Hemodilution Impairs CerebralAutoregulation, Demonstrating theComplexity of Integrative Physiology

J. Kevin Shoemaker, PhD Reflex adjustments to physical and orthostatic stress include a complexseries of neurogenic, cardiac, and vascular reactions that defend cardiacoutput and systemic vascular resistance, so that arterial blood pressure andcerebral perfusion are sustained and near normal levels. In addition, anarray of metabolic, circulating, endothelial, and local pressure-dependentregulatory mechanisms contribute to changes in cerebrovascular resis-tance. The ability of cerebral blood vessels to adjust their caliber andsustain blood flow over a wide range of perfusion pressure is termedautoregulation and has been the focus of research for many decades (1–3).Without such systemic and cerebrovascular responses, hypotension andcerebral hypoperfusion would occur.

During surgery in anesthetized patients where normal physiology maybe compromised, it is the role of anesthesiologists to sustain arterial bloodpressure and cerebral perfusion at levels that are optimal for the circum-stances. This objective often requires the enhancement of circulating bloodvolume with methods that dilute oxygen-carrying capacity. Yet the verypractice of maintaining blood volume and cardiac output by hemodilutionmay be detrimental to cerebral function through reductions in oxygendelivery. The dangers of excessive hemodilution include poor neurologic(4,5) and other life-threatening outcomes after surgery (6). Several largeobservational (7–9) and experimental (10) studies have identified an associa-tion between very low intraoperative hematocrit levels (�30%), alteredcerebral metabolism, risk of in-hospital mortality, or adverse neurologicaloutcomes. Hemodilution challenges cerebrovascular perfusion.

Complex physiology is not regulated completely by simplistic strate-gies. The mechanism by which hemodilution affects cerebral blood flow(CBF) is perhaps as complex as the means by which CBF itself is sustained.One important question is the impact of hemodilution on cerebral auto-regulation (CA). Further, if hemodilution impairs autoregulation, does itreally matter under conditions where cardiac output is sustained underreflexive control?

In the current issue of Anesthesia & Analgesia, Ogawa et al. (11) test thehypothesis that changes in circulating blood volume with hemodilutionaffect CA in conscious humans. This was accomplished by (a) reducingcentral blood volume with two levels of lower body suction (a simulatedorthostatic stress), and (b) infusing normal saline at two rates to achieve upto approximately 5% reduction in hematocrit. With the saline infusion,there was a concurrent increase in circulating blood volume, cardiac fillingpressure, and cardiac output. Examination of CA was accomplished usingthe transfer function gain approach (12–14), whereby spontaneous fluctua-tions in arterial blood pressure are correlated to concurrent variations inCBF velocity at various oscillating frequencies. With this comprehensiveapproach, analysis of static and dynamic autoregulation can be investi-gated along with questions regarding the relationship of cardiac output toCBF and oxygen delivery. This study offers a comprehensive approach instudying CA within the context of central and cerebral hemodynamics.Moreover, it offers opportunities for discussion of several points that are

From the Neurovascular Research Labo-ratory, School of Kinesiology, The Univer-sity of Western Ontario, London, Ontario.

Accepted for publication July 17, 2007.Address correspondence and reprint

requests to J. Kevin Shoemaker, PhD, Neu-rovascular Research Laboratory, School ofKinesiology, Room 3110 Thames Hall, TheUniversity of Western Ontario, London, ONN6A 3K7, Canada. Address e-mail tokshoemak@uwo.ca.

Copyright © 2007 International Anesthe-sia Research SocietyDOI: 10.1213/01.ane.0000282825.13842.02

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Editorial

relevant to those interested in perioperative care.These include 1) the method of spectral analysis toassess autoregulation, 2) what impaired autoregula-tion means in this context, and 3) how altered cere-brovascular control mixes with the altered centralhemodynamics.

Spectral analysis methods have become popular forassessing cardiovascular oscillations, including cere-brovascular control. The relationship between peri-odic changes in arterial blood pressure and CBFvelocity across a range of relevant oscillation frequen-cies has been reported in hundreds of papers since theearly report by Birch et al. (14) in 1995. The method’spopularity is due to 1) ease of use, 2) a wide range ofapplicability, 3) relatively low cost, 4) lack of need toinduce arterial blood pressure changes but, rather, reli-ance on spontaneous fluctuations, and 5) the apparentdiagnostic utility. This transfer function approach reliessolely on the relationship between spontaneous fluctua-tions in arterial blood pressure and mean flow velocity inthe middle cerebral artery, this artery being used as ageneralized indicator of cerebrovascular control. Withintact autoregulation, fluctuations in arterial bloodpressure are not reflected in blood flow velocity (i.e.,low transfer gain) and with loss of autoregulationthere is increased transfer of arterial blood pressure tothe CBF velocity. Despite these benefits, there isconcern that information about variables such as va-somotor tone (15,16) are not included in the determi-nation of coherence between arterial blood pressureand mean flow velocity. Also, the magnitude of im-pairment is difficult to determine from transfer func-tion methods. Certainly, these additional featuresexplain some of the challenges in the interpretation ofspectral analytical results �see (16) for example�.

