Blood biocompatibility analysis in the setting of ventricular assist devices

Ventricular assist devices (VADs) are increasingly applied to support patients with advanced cardiac failure. While the benefit of VADs in supporting this patient group is clear, substantial morbidity and mortality occur during the VAD implant period due to thromboembolic and infective complications. Efforts at the University of Pittsburgh aimed at evaluating the blood biocompatibility of VADs in the clinical, animal, and in vitro setting over the past decade are summarized. Emphasis is placed on understanding the mechanisms of thrombosis and thromboembolism associated with these devices.     

Improved biocompatibility of heparin surface-coated ventricular assist devices.

Heparin surface coated ventricular assist devices (VADs) and cannulas were evaluated in comparison to uncoated VADs in 10 bovine experiments (body weight 77 +/- 6 kg). All systems were primed with cristalloid solution. No systemic heparin was given. Left ventricular assist was started with a blood flow of 4.2 +/- 0.4 l/min and maintained over 6 hours. Besides hemodynamic monitoring, blood samples were taken at regular intervals for blood gas, hematological, biochemical and coagulation studies. All animals in the study group (coated) were assisted for the scheduled 6 hours without device failure. In the control group, however, total occlusion occurred in 1 VAD after 1 hour of left ventricular assist whereas the other 4 VADs remained functional throughout the protocol. Mixed venous oxygens saturation was preassist 56 +/- 12% for coated versus 63 +/- 11% for uncoated and the final value at 60 minutes after weaning was 58 +/- 16% versus 59 +/- 5% (NS). Mean hematocrit dropped from a baseline value of 33 +/- 4% for coated versus 29 +/- 8% for uncoated to 29 +/- 7% versus 30 +/- 5% (NS) after 6 hours of assist. There was no significant difference between the baseline values (5.7 +/- 3.0 mumol/l for coated versus 4.6 +/- 3.1 mumol/l for uncoated) and the 6-hour values (3.8 +/- 3.7 mumol/l versus 7.6 +/- 6.4 mumol/l) for mean plasma hemoglobine. The normalized platelet levels dropped after 10 minutes of assist to 91 +/- 21% for coated versus 94 +/- 49% for uncoated (NS) and 89 +/- 29% versus 65 +/- 44 at 6 hours (NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cost-benefit analysis of extended antifungal prophylaxis in ventricular assist devices

This report defines the cost and benefit of extended antifungal prophylaxis in ventricular assist device (VAD) patients (pts). Extended antifungal prophylaxis is defined as prophylaxis with fluconazole or nystatin that is given until pts are extubated and off antibiotics. These data are compared with that obtained from earlier VAD patients who only received anti-fungal drugs for documented fungal colonization or infection. Thirty-six patients had HeartMate (n = 15) or Thoratec (n = 21) VADs between 1989 and 1997. Cultures positive for fungus (n = 52 cultures) were obtained from 16 of 36 patients (44% of patients). Forty-three fungal cultures were in the preprophylaxis and nine in the postprophylaxis era. There was one death attributable to fungal sepsis in the preprophylaxis era and none in the postprophylaxis era. The total cost of antifungal drugs in the preprophylaxis era was $3,840 over 1,498 patient days (PD) (mean $2.56 per PD), versus $70,670 over 1,525 PD in the postprophylaxis era (mean $46.34 per PD). Extended antifungal prophylaxis was not cost effective in VAD patients at this institution. However, short-term perioperative antifungal prophylaxis was not addressed by this study. We are now using short-term antifungal prophylaxis with fluconazole and nystatin in VAD patients because of the potential for serious morbidity and mortality that is associated with fungal device infections. A future analysis will determine the usefulness of this change in strategy.     

