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    Abstract
   Introduction
   The Heartware LVAD
   Intraoperative TEE
    Specific Conside...
    Excluding Heartw...
    TEE in the Post-...
   Conclusion
    References
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Table of Contents
REVIEW ARTICLE  
Year : 2013  |  Volume : 16  |  Issue : 4  |  Page : 259-267
Management issues during HeartWare left ventricular assist device implantation and the role of transesophageal echocardiography


1 Department of Cardiothoracic Anaesthesia, Freeman Hospital, High Heaton, Newcastle Upon Tyne, NE7 7DN, United Kingdom
2 Department of Cardiothoracic Surgery, Freeman Hospital, High Heaton, Newcastle Upon Tyne, NE7 7DN, United Kingdom
3 Department of Cardiology, Freeman Hospital, High Heaton, Newcastle Upon Tyne, NE7 7DN, United Kingdom

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Date of Submission03-Dec-2012
Date of Acceptance18-Jul-2013
Date of Web Publication1-Oct-2013
 

   Abstract 

Left ventricular assist devices (LVAD) are increasingly used for mechanical circulatory support of patients with severe heart failure, primarily as a bridge to heart transplantation. Transesophageal echocardiography (TEE) plays a major role in the clinical decision making during insertion of the devices and in the post-operative management of these patients. The detection of structural and device-related mechanical abnormalities is critical for optimal functioning of assist device. In this review article, we describe the usefulness of TEE for optimal perioperative management of patients presenting for HeartWare LVAD insertion.

Keywords: HeartWare; Left ventricular assist device; Transesophageal echocardiography

How to cite this article:
Patangi SO, George A, Pauli H, O'Leary D, Roysam C, Butt T, Schueler S, Prabhu M, MacGowan G. Management issues during HeartWare left ventricular assist device implantation and the role of transesophageal echocardiography. Ann Card Anaesth 2013;16:259-67

How to cite this URL:
Patangi SO, George A, Pauli H, O'Leary D, Roysam C, Butt T, Schueler S, Prabhu M, MacGowan G. Management issues during HeartWare left ventricular assist device implantation and the role of transesophageal echocardiography. Ann Card Anaesth [serial online] 2013 [cited 2019 Oct 13];16:259-67. Available from: http://www.annals.in/text.asp?2013/16/4/259/119173



   Introduction Top


Heart failure affects 1-2% of the adult population in the United Kingdom and depending upon the severity of failure, its annual mortality ranges from 10% to 50%. Health-care for these patients costs £625 million every year to the National Health Service. [1] Heart transplantation remains the gold standard treatment for patients in advanced heart failure. However, due to donor limitation, there has been a 46% reduction in heart transplantation in the UK over the past 10 years. [2] Mechanical circulatory support is being used increasingly to treat patients with advanced heart failure. Since 1980s, the left ventricular assist devices (LVAD) have been used to provide a broad spectrum of support including short-, intermediate-or long-term support [3],[4] as a bridge to transplantation (BTT) [5] or recovery or as a destination therapy (DT). [6],[7] The randomized evaluation of mechanical assistance for the treatment of congestive heart failure trial demonstrated that the use of LVAD resulted in a clinically meaningful survival benefit and improved quality-of-life of patients with New York Heart Association Class IV heart failure. [7] Over the past few years, first-generation pulsatile flow pumps have been replaced by continuous flow second and third generation pumps. Because of these technological advances, long-term LVAD implantation is being used successfully as therapy in this group of patients. [8],[9],[10]


   The Heartware LVAD Top


The HeartWare LVAD is a third-generation continuous flow device that has been used for BTT in multiple centers world-wide. The outcomes in patients receiving this device have demonstrated its non-inferiority to other devices inserted during the same period. [9] The HeartWare LVAD consists of an implantable pump with an outflow graft, a driveline, an external controller and power source [Figure 1]a. The pump contains a single moving component, an impeller suspended in a chamber, allowing contact-free rotation. [11],[12],[13],[14] The HeartWare LVAD lies within the pericardial space and its integrated inflow cannula (IFC) is surgically placed in the left ventricle (LV). Blood flows from the LV, through the pump and exits through the outflow graft attached to the ascending aorta [11] [Figure 1]b.
Figure 1: (a) The HeartWare left ventricular assist devices pump, with an outflow graft and driveline, prior to implantation. (b) The intra-pericardial placement of the HeartWare device (reproduced with the manufacturer's permission)

