There are occasionally intraoperative circumstances in which reduction of mean arterial pressure (MAP) to levels well below those that occur in nonanesthetized adultsa is necessary or unavoidable. In these situations, clinicians are inevitably concerned about the limits of the tolerance of the central nervous system (CNS) for MAP reduction. Simply put, what are the thresholds at which the risk of ischemic injury becomes substantial in adult humans? That is the question that this submission attempts to address. The question invites answers expressed as numeric thresholds. However, it should be understood at the outset that any numeric values that are offered represent population averages. There are large SDs on most biological responses, and pushing physiology on the basis of averages will almost certainly lead practitioners occasionally to discover individual outliers who are less tolerant of hypotension. There is a second variable, “time,” in the injury/no injury equation. Inevitably, there are MAPs that will be tolerated when hypotension is brief but that will not be tolerated when it is sustained. In the “MAP × time = sufficient to cause injury” equation, MAP and time will inevitably be inversely proportional, and the threshold values will be impossible to predict for individual patients.
Any discussion of the tolerance of the CNS to relative hypotension will inevitably give emphasis to the topic of CNS blood flow autoregulation. Cerebral blood flow autoregulation refers to the capacity of the CNS to maintain blood flow levels relatively constant across a range of MAPs, assuming that other elements of physiology are held constant. Figure 1 includes a typical cerebral blood flow autoregulation “curve” (the solid line) depicting the relationship between MAP and cerebral blood flow. There is a central plateau bounded by inflection points representing the lower and upper limits of cerebral blood flow autoregulation, below and above which, respectively, the cerebral circulation is pressure passive, with cerebral blood flow varying pari passu with MAP. In Figure 1, the lower limit of cerebral blood flow autoregulation and the upper limit of cerebral blood flow autoregulation are represented as a value in the low 70s and 150 mm Hg, respectively. The parameter on the x-axis of cerebral blood flow autoregulation curves is sometimes cerebral perfusion pressure, rather than MAP. Cerebral perfusion pressure is calculated as MAP – intracranial pressure (ICP). Cerebral perfusion pressure is used less often because a measure of ICP measures is often unavailable. Normal ICP is 5–10 mm Hg. A MAP of 70 mm Hg can be viewed as equivalent to a cerebral perfusion pressure of 60–65 mm Hg. The details of the physiological mechanisms of cerebral blood flow autoregulation are not critical to this review. While other processes may be involved,1 cerebral blood flow autoregulation is probably largely myogenic (ie, a function of local vascular smooth muscle response to changing intraluminal pressure in vessels between the distal carotid and vertebrobasilar arteries and pial arteries down to diameters in the vicinity of 100–200 μm).2
MISUNDERSTANDINGS ABOUT AUTOREGULATION
There appear to be several aspects of the cerebral blood flow autoregulation phenomenon that may not be fully appreciated by all clinicians. Chief among them are: (1) that the average lower limit of cerebral blood flow autoregulation (ie, that MAP below which cerebral blood flow is pressure passive and MAP and cerebral blood flow vary linearly), resides at a MAP significantly greater than the widely advertised value of 50 mm Hg; and (2) that the effectiveness of cerebral blood flow autoregulation varies enormously from individual to individual. While an autoregulatory plateau, as depicted in Figure 1, is readily demonstrable in some normal subjects, in others it is less evident.3 One consequence of this variability is that cerebral blood flow autoregulation represents a much more effective buffer against the injurious potential of hypotension in some individuals than in others.
- 1. The lower limit of autoregulation: There is probably considerable misunderstanding about the numerical value of the average adult lower limit of cerebral blood flow autoregulation. While diagrams that have appeared for many years in standard textbooks have commonly depicted the adult human lower limit of cerebral blood flow autoregulation as approximately 50 mm Hg, the actual average lower limit of cerebral blood flow autoregulation for a nonanesthetized adult is unlikely to be anything less than an average MAP value in the low 70s, with considerable variation among individuals. Nonetheless, 50 mm Hg has been widely cited for decades as the human lower limit of cerebral blood flow autoregulation (and this author certainly on the list of those who have promulgated that misinformation4). While that value may apply in several small animal species, it most definitely is not applicable to humans. The widely quoted “50” is probably derivative of a figure (Figure 2) that appeared in a review of cerebral physiology by Lassen,5 published in 1959. The figure displayed a composite of the then available data on a graph of MAP versus global cerebral blood flow. The hand-drawn curve through the various points on that graph certainly appears to indicate a lower limit of cerebral blood flow autoregulation of approximately 50 mm Hg. The left-hand end of that curve is anchored by data from an investigation by Finnerty et al.6 In that study, blood pressure was lowered in nonanesthetized subjects sufficiently to produce symptoms of cerebral ischemia, and the data points that anchor the left-hand end of Lassen’s curve, identified as “1” and “2” and circled in Figure 2 are cerebral blood flow values recorded at the ischemic symptom MAP threshold. The origin of those data points is not specified by Lassen.5 In Finnerty et al’s6 total population of 37 subjects, some of whom had untreated hypertension, symptoms occurred at an average MAP of 48 mm Hg and were associated with a roughly 40% reduction in global cerebral blood flow. My extraction of Finnerty et al’s6 data for 12 normotensive subjects (baseline MAP 91 ± 10, range 75–103 mm Hg and average age 46 ± 13 years) indicates a MAP ischemia threshold of 38 ± 11 mm Hg, with a cerebral blood flow reduction of 35%. Whichever of Finnerty et al’s6 patients are represented on the Lassen5 figure, it seems unlikely that the lower limit of cerebral blood flow autoregulation is actually the value suggested by his graph. The lower limit of cerebral blood flow autoregulation is likely to be substantially greater than the MAP at which symptoms and a 35%–40% reduction of cerebral blood flow are observed. Furthermore, in several other investigations, the average threshold for the onset of ischemic symptoms was determined to occur at MAPs that support the improbability of an average lower limit of cerebral blood flow autoregulation of 50 mm Hg in adult humans: Morris et al,8 62 mm Hg; Moyer et al,9 “approaching” 55 mm Hg; Strandgaard,10 43 mm Hg; and Njemanze7 (vide infra), 49 mm Hgb. Nonetheless, the apparent impact of the Lassen5 publication has been remarkably durable. One continues to see reference, in nominally rigorously reviewed forums, to a lower limit of cerebral blood flow autoregulation of 50 mm Hg.11
The Table presents the results of the available studies performed in neurologically normal adult humans which yielded either specific determinations of the lower limit of cerebral blood flow autoregulation10,12–16 or data that provide insight into the MAP range above or below where it must reside.9,17,18 All of the studies, except that of Joshi et al,16 entailed static determinations (ie, they used a measure of cerebral blood flow or some variable that can reasonably be expected to vary in a linear relationship with cerebral blood flow, during sustained periods of stable MAP). The data collectively indicate that average lower limit of cerebral blood flow autoregulation for a nonanesthetized adult cannot be less than a MAP in the low 70s. Two of the entries are superficially inconsistent with that conclusion. The study by McCall16 used hydralazine or veratrum viride to induce hypotension in pregnant women late in the third trimester. The effects of late pregnancy on the cerebral circulation are not well characterized; and hydralazine is known to be a cerebral vasodilator. The effect of veratrum viride is obscure. The report by Joshi et al16 offers the lowest estimated average human lower limit of cerebral blood flow autoregulation (66 mm Hg, CI, 43–90) and deserves detailed comment, in large part because it is the only entry in the Table that involves anesthetized subjects. First, for at least for 2 reasons, the observed mean lower limit of cerebral blood flow autoregulation of 66 mm Hg is not inconsistent with the conclusion offered above that average adult lower limit of cerebral blood flow autoregulation is not less than a MAP in the low 70s. That investigation was performed in patients on cardiopulmonary bypass (CPB). The experimental conditions were such that a given MAP would be likely to achieve a better than typical cerebral perfusion pressure (cerebral perfusion pressure = MAP − ICP). Under the conditions of the study, the patients probably had very low ICPs. The combination of depressed cerebral metabolic rate (isoflurane 0.5%–1.0%, 33°C) and very low venous pressures because of gravity drainage of the right heart drainage on CPB was likely to render ICP as low as it is in any physiological circumstance. Second, the authors identified impaired cerebral blood flow autoregulation on the basis of a dynamic cerebral blood flow autoregulation index derived from %Δcerebral blood flow velocity/%ΔMAP, using 0.4 as the threshold value to define impaired cerebral blood flow autoregulation. As acknowledged by the authors, the choice of threshold was arbitrary. Had they selected the lower threshold values (eg, 0.3) used by others (see Table 1 in the review by Rivera-Lara et al19), their calculated lower limit of cerebral blood flow autoregulation would have been a MAP >70 mm Hg.
