release from vascular endothelium and altered baroreceptor responses to pulsatility.14,15 Approximately 50% of total CVR is in smaller more distal vessels where changes in diameter might have too small an effect to cause detectable changes in MAP and total systemic vascular resistance. Further support for a role for increased pulsatility in CBF augmentation are the increases in CBF, or improvement in neurological function, observed in association with intra-aortic balloon counter-pulsation (typically associated with increased CO and pulsatility) that have been observed in patients with stroke and subarachnoid hemorrhage.16,17

Although SNS-mediated vasoconstriction and increased pulsatility have been presented as independent mechanisms, it is probable that they are often in play simultaneously. Interventions that increase CO will often be associated with increased pulsatility and vice versa (Fig. 1).

FIGURE 1
FIGURE 1:
Proposed mechanisms for the effects of cardiac output on cerebral blood flow. The underlying mechanisms (decreased output from the cervical sympathetic ganglia and increased pulsatility) are indicated by bold outline. Lg indicates large; Sm, small; ↑, increased; (+/−), the mechanism may not be operative when cardiac output is initially normal; Δ, change in; ↓, decreased.

Again, I acknowledge that the variability and mechanistic uncertainty of the effects of CO on CBF make the limited recognition of the CO-CBF connection somewhat understandable. But in the face of the information that is available, I will make so bold as to suggest that a very relevant application of this phenomenon attends the anesthesiologist facing intraoperative hypotension, and the attendant CO reduction, that are the derivatives of hypovolemia. Flogging the circulation with α1 agonists in this situation, to augment BP in the name of supporting flow to the central nervous system, may well have exactly the opposite effect via further reduction of CO. Second, while the supporting data are not strong enough to advocate introducing dobutamine in the face of conditions associated with cerebral ischemia when hemodynamic support is not otherwise warranted, they are sufficient to support the suggestion that dobutamine might be a good first choice agent when need for that support arises. Although the slipper may not fit on all physiological occasions, it occasionally does, and CO will then be an important member of the CBF physiology family.

John C. Drummond, MD, FRCPC*†
*Department of Anesthesiology, The University of California
†Anesthesia Service, Veterans Affairs Medical Center San Diego, CA

REFERENCES

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