Control of cerebral blood flow (CBF) is vital in the management of patients suffering from intracranial catastrophe. Manipulation of mean arterial pressure (MAP) and intracranial pressure (ICP) provides some control over CBF, but titration to extremes of MAP is not without risk.1,2 In brains with intact autoregulation changes in CBF may parallel changes in cardiac output (CO) independent of MAP.3,4 This coupling of CO and CBF may be related to factors that impact both CO and established determinants of CBF, such as MAP, ICP or arterial partial pressure of CO2 (PaCO2). Conversely, it may represent true cardio-cerebral coupling with significance for both the pathophysiology and treatment of cerebrovascular disorders. Here we review the literature investigating the relationship between CO and CBF, discuss possible mechanisms by which CO could alter CBF, and highlight implications for the management of neurocritically ill patients.
A PRIMER ON THE PHYSIOLOGY OF CEREBRAL BLOOD FLOW AND CO
Before reviewing the evidence for cardio-cerebral coupling, we present an overview of the physiology of CBF and CO to underline the context of any relationship between these important variables. CBF is highly regulated, tightly coupled to local cerebral metabolic rate (neurovascular coupling), and stable over a range of perfusion pressures (pressure autoregulation), although many other factors are also at play (Fig. 1).
Cerebral Perfusion Pressure (CPP)
CPP is the difference between MAP and ICP:
CPP is the driving pressure of the cerebral circulation. The flow rate through any vessel can be estimated from the driving pressure using the Hagen-Poiseuille equation, a solution to the Navier-Stokes equations when blood is assumed to be Newtonian and incompressible, flow is assumed to be laminar with a linear pressure gradient and nonslip boundaries, and vessel walls are not deformable:
where ΔP is the driving pressure (CPP in this case), Q is the flow rate, r is vessel radius, η is blood viscosity and L is vessel length.
Thus, instantaneous changes in flow through a cerebral vessel are dependent not only on changes in CPP but also on vessel radius and blood viscosity.
Wall shear stress is an important mediator of vessel caliber, which the endothelium aims to maintain at a set-point through changes in vessel radius. Wall shear stress is estimated by the following equation (which does not take account of the oscillatory stress associated with pulsatile flow):
where Q is the flow rate, η is blood viscosity and r is vessel radius.
Blood Viscosity and Carbon Dioxide Tension
Fluctuations in blood viscosity, which is inversely related to flow, also trigger compensatory changes in the cerebrovascular bed through a process termed viscosity autoregulation.5 PaCO2 is another major determinant of cerebral vessel caliber; CBF changes by ~2 mL/100 g/min (3% to 4% of CBF) for every 1 mmHg change in PaCO2. End-tidal CO2 (ETCO2) is proportional to PaCO2 but slightly lower due to alveolar dead space, and varies with pulmonary perfusion and pulmonary disease states that increase dead space.6
The cerebrospinal fluid (CSF) contributes to total ICP. The component of ICP contributed by CSF (ICPCSF) is dependent upon the rate of CSF production and the resistance to its absorption, as described by the Davson equation:
where Rout is the resistance to CSF absorption, If the rate of CSF production and PVS the pressure within the dural venous sinuses.
Note that ICPCSF must always be greater than the pressure within the dural venous sinuses. Central venous back-pressure is readily transmitted to the cerebral venous sinuses because competent valves in the internal jugular system are uncommon.7 In the erect posture however, collapse of the jugular venous system isolates the cerebral venous system from the heart, thereby preventing substantially negative ICP.8
CO and Circulatory Physiology
The systemic circulation can be modelled by the ohmic expression that relates CO, the product of heart rate and stroke volume, or its equivalent venous return, to the pressures and resistances acting on blood as it circulates back toward the heart, namely mean systemic filling pressure, right atrial pressure, and resistance to venous return9:
where Pms is mean systemic filling pressure, RAP is right atrial pressure and RVR resistance to venous return.
A vessel holds a certain volume of blood that fills its lumen to a cylindrical, unstressed state. Additional volume above this unstressed state, called the stressing volume, stretches the vessel wall and causes the pressure inside the vessel to rise as a function of vessel wall compliance, which itself is a function of vascular smooth muscle tone and vessel wall composition:
where Pv is the pressure inside the vessel, Ve is the stressing volume, and C is vessel wall compliance.
