Pulsatile and nonpulsatile perfusion: The continuing controversy

Pulsatile and Nonpulsatile Perfusion: The Continuing Controversy Philip Hornick, BSc, MB, BChir, FRCS, and Kenneth Taylor, MD, FRCS This report discusses pulsatile and nonpulsatile perfusion with regard to hemodynamics, cell metabolism, and the visceral consequences of these forms of cardiopulmonary bypass. It argues that differences between the two modes and a benefit for pulsatile perfusion, are most clearly mani-

fested in identifiable high-risk patient groups. Copyright © 1997 by W.B. Saunders Company

HE RELATIVE benefits of pulsatile and nonpulsatile perfusion systems are an issue beset by controversy. The initial unsuccessful attempts at the inception of cardiac surgery to develop pulsatile systems that would reproduce normal physiological pulsatile blood flow led to the adoption of nonpulsatile cardiopulmonary bypass (CPB). These systems were Compatible with patient survival, 1 and as confidence increased, nonpulsatile perfusion has become routinely established in ciirdiac surgical practice. William Harvey would surely have thought this state of affairs something of a paradox; if the normal heart pumps against a continually changing peripheral vascular resistance and produces a pulse, surely cellular and organ function must be compromised by an artificial mechanical system delivering Continuous, that is, nonphysiological blood flow. Clearly, if the total population undergoing CPB is viewed as a whole, use of nonpulsatile flow has not unequivocally been shown to be the causative factor in terms Of perioperative and postoperative mortality in either a unifactorial or a multifactorial analysis. Some part of this is doubtlessly attributable to improved techniques of myocardial preservation and the use of vasodilator drugs after the termination of CPB. Thankfully, this has not dissuaded research workers from investigating the differences between the two systems. Just because a system works is no reason (1) to accept this Set point, and (2) that it cannot be improved. Furthermore, within any population there may be subgroups who could benefit (in morbid or mortal terms) from a more physiological perfusion system. The development of safe, simple, reliable, and costeffective pulsatile pumps has allowed effective comparisons to be made, questioning the traditional compromise. This review examines the effects of these tWO modes of perfusion With regard to the primary and fundamental effects of hemodynamics, cellular metabolism, and on the visceral consequences of such CPB systems. It concludes with the identification of patient groups that are particularly likely to benefit from particular modes of CPB.

into the early postoperative period.2-6 Vasodilator agents are therefore necessary during any CPB procedure.7 Vasoconstriction leads to peripheral circulatory inadequacy and hence reduced visceral perfusion. An increase in peripheral vasoconstriction also increases left ventricular work. s The latter state of affairs is offset by corresponding increases in myocardial performance and left ventricular work: However, the increased afterload can be deleterious if left ventricular performance is already suboptimal. In this context, a vicious circle may develop, leading to a low-output syndrome and hence visceral damage and dysfunction. 3,9 The patterns of peripheral vascular resistance and cardiac performance before, during, and after CPB are shown in Figs 1 and 2. The progressive increase in the peripheral vascular resistance index during CPB will present the left ventricle with an increase in work at the termination of bypass; Such an increase in work could not occur at a worse time, because the heart at this stage is recovering from the period of aortic cross-clamping and ischemic arrest required during the cardiac surgical procedure. A detrimental hemodynamic environment thus ensues. From the data, it appears that pulsatile flow is able to significantly minimize such hemodynamic alterations. Myocardial preservation techniques have ensured superior contractile function of the myocardium in the postbypass periodJ TM However, it is also logical that maintenance of a normal vascular resistance index will be associated with superior myocardial performance in the immediate postoperative period. Subsequent studies have indicated that where high peripheral vascular resistance levels are reduced after Cardiac surgery (eg, with sodium nitroprusside), a significant increase in cardiac performance results.7,12 One of the principal theories proposed for the physiological effects Of pulsatile arterial blood flow relates to neuroendocrine reflex mechanisms, which are triggered by baroreceptor discharge. Angell-James and de Burgh 13 have shown that carotid baroreceptors exhibit a marked increase in discharge frequency when arterial flow is changed from pulsatile to nonpulsatile fl0w. Other workers have suggested that this baroreceptor mechanism might induce reflex vasoconstriction in the periphery by direct neurohumoral reflexes (eg, angiotensin, vasopressin, and catecholamines).14

