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Ann Thorac Surg 2002;74:1080-1085
© 2002 The Society of Thoracic Surgeons
a Oxford Heart Centre, Oxford, United Kingdom
b Department of Cellular Pathology, Oxford, United Kingdom
c Terumo Cardiovascular System Corp, Ann Arbor, Michigan, USA
* Address reprint requests to Dr Saito, Oxford Heart Centre, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, United Kingdom
e-mail: satoyum{at}aol.com
Presented at the Poster Session of the Thirty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2002.
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Abstract |
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Methods. Fifteen healthy sheep (65 to 85 kg) were allocated to either left ventricular assist device (n = 9) or control (n = 6) groups. We implanted the device through a left thoracotomy and determined the flow rate at which pulse pressure was absent. The flow rate was then adjusted to exceed that rate (4.2 ± 1.5 L/min), and all variables of pump function were continuously monitored by computer. Blood tests were taken serially for hepatic and renal function and plasma renin levels. The sheep were sacrificed electively at 30 (n = 3), 90 (n = 4), 180 (n = 1), and 340 (n = 1) days. Detailed histologic examination was made of the brain, liver, kidney, myocardium, and major arteries.
Results. All animals remained in good condition until sacrifice. All measures of end-organ function remained within normal limits for both groups. There were no histologic differences between the organs of pulsatile and nonpulsatile animals. Although there was no significant difference in mean blood pressure, plasma renin levels were substantially elevated in pulseless animals (1.4 ± 0.3 pg/mL versus 2.9 ± 0.3 pg/mL; p < 0.05). We also identified thinning of the medial layer of the ascending aorta in nonpulsatile sheep (1.8 ± 0.4 mm in left ventricular assist device animals versus 2.6 ± 0.6 mm in control sheep; p < 0.05).
Conclusions. Chronic nonpulsatile circulation was well tolerated, and we found neither functional nor histologic changes in major end organs. The renin-angiotensin system was upregulated, but this did not provide a significant rise in blood pressure. The changes in the aortic wall merit further investigation. As a result of these findings, we consider that nonpulsatile devices can be used safely for long-term circulatory support.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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The mammalian heart produces pulse by contraction, stroke volume ejection, then relaxation with one-way valves. Given this mechanism, pulse pressure is obligatory, as is a resting phase for the myocyte. However, systolic thrust generated by the heart represents only one third of a cardiac cycle. Pulse is diminished at the capillary and cellular level, and there is little understanding as to whether or not pulse pressure is required for normal end-organ function.
The closest scenario is our use of the Jarvik 2000 Heart (up to 22 months), although the native heart provides diminished pulse pressure in these patients [2]. The question as to whether pulse pressure is important in the mammalian circulation can only be answered by experimental findings in an animal model.
We established reliable nonpulsatile circulation in the sheep using a magnetically suspended centrifugal blood pump [3, 4]. The objective of this study was to compare organ function between chronically pulseless and normal control animals.
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Material and methods |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Animal experiments
Fifteen healthy Welsh male sheep (65 to 85 kg) between 3 and 4 years of age were allocated to either centrifugal LVAD (n = 9) or control (n = 6) groups. All animal data were prospectively entered into a database to record device-related events, non-device-related events, pump function (driving speed and energy consumption), and autopsy findings.
Sheep in the LVAD group underwent implantation of the TLVAS, whereas those in the control group did not. Control animals were kept in adjacent pens as companion sheep. The surgical procedures and postoperative care were undertaken humanely by licensed personnel in compliance with United Kingdom Home Office guidelines.
Operation
The device was implanted through a left thoracotomy without the use of cardiopulmonary bypass (CPB). Heparin (5,000 U) was given before the pump was connected. The inflow cannula was placed in the left ventricular apex, and a polyethylene terephthalate fiber (Dacron [Terumo Cardiovascular System Corp, Ann Arbor]) outflow graft was anastomosed to the descending thoracic aorta. Air was carefully removed from the system before switching the device on at 1,000 rpm.
