Hemodynamics of chronic nonpulsatile flow: implications for LVAD development

Surg Clin N Am 84 (2004) 61–74

Hemodynamics of chronic nonpulsatile flow: Implications for LVAD development Satoshi Saitoa, Tomohiro Nishinakab, Stephen Westabyb,* a Tokyo Women’s Medical University, Tokyo, Japan The John Radcliffe Hospital, Headington, Oxford, UK

b

The mammalian heart produces pulse by contraction, stroke volume ejection, and then relaxation, with one-way valves. Given this mechanism, a pulsatile circulation is obligatory, as is a resting phase for the myocyte. The success of pulsatile blood pumps in the bridge-to-transplant setting has led to their application for long-term circulatory support in non transplant-eligible patients. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure (REMATCH) trial demonstrated a somewhat disappointing survival advantage for the ThermoCardio Systems HeartMate (Thoratec Corp., Pleasanton, California) left ventricular assist device (LVAD) over medical treatment and highlighted the substantial risk of mechanical failure and device-related complications inherent with firstgeneration technology [1]. The displacement blood pumps were designed to produce stroke volume and pulsatility in the belief that the latter was a physiological requirement for normal end-organ function. In contrast, continuous flow devices can be miniaturized and made simpler, with fewer components subject to mechanical failure. Nevertheless, doubts remain about the safety of continuous-flow or reduced pulse pressure in the long term. The systolic thrust generated by the ventricle represents only the one third of the cardiac cycle, and pulse is so diminished at capillary and cellular level that end-organ perfusion is essentially nonpulsatile. To date there is no definitive study of long-term continuous (nonpulsatile) blood flow in humans. The closest clinical scenario is our use of the Jarvik 2000 Heart (Jarvik Heart, New York, New York) up to 3.5 years, though the native * Corresponding author. Department of Cardiac Surgery, Oxford Heart Centre, The John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9D3, UK. E-mail address: [email protected] (S. Westaby). 0039-6109/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0039-6109(03)00220-2

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heart provides diminished pulse pressure in these patients [2]. The question as to whether pulse pressure is necessary for normal end-organ function in mammals can only be answered by experimental findings in an animal model. In this article we review the differences between chronically nonpulsatile and normal circulation as pertains to the development of continuous-flow devices and their use in destination therapy. Summary of cardiopulmonary bypass studies Short-term nonpulsatile cardiopulmonary bypass (CPB) has been used very successfully since the early 1950s. More complex pulsatile systems were developed in an attempt to attenuate the damaging effects of CPB, though these were largely attributable to blood/foreign surface interactions. Early studies indicate no important differences in outcome after short-term nonpulsatile or pulsatile blood flow, thus supporting the widespread use of nonpulsatile CPB machines in routine cardiac surgery [3]. Acute physiological responses nevertheless occur in the transition from normal to continuous-flow circulation. As continuous flow begins, there is an acute vascular response, with loss of vasomotor inhibition by the carotid sinus nerve [4], and renal secretion of renin [5]. These adrenergic responses to absence of pulse pressure are flow-dependent, being more marked at low flows but negligible at high flows. Short-term CPB studies have shown that pulsatile flow reduces systemic vascular resistance, attenuates the catecholamine response, improves splanchnic, renal and myocardial perfusion, and promotes recovery [6,7]. Minami [8] suggested that attenuation of the catecholamine response by pulsatile support reduces fluid overload and extubation time. Buket [6] showed that T3 was reduced less with pulsatile support and that pulsatile flow during CPB maintains thyroid hormone metabolism. Gaer [7] recently demonstrated that gastric mucosal pH is reduced less with pulsatile flow. Splanchnic blood flow is better preserved with pulsatile flow versus nonpulsatile flow. In addition, pulsatile CPB has been shown to prevent increases in endogenous endotoxin levels, probably reflecting improved intestinal circulation. Ciardullo [9] examined blood flow in the fibrillating heart distal to a critical coronary stenosis. This group showed that regional ischemia distal to the critical coronary lesion was reduced by pulsatile perfusion and that the mechanism for the reduction in ischemia was improved myocardial blood flow. Minami [10] also reported that pulsatile CPB improved myocardial recovery and allowed earlier reduction of inotropic support. In addition, pulsatile circulatory assistance eliminated the need for intraaortic balloon pump (IABP). Taylor [11] investigated the clinical outcome following CPB using pulsatile versus nonpulsatile support systems. These