It is notable that the report by Joshi et al16 represents the only published determination of the lower limit of cerebral blood flow autoregulation in anesthetized, neurologically normal adult humans. It is possible that the use of vasodilating anesthetic agents and/or the blunting by anesthetic agents of the sympathetic response to hypotension might result in lower limit of cerebral blood flow autoregulation values than those that are presented for the nonanesthetized subjects in the Table. However, it appears unreasonable to this reviewer to entrust the well-being of our patients to speculation of that nature. Pending additional data, it seems appropriate to assume that the average lower limit of cerebral blood flow autoregulation in adult humans is not <70 mm Hg.
- 2. The intersubject variability of autoregulation: The Table also provides the ranges, SDs, or CIs associated with the observed average lower limit of cerebral blood flow autoregulations. The intersubject variability is remarkable. From those data, it might reasonably be concluded that at least some of the normal subjects included in these studies probably did not have cerebral blood flow autoregulation plateaus within the range of MAPs that are likely to occur during general anesthesia. In fact, in an investigation by Lucas et al3 that examined variation in cerebral blood flow velocity with MAP (though it did not attempt to calculate a lower limit of cerebral blood flow autoregulation), no apparent autoregulatory plateau was evident in any of 11 normal subjects.
The typical “one-size-fits-all” diagrammatic representations of cerebral blood flow autoregulation that have appeared widely in standard texts are likely to be misleading in several respects. First, some misrepresent (underestimate) the average lower limit of cerebral blood flow autoregulation. Second, in some subjects, the plateau is considerably narrower than the 80–100 mm Hg width often suggested.20 Third, the absolutely horizontal representation of the cerebral blood flow autoregulation plateau is likely to be inaccurate. When a cerebral blood flow autoregulation plateau exists, it probably has a slightly positive slope.1 Cerebral blood flow autoregulation diagrams would be more representative of normal physiology if they were presented as a family of curves (Figure 1) to emphasize the interindividual variability of cerebral blood flow autoregulation.
ADDITIONAL COMMENTS ABOUT AUTOREGULATION
Before discussing the clinical implications of the foregoing, there are 2 additional topics of relevance to clinicians attempting to understand the literature on cerebral blood flow autoregulation: (1) the use of term “impaired autoregulation”; and (2) the influence of cardiac output (CO) on cerebral blood flow autoregulation.
- Impaired autoregulation: One often hears or reads that such and such “impairs autoregulation.” With some frequency, those using that phrase fail to specify whether they are referring to the cerebral blood flow autoregulation response to increasing blood pressure or decreasing blood pressure (or both). It is the latter, decreasing blood pressure, that is likely to be of greater clinical importance. An impaired response to increasing blood pressure will result in sustained vascular engorgement in the event of hypertension. Isoflurane, for instance, impairs the response to increasing blood pressure more so than sevoflurane,21,22 but this is infrequently likely to be a matter of intraoperative consequence. Furthermore, a rapid change in blood pressure will result in a transient (ie, 3–4 minutes) alteration in cerebral blood flow even when cerebral blood flow autoregulation is intact. Impairment of the response to decreasing blood pressure, and therefore a reduced ability to maintain cerebral blood flow in the event of hypotension, is of greater concern. However, even agents that render the cerebral circulation pressure passive (eg, some volatile agents and blood pressure–lowering drugs), and, therefore by definition, “impair autoregulation,” may not actually be deleterious to the maintenance of perfusion. Whether or not they differ in their effects on cerebral blood flow autoregulation, there is nothing to choose between isoflurane and sevoflurane in terms of cerebral blood flow during hypotension. While isoflurane and sevoflurane do not actually cause an increase in cerebral blood flow during blood pressure reduction, both cause a state of relative luxury perfusion during hypotension.23,24 Furthermore, the vasodilation caused by some agents that impair autoregulation may actually result in a greater cerebral blood flow at a given MAP. Pharmacologically impaired autoregulation does not always represent a bogeyman that must be dreaded and avoided.
- The influence of CO on autoregulation: While the widely reproduced diagrams of cerebral blood flow autoregulation depicting cerebral blood flow as a function of MAP (or cerebral perfusion pressure) do not acknowledge CO as a relevant variable, there is, in fact, considerable evidence that, in at least some circumstances, it is.25–33 Ogoh et al29 reported a linear relationship between CO and middle cerebral artery mean blood velocity at rest and during exercise that was independent of Paco2. Ide et al25 observed that the increase in cerebral blood flow velocity that normally occurs during intense exercise was attenuated by beta blockade. Because beta blockade had no effect on cerebral blood flow velocity during minimal exercise, they surmised that the effect was the result of limitation of CO. The same authors reported that patients with atrial fibrillation also had a reduced ability to increase cerebral perfusion during exercise, which they attributed to their impaired ability to increase the CO.26,31 A study by Kim et al27 revealed that increases in CO without changes in MAP increased cerebral blood flow in the setting of cerebral vasospasm after subarachnoid hemorrhage. The relationship is not evident in the face of all pathology, and the mechanisms are uncertain. However, sympathetic innervation of the cerebral vessels may be involved. The sympathetic response to a decrease in blood pressure has been shown to contribute to the reduction of cerebral blood flow that occurs during hypotension.34 This is thought to be mediated, at least in part, via adrenergic innervation of extracranial and proximal intracranial arteries,35,36 because cerebral blood flow reduction is attenuated by blocking or extirpating the cervical sympathetic chain.34 Whatever the mechanism, clinicians who seek to maintain CNS blood flow by support of MAP should probably be mindful of the possibility that increasing MAP at the expense of CO may not achieve the desired CNS blood flow augmentation.
