TITLE:
AUTHOR:
Institution:
Care of the End-Stage Heart Disease Patient: Drugs to Devices
Robert N. Sladen, MBChB, FCCM
Columbia University Medical Center, New York, NY
Learning Objectives:
1. Discuss the latest medical therapies in the care of the critically ill patient with end-stage heart
disease
2. Review management of critically ill patients who require mechanical circulatory support, including
ventricular assist devices and extracorporeal membrane oxygenation.
Medical Therapy for End-Stage Heart Disease
Medical Therapy for End-stage Heart Disease (EHSD)
Patients with ESHD have reached New York Heart Association (NYHA) Stage III (dyspnea
with personal activities) and IV (dyspnea at rest).
Systolic heart failure is the dominant form of ESHD, with progressive loss of cardiac
contractility. Maintenance therapy includes afterload reduction with angiotensin converting enzyme
(ACE) inhibitors (e.g. lisinopril) or angiotensin receptor blockers (e.g. losartan); and careful
combined beta- and alpha blockade (e.g. carvedilol) with or without oral inotropic agents (digoxin).
Diuresis is provided by a combination of aldosterone antagonists (e.g. spironolactone), loop diuretics
(e.g. furosemide, bumetanide, torsemide) and/or thiazide diuretics.
Diastolic heart failure is characterized by impaired ventricular relaxation and abnormal
filling, and its management emphasizes beta-blockade (e.g. metoprolol), maintenance of intravascular
volume, and avoidance of inotropic, chronotropic or vasodilator agents.
About a third of patients with ESHD develop cardiac dyssynchrony, manifested by prolonged
QRS (> 120 msec) on ECG. The condition should be renamed pan-dyssynchrony because it affects
interatrial, interventricular and atrio-ventricular interaction, impedes reparative remodeling after
myocardial infarction, and exacerbates symptoms and mortality of ESHD. Cardiac resynchronization
therapy (CRT) involves placement of atrial, right ventricular (RV) and left ventricular (LV) leads,
with atrio-biventricular pacing that restores sequential and synchronous contraction of all chambers 1.
There is strong evidence that CRT can improve cardiac function, exercise tolerance and mortality 2,
although it is less effective when RV failure is present 3.
A subset of patients with ESHD will develop advanced decompensated heart failure (ADHF)
despite optimal medical therapy with or without CRT, and require surgical intervention and
mechanical circulatory support.
Inodilator Therapy for Systolic Heart Failure
Inodilator therapy has the advantage or simultaneously providing inotropic support and
afterload reduction. Drugs used most often include milrinone, a phosphodiesterase (PDE) III
inhibitor, and dobutamine, a direct acting beta-1 and beta-2 agonist. PDE III inhibition decreases
breakdown of cyclic adenosine monophosphate (cAMP), while beta-1 and -2 stimulation increases its
production. The net effect is cardiac muscle contraction and vascular smooth muscle relaxation.
Milrinone’s vasodilator effects on blood pressure may require concomitant vasopressor therapy with
norepinephrine (NE), epinephrine (EPI) and arginine vasopressin (AVP). Dobutamine preserves
blood pressure but its chronotropic and bathmotropic effects promote arrhythmias. Combining a PDE
inhibitor with a beta-adrenergic agonist provides superior enhancement of RV stroke volume (SV)
than either drug used alone4, and allows much lower dosage of each drug, with fewer side effects.
Levosimendan, a potent inodilator not currently available in the USA, acts independently of
the beta receptor or cAMP by stabilization of the troponin C-calcium complex in myofibrils,
strengthening the actin-myosin cross bond5. It does not increase intracellular calcium or myocardial
oxygen demand. Levosimendan may have a more sustained benefit on postoperative stroke volume
(SV) than milrinone and require less NE vasoconstrictor support6. In patients with low EF, the
combination of levosimendan with dobutamine is more effective in improving SV than milrinone plus
dobutamine. There is preliminary evidence that levosimendan may improve renal function after
cardiac surgery, but not mortality7. Levosimendan undergoes biotransformation to an active
metabolite (OR-1896) that exerts potent effects for up to a week, so it is not infused for more than 24
hrs, and there may be a benefit to starting the infusion 48 hrs before surgery.