At rest, almost all vessels have a stressing volume and thus a positive pressure inside the vessel which drives blood back to the heart. However, when the heart stops intravascular volume equilibrates and the pressure in the systemic circulation (Pms) is the pressure that drives venous return, which is dependent on the stressing volume and vascular compliance of the systemic circulation, but not on cardiac performance per se.
Right atrial pressure represents the sum of the internal and external pressures acting on the atrium:
where VRAe is stressed atrial volume, CRA is atrial compliance, Pit is intrathoracic pressure, and Pip intrapericardial pressure.
As seen from the above equation, right atrial pressure is a complex variable determined by multiple factors. Stressed atrial volume is dependent on volume state, systemic and pulmonary vascular resistances, the volume required to fill the atrium to its full but unstressed state, cardiac performance, and right atrial pressure itself.10 Thus, right atrial pressure is a poor marker of volume status.11
Resistance to venous return can be thought of as the resistance between the capacitance vessels of the circulation (small veins and venules) and the heart, and is dependent on the tone of the vasculature, primarily the large veins, and blood rheology.12 The hemodynamic significance of resistance to venous return is highlighted by studies demonstrating that vasoconstriction from cool fluids13,14 and rheological improvement through hemodilution15 may account for the entirety of the hemodynamic benefits of a fluid bolus.
How CO Could Affect Cerebral Blood Flow
From a steady state, a theoretical isolated increase in CO would be associated with a decrease in right atrial pressure, an increase in pulse pressure and a decrease in systemic vascular resistance. MAP typically remains constant with changes in CO due to baroreceptor signaling and reflex withdrawal of sympathetic tone (reflex sympatholysis), culminating in vasodilation. The following hypotheses provide a rationale for potential cardio-cerebral coupling (Fig. 2).
Pulse pressure is one measure of the “pulsatility” of the systemic circulation; with increases in stroke volume come increases in pulse pressure. Peripheral baroreceptors are more sensitive to pulsatile pressure than to constant pressure,16 thus reflex sympatholysis of endogenous sympathetic tone may occur with increases in pulsatility and lead to vasodilation. Surgical ablation of sympathetic supply to the cerebral vasculature is associated with increases in CBF,17–20 suggesting that reflex sympatholysis associated with increased CO would also influence the cerebral circulation. Heart rate also affects pulsatility. Changes in ventricular filling time not only affect stroke volume but also pulse pressure through distal pulse amplification and summation of harmonics of reflected pulse waves.21
Wall shear stress is the most important regulator of vessel morphology and tone,22 and increasing pulsatility may lead to increases in (oscillatory) wall shear stress which induce vasodilation.23 Substantial increases in pulsatility through small collateral vessels may open the cerebral collateral circulation when systolic peaks surpass the critical closing pressure of these small vessels, particularly as the cerebral autoregulation time constant is slower than the interpulse interval in the normal brain, and even slower (or absent) in the injured brain.24,25
Finally, steady state increases in CO reduce central venous pressures (ie, right atrial pressure). The cerebral venous system drains through a functionally valveless system into the central veins; thus, changes in right atrial pressure are transmitted to the venous sinuses. Although of more limited magnitude in the erect posture, decreasing venous backpressure would reduce the contribution of CSF to ICP, thus increasing CPP and CBF.
A review of the literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.26 Included studies were analysed for bias per the Cochrane Handbook guidelines.27 MEDLINE and EMBASE electronic bibliographic databases were searched for articles in the English language published up to January 2020 using the search string “(Cardiac Output OR Cardiac Index) AND Cerebral Blood Flow.” The references from included papers were hand-searched for other relevant publications. Trials were included if they studied the effects of changes in CO on CBF; where multiple publications utilized the same data set, only the most recent study was included. Single case reports, manuscripts not in English, and studies for which data extraction was not possible were excluded.
The following data were extracted from the included studies: study design, study population, MAP, CO, PaCO2, CBF, and the methods utilized to measure CO and CBF. To control for hemodynamic changes inherent to each intervention, studies were stratified by the type of intervention employed to modulate CO. Where studies included multiple interventions, results were separated into the appropriate strata.
