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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

ISHLT consensus statement for the selection and management of pediatric and congenital heart disease patients on ventricular assist devices Endorsed by the American Heart Association

      Background

      Heart failure (HF) is a significant cause of mortality in children and therefore there is interest in understanding the optimal way to support these children with Ventricular Assist Devices (VAD) to improve outcomes. VAD therapy is now regarded as an important treatment option in pediatric HF. The 2019 International Society for Heart and Lung Transplantation (ISHLT) registry report shows that there is an increasing trend towards using VADs as a bridge to transplant (BTT) with currently over one-third of patients transplanted being bridged with a VAD.
      The immediate aim of VAD therapy is to provide hemodynamic stability for a failing circulation unresponsive to medical therapy. The VAD should be implanted before the development of severe end-organ dysfunction in order to optimize clinical outcomes. The goal is to improve tissue and organ perfusion, improve quality of life (QoL) and improve waitlist survival. Importantly, VAD therapy may not only lead to patient stability but may also afford the opportunity for patient rehabilitation prior to heart transplantation (HT).
      Despite the increase in VAD use within pediatrics over the last decade, the majority of centers implant less than 10 VADs in children per year.
      • Blume ED
      • Rosenthal DN
      • Rossano JW
      • et al.
      Outcomes of children implanted with ventricular assist devices in the United States: first analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      Thus, local data is limited for analysis of outcomes and therefore multi-center collaboration and consensus is essential in understanding this complex and dynamic field.
      ISHLT has recognized the importance of a consensus statement on the selection and management of pediatric and congenital heart disease (CHD) patients undergoing VAD implantation. The purpose of this document is to provide expert-consensus derived recommendations and whenever possible, these recommendations shall be guided by evidence. The creation of this consensus document required multiples steps including the engagement of the ISHLT councils, identification and selection of experts in the field, and the development of 13 Tasks Forces. Extensive literature searches were performed but due to the lack of comparative trials in pediatrics, this document was written as a literature review with expert opinion rather than based on level of evidence.

      Patient selection

      Timing of VAD

      Optimal timing for the implantation of a VAD in pediatric patients should be determined by an assessment of the potential risks and benefits of the intervention. The complexity of this decision-making is amplified by the numerous variables impacting VAD risk profile, including patient age/size,
      • Conway J
      • St Louis J
      • Morales DL
      • Law S
      • Tjossem C
      • Humpl T
      Delineating survival outcomes in children <10 kg bridged to transplant or recovery with the Berlin Heart EXCOR Ventricular Assist Device.
      • Miera O
      • Morales DLS
      • Thul J
      • Amodeo A
      • Menon AK
      • Humpl T.
      Improvement of survival in low-weight children on the Berlin Heart EXCOR ventricular assist device supportdagger.
      • Law SP
      • Oron AP
      • Kemna MS
      • et al.
      Comparison of transplant waitlist outcomes for pediatric candidates supported by ventricular assist devices versus medical therapy.
      anatomy,
      • Peng DM
      • Koehl DA
      • Cantor RS
      • et al.
      Outcomes of children with congenital heart disease implanted with ventricular assist devices: an analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs).
      • Morales DLS
      • Zafar F
      • Almond CS
      • et al.
      Berlin Heart EXCOR use in patients with congenital heart disease.
      • Dipchand AI
      • Kirk R
      • Naftel DC
      • et al.
      Kirklin JK and pediatric heart transplant study I. Ventricular assist device support as a bridge to transplantation in pediatric patients.
      developmental hemostasis,
      • Attard C
      • van der Straaten T
      • Karlaftis V
      • Monagle P
      • Ignjatovic V.
      Developmental hemostasis: age-specific differences in the levels of hemostatic proteins.
      and device type,
      • Rossano JW
      • Lorts A
      • VanderPluym CJ
      • et al.
      Outcomes of pediatric patients supported with continuous-flow ventricular assist devices: a report from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      • Blume ED
      • VanderPluym C
      • Lorts A
      • et al.
      Second annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      as well as factors related to illness severity and comorbidities prior to implantation.
      • Morales DLS
      • Zafar F
      • Almond CS
      • et al.
      Berlin Heart EXCOR use in patients with congenital heart disease.
      ,
      • Blume ED
      • VanderPluym C
      • Lorts A
      • et al.
      Second annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      ,
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      Many of these factors are interdependent. Paracorporeal devices are most often placed in younger, smaller patients who are more likely to be sicker, have CHD, and end-organ dysfunction at the time of VAD implantation, making it difficult to assess which of these factors drives inferior outcomes.
      • Blume ED
      • VanderPluym C
      • Lorts A
      • et al.
      Second annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      • Butto A
      • Teele SA
      • Sleeper LA
      • et al.
      The impact of pre-implant illness severity on the outcomes of pediatric patients undergoing durable ventricular assist device.
      While this complex reality precludes the formulation of any generalizable guidelines for the optimal timing of VAD placement for all pediatric patients, one consistent theme to emerge from the literature is the inferior outcomes of VAD support for pediatric patients in cardiogenic shock (INTERMACS Profile 1) or with end-organ dysfunction prior to implant.
      • Blume ED
      • VanderPluym C
      • Lorts A
      • et al.
      Second annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      ,
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      ,
      • Almond CS
      • Morales DL
      • Blackstone EH
      • et al.
      Berlin Heart EXCOR pediatric ventricular assist device for bridge to heart transplantation in US children.
      (Figure 1) Despite these data, the most recent Pedimacs report reveals that 33% of patients are still INTERMACS Profile 1 at the time of implant, including 40% of patients receiving paracorporeal pulsatile devices, 49% of patients receiving paracorporeal continuous flow devices, and 19 % of patients receiving intracorporeal continuous flow devices .
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      Similarly, the last Paedi-Euromacs report showed that 21% of patients were implanted as INTERMACS Profile 1.
      • de By T
      • Antonides CFJ
      • Schweiger M
      • et al.
      The European Registry for Patients with Mechanical Circulatory Support (EUROMACS): second EUROMACS Paediatric (Paedi-EUROMACS) report.
      Figure 1:
      Figure 1Survival curves from 3rd Annual Pedimacs report.
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      Although, patients have better outcomes if implanted before they become too ill, there are times when pediatric patient present in cardiogenic shock and/or with end-organ injury. In these cases, attempting to reverse the shock process before implantation of a durable VAD may possibly result in better outcomes. The role of paracorporeal continuous flow (CF) and percutaneous VADs, or venoarterial extracorporeal membrane oxygenation (ECMO) in stabilizing/salvaging critically ill pediatric patients with advanced HF to make them better candidates for long term support is not well understood to date. There is evidence that end-organ dysfunction in children can improve significantly with a paracorporeal CF device and this may have a beneficial effect on outcomes.
      • Friedland-Little JM
      • Hong BJ
      • Gossett JG
      • et al.
      Changes in renal function after left ventricular assist device placement in pediatric patients: a pedimacs analysis.
      ,
      • Adachi I
      • Khan MS
      • Guzman-Pruneda FA
      • et al.
      Evolution and impact of ventricular assist device program on children awaiting heart transplantation.
      ,
      • Grimm JC
      • Magruder JT
      • Do N
      • et al.
      Modified Model for End-Stage Liver Disease eXcluding INR (MELD-XI) score predicts early death after pediatric heart transplantation.
      ECMO support prior to VAD implantation has not been associated with better survival post VAD,
      • Dipchand AI
      • Kirk R
      • Naftel DC
      • et al.
      Kirklin JK and pediatric heart transplant study I. Ventricular assist device support as a bridge to transplantation in pediatric patients.
      ,
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      although it is difficult to separate the impact of ECMO from the level of illness requiring ECMO in interpreting this data.

      Indications for VAD

      Failure of medical management: In many cases, medical management does allow stabilization of patients with HF. In some cases, HF progresses and VAD therapy is the only option for stabilization. Progressive respiratory (requiring non-invasive and invasive support) decompensation, liver dysfunction, kidney injury and feeding intolerance are commonly reported measures of congestion and/or inadequate cardiac output (CO) that may develop despite optimal medical management. End-organ dysfunction is common in pediatric VAD patients prior to implantation, with 45% of patients intubated (paracorporeal devices 75-85% of patients compared to intracorporeal devices 21%), 94% on inotropes, 64% requiring feeding tubes/TPN, 40% with hyperbilirubinemia and 30% having a glomerular filtration rate (GFR) < 60 mL • min−1 •1.73 m.
      • Blume ED
      • Rosenthal DN
      • Rossano JW
      • et al.
      Outcomes of children implanted with ventricular assist devices in the United States: first analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      ,
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      These findings are notable given end-organ dysfunction is associated with poor outcomes among VAD patients and following transplantation
      • Conway J
      • St Louis J
      • Morales DL
      • Law S
      • Tjossem C
      • Humpl T
      Delineating survival outcomes in children <10 kg bridged to transplant or recovery with the Berlin Heart EXCOR Ventricular Assist Device.
      ,
      • Morales DLS
      • Zafar F
      • Almond CS
      • et al.
      Berlin Heart EXCOR use in patients with congenital heart disease.
      ,
      • Almond CS
      • Morales DL
      • Blackstone EH
      • et al.
      Berlin Heart EXCOR pediatric ventricular assist device for bridge to heart transplantation in US children.
      ,
      • Grimm JC
      • Magruder JT
      • Do N
      • et al.
      Modified Model for End-Stage Liver Disease eXcluding INR (MELD-XI) score predicts early death after pediatric heart transplantation.
      and timely implantation can result in reversal of end-organ dysfunction and better outcomes.
      • Friedland-Little JM
      • Hong BJ
      • Gossett JG
      • et al.
      Changes in renal function after left ventricular assist device placement in pediatric patients: a pedimacs analysis.
      ,
      • May LJ
      • Montez-Rath ME
      • Yeh J
      • et al.
      Impact of ventricular assist device placement on longitudinal renal function in children with end-stage heart failure.
      Post-cardiotomy failure to wean from cardiopulmonary bypass (CPB): The presence of a previous sternotomy or additional cardiac surgery in pediatric VAD patients ranges from 23% to 39%.
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      ,
      • Conway J
      • Miera O
      • Adachi I
      • et al.
      Worldwide experience of a durable centrifugal flow pump in pediatric patients.
      Post-cardiotomy patients (in most circumstances those with CHD), who fail to wean from cardiopulmonary bypass (CPB) are more likely to be converted to ECMO or implanted with paracorporeal CF devices. With respect to the use of more durable VADs, failure to wean from CPB or decompensation during the index hospitalization after cardiac surgery is a significant risk factor for mortality among patients supported with a EXCOR.
      • Morales DLS
      • Zafar F
      • Almond CS
      • et al.
      Berlin Heart EXCOR use in patients with congenital heart disease.
      Uncontrollable Arrhythmias: Cardiogenic shock from uncontrolled tachyarrhythmia is rare and most of the literature pertaining to mechanical circulatory support (MCS) involves case reports and the use of ECMO. VAD support was deemed necessary in 10% (n = 39) of patients in the only multicenter retrospective review
      • Silva JN
      • Erickson CC
      • Carter CD
      • et al.
      Participating Members of P and Congenital Electrophysiology S. Management of pediatric tachyarrhythmias on mechanical support.
      of pediatric patients with arrhythmias.

