Mechanical Circulatory Support

#### **Chapter 4**

## Durable Ventricular Assist Device for Bridge to Transplantation

*Minoru Ono*

#### **Abstract**

A durable ventricular assist device (VAD) is a key mechanical circulatory support to safely bridge a heart transplant candidate to transplantation over a long waiting period. Recent UNOS policy change has a great impact on the role of continuous-flow VAD as a bridging device. The rest of the majority of countries still rely on a cf-VAD as a safe and effective support device. A sole durable VAD for bridge to transplantation in pediatric patients is Berlin Heart EXCOR, for which there is a growing demand through the improvement of a long-term result. In this chapter, I will overview the history and the present status of durable VAD for bridge to transplantation in both adult and pediatric patients.

**Keywords:** heart transplantation, ventricular assist device, bridge to transplantation

#### **1. Introduction**

The first bridge to transplantation strategy was started in the 1980s, but a patient needed to stay in hospital due to a huge driving console, even if the device was implantable. First-generation of implantable ventricular assist device (VAD) was not widely implanted due to its huge size and a limited reliable support period. Development and introduction to the clinical arena of a rotary blood pump in the early 2000 completely changed the landscape. The smaller pump size enabled easier implantation in smaller body size patients and an operation of the device by portable batteries paved a way to outpatient management. A so-called secondgeneration device is driven in the presence of contact bearings, which were found to lead to several tough complications, such as pump thrombosis and gastrointestinal bleeding. Advent of the third-generation device, in which an impeller is rotated without contact to an inner housing by magnetic and/or hydrodynamic levitation systems. Most updated devices are manufactured by incorporating a magnetic levitation system. Thanks to these technological refinements and improvements of continuous-flow VAD (cf-VAD) support patients, the survival of patients on a VAD has been steadily prolonging. In this chapter, the current status and survival of cf-VAD patients for bridge to transplantation (BTT) in Japan and the United States (US) are reviewed.

#### **2. Bridge to transplantation in Japan: analysis of J-MACS report**

Two Japan-made cf-LVAD (EVAHEART, Sun Medical Research Corp., Nagano, Japan and DuraHeart, Terumo Heart Inc., Ann Arbor, MI) were approved for health insurance coverage as a BTT in April 2010. Subsequently, HeartMate II (Abbott, Chicago, IL) in April 2013, Jarvik 2000 (Jarvik Heart Inc., New York, NY) in January 2014, HVAD (Medtronic, Minneapolis, MN) in February 2019 and HeartMate 3 (Abbott, Chicago, IL) in July 2019 were approved for a BTT. Similar to Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) in the US, we have the Japanese Registry for Mechanically Assisted Circulatory Support (J-MACS) as a mandatory registry system of cf-LVAD. J-MACS was established in 2009 with an intention of harmonization by doing with Food and Drug Administration (FDA) in the US [1].

Registry summary report is published every year, and the most recent one was published online in March 2021 [2]. HeartMate 3 was approved as the first DT device in May 2021, so the most recent J-MACS registry report included solely data regarding a BTT strategy. This report analyzed data of cf-LVADs which were implanted by October 31, 2020. The total number of implantation was 1353, among which primary implantation was in 956 (70.7%), bridge to bridge (BTB, conversion from paracorporeal device to cf-LVAD) in 218 (16.1%) and device exchange from cf-LVAD in 179 (13.2%). The total number of patients was 1174 (primary VAD + BTB). There were 871 male patients (74.2%) with an average age of 43.5 years. The distribution of the age in decade is shown in **Table 1**. The height, weight, body mass index (BMI) and body surface area (BSA) were 167.0 +/− 8.7 cm, 57.6 +/− 11.8 kg, 20.5 +/− 3.3 kg/m2 and 1.64 +/− 0.19 m2 , respectively (**Table 2**). The majority of the patients were implanted for non-ischemic dilated cardiomyopathy (DCM; 64.8%), followed by ischemic heart disease (12.2%) and dilated-phase of hypertrophic cardiomyopathy (10.6%) (**Table 3**). The severity INTERMACS/J-MACS profile of the patients before cf-LVAD implantation was shown in **Table 4**. Almost half of the patients were implanted at profile 3 (46.7%), and only 9.1% belonged to profile 1. Kaplan–Meier survival curve showed that 1- and 2-year survival rates were 92% and 89% (**Figure 1**). The longest support exceeded 5 years.


#### **Table 1.**

*Gender and age distribution.*


#### **Table 2.**

*Patient demographics. BMI: Body mass index, BSA: Body surface area.*


*CHD: congenital heart disease, IHD: ischemic heart disease, HCM: hypertrophic cardiomyopathy, VHD: valvular heart disease, DCM: idiopathic dilated cardiomyopathy, RCM: restrictive cardiomyopathy.*

#### **Table 3.**

*Causative diseases.*


#### **Table 4.**

*Preimplant INTERMACS/J-MACS profile.*

**Figure 2** shows Kaplan–Meier survival stratified by the age group by decade. Patients with age in 50s and over 60 years had significantly worse survival (p < 0.0001). **Figure 3** shows the survivals divided by preoperative J-MACS profiles, demonstrating a significantly worse survival in profile 1 (p = 0.032). **Figure 4** shows the competing

**Figure 1.** *Actuarial survival after BTT cf-LVAD implantation.*

#### **Figure 2.**

*Actuarial survival after BTT cf-LVAD implantation stratified by age group.*

outcomes. Waiting time for heart transplantation is more than 4 years recently, so the curve of survival on the device crosses that of transplantation around 1500 days.

Pump thrombosis-free curve is shown in **Figure 5** with 1- and 2-year event-free rates of 97% and 97% for the primary implant, which is much less compared to an INTERMACS report. Driveline infection-free curve is shown in **Figure 6**, demonstrating that 1- and 2-year event-free rates are 78% and 67% for a primary implant.

**Figure 4.** *Competing outcomes.*

**Figure 7** shows stroke-free curve including all stroke events of any grade. The gastrointestinal bleeding-free curve is shown in **Figure 8**, demonstrating 1- and 2-year event-free rate of 95% and 93% for primary implantation, which is much more infrequent compared to the US. **Figure 9** shows the readmission-free rate. Almost twothirds of the patients were readmitted within 1 year and three-quarters in 2 years, which is still an important issue to be solved. **Figure 10** shows a pump exchange free rate with a 1- and 2-year event-free rate of 96% and 92% for primary implantation.

**Figure 5.** *Pump thrombosis-free rate divided by primary VAD and BTB.*

#### **Figure 6.**

*Driveline infection-free rate divided by primary VAD and BTB.*

#### **3. Heart transplantation in Japan: analysis of heart transplantation registry**

Five hundred sixty-six heart transplantations (512 adult and 54 pediatric HTx) were performed by December 2020 in Japan since the Organ Transplantation Act came into force in October 1997 [3]. **Figure 11** shows the number and the type of circulatory support device on which the recipient was placed at the time of HTx [4]. There were only three recipients who were not on any circulatory support including inotropes. All these

**Figure 8.**

*Gastrointestinal bleeding-free rate divided by primary VAD and BTB.*

three were pediatric patients. Thirty-two recipients (5.7%) were on continuous inotropic support. Thus, the majority of the recipients (93.8%) were on any type of mechanical circulatory support. Paracorporeal air-driven LVAD was used in 126 patients (22.3%), including 110 Nipro VAD (Nipro, Osaka, Japan) and 16 Berlin Heart Excor pediatric VADs (Berlin Heart GmbH, Berlin, Germany). Implantable LVAD was used in 393 recipients (69.4%) and 12 patients (2.1%) were on biventricular VAD (BIVAD) support. Most frequently implanted cf-LVAD device was HeartMate II in 166, followed by EVAHEART in 86, Jarvik 2000 in 61, DuraHeart in 56 and so on. A small number of first-generation implantable pulsatile devices were used in the early years (n = 11).