We then implanted an ultrasonic flow probe (Transonic System, Ithaca, NY) around the outflow graft to determine flow through the device at different rotational speeds. After restoring circulating blood volume and central venous pressure to preoperative levels, we determined the pump speed (1,600 to 1,800 rpm) at which pulse pressure disappeared through capture of all transmitral flow. The process was undertaken at least twice as preload was increased from a central venous pressure of 8 to 12 cm H2O. This established that pulse pressure was abolished even at high preload. At greater speeds (>2,000 rpm) there was no pulse pressure in the systemic circulation as confirmed by postoperative invasive monitoring for 48 hours, then again before sacrifice. An intercostal drain was inserted, and the wound was then closed in layers. Anesthesia was discontinued, and the sheep were transferred from the operating room to the pen. No anticoagulation was used after the surgical procedure.
For reasons of animal welfare the control animals were anesthetized for invasive monitoring before sacrifice but did not undergo a sham operation. They were identical to the LVAD animals for age, body weight, and species. We also did not attempt to insert an arterial catheter into awake animals during the course of the support period; we believed that this risked substantial morbidity such as bleeding and device endocarditis.
Pump flow
Data from the device including motor suspension current, energy requirements, and calculated pump flow were monitored constantly by the online computer. Pump flow was also measured daily by the implanted ultrasound flow probe throughout the study period (Fig 1).
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Recovery
The sheep were extubated after 30 to 60 minutes of spontaneous respiration and documentation of satisfactory blood gases and acid-base balance. A vest was placed around the thorax to carry the controller and connect with the electrical power line. Before removal of invasive arterial pressure monitoring at 48 hours, we were able to confirm that the systemic circulation remained nonpulsatile even during vigorous activity during handling.
The animals were then free to mobilize, drink, feed, and roam around the sheep pen.
Assessment
The sheep were examined for signs of neurologic events, heart failure, systemic thromboembolism, or abnormal behavior.
Renal and hepatic function were assessed serially by measurement of blood urea, creatinine, bilirubin, and liver enzymes. Plasma renin activity was measured by standard radioimmunoassay for both groups.
Autopsy studies
Sheep in the LVAD group were electively sacrificed at 30 (n = 3), 90 (n = 4), 180 (n = 1), and 340 (n = 1) days. Before sacrifice all animals were anesthetized and invasively monitored with an arterial line and Swan-Ganz catheter. The relationship between pump speed and absence of pulse pressure was checked again. Computerized arterial pressure traces before sacrifice are shown in Figure 2.
Heparin (5,000 IU/kg) was given intravenously to avoid clot formation on the blood-contacting surfaces of the pump and cannulas. The six control sheep were anesthetized and invasively monitored. They were then sacrificed to compare end-organ morphology.
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Histologic examination of major organs
Formalin-fixed, paraffin-embedded tissues from LVAD and control sheep were cut into 3-µm-thick sections and stained with hematoxylin and eosin. Differences between LVAD and control specimens were assessed by two independent pathologists who were blind to the origin of the samples.
The ascending aorta was cut horizontally into three segments that were embedded in paraffin sections. Sections of 3 µm thickness were cut from each block and stained with hematoxylin and eosin. The thickness of the medial layer was determined by computed morphometry (NIH images, Bethesda, MD).
Statistical analysis
All results for continuous variables were expressed as means ± standard deviations. The paired or unpaired Student’s t test, or Mann-Whitney U test if appropriate, was used to compare continuous variables between two subgroups. Probability values of less than 0.05 were considered to indicate statistical significance.
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Results |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Renal and hepatic function
Blood tests showed the blood urea and creatinine levels remained stable and within normal limits (Table 1).
There were no significant differences between the LVAD and control groups. Indices of hepatic function are shown in Table 2.
Hepatic function remained normal for the duration of the study with no difference between the LVAD and the control groups.
