Edited by: Patrice Brassard, Laval University, Canada
Reviewed by: James Todd Pearson, Monash University, Australia; Johannes J. Van Lieshout, University of Amsterdam, Netherlands
*Correspondence: Caroline A. Rickards, Department of Integrative Physiology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA e-mail:
This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology.
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Variability in arterial pressure and cerebral blood flow has traditionally been interpreted as a marker of cardiovascular decompensation, and has been associated with negative clinical outcomes across varying time scales, from impending orthostatic syncope to an increased risk of stroke. Emerging evidence, however, suggests that increased hemodynamic variability may, in fact, be protective in the face of acute challenges to perfusion, including significant central hypovolemia and hypotension (including hemorrhage), and during cardiac bypass surgery. This review presents the dichotomous views on the role of hemodynamic variability on clinical outcome, including the physiological mechanisms underlying these patterns, and the potential impact of increased and decreased variability on cerebral perfusion and oxygenation. We suggest that reconciliation of these two apparently discrepant views may lie in the time scale of hemodynamic variability; short time scale variability appears to be cerebroprotective, while mid to longer term fluctuations are associated with primary and secondary end-organ dysfunction.
Traditionally, clinicians have assessed the cardiovascular status of their patients with static “snapshot” techniques, such as radial pulse for heart rate, brachial sphygmomanometry for arterial pressure, and chest excursions for respiration rate. Subsequently, clinical judgment about health status and identification of potential risk factors was based on average values, without consideration of the inherent dynamic nature of these variables. While the notion that arterial blood pressure is not constant, but fluctuates dynamically over time has been known since the 18th century, the clinical importance of this phenomenon is only now being recognized. There is growing recognition that assessment of hemodynamic variability (e.g., heart rate and arterial pressure) across multiple time scales may provide important insight into acute and long-term clinical outcomes, such as risk of stroke (Shimbo et al.,
In particular, the advent of transcranial Doppler (TCD) ultrasound monitoring in the 1980s by Aaslid et al. (
The evolving appreciation that measurement of hemodynamic variability provides important physiological insight is demonstrated by Newell et al. in the early 1990s who cautioned that the variability of cerebral blood velocity obtained from TCD may “interfere” with measurement of mean values (Newell et al.,
Furthermore, the potential role of increased variability in arterial pressure and cerebral blood flow on clinical outcome is somewhat disparate, with studies suggesting both protective (e.g. Sanderson et al.,
Fluctuations in arterial pressure and cerebral blood flow occur across multiple time scales, from beat-to-beat (Figure
The underlying physiological mechanisms associated with these different methodological approaches align with the time scale of measurement. For example, changes in mean and standard deviations of pressure and flow over hours to days are most likely associated with long time scale cycles, such as circadian rhythms, hormonal fluctuations, hydration status, fatigue, and associated variations in vascular properties such as compliance (Kotsis et al.,
It is important to note that the terminology used to describe hemodynamic variability differs between disciplines; while in the clinical setting, “short-term” variability may describe changes in arterial pressure every 15 min over a 24-h period (Schillaci et al.,
The idea that exaggeration of hemodynamic variability may be detrimental for vital organs such as the brain is both physiologically plausible and intuitive. Because the brain has a high metabolic demand for oxygen, any process that enhances perfusion variability has the potential to destabilize tissue oxygenation leading to ischemic injury. Conversely, excessive perfusion can result in the breakdown of the blood-brain barrier, permit the transudation of fluid into the interstitium, and incite hyperperfusion syndromes that are characterized by debilitating neurological sequelae including seizures, headaches, encephalopathy and stroke (van Mook et al.,
However, while it is generally recognized that blood pressure is an important determinant of cerebral blood flow, the exact relationship between pressure and flow is more complex when viewed in light of a contemporary model of cerebral autoregulation (CA) (Tzeng and Ainslie,
Unlike the case for cerebral perfusion variability being a “friend” with protective properties, little data exists that directly implicate perfusion variability being a “foe” for organ function. Rather, the case for exaggerated haemodynamic variability being a negative predictor for organ dysfunction is mainly built on studies of blood pressure dynamics that came initially with the advent of ambulatory blood pressure monitoring in the 1960s (Parati et al.,
As previously described, short-term variations in blood pressure are commonly characterized in the frequency domain using power spectral analysis typically of short recordings (e.g. range 5–10 min) (Tzeng and Macrae,
Mid-term blood pressure variations are usually defined as blood pressure fluctuations that occur within a 24-h period. There is considerable overlap in the mechanisms that are responsible for both mid-term and short-term blood pressure variations. Therefore, impairment of baroreflex function, or central sympathetic drive can both augment mid-term BPV. In an early investigation into the link between elevated mid-term BPV to end organ damage, Parati et al., showed that 24-h mean blood pressure and 24-h BPV were independently associated with the magnitude of mid-term BPV (Parati et al.,
