____________________________ CURRENT REVIEW

Hemodynamic Analysis Could Resolve the PulsatileBlood Flow ControversyGordon Wright, PhD

Department of Biomedical Engineering and Medical Physics, University of Keele, Staffordshire, England

Reasons for fluctuations in the popularity of pulsatilecardiopulmonary bypass are discussed. The advantagesof pulsatile flow have previously been stated in terms ofphysiologic parameters. This has produced a weak theo­retic framework that has led to serious misunderstand­ings of the fundamental mechanical properties of pulsa­tile flow. Failure to consider these properties in the past

Long before the birth of open heart surgery, mechanicalpumps had been designed, manufactured, and used

to establish circulatory support in isolated organs andwhole animals [1, 2]. By the time technologic develop­ments had proceeded sufficiently to permit the first openheart operation with cardiopulmonary bypass [3], it waswidely believed that pulsatile flow was better than non­pulsatile flow because the body was adapted to it. How­ever, the practice of open heart surgery was commencedand continued for many years with the aid of ripple(nonpulsatile) flow, extracorporeal circulation. There wereprobably three main reasons for this.

First, the case for pulsatile flow rested on classic physi­ologic theory [1, 4-6], and evidence from studies ofkidney, limb, and total body perfusion suggested that therewere no changes in reactivity, function, or survival timeassociated with nonpulsatile flow, so long as blood flowrates and mean arterial pressures were maintained withinthe normal range [7-9]. Wesolowski's publications duringthe early 1950s were an influential barrier to the adoptionof pulsatile flows for extracorporeal circulation. He and hiscolleagues showed that nonpulsatile right heart bypass indogs was compatible with normal respiratory functionsand associated with no permanent alterations in circula­tory dynamics [10]. This was later confirmed by Clarke [11]and Wemple [12] and their colleagues. In the same series ofexperiments, Wesolowski's group produced preliminaryevidence that pulsatile perfusion caused less systemichypotension than did nonpulsatile perfusion, but thispoint was subsequently negated by their finding no signif­icant differences in the hemodynamics, kidney function,vascular tone, recovery rate, blood indices, and organhistologic characteristics [13].

The criticism later made of these results was that We­solowski's use of high-flow rates probably eliminated thedifferences [14]. However, by this time, operative mortality

Address reprint requests to Dr Wright, Department of Biomedical Engi­neering and Medical Physics, University of Keele, Staffordshire ST5 5BG,England.

© 1994 by The Society of Thoracic Surgeons

may have allowed modified roller pumps to be acceptedas "pulsatile," even though their pulsatile power outputsare small compared with those of the human heart. Afresh approach is required in which pulsatile blood flowis analyzed in terms of hemodynamic power and imped­ance parameters.

(Ann Thorae Surg 1994;58:1199-204)

was declining rapidly and standard procedures were be­coming established. Mortality rates below 10% were con­sidered satisfactory and postoperative morbidity was be­coming less severe, if not less frequent. Current techniquesof extracorporeal circulation were perceived to be success­ful, so it is understandable that perfusionists and surgeonswere reluctant to make fundamental changes in theirprocedures.

Second, although pulsatile pumps were used for animalperfusions, there was no pulsatile pump for use in patientsbecause of the inherent complexity of available devices andbecause of problems of cost, unreliability, and sterilization.The roller pump had been available for some time [15, 16].In early versions, the machining tolerances were relativelywide and high compression and shear forces were gener­ated by the rollers. This resulted in high levels of hemoly­sis, but, even so, the roller pump was preferred to any thencurrently available pulsatile pump, or the even morehemolytic multiple-finger pump [17]. An excellent reviewof blood pump technology during that period was pre­sented by Galletti and Brecher [18] and later reproduced inthe American Physiological Society'S Handbook of Physiol­ogy [19].