After removal of duplicates, 866 manuscripts were screened and 86 were identified for full text review. Forty-one that met the inclusion criteria28–68 were included in the analysis (Fig. 3); 6 of these studies were conducted in animals.54–56,59,60,62 The majority of the human studies were small cohort and case-control studies; the largest included 314 participants. None of the included studies were randomized controlled trials, and all were at high risk of bias across all domains (Selection, Performance, Detection, Attrition, and Reporting) per the Cochrane guidelines.27
Methods of measuring CBF included cerebral artery mean velocity28–46 and mean flow assessed using transcranial Doppler (TCD) sonography,47,48,50–52 radiotracers,53–63,68 magnetic resonance perfusion,64–66 thermal diffusion flowmetry,49 and jugular venous oximetry.67 CO was also measured in a variety of ways including with thermodilution through right-heart catheterization,29,34,44,45,47,49,53–55,57–60,67,68 arterial pulse wave pressure analysis,28,30,32,33,35–37,40,50,52,64 real time cardiac imaging (echocardiography and magnetic resonance imaging),31,48,51,65,66 aortic flow,56 impedance cardiography,39,41,43 and inert gas rebreathing techniques.38,42
Results were heterogenous, with both corroboration and confutation of a relationship between CO and CBF in both normal and abnormal cerebrovascular states. Below, we present the data stratified by the method used to change CO and by the presence or absence of brain injury (Table 1).
TABLE 1 -
Summary of the Impact of Interventions to Alter Cardiac Output on Cerebral Blood Flow in the Normal and Injured Brain
||Cerebral Blood Flow
|Method to Alter Cardiac Output
|Lower body negative pressure
The data presented are based only on the studies included in this review, and are limited for the injured brain.
*Inodilators include phosphodiesterase inhibitors and the beta-adrenoceptor agonist dobutamine. There is evidence that these agents, especially phosphodiesterase inhibitors, may directly dilate the cerebral circulation.
†Vasopressors are generally alpha-adrenoceptor agonists, and do not commonly have any direct action of cerebral arteries.
↑ indicates increase; ↓, decrease; ↔, no change; CO, cardiac output; LBNP, lower body negative pressure.
The effect on CBF of multiple vasoactive agents, including dobutamine,34,43–45,48,58 olprinone,49 norepinephrine,33,46 nimodipine,56 phenylephrine,53 and isoprenaline,54 were analyzed. CBF was primarily measured with TCD33,34,43–46,48 and radiotracers53,54,56,58 (Supplementary Table 1, Supplemental Digital Content 1, https://links.lww.com/JNA/A368). Dobutamine consistently increased CO and MAP,34,44,45,48 and was associated with increases in middle cerebral artery flow velocity (Vmca)34,44,45; however, PaCO2 was inconsistently controlled in these studies. One dissenting study (n=12) reported no increase in internal carotid artery flow velocity during dobutamine infusion.48
Studies of norepinephrine were limited by large variations in hemodynamic variables46 and lack of PaCO2 measurement.33,46 With these limitations in mind, Vmca was found to correlate with CO during norepinephrine infusion, but was more strongly associated with concomitant changes in MAP.33 When controlled for changes in PaCO2, isoprenaline increased CO but not CBF, while propranolol decreased CO and CBF, although data for MAP were not collected in this study.54
Four studies investigating vasoactive agents were conducted in brain injured patients.43,49,53,58 In the single study that quantitatively assessed the state of autoregulation, phenylephrine increased CBF in traumatic brain injury patients in regions with impaired autoregulation but not in those regions with intact autoregulation, and was associated with substantial (but statistically insignificant) changes in MAP and CO.53 In patients with subarachnoid hemorrhage, inodilators such as the olprinone (a phosphodiesterase-3 inhibitor) and dobutamine (a beta adrenoceptor agonist) increased CO and CBF in parallel despite associated decreases in MAP,49,58 while phenylephrine increased MAP and CBF in patients with cerebral vasospasm.58 Conversely, a combination of dobutamine and dopamine increased CO, MAP, and Vmca in patients with middle cerebral artery stroke; the change in Vmca were less in the affected hemisphere.43
Lower Body Negative Pressure
All studies investigating the effects of lower body negative pressure and tourniquets used TCD to measure CBF30,31,38,39,41,42 (Supplementary Table 2, Supplemental Digital Content 2, https://links.lww.com/JNA/A369), and were performed exclusively in healthy volunteers. Lower body negative pressure decreased CO,30,38,39,41,42 with no38,39,41,42 or minimal30 change in MAP and PaCO2,42 though data on the latter were limited. Vmca also decreased with lower body negative pressure,30,38,39,41,42 primarily due to reductions in systolic flow velocity,39 while cerebral vascular resistance and middle cerebral artery (Gosling) pulsatility ratio decreased.39
Inflation of a thigh tourniquet increased CO and MAP but did not alter flow in the middle or anterior cerebral arteries as measured by TCD. When the tourniquet was released, MAP transiently decreased as did Vmca, but CO increased.31 Moreover, even volunteers having large increases in CO (>0.92 L/min/m2) or stroke volume after cuff deflation did not demonstrate beat-to-beat dynamic changes in Vmca.