WHY SO LITTLE HARM?
If the 2 “misunderstandings” that have just been asserted are, in fact, prevalent, clinicians who have seen a great many patients with sustained MAPs <70 mm Hg, might well ask, “Why has there not been a greater incidence of cerebral injury?” There are 2 principal reasons: (1) The CNS blood flow reserve; and (2) the predominant use of horizontal positions for the performance of surgery.
- 1. The CNS blood flow reserve: The healthy human nervous system lives in a state of luxury perfusion. Resting CNS flow considerably exceeds the minimum required to deliver adequate energy-yielding substrates. Herein, the difference between resting CNS flow and the flow at which the earliest symptoms of CNS ischemia occur will be referred to the as the “CNS blood flow reserve.” Some clinicians may not be aware of the CNS blood flow reserve and may therefore not be sensitive to situations in which the reserve may not be present and in which patients are therefore likely to be more vulnerable to hypotension than would be the case in the face of normal physiology. The brain can tolerate a reduction of the baseline cerebral blood flow of approximately 35%–40% before the onset of ischemic symptomatology.6,7 Note that even the ischemic symptom threshold is highly unlikely to be the threshold for injury unless the reduced blood flow is very sustained. The investigation by Finnerty et al,6 which observed symptoms at an average cerebral blood flow reduction of 40%, has been mentioned above. Njemanze,7 using a tilt table, studied cerebral blood flow velocity changes in patients susceptible to postural hypotension. His observations in 40 patients 56 ± 18 years of age were that ischemic symptomatology began with average cerebral blood flow velocity reductions from baseline of 35%, and that syncope ensued at average reductions of 50%. Probably of greater interest to clinicians are the MAPs at which those symptom thresholds occurred. For Finnerty et al’s6 entire 37-subject group, which included some untreated hypertensives, symptoms occurred at an average MAP of 48 mm Hg. For his normotensive subjects, the average was 38 mm Hg.6 In the study by Njemanze,7 blood pressure was measured with a blood pressure cuff applied to the arm.7 By assuming a vertical distance from midcuff to the external auditory canal of 12 inches, I estimate that the MAP at the symptom threshold was 40 mm Hg. In an additional investigation, Strandgaard10 identified a MAP of 43 ± 8 mm Hg as the threshold for cerebral ischemic symptoms in normotensive subjects in whom blood pressure was reduced with trimethaphan. Cerebral blood flow was not measured at the time of symptom onset. A reasonable summary of the available literature is that the first signs of insufficient oxygen delivery to the brain will occur in normotensive adult subjects at MAPs between 40 and 50 mm Hg at the level of the circle of Willis. Note that these numbers are MAPs and not cerebral perfusion pressures, and should be assumed to apply only when ICP is normal (ie, relatively low).
The CNS blood flow reserve serves as a critical buffer against the adverse effects of hypotension and is the principal reason why blood pressures well below resting normal levels are so frequently well tolerated in the operating room environment. However, it is my perception that this CNS blood flow reserve phenomenon is not emphasized in the training received by anesthesiologists, and that at least some clinicians are minimally aware of the phenomenon. As a result, some clinicians may fail to recognize situations in which the normal CNS blood flow reserve has already been compromised, rendering individual patients relatively more vulnerable to hypotension. There are at least 5 situations (discussed later in the section, “Compromise of the CNS Blood Flow Reserve”) in which this may occur: (1) recent central nervous injury; (2) raised local tissue pressure; (3) chronic hypertension; (4) loss or absence of collateral blood flow pathways; and (5) vertical hydrostatic blood pressure gradients between the heart and the brain.
- 2. Horizontal surgical positions: In any fluid column that is directed upward by an ejecting force, the pressure within that column diminishes in proportion to the height above the source. If a garden hose is pointed upward, the water rises until the weight of the vertical column produces a pressure equal to that at the nozzle. This same reduction in pressure occurs in a vertically oriented arterial system. The magnitude of the effect, based on the density of blood, is such that for every inch (2.54 cm) of vertical displacement, pressure within the column can be expected to decrease by 2 mm Hg. If the MAP of the blood exiting the aortic valve is 95 mm Hg, by the time it has traveled roughly 12 inches vertically to the level of the circle of Willis, the pressure will be 95 − (12 × 2 = 24) = 71 mm Hg. This leads to the second explanation (the first is the CNS blood flow reserve, vide supra) for the apparent tolerance of the human brain to the relative hypotension that is so common during general anesthesia. In a patient anesthetized with the head at the level of the heart, an intraoperative MAP of 70 mm Hg is “normal” in terms of cerebral perfusion pressure. (In the horizontal position, ICP is inevitably greater than in the vertical position. Therefore, at a constant MAP at the circle of Willis, cerebral perfusion pressure will actually be slightly lower in the horizontal position.) This arithmetic means that the first 20%–25% reduction in MAP as measured by a blood pressure cuff on the arm is literally “free” in terms of its effects on cerebral perfusion pressure. At a MAP of 70 mm Hg in a horizontal position, cerebral perfusion pressure is very little different from that which occurs in the sitting or standing positions. This explains the absence of intraoperative cerebral harm, which, in turn, has probably contributed to the relatively casual prevailing attitudes about relative hypotension intraoperatively. This bit of physiological naivety has been reinforced by investigations purporting to demonstrate the absence of adverse cerebral effects of “hypotension,” using a MAP of 70 mm Hg as the definition of hypotension.37 It also is probably part of the explanation for why the superficially logical relationship between the incidence of stroke and intraoperative hypotension has not been conspicuous across many investigations.38–40 CPB has been the context in which the stroke–hypotension relationship has been examined most extensively. However, there are 2 limitations with that literature. The first is the problem that any conclusion derived from the high stroke-risk patients common in the context of CPB may not be broadly relevant. Second, and more significant, is the difficulty that the studies comparing MAP ranges during CPB present contradictory conclusions.40 Two recently published studies highlight that difficulty. The retrospective investigation by Sun et al41 reported an association between stroke and intraoperative MAP of <64 mm Hg. However, a randomized, prospective investigation by Vedel et al42 comparing MAPs of 40–50 vs 70–80 mm Hg reported no differences in stroke rate (with any trends leaning in favor of the lower MAP). Whatever the causative role of hypotension in the occurrence of stroke, it has been theorized that hypotension may be more important as an aggravator of thromboembolic strokes that have occurred independently by reducing clearance of microemboli or perfusion in boundary zones.43–45
COMPROMISE OF THE CNS BLOOD FLOW RESERVE
At least 5 circumstances can result in a reduction of the blood flow reserve that normally serves so well to buffer the healthy human CNS against the adverse effects of hypotension.