Vasodilator Therapy for Systolic Heart Failure
Nesiritide is the recombinant form of B-type natriuretic peptide (BNP), whose synthesis in
the ventricles is stimulated by increased wall stress. BNP promotes arterial and venous dilation (i.e.
afterload and preload reduction), renal natriuresis, and suppression of the renin-angiotensinaldosterone (RAAS) and sympathetic nervous system. In 2001 nesiritide was approved in the USA
(but not Europe) for the treatment of ADHF. However, in a recently published randomized controlled
trial (RCT) on more than 7000 patients, nesiritide infusion slightly improved dyspnea but did not
significantly affect urine output, readmission or survival8. The drug is very expensive and its use in
the OR and ICU is limited.
Istaroxime is a novel agent that enhances intramyocardial calcium metabolism to promote
diastolic relaxation and systolic contraction (lusi-inotropic effect), while decreasing filling pressures
and heart rate9. It does so by stimulating sarcoplasmic-endoplasmic reticulum calcium adenosine
triphosphatase-2a (SERCA-2a) and inhibiting sodium-potassium adenosine triphosphatase (a digoxinlike effect)10. It is currently undergoing clinical trials.
Mechanical Circulatory Support
Extracorporeal Membrane Oxygenation (ECMO)
Veno-arterial (VA) ECMO is analogous to cardiopulmonary bypass (CPB), in which the
function of the heart is replaced or supplemented by the ECMO pump, with our without lung
replacement. VA-ECMO is primarily indicated as rescue therapy in cardiogenic shock, as a bridge to
recovery – or more often, bridge to a decision. It supports circulatory resuscitation, stabilization and
assessment of neurologic status, as well as evaluation of myocardial recovery or candidacy for
insertion of a ventricular assist device (VAD)11, 12.
For many years the risks of VA-ECMO were similar to CPB, and in the ICU necessitated the
full time presence of a perfusionist at the bedside. However in recent years there has been remarkable
miniaturization and improvement in safety, with the development of a poly-methylpentene (PMP)
membrane oxygenator (Quadrox D). This is very small and portable, driven by a centrifugal pump,
and avoids the plasma leakage associated with conventional standard hollow-fiber oxygenators. This
markedly decreases the risk of thrombogenesis, thrombocytopenia, disseminated intravascular
coagulation (DIC), bleeding and blood and blood product transfusion.
Central VA-ECMO is placed only in the OR, when there is failure to wean off CPB. It
involves venous cannulation of the atria or superior vena cava, and arterial cannulation of the aorta.
Large diameter tubing enables high flows with good anterograde supply of oxygenated blood to the
heart and brain. However, the sternum has to be left open, so within 24-48 hrs the patient either has
to recover sufficiently to be weaned off ECMO, or transitioned to another modality (peripheral
ECMO or CentriMag – see below).
Peripheral VA-ECMO can be done relatively quickly in the catheterization lab, OR, ICU or
emergency department, utilizing femoral vein and femoral arterial cannulas. However, oxygenated
blood must be pumped retrograde up the aorta to reach the heart and brain, which may be a problem if
there is concomitant acute lung injury. Additional veno-venous circuits to the upper vasculature can
ameliorate this situation13. Distal leg ischemia is always a potential threat and may necessitate
placement of a reperfusion catheter adjacent to the arterial cannula or in the posterior popliteal
artery14.
Despite the enhanced equipment now available, VA-ECMO is an expensive, complex,
resource-intensive modality that requires considerable expertise. The Quadrox oxygenator is quite
thrombus tolerant and anticoagulation can be safely deferred until there is no further concern for
postoperative bleeding, but ultimately full systemic anticoagulation is required to prevent contact
activation-induced thrombosis. Risks of major bleeding, coagulopathy, thromboembolism, stroke,
sepsis, and multisystem failure remain in these very sick patients, and mortality remains 55-65% 15.
The Ventricular Assist Device (VAD)
Indications
The VAD may be placed as a (1) bridge to decision - a rescue intervention during a lifethreatening crisis to provide support until a decision can be made regarding further definitive therapy;
(2) bridge to a bridge - a short-term rescue device that is emergently placed to provide support until a
longer-term, larger device can be placed; (3) bridge to recovery – to provide life-saving support
during an acute crisis, until the ventricle recovers and the patient can be weaned off the VAD; (4)
bridge to transplant (BTT) - at least 50% of patients awaiting heart transplant die on the waiting list;
and (5) destination therapy (DT) - for patients with ESHD who are not candidates for heart
transplantation.