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Plasma renin activity after LVAD implantation was significantly elevated compared with the preoperative values (2.9 ± 0.3 pg/mL versus 1.3 ± 0.4 pg/mL; p < 0.05). There was also a significant difference between the LVAD animals and the control group (2.9 ± 0.3 pg/mL versus 1.4 ± 0.3 pg/mL; p < 0.05; Fig 3).
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Comment |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Until recently it was inconceivable that a rotary blood pump could function for many months in an animal model without anticoagulation. With careful alignment of the TLVAS inflow cannula we were able to provide consistently nonpulsatile blood flow for virtually 12 months. Measurements of calculated flow correlated well with ultrasonic flowmeter measurements of graft flow, and these levels were constantly above that required to abolish pulse pressure during invasive arterial monitoring and elevated preload. Even when the aortic valve remains continuously closed the left ventricle may generate preload to the device, which can be transmitted as pulse pressure to the circulation [2]. Consequently we set the TLVAS at a level at which even this level of pulse pressure could not occur.
The most encouraging finding was that long-term circulatory support without pulse pressure can maintain normal end-organ structure and function. Activity, behavior, and neurologic function did not differ from control animals. This outcome gives us confidence that both centrifugal and axial flow blood pumps should provide safe and effective long-term circulatory support in the patient with heart failure. Early clinical experience with axial flow pumps has already shown that diminished pulse pressure and periods without pulse are compatible with recovery from heart failure and improvement in end-organ function [2].
In the absence of a reliable nonpulsatile animal model, most previous investigations of pulseless circulation have centered on CPB [5, 6]. Pulsatile CPB systems were said to result in less endothelial damage, reduced systemic vascular resistance, and normal nitric oxide release [6]. Pulsatility plays a role in the movement of lymph in and out of the tissues, perhaps preventing edema and capillary sludging [7]. In the CPB model, cerebral microcirculation was improved by pulsatility, and pulse pressure influenced the activity of the renin-angiotensin system and catecholamine release [8]. In reality these short-term CPB studies fail to predict the effects of long-term pulseless circulation because of the body’s ability to adapt to changes in physiology. In any event pulse pressure is greatly diminished or absent at the capillary level.
In nonpulsatile animals upregulation of plasma renin activity could be an adaptive response to lack of pulse pressure. This elevates mean perfusion pressure by increasing the systemic vascular resistance. Systemic vascular resistance is raised during nonpulsatile CPB when compared with pulsatile CPB [9]. Nishimura and colleagues [10] reported that the systemic vascular response to norepinephrine administration decreased markedly in a chronic nonpulsatile left heart bypass model (up to 137 days), although there was no difference in the plasma norepinephrine levels between pulsatile and nonpulsatile animals. This group also reported atrophic changes in the aorta of nonpulsatile goats in comparison with goats with pulsatile left heart bypass [11].
We showed that the medial layer of the ascending aorta in the LVAD group was consistently thinner than in control sheep. This striking and reproducible finding suggests that we succeeded in providing pulseless circulation throughout the duration of the experiment. The arterial changes can be explained by a reduction in cyclic mechanical load, which leads to atrophy of the medial smooth muscle cells, and we are examining this further. The effect of a change in pulse pressure on the arterial wall has been investigated using an in vitro model of cyclic mechanical stretching on cultured vascular endothelial cells and smooth muscle cells [12]. These experiments also showed that a reduction in a pulse pressure resulted in atrophic changes. Assuming that these morphologic changes extend to the entire arterial system, vascular endothelial function such as blood flow regulation and pressure control could also be compromised, although we were unable to define differences in the sheep.
In conclusion, chronic pulseless circulation was well tolerated in the sheep model, and we could not identify changes in major end organs. The renin-angiotensin system was upregulated, although mean blood pressure was not significantly elevated. Although pulseless circulation caused thinning of the aortic wall, our findings still suggest that continuous flow devices can be used safely for long-term circulatory support.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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References |
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