T

HEMODYNAMICS Vasoconstriction During Cardiac Surgery

KEY WORDS: cardiopulmonary bypass, extracorporeal circulation, pulsatile perfusion, cardiac surgery

Progressive systemic arterial vasoconstriction is the inevitable consequence of CPB. This phenomenon commences at the onset of bypass and continues through the procedure, extending

Mechanisms of Vasoconstriction After Cardiac Surgery

From the Department of Cardiothoracic Surgery, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK. Address reprint requests to Philip Hornick, BSc, MB, BChir, FRCS, Lecturer in Cardiothoracic Surgery, Department of Cardiothoracic Surgery, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 OHS. Copyright © 1997 by W.B. Saunders Company 1053-0770/97/1103-000753. 00/0

The causative mechanisms that have been proposed include catecholamine release, activation of the renin-angiotensin system, increased secretion of vasopressin, and the production of local tissue vasoconstrictor agents (eg, thromboxane A2). The role of nitric oxide (NO) is also emerging as an important candidate in the regtilation of postoperative hemodynamics. A number of reports have indicated that there is an increase in catecholamine secretion during and after CPB. This may be related to the use of hyp0thermia during bypass, but may also be

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Journal of Cardiothoracic and VascularAnesthesia, Vol 11, No 3 (May), 1997:pp 310-315

PULSATILE AND NONPULSATILE CARDIOPULMONARY BYPASS

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a response to the altered perfusion associated with nonpulsatile flow 15.16 A loss of pulsatile blood flow within the renal arteries despite maintenance of mean flow and pressure causes increased renin release. 2°,21 The renin-angiotensin system is activated with the production of the vasoconstrictor angiotensin II. An elevation of angiotensin II has been shown both during and after CPB. 6,9,12 Subendocardial myocardial ischemia is also produced by angiotensin II. The principal role of angiotensin II in the context of postoperative CPB hemodynamics has been shown when elevated angiotensin II levels were reduced rapidly using a specific angiotensin VII converting enzyme inhibitor. A highly significant decrease in peripheral vascular resistance was seen with a concomitant increase in cardiac index (Fig 3, 4)} 2 Vasopressin and renin-angiotensin activation have been directly related to nonpulsatile perfusion. The lack of pulsatility in the arterial circulation appears to trigger both of these mechanisms. The speed of response of vasopressin release 17appears to be more rapid than does that of renin-angiotensin activation, which has been extensively studied. 6,9,12 Platelet-derived thromboxane A2 has more recently been ascribed to having a potential role in the post-CPB vasoconstrictive response. It has been shown 18 that the rise in thromboxane A2 is attenuated with the use of pulsatile perfusion, and

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increased production of thromboxane may be the result of nonpulsatile perfusion. However, platelet activation consequent to extracorporeal circulation and the contact of blood with nonendothelialized surfaces may be just as important. It is likely that the dynamic characteristics of flow modulate the production of vasoactive mediators; for example, NO. Noris et al, 19 using an in vitro endothelial cell culture system, investigated the hypothesis that dynamic flow characteristics modulate the production of NO by human umbilical vein endothelial cells. Cells were exposed in a cone-and-plate

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• mean of total • *mean of treated Fig 4. Effect of angiotensin-converting enzyme inhibitor (SQ14225) on cardiac index after nonpulsatile CPB. These results are taken from the same experimental subjects as in Fig 3. Note the substantial rise in cardiac index in the SQ14225 group associated with the abolition of vasoconstriction. (Reprinted from Cardiovascular Research, Vol 14, Taylor et al, Haemodynamic effects of SQ14225 after cardiopulmonary bypass, pp 199-205, 1980 with kind permission of Elsevier Science--NL, Sara Burgerhartstraat 25, 1055 KV Amsterdam, The Netherlands. 22)

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apparatus to different types of flow. They found that pulsatile flow induced NO release by endothelial cells. When these cells were subjected to step-change increases of laminar shear, a further increase of NO synthesis was observed, compared with steady laminar shear of the same magnitude. Local blood flow conditions would appear to modulate the production of vasoactive substances by vascular endothelium. This may affect vascular cell functions such as nonthrombogenicity,blood flow regulation, and vascular tone. CLINICAL STUDIES ON THE HEMODYNAMIC EFFECTS OF PULSATILE PERFUSION