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Echocardiography and other non-invasive imaging modalities can be used to assess cardiac structure and function in patients with LVADs. [15] Transesophageal echocardiography (TEE) is an important tool in the perioperative management of patients undergoing LVAD implantation. TEE can provide important information of pre-insertion abnormalities and evaluate the post-insertion function. [16],[17] TEE also provides unique insights into physical, physiologic and mechanical issues associated with the implantation of these devices. [18]


   Intraoperative TEE Top


A complete TEE examination should be performed before and after cardiopulmonary bypass (CPB) [Table 1] and [Table 2]. The objectives are to assess ventricular structure and function, valvular function and HeartWare LVAD function or dysfunction. [19] When the HeartWare LVAD pump flow is initiated, there is an expected secondary increase in blood flow through the right ventricle (RV). In the presence of a well-placed and functioning device, the function of the LV can be disregarded and the overall goal is to preserve and optimize RV function. To achieve this, TEE can diagnose and rule out septal defects, valvular pathology, inadequate device position and function and any deterioration in RV function.
Table 1: The pre CPB TEE checklist

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Table 2: The post-CPB TEE checklists

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   Specific Considerations Top


Patent foramen ovale

With the initiation of LVAD flow there is a remarkable fall in the LV and left atrial (LA) pressures, sometimes even below the right atrial (RA) pressures. [23] The presence of a PFO could lead to right-to-left shunting of blood causing systemic desaturation and a risk of paradoxical embolus. [24],[25] The presence of a PFO is relatively common. [26] Detecting a PFO is important as its repair would necessitate bicaval venous cannulation. The existence of a PFO is detected by agitated saline technique as well as color flow (CF) Doppler in the mid-esophageal (ME) bicaval view with the color gain turned down to the range of around 20-25 cm/s. Alternatively, the pulmonary artery may be manually occluded to simulate a drop in LA pressure and an increase in the pressure gradient across the inter-atrial septum prior to performing a bubble test. [27] When biventricular failure is present increased RA and LA pressures reduce the inter-atrial pressure gradient and may hinder PFO detection by both CF Doppler and agitated saline. In such cases, after LVAD insertion and LV unloading there is a decrease in LA pressure, which, in the presence of a maintained or increased RA pressure, may uncover an unsealed PFO. [28] The presence of a PFO must be excluded after discontinuing CPB and before decannulation. Traumatic atrial septal defects may also occur intra-operatively and produce profound hypoxemia on initiation of LVAD. [29] The degree of shunting across an atrial septal defect may be aggravated by chest closure, which in the presence of positive pressure ventilation, may cause an increase in RA pressure due to direct transmission of increased pleural pressures to the RA, a decrease in the effective compliance of the RV and a reduction in LV filling. [29],[30]

Aortic regurgitation

The HeartWare LVAD draws blood from the LV and ejects it at arterial pressure into the aorta, creating sub-physiologic LV pressures. The retrograde aorta to LV gradient is very high. Furthermore, during normal LVAD function, the aortic valve (AV) may remain permanently closed and thus endures this gradient constantly. The presence of AR increases the HeartWare LVAD preload and causes an increase in pump flow and a fall in systemic blood flow. TEE evaluation of AR before LVAD insertion can be difficult; in heart failure patients, the degree of AR may be underestimated due to increased LV end-diastolic pressures and low aortic diastolic pressures resulting in diminished transvalvular gradients. [31] Identification of severe and, possibly, moderate AR indicate the need for surgical replacement or repair of the valve. [32],[33] Suture-closure of the native AV is recommended in the presence of significant (moderate or severe) AR. The pressure half-time of the regurgitant jet measured in the deep transgastric long-axis view and the ratio of the width of the regurgitant jet to the diameter of the LV outflow tract (Perry Index > 25%), assessed in the ME long-axis view are used to assess the magnitude of AR. [34]