We now know that blood trauma is not primarilydetermined by the type of flow but rather by the mechan­ical forces applied to the blood by the pumping mecha­nism. Positive displacement mechanisms, such as piston­actuated ventricles, are inherently less traumatic thanroller pumps, but cam-operated valves can increase thetrauma if they are not carefully designed and set. In anyevent, blood trauma during cardiopulmonary bypass isprimarily due to cardiotomy suction, not to blood pump­ing [20-22].

The third reason why pulsatile flow was not favored forextracorporeal circulation may have been that pulsatilepumps generate very high levels of energy in the arterialline. Dislodgement of tubing connectors is not unknownwith the use of high-amplitude pulsatile pumps, and this isa risk that cannot be taken when human lives are involved.

Consequently, pulsatile flow was not adopted for car-

0003-4975/94/$7.00

1200 REVIEW WRIGHTPULSATILE BLOOD FLOW

diopulmonary bypass until the practical problems hadbeen solved. The solution represented a massive compro­mise. An additional electronic control system was devel­oped so that the familiar roller pump could provide a newkind of pulsatile flow that fluctuated in time but bore littleresemblance to the pulsatile flow generated by the naturalheart, except in terms of the radial artery pressure pulseamplitude [23, 24].

By this time, additional experimental evidence had beenreported, and most of this favored the use of pulsatile flow.It was then necessary to ask whether the much modifiedpulsatile flow generated by roller pumps is really adequateto obtain the benefits attributed to pulsatile flow shown bylaboratory experiments. Taylor's group, working in Glas­gow, acquired relevant biochemical and physiologic evi­dence during human open heart procedures. When theStockert roller pump was operated in its "pulsatile" moderather than its "continuous" mode, they found less stim­ulation of the renin-angiotensin system and lower periph­eral vascular resistance [25]; less depression of the usualstress response to operation as the result of anteriorpituitary secretion of adrenocorticotropic hormone andcortisol release [26]; and less pituitary hypofunction [27]. Ina review of 1,217 patients who underwent open heartprocedures, Taylor [24] claimed a significant reduction inthe number of operative and low-output-related deathswithin the first 24 hours after operation.

Primary Mechanisms of Pulsatile Flow

The Glasgow group attributed the benefits of pulsatileperfusion with the modified roller pump to the concept ofenergy-equivalent pressure, capillary critical closing pres­sure and microcirculatory patency, and neuroendocrinereflex mechanisms triggered by baroreceptor discharge[24].

Energy-Equivalent PressureThe concept of energy-equivalent pressure was introducedby Shepard and colleagues [28], but has been little usedsince then. Energy-equivalent pressure (EEP) is a way ofexpressing stroke work (joules) in the more familiar unitsof pressure (millimeters of mercury). It is calculated as:

fpqdtEEP=--

f.,where p is pressure and q represents flow.

When the flow is purely nonpulsatile, the integral signscan be removed and energy-equivalent pressure equals themean pressure, but, when the flow is pulsatile, the energy­equivalent pressure includes energy within the pressureand flow waveforms. In the normal human heart, thedifference is approximately 10%. Energy-equivalent pres­sure is therefore not a mechanism, but only a mathematicaldevice to measure variables that are not familiar to clini­cians, namely energy and work. Actually, the concept ofenergy is fundamental to an understanding of pulsatile

Ann Thorae Surg1994;58:1199 -204

flow mechanics and should not be circumvented in thismanner, first because it paralyzes further progress towardan understanding of more complex problems in hemody­namics, and second because of the principle that measure­ment units should not be misused.

