As continuous flow left ventricular assist devices (cfLVADs) become more reliable and the proportion implanted as destination therapy increases, emphasis in management has shifted towards enhancing activities of daily living. Despite good support at rest, cfLVAD patients continue to be limited by exertional fatigue,1 and the inability to adequately augment cardiac output with exercise is a significant factor.2,3 Continuous flow left ventricular assist devices in commercial use are currently operated at fixed speeds regardless of the level of activity. Given the strong linear relationship between pump speed and flow,4 it is logical to investigate whether there is merit in increasing pump speed with activity. The option of speed modulation was first proposed with the Jarvik pump5 with increased pump speed associated with enhanced cardiac output during exercise compared to baseline in some,6,7 but not all.8 As these studies are small and all used different pumps, direct comparison is not appropriate. Those studies did not assess the interaction in left ventricular (LV) and right ventricular (RV) filling pressures or effect on pulmonary any systemic vascular tone. In our study, we hypothesized that a higher pump speed during graded exercise would result in improved invasively measured central hemodynamics. This has not been previously demonstrated.
Fourteen stable, ambulatory outpatients implanted with an isolated HeartWare HVAD undergoing routine right heart catheterization were recruited for pump speed titration and exercise testing. The study (HREC/13/SVH/32) was approved by the St Vincent’s and Mater Health Human Research Ethics Committee. To be considered eligible, patients were required to be consenting adults and at least 2 months post pump insertion and exercise testing. Conditions which precluded exercise included active infection, exercise-induced myocardial ischemia, and significant arrhythmias. Patients in whom pump speed could not be sufficiently up-titrated without inducing suction were also excluded.
Each patient underwent right heart catheterization at rest followed by incremental exercise on a supine bicycle ergometer with the Swan-Ganz catheter in situ. Patients were monitored throughout the study with the use of a continuous cardiac output monitor (Vigilance II Monitor; Edwards Lifesciences, Irvine CA), 12-lead electrocardiogram (ECG), transthoracic echocardiography (Acuson Cypress, Acuson Corp, Mountainview CA) and a computerized data acquisition system, which records the LVAD parameters speed, power and estimated flow at a sampling rate of 50 Hz onto a portable computer hard drive.
Following administration of 2% xylocaine, right heart catheterization was performed under ultrasound guidance (SonoSite Inc., Bothel, WA) through the right or left internal jugular vein using a 7.5 French double transducer Swan-Ganz catheter (CCOmbo; Edwards Lifesciences, Irvine, CA). Right atrial pressure (RAP), mean pulmonary arterial pressure (MPAP), and pulmonary capillary wedge pressure (PCWP) were measured. Blood was sampled from the pulmonary artery for mixed venous oxygen saturation (SvO2) calibration. Heart rate was monitored using ECG while mean arterial pressure (MAP) was measured noninvasively with Doppler-guided sphygmomanometry. Left ventricular assist device parameters speed, power, and flow were recorded from the HeartWare monitor. Left ventricular end-systolic dimension (LVESD) and left ventricular end-diastolic dimension (LVEDD), the opening of the aortic valve and the presence of any aortic or mitral regurgitation were also noted. These parameters were recorded at each stage of speed titration and exercise. Blood samples were also taken immediately pre- and postexercise to determine B-type natriuretic peptide (BNP), lactate dehydrogenase (LDH), and lactate levels.
Speed Titration Protocol
With the patient resting supine, all baseline hemodynamic, echocardiographic, and pump parameters were recorded. With the patient still at rest, pump speed was then increased by 80 revolutions per minute (rpm) every 2 minutes. Up-titration was stopped at 320 rpm above baseline speed or in the event that LVEDD reduced to less than 80% of baseline, flow exceeded 130% of baseline or suction, or significant arrhythmia occurred. Once a safe working maximum had been established, pump speed was reduced back to baseline in 80 rpm decrements. Pump speed was maintained at baseline for a minimum of 5 minutes to allow for re-equilibration before proceeding with the exercise protocol.
Patients performed graded exercise on a supine bicycle ergometer (Lode B.V., Groningen, The Netherlands). Exercise workload was increased from zero watts in 15W increments to a peak of 60W or until exhaustion with patients pedaling at a cadence of 50 rpm. Light exercise, taken as 15W, was performed for 1 minute at baseline speed and then at maximum speed, as determined by the speed titration protocol. Workload was increased every minute thereafter with the patient exercising at maximum speed (see Figure 1, Supplemental Digital Content, http://links.lww.com/ASAIO/A397). In the final stage of exercise, nine patients were assigned to exercise at maximum speed followed by baseline speed and five patients were assigned to exercise at baseline speed followed by maximum speed to account for the confounding effects of fatigue on the results. Parameters were recorded at each stage and in the recovery period following exercise.