The use of pulsatile perfusion in clinical practice has produced reports of a beneficial effect on the hemodynamic status in the immediate postoperative period after CPB. Some groups have reported a decrease in postoperative inotropic requirements or a reduced requirement for intraaortic balloon counterpulsation. 23,24 A reduction in perioperative myocardial infarction has been reported with a significant reduction in hemodynamic-related mortality and a lower incidence of intraoperative and low cardiac output-associated mortalityY Such clinical studies show the hemodynamic superiority of pulsatile perfusion, particularly in those patients with impaired LV function. The impact of perfusion technique and mode of pH management during cardiopulmonary bypass have been characterized recently by Murkin et a126in a double-blind randomized study of 316 patients undergoing coronary artery bypass surgery. The duration of cardiopulmonary artery bypass, age, and use of nonpulsatile perfusion all correlated significantly with adverse outcome: myocardial infarction, death, and major complications. METABOLIC AND VISCERAL CONSEQUENCES OF PULSATILE AND NONPULSATILE PERFUSION

This is conceivably because of preservation of capillary diameter and cerebral blood flOW. 37 Nonpulsatile perfusion is likely to produce a functional disturbance rather than irreversible cell damage unless there is a coexisting tight stenosis of the carotid artery. 16,38Sadahiro and MohrP 9 have published data to suggest that, compared with nonpulsatile perfusion, pulsatile bypass generates a higher blood flow at cerebral perfusion pressures less than 50 mmHg. The normal physiological response to surgical trauma is not seen when nonpulsatile perfusion is used. A state of abnormal function of the hypothalamic-pituitary-adrenal axis has been observed. 4°-44The anterior pituitary remains unresponsive to a trophic stimulus of thyrotrophin-releasing hormone (TRH),45 which is in contrast to the normal response seen during major noncardiac surgery. Such reduction in function is also seen in the decrease of adrenocorticophic hormone (ACTH) secretion to substress levels and the consequent reduction in cortisol secretion by the adrenal cortex. 40,41 Abnormal hypothalamicpituitary adrenal function, which occurs during nonpulsatile perfusion, returns to normal within 30 minutes of the termination of CPB. In comparative studies of patients matched and perfused at the same levels of mean flow and perfusion pressure, those patients perfused with pulsatile flow (Fig 5) retained normal TRH response patterns and normal stress levels of ACTH and cortisol secretion (Fig 6).43,44 Comparable results have been reported in relation to the posterior pituitary and its secretion of vasopressin.~7 These observations are suggestive of reduced cerebral perfusion leading to abnormal cerebral function by reduced hormonal release. Tranmer et a146 have reported significantly higher cerebral blood flow values under pulsatile flow conditions in experimental models. Significant reductions in cerebral oxygen

Cell Metabolism The overall state of capillary flow and the adequacy of tissue perfusion are reflected by the oxygen consumption and development of metabolic acidosis by the perfused tissues. 2,4,27 Reduced oxygen consumption and increasing metabolic acidosis are accepted as inevitable accompaniments of nonpulsatile peffusion. 2,4,28 Such alterations in cell metabolism are likely to reflect the reduction in peripheral tissue perfusion in response to the vasoconstrictive effect of nonpulsatile flow. The suggestion that normal cell metabolism may be attained by increasing flow rates above 110/mL/kg/min ~9,3°is controversial and impractical. There is a consensus that at conventional flow rates of 60 to 100 mL/kg/min, the disturbance to cell metabolism may be prevented by using pulsatile perfusion. 27,28,~1

Visceral Function During Pulsatile and Nonpulsatile Perfusion A range of neurological and neuropsychological abnormalities is seen after CPB. The incidences of these complications have been recorded by Shaw et al. 32-36 Maintaining the hypothesis that the primary effect of pulsatile perfusion is the prevention of vasoconstriction that is associated with nonpulsatile flow, animal studies have provided evidence that pulsatile flow does not produce the metabolic and hemodynamic disturbances in the brain that are observed with nonpulsatile methods.

