We Always Need a Pulse, Or Do We??

Leslie Miller

Received: 10 January 2012 /Accepted: 6 March 2012 /Published online: 3 May 2012# Springer Science+Business Media, LLC 2012

Keywords LVAD . Complications . Heart failure . Pulse .

GI bleeding . Heart . Circulatory physiology

The circulatory physiology of humans and all primates ischaracterized by pulsatile blood flow. This observation wouldseem to suggest that pulsatility is essential to normal functionof most critical organs, including the brain and kidneys. How-ever, there is now clear evidence from clinical trials ofthousands of patients that have demonstrated that pulsatileflow is in fact not essential to normal organ or cognitivefunction [1–3]. The proof of this comes from the developmentof a new generation of ventricular assist devices (VADs) whichare used to support the circulation of patients with very ad-vanced heart failure or shock. The transition from pulsatile tonon-pulsatile design of left ventricular assist devices (LVADs)was not predicated on the belief that continuous flow wouldprovide better support but on the need tomove to that design toallow a miniaturization of the pump for both patient comfortand a reduced risk of drive-line and/or pocket-related infection.

The initial experiments were done in calves in whichbiventricular continuous-flow devices were implanted atbirth [4]. These animals demonstrated normal growth, de-velopment, and organ function. This finding led to pilotclinical trials that showed no adverse impact on organ func-tion and set the stage for large clinical trials, which haveconfirmed normal organ function with transition from pul-satile to non-pulsatile blood flow [5, 6].

The first generation of VADs mimicked normal humanphysiology and followed electrical activation of the ventri-cle and ejected the preload present in the ventricle at eachbeat in a pulsatile manner into the systemic circulation.These first generation pumps were, however, quite largeand had limited durability due to use of bearings and mul-tiple parts, such that 50 % of the pumps had to be replacedby 18 months of use [7]. The problem with durability was solimiting that it led to the development of a whole newgeneration of VADs, which in order to miniaturize the sizeand enhance durability, required significant engineeringchanges. This included a pump with a single moving part,in a chamber that was one-seventh the size and one fifth theweight of the first generation pump [1] (Fig. 1). Moreimportantly, these pumps draw blood from the left ventricleon a continuous basis via a drainage cannula placed in theLVapex by use of a rotary pump and propels the blood backinto the circulation in a non-phasic flow pattern through areturn cannula connected to the aorta (Fig. 2). One aspect ofthe engineering of the continuous flow LVADs is that thespeed of the rotary pump can be adjusted in real time todirectly alter LV volume to increase or decrease preload andtherefore peripheral output and blood pressure (Fig. 3). Theinteraction of the left and right ventricle is a dynamic processas the pump can too rapidly reduce LV volume, with resultantshift of the interventricular septum to the left, which can leadto both worsening RV function and potential direct contact ofthe drainage cannula with the ventricular wall or septum andruns of ventricular tachycardia (Fig. 4). The clinical trials withcontinuous flow VADs, including both centrifugal and axialflow [8], have all shown equal, if not superior end-organfunction compared to the first generation of pulsatile flowpumps. This data clearly demonstrate that pulsatile blood flow

J. of Cardiovasc. Trans. Res. (2012) 5:296–301DOI 10.1007/s12265-012-9360-0

L. Miller (*)2 Tampa General Circle,Tampa, FL 33606, USAe-mail: lmiller5@health.usf.edu

is not important to normal organ function, which is moredependent on mean arterial pressure.

The original pulsatile pumps were able to generate veryhigh rates of dp/dt as well as pressure and flow. Initially,investigators thought this enhanced flow or output would begood for the circulation and the patient, who had beentypically suffering from very reduced cardiac output. How-ever, use of these pumps at high flows at times resulted incerebral edema, as the new increase in pressure and flow,which was delivered with a nearly vertical upstroke on thepressure tracing caused passive fluid extravasation into the

brain, typically the cerebellum and posterior circulation,resulting in obtundation and death if not recognized [8]. Theflows not surprisingly also led to systemic hypertension, as thecirculation was unable to rapidly adapt with reduction inperipheral resistance to such rapid increases in flow. However,once this problem was recognized, the manufacturer mademodifications such that the pump dp/dt and rate could beadjusted to prevent excessive flow or pressure. One lessonfrom the new continuous flow pumps is that the developmentof cerebral edema seems almost totally dependent on both thepeak pressure and rate of rise of pulsatile flow, as the newercontinuous flow pumps have not been associated with thisproblem in over 2,000 patients studied [2, 3].