      Intent of VAD

      The primary indication for pediatric VAD use in North America remains BTT, with 55% of patients listed at time of implantation and 34% being assessed for candidacy.
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      Additional, implantation strategies include bridge to recovery (BTR) (6%), and destination/chronic therapy (DT) (2%) and other (3%).
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      Similar frequency of intent has also been recently reported in the second Paedi-EUROMACS report with 85% of patients implanted with an intention to transplant with 56% BTT and possible BTT 29%.
      • de By T
      • Antonides CFJ
      • Schweiger M
      • et al.
      The European Registry for Patients with Mechanical Circulatory Support (EUROMACS): second EUROMACS Paediatric (Paedi-EUROMACS) report.
      Although most patients are implanted with the intent to transplant, pediatric DT is becoming more common especially in patients with muscular dystrophy (MD) and congenital heart disease (CHD) patients.
      • Piperata A
      • Bottio T
      • Toscano G
      • et al.
      Is heart transplantation a real option in patients with Duchenne syndrome? Inferences from a case report.
      • Villa CR
      • Lorts A
      Cardiac destination therapy in pediatrics - Are we there yet?.
      • Tunuguntla H
      • Conway J
      • Villa C
      • Rapoport A
      • Jeewa A.
      Destination-therapy ventricular assist device in children: "The Future Is Now".
      • Perri G
      • Filippelli S
      • Adorisio R
      • et al.
      Left ventricular assist device as destination therapy in cardiac end-stage dystrophinopathies: midterm results.

      Pre-implant planning

      End-Organ Assessment: Although pre-operative renal, hepatic, respiratory and nutritional failure have been associated with worse post-VAD outcomes, many patients have pre-operative end-organ dysfunction.
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      This likely is due to late presentation, late diagnosis or delayed timing for implantation. Irreversible renal dysfunction has been considered a relative contraindication to VAD implantation in the past but identifying irreversible dysfunction remains a significant challenge. Current data is complicated by various definitions of renal dysfunction including: serum creatinine > 1.6 mg/dl for patients aged > 10 years, or creatinine > 1.0 mg/dl for patients aged ≤ 10 years, or by the estimated glomerular filtration rate (eGFR) using the Schwartz formula
      • Conway J
      • St Louis J
      • Morales DL
      • Law S
      • Tjossem C
      • Humpl T
      Delineating survival outcomes in children <10 kg bridged to transplant or recovery with the Berlin Heart EXCOR Ventricular Assist Device.
      ,
      • Blume ED
      • VanderPluym C
      • Lorts A
      • et al.
      Second annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      ,
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      being < 90 ml/min/1.73 m.
      • Blume ED
      • Rosenthal DN
      • Rossano JW
      • et al.
      Outcomes of children implanted with ventricular assist devices in the United States: first analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      In the 3rd Pedimacs report, the threshold was defined as <60 mL/min1/1.73 m2 and found that 30% of patients had renal insufficiency with 5% found to have an eGFR <30 mL/min1/1.73 m2 or requiring dialysis.
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      Post-VAD outcomes have been shown to be worse if the patient has renal dysfunction prior to VAD implantation.
      • Friedland-Little JM
      • Hong BJ
      • Gossett JG
      • et al.
      Changes in renal function after left ventricular assist device placement in pediatric patients: a pedimacs analysis.
      ,
      • Hollander SA
      • Cantor RS
      • Sutherland SM
      • et al.
      Renal injury and recovery in pediatric patients after ventricular assist device implantation and cardiac transplant.
      Congestive hepatopathy resultant from HF has also been associated with both morbidity and mortality post-VAD. Elevated ALT/AST values are reported in up to 22% to 25% of patients, and abnormal bilirubin in 40% to 45% of patients at the time of VAD.
      • Conway J
      • St Louis J
      • Morales DL
      • Law S
      • Tjossem C
      • Humpl T
      Delineating survival outcomes in children <10 kg bridged to transplant or recovery with the Berlin Heart EXCOR Ventricular Assist Device.
      ,
      • Blume ED
      • VanderPluym C
      • Lorts A
      • et al.
      Second annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      ,
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      ,
      • Almond CS
      • Morales DL
      • Blackstone EH
      • et al.
      Berlin Heart EXCOR pediatric ventricular assist device for bridge to heart transplantation in US children.
      Mortality has been shown to be higher in patients with elevated bilirubin levels, and is particularly high for patients with additional risk factors, such as patients, weighing less than 10kg (mortality 70%).
      • Conway J
      • St Louis J
      • Morales DL
      • Law S
      • Tjossem C
      • Humpl T
      Delineating survival outcomes in children <10 kg bridged to transplant or recovery with the Berlin Heart EXCOR Ventricular Assist Device.
      ,
      • Almond CS
      • Morales DL
      • Blackstone EH
      • et al.
      Berlin Heart EXCOR pediatric ventricular assist device for bridge to heart transplantation in US children.
      The use of mechanical ventilatory support is reported in up to 45% to 49% of patients with 23% to 27% requiring ongoing medical paralysis at the time of VAD implantation.
      • Blume ED
      • VanderPluym C
      • Lorts A
      • et al.
      Second annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      ,
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      However, significant differences are seen between the device type implanted, with only 21% of intracorporeal CF-VAD patients intubated at the time at implantation.
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      Poor pre-operative nutrition secondary to poor appetite, abdominal discomfort and nausea may represent symptoms of inadequate gut perfusion from low CO states or venous congestion. The presence of tube feeding, TPN or a combination of both has been reported in up to 64% of patients undergoing VAD implantation.
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      Right Heart Assessment: “Right heart failure” (RHF) in children after LVAD implant is difficult to quantify, but has been shown to have an incidence as high as 42%.
      • Karimova A
      • Pockett CR
      • Lasuen N
      • et al.
      Right ventricular dysfunction in children supported with pulsatile ventricular assist devices.
      Although right ventricular dysfunction is common, this can typically be managed medically as BiVAD is relatively uncommon in the pediatric VAD population (15% of patients in the most recent Pedimacs cohort).
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      Many clinical and imaging parameters have been used to assess the right ventricular (RV) function prior to VAD, however none of the individual parameters have been a sole predictor of the need for RV support. Echocardiography may be used to qualitatively assess RV systolic function, and semi quantitative measures such as tricuspid annular plane systolic excursion (TAPSE) and RV fractional area change can be used for RV functional assessment; however, the value of any individual echocardiographic parameter in predicting RV failure and/or the need for BiVAD support is limited.
      • Neyer J
      • Arsanjani R
      • Moriguchi J
      • Siegel R
      • Kobashigawa J.
      Echocardiographic parameters associated with right ventricular failure after left ventricular assist device: A review.
      Estimation of RV pressure through measurement of tricuspid regurgitation jet velocity and position of the inter ventricular septum can also be used to screen for elevated pulmonary arterial pressures as an indicator of elevated pulmonary vascular resistance (PVR). Cardiac catheterization to measure CO, central venous pressure (CVP), and pulmonary capillary wedge pressure often occurs prior to VAD placement, but this is neither practical nor safe in all patients. Finally, assessment of cardiac rhythm is imperative. Sustained ventricular arrhythmias not controlled by pharmacologic measures may contribute to RHF and need for BiVAD support in the perioperative period.
      • Galand V
      • Flecher E
      • Auffret V
      • et al.
      Early ventricular arrhythmias after LVAD implantation is the strongest predictor of 30-day post-operative mortality.
      ,
      • Gopinathannair R
      • Cornwell WK
      • Dukes JW
      • et al.
      Device therapy and arrhythmia management in left ventricular assist device recipients: a scientific statement from the American Heart Association.
      Numerous clinical, imaging, and hemodynamic parameters have been identified in the adult VAD literature as tools for predicting the need for BiVAD support; these include preoperative mechanical ventilation, preoperative renal replacement therapy, elevated CVP, and severe RV systolic dysfunction.
      • Bellavia D
      • Iacovoni A
      • Scardulla C
      • et al.
      Prediction of right ventricular failure after ventricular assist device implant: systematic review and meta-analysis of observational studies.
      In the pediatric population, data regarding these variables are more limited, but include preoperative ECMO and elevated blood urea nitrogen.
      • Karimova A
      • Pockett CR
      • Lasuen N
      • et al.
      Right ventricular dysfunction in children supported with pulsatile ventricular assist devices.
      Despite these parameters, the decision to proceed with BiVAD support is typically made intraoperatively. If RVAD support is needed, temporary RV support may be considered to allow RV recovery following CPB and decompression of the RV and improvement of fluid overload.
      • Simpson KE
      • Kirklin JK
      • Cantor RS
      • et al.
      Right heart failure with left ventricular assist device implantation in children: an analysis of the Pedimacs registry database.
      Support Type Assessment: After establishing that a patient requires a VAD, an important subsequent step is determining the kind of support needed. This refers to the support of the systemic or LV alone (SVAD or LVAD) versus biventricular support (BiVAD). While support of the RV alone (RVAD) may also be considered, it is uncommon. Consideration of LVAD versus BiVAD support is relevant only to patients with biventricular circulations. For patients with single ventricle circulation, however, it is critical to recognize that adequate support of the circulation with a systemic VAD (SVAD) may result in suboptimal outcomes if the patient's circulatory derangement results wholly or in part from perturbations in the Fontan pathway.

      Carlo WF, Villa CR, Lal AK, Morales DL. Ventricular assist device use in single ventricle congenital heart disease, Pediatr Transplant 21(7), Published online September 15, 2017. doi:10.1111/petr.13031.