Aortic stenosis

Pre-operative AS is usually not critical to the LVAD recipients because systemic blood flow does not depend on antegrade flow through the AV. AS can occur during HeartWare LVAD support due to progressive thrombosis of the AV [35] and commissural fusion. [36] The presence of an AV prosthesis increases the risk of thrombosis and systemic thrombo-embolism as the valve may fibrose or endothelialize. To prevent this, the HeartWare LVAD pump speed should be lowered if permissible, to ensure that the valve opens intermittently, without compromising cardiac output. [33] During TEE, ME long-axis view is used to ensure that the AV opens during systole. Current agreement is that mechanical valves should not be used intra-operatively and if present, they should be substituted by a bioprosthesis or a patch closure. Even tissue valves may require over-sewing to prevent thromboembolism. [31],[37],[38]

Ascending aorta

The ascending aorta should be examined for the presence of aortic atheroma, calcification and aneurysmal dilatation. Atheroma with a thickness greater than 5 mm and/or protruding and/or mobile are associated with increased risk of cerebral embolic events during the cardiac surgery. [39],[40],[41] Epiaortic echocardiography can be used for better assessment of the ascending aorta, particularly when high grade lesions are found in the descending aorta. [42] The presence of an ascending aortic aneurysm requires aneurysm repair. In this case, during LVAD implantation, the HeartWare LVAD outflow cannula (OFC) is anastomosed to the ascending aortic graft.

Mitral regurgitation

MR is common in end stage heart failure. [43],[44] The insertion of a HeartWare LVAD leads to reduced LV size, improved coaptation of the mitral valve leaflets and possibly, a decrease in the pre-existing MR. [45] Persistent and significant MR after LVAD insertion may indicate inadequate LV decompression. The assessment of flow through LVAD by TEE is useful to optimize LVAD flow.

Mitral stenosis

Significant MS restricts the filling of the HeartWare LVAD and leads to low device output and, consequently, low cardiac output. RV failure can also occur due to increased pulmonary vascular resistance. If there is a significant MS, surgical intervention with either a mitral commissurotomy or mitral valve replacement may be required. [31]

Tricuspid regurgitation

Functional TR is relatively common in a patient with heart failure. [43] Adequate RV function is essential after LVAD insertion to optimize the device filling. The presence of significant post-operative TR can significantly contribute to RV dysfunction and the development of a low output state. TV mechanics are dependent upon the preload and afterload conditions of the RA, RV and RV contractility. [46] LVAD insertion produces unloading of the LV, a decrease in PA pressure and improvement in RV function; therefore, it could be expected that TR would be reduced after device insertion. [31],[16] An appreciable influence of LVAD flow settings on the degree of TR by shifting of the interventricular septum with the unloading of the LV can be observed. Excessively high flow settings through the devices can exacerbate TR by tethering and restriction of septal leaflet of TV and distortion of the tricuspid annulus. TEE evidence includes restricted motion of the septal leaflet of the TV with new and worsening eccentric TR. Relative RV overload and increased PA pressures can also contribute to worsening TR. TEE evidence includes a dilated RV with or without deterioration in systolic function. Once identified, the effect of these mechanisms is minimized by adjusting pump flow. This management is in addition to the measures utilized to optimize RV function including use of inotropes and pulmonary vasodilators. Such adjustment reduces TR and also improves RV function. Significant tricuspid annular dilation, without the presence of significant TR, is an important risk factor for the development of post-operative TR. [46] All these factors indicate the importance of a meticulous examination of the TV in the diagnosis of TR and in defining its mechanism before HeartWare LVAD insertion.

Pulmonary valve

Pulmonic insufficiency (PI) greater than moderate is an important finding in patients receiving HeartWare LVAD implantation. PI compromises RV function by volume overload. After separation from CPB, both inotropes and pulmonary vasodilators are used to optimize RV function. Significant PV stenosis (PS) is also a significant finding in HeartWare LVAD patients. PS causes RV pressure overload and may limit RV output.

RV function

RV dysfunction is a well-recognized complication after LVAD insertion. [47] Because the output of the native RV determines the preload of the HeartWare LVAD, [48] a decrease in RV function will reduce its output. An LVAD can have a beneficial effect on the RV by reducing afterload, [49] or a detrimental effect by increasing its preload [50] and/or by leftward shifting of the inter-ventricular septum and impairing its contractility. [51],[52] The ME RV inflow-outflow view and four-chamber view allow for the semi-quantitative assessment of RV function and dilation. This assessment is based on the visual appreciation of both longitudinal function; RV base (TV annulus) to apex motion and free-wall motion. [53] Quantitative analysis may also be performed and is desirable in the clinical setting. Measurements such as the global RV fractional area change, [54],[55] the regional fractional area change [52] and the maximum derivative of the RV pressure (dP/dt max) have been used to quantify systolic function. [56],[57] Of these, the global RV fractional area change is most often used and in patients undergoing LVAD implantation it is usually between 20% and 30%. [16] The TV inflow velocity profile has been used as a measure of RV diastolic function. There is no clear evidence that mechanical LV support affects RV diastolic performance. [58] The tricuspid annular plane systolic excursion (TAPSE) and visual estimates of RV function, [59] and severity of TR [60] have been used, apart from hemodynamic parameters, to predict RV failure after LVAD implantation. Measuring TAPSE, because of cursor alignment difficulty, is not always reliable using intra-operative TEE. [61]

