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Brief Overview of Pharmacotherapy of Right Ventricular Failure in LVADs

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Roy Lee, PharmD, BCPS
Stanford Hospital and Clinics
Stanford, CA, USA

Until recently, patients with advanced heart failure had few options other than cardiac transplantation. With advances in left ventricular assist devices (LVAD), however, these patients now have a viable, long-term alternative with the HeartMate II and Heartware. Unfortunately, right ventricular failure (RVF) is a common complication following implantation of an LVAD and can be associated with increased morbidity and mortality. The incidence of RVF post-implantation has been reported to be between 20%-50% [1]. Risk factors include both patient characteristics and hemodynamic parameters, but definitive risk factors are unknown. Some risk factors may include gender, underlying disease state, increased central venous pressure (CVP), decreased right ventricular (RV) stroke work index, pulmonary hypertension, and signs of end organ damage [1].

Unlike left heart failure, which has been studied extensively and for which many pharmacologic therapeutic options are available, very few options with high quality of evidence exists for RVF. Additionally, no viable long-term right ventricular assist devices exist. Aggressively supporting the right ventricle post-operatively, therefore, is of paramount importance and is achieved by tailoring therapy to its suspected cause. When pharmacologic agents are used, their mechanisms and some aspects of pharmacokinetics should be understood to try and achieve a desired outcome. These agents typically modulate volume status, preload, afterload, inotropy, and rhythm.

Post-operatively, achieving optimal volume status is important and is accomplished mainly by diuretics (e.g. loop diuretics and thiazides) [2]. Underdiuresis is important to avoid, as an increase in preload and central venous pressure (CVP) can lead to RVF which can be difficult to recover from. Continuous infusion of loop diuretics, or a combination of diuretics may be required, especially if intermittent use of diuretics fails to achieve adequate response. Overdiruesis, on the other hand, will prevent adequate preload to the left ventricle, thereby, potentially causing left septum deviation and left ventricular collapse [2]. With this, not enough forward flow from the pump will be achieved and, in the case of the HeartMate II, may lead to a decrease in the PI (pulsatility index). In either case, both scenarios can lead to hemodynamic instability.

There is a dynamic interplay and interdependence between the LVAD and the RV. Successful filling of the left ventricle and LVAD (and, therefore, adequate flow and systemic circulation) also requires the right ventricle to match the LVAD flow. If the problem is increased RV afterload, as evidenced by increased pulmonary vascular resistance or pulmonary artery pressures, then a reduction in afterload on the RV can be achieved by methods that can include the use of inhaled nitric oxide, inhaled epoprostenol, oral sildenafil, nesiritide, or milrinone (which has the added benefit of increasing right-sided inotropy) [3]. (Note: Not all of these agents, nor all possible agents, will be discussed.)

Inhaled epoprostenol in the critically ill is an ideal agent, as it acts locally on the pulmonary vasculature without systemic vasodilation. Epoprostenol, also known as prostaglandin I2 or prostacyclin, activates adenylate cyclase by prostaglandin I receptor stimulation, resulting in the intracellular production of cyclic adenosine monophosphate (cAMP) in vascular smooth muscles and, therefore, vasodilation [4-5]. Originally approved as an intravenous (IV) medication for pulmonary arterial hypertension, it should not be given intravenously in the critically ill, as systemic hypotension will ensue leading to decreased RV perfusion and, thus, decreased RV contraction. Epoprostenol can be titrated rapidly as it has a very short half-life (plasma half-life of 3 minutes) and, unlike inhaled nitric oxide, is substantially cheaper, does not require dedicated equipment, and does not form toxic metabolites (e.g. methemoglobinemia) [4-5].

Milrinone, a phosphodiesterase type 3 inhibitor specific to cardiac and smooth muscle, leads to increased levels of cAMP and, therefore, increased cardiac contractility and vasodilation [6]. The beneficial effects come from increased right heart inotropy and decreased pulmonary vascular resistance (PVR) [7]. It is important to note, however, that milrinone has a particularly long half-life in patients with renal dysfunction and in those on dialysis (up to 20 hours in patients on CVVH) [8]. It should be used with extreme caution in these situations and the dose should be reduced. Additionally, it is important to note milrinone's effect on vascular resistance is not limited to the pulmonary vasculature, but also the systemic vasculature and additional agents may be required to maintain systemic vascular resistance. It is available as an IV medication.

Sildenafil (Revatio®) is an oral phosphodiesterase type 5 inhibitor of smooth muscles cells in the pulmonary vasculature that leads to increased levels of cyclic guanosine monophosphate (cGMP). This results in pulmonary vasculature relaxation and, to a lesser degree, relaxation of the systemic vasculature [9-11]. Although no dose adjustment is needed for renal dysfunction, sildenafil is metabolized hepatically via CYP3A4 (major) and CYP2C9 (minor) and close monitoring should be applied in patients who are started on other medications that inhibit these enzymes (e.g. azole antifungals and nondihydropyridine calcium channel blockers) [9]. Although oral tadalafil (Adcirca®) also falls in the same class as sildenafil and is metabolized by CYP3A4, its long half-life of ~15-35 hours (vs. ~4 hours for sildenafil) may not make it the most suitable candidate in the acute setting [12]. Onset of action for both drugs is expected within 1 hour and may be used to transition patients off inhaled or IV medications. Sildenafil can be used in cases of severe renal dysfunction or those requiring dialysis, while tadalafil is not recommended.

Nesiritide (Natrecor®) is a recombinant B-type natriuretic peptide of cardiac origin that causes an increased level of intracellular cGMP, resulting in vasodilatation and natriuresis [13]. It has been shown to produce a dose-dependent reduction in pulmonary capillary wedge pressure (PCWP) inas quickly as 15 minutes [14]. Unlike milrinone, nesiritide is not eliminated renally. Thus, accumulation of the drug and prolongation of its effects is not expected in patients with renal dysfunction. Unfortunately, questions remain regarding the safety of nesiritide. While initial studies in patients with left ventricular failure have shown improved hemodynamics and symptoms, other studies have suggested deterioration in renal function and mortality concerns [15-16]. Less information exists for patients with isolated RVF, though one retrospective study suggests a worsening of kidney function [17].

Finally, managing arrhythmias is important, as this can cause a decrease in right ventricular output and, therefore, cause a decrease in flow. Additionally, arrhythmias can lead to thromboembolic events. One common arrhythmia is atrial fibrillation, which can be managed pharmacologically (e.g. with amiodarone) or via electrical cardioversion. Acutely, beta-blockers will want to be avoided as they are negative inotropes and can depress right ventricular function.

Until more research and data becomes available, management of RVF must be tailored based on cause, understanding of drug mechanics, and the dynamic interplay between the LVAD and right ventricle. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


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