The VAD may be placed to support the left ventricle (LVAD), right ventricle (RVAD), or
both ventricles (BiVAD).
Key Management Considerations
Correction of Cardiac Abnormalities
Key structural abnormalities must be corrected at the time of VAD implantation. Patent
foramen ovale, atrial and ventricular septal defects must be closed to avoid the development of a left
to right shunt when the left atrium (LA) and LV are decompressed by the LVAD. Severe tricuspid
regurgitation (RV dysfunction), aortic regurgitation (recirculation) and mitral regurgitation should be
repaired. Mitral stenosis must be corrected to facilitate ventricular (and VAD) filling from the LA.
Pulmonary Vascular Resistance (PVR) and RV Support
Delivery of blood from the RV to the LA is compromised by elevated PVR, impairing LVAD
filling and output. Elevated PVR contributes to right heart failure (RHF) in the unassisted RV, and
when an RVAD is in place, elevates right atrial pressure (RAP).
Maintenance of effective RV function is essential to ensuring good outcome after LVAD
placement16. RHF may occur in up to 40% of patients receiving an LVAD 17. It is associated with
reoperation for bleeding, postoperative acute kidney injury (AKI), increased ICU length of stay
(LOS), impaired LVAD success as BTT, and early mortality. About a third of the patients with RHF
ultimately require an RVAD.
The principles of the management of RV function16 include (1) maintenance of RV coronary
perfusion pressure (using vasopressors appropriately); (2) avoidance of RV overload (controlling
RAP); (3) pulmonary vasodilation to decrease elevated PVR and RV afterload (inhaled nitric oxide
and prostacyclins); and (4) inodilator therapy (milrinone and/or dobutamine).
2nd and 3rd generation LVADs provide non-pulsatile flow, and maintain a parallel circuit of
flow out of the native aorta. Excessive pump rates may cause the LV volume to fall, which induces
leftward septal shift and RV dyskinesis. This may be revealed on transesophageal echocardiography
(TEE) by conversion of the short-axis round LV to a “D”-shape induced by the flattened or convex
intraventricular septum16. Excessive LV emptying may result in a devastating “suction event” caused
by obstruction of the inflow port18.
Short-Term (Bridging) VADs
The Thoratec CentriMag, introduced in 2007, is an external, short-term, magnetically
levitated centrifugal pump utilized as an LVAD (LA to aorta), RVAD (RA to pulmonary artery) or
BiVAD19. The small cannulas (7 mm) facilitate rapid placement. A bedside console displays rpm
and ultrasound-sensed flow rate. A membrane oxygenator is easily placed in the RVAD circuit to
support acute lung injury20. Cannula vibration or “chatter” may reveal hypovolemia or excessive
ventricular emptying, although it may also be induced by return of ventricular contractility. The
CentriMag LVAD is FDA-approved for 6 hr only, and the RVAD for 30 days, but in our practice and
others the devices are left in place for considerably longer21. Since its introduction in 2007, the
CentriMag has become the predominant short-term VAD for bridge to decision, bridge to a bridge or
even short-term BTT.
Long-Term VADS (BTT or DT)
1st Generation: Pulsatile Flow
The Thoratec HeartMate XVE launched the VAD era and dominated the industry from 1994
through 2005. It served primarily as BTT, but in 2001 the REMATCH study demonstrated doubled
survival compared to maximal medical therapy and introduced the concept of DT22.
The pump was placed in preperitoneal abdominal pocket with porcine valved conduits from
the LV apex (inflow) and out to the ascending aorta (outflow). The HeartMate XVE maintained
pulsatile flow and the septal contribution to RV function, and generated a palpable pulse and cuffmeasurable blood pressure. It set up a circuit in series with the LV, emptying the entire LV stroke
volume (SV) and ejecting it above the aortic valve (AV), which became redundant and could be sewn
closed if diseased. The textured polyurethane lining became endothelialized, greatly reducing
thrombogenesis and requirement for anticoagulation.