LV function

Evaluation of LV function prior to LVAD insertion usually reveals a ventricle with severely impaired systolic function, often associated with a significant diastolic dysfunction. [62],[63],[64] Severe LV dysfunction increases the risk of apical thrombus formation. Apical thrombus, when present, is often located near the planned IFC insertion site. Thus, pre-CPB TEE examination of the LV for the presence of thrombus is essential. TEE views may foreshorten the LV apex. However, the ME four chamber and long-axis aortic views and the deep transgastric long-axis view may be used to assess the presence or absence of a thrombus.

De-airing the LVAD

Initially, the components of the HeartWare LVAD are flushed with saline and prepared for implantation. The implantation involves removing a core of the myocardium at LV apex to allow IFC implantation and an end-to-side anastomosis of the outflow graft to the ascending aorta. TEE is very useful for detecting the presence of air in the heart after LVAD placement. [65],[66],[67] Rigorous de-airing maneuvers are used to ensure complete de-airing and prevent systemic air embolism. The pulmonary vein vent is clamped and the ascending aorta vent is opened and the heart and the HeartWare LVAD are allowed to fill. The final sutures securing the outflow graft to the ascending aorta are not tightened and all saline and air in the device is allowed to come out from the outflow graft. Thereafter, the clamp is removed and the final graft sutures are tightened. The most common locations for air embolism are the right coronary artery and the innominate artery. [68] This may produce RV dysfunction or contribute to post-operative neurocognitive impairment. Three distinct intra-operative periods are relevant for air detection: From the conclusion of device anastomoses to release of the aortic clamp, from aortic clamp release to termination of CPB and from thereafter to the end of surgery. [67] To reduce the risks of air embolism, the LV cavity and the proximal ascending aorta at the site of the outflow graft anastomosis should be inspected in the ME four chamber and the aortic long-axis views. The ME aortic long-axis view allows observation of air efflux from the outflow graft and the presence of air in the ventral regions of the heart chambers, where bubbles usually collect. The ascending aortic vent should remain open until all visible air is removed. A sufficient quantity of air entering the RCA causes RV ischemia and manifest as RV dysfunction. The treatment consists of further de-airing, an adequate coronary perfusion pressure and resting the heart on CPB until RV contractility improves.

The interventricular septum and the AV

Once flow through the HeartWare LVAD is commenced, the aim is to achieve adequate flow based on the patient's body surface area at 2500-2700 rpm. A neutral position of the interventricular septum [Figure 2] indicates adequate LV filling. If the LV is not adequately decompressed after HeartWare LVAD implantation, a rightward septum shift can be seen and a suspicion of insufficient device ejection or cannula obstruction should be immediately raised. In contrast, a leftward septal shift may indicate excessive decompression due to high pump speed, or RV dysfunction. In completely supported patients (there is no LV ejection due to severe impairment) persistent closure of the AV and adequate cardiac output through the device is seen. In these circumstances, because of the blood stasis, HeartWare LVAD support has been associated with aortic root and LV apical thrombosis [Figure 3]. [15] The HeartWare LVAD flow should be adjusted to allow the AV to open every third cardiac cycle wherever tolerated.
Figure 2: A mid-esophageal four chamber view demonstrating a centrally-placed inflow cannula and a neutrally positioned interventricular septum (LA-left atrium, LV-left ventricle, IFC-inflow cannula)

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Figure 3: A transgastric two chamber view demonstrating a large left ventricle thrombus adjacent to the outflow cannula (IC-inflow cannula, LV-left ventricle)

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   Excluding Heartware LVAD Dysfunction Top


