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Ann Thorac Surg 2007;83:1697-1705
© 2007 The Society of Thoracic Surgeons
a Department of Thoracic and Cardiovascular Surgery, University Hospital of Münster, Münster
b Department of Cardiovascular Surgery, University Medical Center of Freiburg, Freiburg, Germany
Accepted for publication January 12, 2007.
* Address correspondence to Dr Etz, Department of Thoracic and Cardiovascular Surgery, University Hospital of Münster, Albert-Schweitzer-Str 33, 48149 Münster, Germany (Email: christian.etz{at}ukmuenster.de).
Presented at the Poster Session of the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006.
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Abstract |
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Methods: In ten patients with severe pulmonary hypertension, refractory to medical treatment, an implantable nonpulsatile LVAD was placed for continuous mechanical left ventricular support. Pulmonary hemodynamics were assessed by right heart catheterization prior to and during LVAD implantation, and after orthotopic heart transplantation.
Results: The mean (±SD) interval of nonpulsatile support was 182 (±118) days. Pulmonary artery pressure (mean ± SD) significantly decreased from 42 ± 13 to 24 ± 5 mm Hg (p < 0.005), the transpulmonary gradient (mean ± SD) decreased from 20 ± 6 to 11 ±5 mm Hg (p < 0.005), and the pulmonary vascular resistance (mean ± SD) from 4.8 ± 1.8 to 2.2 ± 0.8 Wood units (p < 0.005) during an interval of one to six months of LVAD support. No significant increases in pulmonary artery pressure, transpulmonary gradient, and pulmonary vascular resistance were observed during an interval of three to six months after orthotopic heart transplantation.
Conclusions: This study supports that LVAD support and continuous nonpulsatile mechanical unloading of the left ventricle can reverse medically unresponsive pulmonary hypertension and render patients eligible for orthotopic heart transplantation.
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Introduction |
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One of the most important components of the evaluation of a heart transplant candidate is the assessment of the pulmonary circulation and right ventricular function, because preoperative pulmonary vascular resistance (PVR) is an independent risk factor for early death after oHTx [1], and right ventricular dysfunction accounts for approximately 50% of cardiac complications and 20% of early mortality [2].
During the past decade, modern pharmacologic heart failure therapy improved significantly and patients may not develop the end stage of their heart failure syndrome until pulmonary hypertension is well-established and in some instances, refractory to medical treatment [3, 4]. Therefore, new strategies in the treatment of pulmonary hypertension are crucial; in particular for future heart transplant candidates.
In heart failure patients, pulmonary artery pressure (PAP) increases in proportion to increases in pulmonary capillary wedge pressure (PCWP), whereas PVR initially remains normal. However, long-standing elevation of PCWP eventually results in increasing PVR in about one-third of end-stage heart failure patients. The increased PVR leads to an elevation in PAP that is disproportionate to the increase in PCWP, thereby causing an increased transpulmonary pressure gradient (TPG).
The presence of elevated PVR or increased TPG in heart failure patients who are candidates for cardiac transplantation represents a major risk factor for right heart failure after oHTx and is predictive of adverse outcomes [5]. Up to 40% of potential candidates have developed secondary pulmonary hypertension at the time of assessment [3, 4]. In the official adult heart transplant report of the registry of the International Society for Heart and Lung Transplantation in 2004, Taylor and colleagues [6] reported on a significantly better survival rate for heart transplantation in recipients with a PVR of 1 to 3 Woods units (WU) compared with recipients with a PVR of 3 to 5 WU. However, there is evidence from large studies that oHTx is possible with normal risk if the PVR can be medically decreased below 2.5 WU and TPG to a level below 12 mm Hg [7, 8].
Depending on the severity and the duration of heart failure, an elevated PVR and an increased TPG may be responsive to and reversible with vasodilating agents, or fixed and permanent presumably as a result of fibrosis and remodeling in the pulmonary vasculature. The endothelium plays a central role in controlling the pulmonary vascular tone, and thus in the majority of end-stage heart failure patients the pulmonary hypertension is reversible with vasodilators unless structural remodeling of the pulmonary vascular bed has occurred.