TCD was the tool universally used to analyze the effect of exercise on CBF28,30,35–37,40,50,52 (Supplementary Table 3, Supplemental Digital Content 3, https://links.lww.com/JNA/A370); no participants in these studies had a brain injury. CO and MAP increased linearly with increasing exercise intensity35,37,40,50 though these changes could be attenuated with both nonselective35 and selective40 beta-adrenergic blockade. PaCO2 decreased with maximal intensity exercise35,36,40 and ETCO2 increased.28,37,50 The effect of exercise intensity on CBF was variable. In a single study, vertebral artery flow increased linearly with exercise intensity.50 However, in the majority of studies there was a distinctive pattern of CBF change as measured by internal carotid artery flow50 and Vmca28,35,37,40; CBF was maximal at intermediate exercise intensity and decreased with further increases or decreases in exercise intensity. Systolic Vmca increased while diastolic velocity decreased with exercise,28 reflecting increased pulsatility. Handgrip increased CO and MAP and was associated with increases in Vmca independent of PaCO2.30,37,40
Moving from sitting to standing decreased CO, right atrial pressure, MAP and PaCO2, though these changes can largely be countered by muscle tensing (Supplementary Table 3, Supplemental Digital Content 3, https://links.lww.com/JNA/A370).36 Concomitant changes in PaCO2 also obscure any potential effect of CO on CBF. Moving from lying to sitting decreased CO and internal carotid flow independent of MAP and PaCO2 in patients with heart failure, but the same was not true in healthy volunteers.52
Blood Volume and Rheology
In healthy volunteer TCD studies, crystalloid41 and colloid42 infusions both increased CO, right atrial pressure and Vmca independent of MAP and PaCO2 (Supplementary Table 4, Supplemental Digital Content 4, https://links.lww.com/JNA/A371). When CBF was measured using radiotracers, infusion of autologous plasma increased CO and tended to increase CBF,60 as did isovolumetric hemodilution,57 although independence from PaCO2 was not reported in the latter study. Conversely, controlled hemorrhage (isoviscous hypovolemia) reduced CO, right atrial pressure and CBF independent of MAP, with maintenance of CO2 responsiveness.54
The effect of changes in volume status in subjects with brain injury was assessed in 3 studies.53,55,59 Following traumatic brain injury53 or experimental cerebral ischemia in animal models,55,59 increases in CO through infusion of colloid were associated with increases in CBF only in brain regions with impaired autoregulation or in the ischemic penumbra, respectively. These CO and CBF changes were reversible through controlled hemorrhage59 and did not seem replicable with isovolumetric hemodilution alone,55 suggesting that changes in volume status contribute independent of viscosity.
Direct Circulatory Control
Five studies investigated the impact on CBF of alterations in CO by direct control of the heart (Supplementary Table 5, Supplemental Digital Content 5, https://links.lww.com/JNA/A372).51,61–63,67 Radiotracers were used to measure CBF directly during cardiopulmonary bypass in 3 studies,61–63 all in participants without preexisting brain injury. During cardiopulmonary bypass, changes in pump flow were variably associated with changes in CBF. In a single study (n=21),63 increases in pump flow resulted in linear increases in CBF independent of MAP; PaCO2 was not measured. In contradistinction, 2 studies did not demonstrate any change in CBF related to changes in pump flow,61,62 although PaCO261 and MAP61,62 were not consistently controlled in either.