However, the HeartMate XVE had numerous limitations that have rendered it obsolete today.
It was extremely noisy; its large size precluded placement in children or small adults, caused gastric
compression and its preperitoneal pocket provided a constant nidus for infection. The new
endothelial lining expressed abnormal antigens that increased the risk of antibody formation and
rejection with a subsequent heart transplant. Ultimately the porcine valves broke down, limiting the
LVAD’s expected life to 1-2 years at best.
Thoratec also produced a pulsatile external device called the PVAD (paracorporeal VAD), a
fist-sized pneumatic pump that lay on the patient’s abdomen and could provide LVAD, RVAD and
BiVAD support for in-hospital BTT or in conjunction with an internal LVAD to provide short or
longer term RV support. The company later created subcutaneous pumps (IVAD, intracorporeal
VAD) with a smaller, portable console that allowed out-patient use as BTT or DT. This device is also
virtually obsolete.
2nd Generation VADs: Continuous Axial Flow
The Thoratec HeartMate® II is a pencil-like impeller pump that rotates at 8000-10000 rpm
and creates axial flow within a long term internal LVAD. It is less than a quarter of the size of the
XVE, requires a small LVAD pocket, does not cause gastric compression, is much quieter, with fewer
moving parts and much greater longevity, 7 yrs or more. It is FDA approved for both BTT and DT.
The physiology of the HeartMate II and other continuous flow LVADs is complex. Although
most blood entering the LV exits through the LVAD, a variable amount is ejected via the native aorta;
thus, the LVAD circuit is in parallel with the native circuit, and the AV must be preserved, or
repaired or replaced if diseased. For the most part flow is non-pulsatile, so cuff BP measurement
requires Doppler assessment. Because outflow from the device is continuous, excessive LVAD rpm
(or severe hypovolemia) may cause the LV chamber to collapse, displace the intraventricular septum
and acutely compromise RV function (a “suction event”)18.
The LV distensibility (an indirect index of filling) is indicated on the HeartMate II monitor by
a unit-less parameter called the pulsatility index (PI), ideally kept 4.0-6.0. Pump flow is calculated
(not measured) based on the power (wattage) and rpm; at the extremes of flow it is subject to error
and may indicate “normal” flow in low flow states such as cardiac tamponade16.
Patients must be fully anticoagulated, and in the last two years there has been increasing
concern with a relatively high incidence of device thrombosis and associated thromboembolism.
Nonetheless, compared to the XVE, the HeartMate II provides significantly greater two year survival
(58% vs. 24%) and freedom from disabling stroke or device malfunction (46% vs. 11%)23.
The Jarvik 2000 is a miniaturized titanium axial flow device that is placed directly into the
apex of the LV (inflow), with an efferent conduit placed either into the ascending or descending
aorta24. The driveline is threaded within the thoracic cavity to emerge at an occipital retro-auricular
skull-mounted pedestal, which decreases the risk of VAD pocket infection and increases patient
mobility25. The Jarvik 2000 controller is extremely simple, consisting of a wattmeter and an rpm
setting adjustable by the patient between 8000-12000 rpm. Every minute the device decreases its
output for 8 sec to allow aortic ejection and maintain AV function and minimize thrombus formation.
The main limitation of the Jarvik 2000 is its peak outflow, about 7L/min, so it is suited for smaller
patients or those with greater intrinsic LV function. In the USA, it is currently undergoing trials as
DT.
3rd Generation VADs: Continuous Centrifugal Flow
The HeartWare® HVADTM is a miniaturized centrifugal device in which the inflow cannula is
cored directly into the LV apex so that, like the Jarvik 2000, the device is intrapericardial and entirely
above the diaphragm26. It has a small driveline that is exteriorized and attached to small portable
battery packs. A major advance is that through magnetic or hydrodynamic levitation there is no
contact between the impeller and the drive mechanism and minimal contact with the blood. The
impeller rotates centrifugally more slowly than the rotary devices, at 2750-3000 rpm. The advantages
claimed are decreased hemolysis and thrombogenesis, and greater mechanical durability. The
HVADTM is approved in the EU and USA as BTT, and its use has been associated with a 91% 6month survival and 84% one-year survival27.
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