Pulsatile pediatric ventricular assist devices

A pulsatile pediatric ventricular assist device (PVAD) is being developed at The Pennsylvania State University to provide mechanical circulatory support in infants and children. The PVAD is based on the design of the adult-sized Pierce-Donachy VAD (Thoratec VAD). The infant-sized PVAD has a dynamic stroke volume of approximately 13 ml. A larger 25-ml size for children is also planned. The stroke volumes, beat rates, and pulsatility are comparable to normal physiologic values. The expected maximum duration of use is 6 months. The PVAD is intended to be placed paracorporeally, although the pump may be implanted for bridge-to-transplant applications. The pneumatically actuated PVAD uses a full-to-empty control mode, which allows maximum flexibility in its application for left, right, or biventricular assistance. The device may be used with atrial or ventricular inlet cannulation, with blood return to the aorta or pulmonary artery. In vitro testing is underway to measure hydrodynamic performance, hemolysis, and flow velocities using particle image velocimetry. In vivo implantation studies will be performed in juvenile goats or sheep after the completion of baseline studies to assess hematology and surgical fit.     

Fungal infections in ventricular assist devices

Device infections in patients supported by a mechanical circulatory support system remain an important problem, particularly as we enter the era of permanent device implantation. This article focuses on fungal infections that occur in patients with ventricular assist devices. The nature of fungal, especially Candida species, colonization and infection in severely ill, hospitalized patients will be described. Information regarding the effect of the artificial surface-blood interface on the immune system's ability to combat fungal organisms will also be presented. Basic aspects of the fungal-host interaction serve as the foundation for a discussion of clinical management protocols for preventing and treating fungal infections in patients supported by a ventricular assist device.     

Hydrodynamic characterisation of ventricular assist devices

A new mock circulatory system (MCS) was designed to evaluate and characterise the hydraulic performance of ventricular assist devices (VADs). The MCS consists of a preload section and a multipurpose afterload section, with an adjustable compliance chamber (C) and peripheral resistor (Rp) as principal components. The MCS was connected to a pulse duplicator system for validation, simulating a wide range of afterload conditions. Both pressure and flow were measured, and the values of the different components calculated. The data perfectly fits a 4-element electrical analogon (EA). The MCS was further used to assess the hydrodynamic characteristics of the Medos VAD as an example of a displacement pump. Data was measured for various MCS settings and at different pump rates, yielding device specific pump function graphs for water and pig blood. Our data demonstrate (i) flow sensitivity to preload and afterload and (ii) the effect of test fluid on hemodynamic performance.     

A review of clinical ventricular assist devices

Given the limited availability of donor hearts, ventricular assist device (VAD) therapy is fast becoming an accepted alternative treatment strategy to treat end-stage heart failure. The field of mechanical ventricular assistance is littered with novel and unique ideas either based on volume displacement or rotary pump technology, which aim to sufficiently restore cardiac output. However, only a select few have made the transition to the clinical arena.Clinical implants were initially dominated by the FDA approved volume displacement Thoratec HeartMate I, IVAD, and PVAD, whilst Berlin Heart's EXCOR, and Abiomed's BVS5000 and AB5000 offered suitable alternatives. However, limitations associated with an inherently large size and reduced lifetime of these devices stimulated the development and subsequent implantation of rotary blood pump (RBP) technology. Almost all of the reviewed RBPs are clinically available in Europe, whilst many are still undergoing clinical trial in the USA. Thoratec's HeartMate II is currently the only rotary device approved by the FDA, and has supported the highest number of patients to date. This pump is joined by MicroMed Cardiovascular's Heart Assist 5 Adult VAD, Jarvik Heart's Jarvik 2000 FlowMaker and Berlin Heart's InCOR as the axial flow devices under investigation in the USA. More recently developed radial flow devices such as WorldHeart's Levacor, Terumo's DuraHeart, and HeartWare's HVAD are increasing in their clinical trial patient numbers. Finally CircuLite's Synergy and Abiomed's Impella are two mixed flow type devices designed to offer partial cardiac support to less sick patients.This review provides a brief overview of the volume displacement and rotary devices which are either clinically available, or undergoing the advanced stages of human clinical trials.     