The current study in volunteers by Ogawa et al.created a relatively small hemodilution with hematocritchanges of �5%. Nonetheless, this moderate level of he-modilution was associated with a higher transfer functiongain across a range of frequencies in the arterial bloodpressure–blood flow velocity frequency spectrum, i.e.,impaired autoregulation. In time-domain and steady-state analysis, saline infusions produced a 20% increasein cardiac output together with a10% increase in CBFwith no change in arterial blood pressure. Higher cere-bral flow velocity at the same arterial blood pressuresuggests that either static autoregulation was impairedor that the pressure-flow autoregulation curve was ad-justed upwards. The spectral-based methods confirmedthe alteration of autoregulation. But what does “im-paired” autoregulation mean in this context? Does itmean that cerebral perfusion is in jeopardy?

A methodological constraint of spectral analysis isthat it cannot provide information on the position ofthe autoregulatory curve. Neither can it describe therange of arterial blood pressures over which autoregu-lation is affected or effective. In fact, this pressurerange has never been assessed adequately in conscious

humans and a “gold standard” method for the assess-ment of autoregulation has not been identified for hu-man investigations. Nonetheless, comparisons acrossmethods indicate that the spectral gain features do reflectaccurately the directional change in autoregulation (2).Also, by itself, this index of CA does not provide amechanistic basis for the change in cerebrovascularcontrol. From this perspective, an attractive feature of theOgawa et al. study is the comprehensiveness of dataacquisition allowing the reader to examine the relation-ships between central and cerebral vasomotor control.

From Ogawa et al.’s data, cerebral hypoperfusiondoes not seem to be the problem in this hypervolemichemodilution condition despite altered autoregula-tion. Rather, it is the reduction in oxygen content (butnot delivery) that appears to be the more potent physi-ological challenge. Also, the maintenance of arterialblood pressure and cardiac output suggests that alteredautoregulation is not due to pressure-dependent mecha-nisms. Using cerebral vascular resistance as the index,the authors indicate that vasodilation occurred in thecurrent study. This dilation likely was related toaltered cerebral metabolism as oxygen content wasreduced. In addition, the authors discuss the potentialfor a baroreflex-medicated reduction in overall sym-pathetic outflow as a result of hemodilution causingcardiac output to increase. The altered sympatheticreflex outflow may affect cerebrovascular tissue andthe autoregulatory response (17). In conscious healthyhumans, sympathetic innervation appears to enhanceautoregulatory control, at least when arterial bloodpressure is high (18). Vasodilation, including thatresulting from a reduction in sympathetic outflow,may alter the autoregulatory response. There is aninverse relationship between cerebrovascular contrac-tile state and the extent of the autoregulatory response(2). The reason is likely related to (a) the diminishedpotential for dilated vessels to dilate further in re-sponse to a decrease in pressure, or (b) a greaterdifficulty to constrict when arterial blood pressureincreases due to heightened competition from localmetabolic dilators. The impaired autoregulatory re-sponse in the current study appears to be related to theindirect effects of hemodilution on the complex factorsthat affect cerebrovascular tone, rather than on thepressure-dependent nature of these vessels, per se. Thisstudy indicates that reduced oxygen transport providesa consistent challenge to multiple cerebrovascular con-trol features, even with moderate degrees of hemodilu-tion. Therefore, hypervolemia with hemodilution mayerode CA through multiple mechanisms.

A major challenge in the literature on CA is puttingthe cerebrovascular response in the context of sys-temic hemodynamics. For example, to what extent isCBF regulated by cardiac output? Ogawa et al. (19)report a relationship that is weaker than previouslyreported. Differences between studies regarding thecoupling of cerebral to systemic hemodynamics re-main to be reconciled. Regardless, the “link” between

1180 Editorial ANESTHESIA & ANALGESIA

cardiac output and CBF is arterial blood pressure as itis impacted by total blood flow. Conditions thatmodify cardiac output with little direct impact oncerebral metabolism or arterial blood pressure, such aspostural shifts in healthy individuals, normally havelittle impact on CBF velocity. Thus, if autoregulation isintact, one would expect a weak relationship betweentotal flow and CBF (assuming local cerebrovascularcontrol factors remain constant). In contrast, eventsthat impair CA or affect a vasodilatory response in thebrain should improve the relationship between car-diac output and CBF. Unfortunately, it is not clearfrom the current results whether this correlation dif-fered between the period of hypovolemia (induced bylower body suction) when autoregulation was un-changed from a control test, and hypervolemia (salineinfusion) when it was impaired. Future studies mightexamine how “impaired” autoregulation directly af-fects the relationship between central and CBFs. None-theless, this study supports the idea that cerebralperfusion is poorly associated with total circulatingblood flow even when autoregulation is impaired.