      Psychosocial Assessment: A thorough patient and family psychosocial assessment is critically important pre-VAD implant.  The goal of the psychosocial assessment is to identify patient and family strengths, weaknesses and intervention needs, particularly as they relate to VAD care demands. Similar to pediatric pre-heart transplant listing, primary domains of the pre-VAD psychosocial evaluation should minimally include: patient and family treatment adherence, barriers to medical management, disease and VAD-related knowledge, cognitive and/or neurodevelopmental functioning, current and historic mental health, substance use, social support, family functioning, and abuse and legal history.
      • Fung E
      • Shaw RJ
      Pediatric Transplant Rating Instrument - a scale for the pretransplant psychiatric evaluation of pediatric organ transplant recipients.
      ,
      • Lefkowitz DS
      • Fitzgerald CJ.
      Mobile health technology for adolescent transplant recipients: what's h'app'ening in adherence promotion?.
      Device “fit”: Innovative imaging techniques using virtual device implantation have become available and evolved as an accepted pre-operative planning tool.
      • Moore RA
      • Lorts A
      • Madueme PC
      • Taylor MD
      • Morales DL
      Virtual implantation of the 50cc SynCardia total artificial heart.
      • Potapov EV
      • Antonides C
      • Crespo-Leiro MG
      • et al.
      2019 EACTS Expert Consensus on long-term mechanical circulatory support.
      • Schweiger M
      • Lorts A
      • Conway J.
      Mechanical circulatory support challenges in pediatric and (adult) congenital heart disease.
      • Ferng AS
      • Oliva I
      • Jokerst C
      • et al.
      Translation of First North American 50 and 70 cc total artificial heart virtual and clinical implantations: utility of 3D computed tomography to test fit devices.
      This is especially relevant to children that are being considered for a device that has been U.S. Food and Drug Administration (FDA)-labeled for a larger-sized patient. Accurately scaled 3-dimensional (3D) surface rendering of the device are placed within a 3D reconstruction of the chest to assess for individual fit. Thus device compression of pertinent intrathoracic structures may be ruled out as well as assessing the ability of the inflow cannula to fit within the ventricular cavity.
      • Moore RA
      • Madueme PC
      • Lorts A
      • Morales DL
      • Taylor MD.
      Virtual implantation evaluation of the total artificial heart and compatibility: beyond standard fit criteria.
      It must be emphasized that these virtual assessments are typically performed on the preoperative geometry of the heart. Cardiac geometry, however, can be significantly different once decompressed with VAD, which has become more predictable as experience has increased.

      Key Points

      • In general, VAD implantation should be considered, prior to significant end-organ dysfunction or clinical deterioration.
      • Patients in cardiogenic shock, or INTERMACS Profile 1, have increased mortality rates post VAD therefore stabilization prior to durable support should be considered.
      • Pre-implant planning is a key step in determining eligibility for VAD therapy and should include assessment of end-organs, surgical planning and psychosocial assessment.

      Device selection

      Devices available for children with end-stage HF can be classified in a number of ways (Table 1). They can be dichotomized by anticipated duration of therapy (temporary or durable) or by design and function (PF or CF). Devices can further be separated by site of implantation (paracorporeal, extracorporeal, intracorporeal, or intravascular) as well as by what form of circulatory support they provide: LV, RV, SV, BiV or total heart replacement (TAH).
      Table 1Devices Used in Children and Adolescents
      PC, Paracorporeal; CF, Continuous Flow; IC, Intracorporeal; IV, Intravascular; C, Corporeal
      Pulsatile Flow Devices: The Berlin Heart EXCOR (Berlin, Germany) is a pneumatically driven paracorporeal VAD, which has been the mainstay of support throughout the world for children for over two decades. In the U.S., the EXCOR is the only device FDA-approved VAD for children. The EXCOR pump comes in a number of sizes (named after their stroke volume) allowing support of children and adults across a broad weight range (3 kg and greater). However, the device is being used most frequently in children <20 Kg.
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      Various implantation options are available and the pump can be used to as a LVAD, RVAD, SVAD or BiVAD configuration. The EXCOR can only be used for inpatients in the U.S., but other countries allow patient discharge on a mobile driver. The Syncardia (t-TAH, Tucson, Arizona, USA) is a pulsatile, durable device that is intracorporeal and pneumatically driven. The device provides biventricular support following cardiectomy. In the pediatric and CHD population, it has played a role in many scenarios including support of the patient with graft failure post-transplant (as immunosuppression can be withdrawn after TAH implantation) and support of complex CHD including the Fontan circulation.
      • Rossano JW
      • Goldberg DJ
      • Fuller S
      • Ravishankar C
      • Montenegro LM
      • Gaynor JW.
      Successful use of the total artificial heart in the failing Fontan circulation.
      • Villa CR
      • Moore RA
      • Morales DL
      • Lorts A.
      The total artificial heart in pediatrics: outcomes in an evolving field.
      • Thangappan K
      • Ashfaq A
      • Villa C
      • Morales DLS.
      The total artificial heart in patients with congenital heart disease.
      Only two sizes of device are available, both FDA approved, one with 70 mL chambers and one with 50 mL chambers. The smaller device used in patients with a Body Surface Area (BSA) <1.5m.
      • Blume ED
      • Rosenthal DN
      • Rossano JW
      • et al.
      Outcomes of children implanted with ventricular assist devices in the United States: first analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      The device was developed with intent to discharge patients post-implantation, and hence mobile drivers exist for use out of the hospital.
      Continuous Flow Devices: Various paracorporeal, temporary pump heads are available that can be used to provide support of either or both ventricles in children. The most commonly used pumps are the RotaFlow (Maquet) centrifugal pump and the Centrimag/Pedimag (Abbott Laboratories) magnetically levitated devices. In either case, various cannulas can be used to surgically connect the pump head to the circulation allowing flexibility in application and the potential to initiate support without going on cardiopulmonary bypass. This flexibility makes these devices useful for both recovery and in challenging settings such as CHD. While these devices are by their nature temporary forms of support that require in hospital admission, they may be utilized as a long-term BTT or BTR.
      • Lorts A
      • Eghtesady P
      • Mehegan M
      • et al.
      Outcomes of children supported with devices labeled as "temporary" or short term: a report from the Pediatric Interagency Registry for Mechanical Circulatory Support.
      ,
      • Conway J
      • Al-Aklabi M
      • Granoski D
      • et al.
      Supporting pediatric patients with short-term continuous-flow devices.
      Other products exist as short-term circulatory support devices primarily targeted at circulatory rescue in adults. The TandemHeart is an intravascular device connected to a centrifugal pump that can be placed intravenously to support the RV with ejection to the pulmonary artery (or the LV through a trans-septal approach) and has been used in pediatrics as an extracorporeal device for Left Ventricular (LV) support and Single Ventricular (SV) support.
      • Yarlagadda VV
      • Maeda K
      • Zhang Y
      • et al.
      Temporary circulatory support in U.S. children awaiting heart transplantation.
      ,
      • Ricci M
      • Gaughan CB
      • Rossi M
      • et al.
      Initial experience with the TandemHeart circulatory support system in children.
      The Impella (Abiomed) device, available in multiple sizes, is also an intravascular device with an axial pump designed to be placed across the aortic valve and into the LV to allow short term emergent ventricular support.
      • Dimas VV
      • Morray BH
      • Kim DW
      • et al.
      A multicenter study of the impella device for mechanical support of the systemic circulation in pediatric and adolescent patients.
      The Impella can also be used for RV support, although there is limited experience in pediatrics.
      Various intracorporeal durable devices are available for adults and are also used (off-label in the U.S.) for larger children and adolescents in many countries. The current implantable continuous flow (CF) devices includes the axial flow, HeartMate II, (Abbott Laboratories, IL, US), centrifugal hydrodynamic flow HVAD System, (Medtronic, Minneapolis, MN, US) and centrifugal full-mag Lev HeartMate 3 (Abbott Laboratories). These devices are designed for long-term support and are implanted with the intention to discharge. The size of these devices limit their use in children and implantation is generally considered at >15 -20 kg (although smaller implantations have been described).
      • Nandi D
      • Miller KD
      • Bober CM
      • et al.
      Systemic atrioventricular valve excision and ventricular assist devices in pediatric patients.
      ,
      • VanderPluym CJ
      • Adachi I
      • Niebler R
      • et al.
      Outcomes of children supported with an intracorporeal continuous-flow left ventricular assist system.
      • Conway J
      • Miera O
      • Adachi I
      • et al.
      Worldwide experience of a durable centrifugal flow pump in pediatric patients.
      • O'Connor MJ
      • Lorts A
      • Davies RR
      • et al.
      Early experience with the HeartMate 3 continuous-flow ventricular assist device in pediatric patients and patients with congenital heart disease: a multicenter registry analysis.
      The HVAD device has been utilized more frequently in smaller children due to the size of the pump, although the new HM3 has gained attention in children due to its shorter inflow and favorable adverse event profile.
      • O'Connor MJ
      • Lorts A
      • Davies RR
      • et al.
      Early experience with the HeartMate 3 continuous-flow ventricular assist device in pediatric patients and patients with congenital heart disease: a multicenter registry analysis.
      ,
      • Goldstein DJ
      • Naka Y
      • Horstmanshof D
      • et al.
      Association of clinical outcomes with left ventricular assist device use by bridge to transplant or destination therapy intent: the multicenter study of MagLev technology in patients undergoing mechanical circulatory support therapy with HeartMate 3 (MOMENTUM 3) randomized clinical trial.
      Similar to the adult intracorporeal devices, a miniature CF axial pump, the Jarvik (Jarvik Heart Inc, New York City, New York, USA), is currently under study through an industry collaboration with the NIH (PumpKIN trial).
      • Adachi I.
      Current status and future perspectives of the PumpKIN trial.

      Key Points

      • After the decision to place a VAD has been made, the next crucial step is to determine the level of support needed (LVAD vs SVAD or BiVAD in biventricular circulation).
      • Important considerations for device selection include patient-device size matching; implant configuration LVAD, SVAD or BiVAD); duration of support and support intent.
      • VADs can be broadly characterized by duration of support (temporary vs durable), design (pulsatile vs continuous flow), or site of implantation (paracorporeal, intracorporeal, or intravascular).
      • Currently intracorporeal CF devices are generally considered in children >15-20kg and use has been increasing over the last decade. The Berlin EXCOR is used mostly in children <20kg. The paracorporeal continuous flow devices are used in patients that may recover, those that need BiVAD support and as a BTT in some high-risk populations such as small children with CHD.
      • TAH can be used in children but has mainly been used in unique situations such as complex CHD and transplant graft failure.