**Figure 9.** *Readmission-free rate divided by primary VAD and BTB.*

#### **Figure 10.**

*Pump exchange-free rate divided by primary VAD and BTB.*

**Figure 12** shows a yearly trend of the type of circulatory support [4]. Paracorporeal VADs were mainly used for a BTT before the year 2011 when two Japan-made cf-LVAD were approved for health insurance coverage. Berlin Heart Excor pediatric was started to be covered by health insurance in 2015. **Figure 13** shows a yearly trend of waiting time for HTx divided by adult and pediatric recipients [4]. Since a shortage of braindead donations is extreme in Japan, a waiting time has continuously prolonged and reached 1625 days in adult recipients in 2020. A waiting time was variable year by year in pediatric recipients, but in general longer than that of Western countries.

*Durable Ventricular Assist Device for Bridge to Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102467*

#### **Figure 11.**

*The number and the type of circulatory support at HTx(n = 566). Cf-VAD: continuous-flow left ventricular assist device, PI VAD: pulsatile implantable left ventricular assist device, P-LVAD: paracorporeal left ventricular assist device.*

#### **Figure 12.**

*The number and the type of circulatory support at HTxin each year. Cf-VAD: continuous-flow left ventricular assist device, PI VAD: pulsatile implantable left ventricular assist device, P-LVAD: paracorporeal left ventricular assist device.*

#### **4. Impact of bridge to transplantation on the results of heart transplantation: from ISHLT registry report**

A cf-VAD has been widely used for a BTT in these two decades due to improvement of long-term safe support, less complications and size miniaturization. **Figure 14** is from ISHLT (International Society for Heart and Lung Transplantation) 2019 Annual Report Slides [5], showing an annual trend of a ratio of adult patients who were bridged to HTx with mechanical circulatory support devices. Including LVAD, BIVAD, VAD + ECMO and isolated RVAD, 52.5% and 49.6% of the recipients were bridged to HTx in 2016 and 2017, respectively. An isolated LVAD support was the

#### **Figure 13.**

*Waiting time for heart transplantation in both adult and pediatric recipients.*

#### **Figure 14.**

*Adult heart transplants. The ratio of patients bridged with mechanical circulatory support by year and device type.*

majority like 49.6% and 47.0% in 2016 and 2017, respectively. **Figure 15** from ISHLT 2019 Report demonstrates that survival (89.9% and 77.6% at 1 and 5 years) in patients with cf-LVAD support is identical with that of no LVAD/no inotrope group (90.0% and 79.0%) or no LVAD/Inotrope group (91.9% and 78.7%) [5]. Cox-hazard analysis of risk factors for 1-year mortality among adult heart transplants between 2012 and June 2017 showed that VAD support was a significant risk factor (p < 0.01; HR 1.241, 95% CI 1.082–1.424). However, VAD bridge was not a significant risk factor for cardiac allograft vasculopathy (CAV) or severe renal dysfunction within 5 years by Cox-hazard analysis of adult heart transplants conditional on survival to discharge between 2008 and June 2013 [5].

**Figure 16** from ISHLT Pediatric HTx 2019 Annual Report shows an annual trend of a ratio of patients who were bridged with mechanical circulatory support [6]. Different from adult recipients, an increasing trend of the MCS bridge ratio was not steady, but there was a trend for increase with 31.8% in VAD or TAH and 1.5% in VAD + ECMO. **Figure 17** demonstrates that about a quarter of pediatric

#### **Figure 15.**

*Adult heart transplants. Kaplan–Meier survival by pre-transplant mechanical circulatory support use (transplants: Jan 2010 –June 2017).*

#### **Figure 16.**

*Pediatric heart transplants. Ratio of patients bridged with mechanical circulatory support by year (transplants: Jan 2005 –Dec 2017).*

#### **Figure 17.**

*Pediatric heart transplants. The ratio of patients bridged with mechanical circulatory support by the device (transplants: Jan 2010 –June 2018).*

#### **Figure 18.**

*Pediatric heart transplants. The ratio of patients bridged with mechanical circulatory support by age group (transplants: Jan 2010 –June 2018).*

#### **Figure 19.**

*Pediatric heart transplants. Kaplan–Meier survival by mechanical circulatory support usage (transplants: Jan 2010 –June 2017).*

recipients were bridged with LVAD (20.2%) or BIVAD (5.4%) between 2010 and June 2018 [6]. Notably, almost a half of the recipients were bridged with LVAD (39.8%) or BIVAD (8.7%) in DCM among transplants between 2010 and June 2018 [6]. **Figure 18** shows a ratio of patients who were bridged with MCS divided by age group [6]. A total of 30% patients with age of 1 to 17 years were bridged with VAD or TAH, or VAD + ECMO [6]. **Figure 19** is a Kaplan–Meier survival curve stratified by device strategies, demonstrating that survivals of the VAD or TAH group (93.7% and 85.2% at 1 and 5 years) are not different from those of no support group (93.1% and 84.8%) [6]. The VAD support was a risk factor for 1-year mortality by Cox-hazard analysis (p = 0.02; HR 1.396, 95% CI 1.047–1.860). However, as in adult HTx, pretransplant VAD use was not associated with CAV progression or renal dysfunction within 5 years conditional on survival to discharge.

#### **5. Most recent publications on bridge to transplantation**

In addition to BTT, a cf-VAD has been implanted for bridge to candidacy or destination therapy. A recent trend of survival after cf-VAD implantation for each strategy was reported in The Society of Thoracic Surgeons (STS) INTERMACS 2020 annual Report [7]. Survival of cf-LVAD patients by a device strategy is shown in **Figure 20**. Patients with a BTT strategy enjoyed better survival than those with other strategies. The absolute difference of survival at each year between BTT and DT strategies ranged from 6.7% to 10.3%. Steady improvement of survival after HTx with cf-VAD support was clearly demonstrated in the ISHLT adult heart transplantation 2021 report [8]. As shown in **Figure 21**, a significant improvement in survival is achieved as years elapsed. A similar finding was also confirmed in pediatric recipients with a BTT strategy [9].

A new heart allocation policy was introduced in October 2018 with an intention to: 1. decrease a wait-list death, and 2. equalize a chance to be transplanted for a severely ill recipient. This policy change made the new donor heart allocation system to prioritize candidates supported by temporary devices. However, waitlist and posttransplant outcomes in candidates with durable LVAD remain to be elucidated. Mullan et al. analyzed the United Network for Organ Sharing (UNOS) database of adults with cf-LVAD at listing or implanted while listed between April 2017 and April 2020, and elucidated that the number of patients listed with LVAD decreased nationally over time from 102 in April 2017 to 12 in April 2020 (p < 0.001). The proportion of patients with LVAD at the time of transplant decreased from 47% to 14% (**Figure 22**) [10]. They also showed that transplantation rates were not different before and after the allocation policy change (85.4% vs. 83.6%; p = 0.225), but waitlist time decreased in the post-period (82 vs. 65 days; p = 0.004). Waitlist survival did not change, but post-transplantation survival was worse in patients with BTT post-change (p < 0.001) [10]. Abrupt decrease of a BTT strategy among cf-LVAD implantation was endorsed by the STS INTERMACS 2020 annual Report (**Figure 23**) [7].