To discriminate between patients with reversible and irreversible pulmonary hypertension, provocative pharmacologic testing is used and the hemodynamic parameters are measured by right heart catheterization. Intravenous vasodilators, such as sodium nitroprusside, nitroglycerin, adenosine, and prostaglandin, are used to assess pharmacologic reversibility. Prostaglandins are widely used to assess reversibility as part of this evaluation because they are readily available and considered as effective as nitric oxide in lowering an elevated PVR [4, 9, 10].
Recent studies among patients with end-stage heart disease and secondary pulmonary hypertension revealed response to medical therapy with normalization of PVR in up to 70% of the patients. One-third of the patients with severe elevated PAP were refractory to medical treatment [3, 4]. Pulmonary hypertension refractory to medical treatment is associated with a significantly increased early mortality after oHTx in all age groups [3, 11, 12]. In these patients oHTx is a high risk strategy [3]. The only options for these patients with end-stage heart failure and severe refractory pulmonary hypertension are heterotopic heart engraftment or heart-lung transplantation; both yielding much less satisfactory outcomes than oHTx. Thus, these patients are often denied a transplant procedure.
However, an increasing number of patients have recently been transferred to left ventricular assist device (LVAD) programs for destination therapy. Reports on declining pulmonary hypertension during long-term left ventricular unloading by LVADs introduced the idea that long-term mechanical support of the failing heart might "surgically" lower PVR in patients with medically refractory secondary pulmonary hypertension [13, 14]. Orthotopic heart transplantation became conceivable in patients formerly deemed ineligible [15].
As compared with their pulsatile counterparts, continuous flow pumps (with nonpulsatile flow patterns), which feature smaller dimensions and a diminutive total surface area, allow for intracorporeal implantation of the entire device (with a percutaneous drive-line for power supply), thereby reducing the incidence of infection [16]. The absence of a bulky extracorporeal pump unit facilitates discharge to ambulatory care and the mobile controller enables handling of the unit (eg, monitoring of flow and impeller speed) by the patients themselves. Yet another advantage of the continuous flow devices is their utility as a long-term device if pulmonary pressure reduction is not attainable and destination therapy eventually becomes the desired option.
We present our experience with the first 10 consecutive patients with severe, refractory pulmonary vascular parameters, who benefited from long-term left ventricular unloading after the implantation of a mechanical nonpulsatile LVAD, some of whom eventually underwent successful oHTx.
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Material and Methods |
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Hemodynamic Evaluation
Right heart catheterization was performed using a Swan-Ganz catheter through the internal jugular vein, enabling continuous measurement of cardiac output and central hemodynamics. Systemic arterial pressure was measured using an arterial cannula placed in a radial artery. All vasoactive drugs were withheld 24 hours before the procedure; no premedication was administered. All hemodynamic measurements were obtained while patients were in the supine position. The recorded hemodynamic variables included systolic-diastolic and mean PAP, PCWP, right atrial pressure, and cardiac output.
Derived hemodynamic variables were calculated using the following formulas: cardiac index (liters/minute/m2) = cardiac output-body surface area; TPG in mm Hg = mean PAP –PCWP; PVR in Woods units (WU).
Provocative pharmacologic testing for reversibility of pulmonary hypertension was accomplished using a high-dose prostaglandin E1 (PGE1, alprostadil) and I2 (PGI2, epoprostenol) protocol testing for acute vasodilator response to a directly infused selective vasodilator into the pulmonary vascular bed at concentrations increased stepwise to 200 ng · kg · min–1 [17]. The PGE1/PGI2 infusion was continued until the maximum dose was reached or acute side effects (such as systemic hypotension, tremors, flushing, nausea, dizziness) occurred.
Failure to respond to high-dose PGE1/PGI2, directly infused into the pulmonary vascular bed, with an attenuated reduction of TPG not below 12 mm Hg and PVR not below 4 WU, was defined as severe medically refractory pulmonary hypertension.
Patients
Ten patients (eight male; mean [± SD] age, 52 ± 9 years) with long-standing end-stage congestive heart failure (mean left ventricular ejection fraction <0.20) and severe medically refractory pulmonary hypertension, all previously classified "high-risk" (n = 5) and (or) denied (n = 5) oHTx, were enrolled in the study.