Statistical analysis was performed using SPSS Version 24 (IBM, Chicago, IL). The effect of exercise and pump speed changes and their interaction were assessed by repeated measures analysis using a general linear model. Post hoc significance was assessed after Bonferroni correction for multiple comparisons. Regression analysis was performed using enter regression. Results are presented as median (range) or mean ± standard deviation unless otherwise specified. The impact of pump speed alone was assessed using paired t-tests. Differences in the proportion of patients with aortic valve opening with exercise were assessed using χ2 test. A p value of < 0.05 was considered statistically significant.
The mean age of the patients studied was 58 ± 9 years, with the median time from pump insertion being 4 months (range, 2–16 months). All patients were implanted with a cfLVAD as a bridge-to-transplant, bar one destination therapy patient. Three patients were interagency registry for mechanically assisted circulatory support (INTERMACS) level 1, nine patients were INTERMACS level 2, and two were INTERMACS level 3 at implant. Half required temporary circulatory support with either an intra-aortic balloon pump or venovenous extracorporeal membrane oxygenation (VA ECMO) before LVAD insertion (INTERMACS 1 or 2 temporary circulatory support (TCS)). There was mild to moderate RV hypokinesis in seven patients and severe impairment of LV systolic function in all patients at the time of the exercise study (left ventricular ejection fraction [LVEF] 24.6 ± 6.9%). All patients were on warfarin and antiplatelet therapy, seven patients were being treated with beta-blockers and seven with anti-arrhythmic agents including digoxin and amiodarone (see Table 1, Supplemental Digital Content, http://links.lww.com/ASAIO/A398).
The median baseline pump speed was 2,600 rpm (range, 2,500–2,800 rpm). All patients were safely titrated to a pump speed 320 rpm above baseline, with one patient titrated to 2,900 rpm, 400 rpm above that patient’s baseline. The median maximum speed was 2,920 rpm, with a maximum pump speed of 3,120 rpm in the two patients with baseline speed of 2,800 rpm. There were no instances of suction or other adverse events during speed titration, and all patients were able to perform exercise without complication. The median workload was 15W (range, 10–15W) at light exercise and 45W (range, 30–60W) at peak exercise.
At rest and during exercise, estimated pump flow was greater with maximum speed compared to baseline speed (Figure 1). Exercise was associated with a significant increase in both right and left heart filling pressures (Figure 2, A and B, respectively). Increasing pump speed reduced the left heart filling pressure (PCWP), p < 0.001, but did not change RAP. Similarly, exercise was associated with a decrease in systemic vascular resistance (SVR), but no change in pulmonary vascular resistance (Figure 3).
Aortic valve opening was assessed using a previously validated algorithm9 in all patients. With increased pump speed, there was an expected decrease in the percentage of patients with aortic valve opening from 51% down to 39% across all states (p = 0.01). Similarly, there was a slight increase in aortic valve opening with exercise, although this was not significant on analysis of variance (ANOVA) with the algorithm, but was significant on visual echocardiographic estimate (binary closed or open to any extent in 10/14 patients with adequate images) (Figure 4, A and B). Heart rate, MAP, RAP, and MPAP were not significantly different between the two speeds. Left ventricular end-diastolic dimension and left ventricular end-systolic dimension remained unchanged. Moderate mitral regurgitation was documented at rest in one patient and mild aortic regurgitation in another. These results are summarized in Table 1.
Lactate increased from a resting average of 1.3 ± 0.4 mmol/L to 4.1 ± 2.0 mmol/L (p = 0.002) postexercise. Serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and LDH did not significantly change. Mixed venous oxygen saturation was marginally enhanced at rest in response to increased pump speed, but was significantly decreased in response to low level and peak exercise. This was unaffected by enhanced pump speed (Table 1). There was no correlation between the maximum pump flow achieved and the SvO2 at peak exercise (r2 = 0.05, p = 0.44), possibly related to variability in baseline cardiac reserve.
The main finding of this study is that exercise with a centrifugal cfLVAD at an increased pump speed results in significantly greater pump flow and lower PCWP than operation at baseline pump speed. Speed was safely increased in all subjects and was not associated with any episodes of suction or significant reductions in ventricular dimensions. Although increased pump speed during exercise limited the increase in left-sided filling pressures, both left and right heart pressures remained significantly elevated. Mixed venous oxygen saturation did not improve with maximum pump speed despite the significant increase in pump flow, consistent with inadequate physiologic cardiac output.