      Operative management

      Optimal surgical technique depends on the device and the patient's unique characteristics. In children, challenges due to anatomic and pathophysiologic variations remain.
      • Morales DL
      • Zafar F
      • Almond CS
      • et al.
      Berlin Heart EXCOR use in patients with congenital heart disease.
      Surgical Considerations: Achieving an ideal inflow configuration is vital and dependent on the patient's anatomy. When positioning an apical cannula, regardless of whether it is an intracorporeal or paracorporeal VAD, the cardinal rule is to position the inflow cannula parallel to the interventricular septum, facing the systemic AV valve. With dilated ventricles, apical cannulation is less challenging; however, in non-dilated hearts such as restrictive, hypertrophic cardiomyopathy or CHD this can be more difficult. In these cases, strategies to accommodate the LV apical cannula including extended LV myectomy, mitral valve leaflet/apparatus excision and even prosthetic valve removal have been successfully reported.
      • Sundararajan S
      • Thiruchelvam T
      • Hsia TY
      • Karimova A.
      New 15-mL ventricular assist device in children with restrictive physiology of the left ventricle.
      However, for the restrictive and hypertrophic diagnoses apical cannulation may not ideal due to contraction around the inflow cannula compromising flow. Alternatively, an atrial cannulation may be considered. This strategy also has the benefits of avoiding a ventriculotomy, and the use of CPB.
      • Boston U
      • Sun JX
      • Kumar TKS
      • Knott-Craig C.
      An innovative ventricular assist device strategy as a Bridge-to-Recovery in an infant with glenn physiology.
      The next challenge can be the outflow graft anastomosis to the ascending aorta due to the length and diameter of the vessels. Several modifications have been reported including the interposition of a vascular graft between the outflow cannula tip and the aortic wall or the innominate artery.
      • Botha P
      • Hasan A
      • Perri G
      • Filippelli S
      • Griselli M.
      Modified technique for the implantation of Berlin heart EXCOR ventricular assist device in children.
      In general, the outflow graft cannula should be positioned as proximal as possible to aid with future transplantation; but making sure it does not impinge on the right ventricle especially with the EXCOR cannulae. Therefore, it should be placed about 45 degrees off the anterior surface of the aorta to the patient's right.
      Pediatric alternatives to inflow implantation sites have include utilization of the diaphragmatic surface of the LV.
      • Gregoric ID
      • Cohn WE
      • Frazier OH
      Diaphragmatic implantation of the HeartWare ventricular assist device.
      Such a technique may not be suitable in small pediatric hearts because of the risk of posterior descending coronary artery injury with the sewing ring and/or sutures.
      • Adachi I
      • Guzman-Pruneda FA
      • Jeewa A
      • Fraser Jr., CD
      • Dean McKenzie E
      A modified implantation technique of the HeartWare ventricular assist device for pediatric patients.
      Some authors describe creation of a small pocket above the left hemi-diaphragm while coring the LV apex.
      • Adachi I
      • Guzman-Pruneda FA
      • Jeewa A
      • Fraser Jr., CD
      • Dean McKenzie E
      A modified implantation technique of the HeartWare ventricular assist device for pediatric patients.
      Placing the pump in the pocket requires relocation of the LV apex medially and caudally, which orients the inflow cannula in a more vertical plane, parallel to the interventricular septum.
      • Adachi I
      • Guzman-Pruneda FA
      • Jeewa A
      • Fraser Jr., CD
      • Dean McKenzie E
      A modified implantation technique of the HeartWare ventricular assist device for pediatric patients.
      For RVAD placement, there are three sites for potential implantation: (1) the right atrium (standard site for EXCOR), (2) the diaphragmatic wall or (3) the free wall of the RV. The location depends on the device and cannulas selected. The EXCOR cannulas are tunneled through the skin and secured on the RA free wall directly opposite the tricuspid valve. For all implant sites, correct orientation of the inflow cannula is crucial to ensure unobstructed flow into the pump. The outflow graft is tunneled through the skin and is anastomosed (with or without a graft extension) to the pulmonary artery.
      Driveline and cannula exit sites are important to plan before incision. For the EXCOR, the LV apical cannula must exit at a few cm below the left costal margin at or lateral to the mid-clavicular line. The LVAD arterial outflow cannula exits a few cm below and to the right of the xiphoid process. An RVAD outflow cannula to the pulmonary artery would be to the left of the midline and the inflow cannula would exist to the right of the LVAD aortic cannula. For proper connection the cannula have to cross either outside the body or within the chest. The latter is rarely done and is in not practical in those less than 10kg. The crossing of the outflow cannulae externally on the upper abdominal wall results in the LVAD EXCOR pump laying upside down (blood side up) compared to the right pump. At least several cm of skin should be preserved between adjacent cannulae exit points to prevent erosion and breakdown. Furthermore, the Dacron cuff on each cannula should extend at least 1 cm beyond the skin exit site to allow for tissue in growth.
      There are times when concomitant surgery must occur. The most common is aortic and atrioventricular (AV) valve repair. Presence of significant aortic incompetence should be addressed with replacement, repair or over-sewing at the time of VAD implantation regardless of chosen device. AV valve stenosis has to be avoided when implanting the inflow cannula into the ventricle but there are mixed reports of treatment of AV valve regurgitation including AV valve repair, replacement or removal.
      In all pediatric VAD patients, determination of the presence of intra and extracardiac shunts is required.
      • Potapov EV
      • Antonides C
      • Crespo-Leiro MG
      • et al.
      2019 EACTS Expert Consensus on long-term mechanical circulatory support.
      ,
      • Feldman D
      • Pamboukian SV
      • Teuteberg JJ
      • et al.
      The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: executive summary.
      • Gelow JM
      • Song HK
      • Weiss JB
      • Mudd JO
      • Broberg CS.
      Organ allocation in adults with congenital heart disease listed for heart transplant: impact of ventricular assist devices.
      • Maxwell BG
      • Wong JK
      • Sheikh AY
      • Lee PH
      • Lobato RL.
      Heart transplantation with or without prior mechanical circulatory support in adults with congenital heart disease.
      • VanderPluym CJ
      • Cedars A
      • Eghtesady P
      • et al.
      Outcomes following implantation of mechanical circulatory support in adults with congenital heart disease: an analysis of the interagency registry for mechanically assisted circulatory support (INTERMACS).
      While some surgeons leave a small Patent Foramen Ovale (PFO) or atrial fenestration intentionally, especially in the Fontan patients, larger intracardiac communications should be closed either percutaneously or at time of VAD placement to avoid cyanosis.
      • Potapov EV
      • Antonides C
      • Crespo-Leiro MG
      • et al.
      2019 EACTS Expert Consensus on long-term mechanical circulatory support.
      Perioperative antimicrobial prophylaxis should be targeted to skin flora as the most likely contaminants of the surgical site. Limited data are available in pediatric VAD
      • Auerbach SR
      • Richmond ME
      • Schumacher KR
      • et al.
      Infectious complications of ventricular assist device use in children in the United States: data from the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs).
      and no randomized data exists looking at surgical prophylaxis for pediatric VAD. Recommendations are based on available guidelines, including ISHLT, for adult VAD therapy.
      • Kusne S
      • Mooney M
      • Danziger-Isakov L
      • et al.
      An ISHLT consensus document for prevention and management strategies for mechanical circulatory support infection.

      Key Points

      • When evaluating for a durable VAD it is important to review cardiac morphology and physiology data, including the presence of shunts, collateral vessels, and the location and course of great vessels.
      • In pediatric patients with residual shunting, shunt closure (exceptions may exist in the Fontan patients) should occur at the time of VAD implant.

      Post-operative hemodynamic goals

      Device settings should be optimized in the operating room with both TEE and hemodynamic monitoring before and after chest closure. After returning to the ICU, the primary postoperative goals are to obtain sufficient systemic perfusion and maintain normal systemic and venous pressure while avoiding VAD-related complications. Establishing appropriate device settings requires identification of physiologically appropriate CO goals as well as careful assessment of imaging and hemodynamic parameters. In biventricular physiology, the goal CI is commonly 2-3 L/min/m2. In the case of single ventricle physiology, a much higher CO goal to achieve pulmonary venous unloading and optimal end-organ perfusion may be needed.
      • Lorts A
      • Villa C
      • Riggs KW
      • Broderick J
      • Morales DLS
      First use of HeartMate 3 in a failing Fontan circulation.
      For the EXCOR, pump parameters should be manipulated to maintain a full device fill and ejection with each cycle. The maximal output of the device is calculated by the product of the device size (stroke volume) and set rate. The actual output is generally less, but difficult to accurately estimate given the volume of a half sphere is related to the radius to the third power. Several strategies targeting both the patient and the device can be employed to increase fill and thus increase output when desired. Decreasing the percent systole, the rate and diastolic pressure will increase the time spent in diastole and thus device filling, but this must be balanced by a commensurate increase in systolic pressure to ensure full device emptying. The broad availability of digital photography/video, particularly slow-motion, has emerged as a useful tool for assessment/troubleshooting.
      For all of the CF devices, optimizing CO must be accomplished by optimizing preload and afterload while simultaneously preventing excessive leftward interventricular septal shift. Each pump is developed to function within a given range of power consumption for a given impeller/rotor set speed. When the relationship of these indices falls outside of that which is expected, an underlying etiology should be sought (excessive/ineffective pump speed, device thrombosis, device malfunction, etc.). Patient management should take into account the interaction between native cardiovascular system, physiology and device function. Though each device intrinsically has a unique pressure-flow response (H:Q) curve, all are innately sensitive to afterload. During diastole there is a large difference in pressure across the pump and therefore lower flow, while during systole the differences is smaller producing a higher flow state.
      For BiVAD support, an imbalance can occur in flow of the pulmonary versus systemic circulation resulting in venous congestion upstream from the relatively under-supported circuit. As such, when RVAD output overwhelms that of LV support, pulmonary edema ensues. Alternatively, when LVAD support is in excess of RVAD support, hepatic, renal and digestive dysfunction may become apparent. Once biventricular support is balanced and unobstructed, the hemodynamic management is focused on avoidance of hypo- or hypervolemia and afterload reduction to achieve a normal CO.

      Key Points

      • EXCOR settings should be targeted to allow a full fill and ejection with each cycle, use of digital image capture with slow-motion can aid in the assessment of membrane movement.
      • CF device support parameters should be individualized to physiologic support needs and optimized not only through changes in parameters but also manipulation of afterload and preload.