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consumption at normothermia have also been reported after nonpulsatile bypass. 47 In the context of profound hypothermia and circulatory arrest, Onoe et al48 have published data to suggest that pulsatile perfusion maintains cerebral blood flow even during profound hypothermia and that it may protect the brain from ischemic and hypoxic damage caused by profound hypothermia and total circulatory arrest in cardiac operations. In the context of resuscitation, although the heart can be revived after CPB support, the brain must recover if such therapy is ultimately to be considered a success. Anstadt et al,49 using histopathological analyses, found in a dog model that ischemic changes were more prevalent when nonpulsatile perfusion had been used in the resuscitation process compared with pulsatile perfusion. In a more detailed study, s° using microsphere technology, cerebral blood flow and oxygen consumption after cardiac arrest were better restored using pulsatile perfusion. Liver dysfunction, as evidenced by hepatic enzyme abnormalities, is a common phenomenon after cardiac surgery. This is exacerbated by preexisting congestive heart failure and preoperative hepatic dysfunction,sl,52 Mathie et a153 investigated the effects of pulsatile and nonpulsatile perfusion on liver hemodynamics and oxygen consumption. They found that pulsatile perfusion maintained significantly lower peripheral vascular resistance in the general circulation and that total hepatic blood flow was sustained more effectively by pulsatile perfusion because of specific preservation of hepatic arterial and portal venous blood flow. Hepatic oxygen consumption was better preserved both during and after pulsatile perfusion. The improvement in total liver blood flow with pulsatile perfusion was attributed to the prevention of hepatic arterial vasoconstriction that was observed with pulsatile flow. Ischemic pancreatitis has been reported after cardiac surgery. 54 The cause has been attributed to the relative ischemia produced within the pancreas as a result of extracorporeal

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perfusion, frequently exacerbated by a postoperative low cardiac output. Isolated studies have indicated that plasma amylase levels are significantly increased after nonpulsatile perfusion. 55 The amylase creatinine clearance ratio (ACCR) was used by Murray et aP 6 as a more sensitive indicator of pancreatic exocrine function. The ACCR showed a marked elevation in patients who had undergone nonpulsatile perfusion, and remained so 48 hours after bypass. In contrast, in a matched patient cohort, there was no elevation in ACCR in patients who had undergone pulsatile CPB. In a clinical study investigating the incidence of intraabdominal complications after cardiopulmonary bypass, 57 a higher incidence of complications was found with nonpulsatile flow. Gastric mucosal tonometry has been used by Gaer et a158 to determine the adequacy of gastrointestinal perfusion in patients undergoing elective myocardial revascularization. Patients were prospectively randomized to receive either pulsatile or nonpulsatile flow during CPB. This group found that CPB using nonpulsatile flow was associated with a significant reduction in gastric mucosal perfusion manifested by a reduction in the gastric mucosal pH that occurred independently of variations in arterial pH. The development of gastric mucosal acidosis is indicative of suboptimal oxygen delivery during nonpulsatile flow and may have implications for the development of infectious and noninfectious complications after bypass. When compared with other viscera, the kidney appears more resistant to the altered hemodynamics of extracorporeal perfusion. Several authors have reported defects in renal excretory function during nonpulsatile flow. s9,6°Additionally, a number of studies have shown that pulsatile perfusion is associated with significantly higher blood flow levels when compared with nonpulsatile flow. 6°,61 It might be, however, that renal vascular autoregulation protects the kidney from many of the deleterious effects of CPB. Data are now emerging that nonpulsatile perfusion may have a detrimental effect on the autonomic nervous system, specifically on circulatory control. Toda et a162 recorded the renal sympathetic nerve activity in goats, whose heart rate and size are similar to humans. Their results suggest that vasotonus may be affected in its periodicity as well as its quantity by the loss of pulsation in the bypass circuit. PULSATILE CARDIOPULMONARY BYPASS IN PERSPECTIVE--IDENTIFICATION OF PATIENT GROUPS AT RISK FROM CARDIOVASCULAR AND PERFUSION INSTABILITY

It is important to form a proper perspective into the disturbances in visceral function reported with nonpulsatile CPB. Such perfusion, although imperfect, appears to result in a functional, reversible deficit from which the patient will suffer no detrimental effects, assuming restoration of normal spontaneous pulsatile circulation at the discontinuation of bypass. For most cardiac surgical patients, such restoration of normal physiological hemodynamics is indeed the case, and rapid functional recovery in vital organs occurs normally within 48 hours of surgery. However, the relative imperfect and unphysiological mode of nonpulsatile CPB can add a further insult to organs damaged in the preoperative period and can deleteriously "prime" vital organs for an additional postoperative