All patients were in NYHA class IV, with a poor prognosis and a cardiac index less than 2.0 L · min–1 · m2 despite maximal heart insufficiency treatment (including angiotensin-converting enzyme inhibitors, beta-blocking agents, and inotropic support). The majority presented with multiorgan dysfunction; ie, imminent renal failure and hepatic insufficiency. Five patients (50%) suffered from end-stage ischemic cardiomyopathy and five (50%) from dilated cardiomyopathy (one of whom had been admitted with acute myocarditis). Demographic data and risk factors are shown in detail in Table 1, and individual patient characteristics in Table 2. All patients fulfilled the criteria for oHTx except for significantly elevated parameters relating to their pulmonary hypertension.
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The MicroMed DeBakey LVAD is a first-generation axial flow pump designed to provide blood flow from the left ventricle to the ascending aorta. The system includes a titanium pump with an attached left ventricular inlet cannula, a percutaneous cable, a flow probe, and a Dacron outflow graft. The impeller spins at 7,500 to 12,500 RPM, and has solid bearings.
The INCOR LVAD is a second-generation axial flow pump with special technological features (Fig 1). The impeller has magnetic bearings; ie, there is no friction compromising long-term function of the device. The controller allows the speed of the turbine to be altered in a range from 5,000 to 10,000 RPM. The conduits are made of silicone and are connected with clip connectors, which can easily be reopened at any time. Because the conduits are perfectly sealed, no oozing from the conduits is seen after implantation. Despite its somewhat large size, the pump can be placed inside the pericardium; no separate device pocket is required.
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The dose of aspirin was increased until arachidonic acid-triggered platelet aggregation dropped to levels below 30%. If the patient remained clinically stable and did not need further invasive interventions, clopidogrel was added. The dose was adjusted to lower the ADP-induced platelet aggregation also to levels below 30%. Oral anticoagulation with phenprocoumon was started at the time of removal of the venous central line, aiming at an international normalized ratio of 2.5 to 4 [19]. Further medications, including dipyridamole and ticlopidine, were only administered if evidence of thromboembolic events was noted despite the effort to assure optimal antiplatelet therapy.
Postoperative Follow-Up Protocol
After hospital discharge, patients were seen once a week in the outpatient clinic for echocardiographic controls. Right heart catheterization was performed at intervals of 60 to 90 days. Figure 3
shows a routine chest X-ray of a patient waiting for elective heart transplantation, three months after hospital discharge.
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Statistics
All data were prospectively entered into the institutional database and transferred to SPSS 11.5 (SPSS Inc, Chicago, IL) for statistical analysis. Results are presented as mean values ± standard deviation. A p value less than 0.05 was considered statistically significant. The comparison of pulmonary vascular parameters over time was analyzed with the nonparametric Wilcoxon test because a normal distribution could not be assumed.
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Results |
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PAP, TPG, and PVR Prior to LVAD Implantation
All ten patients underwent placement of a nonpulsatile LVAD. At the time of LVAD placement, mean PAP in the patient group was 42 ± 13 mm Hg. The mean TPG was 20 ± 6 mm Hg and the PVR averaged 4.8 ± 1.8 WU.
Operative Outcome: LVAD Implantation
The LVAD implantation was carried out with no intraoperative complications in all 10 patients. Intraoperative and postoperative data are shown in Table 3. All patients had an uneventful early postoperative recovery, with no bleeding complications or acute right heart failure. Five patients were discharged home, provided with ambulatory care, and seen as outpatients once a week.
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Two patients suffered severe thromboembolic events while waiting for their donor organ, one of whom developed paraplegia after 90 days of mechanical support and eventually died in septic shock after mesenterial infarction; another patient sustained a lethal stroke four months after VAD implantation. Both patients had reached eligibility criteria for oHTx but had not been transplanted yet due to donor organ shortage. Systemic lyses therapy with recombinant tissue plasminogen activator was conducted in both patients as a last resort, but without success.