What else have we learned from the use of continuous flowdevices? The initial clinical introduction of ventricular assistdevices to support patients with cardiogenic shock and severeheart failure, including both the artificial heart as well aspulsatile flow design, was associated with a significant inci-dence of stroke and peripheral embolization [9, 10]. This ledto years of searching for the least thrombogenic surface to usefor blood contact interface with the pump. One of the mostimpressive engineering changes occurred when researchersbegan to work with vascular biologists who quickly identifiedthe vascular endothelium as the most perfect surface to pre-vent clot formation. In addition, they reminded the engineersthat vascular endothelial cells tend to lay down a syncytiumwhen in contact with roughened or damaged surface. This ledto the most widely used pulsatile VAD, the Heartmate VE(Thoratec Corp., Pleasanton, CA) to employ a lining in thepump reservoir which resembled low-grade sand paper(Fig. 5a). Within one week, a velum of pseudo-endotheliumwas apparent (Fig. 5b) which was so anti-thrombotic, thatonly a low dose of aspirin was used for anticoagulation, withvery low incidence of stroke associated.

In contrast, concerns about the very tight clearance of therotor inside the pump housing of the continuous flow pumpsled to the addition of warfarin to prevent thrombus formationand embolization and stroke in the new continuous flowVADs, although without clinical trials to confirm the needfor this added anticoagulation [10]. The initial clinical expe-rience with the incidence of stroke with the new CF pumpswas still high (10–12 %) and more commonly hemorrhagicthan ischemic in nature. This led to another critical observa-tion which was that with non-phasic flow, the usual bloodpressure measurement with a standard BP cuff was grosslyinaccurate. Instead of the first sound heard being the usualKorotkoff sound representing peak systolic pressure, it actu-ally represented mean arterial pressure. This error resulted inmany patients being exposed to very high arterial pressuresand resultant hemorrhagic stroke. Since this phenomenon wasrealized, BP measurements are only measured with the use ofa Doppler, and goals for BP reduced to less than 90 mmHg,

Fig. 1 Comparison of first generation pulsatile LVAD (a) with secondgeneration continuous flow VAD (b) Thoratec Corporation, Pleasan-ton, CA

Fig. 2 Sagittal view of the second generation continuous flow LVADshowing the one moving part, the central rotor, the speed of which canbe changed in real time to directly alter LV volume. Thoratec Corpo-ration, Pleasanton, CA

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and the incidence of hemorrhagic stroke has been reduced bytwo thirds, with similar target anticoagulation levels.

One of the most unexpected observations from the use ofcontinuous flow pumps is the incidence of gastrointestinalbleeding, which is dramatically higher than was seen withpulsatile pumps, even with added use of warfarin [11, 12].The most common source of the bleeding has been arterio-venous malformations (AVMs) (Fig. 6) which also strangelyare most prevalent in the first part of the small bowel butalso in the stomach [13]. Detection of the source of bleedingwas initially very frustrating, as typical upper endoscopywas limited to the early part of the duodenum, and rarely led

Pulsatility as a Function of Pump Speed

12,000 RPM

11,000 RPM

10,000 RPM

9,000 RPM

8,000 RPM

Frazier et al Circulation 2002;105:2855

Fig. 3 Change in bloodpressure with alteration in speedof the rotor; increasing speedremoves more volume/preloadfrom the left ventricle leading toprogressively smaller strokevolume and pulsatility

Fig. 4 Echocardiogram in parasternal long axis view showing thedrainage cannula of the LVAD at the apex of the left ventricle butangulated and touching the posterior wall of the ventricle, which caninduce sustained ventricular arrhythmias

The Heartmate-VE

Pseudointima

a

b

Fig. 5 Inner lining of Thoratec Heartmate VE LVAD showing texturedsurface (a) inducing deposition of circulating endothelial cells to forma pseudo-endothelium (b)

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to the presumed cause of bleeding. Most centers now do so-called pill endoscopy to examine this likely site of bleeding,as the AVMs respond well to cauterization. The more puz-zling question raised by this observation of AVM develop-ment with use of continuous flow LVADs is the cause oftheir development. The flow is thought to be identicalthroughout the arterial circulation, and therefore why thisunique source of bleeding occurs in an area rarely seen innormal physiology, is a source of much investigation. Re-cently, it has been shown that there is a difference in bloodflow and arterial resistance in the superior mesenteric artery(SMA) that perfuses this section of the bowel, which isdifferent than that in the gastric and inferior mesentericarteries in that in a fasting state the resistance is high in

the SMA versus low in the gastric artery. The role of thisdifference is currently being explored.

The one comparison often sited is the development ofAVMs in the distal colon in patients with calcific aorticstenosis [13, 14], which in the more severe forms has alow pulse pressure, resembling that in the patients supportedwith CF VADs. Of note, the AVMs regress following aorticvalve replacement [15]. Like the prevalence of AVMs andbleeding being more common in elderly patients with thecalcific form of aortic stenosis, bleeding is very age relatedin patients with continuous flow VADs, increasing withadvanced age of the patient.