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early studies suggested a reduction in mortality when pulsatile CPB was used. Death from low cardiac output syndrome was reduced, as was the need for IABP and epinephrine support. Postcardiotomy circulatory support In postcardiotomy patients, Jett [12] reported improved outcomes with pulsatile systems over continuous-flow pumps. Patients supported unsuccessfully with nonpulsatile pumps seemed to follow a similar clinical course. Despite adequate pump flow (2.2 l/min/m2), there was increasing tissue edema, impaired tissue perfusion, and a worsening shock state. This deterioration may be related to the lack of lymphatic flow seen with nonpulsatile circulation during acute support [13]. Impaired lymph flow results in lymph edema, increasing intestinal edema, and poor interstitial perfusion. Pulsatile flow seems to more effectively reverse shock and prevent progressive edema. Lymphatic flow is normally controlled by arterial pulsation, lymphatic contraction, and muscle compression [14]. In the human lymphatics, contraction is very weak and muscular compression is absent in the shock state. With an active patient, however, muscular contractions are present, and therefore pulsatile flow may be less important. This may partly account for the excellent outcomes results seen with chronic nonpulsatile flow [15]. Although Jetts’s results suggested superior results with pulsatile blood pumps, the patient numbers were small. In addition, the US National Circulatory Support Registry showed no difference in clinical outcomes between patients supported with pulsatile and nonpulsatile devices [16]. Early reversal of cardiogenic shock is the principal goal during acute circulatory support. This contrasts with chronic support for heart failure, when a device can be inserted on an elective basis before cardiogenic shock. A recent study demonstrated that pulsatility was more effective than continuous flow in improving and maintaining perfusion of the microcirculation in end organs after acute shock [17]. The authors concluded that pulsatile circulatory support could prevent multiorgan failure after shock. Others have shown [18], however, that when mean blood flow exceeds 95 mL/kg/min there is no difference between pulsatile or nonpulsatile systems for recovery of shocked liver. Oxygen uptake appears to be less efficient at continuous (versus pulsatile) flow of 75 mL/kg/min, but there is no difference with high flows (100 mL/kg/min) [19]. This suggests that flow is more important than pulsation. Pressure (as well as flow) is important for both renal and cerebral perfusion. Renal recovery after ischemia is similar with both pulsatile and nonpulsatile perfusion if normal perfusion pressure is attained [20]. In contrast, under hypotensive conditions, only pulsatile perfusion can improve renal recovery. A recent study with low flow (50 ml/kg/min) showed that pulsatile perfusion reduces sympathetic nerve activity and