Critical Closing PressureThe idea that the microcirculation may collapse at a certaincritical closing pressure was enunciated by Burton in 1954[29]. The only direct experimental evidence that this actu­ally occurs during ripple, or nonpulsatile, perfusion oftissues was supplied by Takeda [30], who described capil­lary collapse and microcirculatory shunting during rippleflow perfusion. However, there is also some indirect evi­dence of this. First, diffuse nerve cell changes that arecharacteristic of tissue ischemia were found in the brains ofdogs subjected to total cardiac bypass for 3 hours using aconventional roller pump [31]. Collapsed capillaries wereassociated with these changes. The second piece of evi­dence comes from unpublished findings from researchperformed in collaboration with Professor C. R. H. Wilde­vuur at the Surgical Research Centre in Groningen, TheNetherlands. Tissue oxygen pressure histograms [32] wereperformed on the sartorius muscle of dogs undergoingtotal cardiopulmonary bypass using either a conventionalroller pump or a ventricle-type pulsatile pump [33].Preperfusion histograms had a Gaussian distribution, andthis was maintained during pulsatile perfusions with theventricle pump, but, during ripple flow perfusions, thehistograms became markedly left skewed, in that there wasa predominance of low oxygen pressures. However, theconversion from ripple to pulsatile perfusion did notimmediately restore the normal histogram. This took ap­proximately 20 minutes, suggesting the presence of micro­circulatory collapse during the period of ripple flow per­fusion that was not easily reversed.

Neuroendocrine ReflexesIt was shown by Ead and colleagues [34] that baroreceptorsin the carotid sinuses respond to both mean and pulsatilepressures and that carotid sinus nerve discharge is de­creased by damping the carotid artery pulse. The sinusnerve exerts an afferent inhibitory effect on vasomotordischarge, so that reflex vasoconstriction occurs when thesinus pulse is damped. A second mechanism was identi­fied by Many and associates [35-37], who showed thatrenin secretion was increased and renal function wasimpaired when blood flow through the abdominal aortawas depulsed by passing it through a high-compliancechamber.

Thus, it appears that there may be at least two separatemechanisms underlying the vascular responses to nonpul­sa tile flow-a loss of vasomotor inhibition by the carotidsinus nerve and renal secretion of renin, with subsequentliberation of the powerful vasoconstrictor angiotensin II. Itis not clear why two mechanisms exist for the samefunction, but there are precedents in other physiologiccontrol systems in which the nervous reflex provides arapid response and the endocrine system provides thesustained response.

Ann Thorae Surg1994;58:1199-204

Other FactorsThere are other factors that have been suggested as pri­mary mechanisms for the improved tissue perfusion ob­served during pulsatile extracorporeal circulation.

THE TELEOLOGIC ARGUMENT. Even primitive hearts gener­ate pulsatile flow. However, during the course of evolu­tion, both the mean arterial pressure and the pulse ampli­tude have increased [39]. The argument is that "natureknows best" and should be emulated. This is a weakargument, because the observation of a trend does notnecessarily constitute any experimental evidence of a ben­efit. However, it may be accepted as circumstantial evi­dence, if one likes.

HIGHER RATES OF TISSUE FLUID MOVEMENT AND THE FLOW

OF LYMPH. The monumental and diligent research of Par­sons and McMaster [39, 40] on the spread of dyes inisolated perfused rabbit ears convincingly demonstratedthat the arterial pulse is important for promoting themovement of tissue fluids, as well as the formation andflow of lymph. There are three mechanisms responsible forthe promotion of lymph flow from the tissues to thelymphatic duct. These are muscular compression, arterialpulsations, and lymphatic contractions. In anesthetizedpatients, muscular contractions should be absent. Withregard to the arterial pulsations, the small lymphaticvessels are wrapped around the arteries and protected bya common sheath. Therefore, arterial contractions aretransmitted to the lymphatics and the flow of lymphtoward the lymphatic duct is ensured by one-way valves.This mechanism depends on pulsatile energy supplied tothe lymphatics, and this is reduced greatly during nonpul­satile extracorporeal circulation. This leaves the low­frequency lymphatic contractions as the only mechanismto move lymph during nonpulsatile extracorporeal circu­lation, and we do not know how effective these contrac­tions are.

However, Anabtawi and colleagues [41] showed thatlymph formation and flow were similar during pulsatileand nonpulsatile perfusions, and that, in the intact animal,they are actually related to the mean arterial pressure andlimited by the flow capacity of the thoracic duct.