      Anticoagulation management

      Post-operative Hemostasis: Bleeding is a significant issue following VAD implantation. The risk for bleeding stems from disturbances in the coagulation profile in pediatric patients and are related to developmental hemostasis, heart failure cachexia, liver dysfunction, and coagulation factor/platelet consumption. Coagulation deficits including thrombin generation factors, adhesive proteins concentrations [fibrinogen and Von Willebrand factor (VWF)], and platelet function should be regularly assessed and normalized to stop bleeding. Thromboelastography (TEG) and ROTEM can diagnose specific deficits in the early post-operative phase. Factor deficiencies resulting from blood and volume administration must be avoided through concurrent use of blood products, coagulation concentrates, and other hemostatic agents guided by functional hemostatic evaluations. Anticoagulation may be considered only after achieving hemostasis.
      Developmental hemostasis: There are qualitative and quantitative changes in hemostasis from fetal to adult life making following adult anticoagulation protocols difficult in pediatric VAD. For example, infants and adults may share similarities in size and numbers of platelets but their pharmacological responses vary. The response to agonists may be decreased in neonatal platelets compared to adults and more so in pre-term infants. However, despite blunted reactivity, infants compensate by having higher levels of VWF and multimers in addition to the higher hematocrit.
      • Van Ommen CH
      • Neunert CE
      • Chitlur MB.
      Neonatal ECMO.
      As well, in the neonate, the plasma levels of pro-coagulant factors (which are produced by the liver), including the vitamin-K dependent ones, are at approximately 50% of what an adult may have. This reflects the differences in neonatal and adult partial thromboplastic time (PTT).
      • Monagle P
      • Barnes C
      • Ignjatovic V
      • et al.
      Developmental haemostasis. Impact for clinical haemostasis laboratories.
      Furthermore, the concentration of antithrombin (AT3), protein C and S are lower in infants compared with adults, and infants have a reduced ability to break down fibrin due to decreased levels of plasminogen. The changes in AT3 concentrations in neonates have led to difficulty with titration of heparin.
      Anticoagulation and Antiplatelet Therapy: Historically, unfractionated heparin (UFH), low molecular weight heparin (LMWH) and vitamin K antagonists (VKA) have been the standard of care for paracorporeal and intracorporeal VADs in children.
      • Fraser Jr., CD
      • Jaquiss RD
      • Rosenthal DN
      • et al.
      Prospective trial of a pediatric ventricular assist device.
      • Steiner ME
      • Bomgaars LR
      • Massicotte MP.
      Antithrombotic therapy in a prospective trial of a pediatric ventricular assist device.
      • Huang JY
      • Monagle P
      • Massicotte MP
      • VanderPluym CJ.
      Antithrombotic therapies in children on durable Ventricular Assist Devices: a literature review.
      However, there has been a shift towards increased use of direct thrombin inhibitors (DTI), namely bivalirudin, for anticoagulation, especially in the setting of paracorporeal VAD support.
      • VanderPluym CJ
      • Cantor RS
      • Machado D
      • et al.
      Utilization and outcomes of children treated with direct thrombin inhibitors on paracorporeal ventricular assist device support.
      • Bates A
      • Buchholz H
      • Freed D
      • MacArthur R
      • Pi DT
      • Conway J.
      Bivalirudin experience in a heterogeneous ventricular assist device population.
      • Medar SS
      • Hsu DT
      • Lamour JM
      • Bansal N
      • Peek GJ
      Use of bivalirudin as a primary anticoagulant in a child during Berlin Heart EXCOR ventricular assist device support.
      Centers have also reported modification of the traditional antiplatelet therapy, with weight-based dosing of anti-platelet drugs in paracorporeal PF devices being associated with lower stroke rate.
      • Rosenthal DN
      • Lancaster CA
      • McElhinney DB
      • et al.
      Impact of a modified anti-thrombotic guideline on stroke in children supported with a pediatric ventricular assist device.
      Monitoring of anticoagulation and antiplatelet therapy remains a challenge, with limitations surrounding the consistency and interpretability of all laboratory tests. UFH can be titrated using activated prothrombin time (aPTT) or anti-Xa level. LMWH is titrated to anti-Xa levels, while VKA is monitored via International Normalized Ratio (INR) with device specific ranges.
      • Huang JY
      • Monagle P
      • Massicotte MP
      • VanderPluym CJ.
      Antithrombotic therapies in children on durable Ventricular Assist Devices: a literature review.
      ,
      • Buck ML
      Bivalirudin as an alternative to heparin for anticoagulation in infants and children.
      ,
      • Adachi I
      • Kostousov V
      • Hensch L
      • Chacon-Portillo MA
      • Teruya J.
      Management of hemostasis for pediatric patients on ventricular-assist devices.
      DTI can be monitored using aPTT and dilute thrombin time (dTT). The DTI appear to have more linear and predictable dose response curves.
      • Buck ML
      Bivalirudin as an alternative to heparin for anticoagulation in infants and children.
      In pediatrics, antiplatelet titration used to be heavily dependent upon Thromboelastography (TEG) with platelet mapping (TEG PM), however recent studies have demonstrated less dose response correlation with platelet mapping.
      • May LJ
      • Liu X
      • Tesoro T
      • et al.
      Usefulness of anti-platelet therapy testing in children supported with a ventricular assist device.
      ,
      • Monroig-Bosque PdC
      • Salazar E.
      Lack of correlation between verify now and TEG-Platelet mapping in ventricular assist device patients.
      VerifyNow and Platelet Function Analyzer-100 (PFA-100) have been used to assess antiplatelet agent resistance; however these have yet to be validated in a pediatric population.
      • Monroig-Bosque PdC
      • Salazar E.
      Lack of correlation between verify now and TEG-Platelet mapping in ventricular assist device patients.
      Many medications (i.e. Milrinone, nitroprusside and inhaled Nitric Oxide) used to support VAD patients have been shown to inhibit platelet function.
      • Wesley MC
      • McGowan FX
      • Castro RA
      • Dissanayake S
      • Zurakowski D
      • Dinardo JA.
      The effect of milrinone on platelet activation as determined by TEG platelet mapping.
      • Harris SN
      • Rinder CS
      • Rinder HM
      • Tracey JB
      • Smith BR
      • Hines R.
      Nitroprusside inhibition of platelet function is transient and reversible by catecholamine priming.
      • Aoki H
      • Inoue M
      • Mizobe T
      • Harada M
      • Imai H
      • Kobayashi A.
      Platelet function is inhibited by nitric oxide liberation during nitroglycerin-induced hypotension anaesthesia.
      Effect of inflammation and infection on anticoagulation: Due to the shared nature between inflammation and anticoagulation, derangement of the normal coagulation function can occur during infection/inflammation. There are several markers of inflammation that can be used clinically including white blood cell counts, platelet counts, C-reactive protein, fibrinogen, and the presence of fevers, though it is not clear which marker is associated with the greatest likelihood of a bleeding or clotting complication. From a practical standpoint, the presence of fevers (in the absence of infection), elevated C-reactive protein levels, and elevated fibrinogen levels may lead to a change in anticoagulation or the addition of corticosteroids.
      • Rosenthal DN
      • Lancaster CA
      • McElhinney DB
      • et al.
      Impact of a modified anti-thrombotic guideline on stroke in children supported with a pediatric ventricular assist device.
      ,
      • Byrnes JW
      • Bhutta AT
      • Rettiganti MR
      • et al.
      Steroid therapy attenuates acute phase reactant response among children on ventricular assist device support.
      While the data are limited regarding the efficacy of this therapy, there are small single-center studies that suggest steroids do decrease markers of inflammation and may decrease the incidence of stroke in patients on EXCOR support.
      • Byrnes JW
      • Bhutta AT
      • Rettiganti MR
      • et al.
      Steroid therapy attenuates acute phase reactant response among children on ventricular assist device support.
      ,
      • Byrnes JW
      • Prodhan P
      • Williams BA
      • et al.
      Incremental reduction in the incidence of stroke in children supported with the Berlin EXCOR ventricular assist device.

      Key Points

      • In North America, there is a shift towards the use of DTI therapy for paracorporeal VAD support in children.
      • In EXCOR patients, post-VAD inflammation may increase the risk of thrombosis, bleeding and stroke and steroids have been used in small single center cohorts to treat the inflammatory state in an attempt to decrease the incidence of stroke.