There is also an emerging body of literature relating BPV and disease outcomes based on clinical measurements of day-to-day or visit-to-visit brachial blood pressures that provide information on long-term blood pressure variability (Mancia et al.,
It needs to be acknowledged that while the majority of research has linked elevated mid- and long-term BPV with increased risk of end-organ disease, there is some data suggesting that the impact of BPV are no greater than can be explained by mean pressure alone. For example, Schutte et al., have argued that in a large unbiased population sample (
Not only are increases in mid- and long-term BPV associated with accelerated end-organ damage and acute primary cardiovascular events (e.g., acute stroke) (Pringle et al.,
The precise mechanisms underpinning the regulation of BPV are multi-factorial and involve factors that drive and attenuate blood pressure changes. Behavioral factors (Pickering et al.,
The precise mechanisms underpinning the links between elevated BPV and end-organ damage are not yet fully understood, but available evidence suggest that both functional impairment and structural vascular changes are involved (Figure
Furthermore, in addition to vascular structural changes, elevated BPV can also lead to end-organ dysfunction by disturbing organ perfusion and oxygenation. Because the vital organs such as the brain and heart have high metabolic demand, any process that enhances perfusion variability has the potential to destabilize tissue oxygenation and therefore result in organ dysfunction. This means that, in addition to BPV, the integrity of flow-stabilizing mechanisms such as CA may partly underlie the relationship between elevated BPV and end-organ disease, particularly in the context of secondary brain injury (Reinhard et al.,
While a wealth of studies have assessed the
In 1972, Sanderson et al. (
Pulsatile flow has also been shown to improve cerebral hemodynamic status in other clinically relevant states, including prolonged cerebral ischemia as a model of stroke (Allen et al.,
Pulsatile flow patterns around the cardiac frequency can also be assessed via calculation of pulsatility, generally derived as systolic-diastolic/mean flow. Studies have reported a role of increased cerebral blood flow pulsatility and tolerance to central hypovolemia in healthy human subjects following head-up tilt and lower body negative pressure (LBNP) (Thomas et al.,
The studies described thus far have utilized pulsatile perfusion therapy at frequencies at or above the cardiac frequency (i.e., ≥1 Hz). Other investigations, however, have also assessed pulsatile flow at much lower frequencies, generally associated with patterns of respiration, sympathetic nerve activity, and myogenic activity, among other factors.
Under conditions of experimentally induced central hypovolemia in healthy human subjects, such as LBNP and head-up tilt, increased oscillatory power in arterial pressure and/or cerebral blood flow has been associated with increased tolerance to these stressors. In a number of studies using head-up tilt alone, or combined with LBNP, individuals with poor tolerance (i.e., display symptoms of presyncope or syncope) exhibited reduced LF oscillations in arterial pressure (Gulli et al.,
In these aforementioned studies where respiration was reported, the elevation in LF power was not associated with breathing rate, as subjects, on average, were breathing outside of the LF range (i.e., >0.15 Hz or >9 breaths/min) (Gulli et al.,
While these improvements in tolerance to central hypovolemia were not associated with the preservation of absolute cerebral blood flow, the effect of LF pulsatile cerebral blood flow on cerebral tissue oxygenation is a plausible underlying mechanism based on the animal and human clinical studies outlined above using pulsatile perfusion at higher frequencies. Some of these studies have demonstrated the role of nitric oxide-induced vasodilation and improved oxygen delivery at high oscillatory frequencies (Nakano et al.,
It has been speculated that the spontaneous generation of oscillations in cerebral blood flow and cerebral oxygenation in the lower frequency ranges (i.e., <1 Hz) is associated with changes in vascular properties, such as arterial compliance (Schroeter et al.,
In this review we have attempted to highlight the complexities inherent in the characterization of hemodynamic variables such as blood pressure and cerebral blood flow. We have contrasted evidence that supports hemodynamic variability as a protective feature of physiology against evidence suggesting that hemodynamic variability heralds expansive damage to organ function. Our review suggests that reconciliation of these two apparently discrepant views may lie in the time scale of hemodynamic variability; short time scale variability appears to be cerebroprotective, while mid-to-longer term fluctuations are associated with primary and secondary end-organ dysfunction. The extent to which knowledge of the positive and deleterious influences of hemodynamic variability will lead to improve health outcomes are presently unknown, but the case is mounting against classical approaches to hemodynamic assessment that focuses narrowly on absolute blood pressure and/or cerebral blood flow.
Caroline A. Rickards and Yu-Chieh Tzeng contributed equally to this manuscript in terms of conception of the work, drafting the work and revising it critically for important intellectual content, and final approval of the version to be published. Caroline A. Rickards and Yu-Chieh Tzeng agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Yu-Chieh Tzeng is supported by grants from the New Zealand Health Research Council (Ref 11/125). Caroline A. Rickards is supported, in part, by a grant from the US Army Medical Research and Material Command (W81XWH-11-2-0137). The content is solely the responsibility of the authors and does not necessarily represent the official views the US Department of Defense.