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peripheral vascular resistance [21]. Cerebral autoregulation remains intact with nonpulsatile flow when perfusion pressure exceeds 50 mmHg. In contrast, pulsatile perfusion provides better cerebral blood flow than nonpulsatile perfusion at perfusion pressures less than 50 mmHg [22]. The effects of pulsatile versus continuous blood flow have been investigated in the lungs. Pulmonary oxygen transfer has been shown to be similar with pulsatile and nonpulsatile perfusion for normal lungs [23]. In edematous lungs, however, pulsatile blood flow was clearly more efficient. Pulsatile circulation maintains the flow distribution in both arterioles and capillaries in the lungs, whereas continuous flow is associated with decreased capillary perfusion. This is largely irrelevant for isolated left-ventricular assist, where the native right ventricle provides pulse pressure in the pulmonary circulation. In summary, acute circulatory support with continuous-flow devices provides similar outcome in postcardiotomy heart failure but there are differences. Fluid requirement increases with nonpulsatile circulation (despite normal blood volume), through peripheral lymph edema. Catecholamine levels are increased with nonpulsatile circulation, resulting in increased peripheral vascular resistance. There also appears to be decreased pulmonary capillary perfusion and impaired gas exchange in edematous lungs. Acute pulsatile support maintains lymphatic flow, thereby decreasing interstitial edema. Pulsatile support also decreases systemic vascular resistance thereby improving peripheral perfusion. Prolonged circulatory support Of the LVADs currently employed, continuous-flow centrifugal blood pumps are used most frequently. These are relatively simple to operate, available to all surgeons, and are inexpensive compared with other devices. Blood enters the pump axially from an inlet pipe and is caught up between veins and whirled outward. Centrifugal pumps provide high-volume continuous flow with low pressure rise. Flow is particularly sensitive to afterload. Extracorporeal centrifugal devices were introduced clinically in the 1980s to treat postcardiotomy left or biventricular failure or for short-term (days) bridge to cardiac transplantation. The first fully implantable centrifugal pumps (Terumo, Ann Arbor, Michigan) will be introduced for bridge to transplantation in 2003. The Thoratec external pulsatile LVAD (Thoratec, Pleasanton, California) was first used clinically in 1982 for postcardiotomy support, and in 1984 as a bridge to cardiac transplantation. An implantable version has recently been developed for long-term use. Alternating positive and negative air pressures actuate a flexible blood sac within the rigid outer casing. Monostrut tilting disk valves in the inflow and outflow ports provide unidirectional blood flow. Left, right, or biventricular support is possible

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with the Thoratec VAD. The Abiomed BVS-5000 (Abiomed, Danvers, Massachusetts) was the first cardiac-assist device to be approved by the US Food and Drug Administration (FDA) for postcardiotomy support (in 1992) and rapidly became the second most popular postcardiotomy VAD after the intra-aortic balloon pump. The first long-term implantable pulsatile device was used in 1984 when Oyer and colleagues implanted the electric Novacor LVAD (Novacor, Cedex, France) into a moribund 51year-old man with ischemic cardiomyopathy. The patient was transplanted 9 days later in the first successful bridge to cardiac transplantation with an LVAD designed for long-term use. Frazier implanted the first pneumatic Thermo Cardio Systems (Thoratec, Pleasanton, California) HeartMate LVAD in 1986, followed by the first electric HeartMate LVAD in 1994. The first successful use of an implantable centrifugal blood pump was by Westaby in 1998 when the AB-180 (Cardiac Assist Technologies, Pittsburgh) was used for mechanical bridge to recovery in fulminant myocarditis. Implantable miniaturized axial flow pumps providing continuous flow were introduced clinically between 1998 and 2000 with the use of the Micromed DeBakey LVAD (Micromed Technology, Houston, Texas) and the Jarvik 2000 intracardiac pump. Duration of support with the Jarvik 2000 now exceeds 3.5 years for non-transplant–eligible (destination therapy) patients in UK. In the large spectrum of patients treated by mechanical circulatory support, survival seems to depend more on the underlying condition of the patient and reversibility of the myocardial pathology than on the type of assist device employed. Currently, LVADS that provide stroke volume and pulse pressure are widely used for bridge to transplantation but, because of their size and complication rate, they are less suited (and not sufficiently durable) for permanent use. They are also too large for most women and virtually all children. In contrast, the silent continuous-flow LVADS are much smaller, with minimally thrombogenic blood/foreign-surface interface, no stasis, and no artificial valves. In the clinical situation, pulse pressure is usually transmitted to the systemic circulation from the unloaded native left ventricle. Skepticism regarding the safety of continuous-flow devices for permanent support is now dispelled by long-term clinical experience. Brief cardiopulmonary bypass (CPB) studies have no predictive value for the outcome of long-term nonpulsatile circulation because of the body’s ability to adapt to changes in physiology. To date there is no definitive study of long-term nonpulsatile circulation in humans. With the powerful Terumo centrifugal LVAS, however, the Oxford group have provided blood flow completely free from pulse pressure for periods up to 1 year. In subject animals, there was no detectable deterioration in end-organ function. Many other studies have addressed the physiological reactions to longterm left- or right-heart continuous-flow bypass.