One patient experienced severe device malfunction due to thromboembolic events, repeatedly requiring systemic lyses therapy. Subsequently, he experienced an intracerebral bleeding and, because the patient’s PVR had been lowered to 3.5 WU, emergent heart transplantation was conducted as a last resort. Postoperatively, the patient developed right heart failure and died.
Orthotopic Heart Transplantation
Five patients underwent successful oHTx after PVR had declined below 2.5 WU. Figure 6
exemplifies the course of pulmonary vascular parameters in a patient who reached the target values within 30 days. Intraoperative and postoperative data are shown in Table 3. One patient died 44 days after heart transplantation in septic shock. One patient with dilative cardiomyopathy, who had underwent emergent device placement for acute low output, was successfully weaned off on day 97, after recovery from acute myocarditis. One patient is still on support.
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Comment |
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Taylor and colleagues reported, in the registry of the International Society for Heart and Lung Transplantation in 2004 [6], that there is a significantly better survival after transplantation in recipients with a PVR of 1 to 3 WU compared with recipients with a PVR of 3 to 5 WU, with a dismal outcome for recipients with a PVR higher than 5 WU. A PVR exceeding two thirds of the systemic pressure or a PVR above 6 to 8 WU, which is unresponsive to medical therapy, are considered contraindications to oHTx by most centers. However, the recommendations of national cardiothoracic societies differ with regard to the criteria for accepting patients for oHTx.
Pharmacologic testing of the reversibility of increased PVR and TPG is of paramount importance in differentiating between low-risk and high-risk heart transplant candidates [8, 20]. Various short-acting vasodilators, such as sodium nitroprusside, nitroglycerine, prostacyclin, adenosine, prostaglandin, milrinone, nesiritide, and hydralazine, can be utilized to test for reversibility of the secondary pulmonary hypertension [21–23].
However, high-dose therapy is often required and systemic vasodilatation is the main limitation to dose titration, particularly in marginally compensated patients in NYHA class IV with an ejection fraction less than 0.20 [22]. Inhaled nitric oxide (NO; in doses of 40 to 80 ppm) is a selective pulmonary vasodilator and has been used as an alternative to PGE1 [17, 24]. Its influence on cardiac contractility and concomitant systemic hypotensive effects, particularly in NYHA IV patients, remains controversial [9, 25]. Prostaglandin E1 is widely considered to be the most potent and efficient treatment for pulmonary hypertension, and protocols utilizing PGE1 have been shown to lower TPG and PVR more effectively than other drugs in patients with congestive heart failure [9, 21]. Therefore, at our institution PGE1/PGI2 protocols preferably have been used during the past decade.
Successful long-term treatment with prostaglandin and milrinone has also been reported [22]. The beneficial long-term effects of PGE1 are likely attributable to vascular remodeling [26]. Milrinone has sustained inotropic and vasodilator effects when administered intravenously [27]. These significantly less expensive options are used for stable patients in NYHA class III (or compensated NYHA IV patients not requiring inotropic support) at our institution. However, in patients with progressive, decompensated NYHA IV with inotropic support, it is our experience that highly potent long-term vasodilators can be a high-risk option.
All patients included in this study belong to the latter category, NYHA IV, on inotropic support; three of whom were decompensated emergency admissions. Each patient’s individual risk of long-term vasodilator treatment had been estimated higher than LVAD placement.
Initially, repeat right heart catheterization was performed in several LVAD patients and, when the first data became available confirming that the PVR drops with improving left ventricular function, 10 patients were enrolled in this pilot study. The first three patients had already been accepted as candidates for heart transplantation prior to being entered into the LVAD study, but subsequently, in view of the encouraging results, patients with pulmonary vascular parameters, which definitely contraindicated transplantation, were also accepted into the LVAD trial.
The observations were uniformly positive; all patients improved with regard to the relevant parameters. Accordingly, all patients were considered transplant candidates after repeat right heart catheterization at three months. However, there was variability in how much the pulmonary vascular parameters could be improved. Evaluating the success of the treatment has been complicated by the difficulty in defining an exact time one should allow for improvement, and the impossibility (as progress must really be monitored by cardiac catheterization and cannot be undertaken too frequently) to define a rate at which improvement should occur to provide hope of a good prognosis. In addition, a relationship between the outcome after LVAD implantation and the underlying etiology of the heart disease causing left ventricular failure could not be established in such a small study.