Cannula position

Immediately after CPB, the positions of the IFC and OFC, the blood flow pattern, velocity and the direction is assessed using color and spectral Doppler. [15] The HeartWare LVAD, should have consistently phasic, slightly pulsatile, low-velocity inflow and outflow patterns, with peak velocities < 2.0 m/s and typically < 1.5 m/s. The IFC can be interrogated in ME four chamber view, ME aortic long-axis view and deep trans-gastric long axis view. The cannula orifice should ideally be centrally placed in the apical cavity, not abutting on any wall [Figure 2]. In practice, however, the cannula is often angulated anteroseptally. This is usually not a problem in severely dilated ventricles. However, as the degree of angulation increases, the orifice of the cannula starts to become obstructed by the ventricular wall. Chest closure can exaggerate this anteroseptal angulation. CF Doppler is an important component of the examination. A properly aligned IFC should have laminar and unidirectional flow from the LA through the MV to the device [Figure 4]. Abnormally high velocity or turbulent flow suggest obstruction of the IFC, due to device thrombus or partial obstruction of the cannula by the ventricular wall. [15],[69] Continuous wave (CW) and pulsed wave (PW) Doppler are used for quantification of the blood flow velocity from the left atrium to the LV and through the IFC to the HeartWare LVAD. The Doppler beam should be aligned with the central axis of the cannula in a ME four-chamber or long axis view. Cases of IFC obstruction secondary to malposition, hypovolemia or cannula thrombus have been reported in VAD literature. [17],[70] The presence of turbulent flow is a criterion for an obstructed cannula. Intermittent interruptions of the usually continuous laminar flow into the IFC on CW and PW Doppler interrogation [17] or a peak velocity greater than 2.3 m/s [12] indicates IFC obstruction. The OFC is vizualised in ME long-axis view of the ascending aorta at the level of the right PA and usually show the OFC joining the ascending aorta. CF Doppler is used to identify the cannula position; thereafter, PW Doppler is used to assess the flow velocity [Figure 5] and [Figure 6]. Simulation studies have shown that flow patterns in the OFC are significantly affected by its angle of insertion into the native aorta. [71] Zones of flow recirculation and high shear stress on the aortic wall can be observed when the cannula is at a 90° angle with the ascending aorta, gradually decreasing in size with decreasing angle. Connecting the LVAD outflow conduit at a shallower angle to the proximal aorta produces fewer secondary flows. However, this inhibits the washing of the AV, which helps to reduce thrombus formation in the proximal aorta. Outflow graft distortion results in acceleration of Doppler velocities in the proximal graft compared with the values measured more distally. [17],[72] CF Doppler is characterized by a turbulent high-velocity flow at the cannula orifice with a clear flow convergence area. Cannula obstruction can be caused by obstruction of the cannula orifice [73] or intrinsic obstructing lesions (thrombus) [74] and result in increased CW and PW Doppler velocities at the site of obstruction. [17] Complete cannula obstruction cause loss of Doppler flow signals. [73] Cannula perforation is an unusual event. One case each of inflow and OFC perforation have been reported in a series of 68 LVAD patients. [75]
Figure 4: A mid-esophageal four chamber view with color flow Doppler to demonstrate laminar flow from the mitral valve towards the inflow cannula (LA-left atrium, LV-left ventricle, IFC-inflow cannula, Ao-aorta)

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Figure 5: A mid-esophageal ascending aortic long axis view with color flow Doppler interrogation of flow through the outflow cannula (RPA-right pulmonary artery, OFC-outflow cannula)

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Figure 6: A mid-esophageal ascending aortic long axis view with pulsed wave Doppler interrogation of flow through the outflow cannula

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Estimating flow through the LVAD is computed based on the electrical current, the pump speed and a fixed viscosity value (adjusted according to the patient's hematocrit). Using these parameters, a current-flow curve allows estimation of the instantaneous and average flow through the pump. [11] The flow is usually confirmed using a right heart catheter in the peri-operative period. In the absence of a right heart catheter, PW Doppler allows for the confirmation of HeartWare LVAD flow. PW Doppler of the RV outflow tract can be used to indirectly calculate device flow in LVADs providing partial circulatory support. [15],[76]