In a small study extrapolating CBF from cerebral metabolic rate,67 heart rate was incrementally increased with a pacemaker while PaCO2 and MAP remained stable. CO and CBF increased significantly after initiation of pacing, but both plateaued with further increases in heart rate. Similarly, internal carotid and vertebral artery flow increased following restoration of CO after cardiac resynchronization,51 although PaCO2 was not measured.
Using inter-subject data from preoperative patients (n=45)29 and healthy adults (n=31),65 no relationship could be established between CO and internal carotid artery flow or CBF, respectively (Supplementary Table 6, Supplemental Digital Content 6, https://links.lww.com/JNA/A373). Similarly, there was no correlation between CO and CBF in case-control studies comparing patients with distributive and nondistributive shock states,47 or in those with idiopathic dilated cardiomyopathy compared with controls.64
During 24 h monitoring, there was an association between Vmca, stroke volume and CO, and to a lesser extent with MAP, in healthy subjects.32 In 314 healthy adults, cardiac index was associated with CBF changes only in the temporal lobe, although MAP was not controlled in this study.66
Studies assessing the relationship between CO and CBF are heterogenous, poorly controlled, and inherently limited by the interventions used to modulate CO. Vasoactive agents which are often used to improve CO clinically have their own unique effects on the cerebral circulation, dependent not only on their systemic hemodynamic effects but also on whether they directly affect the cerebral vasculature. While lower body negative pressure reduces systolic Vmca and CO independent of MAP, the same is not the case with thigh tourniquets. Exercise induces a biphasic response in Vmca which seems to be independent of the linear association between CO and exercise intensity. Changes to volume status through hemodilution and controlled hemorrhage induce parallel changes in CO and CBF that seem independent of MAP, although concomitant alterations in blood rheology may confound these findings. In brain injured patients with impaired autoregulation, changes in volume status and, by definition, MAP seem to influence CBF more readily; however, CO may still affect CBF in the injured brain. Increasing CO in heart failure patients by epicardial pacing is associated with improvements in CBF until a plateau is reached. This suggests that, although compensated low CO states may reduce CBF, once physiological CO is restored further increases are not reflected in the cerebral circulation.
Forty-one studies were included in this review, of which 35 were clinical studies and 6 were animal studies. None of the clinical studies were randomized or adequately controlled, and many included small numbers of participants. Moreover, only 7 of the clinical studies analyzed patients with intracranial pathology.34,43,49,53,57,58,68 This heterogeneous mix of human and animal studies with and without cerebral pathology precluded data pooling and comparison. We also found significant heterogeneity in methodology and measurement of CO and CBF, with heavy reliance on single vessel TCD for the latter. Many studies failed to monitor other relevant variables such as MAP and PaCO2, and these variables often varied considerably in those studies that did monitor them, thereby confounding interpretation of any measured change in CBF. Moreover, many of the interventions might have impacted CBF through mechanisms other than their effect on CO. All the studies supporting a relationship between CO and CBF had at least one methodological limitation (Supplementary Table 7, Supplemental Digital Content 7, https://links.lww.com/JNA/A374).
Although brain-injured subjects were included in this review, pressure autoregulation status was objectively measured only in a single human study.53 Although by definition pressure autoregulation should not directly affect cardio-cerebral coupling, impaired pressure autoregulation may be a marker of impairment of other autoregulatory systems, such as viscosity and shear stress autoregulation, which may themselves contribute to cardio-cerebral coupling. Cerebrovascular reactivity may be assessed with continuous ICP monitoring using the pressure-reactivity index (PRx), which is usually calculated as the moving Pearson correlation-coefficient between mean ICP and MAP over 10 seconds, averaged over 30 consecutive episodes.69,70 Averaging over 10 seconds creates a low-pass filter such that Lundberg-C waves and respiratory waves, which do not carry information about autoregulation, are filtered out.25 A normal value for PRx is negative (a rise in MAP is associated with a decrease in ICP under normal circumstances), and deranged cerebrovascular reactivity has been defined (based on clinical outcomes) as PRx >0.2.71 Although not strictly synonymous,72,73 cerebrovascular reactivity measured by PRx may be used as a surrogate for cerebral pressure autoregulation.74 Lack of objective assessment of pressure autoregulation in the studies included in this review limits comparisons between brain-injured and nonbrain injured patients as contrary responses can be seen from the same physiological perturbation depending on autoregulation state. Importantly, it should not be assumed that all brain injured patients have absent cerebral autoregulation. Indeed, fewer than half of patients with subarachnoid hemorrhage75 or severe traumatic brain injury76 demonstrate impaired autoregulation. Furthermore, impaired autoregulation is dynamic, often changing throughout the course of the illness,77 and is not necessarily global but may be specific to vascular regions. Thus, stratification of the effects of CO on CBF should ideally be based on robust, quantitative metrics of the state of autoregulation, including PRx, rather than merely on the presence or absence of acute intracranial pathology. Given the lack of autoregulation measurement in the studies included in this review, we were only able to stratify by presence or absence of brain injury.