Edelson et al. conducted an ISHLT data analysis to seek the influence of mechanical circulatory support on post-transplant outcomes in pediatric patients [11]. Among

#### **Figure 20.**

*Kaplan–Meier survival curves for primary cf-LVAD for 2015–2019 by implant strategy. BTC: Bridge to candidacy, BTT: Bridge to transplant, Cf-LVAD, continuous-flow left ventricular assist device, DT: Destination therapy.*

**Figure 21.**

*Adult heart transplants with cf-VAD BTT. Kaplan–Meier survival within 12 months by recipient era (transplants: Jan 2000 -Jun 2017).*

**Figure 22.**

*Trends in LVAD utilization in patients listed for heart transplantation.*

5095 patients between 2005 and 2017, 26% of patients received MCS prior to transplant: 240 (4.7%) on extracorporeal membrane oxygenation (ECMO), 1030 (20.2%) on VAD, and 54 both. They found that survival in congenital heart disease (CHD) and DCM was similar in patients with no MCS or those with VAD, while pretransplant ECMO use is strongly associated with death after transplant particularly in children with CHD. HTx in patients with Fontan operation has been challenging, and a durable LVAD has been used to bridge a post-Fontan patient anecdotally. The first collective study of durable VAD support in Fontan patients was reported in 2021. Cedars

*Durable Ventricular Assist Device for Bridge to Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102467*

#### **Figure 23.**

*Implant strategy by implant year for primary continuous-flow LVADs.*

et al. conducted a retrospective analysis of data collected in the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) registry, a multicenter learning network of pediatric hospitals actively involved in the implantation and management of VADs in children and adults with CHD [12]. They identified 45 Fontan patients implanted with a VAD. The average age of patients was 10 years (interquartile range: 4.5–18). The majority of patients were INTERMACS Profile 2 (56%). The most commonly employed device was the Medtronic HVAD (56%). A total of 13 patients were discharged on device support, and 67% of patients experienced adverse events, the most common of which were neurologic (25%). At 1 year after device implantation, the rate of transplantation was 69.5%, 9.2% of patients continued to be VAD supported, and 21.3% of patients had died.

#### **6. Conclusions**

In this chapter, the author reviews durable VAD used for a BTT. BTT strategy both in adult HTx by cf-LVAD and in pediatric HTx by Berlin Heart Excor or cf-LVAD is mandatory in Japan because a waiting time is over 4 years in adults and over 2 years in children due to a severe donor shortage. A total of 95% of adult HTx and 80% of pediatric HTx were bridged with a durable LVAD as of December 2020. As shown by J-MACS registry data, the survival of cf-LVAD patients was favorable. In the majority of European countries and the US cf-VAD use for a BTT was steadily increasing. VAD support was employed successfully in about 50% in adult and about 30% in pediatric HTx recipients. Survival after HTx with durable VAD support has been improving, and no survival difference is observed compared to that of recipients without VAD support. Recent heart allocation policy change in the US had a great impact on a judgment to choose a durable LVAD for a BTT. A chance to choose BTT strategy by using cf-LVAD will be declining undoubtedly, but nobody still knows what will be a future outcome.

### **Author details**

Minoru Ono Department of Cardiovascular Surgery, The University of Tokyo, Tokyo, Japan

\*Address all correspondence to: ono-tho@h.u-tokyo.ac.jp

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Nakatani T, Sase K, Oshiyama H, Akiyama M, Horie M, Nawata K, et al. J-MACS investigators. Japanese registry for Mechanically Assisted Circulatory Support: First report. The Journal of Heart and Lung Transplantation. 2017;**36**(10):1087-1096

[2] J-MACS statistical report. Available from: https://www.jpats.org/society/ jmacs/report.html [Accessed: December 3, 2021]

[3] Numbers of donated and transplanted organs in Japan. Available from: https:// www.jotnw.or.jp/data/offer03.php [Accessed: December 10, 2021]

[4] The number and the type of circulatory support at heart transplantation in Japan. Available from: http://www.jsht. jp/2021/04/17/registry/japan/20201231%E 3%83%AC%E3%82%B8%E3%82%B9%E 3%83%88%E3%83%AA2.pdf [Accessed: December 11, 2021]

[5] ISHLT adult heart transplantation statistics in 2019. Available from: https:// ishltregistries.org/registries/slides. asp?yearToDisplay=2019 [Accessed: December 11, 2021]

[6] ISHLT pediatric heart transplantation statistics in 2019. Available from: https:// ishltregistries.org/registries/slides. asp?yearToDisplay=2019 [Accessed: December 11, 2021]

[7] Molina EJ, Shah P, Kiernan MS, Cornwell WK 3rd, Copeland H, Takeda K, et al. The Society of Thoracic Surgeons Intermacs 2020 Annual Report. The Annals of Thoracic Surgery. 2021;**111**(3): 778-792

[8] Khush KK, Hsich E, Potena L, Cherikh WS, Chambers DC, Harhay MO, et al. Stehlik J; International Society for

Heart and Lung Transplantation. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirtyeighth adult heart transplantation report - 2021; Focus on recipient characteristics. The Journal of Heart and Lung Transplantation. 2021;**40**(10):1035-1049

[9] Singh TP, Cherikh WS, Hsich E, Chambers DC, Harhay MO, Hayes D, et al. International Society for Heart and Lung Transplantation. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Twenty-fourth pediatric heart transplantation report - 2021; Focus on recipient characteristics. The Journal of Heart and Lung Transplantation. 2021;**40**(10):1050-1059

[10] Mullan CW, Chouairi F, Sen S, Mori M, Clark KAA, Reinhardt SW, et al. Changes in Use of Left Ventricular Assist Devices as Bridge to Transplantation With New Heart Allocation Policy. JACC Heart Fail. 2021;**9**(6):420-429

[11] Edelson JB, Huang Y, Griffis H, Huang J, Mascio CE, Chen JM, et al. The influence of mechanical Circulatory support on post-transplant outcomes in pediatric patients: A multicenter study from the International Society for Heart and Lung Transplantation (ISHLT) Registry. The Journal of Heart and Lung Transplantation. 2021;**40**(11):1443-1453

[12] Cedars A, Kutty S, Danford D, Schumacher K, Learning Network Investigators ACTION, Auerbach SR, et al. Systemic ventricular assist device support in Fontan patients: A report by ACTION. The Journal of Heart and Lung Transplantation. 2021;**40**(5):368-376 Erratum in: J Heart Lung Transplant. 2021 Dec;40(12):1685

#### **Chapter 5**

## Heart Transplant after Mechanical Circulatory Support

*Elena Sandoval and Daniel Pereda*

#### **Abstract**

Heart transplant is the gold-standard treatment for end-stage heart failure. However, the aging of the population, increase in the prevalence of heart failure and the shortage of available donors have led to a significant increase in the wait-list times. This increase in waiting time may cause some patients clinically deteriorate while on the list. Several bridging strategies have been developed to help patients reach heart transplant. It is mandatory to know the current results of these techniques and the specific tips and tricks these different devices may have. Survival results would also be presented to help us decide the best strategy for each of our patients.

**Keywords:** heart transplant, short-term mechanical circulatory support, ECMO, long-term mechanical circulatory support, survival

#### **1. Introduction**

Heart transplant is the gold-standard treatment for end-stage heart failure since the first case, performed by Christiaan Barnard, on December 3, 1967 in Cape Town [1]. This first case was the results of previous works led mainly by Norman Shumway at Stanford. After an initial spread of the technique and the development of different transplant programs, the actual number of heart transplants declined due to impaired outcomes, mostly due to infections and rejection [2]. Only a few groups, mainly Stanford in the USA and the Pitié-Salpêtrière in Europe, continued investigating and working on trying to improve their patients' outcomes. It was not until the introduction of cyclosporine as an immunosuppressor, that solid organ transplant outcomes significantly improved [3]. This significant change in patient management led to the final expansion of the technique and the development of multiple programs across the world.

Technical and medical developments have caused previously lethal conditions that evolve into chronic ones, increasing the prevalence of end-stage heart failure. This increase, in addition to the aging of the population, has led to a disbalance in the number of donors available, which has remained stable over the last years according to ISHLT data [4]. This disbalance has caused an increase in the waiting time period, leading to the development of different strategies to sustain patients.