The underlying mechanisms as to how LVAD support reduces PVR and TPG in patients with secondary pulmonary hypertension are certainly complex and remain speculative. Unloading of the left ventricle alleviates left atrial pressure and decreases PCWP, inducing a decline in PAP. Relieved pulmonary congestion and improved pulmonary hemodynamics might reduce overproduction of intrinsic vasoconstrictors, triggered by shear stress.
There are three major pathways involved in abnormal proliferation and contraction of the smooth muscle cells of the pulmonary artery; the endothelin pathway (by endothelin receptor A), the nitric oxide pathway (by cGMP), and the prostacyclin pathway (by cAMP) [28].
The endothelin pathway is involved in the pathologic process of secondary pulmonary hypertension [29]. Endothelin plays an important role in the control of the pulmonary vascular tone by triggering vasoconstriction and proliferation. Long-term LVAD therapy has been suggested to improve neuroendocrine plasma level activity [30].
Pulsatile VADs have been successfully used in patients with pulmonary hypertension secondary to congestive heart failure, as reported in two large series; one by Gallagher and colleagues in 1991 [31] (Novacor, n = 16), and one by Smedira and colleagues in 1996 [32] (TCI HeartMate, n = 63). Limited experience exists with the paracorporeal Thoratec BiVAD (Thoratec Corp, Pleasanton, CA) (in 2003 [33], PVR in a patient with congenital heart disease from 12.2 to 3.1) and the Abiomed LVAD (ABIOMED, Danvers, MA) (Baldovinos and colleagues, in 2000 [34]; n = 7). Martin and colleagues [14] reported on the successful treatment of fixed pulmonary hypertension with pulsatile LVADs in a series of six patients; elevated PVRs (ranging from 4.4 to 6.5 WU) decreased significantly (to 0.8 to 3.6 WU) after a comparable support interval of three to six months (191 ± 86 days). These studies, and our experience with pulsatile devices, suggest that PVR can be lowered successfully with pulsatile devices within an interval of three to six months. A series on the use of axillary flow pumps to continuously decrease left ventricular filling pressures in contrast to pulsatile pumps has not yet been reported.
During the time of this study, we mainly used the BerlinHeart INCOR and the MicroMed DeBakey systems. Both are small continuous flow pumps. When intended for long-term use, the axillary flow pumps have some advantages over the pulsatile systems. They are significantly smaller then their pulsatile counterparts and thus less susceptible to infections (eg, pocket infections). Nonetheless, we use the pulsatile systems increasingly for emergency cases.
After successful oHTx, PVR and PAP appear to stay as low as after LVAD treatment, suggesting that LVAD therapy may accomplish an enduring normalization of pulmonary vascular tone. Therefore, the LVAD is a promising option for end-stage heart failure patients in NYHA class IV. However, it should not be forgotten that long-term LVAD support is associated with certain risks. Increasing experience almost completely eliminated perioperative bleeding and right heart failure [35, 19]. With the small axial flow pumps, infectious complications are increasingly rare. But in the long term, thromboembolism and bleeding may jeopardize patients’ recovery [36]. While bleeding is often associated with excessive anticoagulation or liberal use of pleural punctures and is therefore theoretically avoidable, transient ischemic attacks and strokes may develop despite so-called "optimal" anticoagulation. There is no consensus as of yet regarding optimal anticoagulation or the means to achieve it [35].
In conclusion, this small study illustrates that continuous long-term unloading of the left ventricle with a nonpulsatile LVAD can reverse medically unresponsive pulmonary hypertension and render patients eligible for oHTx. The pathomechanism that allows for this improvement and its relation to underlying heart disease and the time course of hemodynamic improvement, are not yet clear. In the absence of this understanding, LVAD treatment should be considered for any patient with end-stage heart disease on inotropic support, whose pulmonary hypertension is the main obstacle in consideration for heart transplantation.
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