- CNS injury: Autoregulation is a physiologically fragile phenomenon. Many CNS injury states,46 but most particularly, subarachnoid hemorrhage47 and traumatic brain injury,48 and probably spinal cord injury and stroke,49 have the potential to impair the cerebral blood flow autoregulation response to hypotension and to render blood flow pressure passive in response to blood pressure reduction. In addition, acute traumatic brain injury and subarachnoid hemorrhage commonly result in resting cerebral blood flow values that are approximately 50% of those seen in normal subjects. These 2 phenomena, impaired cerebral blood flow autoregulation and reduction in resting CNS blood flow, are well demonstrated in the setting of human traumatic brain injury and subarachnoid hemorrhage.50,51 They are less well demonstrated for spinal cord, but the physiology of the spinal cord is a “microcosm of the brain,”52 and it is reasonable to assume, pending information to the contrary, that impaired autoregulation and low baseline flow occur there as well. The implications are presented graphically in Figure 3, in which the line of pressure passivity is drawn through a CNS blood flow value that is approximately half of normal. Reduction of MAP in a normal subject to 50 mm Hg might encroach significantly but not critically on the CNS blood flow reserve, but the same blood pressure reduction occurring in the face of recent CNS injury might reduce flows to injurious levels.53–55 The duration of this impaired autoregulation/low flow state is known to be at least 72 h and sometimes considerably longer after traumatic brain injury.48,56 It has been shown to persist for 7 days in animal models of spinal cord injury, and the current clinical recommendation is for 7 days of MAP support.57,58 The assumption that at least 7 days of MAP support is appropriate in all acute CNS injury situations appears prudent.
- Raised local tissue pressure: Anything that exerts direct local pressure on the CNS and thereby raises local tissue pressure reduces the net perfusion pressure achieved by a given MAP. While discussions of acceptable intraoperative blood pressures frequently focus on MAP, it is really perfusion pressure that is the important variable. Perfusion pressure is the difference between MAP and venous pressure or local tissue pressure, whichever is greater. In many instances, venous pressure and local tissue pressure are unknown. However, in many normal circumstances, those pressures are relatively low, and, as a result, MAP becomes a reasonable surrogate for perfusion pressure. However, when local tissue pressures are raised, MAP may substantially underestimate perfusion pressure. This consideration is already familiar in some contexts. The importance of taking ICP into consideration in determining cerebral perfusion pressure is well established, but there are other circumstances in which this local pressure phenomenon is relevant, including cervical spinal stenosis, any situation in which CNS tissue is under pressure from a surgical retractor, and perhaps in the circumstances of raised intraocular pressure during prone surgery. To conceptualize this difference clearly, it may be helpful to distinguish between perfusion pressure, as calculated by the difference between MAP and venous pressure, and “transmural pressure,” calculated as the difference between intraluminal vascular and local tissue pressures. When pressure is applied locally to CNS tissue, the determinant of flow through the local capillaries is transmural pressure (ie, the pressure differential between the vessel lumen and the local extravascular pressure). One encounters only infrequent use of that term, probably because a measure of that local tissue pressure is frequently not available. Figure 4 is an attempt to indicate the qualitative importance of transmural pressure. In that figure, flow through a capillary bed that is under local pressure will be determined not by the perfusion pressure as calculated by the difference between arterial and venous pressure, but rather by the transmural pressure. While the morbidity that is actually associated with this local pressure phenomenon is very difficult to discern in the published literature, this author’s anecdotal experience is that underappreciation of this phenomenon has most certainly led on many occasions to morbidity in the context of cervical spinal stenosis.
- Hypertension: It has been demonstrated in both animals and humans that chronic hypertension results in “right shifting” of the cerebral blood flow autoregulation curve.10 Both the lower limit of cerebral blood flow autoregulation and the upper limit of cerebral blood flow autoregulation are shifted to greater MAP values than occur in normotensive subjects.59 The teleological explanation for this phenomenon is that to reduce vessel distension and the risk of rupture, mother nature thickens the intima and media of cerebral vessels. The downside of this protective mechanism is that these vessels dilate less readily, which results in the right shifting. Important for the clinician is Strandgaard’s10 observation that, in his subjects, there was a good correlation between resting MAP and both the lower limit of cerebral blood flow autoregulation and the MAP at which ischemic symptoms first occurred. While it is frequently said that treating hypertension “resets” (ie, left shifts), the autoregulatory curve, to my knowledge, it is only the investigation by Strandgaard10 that provides human data to support that assertion. Among his study groups were: (1) “well-controlled” hypertensive subjects (n = 9); and (2) normotensive subjects (n = 10). Their baseline MAPs were, respectively, 116 ± 18 and 98 ± 10 mm Hg; and their lower limit of cerebral blood flow autoregulations were 96 ± 17 and 73 ± 9 mm Hg. The relatively constant difference between the baseline and lower limit of cerebral blood flow autoregulation MAPs in the 2 groups suggests that the hypertensive subjects, all of whom had been treated for from 1 to 8 years after an average intake MAP of 148 ± 12 mm Hg had, in fact, left-shifted in proportion to the MAP reduction that had occurred with treatment (from 149 to 116 mm Hg). However, the time course of this left shifting is unknown. In a separate group of 4 severely hypertensive patients, studied before and after 8–12 months of antihypertensive treatment, only 1 demonstrated apparent left shifting of the cerebral blood flow autoregulation curve. This leads to the uncomfortable clinical implication that what resetting occurs may not be accomplished quickly. In addition, there are no data to indicate whether the antihypertensive agent that is used is relevant to the extent or time course of resetting.
- Collateral blood supply: Part of the explanation for the tolerance of the CNS for relative hypotension is generous collateralization. Blood has more than 1 way of reaching most parts of the CNS; but as a result of vascular disease, congenital variation, and iatrogenesis (surgery), collateralization may vary from individual to individual, making some vascular beds almost unpredictably more vulnerable to hypotension. This variation may be particularly relevant in 3 vascular distributions: (a) The circle of Willis; (b) the anterior spinal artery; and (c) the optic nerve.