This abovementioned shortage of donors, which is common to most countries, forced the transplant programs to expand their acceptance criteria with the such called "extended-criteria donors." This means that older donors with longer ischemic times were now accepted. Despite the initial concerns, results have been acceptable, with similar survivals at 1-year, 89% vs. 86% in the published reports [5, 6]. The increase achieved in the donor pool was still insufficient, so additional donors were evaluated. The pediatric groups developed the ABO group non-compatible heart transplant [7], while adult groups developed strategies for accepting HCV+ donors [8], treating recipients with the new antiviral in the immediate postoperative period, or started programs of donation after circulatory death (DCD donors) [9, 10]. It is important to remark that these different strategies to expand the donor pool have accomplished similar survival, both short (96% vs. 89% at 1-year) and medium-term (94% vs. 82% at 5 years) results, as the conventional donors [11].

As mentioned, the shortage in the donor pool leads to prolonged times on the waiting list. Some patients, however, would deteriorate during this waiting time. Different support strategies have been developed to sustain declining patients to allow for organ recovery and patient rehabilitation before the transplant. These bridging strategies can be classified into two main groups—short-term support and long-term support. Both of them have particularities that will be further developed.

#### **2. Short-term mechanical circulatory support (ST-MCS)**

Short-term support devices are the first line of support in patients who need emergent support, such as INTERMACS 1 patients, as they provide immediate hemodynamic support with an almost immediate deployment time, in some of them, such as ECMO or Impella®. In addition to those, there are other devices, such as Levitronix-Centrimag®, that need a surgical implant. It is worth mentioning that whereas ECMO provides complete circulatory support with one device, the other ones would need two pumps to provide full biventricular support.

Recently, several allocation systems changed their distribution policies aiming at providing a fair allocation of donors. These modifications meant that patients under ST-MCS achieve the highest priority on the waiting list [12].

#### **2.1 Indications**

All ST-MCS devices share common indications, the most common ones are as follows [13]:


The choice of the device would depend mostly on availability and patient factors. The different devices provide variable degrees of support and have inherent implantation requirements; there is general agreement that ECMO would be the device of choice in cases with cardiac arrest as it can be implanted percutaneously at the bedside. It would also be the preferred option in cases of respiratory compromise and biventricular failure.

Impella*®* support is most commonly used for cardiogenic shock secondary to myocardial infarction; the smaller (2,5 and CP) devices can be inserted percutaneously but the bigger ones (5,0 and 5,5) require insertion through a prosthesis.

Levitronix Centrimag*®* requires a surgical implant. It is commonly used in postcardiotomy shock, primary graft failure, or isolated right ventricular failure after a long-term ventricular assist device. It allows for the longest support; so, it is the preferable device in cases of the bridge to recovery.

#### **2.2 General management**

During the recovery period or the waiting time, it is recommended to extubate patients if possible. If this can be accomplished, oral nutrition is the preferred option. If the patient cannot be extubated, tube feedings would be the best option, above parenteral nutrition; this should be reserved for patients with significant instability and the need for high-dose pressors.

Volume status should be maintained as neutral as possible, initially with diuretics, but it is not uncommon that patients under ST-MCS develop acute kidney injury and need renal replacement therapies (RRT). In our group, we promote early use of RRT to help to manage the volume status and avoid hypervolemia at the time of the transplant.

In addition to recovering the organ, it is important to keep the muscular tone with daily physical therapy, even with static bicycle or ambulation within the unit, whenever possible.

Simultaneously to recovering the patient, special attention should be paid to the management of the device. It should provide enough support to allow for organ recovery minimizing the potential complications. To prevent them, it is recommended to perform daily echocardiograms and keep close monitoring of central venous pressure and pulmonary pressure. Blood pressure control is mandatory to reduce the risk of neurological complications but also to reduce afterload that may interfere with the device function; the higher the afterload, the lower the left ventricular unloading. We would suggest avoiding medications with a long half-life to minimize the risk of vasoplegia during the transplant.

#### **2.3 Specialized management**

#### *2.3.1 Anticoagulation*

All devices require systemic anticoagulation; unfractionated heparin is the most common anticoagulant used. A single bolus, normally 1 mg/kg, is administered at the time of ECMO or Levitronix implant. Systemic infusion is not started until the coagulation parameters have been normalized and there are no signs of bleeding. For example, in cases of central cannulation, anticoagulation would be started once the chest tube output is less than 50–80 ml/h for 6 hours.

ECMO is a device that requires a higher dose as it has an oxygenator. The patient receives a bolus of heparin at the time of the implant and after that ACT is kept around 180–200 seconds and/or aPTT around 60–80 seconds [14].

Impella systems *®* require a heparinized dextrose-based purge solution and systemic heparinization with ACT around 160–160 seconds for its proper functioning. A recent publication by Beavers [15] proposes variations of the purge solution that can be modified depending on the patients' status.

Levitronix-Centrimag *®* also requires systemic anticoagulation; the usual aPTT goal is 50–70 seconds. In all cases, systemic anticoagulation is maintained until the time of the transplant.

During the time on support, careful attention should be paid to the platelet count; in case, a sudden drop is noticed we would recommend to test for heparin-induced thrombocytopenia. Type 2 HITT may be a terrible complication that limits a patient's options. If suspected, heparin should be immediately replaced by bivalirudin or argatroban.

#### *2.3.2 Infections*

There is no general consensus regarding antibiotic prophylaxis while on shortterm support. However, most groups administer it, especially if the implant has been performed in emergent circumstances. Regarding the duration of the therapy, the ELSO ID Taskforce [16] does not recommend using antibiotic prophylaxis for more than 48 hours. In cases of central cannulation when the chest is left open, most groups would maintain the prophylaxis while the sternum is open.

Patients on short-term support are highly instrumentalized, with increased transfusion requirements and a higher incidence of renal failure compared to the general intensive care unit population; all these factors increase the risk of systemic infections. Biffi et al. reported bacteriemia rates around 20% and lower respiratory tract infections that oscillated between 4 and 55% [17].

Due to the higher instrumentalization, the most common pathogens are coagulase-negative *staphylococci*, followed by *Candida spp* and *Pseudomonas pp*. The use of parenteral nutrition in these patients increases the risk of fungal infections.

Infections while on support can significantly impact the patients' treatment options. A recent publication by the Spanish transplant group proved that infections while of support reduced the options of reaching a heart transplant [18].

#### **2.4 Pretransplant assessment**

At the time of the transplant, specific considerations should be taken into account depending on the device the patient is being bridged with:

#### *2.4.1 ECMO or extracorporeal membrane oxygenator*

ECMO has increased its use as a bridging device, as it provides immediate support for rapidly declining patients and those unstable or in cardiogenic shock. When using ECMO as a bridging strategy, several aspects should be taken into account. From the technical perspective, there are two key points. The first one is venous cannulation; careful attention must be paid to reduce the ECMO flows at

#### *Heart Transplant after Mechanical Circulatory Support DOI: http://dx.doi.org/10.5772/intechopen.102589*

the time of venous cannulation to avoid air entry. If this occurs, the device may stop or the patient may suffer systemic emboli. Secondly, ECMO support has the risk of developing left-sided intracavitary stasis with its inherent risk of systemic emboli. Unnecessary cardiac manipulation should be avoided before applying the aortic clamp.

From the medical standpoint, the team must be aware that ECMO support may cause lung congestion, which may be not evident while on support, but that may appear when trying to abandon cardiopulmonary bypass. This pulmonary impairment may cause hypoxemia or right ventricular failure.

#### *2.4.2 IMPELLA®*

This percutaneous axial pump is normally placed through the femoral artery or the axillary artery, inside the left ventricle. When used as a bridge-to-transplant, the axillary artery insertion is preferable as it allows the patient to ambulate and facilitates the patient's rehabilitation.

At the time of the transplant, as the device crosses the aortic valve, surgeons should remove it into the aorta before applying the aortic clamp. After the implant is performed, attention should be paid to repairing the arterial entry site.