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Hemodynamic changes Valdes [24] suggested that nonpulsatile circulation required a 20% increase in systemic flow to maintain homeostasis. In contrast, the National Cardiovascular Center of Japan (Osaka) [25] could not define any significant difference between nonpulsatile and pulsatile circulation with regards to oxygen metabolism at rest. Tatsumi [26] and Yozu [15] independently confirmed that chronic nonpulsatile circulation did not change peripheral perfusion or oxygen metabolism. In chronic animal experiments, the serum lactate concentration and pH did not differ between nonpulsatile and pulsatile circulation. Tatsumi evaluated the peripheral circulatory changes using thermography and a laser Doppler tissue flow meter to image capillary flow in the auricle [25]. Although nonpulsatile flow maintained tissue perfusion in the normal range, the capillary flow had intermittent vasomotion with 10 to 20 mL/min frequency. This suggests capillary autoregulation to maintain appropriate regional blood flow. Humoral factor changes Golding [27] reported elevation of plasma catecholamine levels immediately after beginning nonpulsatile blood flow, but the levels decreased to normal 2 weeks later. When blood flow was switched to the nonpulsatile mode in conscious animals with stable hemodynamics, however, the serum catecholamine level did not change [25]. This suggests that an increase in serum catecholamine levels during nonpulsatile flow was caused by the surgical intervention rather than adaptation to nonpulsatile circulation. With regard to the renin-angiotensin system, Golding [14] could find no significant change of plasma renin activity in up to 3 months of nonpulsatile support as long as the mean blood pressure remained within normal limits. Our chronic sheep experiments with the implantable Terumo centrifugal pump showed an increase in plasma renin levels in nonpulsatile animals, even though the mean blood pressure was not significantly different from sheep with normal pulse pressure [28]. Measurement of thromboxane A2 and prostaglandin I2 showed no difference between pulsatile and nonpulsatile circulation [29]. Using an invitro method, Hakim [30] showed that flow-mediated nitric oxide production was significantly greater in the pulsatile circulation. These vasoactive substances may play a substantial role in the process of adaptation to chronic nonpulsatile blood flow. Neurological changes The autonomic nervous system plays an important regulatory role in the circulation and may be influenced by continuous flow circulation. Some studies have reported changes in renal sympathetic nervous activity during nonpulsatile circulation in acute animal experiments under general