HIGHER RATES OF METABOLISM. Shepard and Kirklin [42]showed that oxygen consumption is higher during pulsa­tile perfusions than during nonpulsatile perfusions, andspeculated that the possible mechanisms for this may be,first, that "jiggling of the tissues during pulsatile flow ...may act to change the boundary layer of interstitial fluidaround cell membranes and thus enhance diffusion"; sec­ond, that the increased lymph and interstitial fluid flowmay minimize the development of increased diffusiondistances between capillaries and cells; or, third, "thatpulsatile energy may be required to ensure that a normalpercentage of the total number of arterioles in a vascularbed are open at anyone time.... r r

REVIEW WRIGHT 1201PULSATILE BLOOD FLOW

Hemodynamic Energy Transmission

The preceding discussion suggests that there is consider­able disagreement about the primary physiologic mecha­nisms by which pulsatile flow confers benefits in terms oftissue perfusion. In fact, several of these mechanisms maybe involved, but they are not the primary ones, and toconsider them as such may be misleading. As in allbiologic systems, the primary mechanism is energy trans­duction. In the case of the cardiovascular system, theparticular transduction mechanism is the conversion ofchemical energy into mechanical energy. The lack of ap­preciation of this fundamental mechanism and of themechanical properties of the vascular bed that facilitate thetransmission of mechanical energy through the vascularbed to the tissues forms the intellectual background thathas resulted in the development of mechanical pumps thatgenerate various types of blood flow that are labeled"pulsatile," but which are not designed to be matched tothe vascular impedance.

For optimal design methods to be feasible, some under­standing of pulsatile flow hemodynamics is required, andthis must involve further consideration of the mechanicalproperties of both the heart, or pump, and the vascularbed, and of the interactions between them. We need toconsider the heart, or pump, as a complex power sourceand the vascular load as a complex impedance possessingboth resistive and reactive properties. Methods of comput­ing these variables have been described [43-47] and text­books on the topic are available [48-50], but the methodsare rarely mentioned in the cardiopulmonary bypass liter­ature.

The techniques are based on the Fourier transformationof blood pressure and flow data recorded from the proxi­mal aorta. The techniques have limitations and only pro­vide a starting point [51]. There is much more to belearned, especially about the interactions between the heartand the vascular load, and it may be that nonlinearrelationships and additional dimensions will have to beincorporated to obtain a sufficiently comprehensive math­ematical description of all of the properties of the cardio­vascular system. Nevertheless, this approach offers realinsights into the pulsatile properties of cardiovascularfunction that cannot be obtained by a purely physiologicapproach.

The basic philosophy is that the cardiovascular system isanalogous to an electrical transmission line, and thussimilar mathematical techniques can be used to describe itsperformance. Then, left ventricular function is defined interms of its total hemodynamic power output consisting ofmean and pulsatile components. The load that the leftventricle works against is the aortic input impedance,which has resistive and reactive properties, and the reac­tive components are arterial compliance and the inertia ofblood.

These parameters are not independent. Power and im­pedance interact and the pulsatile properties of the heartare dependent on the reactive properties of the vascularimpedance. In addition, the individual components of leftventricular power output (mean and pulsatile) interact,

1202 REVIEW WRIGHTPULSATILE BLOOD FLOW

and so do the individual components of the vascularimpedance. For instance, increasing the peripheral resis­tance by the addition of the vasoconstrictor drug methox­amine immediately increases the characteristic resistance,reduces arterial compliance, and reduces inertia [47]. Theseimpedance changes are reversed by administering thevasodilator drug hydralazine. However, to complicate theissue further, arterial reactive changes later ensue to offsetthe immediate changes in the characteristic resistance andcompliance. Evidently, these parameters are under theinfluence of a physiologic control system, and this must berelated to the pulsatile power output of the left ventriclebecause the mean power output is unaffected by thesechanges.