In vivo performance and biocompatibility of the MagScrew ventricular assist device

Currently available ventricular assist devices (VADs) have limitations in long-term durability and blood compatibility. We evaluated a prototype of a pulsatile MagScrew VAD for in vivo hemodynamic performance and biocompatibility. The device is composed of an actuator, blood pump housing, diaphragm, pusher plate, and bioprosthetic valves. Its protein-coated ("biolized") blood-contacting surface inhibits clot formation. Forces between moving parts of the actuator are transmitted magnetically, eliminating a primary source of friction and wear. The pump fills passively and is highly preload sensitive. The device was implanted into three calves for 90, 10, and 57 days, respectively. No anticoagulants were given postoperatively. The device functioned without technical problems during the entire course of each experiment, with mean device flow ranging between 5.4 and 9.0 L/min. Autopsy of the first two calves revealed no sign of embolization and clean blood-contacting surfaces of the devices. The third experiment was complicated by a prosthetic valve endocarditis with infectious embolization, and a few small depositions were found in the pump. In conclusion, the MagScrew VAD has demonstrated a high level of performance and biocompatibility in three calves studied for 10-90 days. Vigorous development is in progress to bring this device to preclinical readiness and thus provide surgeons with the VAD of choice for permanent implantation.     

Current status of extracorporeal ventricular assist devices in Japan

Extracorporeal VADs are less expensive, their prices reimbursable by the health insurance being about one-sixth of those of implantable VADs in Japan. However, a disadvantage is that, in Japan, their use is restricted to hospitals, necessitating prolonged hospitalization, reducing the patients’ quality of life. According to the Japanese registry for Mechanically Assisted Circulatory Support, the survival rate does not differ significantly between patients with extracorporeal and implantable VADs. As in Europe and North America, extracorporeal VADs in Japan are commonly used as Bridge to Decision or Bridge to Recovery. Extracorporeal VADs are switched to implantable VADs as a Bridge-to-Bridge strategy after stabilization or when cardiac function recovery fails. They are also used as right ventricular assist devices (RVADs) in patients with right heart failure. A special characteristic of extracorporeal VADs in Japan is their frequent use as a Bridge to Candidacy. In Japan, indications for implantable VADs are restricted to patients registered for heart transplantation. Therefore, in patients who cannot be registered for transplantation because of transient renal dysfunction, etc., due to heart failure, extracorporeal VADs are used first, and then replaced by implantable VADs after transplant registry is done. Here, we describe the current status of extracorporeal VADs in Japan, focusing on the environmental backgrounds, along with a review of the relevant literature.     

Role of ventricular assist devices in the German heart allocation system

The Eurotransplant (ET) allocation algorithm, newly implemented in 2000, gives priority for heart transplantation (HTx) to patients with high urgency (HU) status, but now this status is rescinded upon ventricular assist device (VAD) implantation and only regained if severe complications occur during mechanical circulatory support (MCS). We studied the effects of this change on the patients in our institute who were waiting for HTx with MCS. The median duration of MCS until HTx in adult patients gradually increased from 3.1 months in 1994, reaching a peak of 16.7 months in 2000, and then gradually decreased to 6.0 months in 2003. Among the patients with VAD implantation as a bridge to HTx, two patients were on MCS for more than 1 year (the longest duration of MCS being 1.6 years) at the end of 1999, and this figure increased to nine patients and a maximum MCS duration of 3.7 years at the end of 2003. These data imply that the patients in whom a complication occurred in the early phase of MCS and who had overcome this complication underwent HTx early with HU status, and those who were stable during MCS waited a long time for HTx. Furthermore, the number of patients in the latter group is increasing. The new allocation algorithm imposes on patients with MCS waiting for HTx who are relatively young and free from complications and serious coexisting disease, very long-term MCS without an end to VAD bridging, which is almost equivalent to destination therapy. Part of this paper was presented at the 42nd JSAO Conference (Tokyo, October 5–7, 2004)     