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anesthesia [31]. Nishinaka [32,33] investigated changes of heart rate variability (HRV) during long-term pulsatile and continuous-flow left-heart bypass in a goat model. This group showed continuous flow to produce an increase in cardiac vagal activity. Shoor [34] has reported that the responses to exercise in calves with a biventricular centrifugal pump were compatible to those achieved with calves with a pulsatile total artificial heart. Tominaga [35] has reported that autonomic nerve reflex control of the cardiovascular system functioned normally during physical exercise in calves with chronic nonpulsatile blood flow using a biventricular pump. Effects on the heart In the normal heart, coronary and myocardial blood flow is decreased during ventricular fibrillation compared with the beating heart. In animal LVAD experiments, pulsatile flow synchronized with native heart contraction provided significantly higher coronary and myocardial blood flow than nonpulsatile blood flow [36]. The effects of pulsatility on myocardial metabolism remain unclear. Some reports show a beneficial effect of pulsatility on myocardial oxygen consumption and lactate metabolism [37], whereas others could not demonstrate a difference [38]. Recent studies have showed no difference in myocardial high-energy phosphate metabolism between pulsatile and nonpulsatile flow [39]. Effects on the lungs In the healthy adult, mean pulmonary pressure is 1/5 to 1/8 of systemic pressure (10–15 mmHg). The pulse pressure in the pulmonary circulation is 10 mmHg to 25 mmHg, but only 50% of this pulsatility reaches the 100 lm size arteriole, and 35% passes to capillary level. In the Fontan or Glenn procedure for cyanotic congenital heart disease, pulsatility in the pulmonary circulation is significantly decreased. Chronic changes in pulmonary microvasculature may relate to the loss of pulsatility. Acute clinical studies of continuous-flow right-heart bypass show that nonpulsatile circulation causes an elevated mean pulmonary artery pressure and higher pulmonary vascular resistance, with a greater susceptibility to pulmonary edema [40,41]. The depulsation of bronchial arteries and secondary changes in the pulmonary circulation due to systemic nonpulsatile flow do not appear to cause significant changes in gas exchange or intrapulmonary shunt ratio [42]. In chronic animal experiments, Golding [27] showed an elevation of mean pulmonary artery pressure and pulmonary vascular resistance in a biventricular continuous flow setting. In contrast, Sakaki succeeded in exchanging pulsatile flow with extracorporeal right-heart bypass pumps in an awake animal model to evaluate the effects of depulsation. This group

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found no change in pulmonary hemodynamics after depulsation, with mean pressure and pulmonary vascular resistance remaining the same [43]. The respiratory function, dry/wet ratio, histology, and the serum level of angiotensin-converting enzyme were not different between pulsatile and nonpulsatile pulmonary blood flow. Effects on the brain The effects of nonpulsatile blood flow on the brain are unclear. In acute CPB studies, Anstadt [44] suggested that pulsatile flow maintained better cerebral blood flow and oxygen consumption during reperfusion after hypothermic circulatory arrest. Henze [45] reported that there were no significant differences in postoperative electroencephalograph (EEG) changes, cerebral blood flow, oxygen and glucose uptake, and neurocognitive tests among patients who underwent pulsatile versus nonpulsatile CPB. Tominaga [46] evaluated the carotid blood flow in calves with a continuous-flow biventricular assist device and showed that cerebral autoregulation was maintained without abnormality. Nishinaka [47] found that cerebral oxygen metabolism was not changed by continuous-flow leftheart bypass. Effects on the kidneys Studies on renal morphology, renin secretion, and cortical blood flow using nonpulsatile versus pulsatile acute CPB suggest beneficial effects for pulsatile flow. In contrast, our chronic sheep experiments show renal function (creatinine levels and creatinine clearance) to be maintained within normal limits for up to 1 year with completely pulseless circulation. Nojiri has extended the duration of nonpulsatile support up to 860 days with normal renal function and histology [48]. Ohnishi [49,50] reported that prolonged continuous-flow left-heart bypass caused proliferation of smooth muscle cells in the afferent arterioles and their perivascular tissue. Kihara [51] also reported a relationship between smooth muscle cell hypertrophy in renal cortical arteries and continuous flow ventricular assist. Effects on the vascular system The major arteries are exposed to more than 100,000 pulse waves per day. Arterial structure and function are influenced by changes in arterial pressure, blood flow, and various kinds of growth factors [52,53]. The effects of pulse pressure on the arterial wall have been investigated by cyclical mechanical stretching of cultured vascular smooth muscle cells (SMCs) in vitro [54]. Cyclic stretch causes SMC proliferation and production of an autocrine growth factor. Nishimura evaluated aortic wall changes using a chronic nonpulsatile left-heart bypass model with a centrifugal pump in conscious adult goats for a mean of 103 days [55].