It may be that the role of this control system is to ensurethat the total hemodynamic energy level is maintained at anear constant level, or that the ratio between pulsatile andnonpulsatile energy is maintained. The results of experi­ments in which the impedance parameters were artificiallyvaried are currently being studied in an attempt to definethese properties.

We have noticed that the initial vascular responses justdescribed also occur in perfused mechanical models, aphenomenon that cannot be adequately explained by theanalogy with an electrical transmission line theory appliedto alternating currents, indicating that the techniques are inneed of further refinement. However, the delayed reactiveresponses do not occur in mechanical models, and thisshows that they are not merely mathematical phenomenabut may have real physiologic significance. If a mechanismexists to compensate for changes in impedance and pulsa­tile energy levels, this implies that it is important tomaintain the pulsatile component of energy.

It also implies that some arterial receptor mechanismexists to monitor the pulsatile energy content of the blood.This mechanism may be the carotid baroreceptors, whichare actually misnamed because they respond to sinus wallstretch, not to sinus pressure. They are therefore affectedby radial, rather than perpendicular, forces, and respond toboth mean and pulsatile applications of these forces. Thedischarge rate from individual baroreceptor units is in­creased by sinus pulsations, but additional units are alsorecruited [34,52]. Thus, the sensory mechanism for recog­nizing arterial pulsations may reside in the selective re­sponse of individual baroreceptor units within the carotidsinus.

It follows from this discussion that the pulsatile poweroutput of the left ventricle may be matched to the reactiveproperties of the aortic input impedance, thereby optimiz­ing the transmission of mechanical energy from the heartto the tissues. Replacement of the normal aortic inputimpedance by an abnormal load is likely to impair the leftventricular hemodynamic power output. This appears tobe confirmed in the setting of isolated rat hearts ejectinginto a mechanical model of the rat's aortic input imped­ance. As the model's arterial compliance was reduced, leftventricular hemodynamic power output decreased and, ata critical value of compliance that is approximately 40% ofthe normal value in the circulation, it approached zero. Theconverse of this is that replacement of the left ventricle by

Ann Thorae Surg1994;58:1199-204

a mechanical pump delivering levels of pulsatile powerthat are not matched to the reactive properties of the aorticinput impedance is likely to result in the suboptimaldelivery of energy to the tissues. Otherwise, pulsatilepower transmission to the vascular beds will be less thanoptimal and the benefits of pulsatile flow may not beachieved. This may be the crucial factor.

With this hypothesis in mind, it is instructive to examinethe pulsatile power output of the human left ventricle andto compare this with those of available so-called pulsatilepumps. Sample pressure and flow waveforms generatedby the human heart and various pulsatile pumps areavailable [53-55]. There is a wide range of flow waveformsgenerated by pumps that have been labeled "pulsatile,"and the pulsatile power outputs of these pumps aremarkedly affected by the vascular impedance and by themechanical characteristics of the arterial line [54,55]. Basedon measurements of aortic blood pressure and flow inpatients undergoing open heart surgical procedures, wecomputed left ventricular pulsatile power outputs of 111 ::':::14 mW (standard error of the mean) [56,57]. The pulsatilepower output of the Stockert roller pump, operated underthe most favorable conditions (automatic control set tomaximum, a stiff 12.6-mm [inner diameter] pump tube,and no inclusions in the arterial line) was found to be 12 ::':::1 mW (standard error of the mean), or 10.8% of thepulsatile power output of the human heart, depending onthe impedance of the vascular load. When the pump wasset to prevent negative pressure from developing by ad­justing the automatic control to 80% of maximum, thepulsatile power output was even lower, that is, 4.5 mW, or4.05% of the pulsatile power output of the human heart; inthe continuous mode, the pulsatile power output wasapproximately 2 mW, or 1.8% of the pulsatile poweroutput of the human heart. The difference in power out­puts between the two modes of operation was thereforeonly 2.7%. In contrast, the Keele ventricle pump generatedpulsatile power outputs higher than those of the humanheart.