#### *2.4.3 Levitronix-centrimag®*

This magnetically levitated device provides up to 8 l/min of support and it is approved for 30 days support. It requires surgical intervention for its implant, in general, through a median sternotomy. However, some minimally invasive strategies have been proposed [19].

Its surgical implant should be performed considering the current patients' clinical status but also the future transplant. For instance, when tunneling the cannulas, it is recommended to keep the exit site far away from the sternotomy, to avoid any potential cross-contamination. In addition, surgeons should also keep in mind the future transplant; to ease that, it is our preferred approach to place the arterial cannula low in the aortic root; so, the entry site is removed at the time of the implant and we have enough ascending aorta to cannulate and perform the aortic anastomosis. If the patient has some residual ventricular function and the surgical team decides to cannulate the left atrium as an inflow cannula, our suggestion would be to cannulate the left atrial roof. This structure would be removed while doing the cardiectomy and avoid manipulation of the pulmonary veins.

At the time of the transplant, the surgical team must take into account the time needed for surgical dissection; if the patient has been supported for more than 10 days, some extra time might be necessary to isolate the different cardiac structures. In addition, some technical details should also be considered; special attention should be placed to avoid unnecessary manipulation of the cardiac structures before applying the aortic clamp. Some small clots might have formed in the cardiac chambers and there is the risk of systemic emboli in cases of aggressive manipulation.

Cannulation is also an important step, particularly at the time of the double venous cannulation in the patient under biventricular support. In these cases, special attention must be paid to ensure the right-side device flow reduction at the time of the cannula insertion to avoid air entry. Both cannulas should be placed already clamped to prevent air entry.

As mentioned, we prefer to place the outflow cannula low in the aortic root, but if the cannula is placed in the ascending aorta, the surgical team would have to decide if the left side device is interrupted and the arterial cannula reused for the cardiopulmonary bypass (CPB) machine or if a second arterial cannula is necessary.

At the end of the procedure, it is mandatory to achieve careful hemostasis to minimize postoperative bleeding; some groups propose to leave the chest open to reduce the risk of tamponade and bleeding.

#### **2.5 Surgical considerations**

Short-term mechanical support is normally implanted in patients under cardiogenic shock. This extremely acute situation, with patients that are usually under mechanical ventilation and who can barely move due to a peripheral device, makes it difficult to complete the detailed transplant evaluation that would be performed in an ambulatory situation. Despite the urgency of the situation, we would encourage to follow a so-called "parallel pathway," while recovering the patient like in **Figure 1**, an evaluation as complete as possible is performed, even more, if the patient has not been previously managed by the team. Our group has diagnosed end-stage neoplasm during these preoperative studies (**Figures 2** and **3**).

#### **2.6 Results**

Despite the systemic recovery achieved with these devices, several groups have shown their concerns regarding the outcomes of transplants with this ST-MCS bridging strategy. In 2018, the Spanish Transplant working group published a manuscript showing a 33% mortality when patients were bridged with ECMO and 11.9% when bridged with short-term left-sided devices [20]. Other reports have also shown reduced initial survival results when patients are bridged with ST-MCS [21, 22]. In previous publications, ECMO reveals as the bridging strategy with the shortest waiting times but also the worst post-transplant survival results. These

#### **Figure 1.**

*Shows a patient, who is under biventricular temporary support, sitting on a chair during his/her intensive care unit stay. The patient was able to eat by himself/herself and do some physical therapy.*

*Heart Transplant after Mechanical Circulatory Support DOI: http://dx.doi.org/10.5772/intechopen.102589*

#### **Figure 2.**

*Shows a lung tumor found in the pre-transplant assessment of patient support with peripheral ECMO.*

#### **Figure 3.**

*(a) shows the entry site of the arterial cannulas from a biventricular Levitronix-Centrimag®. (b) displays the abdominal study of the same patient, where a right renal tumor can be observed.*

worst results may be due to an early transplant with incomplete recovery of the organs in addition to pulmonary impairment due to insufficient left ventricular unloading.

In addition to this increased early mortality, different publications show a higher rate of postoperative transfusions and longer hospital length of stay compared to direct heart transplant or even, transplant with long-term devices [23].

#### **3. Long-term mechanical circulatory support (LT-MCS)**

As stated before, the increase in waiting list times may cause the clinical deterioration of patients awaiting a suitable organ. Long-term mechanical circulatory support offers these patients clinical stability and avoidance of multiorgan deterioration during this waiting time. Several devices have been developed, such as the Heartmate XVE*®*, the Heartmate II*®*, Heartware-HVAD*®*, Jarvik*®*, Syncardia*®*, and the HeartMate 3*®*. The last one is the most commonly used nowadays.

Most of them provide only univentricular support, mostly to the left ventricle. In cases where biventricular support is needed, a second device can be used "of-label' to provide right ventricular support. Syncardia*®* and Carmart*®* are also known as "total artificial hearts" providing biventricular support with a single device. The major drawback of all these devices is the need for an additional surgical intervention before the heart transplant.

#### **3.1 Indications**

The primary indication of LT-MCS devices is end-stage chronic heart failure. Most left ventricular assist devices require a minimal end-diastolic left ventricular diameter for their implant, which is easily accomplished in cases of ischemic or dilated cardiomyopathy. In cases of restrictive cardiomyopathy, with small left ventricular cavities or cases with biventricular failure, a total artificial heart would be indicated.

The hemodynamic indications according to ISHLT guidelines [13, 24] are as follows:


#### **3.2 Specialized management**

#### *3.2.1 Anticoagulation*

LT-MCS requires antithrombotic treatment since the early postoperative period to prevent thrombotic events [25, 26]. Each manufacturer has its own specific recommendations; however, in general, most centers follow the below strategy:


The target INR is 2.0–3.0. The antithrombotic treatment should be tailored to the patient's clinical status.

In cases of heparin-induced thrombocytopenia, intravenous direct thrombin inhibitors, such as bivalirudin or argatroban, can be used. New oral anticoagulants have not been validated for the treatment of long-term MCS devices.

#### *3.2.2 Infection*

Infections will occur in nearly 60% of the implanted patients and the rate increases with the duration of support [27, 28]. The most common pathogens are gram-positive bacteria that colonize the skin and adhere to the implanted material creating biofilms; *staphylococci spp* account for more than 50% of infections followed by *enterococci spp.* Between the gram-negative rods, *Pseudomonas spp* is the most frequent, being responsible for 22–28% of infections [28].

Before a scheduled implant, it is recommended to remove all unnecessary lines and ensure there are no active infections. In cases of active infection, in special if bacteriemia, it is recommended to delay the implant until clearance of the infection, whenever possible.

A few years ago, antibiotic prophylaxis included gram-positive cocci, gramnegative rods, and fungi and it was maintained for days. The most current recommendations moved to the general cardiac surgery prophylaxis, using a cephalosporin that is maintained for 24–48 hours. In addition, MRSA should be discarded with a preoperative nasal swab and nasal mupirocine is applied [25].

Once the device has been implanted if an infection develops, it can be classified as [26, 27]:


Device-specific infections are the ones that actually involve the device and they vary from driveline infection to pump infection with mediastinitis. The most important aspect is prevention. For example, during the surgical implant, it is recommended to keep all the velour parts of the driveline covered and ensure proper fixation of the driveline to avoid excessive movements.

It is of extreme importance that both the patient and the caregiver learn how to perform the sterile dressing changes of the driveline; patients also need to recognize signs of alarm, such as erythema or purulent discharge. Keeping a photographic diary might be helpful. It is also important that the wound is periodically evaluated during the clinic visits.

Driveline infections should be individually addressed; if the patient has no general symptoms, treatment can start with increased dressing changes and culture-directed antibiotics. On the other hand, in case of systemic symptoms, intravenous antibiotics should be started. In these cases, a PET-CT scan might be performed to assess the extension of the infection. If image tests reveal the presence of collections, re-routing of the driveline might be necessary. If the infection has affected the actual device, pump exchange or transplant might be the only curative option and it is recommended that blood cultures are negative at the time of the surgery.