Racial differences in patients with left ventricular assist devices

We examined clinical outcomes based on ethnicity in patients undergoing left ventricular assist device (LVAD) implantation. We hypothesized that treatment in a specialized, comprehensive heart failure program results in similar survival between African Americans and whites. We retrospectively reviewed patient data implanted with HeartMate II (HM-II) LVAD over 2 years. There were 79 patients: 34 (43%) whites, 33 (42%) African Americans, and 12 (15%) patients belonging to other ethnicities there was no difference in demographics. The etiology of cardiomyopathy was more commonly ischemic in white patients compared to nonischemic in African American patients (p = 0.01). The mean left ventricular ejection fraction was 22.21 ± 10.66% in African American patients and 15.21 ± 5.54% in white patients (p = 0.008). The left ventricular end-diastolic (p = 0.06) and end-systolic (p = 0.03) diameters were greater in white patients compared to African American patients. Hypertension was seen in 79% of African American patients compared to 56% in white patients (p = 0.07). Survival by Kaplan-Meier analysis revealed an unadjusted survival advantage in African American patients (p = 0.04 by log-rank test), but this survival advantage was lost in multivariable Cox regression analysis after adjustment for other covariates. There was no difference in readmissions (p = 0.36). In patients with advanced heart failure undergoing HM-II LVAD implantation, African American patients had a similar survival and no difference in readmissions when compared with white patients despite significant differences in baseline clinical characteristics.     

Preliminary report on the cost effectiveness of ventricular assist devices

The aim of the present study was to perform a cost-effectiveness analysis (CEA) of ventricular assist devices (VAD) implantation surgery in the Japanese medical reimbursement system. The study group consisted of thirty-seven patients who had undergone VAD implantation surgery for dilated cardiomyopathy (n = 25; 67.6 %) or hypertrophic cardiomyopathy (n = 4; 10.8 %), and others (n = 8; 21.6 %). Quality-adjusted life years (QALYs) were calculated using the utility score and years of life. Medical reimbursement bills were chosen as cost indices. The observation period was the 12-month period after surgery. Then, the incremental cost-effectiveness ratio was calculated according to the VAD type. In addition, the prognosis after 36 months was estimated on the basis of the results obtained using the Markov chain model. The mean preoperative INTERMACS profile score was 2.35 ± 0.77. Our results showed that the utility score, which indicates the effectiveness of VAD implantation surgery, improved by 0.279 ± 0.188 (ΔQALY, p < 0.05). The cost of VAD implantation surgery was 313,282 ± 25,275 (ΔUS$/year) on the basis of medical reimbursement bills associated with therapeutic interventions. The calculated result of CEA was 364,501 ± 190,599 (ΔUS$/QALY). The improvement in the utility score was greater for implantable versus extracorporeal VADs (0.233 ± 0.534 vs. 0.371 ± 0.238) and ICER was 303,104 (ΔUS$/ΔQALY). Furthermore, when we estimated CEA for 36 months, the expected baseline value was 102,712 (US$/QALY). Therefore, VAD implantation surgery was cost effective considering the disease specificities.     

Infection in ventricular assist devices: the role of biofilm.

Ventricular assist devices improve hemodynamics in patients with heart failure, but like most implantable medical devices, they are prone to infection; organisms that are adept at forming biofilm cause most of these. Biofilm confers many advantages to the organisms, including protecting them against natural host defenses and antimicrobial therapies. This review will focus on the mechanisms of biofilm formation, including quorum sensing and subsequent changes in microbial gene and protein expression. Novel therapies targeting these processes, as well as improvements in device design and clinical management, have begun to emerge and will aid in the management of these recalcitrant infections.     

Total heart replacement with dual centrifugal ventricular assist devices

In an ovine feasibility study, we implanted two HeartMate-III centrifugal ventricular assist devices (VADs) for total heart replacement. With cardiopulmonary bypass support, both ventricles were transected at the atrioventricular groove, preserving a rim of ventricular tissue. The atrioventricular valves were excised, and the aorta and pulmonary artery were transected above the ventriculoarterial valves. An interatrial septal window was created by excising the foramen ovale. The VADs' sewing rings were attached to the left and right ventricular remnants, respectively. Outflow grafts were anastomosed to the aorta and pulmonary artery. The left VAD operated continuously at 4,500 rpm. Right VAD speed increased from 2,000 to 4,500 rpm in 500 rpm increments. Outflow graft flow, pressure, oxygen saturation, and shunt direction were recorded. The pulmonary artery to aortic ratio of flow and pressure increased from 0.26 and 0.15 (at 2,000 rpm) to 1.21 and 0.53, respectively (at 4,500 rpm). The interatrial shunt, which was right to left at lower right VAD speeds, progressed to bidirectional, then to left dominant as right VAD speed increased. Outflow-graft oxygen saturation was reflective of the shunt direction. In this acute experiment, total heart replacement with continuous flow VADs satisfactorily balanced left and right ventricular flows and preserved the physiologic circulatory response.     