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The results were compared with those from normal animals and from goats with prolonged pulsatile left-heart bypass. The wall thickness of fixed aortic specimens was measured under the light microscope and was found to be thinner in the goats with nonpulsatile left-heart bypass [56]. We established completely nonpulsatile blood flow in a sheep model using the Terumo implantable centrifugal pump and identified thinning of the medial layer of the ascending aorta [28]. We measured the number of SMCs in the media and found a significant reduction in nonpulsatile sheep. TUNEL-positive cells were identified in the media, suggesting that apoptosis was the mechanism of the medial degeneration. Nishimura assessed the distribution of elastin, collagen, and SMCs in the aorta by a computed imaging system. In nonpulsatile animals, the proportion of smooth muscle cells was significantly decreased and elastin was increased. This group also reported that prolonged nonpulsatile circulation causes atrophic changes in the aortic SMCs [55,56]. The arteries can regulate perfusion by rapid contraction and relaxation of smooth muscle. Nishimura has investigated in-vivo dynamic mechanical properties using pulse wave velocity, which reflects arterial wall stiffness. Pulse wave velocity during both pulsatile and nonpulsatile left-heart bypass was considered to be within the normal range, with no significant difference between systems [57]. The reason for the stability in mechanical properties may be the adaptation of arterial structure to the reduced pulse pressure. Nishimura reported that the systemic vascular resistance response to norepinephrine infusion decreased markedly in prolonged nonpulsatile circulation, although the plasma norepinephrine level was not changed [58]. Nishinaka also investigated the constrictive function of the vascular system after prolonged continuous-flow left-heart bypass. This group showed that prolonged continuous-flow left-heart bypass caused a significant decrease in the systemic vascular resistance response to phenylephrine, indicating a decrease of vasoconstrictive function [59]. In addition, systemic vascular resistance response to nitroglycerin and baro-receptor sensitivity were unchanged [60]. Clinical experience with continuous-flow pumps In the clinical situation, continuous-flow pump patients have pulse pressure transmitted to the systemic circulation by the unloaded left ventricle. Experience with both the Jarvik 2000 Heart [2,61] and DeBakey LVAD [62–64] confirms systemic pulsatility, together with well preserved hepatic and renal function. The unloaded left ventricle provides pressure changes at the pump inlet, which accelerate the flow through the pump and induce pulsatile flow in the outflow graft and aorta. Pulsatility occurs even when the aortic valve remains closed, and does not appear to be consistently dependent on pump flow, blood pressure, or systemic vascular resistance; however, axial flow pumps are highly sensitive to the differential pressure

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across the pump (afterload), which has an important bearing on the pharmacological management after pump insertion. Angiotensin-converting enzyme (ACE) inhibitors, with or without b blockade, are required to lower systemic vascular resistance. Perioperative management of pulseless heart failure patients has a steep learning curve. We employ a radial arterial line and a continuous cardiac output monitoring catheter in the pulmonary artery. Central venous pressure, mean arterial pressure, and cardiac output are continuously displayed, and mixed venous oxygen saturation is measured intermittently in samples taken from the pulmonary artery catheter. In the early postoperative period, transesophageal echocardiography is used to monitor cardiac filling atrial and ventricular size. Our approach with the Jarvik 2000 patients is to off-load the heart completely for the first 48 hours with a pump speed of 10,000 rpm. This provides a cardiac output of 6 to 8 l/min with a mean systemic pressure of 55 to 66 mHg and a pulse pressure of 0 to 10 mmHg. Systemic vascular resistance is reduced pharmacologically to between 400 and 600 dyne/sec. Heart rate is 90 to 120/min. Right atrial pressure is normally 10 to 20 mmHg. Unloading of the left ventricle leads to a change in the geometry of the right ventricle and an improvement in right ventricular function. Right ventricular afterload reduction is the most likely mechanism by which Right Ventricular Ejection Fraction (RVEF) improves. In turn, improved right ventricular function boosts blood flow through the lungs and improves preload to the device. Inhaled nitric oxide gas is used to reduce pulmonary vascular resistance when necessary. With these parameters, tissue perfusion is maintained with warm peripheries, normal acid base balance, and adequate urine output, despite absent or reduced pulse pressure. Mixed venous oxygen saturation is between 65% and 70%. At an early stage in the postoperative management, we assess pulmonary artery flow for different pump speeds and different afterload pressures. Native heart function and filling are monitored at each pump speed, and the relationship of cardiac output to pump speed is assessed at different levels of afterloads. LVAD filling depends on blood flow through the lungs, and inotropic support may be required for the right ventricle in the postoperative period. The determinants of pump flow are the impeller speed and the differential pressure across the device (afterload/preload). Use of vaso-pressors will increase mean arterial pressure, but may dramatically reduce cardiac output through the pump. At moderate speed settings (10,000 rpm), the pump may not off-load the heart if the systemic pressure is allowed to rise. In our experience, the best hemodynamic results were obtained with a mean arterial pressure between 65 and 75 mmHg. Afterload status remains important after the patient leaves hospital. Our first Jarvik 2000 patient was a long-standing hypertensive. After discharge home without ACE inhibitor or diuretics, his blood pressure gradually increased, resulting in failure to off-load the left ventricle, then dyspnoea