When transplanting a patient with an infected device, the surgical must minimize deeper contaminations; for example, in cases of driveline infection, the exit site must be sealed from the rest of the surgical fields avoiding contact between infected and non-infected fields. In cases of device-specific infections involving blood contact surfaces, surgeons should minimize the embolic risk by early initiation of cardiopulmonary bypass, stoppage of the pump, and application of the aortic clamp. If active mediastinal infection is found, extensive debridement and antibiotic irrigation are recommended. After that, all surgical materials should be changed. In these circumstances, some groups would leave the chest open with antibiotic irrigation. After the surgery, antibiotic treatment should be targeted to prior cultures.

It may seem controversial to transplant patients with a current infection. However, several reports have shown no differences in survival compared with patients transplanted on LT-MCS support without infection [29].

#### *3.2.3 Blood pressure control*

Blood pressure control is mandatory while on long-term support. Hypertension leads to increase afterload, thus reducing the device flows and the left ventricular unloading. In addition, there is a significant relationship between high blood pressure and adverse events, such as stroke or aortic regurgitation [30, 31].

As the devices are continuous flow, it is possible that patients have no pulse; in an intensive care unit, it is recommended to use invasive lines to monitor the blood pressure; whereas if the patient is ambulatory, a doppler measurement of the blood pressure is the preferred system [25]. The doppler reading is equivalent to the mean blood pressure.

For blood pressure control, the current recommendations include the use of reninangiotensin-aldosterone system antagonists as first-line; beta-blockers are recommended in cases of arrhythmias but should be carefully used if the right ventricular function is poor. Calcium channel blockers would be the third option for blood pressure control [24, 25].

#### **3.3 Surgical implant**

When a bridge-to-transplant strategy is considered in a patient who is going to receive an LT-MCS device, the surgical implant must be carefully planned to ease the future heart transplant.

The device could be divided into different components, the inlet cannula and the pump, the outflow graft, and the driveline.

The inlet cannula is placed inside the left ventricle and secured with a sewing ring. Some groups reinforce this ring with surgical glues, which may lead to increased adhesions.

Careful attention should be paid to the length and layout of the outflow graft, in special at the time of the chest closure. It should run smoothly along with the right-side cavities. A short graft would lay immediately under the sternum (**Figure 4A**), increasing the risk of damaging it during the reesternotomy. An excessively long graft is at risk of twisting, impairing the pump function. Its anastomotic site in the ascending aorta should be performed, taking into account that it should be removed at the time of the transplant and that enough ascending aorta should be left to perform the anastomosis.

The driveline should also be carefully placed. Our group does a double route; we exteriorize the driveline into the subcutaneous tissue at the left upper quadrant and

#### **Figure 4.**

*A shows an outflow tract running immediately below the sternum. In this case, the implant was performed minimally invasive, so the risk of injury at the time of the transplant was lower. B shows non-conventional outflow tract layouts; this patient had the outflow anastomosis placed at the descending aorta. This risk of injury was lower at the reesternotomy but achieving control of it might be more difficult.*

then tunnel it to the right upper quadrant, leaving a short intrapericardial portion away from the sternum, to avoid damaging it during the mediastinal reentry at the transplant time.

Reinterventions in patients with long-term devices are challenging due to extensive adhesion formation [32]. Several strategies have been developed to facilitate these reinterventions. The most extended one is covering the device and the outflow tract with PTFE sheets that would reduce the adhesions and, at the same time, might protect the pump components during the dissection [33, 34]. A different approach would be pursuing a less-invasive approach, either with two thoracotomies or a left thoracotomy and a mini-sternotomy. In these less invasive approaches, the avoidance of an extended pericardial opening and limited cardiac manipulation reduces the development of adhesions [35].

#### **3.4 Transplant surgery**

Despite the careful surgical implant, we would suggest that every patient with an LT-MCS who is a transplant candidate should have a postimplant computed tomography to know the final position of the different device components (**Figure 4A** and **B**).

At the time of the implant, the surgical team must carefully plan the times as surgical dissection may be more difficult and time-consuming than conventional reinterventions. Once we accept the organ, it is our preferred approach to reverse anticoagulation with prothrombin complex to avoid volume overload and start the anesthetic process. Our advice would be to start the reintervention enough in advance to be able to perform an extremely careful dissection in order to minimize intraoperative and postoperative bleeding.

We suggest that both the abdomen and the groins should be prepped; the abdomen should be accessible to remove the driveline and femoral vessel cannulation may be necessary in some cases.

Once the reesternotomy is performed, the main goal is achieving control of the aorta and, both cava veins and the outflow graft, so, cardiopulmonary bypass (CPB) can be started. Most groups suggest completing the device dissection while on CPB support. It is important to stop the LT-MCS device and occlude its outflow graft when starting the CPB machine to avoid backward flow. In cases of different outflow graft implant sites, for example, in the descending aorta, control of it should also be

achieved before starting the CPB machine. Once CPB is supported, the pump removal can be performed. The cardiectomy is completed in the usual way, making sure the outflow anastomotic site is removed.

After completion of the implant, it is mandatory to achieve proper hemostasis to minimize the need for blood products and reduce the risk of postoperative tamponade.

Following protamine administration, the driveline should be removed. In cases of driveline infection, as previously mentioned, the driveline exit site would be kept in a different surgical field to minimize the contamination of the mediastinum; thus, the internal part of the driveline would be removed from the inside and the infected part would be pulled once the chest is closed. As all foreign material should be removed, two incisions may be necessary to remove the totality of the driveline; we suggest doing extensive debridement of the exit site in cases of infection and ensure proper closing of the wounds to reduce the risk of collection development, even with the use of vacuum-assisted therapy.

#### **3.5 Results**

With the development of LT-MCS, several transplant programs report their concern regarding the impact of this bridging strategy on the transplant outcomes [36, 37]. However, long-term devices have proved themselves as successful bridgeto-transplant devices. Despite being a challenging surgery, survival results are comparable to direct transplant strategies in recent publications [23, 38, 39]and recent publications only showed a higher post-transplant transfusion need in the bridged group [23, 36].

Recent ISHLT data from its transplant registry show 90% 1-year survival in either direct transplant or bridge with left ventricular assist device; these same data showed decreased initial survival if patients were bridged with either biventricular support or total artificial heart, probably due to a worse preoperative status [40].

In addition to survival, the other main concern with this bridging strategy is post-transplant vasoplegia. Contradictory results have been published in this regard [41, 42].

#### **3.6 Bridge-to-bridge**

As previously developed, recent changes in the allocations systems give the highest priority to the sickest patients. However, this might lead to transplant patients who have had not enough time to recover organ function or who could have not been fully evaluated worsening transplant results. A way of avoiding this phenomenon would be the bridge-to-bridge strategy, which means that a patient under ST-MCS would be transitioned to a long-term device and transplanted once fully recovered and rehabilitated.

Before the surgery, a careful assessment of right ventricular function and associated valvular lesions, such as significant aortic regurgitation or tricuspid regurgitation, must be performed. The presence of intracavitary thrombi should also be evaluated. The presence of any of these lesions in addition to the initial device would impact the surgical technique and the approach. For example, if the patient is under ECMO support, the long-term device implant could be performed under the same support. In these cases, if concomitant lesions have been discarded, it is even possible to perform a minimally invasive device insertion. However, teams must keep in mind

that right ventricular function is difficult to evaluate while on ECMO support. Thus, in addition to potential pulmonary congestion leads to a significantly higher incidence of postoperative right ventricular failure [43].