- The Circle of Willis. Standard anatomic diagrams (Figure 5) suggest that blood has at least 2 alternative pathways for arriving at any of the 3 principal cerebral arteries. However, postmortem examination studies have revealed that only approximately 50% of normal subjects have a complete circle of Willis,60 that up to 25% of adults do not have functional posterior communicating arteries,61 that 3%–5% of adults do not have an anterior communicating artery62,63; and that approximately 7% of adults have 1 carotid artery distribution, more often the left, that is isolated (ie, without collateral communication via an anterior or a posterior communicating artery). There is additional collateralization potential via leptomeningeal vessels and/or the ophthalmic artery; but these, too, are variable. This author has encountered instances in which those congenital variations appear to have made individual patients unpredictably more vulnerable to hypotensive insults.64,65
- The anterior spinal artery. The arterial supply to the anterior spinal artery system is very variable, with the number of feeding vessels varying substantially among subjects. The most constant of these is the arteria radicularis magna, also known as the artery of Adamkiewicz. The arteria radicularis magna typically enters the spinal canal via an intervertebral foramen between the T8 and L1 vertebral bodies, usually on the left side. The arteria radicularis magna then makes a “hairpin” turn in a caudal direction as it joins the anterior spinal artery.66 It serves to deliver blood principally to the conus medullaris. In some individuals, the blood delivery of the arteria radicularis magna to the conus medullaris is supplemented by arteries that travel cephalad with the roots of the cauda equina. These vessels typically originate from the internal iliac artery.66 The arteria radicularis magna probably delivers very little cephalad flow in the anterior spinal artery in most subjects and the diameter of the anterior spinal artery cephalad to the junction with the arteria radicularis magna is typically very narrow.66 In some individuals, the anterior spinal artery is discontinuous at this level.67 This means that the majority of the blood supply to the spinal cord at and above approximately the T10 vertebral level is descending caudally from the upper portions of the anterior spinal artery. In some individuals, there is, as a result, a boundary zone, or “watershed,”c territory in the mid-thoracic and low thoracic spinal cord region.66 These vascular variations have the potential to make some individuals unpredictably more vulnerable to spinal cord ischemia in the event of hypotension or the loss of or sacrifice of intercostal or intervertebral feeding vessels. The author has encountered an instance in which it appeared that induced hypotension resulted in infarction of the conus medullaris and the upper portions of the cauda equina.68
- The optic nerve. Two regions of the optic nerve are variably and potentially precariously collateralized. The first is the optic disk. The blood supply to the optic disk comes via the posterior ciliary arteries, which are noncollateralized end arteries that are variable in number.69 Well before the phenomenon of postoperative visual loss after spine surgery brought ischemic optic neuropathy to prominence, anterior ischemic optic neuropathy was well known to ophthalmologists. Anterior ischemic optic neuropathy presents most often as partial or “altitudinal” visual loss, typically in patients with optic discs with specific anatomic characteristics (small disk, small cup-to-disk ratio, “crowded” disk) and with risk factors for vascular disease, and especially in patients in whom nocturnal hypotension, often in association with new treatment of hypertension, has occurred.69–71 Posterior ischemic optic neuropathy was much less familiar before the phenomenon of blindness after prolonged prone surgery.72 The precise location of the pathology of posterior ischemic optic neuropathy occurring after spine surgery is not well characterized73 because (fortunately) patients are rarely submitted to postmortem examination after spine surgery. However, Baig et al74 has proposed that there is a region of relatively sparse collateralization in the midportion of the optic nerve (ie, midway between the globe and the optic canal), where the nerve is usually supplied entirely by centripetal arterioles arising from the pia on the surface of the nerve, and that this is where the insult of posterior ischemic optic neuropathy occurs. Insufficiency of this blood supply pathway would be expected to produce a lesion in the axial center of the nerve, which would, in turn, be expected to cause the central visual deficit that is, in fact, most common with posterior ischemic optic neuropathy.72 Furthermore, posterior ischemic optic neuropathy occurring in other surgical situations (gastrointestinal bleeding and radical neck dissection) has yielded pathologic specimens in which the location of the lesion is consistent with Baig et al’s74 hypothesis.75,76 I should hasten to mention that while this author believes that posterior ischemic optic neuropathy is often a boundary zone ischemia phenomenon to which relative hypotension may contribute, that opinion is not confirmed by the existing literature. In particular, the American Society of Anesthesiologists’ Advisory on Post Operative Visual Loss states specifically “that the use of deliberate hypotensive techniques during spine surgery has not been shown to be associated with the development of perioperative visual loss.”77
Acute Focal Cerebral Ischemia
The management of the patient with acute focal cerebral ischemia (stroke) merits mention in the context of a discussion of collateral blood flow. It is almost entirely in the setting of neurovascular interventions (thrombectomy, thrombolysis) after acute stroke that anesthesiologists provide general anesthesia for individuals known to have recently experienced a focal stroke. In that situation, it is generally understood that perfusion of the potentially salvageable tissue at the periphery of a stroke, the so-called penumbra, is dependent on collateral perfusion, sometimes across boundary zone territories between cerebral artery distributions, and that this type of perfusion requires the maintenance of high-normal MAPs. Few anesthesia providers need to be instructed that maintenance of blood pressure in this situation is important.78 However, focal ischemic lesions (strokes) occasionally occur spontaneously during anesthesia.38,79 It seems likely, albeit unproven, that the effects of such insults will be aggravated that by relative hypotension during general anesthesia.45 This possibility provides another incentive not to induce or permit degrees of hypotension that are not specifically necessary for the conduct of the surgical procedure, especially in patients at risk for stroke.80
- 5. Vertical hydrostatic gradients: Intraoperative patient positions in which the head is substantially above the heart result in vertical hydrostatic gradients. It is this author’s conclusion that such gradients have important physiologic implications and that blood pressure should be obtained or arithmetically corrected to the cranial level.81 The lack of adverse effects on the brain of a 25% reduction from a typical awake MAP in the common horizontal surgical positions has contributed to the casual attitude toward blood pressure reductions of this order. However, bringing this same attitude to situations in which the surgical position results in the head being substantially above the heart has resulted, in this author’s opinion, in a significant incidence of neurological injury.82 Since before the time that the term “neuroanesthesia” achieved currency, it has been an article of faith among neuroanesthetists that blood pressure during sitting neurosurgical procedures be transduced and maintained at the level of the external auditory canal. However, when the beach chair position was introduced into orthopedics, somehow the laws of physics were perceived to be different when the surgical objectives were bones rather than brains. Figure 6 attempts to depict the issues. If a MAP that is widely deemed to be acceptable in a supine orientation (eg, 65 mm Hg, as measured by a blood pressure cuff on the arm is accepted during beach chair position surgery), the MAP at the external auditory canal is approximately 41 mm Hg. Normotensive individuals in a head-up posture should tolerate a MAP of 41, although some will have presyncopal symptomatology. However, perfusion would probably be sufficient in most subjects to prevent neurologic injury unless this level of hypoperfusion was very sustained. However, if it was necessary to place the blood pressure cuff on the calf, the vertical gradient becomes larger. In the beach chair position configurations used in this author’s institution, the increment to the gradient is only 6 inches. But, a MAP of 65 at the calf therefore results a calculated MAP at the external auditory canal of 29 mm Hg. This has the potential to be much more rapidly injurious.