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insult should cardiovascular instability occur. For such patients, the use of nonpulsatile flow means that they are exposed to a suboptimal perfusion system with the risk of developing the full picture of single or multiorgan failure. In such cases, complete renal failure, hepatic failure, ischemic pancreatitis, coma, and sepsis have all been reported. High-risk patient groups have been identified. Ideally, for all patients, but particularly in the following subgroups, optimal perfusion is of paramount importance. Cardiovascular stability should exist before the institution of CPB, and the principal focus of postoperative care should be in optimizing and maintaining cardiovascular stability. Such high-risk groups include the following: 1. Patients with occult coronary artery disease unable to equalize myocardial energy supply/demand, who become particularly at risk of myocardial ischemia and infarction when left ventricular work and cardiac output increase. 2. Patients with significant arterial disease, in particular those who have flow-limiting stenosis in the arterial supply to vital organs. Under such circumstances, flow distal to the stenosis and circulatory autoregulation is compromised. An example of such a situation is carotid artery stenosis in a patient undergoing CPB for a coronary artery bypass procedure. In such a case, the

patient is at risk of sustaining a significant hypoperfusion injury to the brain. 3. Patients with chronic arterial hypertension. In such patients the cerebral blood flow autoregulation curve shifts to the right, and these patients require higher perfusion pressures to maintain cerebral autoregulation. 63 4. Patients with existing chronic vital organ insufficiency. Where chronic renal failure or chronic hepatic insufficiency exists, even modest reductions in perfusion during cardiac surgery may induce disproportionate organ dysfunction and injury. The simplicity, safety, reliability, and cost-effectiveness of pulsatile perfusion systems combine demonstrable superiority in terms of cellular and visceral physiology with beneficial effects on patient outcome. The single definitive "allencompassing" study has yet to be performed--and it probably never will be. The benefits of pulsatile flow are undoubtedly manifest to their greatest extent in the context of any patient who has already sustained or is likely to experience suboptimal hemodynamic performance with visceral damage. Such advantages of pulsatile CPB have resulted in its routine use at this institution despite the relative inertia of traditional practice.

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14. Maroudis C: To pulse or not to pulse. Ann Thorac Surg 25:259-271, 1978 15. Minarni K, Korner M, Vyska K, et al: Effects of pulsatile perfusion on plasma catecholamine levels and haemodynamics during and after cardiac operations with cardiopulmonary bypass. J Thorac Cardiovasc Surg 99:82-91, 1990 16. Taylor KM (ed): Cardiopulmonary Bypass. London, UK, Chapman & Hall Medical, 1986 17. Levine FH, Iversen S, Hetzer R, et al: Plasma vasopressin levels and urinary sodium excretion during cardiopulmonary bypass with and without pulsatile flow. Ann Thorac Surg 32:63-67, 1981 18. Watkins DM, Peterson MB, Kong DL, et al: Thromboxane and prostacyclin changes during cardiopulmonary bypass with and without pulsatile flow. J Thorac Cardiovasc Surg 84:250-256, 1982 19. Noris M, Morigi M, Donadelli R, et al: Nitric oxide synthesis by cultured endothelial cells is modulated by flow conditions. Circ Res 76:536-543, 1995 20. Many M, Soroff H, Birtwe11 W, et al: The physiologic role of pulsatile and nonpulsatile blood flow. II: Effects on renal function. Arch Surg 95:726-766, 1967 21. Kohlstaedt K, Page I: The liberation of renin by perfusion of kidneys following reduction of pulse pressure. J Exp Med 72:201-205, 1970 22. Taylor K, Casals J, Brown J, et al: Haemodynamic effects of SQ14225 after cardiopulmonary bypass. Cardiovasc Res 14:199-205, 1980 23. Bregman D, Bowman E Parodi E, et al: An improved method of myocardial protection with pulsation during cardiopulmonary bypass. Circulation 56:157-159, 1977 (suppl 3) 24. Maddoux G, Pappas G, Jenkins M, et al: Effect of pulsatile and nonpulsatile flow during cardiopulmonary bypass on left ventricular ejection fraction early after aortocoronary bypass surgery. Am J Cardiol 37:1000-1004, 1976 25. Taylor K: Why pulsatile flow during cardiopulmonary bypass? in Longmore DB (ed): Toward Safer Cardiac Surgery. Lancaster, MTP, 1981, pp 481-500

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