A comprehensive discussion of the effects of vasoactive agents on the cerebral circulation is beyond the scope of this review, but it is important that any direct action of vasoactive agents on the cerebral circulation are not discounted when interpreting their effects on CO in the context of cardio-cerebral coupling. Pure α1-agonists (phenylephrine, metaraminol, and, to all intents and purposes, norepinephrine) may have small, but not insignificant effects on CBF in the uninjured brain. Phenylephrine may reduce CBF,78,79 as may norepinephrine,80 but the theoretical risk of interference with intra-axial adrenergic control has not been borne out in vivo.58,81 Whether this is due to direct effects on the vasculature, or secondary effects due to pressor related decreases in CO is unclear. β1-agonism increases cerebral metabolic rate and thus CBF,82 especially in the setting of a disrupted blood-brain barrier.83 At low doses, epinephrine is an inodilator and may potentially cause direct cerebral vasodilation.84 During anesthesia, ephedrine increases CBF (as measured by positron emission tomography) compared to phenylephrine, possibly due to increases in CO or β-adrenoreceptor effects on the cerebral vessels85 and direct effects on cerebral metabolic rate. Dopamine increases CBF, and subsequently ICP, and these effects are potentiated by anaesthesia.86 Phosphodiesterase-3 inhibitors, such as olprinone, may directly dilate cerebral arteries.87 Isoprenaline increases CO but not CBF, while propranolol decreases both CO and CBF. Differential ability to cross the blood-brain-barrier may also contribute to the variable effects of vasoactive agents on the cerebral vasculature.88 Thus, the effect of specific vasoactive medications may not be consistent across all agents, nor with other methods of controlling CO. In those with impaired cerebral autoregulation, by definition, vasopressors will increase CBF.
Administration of volume (crystalloid or colloid) increases mean systemic filling pressure and, to a more variable degree, right atrial pressure. Changes to the latter may alter upstream (cerebral venous outflow) pressures, thus reducing the resistance to CSF absorption and reducing ICP. With crystalloid and colloid loading, at least 2 further variables are altered: blood viscosity and temperature. Decrease in viscosity leads to increases in flow, depending on the status of viscosity autoregulation,15 and may also lead to compensatory vasoconstriction thereby decreasing ICP. However, the therapeutic benefit of this theoretical increment is limited by the concomitant decrease of oxygen carrying capacity associated with hemodilution. Temperature is an important determinant of venomotor tone, and fluids administered in the studies included in this review were not warmed. Thus, the results of studies analysing the impact on CBF of volume to increase CO through rheological and venomotor changes may not be generalisable to other methods of increasing CO.