There has not been universal agreement that making allowance for this hydrostatic difference is necessary or important. It has been argued that, because an equivalent reduction in venous pressure, to negative values, occurs simultaneously with the reduction in arterial pressure, the arterial to venous blood pressure difference is unchanged by the head-up position and that cerebral perfusion pressure is therefore unaltered. This “closed-loop” or “siphon” model of the cerebral circulation holds that as long as perfusion pressure is adequate somewhere in a vertically oriented circulatory loop, it will be adequate everywhere in that loop. This author has argued that this rationale is specious because it assumes siphon-like function of the cerebral function.81 Those who have used siphons will appreciate that they function only with rigid tubing. Too much of the cerebral vasculature amounts to nonrigid tubing to entrust our patients’ well-being to the unproven and improbable closed loop model.
THE BOTTOM LINE
Practitioners frequently want to know, “How low can you go?” The very question is unappealing because it implies an element of brinkmanship that is not the modus operandi of anesthesiologists. However, surgical circumstances may occasionally justify induced hypotension and the matter of acceptable minimum pressures becomes relevant. Therefore, I offer the following speculation, which is based largely on ischemic symptom thresholds in nonanesthetized adults and not on outcome data. In a head-up position, when ICP is low, MAPs of 40–50 mm Hg at the level of the circle of Willis should be tolerated by most healthy, normotensive patients who are free of vascular disease. In the supine position, when ICP is likely to be somewhat higher, minimum pressures of 45–55 mm Hg should be tolerated. In the beach chair position, assuming a 12-inch vertical gradient between the midpoint of a blood pressure cuff on the arm and the external auditory canal, a minimum cuff MAP of 65–70 should result in circle of Willis MAPs of 40–45 mm Hg. In the event of the use of a blood pressure cuff on the calf, I suggest minimum MAPs of 80–85 mm Hg. This recommendation entails slightly more than the 12 mm Hg allowance appropriate to the additional 6 inches of gradient attendant on the use of a calf cuff because distal lower extremity blood pressures can be greater than those recorded in the arm.83 In beach chair position surgery, great care should be taken to assure that there is no compression of the jugular veins, which would increase ICP and reduce the net cerebral perfusion pressure achieved by any given MAP.84
All of the foregoing recommendations constitute extremes that should never be routine and should only be approached when surgical circumstances provide a significant incentive for reduced blood pressure. Periods of hypotension should be kept as brief as possible. Intermittent hypotension, in response to varying surgical needs, will be preferable to sustained hypotension. Monitoring of the nervous system has the potential to widen the latitudes. The combination of somatosensory and motor evoked potentials will provide substantial assurance that there is not significant ischemia of the brain and spinal cord. There is increasing interest in the use of near-infrared spectroscopy devices to monitor brain oxygenation in anesthetized patients. However, this author is of the opinion that because of the hyperfocal nature of the brain region monitored, because of performance variation among the clinically available devices, and because of the problem of extracranial contamination, the false negative potential is too great for a “normal” near-infrared spectroscopy signal to give complete assurance as to the well-being of the brain.
In summary, the principal theses offered by this review are: (1) that the average lower limit of cerebral blood flow autoregulation in normotensive adult humans is not <70 mm Hg; (2) that there is considerable intersubject variability in both the lower limit of cerebral blood flow autoregulation and the efficiency of cerebral blood flow autoregulation; (3) that there is as substantial blood flow reserve that buffers the normal CNS against critical blood flow reduction in the face of hypotension; (4) that there are several common clinical phenomena that have the potential to compromise that buffer; and (5) that the average threshold for the onset of CNS ischemic symptoms is probably a MAP of 40–50 mm Hg at the level of the circle of Willis in a normotensive adult in a vertical posture and 45–55 mm Hg in a supine subject. These latter pressures should probably only be approached deliberately when the exigencies of the surgical situation absolutely require it.
Name: John C. Drummond, MD.
Contribution: This author conceived of and wrote the manuscript.
This manuscript was handled by: Gregory J. Crosby, MD.
1. Willie CK, Tzeng YC, Fisher JA, Ainslie PN. Integrative regulation of human brain blood flow. J Physiol. 2014;592:841–859.
2. Kontos HA, Wei EP, Navari RM, Levasseur JE, Rosenblum WI, Patterson JL Jr.. Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am J Physiol. 1978;234:H371–H383.
3. Lucas SJ, Tzeng YC, Galvin SD, Thomas KN, Ogoh S, Ainslie PN. Influence of changes in blood pressure on cerebral perfusion and oxygenation. Hypertension. 2010;55:698–705.
4. Drummond JC, Shapiro HM. Miller RD. Cerebral physiology and the effects of anesthetic agents and techniques. In: Anesthesia. 1994:4th ed. New York, NY: Churchill Livingston, 689–730.
5. Lassen NA. Cerebral blood flow and oxygen consumption in man. Physiol Rev. 1959;39:183–238.
6. Finnerty FA Jr, Witkin L, Fazekas JF. Cerebral hemodynamics during cerebral ischemia induced by acute hypotension. J Clin Invest. 1954;33:1227–1232.
7. Njemanze PC. Critical limits of pressure-flow relation in the human brain. Stroke. 1992;23:1743–1747.
8. Morris GC Jr, Moyer JH, Snyder HB, Haynes BW Jr.. Cerebral hemodynamics in controlled hypotension. Surg Forum. 1953;4:140–143.
9. Moyer JH, Morris G, Smith C. Cerebral hemodynamics during controlled hypotension induced by the continuous infusion of ganglionic blocking agents (hexamethonium, Pendiomide and Arfonad). J Clin Invest. 1954;33:1081–1088.
10. Strandgaard S. Autoregulation of cerebral blood flow in hypertensive patients. The modifying influence of prolonged antihypertensive treatment on the tolerance to acute, drug-induced hypotension. Circulation. 1976;53:720–727.
11. Russell JA. Is there a good MAP for septic shock? N Engl J Med. 2014;370:1649–1651.
12. Waldemar G, Schmidt JF, Andersen AR, Vorstrup S, Ibsen H, Paulson OB. Angiotensin converting enzyme inhibition and cerebral blood flow autoregulation in normotensive and hypertensive man. J Hypertens. 1989;7:229–235.
13. Larsen FS, Olsen KS, Hansen BA, Paulson OB, Knudsen GM. Transcranial Doppler is valid for determination of the lower limit of cerebral blood flow autoregulation. Stroke. 1994;25:1985–1988.
14. Olsen KS, Svendsen LB, Larsen FS, Paulson OB. Effect of labetalol on cerebral blood flow, oxygen metabolism and autoregulation in healthy humans. Br J Anaesth. 1995;75:51–54.
15. Olsen KS, Svendsen LB, Larsen FS. Validation of transcranial near-infrared spectroscopy for evaluation of cerebral blood flow autoregulation. J Neurosurg Anesthesiol. 1996;8:280–285.
16. Joshi B, Ono M, Brown C, et al. Predicting the limits of cerebral autoregulation during cardiopulmonary bypass. Anesth Analg. 2012;114:503–510.