      Adverse events

      See Table 2 from Pedimacs report for common adverse event rates.
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      Table 2Adverse Event Rates from Pedimacs 3rd Annual Report
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      Infection: Infection remains a significant complication following implant of VADs. These infections are grouped according to ISHLT infection guideline nomenclature
      • Kusne S
      • Mooney M
      • Danziger-Isakov L
      • et al.
      An ISHLT consensus document for prevention and management strategies for mechanical circulatory support infection.
      as non-VAD (i.e. pneumonia), VAD-related (i.e. infective endocarditis or mediastinitis) or VAD-specific infections [driveline infections (DLI), pocket infections and pump infections].
      • Hannan MM
      • Husain S
      • Mattner F
      • et al.
      Working formulation for the standardization of definitions of infections in patients using ventricular assist devices.
      Infections account for about 17% of all the adverse events (AE) with these events more commonly occurring >3 months post implant and accounting for nearly 1 out of 3 of readmissions following discharge.
      • Auerbach SR
      • Richmond ME
      • Schumacher KR
      • et al.
      Infectious complications of ventricular assist device use in children in the United States: data from the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs).
      ,
      • de By T
      • Schweiger M
      • Waheed H
      • et al.
      The European Registry for Patients with Mechanical Circulatory Support (EUROMACS): first EUROMACS Paediatric (Paedi-EUROMACS) report.
      ,
      • Hollander SA
      • McElhinney DB
      • Almond CS
      • et al.
      Re-hospitalization after pediatric heart transplantation: incidence, indications, and outcomes.
      Identified risk factors of infections have included: time on device, prior infection and prior non-infectious adverse events.
      • Auerbach SR
      • Richmond ME
      • Schumacher KR
      • et al.
      Infectious complications of ventricular assist device use in children in the United States: data from the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs).
      ,
      • de By T
      • Schweiger M
      • Waheed H
      • et al.
      The European Registry for Patients with Mechanical Circulatory Support (EUROMACS): first EUROMACS Paediatric (Paedi-EUROMACS) report.
      Single-center studies report that approximately 15% - 50% of patients will develop a DLI.
      • Kanaya T
      • Ueno T
      • Taira M
      • et al.
      Impact of long-term support with Berlin heart EXCOR(R) in pediatric patients with severe heart failure.
      • Adachi I
      • Zea-Vera R
      • Tunuguntla H
      • et al.
      Centrifugal-flow ventricular assist device support in children: a single-center experience.
      • Rai V
      • Sacharczuk J
      • Dudynska M
      • et al.
      Initial experience with intracorporeal continuous ow LVAD in pediatric patients in Poland.
      • De Rita F
      • Griselli M
      • Sandica E
      • et al.
      Closing the gap in paediatric ventricular assist device therapy with the Berlin Heart EXCOR(R) 15-ml pump.
      • Di Molfetta A
      • Gandolfo F
      • Filippelli S
      • et al.
      The use of Berlin Heart EXCOR VAD in children less than 10 kg: a single center experience.
      • Miller JR
      • Epstein DJ
      • Henn MC
      • et al.
      Early biventricular assist device use in children: a single-center review of 31 patients.
      • Hsu KH
      • Huang SC
      • Chou NH
      • et al.
      Ventricular assist device application as a bridge to pediatric heart transplantation: a single center's experience.
      • Mackling T
      • Shah T
      • Dimas V
      • et al.
      Management of single-ventricle patients with Berlin Heart EXCOR Ventricular Assist Device: single-center experience.
      • Sandica E
      • Knyphausen EZ
      • Blanz U
      • Rofe D
      • Morshuis M
      Safety of long-term mechanical support with Berlin Heart EXCOR in pediatric patients.
      • Stein ML
      • Robbins R
      • Sabati AA
      • et al.
      Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS)-defined morbidity and mortality associated with pediatric ventricular assist device support at a single US center: the Stanford experience.
      • Gandhi SK
      • Huddleston CB
      • Balzer DT
      • Epstein DJ
      • Boschert TA
      • Canter CE
      Biventricular assist devices as a bridge to heart transplantation in small children.
      The EXCOR trials suggest that while infections overall are common (occurring in 41% - 63% of patients), cannula infections are less common (0% -17%).
      • Fraser Jr., CD
      • Jaquiss RD
      • Rosenthal DN
      • et al.
      Prospective trial of a pediatric ventricular assist device.
      ,
      • Zafar F
      • Jefferies JL
      • Tjossem CJ
      • Bryant 3rd, R
      • Jaquiss RD
      • Wearden PD
      • et al.
      Biventricular Berlin Heart EXCOR pediatric use across the united states.
      While early reports suggested that infection was not associated with decreased survival, recent data from Pedimacs suggests an increased mortality with infection in patients on CF devices.
      • Auerbach SR
      • Richmond ME
      • Schumacher KR
      • et al.
      Infectious complications of ventricular assist device use in children in the United States: data from the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs).
      ,
      • Fragasso T
      • Ricci Z
      • Grutter G
      • et al.
      Incidence of healthcare-associated infections in a pediatric population with an extracorporeal ventricular assist device.
      In the Pedimacs data, 77% of infectious AEs were treated with intravenous antibiotics, 11% with oral therapy and 8% required both surgical and antimicrobial therapy.
      • Auerbach SR
      • Richmond ME
      • Schumacher KR
      • et al.
      Infectious complications of ventricular assist device use in children in the United States: data from the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs).
      Adult-focused recommendations suggest management be based on the site and extent of the infection with consideration for secondary prophylaxis in some patient awaiting transplantation.
      • Kusne S
      • Mooney M
      • Danziger-Isakov L
      • et al.
      An ISHLT consensus document for prevention and management strategies for mechanical circulatory support infection.
      Prevention of VAD-specific infections relies primarily on infection control principles.
      • Kusne S
      • Mooney M
      • Danziger-Isakov L
      • et al.
      An ISHLT consensus document for prevention and management strategies for mechanical circulatory support infection.
      Right Ventricular Failure (RVF): RVF is manifested by elevated CVP, liver dysfunction, ascites, and renal injury. It usually occurs within 2 weeks of LVAD implant and is associated with both morbidity and mortality.
      • Baxter RD
      • Tecson KM
      • Still S
      • et al.
      Predictors and impact of right heart failure severity following left ventricular assist device implantation.
      ,
      • Lampert BC
      • Teuteberg JJ.
      Right ventricular failure after left ventricular assist devices.
      In adults, early RVF is defined as use of inotropes > 14 days, inhaled nitric oxide > 48 hours or unplanned RVAD. Incidence of early RVF in adults with CF-VADs is 15% to 40% but may be lower in children.
      • Bellavia D
      • Iacovoni A
      • Scardulla C
      • et al.
      Prediction of right ventricular failure after ventricular assist device implant: systematic review and meta-analysis of observational studies.
      ,
      • Redlin M
      • Miera O
      • Habazettl H
      • et al.
      Incidence and echocardiographic predictors of early postoperative right ventricular dysfunction following left ventricular assist implantation in paediatric patients.
      • Kang G
      • Ha R
      • Banerjee D
      Pulmonary artery pulsatility index predicts right ventricular failure after left ventricular assist device implantation.
      • Iacobelli R
      • Di Molfetta A
      • Brancaccio G
      • et al.
      Acute and long-term effects of LVAD support on right ventricular function in children with pediatric pulsatile ventricular assist devices.
      • Miera O
      • Kirk R
      • Buchholz H
      • et al.
      A multicenter study of the HeartWare ventricular assist device in small children.
      Etiology of RVF is multi-factorial with contributing factors including shift of the interventricular leftward, increased RV preload, and arrhythmias.
      • Lampert BC
      • Teuteberg JJ.
      Right ventricular failure after left ventricular assist devices.
      ,
      • Santamore WP
      • Dell'Italia LJ.
      Ventricular interdependence: significant left ventricular contributions to right ventricular systolic function.
      A major pre-operatively goal is to implant LVAD before RVF develops, and, if already present, to optimize RV hemodynamics before LVAD implantation.
      • Lampert BC
      • Teuteberg JJ.
      Right ventricular failure after left ventricular assist devices.
      ,
      • Avery R
      • Ebong I
      • Skaria R
      • et al.
      Preoperative risk stratification of right ventricular function utilizing cardiac magnetic resonance imaging compared with echocardiographic and hemodynamic parameters.
      Aggressive pre-operative management of patients with RV dysfunction should focus on diuresis (goal CVP < 15 mmHg), institution of milrinone ± epinephrine for contractility, and pulmonary vasodilators to reduce RV afterload.
      Intra-operatively, TEE monitoring of RV function should occur during LVAD implant.
      • Lampert BC
      • Teuteberg JJ.
      Right ventricular failure after left ventricular assist devices.
      Strategies to preserve RV function include: maintenance of adequate blood pressure, avoidance of pulmonary vasoconstriction and use of pulmonary vasodilators, use of continuous ultrafiltration during bypass, minimization or avoidance of cross clamp time, judicious use of blood products, arrhythmia control, consideration of delayed sternal closure, and maintaining the septum in a midline position.
      • Lovich MA
      • Pezone MJ
      • Wakim MG
      • et al.
      Inhaled nitric oxide augments left ventricular assist device capacity by ameliorating secondary right ventricular failure.
      • Hanke JS
      • Haverich A
      • Schmitto JD.
      Right heart failure after left ventricular assist devices: surgical considerations.
      • Meineri M
      • Van Rensburg AE
      • Vegas A.
      Right ventricular failure after LVAD implantation: prevention and treatment.
      • Harjola VP
      • Mebazaa A
      • Celutkiene J
      • et al.
      Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology.
      If RVF occurs, elective early rather than delayed emergent mechanical RVAD support has been associated with improved outcomes.
      • Fitzpatrick 3rd, JR
      • Frederick JR
      • Hiesinger W
      • et al.
      Early planned institution of biventricular mechanical circulatory support results in improved outcomes compared with delayed conversion of a left ventricular assist device to a biventricular assist device.
      • Takeda K
      • Naka Y
      • Yang JA
      • et al.
      Outcome of unplanned right ventricular assist device support for severe right heart failure after implantable left ventricular assist device insertion.
      • Khorsandi M
      • Schroder J
      • Daneshmand M
      • et al.
      Outcomes after extracorporeal right ventricular assist device combined with durable left ventricular assist device support.
      Such short-term RV mechanical support options include paracorporeal CF VADs, percutaneous VAD, and ECMO; long-term RV support includes biventricular durable intracorporeal CF, TAH, or PF VAD devices.
      • Coromilas EJ
      • Takeda K
      • Ando M
      • et al.
      Comparison of percutaneous and surgical right ventricular assist device support after durable left ventricular assist device insertion.
      ,
      • Shehab S
      • Macdonald PS
      • Keogh AM
      • et al.
      Long-term biventricular HeartWare ventricular assist device support–Case series of right atrial and right ventricular implantation outcomes.
      Post-operatively, signs of RVF include decreased LVAD flow, suction events and decreased CO, acute kidney injury, and hepatic dysfunction. Management should incorporate aggressive use of pulmonary vasodilators as well as inotropes for RV CO support and avoidance of bradycardia until RA pressures are near normal. RV preload should be optimized with diuresis or hemodialysis to maintain CVP < 15 mmHg. Maintenance of sinus rhythm should be aggressively pursued.
      Pump thrombosis (PT): PT is a less common but a significant complication of VAD therapy. It results from a variety of patient and pump factors and can develop slowly over time or have a rapid onset. The definitions and recognition of PT vary by device type with the current EXCOR pumps allowing visual inspection and intracorporeal pumps requiring a combination of abnormal VAD parameters, lab values consistent with hemolysis or symptoms of HF; with conformation only occurring if the pump is removed. Symptoms of hemolysis can include scleral icterus, dark urine (hemoglobinuria), and fatigue with signs including one or more of the following: elevated serum Lactate Dehydrogenase (LDH) (most sensitive marker), elevated plasma free hemoglobin, and low haptoglobin.
      • Maeda K
      • Almond C
      • Hollander SA
      • et al.
      Characteristics of deposits and pump exchange in the Berlin Heart EXCOR ventricular assist device: experience with 67 cases.
      Recent studies have shown the rate of PT in adults to be 4-8% in HeartMate II and HeartWare
      • Kirklin JK
      • Naftel DC
      • Kormos RL
      • et al.
      Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of pump thrombosis in the HeartMate II left ventricular assist device.
      ,
      • Najjar SS
      • Slaughter MS
      • Pagani FD
      • et al.
      An analysis of pump thrombus events in patients in the HeartWare advance bridge to transplant and continued access protocol trial.
      and 1% in the HM3 device.
      • Mehra MR
      • Naka Y
      • Uriel N
      • et al.
      A fully magnetically levitated circulatory pump for advanced heart failure.
      PT in the pediatric patients with a CF-VAD occurs in 11% - 44% of patients, with the largest series reporting a rate of 15%.
      • Rossano JW
      • Lorts A
      • VanderPluym CJ
      • et al.
      Outcomes of pediatric patients supported with continuous-flow ventricular assist devices: a report from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      ,
      • VanderPluym CJ
      • Adachi I
      • Niebler R
      • et al.
      Outcomes of children supported with an intracorporeal continuous-flow left ventricular assist system.
      ,
      • Conway J
      • Miera O
      • Adachi I
      • et al.
      Worldwide experience of a durable centrifugal flow pump in pediatric patients.
      ,
      • Rosenthal DN
      • Almond CS
      • Jaquiss RD
      • et al.
      Adverse events in children implanted with ventricular assist devices in the United States: data from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      Management of PT in adults has largely been based on expert opinion with published algorithms focused on both the device type and presentation.
      • Ertugay S
      • Engin C
      • Daylan A
      • et al.
      Outcomes of various treatment strategies for patients with continuous-flow ventricular assist device thrombosis: a retrospective analysis.
      ,
      • Jorde UP
      • Aaronson KD
      • Najjar SS
      • et al.
      Identification and management of pump thrombus in the heartware left ventricular assist device system: a novel approach using log file analysis.
      These algorithms focus on both medical and surgical interventions, with medical management including augmentation of anticoagulation (ex: Heparin or Bivalirubin) or antiplatelet agents (oral or intravenous), use of thrombolytic therapy and surgical management including pump exchange, heart transplant (HT), or explantation.
      • Ertugay S
      • Engin C
      • Daylan A
      • et al.
      Outcomes of various treatment strategies for patients with continuous-flow ventricular assist device thrombosis: a retrospective analysis.
      • Jorde UP
      • Aaronson KD
      • Najjar SS
      • et al.
      Identification and management of pump thrombus in the heartware left ventricular assist device system: a novel approach using log file analysis.
      • Schlendorf K
      • Patel CB
      • Gehrig T
      • et al.
      Thrombolytic therapy for thrombosis of continuous flow ventricular assist devices.
      • Chetan D
      • Buchholz H
      • Bauman M
      • Anand V
      • Holinski P
      • Conway J.
      Successful treatment of pediatric ventricular assist device thrombosis.
      • Dang G
      • Epperla N
      • Muppidi V
      • et al.
      Medical management of pump-related thrombosis in patients with continuous-flow left ventricular assist devices: a systematic review and meta-analysis.
      • Oezpeker C
      • Zittermann A
      • Ensminger S
      • et al.
      Systemic thrombolysis versus device exchange for pump thrombosis management: a single-center experience.
      The choice between medical and surgical management depends on device type, stage of pump thrombosis, clinical presentation and potential complications of treatment. As there are few reports in children, it is unclear whether these strategies are applicable to pediatrics. One potential approach in pediatrics is to initiate heparin or Bivalirudin with rising LDH with or without changes in pump parameters. If no response and ongoing increases in LDH with changes in the pump parameters, in some institutions, low dose systemic tPA could be considered if no contraindications exist.
      • Chetan D
      • Buchholz H
      • Bauman M
      • Anand V
      • Holinski P
      • Conway J.
      Successful treatment of pediatric ventricular assist device thrombosis.
      Lastly, if there are contraindications to tPA, evidence of rapid progression or no response to any of the above treatments, pump exchange should be considered.
      • Chetan D
      • Buchholz H
      • Bauman M
      • Anand V
      • Holinski P
      • Conway J.
      Successful treatment of pediatric ventricular assist device thrombosis.
      In some institutions pump exchange occurs without a trial of tPA.
      Neurological Events and Stroke: Device-related neurological events (NE) as defined by INTERMACS include: cerebrovascular accidents (CVA), seizures, encephalopathy, asymptomatic neuroradiological findings, confusion and extra-axial bleeding. Using this definition, NE comprise 12% of all adverse events and tend to occur early (23% within 3 months vs 5% thereafter).
      • Rosenthal DN
      • Almond CS
      • Jaquiss RD
      • et al.
      Adverse events in children implanted with ventricular assist devices in the United States: data from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      NE are more common in PF VADs (early 19.6 and late 5.6 events per 100 patient-months) vs. CF VADs (early 4.1 and late 0.7 events per 100 patient-months). However, patient characteristics differ between those receiving PF vs CF devices and in turn event rates are likely not solely related to device type. Ten percent of patients with intracorporeal CF devices had strokes, compared to 24% among paracorporeal CF and 21% among PF devices with most being ischemic.
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      ,
      • Lorts A
      • Eghtesady P
      • Mehegan M
      • et al.
      Outcomes of children supported with devices labeled as "temporary" or short term: a report from the Pediatric Interagency Registry for Mechanical Circulatory Support.
      ,
      • VanderPluym CJ
      • Adachi I
      • Niebler R
      • et al.
      Outcomes of children supported with an intracorporeal continuous-flow left ventricular assist system.
      The ACTION Network has recently undertaken a multi-center quality initiative (QI) to decrease stroke rates through use of standardized blood pressure goals, meticulous anticoagulation including DTI and improved communication between teams.
      • Rosenthal DN
      • Lancaster CA
      • McElhinney DB
      • et al.
      Impact of a modified anti-thrombotic guideline on stroke in children supported with a pediatric ventricular assist device.
      ,