Utilizing exercise to alter CO is cheap and safe in the experimental setting, but it induces parallel changes in systemic vascular resistance, cerebral metabolic rate, temperature, sympathetic outflow, and PaCO2 which greatly confound assessment of impact on CBF.89 A substantial reduction in systemic vascular resistance and increase in pulse pressure alter the pulsatility of the arterial waveform and thus may affect CBF. The variability of PaCO2 with exercise, itself dependant on the balance of peripheral CO2 production and alveolar ventilation, makes isolation of the effect on CBF of exercise-induced changes in CO complex. Indeed, middle cerebral and internal carotid artery flow during exercise seem better correlated with PaCO2 than with CO.50 Other potential confounders include the sympathetic drive associated with exercise (which may increase cerebral vascular tone), and changes in cerebral metabolic rate. Indeed, the biphasic distribution of Vmca with exercise is thought to represent the superposition of the effects of increased cerebral metabolic rate up to ~60% of maximal exercise tolerance, after which hypocapnia secondary to hyperventilation dominates, leading to cerebral vasoconstriction.90
Patients have unique physiology during cardiopulmonary bypass. Body temperature is artificially lowered so as to decrease cerebral and systemic metabolic demand,91 while anaesthetic agents produce their own effects on CBF and cerebral metabolic rate for oxygen92; together these alter cerebral flow-metabolism coupling. Moreover, nonpulsatile flow affects cerebral resistance and removes oscillatory shear stress, while CSF production and circulation are altered in the absence of cerebral pulsation and cooling.93 However, no difference was detected in CBF or cerebral metabolic rate between pulsatile and nonpulsatile cardiopulmonary bypass in a normothermic rabbit model.94 Finally, PaCO2 and acid-base status are altered in the setting of hypothermia, and this may affect cerebral vascular tone and reactivity. Thus, the effects of cardiopulmonary bypass pump settings on CBF may not be generalizable to normothermic patients with pulsatile blood flow. Pacemaker studies, which ostensibly provide the “cleanest” data, are limited by increasing only heart and not stroke volume, thus decreasing pulsatility.
Inter-subject comparisons are inherently flawed as, among other pertinent variables, autoregulatory set point and CO vary considerably between individuals. The use of patients with cardiac disease as a comparator introduces further methodological difficulties. Heart failure patients with reduced ejection fraction have decreased CBF when compared with healthy controls, with CBF correlating directly with brain natriuretic peptide levels,95 left ventricular ejection fraction, and inversely with New York Heart Association class.96 CBF normalizes after cardiac transplantation,97,98 and improves with intra-aortic balloon pump99 and resynchronization therapy.100 The beneficial effects of intra-aortic balloon pump may be related to greater diastolic pressures, endogenous sympatholysis and, possibly, cardio-cerebral coupling. The orthostatic stress of standing may be sufficient to decrease CBF in patients with chronic heart failure and reduced ejection fraction; this effect is due to reduction in CO not MAP.52 Comparison of healthy controls to those with chronic heart failure and reduced ejection fraction is experimentally attractive but, akin to lower body negative pressure, changes associated with reduced CO cannot be assumed to be equal and opposite to those associated with increases in CO. Possibly, such patients have reached the lower limit of pressure autoregulation and their cerebral circulations are pressure passive. Furthermore, the vascular remodelling, hormonal, and autoregulatory changes that occur with chronically low CO delineate a distinct physiology from acute alterations in CO.
Lower body negative pressure simulates hypovolemia and thus decreases CO through a reduction in the pressure that drives venous return (ie, mean systemic filling pressure).101 Compensatory sympathetic drive leads to tachycardia and vasoconstriction to maintain MAP. Increased sympathetic outflow may prompt cerebral vasoconstriction and decrease CBF, while small reductions in MAP, if close to the lower limit of autoregulation, may similarly compromise CBF. Similar to reduced ejection fraction in patients with heart failure or during controlled haemorrhage, changes seen with low CO cannot be assumed to be equal and opposite to those with increases in CO. Tourniquet inflation increases effective circulatory volume, mean systemic filling pressure and thus CO, while deflation leads to reperfusion hyperemia and a decrease in systemic vascular resistance. Tourniquet deflation and release of lower body negative pressure have important time factors, with incremental application and release of lower body negative pressure differing from the near instantaneous release of a tourniquet. The decrease in MAP will have variable effects on CBF dependent on autoregulatory status and the pressure-autoregulation time constant, which may cloud effects through changes in CO.