In summary, the inducement of hypervolemia withhemodilution, while a clinically relevant scenario, is acomplex challenge for cerebral perfusion, as it altersoxygen delivery and reflex autonomic outflow whileenhancing overall blood flow and pressure. As Ogawaet al. acknowledge, it is difficult to isolate independenteffects of acute changes in blood volume withoutaltering variables that exert additional influence onthe measurements of CA. Furthermore, even alter-ations in autoregulation are difficult to interpret inhumans because of limitations to the methods avail-able. Thus, it is difficult to comprehend the integratedeffect of altered central blood volume with hemodilu-tion using the limited tools available for noninvasivestudies in conscious humans. Nonetheless, this studyraises the important issue that it is the integratedresponse that may be most informative to improvedpatient outcomes.

REFERENCES

1. Edvinsson L. Cerebral blood flow and metabolism. New York:Raven Press, 1993

2. Aaslid R, Lindegaard KF, Sorteberg W, Nornes H. Cerebralautoregulation dynamics inhumans. Stroke 1989;20:45–52

3. Paulson O, Strandgaard S, Edvinsson L. Cerebral autoregula-tion. Cerebrovasc Brain Metab Rev 1990;2:161–92

4. Shaw PJ, Bates D, Cartlidge NE, French JM, Heaviside D, JulianDG, Shaw DA. An analysis of factors predisposing to neuro-logical injury in patients undergoing coronary bypass opera-tions. Q J Med 1989;72:633–46

5. Martin WR, Hashimoto SA. Stroke in coronary bypass surgery.Can J Neurol Sci 1982;9:21–6

6. DeFoe GR, Ross CS, Olmstead EM, Surgenor SD, Fillinger MP,Groom RC, Forest RJ, Pieroni JW, Warren CS, Bogosian ME,Krumholz CF, Clark C, Clough RA, Weldner PW, Lahey SJ,Leavitt BJ, Marrin CA, Charlesworth DC, Marshall P, O’ConnorGT; Northern New England Cardiovascular Disease StudyGroup. Lowest hematocrit on bypass and adverse outcomesassociated with coronary artery bypass grafting. Ann ThoracSurg 2001;71:769–76

7. Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ,Shah A. Adverse effects of low hematocrit during cardiopulmo-nary bypass in the adult: should current practice be changed?J Thorac Cardiovasc Surg 2003;125:1438–50

8. Fang WC, Helm RE, Krieger KH, Rosengart TK, DuBois WJ,Sason C, Lesser ML, Isom OW, Gold JP. Impact of minimumhematocrit during cardiopulmonary bypass on mortality in pa-tients undergoing coronary artery surgery. Circulation 1997;96:II-9

9. Karkouti K, Djaiani G, Borger MA, Beattie WS, Fedorko L,Wijeysundera D, Ivanov J, Karski J. Low hematocrit duringcardiopulmonary bypass is associated with increased risk ofperioperative stroke in cardiac surgery. Ann Thorac Surg2005;80:1381–7

10. Sakamoto T, Nollert GD, Zurakowski D, Soul J, Duebener LF,Sperling J, Nagashima M, Taylor G, DuPlessis AJ, Jonas RA.Hemodilution elevates cerebral blood flow and oxygen metab-olism during cardiopulmonary bypass in piglets. Ann ThoracSurg 2004;77:1656–63

11. Ogawa Y, Iwasaki K, Aoki K, Shibata S, Kato J, Ogawa S.Central hypervolemia with hemodilution impairs dynamic ce-rebral autoregulation. Anesth Analg 2007;105:1389–96

12. Dawson SL, Manktelow BN, Robinson TG, Panerai RB, PotterJF. Which parameters of beat-to-beat blood pressure and vari-ability best predict early outcome after acute ischemic stroke?Stroke 2000;31:463–8

13. Panerai RB. Assessment of cerebral pressure autoregulation inhumans–a review of measurement methods. Physiol Meas1998;19:305–38

14. Birch AA, Drinhuber MJ, Hartley-Davies R, Iannotti F, Neil-Dwyer G. Assessment of autoregulation by means of periodicchanges in blood pressure. Stroke 1995;26:834–7

15. Edwards MR, Shoemaker JK, Hughson RL. Dynamic modula-tion of cerebrovascular resistance as an index of autoregulationunder tilt and controlled PET(CO(2)). Am J Physiol Regul IntegrComp Physiol 2002;283:R653–R662

16. Hughson RL, Edwards MR, O’Leary DD, Shoemaker JK. Criticalanalysis of cerebrovascular autoregulation during repeatedhead-up tilt. Stroke 2001;32:2403–8

17. Edvinsson L, Nielsen KC, Owman C, West KA. Sympatheticneural influence on norepinephrine vasoconstriction in brainvessels. Arch Neurol 1972;27:492–5

18. Kimmerly DS, Tutungi E, Wilson TD, Serrador JM, Gelb AW,Hughson RL, Shoemaker JK. Circulating norepinephrine andcerebrovascular control in conscious humans. Clin PhysiolFunct Imaging 2003;23:314–9

19. Ogoh S, Brothers RM, Barnes Q, Eubank WL, Hawkins MN,Purkayastha S, Yurvati A, Raven PB. The effect of changes incardiac output on middle cerebral artery mean blood velocity atrest and during exercise. J Physiol 2005;569:697–704

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