When the initial device is an Impella*®*, due to its peripheral implant, it is possible to perform the insertion both through a minimally invasive approach or through a median sternotomy. If the surgical team prefers to follow the minimally invasive approach without CPB support, we would suggest to have the femoral vessels prepared for cannulation in case the patient collapses at the time of stopping the Impella*®* device.

Once the implant of the new device has been finished, it is important not to forget to repair the cannulation site, ensuring the proper distal flow of the extremity to minimize vascular complications, which may have a high impact on survival.

If the patient is bridged from a Levitronix Centrimag*®*, the most probable approach would be through a median sternotomy; in these cases, we would suggest to transition the temporary support to cardiopulmonary bypass and then perform the implant. This strategy will allow to lift the heart without instability and to inspect the left ventricular chambers to remove any potential debris.

Despite ST-MCS allowing for rapid recovery, these patients can still be considered the sickest ones. As mentioned, the incidence of post-device right ventricular failure may reach up to 20%, higher than in the non-bridged population [43]. In addition, 1-year survival after the implant is also worse compared to the general LVAD population (1-year survival 70% vs. 91%) [39]. Despite these initial poorer results, when these patients recover and are transplanted, results are as successful as transplant after primary LVAD insertion, with 1-year survival around 90% [39].

#### **4. Discussion**

Heart transplant remains the gold-standard treatment for end-stage heart failure since the first case was performed in 1967. Once the initial issues with rejection were solved after the introduction of cyclosporine, results significantly improved and several transplant programs developed.

Simultaneously, several therapeutic advances led to significant improvement of pathologies previously lethal. This new chronicity of several cardiomyopathies in addition to an aging population made heart failure one of the most prevalent diseases, thus increasing the number of heart transplant candidates. On the other hand, the number of potential donors for a heart transplant was actually maintained or even diminished; this situation caused a clear disbalance and the shortage of donors became a reality.

Mechanical circulatory support was initially developed for patients who could not be weaned from CPB, such as the first implant performed by Dr. DeBakey and it became a field in continuous development. However, it was not until the early 2000s when the REMATCH trial [44] showed better survival with LT-MCS than with conventional treatment for end-stage heart failure patients. These results led to a tremendous expansion of the therapy with different devices being developed. Since the first generation XVE to the current HeartMate 3, devices have become smaller and more hemocompatible, significantly improving the results, both of survival and adverse effects. With the huge advances in the field, in addition to the shortage of donors, the heart failure community realized that LT-MCS, despite requiring additional surgery and the inherent technical complexities at the time of the transplant, was the best

option to allow patients to reach the transplant in the best clinical situation possible; until the last allocation system modification, nearly 50% of the recipients in the USA had a previous long-term device.

In addition to the chronic heart failure population, as physicians, we face a significant proportion of patients with acute heart failure. In these circumstances, shortterm MCS would be the preferred option. Short-term devices allow for rapid patient stabilization and organ recovery. In some cases, patients' myocardial function would recover and the device would be explanted, while in other cases, patients would need further therapies, such as heart transplants. This situation might be tricky as the transplant evaluation has to be performed under support, which might limit its depth, and the treating physicians should find the appropriate moment to list the patient finding a weak balance between patient recovery and avoidance of complications. As ST-MCS patients can be considered the sickest ones, the different allocations systems give these patients the highest priority on the transplant list, so they can have more opportunities of being transplanted. However, this strategy also increases the risk of transplanting patients not fully recovered or fully evaluated, which has proved to worsen transplant results [45], especially if ECMO is the bridging device.

The initial impairment of survival using the ST-MCS bridging strategy let to consider alternative strategies; the most used one, whenever possible, would be the bridge-to-bridge, which means transitioning a patient from short-term to a long-term device to allow for complete recovery. In these cases, patients undergo an additional surgical procedure, such as the LT-MCS implant, but they can be fully evaluated and be listed when they are completely recovered. Groups that follow this strategy have already published results comparable to the patients bridged directly with an LT-MCS device.

Aside from the device used, their common goal is to ensure the patient reaches the transplant in the best possible clinical condition. To ensure it, it is fundamental that patients' physical status is improved with adequate nutrition and adapted physical therapy, which should be started as soon as possible, to avoid muscle mass loss. In addition to recovery, the avoidance of adverse effects is of extreme importance; accurate blood pressure control would help to reduce the incidence of neurologic events and also the development of aortic regurgitation. It would also reduce afterload, which would improve the left ventricular unloading and signs of congestion. Prevention of infections is another striking aspect; it starts in the same operating theater with the implant of the driveline and it continues during the whole time on support, with accurate dressing changes and accurate follow-up [25, 26]. In the cases of ST-MCS, the same rules apply; in these cases, removal of unnecessary lines and careful assessment of the cannulas exit site might help in the reduction of infections.

Once at the time of the transplant, the surgical team should be aware of the different particularities of each device and plan the procedure accordingly. Dissection of long-term devices might need additional time compared to other cardiac reinterventions or ST-MCS devices may need an earlier aortic clamp than other cases. As important as surgical timing is planning additional procedures that might be required, such as vascular repair, wound debridement, or removal of an infected driveline. In this last case, special care should be taken to avoid mediastinal contamination.

Post-transplant care has no differences compared to non-bridged patients; immunosuppression regimens and rejection surveillance are kept the same; the only specific situation would be the extension of antibiotic treatment in cases of device infection and it should be individually discussed with the ID team.

Despite the initial concerns regarding transplant outcomes after the use of a mechanical device, results have proved to be excellent, with survival rates similar to the non-bridged population in the case of LT-MCS. ST-MCS might not seem a good strategy due to worse initial results. However, physicians should take into consideration that we are facing the sickest patients and that these temporary devices may be the only option available for these acute patients [39].

#### **5. Conclusions**

Mechanical circulatory support as a bridge-to-transplant strategy allows for patient recovery, increased functional capacity, and a reduction in wait-list mortality.

Despite the surgical challenges the different support strategies associate, posttransplant survival results have proved them a good strategy to safely bridge patients to heart transplant.

#### **Conflict of interest**

None of the authors has any conflict of interest regarding this manuscript.

### **Author details**

Elena Sandoval\* and Daniel Pereda Cardiovascular Surgery Department, Hospital Clínic, Barcelona, Spain

\*Address all correspondence to: esandova@clinic.cat

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Barnard CN. Human heart transplantation. Canadian Medical Association Journal. 1969;**100**:91-104

[2] Baumgartner WA, Reitz BA, Bieber CP, Oyer PE, Shumway NE, Stinson EB. Current expectations in cardiac transplantation. The Thoracic and Cardiovascular Surgeon. 1978;**75**:525-530

[3] Oyer PE, Stinson EB, Jamieson SW, et al. Cyclosporine a in cardiac allografting: A preliminary experience. Transplantation Proceedings. 1983;**15**: 1247-1252

[4] Khush KK, Cherikh WS, Chambers DC, Goldfarb S, Hayes D, Kucheryavava AY, et al. The international thoracic organ transplant registry of the International Society for Heart and Lung Transplantation: Thirty-fifth adult heart transplantation report- 2018; focus theme: Multiorgan transplantation. The Journal of Heart and Lung Transplantation. 2018;**37**(10):1155-1206

[5] Samsky MD, Patel CB, Owen A, Schulte PJ, Jentzer J, Rosember PB, et al. Ten-year experience with extended criteria cardiac transplantation. Circulation. Heart Failure. 2013;**6**(6): 1230-1238. DOI: 10.1161/ CIRCHEARTFAILURE.113.000296

[6] Schüler S, Parnt R, Warnecke H, Matheis G, Hetzer R. Extended donor criteria for heart transplantation. The Journal of Heart Transplantation. 1988;**7**(5):326-330

[7] Gil-Jaurena JM, Perez-Caballero R, Murgoitio U, Pardo C, Pita A, Camino M, et al. A neonatal ABO non-compatible heart transplant from a circulatorydetermined death donor using NRP/

cold storage. Pediatric Transplantation. 2021;**Oct 18**:e14169. DOI: 10.1111/ petr.14169