This is the first study to examine the impact of maximum pump speed on exercise-induced changes in invasive hemodynamics, accounting for the confounding effects of exercise fatigue within the study protocol. This information is fundamental in assessing whether there is any value of pump controller algorithms in exercise augmentation by pump speed changes. There are limited previous studies assessing the impact of pump speed on exercise measurements. The two largest studies have assessed the effect of change in pump speed on sequential cardiopulmonary exercise tests by Gustafsson and colleagues.10,11 These have shown an augmentation of peak oxygen consumption (VO2)11 and an increase in exercise time.10 The additional information from the current study is the demonstration of the impact of the pump speed changes on LV filling pressures as well as pulmonary and SVRs. We have previously demonstrated changes in pump flows and invasive hemodynamics with exercise12; however, in that study there was a systematic bias as pump speed was increased sequentially with increased exercise, and the progressive increase in filling pressures (PCWP) despite increase in pump speed in that study is likely to be because of the progressive changes associated with ongoing exercise.
Pump flow through a cfLVAD is driven by the impeller speed and pressure gradient across the pump. This head pressure, the difference between aortic pressure and LV pressure, is inversely related to pump flow.13 The spontaneous increase in pump flow from rest to exercise, regardless of speed adjustment, is largely attributed to an increase in venous return and preload and has been well documented in a number of other studies.7,14–18 The rationale for pump speed adjustment is that higher pump speeds may be able to generate the higher flows at substantially greater head pressures. Therefore, despite greater unloading of the left ventricle (shown by lower PCWP at higher pump speed), pump flow remains increased.13 The importance of assessment during exercise, rather than at rest or with mock loop models, is that exercise is associated with changes in multiple hemodynamic inputs, including heart rate, vascular loading conditions (as shown with the change in SVR), LV loading (PCWP), and aortic ejection (assessed with aortic valve opening) as shown in the current study. Further studies, currently only available in animal studies, examining simultaneous intra-arterial pressure waveform analysis and pump function analysis are required to more definitively determine the factors required for dynamic pump control.
In our study, the 14% increase in flow observed with maximum pump speed over baseline speed during peak exercise is slightly more conservative than what has been reported in the literature. Salamonsen et al.7 observed a 35% increase in flow with high pump speed compared to decreased baseline pump speed with the Ventrassist device; however, the result is very similar to the current study when compared to response at baseline pump speed (15% increase) from that study. Schima et al.6 reported an increase of 21% using a variable speed control algorithm with the DeBakey LVAD. Although we found that maximum pump speed at peak exercise afforded a 46% increase from resting flow at baseline pump speed, this still falls well short of the threefold increase in cardiac output with exercise reported in normal subjects.19,20 Inadequate augmentation of cardiac output to meet the increase metabolic demand during exercise explains why SvO2 levels remained low in our study. Unchanged LV dimensions suggested that pump speed could have been increased further, however the median maximum pump speed achieved in this study (2,920 rpm) neared the manufacturer recommended maximum (3,200 rpm) and it is unlikely further increases would have yielded appreciably different results or that automated changes in pump speed changes would be as great in the unmonitored situation.
Although increased pump speed significantly improved PCWP during all stages of activity compared to baseline pump speed, there were no significant reductions in RAP or MPAP. These results show that although increasing pump speed helps with unloading of the left heart, this does not translate to reductions in right heart pressures. This may be due to limited pulmonary vasodilation restricting forward flow, or the effect of independent resting RV impairment, as was present in half of the study population. RV function during exercise was not assessed. This is in contrast to findings presented by Schima et al.6 which demonstrated a substantial reduction in MPAP in addition to PCWP, although RV function was not reported in that study.
Intuitively, reducing PCWP by increasing pump speed and unloading of the left ventricle should prevent interstitial fluid accumulation and reductions in lung compliance, improving dyspnoea. However, general consensus in the literature is that elevated PCWP may not be associated with dyspnoea or reduced exercise capacity in patients with long-standing heart failure as a result of structural remodeling.21–24 Structural remodeling involves alveolar fibrosis, thickening of capillary and alveolar basement membranes, muscularization of pulmonary arteries and veins, and dilation of lymphatic vessels, enabling chronic heart failure patients to withstand high PCWP without developing pulmonary oedema.25 Notwithstanding this, pulmonary venous congestion causes reactive increases in PVR and can lead to right heart failure which correlates strongly with increased mortality and poorer exercise capacity in unsupported heart failure patients.26–28 This study is the first invasive examination of changes pulmonary and SVR with varying pump speed. The previous study by Martina et al.29 used noninvasive estimate of cardiac output and calculated SVR assuming zero central venous pressure. It can be seen from this study, and others12 however, that the RAP increases significantly (doubling) with exercise, similar to that of the left heart filling pressures. Assuming a stable venous pressure would be expected to overestimate SVR at peak exercise.