Single vessel TCD was the most common method of CBF measurement in the studies in this review. TCD measures velocity of blood flow, which, if multiplied by a previous measure of vessel cross-sectional area, yields total flux (flow) (Fig. 4). CBF is only proportional to blood flow velocity when the cross-sectional area of the vessel is constant; thus dynamic changes in vessel caliber are not accounted for. This is specifically relevant when attempting to assess the effect of CO on CBF as the candidate mechanisms for cardio-cerebral coupling involve instantaneous changes in vessel caliber. Indeed, the hypothesis that highly pulsatile flow can induce cerebral vasodilation was supported in the only study reporting data for both pulse pressure and CBF59; the Pearson correlation coefficient between the 2 was 0.68 (P<0.01) (our calculation). Moreover, TCD assessments were often limited to the carotid and middle cerebral arteries, raising the potential for missed asymmetric responses in anterior and posterior circulations. Similarly, given that the proposed mechanisms of cardio-cerebral coupling rely on instantaneous changes in resistance vessel caliber, TCD measures of flow velocity would not detect these CBF changes owing to its application being limited to measuring changes in large conductance vessels in the Circle of Willis and not in the more distal resistance vasculature. The only previous review of cardio-cerebral coupling included only studies measuring flow velocity (and not flux).4 The authors of that review concluded that CO is an independent regulator of CBF, despite evidence that flow velocity is not an appropriate surrogate for CBF, especially in those with cerebrovascular disease.102,103 One potential solution is to measure both CBF and cerebral blood volume, as changes in vessel caliber would be paralleled by proportional changes in the latter. This would facilitate testing of the hypothesis that cardio-cerebral coupling relies on changes in vessel caliber. Unfortunately, no study in our literature search investigated this issue.
Implications for Therapy
Cardio-cerebral coupling has important applications for the clinical management of intracranial catastrophe as well as perioperative care of neurosurgical patients. Delayed vasospasm after subarachnoid hemorrhage is often treated with induced hypertension to improve CBF in vasospastic territories, despite a lack of evidence that hypertension improves CBF or clinical outcomes.104 Hypertension is often induced by vasopressors such as norepinephrine which can decrease CO and may potentially affect the cerebral circulation directly. Cardio-cerebral coupling would provide clinicians with a tool to optimize CBF without altering MAP, with the potential to avoid the risks of hypertensive therapy, such as pulmonary edema and posterior reversible encephalopathy syndrome, while still providing increases in CBF. Furthermore, increased CO may lead to down-regulation of endogenous sympathetics and reduce the risk of the stress cardiomyopathy that is common after subarachnoid hemorrhage. Systolic blood pressure control is vital immediately after intracerebral and subarachnoid haemorrhage to reduce the risk of rebleeding. However, reductions in CBF from acute vasospasm and increased ICP delineate this as a critical timepoint for acute ischemia. Theoretically, increasing CO without increasing MAP (eg, with an inodilator) would achieve the same purpose as hypertensive therapy without increasing the risk of rebleeding. However, the effect on ICP from vasodilation must be considered.
Improving CBF to the ischemic penumbra is the cornerstone of stroke care. Increased CO and volume expansion (with colloid, which may have confounding rheological effects) improves CBF ipsilateral to the ischemia independent of MAP.59 This may occur due to changes in pulsatility, especially in regions with impaired autoregulation. During intracranial surgery, control of CO would allow for optimization of CBF without compromising hemostasis as might occur with hypertension. Similarly, it could afford maintenance of high CBF and reduction of risk of aneurysm rupture during clipping of unruptured intracranial aneurysms, or maintenance of cerebral perfusion during evacuation of intracranial hematomas.
Several important questions remain unanswered. Foremost is the lack of definitive evidence that cardio-cerebral coupling exists, and future studies should endeavor to elucidate this relationship further. Such studies will require diligent control of cerebral metabolic rate, PaCO2 and MAP, measurement of CBF (and ideally also cerebral blood volume) with techniques that monitor beat-to-beat flux,105,106 and interventions that only change CO. Further investigations should also aim to establish the mechanism (if any) that underpins cardio-cerebral coupling, and analyze blood pressure pulsatility, ICP and cerebral vessel caliber, with subjects stratified by pressure-autoregulation status. Further outstanding questions include the pattern of the CO-CBF relationship (ie, is it linear, parabolic and does it have a plateau section), whether a CO-CBF relationship exists in both autoregulating and non-autoregulating brain regions, the magnitude of an effect of CO on CBF and whether it is sufficiently large to be clinically useful, and, finally, whether different interventions to change CO are equally efficacious.
Despite theoretical, physiologically sound mechanisms for the existence of cardio-cerebral coupling, there is mixed evidence in the literature supporting this. While most studies ostensibly support a relationship between CO and CBF in the normal as well as injured brain, many of the reported effects, such as changes in sympathetic outflow, drug effects, carbon dioxide tension, and acidosis, are likely indirect. Heterogenous study participants, reliance on TCD measurements of blood flow velocity and concurrent changes in other variables pertinent to CBF limit the generalizability of the results.
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