Research into this problem has shown that continuousflow physiology results in a fairly rapid and almost total loss

Arteriovenous Malformation

Letsou GV, Shah N, Gregoric ID, Myers TJ, Delgado R, Frazier OH. Gastrointestinal bleeding from arteriovenous malformations in patientssupported by the Jarvik 2000 axial-flow left ventricular assist device. J Heart Lung Transplant. 2005;24(1): 105-109.

Fig. 6 Endoscopy of smallbowel showing arteriovenousmalformation on mucosalsurface which has been shownto be highly associated withnon-pulsatile blood flow fromcontinuous flow LVAD

Fig. 7 Multimers of VonWillebrand factor on the surfaceof the endothelium which arerapidly and nearly totallydepleted in association withnon-pulsatile blood flow fromcontinuous flow LVAD

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of the multimers of the Von Willebrand factor on the surfaceof the endothelium (Fig. 7) [16, 17]. These proteins arecritical to normal hemostasis. Studies have shown that whilenearly all patients supported with a continuous flow VADdevelop severe depletion of VWF levels, not all patientsexperience clinical bleeding, but the levels are almost im-measurable in all patients who do bleed. The cause andeffect relationship of continuous flow physiology to thedevelopment of AVMs and bleeding was made clear by astudy from Columbia University [16] that showed thatpatients who underwent heart transplant while on a pulsatileVAD had normal levels of VWF at transplant, and minimalbleeding post Tx, compared to patients supported with acontinuous flow VAD who had very reduced levels of VWFat transplant and had significantly increased rates of bleedingrequiring transfusion following surgery. The final piece ofevidence to confirm the cause and effect relationship withcontinuous flow and depletion of VWF is the rapid normali-zation of VWF levels post transplant in those supported withthe continuous flow VADs. Clinicians have been anxious tofind a bioassay that would help guide anticoagulation orpredict increased risk of bleeding in patients on continuousflow VADs, and seemingly, the VWF levels could be used.However, the fact that most patients with CF VADs do nothave evidence of bleeding despite low levels of VWF makesthat assay not predictive enough to be clinically useful.

How have clinicians dealt with this problem of bleedingwith continuous flow VADs? If the analogy with aorticstenosis is related, and the AVMs are somehow linked tolack of pulsatile flow, one logical approach would be toreduce the pump speed to allow much more pulsatility ofthe blood pressure. However, while not studied well orprospectively, anecdotal experience has suggested that anincrease in the percentage of pulsatile beats that can becreated by reduced pump speed, has not been effective inreducing bleeding. However, some investigators have sug-gested than another side effect of running the VAD at speedsthat maximize LV remodeling but are associated with nopulsatility, leads to thrombus generation in the sinuses ofValsalva, and potential embolization and ischemic stroke.Many centers now try to adjust the pump speed to allow theaortic valve to open at least 10 % of the time.

Since many patients have had multiple episodes of bleedingon the CF VAD requiring invasive endoscopies, hospitaliza-tions, and transfusions, many clinicians have taken the boldstep to stop all anticoagulation, sometimes for periods ofmonths. Surprisingly, this has only rarely been associated withpump thrombosis, except in a few patients with an activeinfection. One explanation could be that the pump becomesseeded with some type of pseudo-endothelium, as was createdintentionally in the pulsatile Heartmate VE pump (ThoratecCorp., Pleasanton, CA) (Fig. 5a, b). However, examina-tion of a significant number of pumps explanted at the time of

transplant, or due to other problems, have failed to demon-strate any microscopic evidence of this happening. What thenprevents the pump from thrombosis despite no anticoagula-tion for relatively long periods of time is unclear, but obvi-ously the focus of significant ongoing research. There is alsoresearch into new ways to line the pumps with endothelialcells that won’t also impede function of the pump. Currentlythere is no clear etiology of this problem, as is reflected in thecontroversy in the field as to whether anti-platelet or anti-coagulation therapy, or both, is needed. Newer magneticallylevitated pumps with no direct contact of blood with metallicsurfaces have had similar incidence of bleeding, which seemsto clearly point to continuous flow physiology as the cause ofthe problem, and the eventual solution.

The limitations and problems or consequences that mayresult from long-term support with continuous flow physiolo-gy may not yet be evident. One theoretical problem that mightresult from years of continuous rather than pulsatile flow to thearterial circulation is whether this will lead to atrophy of thearterial media, with subsequent development of dilation of thevessel, and eventual aneurysm formation. This has not beenevident to date as hundreds of patients have now been sup-ported with continuous flow VADs for over 5 years with noevidence of aneurysm formation in the short run.

So, while it has become very clear that human physiologywas created with a pulsatile circulation, adequate organ andwhole body function is not dependent upon pulsatile bloodflow [18]. We are learning many surprising lessons about thebody’s response to loss of pulsatile circulation, which willundoubtedly enhance our knowledge of circulatory physiology.

References

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