Mixed Venous Oxygen Saturation
The body maintains adequate tissue oxygen consumption by either increasing oxygen delivery to the periphery, mainly as a result of increasing cardiac output, or failing that, increasing the amount of oxygen extracted from the blood. Increased oxygen extraction manifests as a decrease in SvO2. The patients in this study were able to achieve remarkably high levels of oxygen extraction, with one patient demonstrating a SvO2 as low as 12%. It has been postulated that heart failure patients have higher erythrocyte levels of 2,3-diphosphoglycerate which shifts the oxygen–hemoglobin dissociation curve to the right, causing a reduction in hemoglobin affinity for oxygen allowing greater unloading at the metabolizing tissues.30 Anaerobic metabolism occurs when oxygen delivery is insufficient to maintain oxygen consumption, despite maximal oxygen extraction, and was evidenced in our patients as a lactate level of nearly two times the upper limit of normal. The early and increased production of lactic acid with exercise in patients with heart failure is buffered by bicarbonate (HCO3–) to produce a greater amount of CO2 for a given work rate than in normal subjects, increasing ventilatory drive and the sensation of breathlessness.31 The lack of significant improvement in SvO2 at maximum pump speed, despite a significant increase in pump flow, suggests that systemic blood flow remains a limiting factor during exercise in our study patients. Abnormalities with the peripheral vasculature have been well documented in patients with heart failure32 and may still limit the benefit of dynamic speed control with exercise.
Despite active speed control being demonstrated in vivo more than 10 years ago,6 pump development timelines have not resulted into any changes to the concept of fixed speed continuous flow (notwithstanding the asynchronous pump speed increases and decreases in HeartMate-3 artificial pulse33 and HVAD Lavare cycle34). As shown in this study, less than half of the patients have sufficient ventricular contractility to augment cardiac output with aortic valve opening at rest, with only a slight increase with exercise. As has been pointed out previously; however, often aortic valve opening itself does not suggest a significant additive stroke volume in these patients.8 Due to design constraints of size, maximum flows generated by current LVADs are typically less than 8–10 L/min for a head pressure of 100 mmHg. Given that normal exercise response, involves a cardiac output nearly twice that,35 further enhancements are required to achieve a normal exercise response during LVAD in the unrecovered heart. Whether significantly (> 30%, compared to the ~15% in most clinical studies) increasing pump speed intermittently during exercise would have a significant benefit is not clear. As seen in the current study, both RV and LV filling pressures are markedly increased during exercise. Augmenting LV unloading alone by adjustments in pump speed during exercise is unlikely to be the complete solution. Further assessment of the impact of pulsatile losses in the outflow conduit are also required.
A number of limitations of this study deserve consideration. Although the results of this study apply to the HeartWare HVAD, the results are consistent with other noninvasive assessments with other pumps as mentioned above. Despite a relatively small cohort, significant improvement in LV filling pressures and cardiac outputs were seen. The current study remains the largest invasive assessment of hemodynamics during pump speed augmentation during exercise.
Given the greater venous return in patients studied supine, it is uncertain whether speed increases of the same magnitude can be achieved in upright, ambulatory patients without inducing suction. Increases in pump flow in upright patients may be more conservative as a result of reduced preload, although we have shown that even minor activation of leg muscle groups can maintain venous return in the setting of passive tilt.36 Indeed, although more aggressive speed titration may have been possible with patients exercising supine, translation of results into upright exercise needs further study due to differences in venous return. Whether more aggressive control algorithms imposing higher pump speed can mitigate the limitation in cardiac output in these patients is one area of future research. The outcome clearly demonstrated by the current study is that a significant increase in pump speed, far greater than that made in routine patient management, has only limited impact on the exercise-induced increase in LV filling pressure.
Higher pump speeds synergistically augment the increase in pump flow associated with exercise while blunting the rise in PCWP, potentially improving exercise capacity. However, improvements were modest and it appears unlikely that active pump speed control will achieve a normal physiologic response to exercise with the current technology. Regardless, the improvements observed, may enhance activities of daily living, and encourage further investigation into the potential incorporation of speed control systems into future LVAD designs.
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