Unfortunately, it is the modified roller pump that hasbeen most commonly used to generate "pulsatile" flow forcomparative clinical investigations, and it is probablybecause of the low pulsatile power output of this pump,and some other pumps, combined with various vascularimpedances (particularly arterial compliance), that someinvestigators have been unable to find any differencesbetween "pulsatile" and "continuous" perfusions (seereviews by Mavroudis [58] and Hickey and colleagues[59]). Interest in pulsatile perfusion for open heart surgicalprocedures has declined, probably because the pumps donot generate sufficient pulsatile power to achieve many ofthe theoretic advantages of pulsatile power, but also be­cause of the increased use of arterial line membraneoxygenators, which dampen the pulse to levels below 3mW.

Experimental and clinical benefits that have been attrib­uted to pulsatile flow include improved preservation ofkidney, heart, pancreas, thyroid, and brain function; elim­ination of the depressed renal function associated withnonpulsatile perfusion; reduced levels of postoperative

Ann Thorac Surg1994;58:1199-204

systemic hypertension; and reduced postoperative mortal­ity. However, many contradictory findings have also beenreported, and these showed that pulsatile flow was nobetter than nonpulsatile flow in some respects. The expla­nation offered by Hickey and colleagues [59] for thisdilemma was that "different investigators employ differentforms of pulsatile perfusion, only some of which areeffective." This is my view also, but I would define"effective" to mean "matched to the reactive properties ofthe vascular impedance."

However, there is one irritating problem with this con­clusion, and this is that some investigators have attributedmajor benefits to pulsatile flow delivered by modifiedroller pumps, which clearly are unable to deliver morethan a small fraction of the pulsatile power delivered bythe human left ventricle. Does this imply that even a smallamount of pulsatile power is sufficient to improve tissueperfusion if it is matched to the vascular impedance, or isthe explanation that the benefits observed were actuallydue to factors other than pulsatile flow? One such possi­bility is that the flow rates may have been different in thepulsatile and nonpulsatile groups. Usually the method ofrecording the pump flow rate is not declared, so wepresume that it was read from the pump display. This isdifficult to read with any degree of accuracy and theauthors do not say how, or how frequently, the displaywas calibrated.

Conclusion

The use of pulsatile flow for cardiopulmonary bypass inhuman patients was most popular during the 1980s. Morerecently, its use has declined, and there are several possiblereasons for this. First, there has been a lack of understand­ing of the basic mechanical properties of the left ventricleand major arteries and of the interactions between them.Second, there has not been a satisfactory definition ofpulsatile flow, and this has led to the use of pumps thatdeliver different types of flow for experimental purposes.A third reason for the declining use of pulsatile flow forcardiopulmonary bypass has been the recent developmentof membrane gas-exchange devices that dampen the pulseand that are intolerant to high pressures in the arterial line.The concerted use of modified roller pumps to generateso-called pulsatile flow, even though this bears little resem­blance to the pulsatile flow generated by the natural heart,is a fourth reason.

All experimental and clinical investigations should be­gin with the definition of new terms and the developmentof a suitable theoretic framework. This procedure has notbeen followed in the work on pulsatile flow. Such aframework is available and makes use of the concepts ofhemodynamic power and vascular impedance. Furtherelaboration of the framework is required, but, even in itspresent form, it offers far greater insights into the funda­mental mechanisms by which pulsatile flow may improvetissue perfusion than do the hitherto used physiologicexplanations. In particular, it may explain why some flowwaveforms are beneficial, while others are not, based on aknowledge of the pulsatile power output of the pump in

REVIEW WRIGHT 1203PULSATILE BLOOD FLOW

relation to the reactive properties of the vascular imped­ance. So far, the only pump that is guaranteed to generateoptimal pulsatile power output in the human circulation isthe human heart.

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