Aortic dissection

Aortic dissection can be caused during suturing of the outflow graft to the ascending aorta. There are reports of LVAD patients who have suffered fatal aortic dissection detected using TEE. [77] TEE is a sensitive and specific technique for the diagnosis of aortic dissection, [78] allowing for visualization of intimal flaps and tears, identification of true and false lumens and documentation of complications such as AR or pericardial effusion. [79] The presence of competing flow in the ascending aorta, anterograde flow from the trans-aortic output and retrograde from HeartWare LVAD, particularly in patients with the OFC anastomosed to the descending aorta, can lead to the suspicion of dissection. [80] TEE can detect the presence of an intimal tear and, using color and spectral echocardiography, it can examine the characteristics of flow in the ascending aorta. [80]


   TEE in the Post-Operative Care of Heartware LVAD Patients Top


Unexplained hemodynamic instability and suspicion of HeartWare LVAD dysfunction in the post-operative period often require TEE in order to confirm a diagnosis and particular attention should be paid to the following: [15]

Pericardial effusion with or without cardiac tamponade

Clinical signs of tamponade are often accompanied by warning alarms that indicate HeartWare LVAD dysfunction. Alarms are triggered when instantaneous flow drops 40% below the estimated baseline flow for 10 s. [11] This is accompanied by an increase in pump power. At a constant impeller rotational speed, the amount of blood flow through the pump is determined by the pressure differential across the pump. Motor current changes as the pressure differential changes. [11] In the presence of poor pump preload, the pressure differential increases dramatically, with a surge in power requirements. Transthoracic or TEE should be used to confirm the diagnosis.

RV failure

Outcomes in patients having a HeartWare LVAD implanted are critically dependent on RV function. The RV must provide sufficient flow through the pulmonary vasculature to fill the HeartWare LVAD and ensure optimal performance. [81],[82] In heart failure patients with chronic venous congestion, LVAD implantation may lead to a significant increase in venous return and RV overload, leading to an exacerbation of RV impairment or new RV impairment. TEE is a valuable aid for confirming postoperative RV failure and for monitoring the response to treatment. An increase in RV size, a reduction in RV systolic function and the presence of significant TR [59] may be demonstrated on TEE.

Inadequate LV filling

To prevent overfilling of the RV, patients after LVAD implantation are routinely managed with low filling pressures. Diuretics and/or ultra-filtration are used throughout the peri-operative period to reduce filling pressures. In excess, this may lead to inadequate LV filling and reduced HeartWare LVAD flows, triggering alarms similar to those seen during suspected cardiac tamponade. On TEE examination, a small and under-filled LV cavity will be evident.

HeartWare LVAD induced ventricular tachycardia or ectopy

An under-filled LV may lead to abutting of the IFC on the LV septum which may precipitate ventricular tachycardia or ectopy. Volume resuscitation can reduce the incidence of arrhythmias.

Intracardiac thrombus

Blood stasis related to prolonged AV closure may lead to thrombus formation in the aortic root and the LV apex. Thrombus may also form in both atria. [15]

Cannula obstruction

LV thrombus, pump thrombus and outflow graft thrombus may all cause partial or complete flow obstruction through the HeartWare LVAD. Color and spectral Doppler interrogation of both cannulae as described earlier is required if there is a clinical suspicion of obstruction.


   Conclusion Top


HeartWare implantation is increasingly used in patients with terminal heart failure as a BTT, for recovery and as DT. TEE plays an important role in evaluating the peri-operative structure and function related to patient's heart and large vessels and to the implanted device. The pre-HeartWare implantation examination of the heart and large vessels addresses the structural and functional factors relevant to anesthetic and surgical management including AR, TR, MS, PFO and other cardiac abnormalities that could lead to right-to-left shunt after LVAD placement. The post-HeartWare implantation examination addresses device function and reassessment of the heart and large vessels. The examination of the device aims to confirm heart de-airing, cannula alignment and patency and the competency of heart valves using 2D and color and spectral Doppler echocardiography. The examination of the heart is targeted to exclude AR or an undetected right-to left shunt and to assess RV function, LV unloading and the effect of device settings on global heart function. Performance of an echocardiographic assessment firmly based on the principles detailed in this review can optimize peri-operative clinical management and provide information for objective decision-making in patients receiving HeartWare LVADs.

 
   References Top

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Correspondence Address:
Anthony George
Freeman Hospital, Freeman Road, High Heaton, Newcastle Upon Tyne NE7 7DN
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DOI: 10.4103/0971-9784.119173

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