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and ankle edema. These symptoms resolved rapidly when ACE was introduced and the mean pressure was reduced again to 70 to 80 mmHg. With the Jarvik 2000 Heart, we aim for synergy between the pump and the native left ventricle. After an initial period of complete left ventricular unloading in the perioperative period, we progressively encourage the native left ventricle to perform work. At low pump speed (8.000–10,000 rpm), cardiac output is derived from both the pump in the apex and stroke volume ejection through the aortic valve. Whether this strategy encourages left ventricular recovery (in comparison to complete unloading) remains to be seen. Summary Both experimental and clinical evidence suggest that pulse pressure is not required from a blood pump. End-organ function is well maintained with nonpulsatile systems, though pulse pressure may accelerate recovery from cardiogenic shock. Form follows function, so the effects of reduced pulse pressure on the arterial wall are not surprising. The ability to alter aortic wall morphology by reducing pulse pressure may have important implications for the future treatment of arterial pathology. Both centrifugal and axial-flow pumps can be miniaturized and are silent. Their reliability and user-friendly status may soon allow implantation at an earlier stage of cardiac deterioration. Doubts about the feasibility of long-term pulseless circulation are disappearing. References [1] Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a left ventricular assist device for end stage heart failure. N Engl J Med 2001;345:1435–43. [2] Westaby S, Banning AP, Saito S, et al. Circulatory support for long term treatment of heart failure. Experience with an intraventricular continuous flow pump. Circulation 2002;105: 2588–91. [3] Wesolowski SA, Sauvage LR, Pinc RD. Extracorporeal circulation: the role of the pulse in maintenance of the systemic circulation during heart lung bypass. Surgery 1955;37:663. [4] Ead HW, Green JH, Nell EA. Comparison of the effects of pulsatile and nonpulsatile blood flow through the carotid sinus on the reflexogenic activity of the sinus baroreceptor in the cat. J Physiol 1952;118:509–19. [5] Marry M, Ciron F, Birrwell WC, et al. Effects of de-pulsation of renal blood flow upon renal function and renin secretion. Surgery 1969;66:242–9. [6] Buket S, Alaytmt A, Ozbaran M, et al. Effects of pulsatile flow during cardiopulmonary bypass on the thyroid hormone metabolism. Ann Thorac Surg 1994;57:93–6. [7] Gaer JAR, Shaw ADS, Wild R, et al. Effects of cardiopulmonary bypass on gastrointestinal perfusion and function. Ann Thorac Surg 1994;57:371–5. [8] Minami K, Komer MM, Vyska K, et al. Effects of pulsatile perfusion on plasma catecholamine levels and haemodynamics during and after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990;99:82–91. [9] Ciardullo RC, Schaff HV, Flaherty JT, et al. Comparison of regional; myocardial blood flow and metabolism distal to a critical coronary stenosis in a fibrillating heart during alternative periods of pulsatile and nonpulsatile perfusion. J Thorac Cardiovasc 1978;75:371–5.

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