      Advanced Cardiac Therapies Improving Outcomes Network, ABC's Stroke Prevention QI Bundle, 2018, Advanced Cardiac Therapies Improving Outcomes Network. Accessed May 27, 2021. https://www.actionlearningnetwork.org.

      Additionally, VAD-related stroke management has challenges in pediatrics due to lack of standardized protocols. The ACTION Network has recently developed a stroke management bundle aimed at developing algorithm for pediatric stroke management. This emphasizes early recognition of stroke symptoms as critical, urgent neurological evaluation including a non-contrast head CT (within 30 minutes). If non-contrast head CT is negative but neurological symptoms persist, consideration should be for a CT angiogram. Institution of neuroprotective measures, intracranial pressure monitoring and potential interventions including thrombectomy or cranial decompression may be considered. In setting of ischemic stroke with evidence of vessel occlusion and large territory involvement, thrombectomy or intravenous tPA may be potential options for intervention.
      • Rhee E
      • Hurst R
      • Pukenas B
      • et al.
      Mechanical embolectomy for ischemic stroke in a pediatric ventricular assist device patient.
      • Godown J
      • Dodd DA
      • Doyle TP
      • Smith AH
      • Janssen D
      • Mettler BA
      Tissue plasminogen activator treatment of bilateral pulmonary emboli in a pediatric patient supported with a ventricular assist device.

      Ferriero DM, Fullerton HJ, Bernard TJ, et al. Management of stroke in neonates and children: a scientific statement from the American Heart Association/American Stroke Association. Stroke.2019;50:e51–e96.

      For patients with paracorporeal VAD, pump exchange should be considered if there is evidence of a clot. Anticoagulation management after VAD-related CVA is challenging. If invasive interventions are being considered, or for large territory ischemic strokes with high risk for hemorrhagic conversion, holding and potentially reversing anti-thrombotic therapy should be discussed. In setting of hemorrhagic stroke, if bleeds are small without neurological deficits, antithrombotic therapy should be held and resumed if stable neuroimaging and neurological exam. However, if there is interval expansion or large hemorrhagic involvement, antithrombotic therapy should be held and potentially reversal. Timing of re-initiation of antithrombotic therapy should be discussed among care team with consideration of repeat CT after initiation.
      Bleeding : Bleeding is a major complication of VAD implantation and affects approximately 30% of pediatric patients.
      • Blume ED
      • Rosenthal DN
      • Rossano JW
      • et al.
      Outcomes of children implanted with ventricular assist devices in the United States: first analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      ,
      • Rosenthal DN
      • Almond CS
      • Jaquiss RD
      • et al.
      Adverse events in children implanted with ventricular assist devices in the United States: data from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      The highest hazard for bleeding is in the immediate perioperative period when patients are extremely susceptible from suture lines and dissection planes.
      • Blume ED
      • Rosenthal DN
      • Rossano JW
      • et al.
      Outcomes of children implanted with ventricular assist devices in the United States: first analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      ,
      • Rosenthal DN
      • Almond CS
      • Jaquiss RD
      • et al.
      Adverse events in children implanted with ventricular assist devices in the United States: data from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      Bleeding is diagnosed when chest tube output is excessive and drops in hemoglobin necessitate transfusion. Bleeding can lead to pericardial tamponade when blood is not adequately evacuated via chest tubes. In LVAD patients, the initial clinical presentation of pericardial tamponade is typically an increase of CVP, followed by a decrease in LVAD flow (depending on the amount of RA/RV compression). As a consequence, blood pressure is usually decreased and frequently vasoactive substances have to initiated or increased. Other clinical signs for the impaired hemodynamic state are decrease in urine output and rise of serum lactate. The clinical presentation of tamponade in BiVAD patients can be very vague. Often, only an increase of CVP is initially observed which can early on be accompanied by a decrease of urine output (due to elevated CVP). Adequate hemodynamics can be obtained for a long time, depending on adequate volume replacement and VAD flow only decreases when venous return is severely compromised by compression. The threshold for surgical revision usually is persisting chest tube output despite normalization of coagulation parameters. Hemodynamic instability or tamponade should prompt immediate surgical exploration.
      The hazard for bleeding decreases with increasing support times.
      • Blume ED
      • Rosenthal DN
      • Rossano JW
      • et al.
      Outcomes of children implanted with ventricular assist devices in the United States: first analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      ,
      • Stein ML
      • Robbins R
      • Sabati AA
      • et al.
      Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS)-defined morbidity and mortality associated with pediatric ventricular assist device support at a single US center: the Stanford experience.
      ,
      • Rosenthal DN
      • Almond CS
      • Jaquiss RD
      • et al.
      Adverse events in children implanted with ventricular assist devices in the United States: data from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      While perioperative bleeding usually originates from areas affected by the VAD implantation, late bleeding events typically affect other regions and are a consequence of medication levels and vWF degradation that is a result of VAD induced blood trauma. The most frequent source of late bleeding is the gastrointestinal tract, although less frequent than the adult population.
      • Singh G
      • Albeldawi M
      • Kalra SS
      • Mehta PP
      • Lopez R
      • Vargo JJ.
      Features of patients with gastrointestinal bleeding after implantation of ventricular assist devices.