17. Morris GC Jr, Moyer JH, Synder HB, Haynes BW Jr.. Vascular dynamics in controlled hypotension; a study of cerebral and renal hemodynamics and blood volume changes. Ann Surg. 1953;138:706–711.
18. McCall ML. Cerebral circulation and metabolism in toxemia of pregnancy; observations on the effects of veratrum viride and apresoline (1-hydrazinophthalazine). Am J Obstet Gynecol. 1953;66:1015–1030.
19. Rivera-Lara L, Zorrilla-Vaca A, Geocadin RG, Healy RJ, Ziai W, Mirski MA. Cerebral autoregulation-oriented therapy at the bedside: a comprehensive review. Anesthesiology. 2017;126:1187–1199.
20. Tan CO. Defining the characteristic relationship between arterial pressure and cerebral flow. J Appl Physiol (1985). 2012;113:1194–1200.
21. McCulloch TJ, Turner MJ. The effects of hypocapnia and the cerebral autoregulatory response on cerebrovascular resistance and apparent zero flow pressure during isoflurane anesthesia. Anesth Analg. 2009;108:1284–1290.
22. Gupta S, Heath K, Matta BF. Effect of incremental doses of sevoflurane on cerebral pressure autoregulation in humans. Br J Anaesth. 1997;79:469–472.
23. Reinsfelt B, Westerlind A, Houltz E, Ederberg S, Elam M, Ricksten SE. The effects of isoflurane-induced electroencephalographic burst suppression on cerebral blood flow velocity and cerebral oxygen extraction during cardiopulmonary bypass. Anesth Analg. 2003;97:1246–1250.
24. Reinsfelt B, Westerlind A, Ricksten SE. The effects of sevoflurane on cerebral blood flow autoregulation and flow-metabolism coupling during cardiopulmonary bypass. Acta Anaesthesiol Scand. 2011;55:118–123.
25. Ide K, Pott F, Van Lieshout JJ, Secher NH. Middle cerebral artery blood velocity depends on cardiac output during exercise with a large muscle mass. Acta Physiol Scand. 1998;162:13–20.
26. Ide K, Gulløv AL, Pott F, et al. Middle cerebral artery blood velocity during exercise in patients with atrial fibrillation. Clin Physiol. 1999;19:284–289.
27. Kim DH, Joseph M, Ziadi S, Nates J, Dannenbaum M, Malkoff M. Increases in cardiac output can reverse flow deficits from vasospasm independent of blood pressure: a study using xenon computed tomographic measurement of cerebral blood flow. Neurosurgery. 2003;53:1044–1052.
28. Brown CM, Dütsch M, Hecht MJ, Neundörfer B, Hilz MJ. Assessment of cerebrovascular and cardiovascular responses to lower body negative pressure as a test of cerebral autoregulation. J Neurol Sci. 2003;208:71–78.
29. Ogoh S, Brothers RM, Barnes Q, et al. The effect of changes in cardiac output on middle cerebral artery mean blood velocity at rest and during exercise. J Physiol. 2005;569:697–704.
30. Moritz S, Rochon J, Völkel S, et al. Determinants of cerebral oximetry in patients undergoing off-pump coronary artery bypass grafting: an observational study. Eur J Anaesthesiol. 2010;27:542–549.
31. Meng L, Cannesson M, Alexander BS, et al. Effect of phenylephrine and ephedrine bolus treatment on cerebral oxygenation in anaesthetized patients. Br J Anaesth. 2011;107:209–217.
32. Moerman A, Denys W, De Somer F, Wouters PF, De Hert SG. Influence of variations in systemic blood flow and pressure on cerebral and systemic oxygen saturation in cardiopulmonary bypass patients. Br J Anaesth. 2013;111:619–626.
33. Bombardieri AM, Sharrock NE, Ma Y, Go G, Drummond JC. An observational study of cerebral blood flow velocity during hypotensive epidural anesthesia. Anesth Analg. 2016;122:226–233.
34. Fitch W, MacKenzie ET, Harper AM. Effects of decreasing arterial blood pressure on cerebral blood flow in the baboon. Influence of the sympathetic nervous system. Circ Res. 1975;37:550–557.
35. Hamel E. Perivascular nerves and the regulation of cerebrovascular tone. J Appl Physiol (1985). 2006;100:1059–1064.
36. ter Laan M, van Dijk JM, Elting JW, Staal MJ, Absalom AR. Sympathetic regulation of cerebral blood flow in humans: a review. Br J Anaesth. 2013;111:361–367.
37. Hsieh JK, Dalton JE, Yang D, Farag ES, Sessler DI, Kurz AM. The association between mild intraoperative hypotension and stroke in general surgery patients. Anesth Analg. 2016;123:933–939.
38. Bijker JB, Persoon S, Peelen LM, et al. Intraoperative hypotension and perioperative ischemic stroke after general surgery: a nested case-control study. Anesthesiology. 2012;116:658–664.
39. Bijker JB, Gelb AW. Review article: the role of hypotension in perioperative stroke. Can J Anaesth. 2013;60:159–167.
40. Cheung AT, Messé SR. Preventing brain injury after cardiopulmonary bypass will require more than just dialing up the pressure. Circulation. 2018;137:1781–1783.
41. Sun LY, Chung AM, Farkouh ME, et al. Defining an intraoperative hypotension threshold in association with stroke in cardiac surgery. Anesthesiology. 2018;129:440–447.
42. Vedel AG, Holmgaard F, Rasmussen LS, et al. High-target versus low-target blood pressure management during cardiopulmonary bypass to prevent cerebral injury in cardiac surgery patients: a randomized controlled trial. Circulation. 2018;137:1770–1780.
43. Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol. 1998;55:1475–1482.
44. Bergui M, Castagno D, D’Agata F, et al. Selective vulnerability of cortical border zone to microembolic infarct. Stroke. 2015;46:1864–1869.
45. Drummond JC. Stroke and intraoperative hypotension: to sleep, perchance to stroke-ay, there’s the rub. Anesth Analg. 2016;123:814–815.
46. Rivera-Lara L, Zorrilla-Vaca A, Healy RJ, et al. Determining the upper and lower limits of cerebral autoregulation with cerebral oximetry autoregulation curves: a case series. Crit Care Med. 2018;46:e473–e477.
47. Rasulo FA, Girardini A, Lavinio A, et al. Are optimal cerebral perfusion pressure and cerebrovascular autoregulation related to long-term outcome in patients with aneurysmal subarachnoid hemorrhage? J Neurosurg Anesthesiol. 2012;24:3–8.
48. Schramm P, Klein KU, Pape M, et al. Serial measurement of static and dynamic cerebrovascular autoregulation after brain injury. J Neurosurg Anesthesiol. 2011;23:41–44.
49. Novak V, Chowdhary A, Farrar B, et al. Altered cerebral vasoregulation in hypertension and stroke. Neurology. 2003;60:1657–1663.