The use of computational fluid dynamics in the development of ventricular assist devices

Progress in the field of prosthetic cardiovascular devices has significantly contributed to the rapid advancements in cardiac therapy during the last four decades. The concept of mechanical circulatory assistance was established with the first successful clinical use of heart-lung machines for cardiopulmonary bypass. Since then a variety of devices have been developed to replace or assist diseased components of the cardiovascular system. Ventricular assist devices (VADs) are basically mechanical pumps designed to augment or replace the function of one or more chambers of the failing heart. Computational Fluid Dynamics (CFD) is an attractive tool in the development process of VADs, allowing numerous different designs to be characterized for their functional performance virtually, for a wide range of operating conditions, without the physical device being fabricated. However, VADs operate in a flow regime which is traditionally difficult to simulate; the transitional region at the boundary of laminar and turbulent flow. Hence different methods have been used and the best approach is debatable. In addition to these fundamental fluid dynamic issues, blood consists of biological cells. Device-induced biological complications are a serious consequence of VAD use. The complications include blood damage (haemolysis, blood cell activation), thrombosis and emboli. Patients are required to take anticoagulation medication constantly which may cause bleeding. Despite many efforts blood damage models have still not been implemented satisfactorily into numerical analysis of VADs, which severely undermines the full potential of CFD. This paper reviews the current state of the art CFD for analysis of blood pumps, including a practical critical review of the studies to date, which should help device designers choose the most appropriate methods; a summary of blood damage models and the difficulties in implementing them into CFD; and current gaps in knowledge and areas for future work.     

Use of ventricular assist devices in patients with postcardiotomy shock.

Over the last three years, we have used ventricular assist devices (VAD) in 7 patients. Of these 7, four patients with combined aortic and mitral valvular disease underwent double valve replacement; one patient with annuloaortic ectasia underwent a Cabrol's operation; another had aortic valve replacement; the last patient had triple coronary artery bypass grafts. The only patient who could be weaned from CPB developed cardiogenic shock after the operation. LVADs supported 6 patients for 4 to 8 days and a BVAD supported one patient for 9 days. All patients survived the weaning procedure. Three were discharged from the hospital and survived 7 to 21 months. The 4 other patients died of multiple organ failure. Three of these four suffered from both renal failure and infection, while one patient had arrhythmia and died of ileus. These data suggest that renal failure and major infection can be serious detrimental complications to VAD support.     

Retrospective hemolysis comparison between patients with centrifugal biventricular assist and left ventricular assist devices

Little is known about the hemolysis rate in the case of concomitant implantation of two continuous flow pumps for the treatment of biventricular heart failure. We present a retrospective study comparing the hemolysis parameters in patients supported with one implantable centrifugal pump of the type HeartWare HVAD used as a left ventricular assist device (LVAD) and with two pumps as a biventricular assist device (BiVAD). A total of 20 consecutive patients who received HeartWare BiVAD (n = 10) and LVAD (n = 10) support at our institution between September 2009 and September 2010 were examined. Hemolysis- and anemia-related parameters were analyzed after 2 weeks, 5 weeks, 3 months, and 6 months of support. Preoperative levels of hemoglobin, lactate dehydrogenase (LDH), and total bilirubin were similar in both groups. There were no differences in LDH, plasma-free hemoglobin (fHB), or total bilirubin levels postoperatively for up to 6 months. Only the haptoglobin level was lower in BiVAD recipients up to 3 months after surgery: 2nd week (63.5 [range: 8-237] mg/dl vs. 151 [range: 11-263] mg/dl, p = 0.05), 5th week (67 [range: 8-196] mg/dl vs. 215 [range: 56-292] mg/dl, p = 0.046), and after 3rd month (42 [range: 8-205] mg/dl vs. 220 [range: 157-256] mg/dl, p = 0.048). Our retrospective analysis of BiVAD HeartWare and LVAD HeartWare recipients showed a lack of a clinically important degree of hemolysis when two centrifugal HeartWare pumps are used for biventricular support.