      Support strategies for unique pediatric populations

      CF VAD in small patients: The encouraging outcomes in adult VAD technology have had a profound impact on its use in children. In children, with a weight >15-20 kg requiring VAD, the use of an implantable LVAD may be feasible with results that are non-inferior to the extracorporeal devices,
      • VanderPluym CJ
      • Cedars A
      • Eghtesady P
      • et al.
      Outcomes following implantation of mechanical circulatory support in adults with congenital heart disease: an analysis of the interagency registry for mechanically assisted circulatory support (INTERMACS).
      ,
      • Blume ED
      • Rosenthal DN
      • Rossano JW
      • et al.
      Outcomes of children implanted with ventricular assist devices in the United States: first analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      ,
      • Cabrera AG
      • Sundareswaran KS
      • Samayoa AX
      • et al.
      Outcomes of pediatric patients supported by the HeartMate II left ventricular assist device in the United States.
      and discharge from the hospital is possible, resulting in a better QoL,
      • Rossano JW
      • Lorts A
      • VanderPluym CJ
      • et al.
      Outcomes of pediatric patients supported with continuous-flow ventricular assist devices: a report from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      ,
      • VanderPluym CJ
      • Cedars A
      • Eghtesady P
      • et al.
      Outcomes following implantation of mechanical circulatory support in adults with congenital heart disease: an analysis of the interagency registry for mechanically assisted circulatory support (INTERMACS).
      ,
      • Blume ED
      • Rosenthal DN
      • Rossano JW
      • et al.
      Outcomes of children implanted with ventricular assist devices in the United States: first analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      ,
      • Schweiger M
      • Miera O
      • de By T
      • et al.
      Cerebral strokes in children on intracorporeal ventricular assist devices: analysis of the EUROMACS Registry.
      • Conway J
      • Miera O
      • Henderson H.T.
      • et al.
      Global experience with the heartware HVAD in pediatric patients: a preliminary analysis.
      • Schweiger M
      • Vanderpluym C
      • Jeewa A
      • et al.
      Outpatient management of intra-corporeal left ventricular assist device system in children: a multi-center experience.
      decreased costs,
      • Evers PD
      • Villa C
      • Wittekind SG
      • Hobing R
      • Morales DLS
      • Lorts A.
      Cost-utility of continuous-flow ventricular assist devices as bridge to transplant in pediatrics.
      and the potential for chronic therapy. It remains unclear what the size cut off is for the use of these devices in smaller children.
      • Adachi I
      • Fraser Jr., CD
      Mechanical circulatory support for infants and small children.
      • Peng E
      • Kirk R
      • Wrightson N
      • et al.
      An extended role of continuous flow device in pediatric mechanical circulatory support.
      • Jefferies JL
      • Morales DL
      Mechanical circulatory support in children: bridge to transplant versus recovery.
      • Schweiger M
      • Dave H
      • Lemme F
      • et al.
      Acute chemotherapy-induced cardiomyopathy treated with intracorporeal left ventricular assist device in an 8-year-old child.
      The limited thoracic space might not be large enough to ensure proper position of an intra-corporeal device. Distortion of the rotor housing can position the inflow cannula in a plane that significantly increases the risk of inadequate drainage, suction events and/or pump thrombus formation. If necessary the pump housing may be placed in a pre-peritoneal pocket fashioned by dividing the left diaphragm anteriorly
      • Adachi I
      • Guzman-Pruneda FA
      • Jeewa A
      • Fraser Jr., CD
      • Dean McKenzie E
      A modified implantation technique of the HeartWare ventricular assist device for pediatric patients.
      or to allow the device to sit within the left pleural cavity, caudal to the left lower lobe and posterior to the diaphragm at the costo-diaphragmatic angle. In smaller patients, not only the angle of the inflow cannula, but its depth in the ventricular cavity should be considered. If placed in a small heart, the tip of the inflow cannula may approach the mitral valve, which could either impede mitral valve function or, importantly obstruct the inflow cannula. Therefore LV apex to mitral valve distance must be precisely measured on preoperative imaging.
      • Peng E
      • O'Sullivan JJ
      • Griselli M
      • et al.
      Durable ventricular assist device support for failing systemic morphologic right ventricle: early results.
      ,
      • Schweiger M
      • Kruger B
      • Cavigelli-Brunner A
      • Dave H
      • Schmiady M
      • Hubler M.
      Biventricular intracorporeal ventricular assist device in a 10-year-old child.
      Of note, the newer HM3 has a shorter inflow when compared to the HVAD (22 mm vs 32.2 mm).
      • Adachi I.
      Current status and future perspectives of the PumpKIN trial.
      Alternatively, if the mitral valve is obstructing inflow, excision of the valve may be considered with a CF device.
      Muscular Dystrophies (MD): HF is a significant cause of mortality in patients with MD.
      • Kamdar F
      • Garry DJ.
      Dystrophin-deficient cardiomyopathy.
      Patients with MD are often not candidates for HT because of the progressive nature of their multi-system disease, affecting pulmonary, neurological functioning and mobility. Some centers have reported the use of DT VADs for medically-resistant HF in these patient groups.
      • Perri G
      • Filippelli S
      • Adorisio R
      • et al.
      Left ventricular assist device as destination therapy in cardiac end-stage dystrophinopathies: midterm results.
      ,
      • Ryan TD
      • Jefferies JL
      • Sawnani H
      • et al.
      Implantation of the HeartMate II and HeartWare left ventricular assist devices in patients with Duchenne muscular dystrophy: lessons learned from the first applications.
      The use of DT in these patients require ethical and local institutional considerations.
      • Stoller D
      • Araj F
      • Amin A
      • et al.
      Implantation of a left ventricular assist device to provide long-term support for end-stage Duchenne muscular dystrophy-associated cardiomyopathy.
      Chemotherapy-Induced Cardiomyopathies (CCMP): Improvements in oncologic therapies has increased life expectancy and cure rates for many types of cancer. The cardiotoxicity risk of many chemotherapeutic regimens are well documented.
      • Babiker HM
      • McBride A
      • Newton M
      • et al.
      Cardiotoxic effects of chemotherapy: A review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system.
      ,
      • Lipshultz SE
      • Adams MJ
      • Colan SD
      • et al.
      American Heart Association Congenital Heart Defects Committee of the Council on Cardiovascular Disease in the Young CoBCSCoC and Stroke Nursing CoCR. Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association.
      VADs have been used for DT in patients with CCMP, or for BTT in patients with sustained remission. Pediatric data is limited and consistent with this being an uncommon indication for VAD therapy or HT.
      • Krasnopero D
      • Asante-Korang A
      • Jacobs J
      • et al.
      Case report and review of the literature: the utilization of a ventricular assist device as bridge to recovery for anthracycline-induced ventricular dysfunction.
      ,
      • Bock MJ
      • Pahl E
      • Rusconi PG
      • et al.
      Cancer recurrence and mortality after pediatric heart transplantation for anthracycline cardiomyopathy: a report from the Pediatric Heart Transplant Study (PHTS) group.
      In adult populations, it is estimated that 2% to 3% of patients undergoing VAD have CCMP.
      • Oliveira GH
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      • et al.
      Increased need for right ventricular support in patients with chemotherapy-induced cardiomyopathy undergoing mechanical circulatory support: outcomes from the INTERMACS Registry (Interagency Registry for Mechanically Assisted Circulatory Support).
      Considerations including the increased risks related to RV dysfunction, bleeding and sternotomy after radiation therapy should be noted prior to VAD implantation.
      • Oliveira GH
      • Dupont M
      • Naftel D
      • et al.
      Increased need for right ventricular support in patients with chemotherapy-induced cardiomyopathy undergoing mechanical circulatory support: outcomes from the INTERMACS Registry (Interagency Registry for Mechanically Assisted Circulatory Support).
      Support Strategies for Adult Congenital Heart Disease (ACHD): The prevalence of HF in ACHD is diagnosis-specific, increases with age
      • Rossano JW
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      • et al.
      Outcomes of pediatric patients supported with continuous-flow ventricular assist devices: a report from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).
      and exceeds that in the general population.
      • Blume ED
      • VanderPluym C
      • Lorts A
      • et al.
      Second annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      HT has been the optimal therapy for end-stage HF in ACHD.
      • Piperata A
      • Bottio T
      • Toscano G
      • et al.
      Is heart transplantation a real option in patients with Duchenne syndrome? Inferences from a case report.
      • Villa CR
      • Lorts A
      Cardiac destination therapy in pediatrics - Are we there yet?.
      • Tunuguntla H
      • Conway J
      • Villa C
      • Rapoport A
      • Jeewa A.
      Destination-therapy ventricular assist device in children: "The Future Is Now".
      • Perri G
      • Filippelli S
      • Adorisio R
      • et al.
      Left ventricular assist device as destination therapy in cardiac end-stage dystrophinopathies: midterm results.
      Experience is limited using VAD and/or TAH in ACHD patients as a bridge to transplant. Overall, <1% of all VADs in adults are implanted in ACHD patients. Nevertheless, ACHD patients spend more time awaiting HT
      • Silva JN
      • Erickson CC
      • Carter CD
      • et al.
      Participating Members of P and Congenital Electrophysiology S. Management of pediatric tachyarrhythmias on mechanical support.
      ,
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      ,
      • Hollander SA
      • Cantor RS
      • Sutherland SM
      • et al.
      Renal injury and recovery in pediatric patients after ventricular assist device implantation and cardiac transplant.
      and the sickest are more likely to deteriorate while awaiting HT than the non-ACHD population.
      • Karimova A
      • Pockett CR
      • Lasuen N
      • et al.
      Right ventricular dysfunction in children supported with pulsatile ventricular assist devices.
      ,
      • Neyer J
      • Arsanjani R
      • Moriguchi J
      • Siegel R
      • Kobashigawa J.
      Echocardiographic parameters associated with right ventricular failure after left ventricular assist device: A review.
      In this setting, VAD support has the potential for benefit in the ACHD population
      • Morales DLS
      • Rossano JW
      • VanderPluym C
      • et al.
      Third annual pediatric interagency registry for mechanical circulatory support (Pedimacs) report: pre-implant characteristics and outcomes.
      ,
      • Galand V
      • Flecher E
      • Auffret V
      • et al.
      Early ventricular arrhythmias after LVAD implantation is the strongest predictor of 30-day post-operative mortality.
      without impacting post-transplant outcomes.
      • Gopinathannair R
      • Cornwell WK
      • Dukes JW
      • et al.
      Device therapy and arrhythmia management in left ventricular assist device recipients: a scientific statement from the American Heart Association.
      Earlier use of VAD therapy may help to decrease the early hazard associated with HT among ACHD patients by decreasing end-organ dysfunction and relieving pulmonary hypertension secondary to CHD.
      • Stout KK
      • Broberg CS
      • Book WM
      • et al.
      Chronic heart failure in congenital heart disease: a scientific statement from the American Heart Association.
      Although ACHD patients that receive VAD have an earlier rate of mortality post VAD they have similar rates of adverse events and improved functional capacity if they survive the first 30 days.
      • Cedars A
      • Vanderpluym C
      • Koehl D
      • Cantor R
      • Kutty S
      • Kirklin JK.
      An Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of hospitalization, functional status, and mortality after mechanical circulatory support in adults with congenital heart disease.
      There are times when an underlying anatomical issue leads to HF in a patient with ACHD and in these cases correction of the underlying lesion if possible and utilization of temporary MCS strategies to support the patient perioperatively should be considered. This approach has been shown in select cases to lead to excellent outcomes avoiding long-term VAD support and HT.
      • Bellavia D
      • Iacovoni A
      • Scardulla C
      • et al.
      Prediction of right ventricular failure after ventricular assist device implant: systematic review and meta-analysis of observational studies.
      Durable VADs may still be required despite best efforts to address the etiology of ventricular failure. Underlying lesions should be corrected at the time of VAD implant including uncorrected shunts, stenotic lesions of the left AV valve and regurgitation of the aortic valve to allow optimal VAD function. If multiple residual lesions requiring surgical intervention are present or BiV support may be necessary, consideration should be given to the use of a TAH.
      Use of VADs in patients with a morphologic systemic LV is generally more conventional and fits the paradigm of non-CHD patients. Still, additional obstacles must be appreciated such as dextrocardia/heterotaxy syndrome and the risk of multiple sternotomies should not be underestimated. Furthermore, the possible need for BiVsupport should be assessed during surgical planning and be available in the operating room. Adults with a morphologic systemic RV and a sub-pulmonary morphologic LV typically have a diagnosis of either D-TGA following atrial switch or unrepaired ccTGA, or ccTGA following physiologic repair. The systemic RV is predisposed to systemic atrioventricular valve regurgitation (AVVR), ventricular dysfunction, and pump failure. Outcomes of VAD support for systemic RVF are limited to case series, but survival appears to be acceptable.
      • Fung E
      • Shaw RJ
      Pediatric Transplant Rating Instrument - a scale for the pretransplant psychiatric evaluation of pediatric organ transplant recipients.
      • Lefkowitz DS
      • Fitzgerald CJ.
      Mobile health technology for adolescent transplant recipients: what's h'app'ening in adherence promotion?.
      • Moore RA
      • Lorts A
      • Madueme PC
      • Taylor MD
      • Morales DL
      Virtual implantation of the 50cc SynCardia total artificial heart.
      Implantation may be complicated by changes in RV anatomy; the free wall and septum are much thicker and more trabeculated than in a normal RV. For intracorporeal CF-devices three different implantation sites for the RV that have been reported: diaphragmatic,
      • Huebler M
      • Stepanenko A
      • Krabatsch T
      • Potapov EV
      • Hetzer R.
      Mechanical circulatory support of systemic ventricle in adults with transposition of great arteries.
      ,
      • Loforte A
      • Montalto A
      • Della Monica PL
      • Contento C
      • Musumeci F
      Biventricular support with the HeartWare implantable continuous flow pump: an additional contribution.
      free wall
      • Huebler M
      • Stepanenko A
      • Krabatsch T
      • Potapov EV
      • Hetzer R.
      Mechanical circulatory support of systemic ventricle in adults with transposition of great arteries.
      and right atrium (RA).
      • Krabatsch T
      • Stepanenko A
      • Schweiger M
      • et al.
      Alternative technique for implantation of biventricular support with HeartWare implantable continuous flow pump.