50. Bouma GJ, Muizelaar JP, Choi SC, Newlon PG, Young HF. Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia. J Neurosurg. 1991;75:685–693.
51. Ishii R. Regional cerebral blood flow in patients with ruptured intracranial aneurysms. J Neurosurg. 1979;50:587–594.
52. Hickey R, Albin MS, Bunegin L, Gelineau J. Autoregulation of spinal cord blood flow: is the cord a microcosm of the brain? Anesthesiology. 1985;63:A571.
53. Schmidt JM, Ko SB, Helbok R, et al. Cerebral perfusion pressure thresholds for brain tissue hypoxia and metabolic crisis after poor-grade subarachnoid hemorrhage. Stroke. 2011;42:1351–1356.
54. Chesnut RM, Marshall SB, Piek J, Blunt BA, Klauber MR, Marshall LF. Early and late systemic hypotension as a frequent and fundamental source of cerebral ischemia following severe brain injury in the Traumatic Coma Data Bank. Acta Neurochir Suppl (Wien). 1993;59:121–125.
55. Squair JW, Bélanger LM, Tsang A, et al. Spinal cord perfusion pressure predicts neurologic recovery in acute spinal cord injury. Neurology. 2017;89:1660–1667.
56. Sviri GE, Aaslid R, Douville CM, Moore A, Newell DW. Time course for autoregulation recovery following severe traumatic brain injury. J Neurosurg. 2009;111:695–700.
57. Streijger F, So K, Manouchehri N, et al. Changes in pressure, hemodynamics, and metabolism within the spinal cord during the first 7 days after injury using a porcine model. J Neurotrauma. 2017;34:3336–3350.
58. Ryken TC, Hurlbert RJ, Hadley MN, et al. The acute cardiopulmonary management of patients with cervical spinal cord injuries. Neurosurgery. 2013;72(suppl 2):84–92.
59. Strandgaard S, Olesen J, Skinhoj E, Lassen NA. Autoregulation of brain circulation in severe arterial hypertension. Br Med J. 1973;1:507–510.
60. Alpers BJ, Berry RG. Circle of Willis in cerebral vascular disorders. The anatomical structure. Arch Neurol. 1963;8:398–402.
61. Macchi C, Lova RM, Miniati B, et al. The circle of Willis in healthy older persons. J Cardiovasc Surg (Torino). 2002;43:887–890.
62. Macchi C, Catini C, Federico C, et al. Magnetic resonance angiographic evaluation of circulus arteriosus cerebri (circle of Willis): a morphologic study in 100 human healthy subjects. Ital J Anat Embryol. 1996;101:115–123.
63. Dimmick SJ, Faulder KC. Normal variants of the cerebral circulation at multidetector CT angiography. Radiographics. 2009;29:1027–1043.
64. Drummond JC, Englander RN, Gallo CJ. Cerebral ischemia as an apparent complication of anterior cervical discectomy in a patient with an incomplete circle of Willis. Anesth Analg. 2006;102:896–899.
65. Drummond JC, Lee RR, Howell JP Jr.. Focal cerebral ischemia after surgery in the “beach chair” position: the role of a congenital variation of circle of Willis anatomy. Anesth Analg. 2012;114:1301–1303.
66. Dommisse GF. The blood supply of the spinal cord. A critical vascular zone in spinal surgery. J Bone Joint Surg Br. 1974;56:225–235.
67. Lazorthes G, Gouaze A, Zadeh JO, Santini JJ, Lazorthes Y, Burdin P. Arterial vascularization of the spinal cord. Recent studies of the anastomotic substitution pathways. J Neurosurg. 1971;35:253–262.
68. Drummond JC, Lee RR, Owens EL. Spinal cord ischemia occurring in association with induced hypotension for colonic surgery. Anesth Analg. 2012;114:1297–1300.
69. Hayreh SS. Posterior ciliary artery circulation in health and disease: the Weisenfeld lecture. Invest Ophthalmol Vis Sci. 2004;45:749–757; 748.
70. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL. Nonarteritic anterior ischemic optic neuropathy: role of nocturnal arterial hypotension. Arch Ophthalmol. 1997;115:942–945.
71. Athappilly G, Pelak VS, Mandava N, Bennett JL. Ischemic optic neuropathy. Neurol Res. 2008;30:794–800.
72. Hayreh SS. Posterior ischaemic optic neuropathy: clinical features, pathogenesis, and management. Eye (Lond). 2004;18:1188–1206.
73. Drummond JC, Lee RR. Where is the lesion in posterior ischemic optic neuropathy occurring after prone spine surgery? A A Case Rep. 2016;7:53.
74. Baig MN, Lubow M, Immesoete P, Bergese SD, Hamdy EA, Mendel E. Vision loss after spine surgery: review of the literature and recommendations. Neurosurg Focus. 2007;23:E15.
75. Johnson MW, Kincaid MC, Trobe JD. Bilateral retrobulbar optic nerve infarctions after blood loss and hypotension. A clinicopathologic case study. Ophthalmology. 1987;94:1577–1584.
76. Nawa Y, Jaques JD, Miller NR, Palermo RA, Green WR. Bilateral posterior optic neuropathy after bilateral radical neck dissection and hypotension. Graefes Arch Clin Exp Ophthalmol. 1992;230:301–308.
77. American Society of Anesthesiologists Task Force on Perioperative Visual L. Practice advisory for perioperative visual loss associated with spine surgery: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Visual Loss. Anesthesiology. 2012;116:274–285.
78. Heyer EJ, Anastasian ZH, Meyers PM. What matters during endovascular therapy for acute stroke: anesthesia technique or blood pressure management? Anesthesiology. 2012;116:244–245.
79. Mashour GA, Shanks AM, Kheterpal S. Perioperative stroke and associated mortality after noncardiac, nonneurologic surgery. Anesthesiology. 2011;114:1289–1296.
80. Mashour GA, Moore LE, Lele AV, Robicsek SA, Gelb AW. Perioperative care of patients at high risk for stroke during or after non-cardiac, non-neurologic surgery: consensus statement from the Society for Neuroscience in Anesthesiology and Critical Care. J Neurosurg Anesthesiol. 2014;26:273–285.
81. Drummond JC, Hargens AR, Patel PM. Hydrostatic gradient is important - blood pressure should be corrected. Anesthesia Patient Safety Foundation Newsletter. 2009;24:6.
82. Drummond JC. A beach chair, comfortably positioned atop an iceberg. Anesth Analg. 2013;116:1204–1206.
83. Choi JC, Lee JH, Lee YD, Kim SY, Chang SJ. Ankle-brachial blood pressure differences in the beach-chair position of the shoulder surgery. Korean J Anesthesiol. 2012;63:515–520.
84. Drummond JC. The “beach chair” position, jugular compression and cerebral perfusion pressure. Anesthesia Patient Safety Foundation Newsletter. 2012;27:35.