[8] Woolley AE, Singh SK, Goldberg HJ, Mallidi HR, Givertz MM, Mehra MR, et al. Heart and lung transplants from HCV-infected donors to uninfected recipients. The New England Journal of Medicine. 2019;**380**(17):1606-1617

[9] Dhital KK, Chew HC, Macdonald PS. Donation after circulatory death heart transplantation. Current Opinion in Organ Transplantation. 2017;**22**:189-197

[10] Messer S, Page A, Colah S, et al. Human heart transplantation from donation after circulatory-determined death donors using normothermic regional perfusion and cold storage. The Journal of Heart and Lung Transplantation. 2018;**37**:865-869

[11] Dhital K, Ludhani P, Scheuer S, Connellan M, Macdonald P. DCD donations and outcomes of heart transplantation; the Australian experience. Indian. The Journal of Thoracic and Cardiovascular Surgery. 2020;**36** (Suppl. 2):224-232. DOI: 10.1007/ s12055-020-00998

[12] UNOS/OPTN. Adult Heart Allocation Changes. https://optn.transplant.hrsa. gov/learn/professional-education/ adult-heart-allocation/

[13] McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal. 2021;**42**:3599-3726. DOI: 10.1093/ eurheartj/ehab368

[14] ELSO anticoagulation guidelines. 2015. www.elso.org

*Heart Transplant after Mechanical Circulatory Support DOI: http://dx.doi.org/10.5772/intechopen.102589*

[15] Beavers CJ, DiDomenico RJ, Dunn SP, Cox J, To L, Weeks P, et al. Optimizing anticoagulation for patients receiving Impella support. Pharmacotherapy. 2021;**41**(11):932-942. DOI: 10.1002/ pharm.2629

[16] ELSO ID Taskforce recommendation summary. www.elso.org

[17] Biffi S, DiBella S, Scaravilli V, Peri AM, Graselli G, Alagna L, et al. Infections during extracorporeal membrane oxygenation: Epidemiology, risk factors, pathogenesis and prevention. International Journal of Antimicrobial Agents. 2017;**50**:9-16. DOI: Doi.org/10.1016/j.antimicag. 2017.02.025

[18] Solla-Buceta M, González-Vílchez F, Almenar-Bonet L, Lambert-Rodríguez JL, Segovia-Cubero J, González-Costello J, et al. Infectious complications associated with shortterm mechanical circulatory suport in urgent heart transplantation candidates. Revista Española de Cardiología (English Edition). 2021;**26**:S1885-S5857. DOI: 10.1016/jrec.2020.11019

[19] Sandoval E, Fernández-Cisneros A, Pereda D. Asian Cardiovascular & Thoracic Annals. 2020;**28**(9):604-606. DOI: 10.1177/0218492320951014

[20] Barge-Caballero E, Almenar-Bonet L, González-Vílchez F, Lambert-Rodríguez JL, González-Costello J, Segovia-Cubero J, et al. Clinical outcomes of temporary mechanical circulatory support as a direct bridge to heart transplantation: A nationwide Spanish registry. European Journal of Heart Failure. 2018;**20**:178-186

[21] Yin MY, Wever-Pinzon O, Mhera MR, Selzman CH, Toll AE, Cherikh WS, et al. Post-transplant outcome in patients bridged to transplant with temporary mechanical circulatory support

devices. The Journal of Heart and Lung Transplantation. 2019;**38**(8):858-869. DOI: 10.1016/j.healun.2019.04.003

[22] Moonsamy P, Axtell AL, Ibrahim NE, Funamoto M, Tolis G, Lewis GD, et al. Survival after heart transplantation in patients bridged with mechanical circulatory support. JACC. 2020;**75**(23):2892-2905. DOI: 10.1016/j. jacc.2020.04.037

[23] Finnan MJ, Bakir NH, Itoh A, Kotkar KD, Pasque MK, Damiano RJ, et al. 30 years of heart transplant: Outcomes after mechanical circulatory support from a single center. The Annals of Thoracic Surgery. 2021;**113**(1):41-48. DOI: 10.1016/j.athoracsur.2021.01.064

[24] Pagani F, Schueler S, Uriel N, Maltais S. ISHLT Monograph Series: Mechanical Circulatory Support Series. Vol. 14. Birmingham, Alabama: UAB; 2020

[25] Potapov E, Antonides C, Crespo-Leiro MG, Combes A, Färber G, Hannan MM, et al. 2019 EACTS expert consensus on long-term mechanical circulatory support. European Journal of Cardio-Thoracic Surgery. 2019;**56**(2):230-270. DOI: 10.1093/ejcts/ ezz098

[26] Kirklin JK, Pagani FD, Goldstein DJ, John R, Rogers JG, Atturi P, et al. American Association for Thoracic Surgery/International Society for Heart and Lung Transplantation guidelines on selected topics in mechanical circulatory support. The Journal of Heart and Lung Transplantation. 2020;**39**(3):187-219. DOI: 10.1016/j.healun.2020.01.1329

[27] Hannan MM, Husain S,

Mattner F, Danziger-Isakov L, Drew RJ, Corey GR, et al. Working formulation for the standardization of definitions of infections in patients using ventricular

assist devices. The Journal of Heart and Lung Transplantation. 2011;**30**(4):375- 384. DOI: 10.1016/j.healu.2011.01.717

[28] Hannan MM, Xie R, Cowger J, Schueler S, de By T, Dipchand AI, et al. Epidemiology of infection in. Mechanical circulatory support: A global analysis from the ISHLT mechanically assisted circulatory support registry. The Journal of Heart and Lung Transplantation. 2019;**38**:364-373. DOI: doi.org/10.1016/j. healun.2019.01.007

[29] Jiritano F, Serraino GF, Rossi M. Ventricular assist device driveline infection: Treatment with plateletrich plasma. The Annals of Thoracic Surgery. 2013;**96**:e37-e38. DOI: 10.1016/j. athoracsur.2013.01.093

[30] Tchoukina I, Smallfield MC, Shah KB. Device management and flow optimization on left ventricular assist device support. Critical Care Clinics. 2018;**34**(3):453-463. DOI: 10.1016/j. ccc.2018.03.002

[31] Saeed O, Jermyn R, Kargoli F, Madan S, Mannem S, Gunda S, et al. Blood pressure and adverse events during continuous flow left ventricular assist device support. Circulation. Heart Failure. 2015;**8**(3):551-556. DOI: 10.1116/ CIRCHEARTFAILURE.114.002000

[32] Kocher A, Coti I, Laufer G, et al. Minimally invasive aortic valve replacement through an upper hemisternotomy: The Vienna technique. European Journal of Cardio-Thoracic Surgery. 2018;**53**(suppl. 2):ii29-ii31

[33] Leprince P, Rahmati M, Bonnet N, et al. Expanded polytetrafluoroethylene membranes to wrap surfaces of circulatory support devices in patients undergoing bridge to heart transplantation. European

Journal of Cardio-Thoracic Surgery. 2001;**19**:302-306

[34] Vitali E, Russo C, Tiziano C, Lanfranconi M, Bruschi G. Modified pericardial closure technique in patients with ventricular assist device. The Annals of Thoracic Surgery. 2000;**69**:1278-1279

[35] Schmitto JD, Krabtasch T, Damme L, Netuka I. Less invasive HeartMate 3 left ventricular assist device implantation. Journal of Thoracic Disease. 2018;**10** (Suppl. 15):S1692-S1695. DOI: 10.21037/ jtd.2018.01.26

[36] Russo MJ, Hong KN, Davies RR, et al. Posttransplant survival is not diminished in heart transplant recipients bridged with implantable left ventricular assist devices. The Journal of Thoracic and Cardiovascular Surgery. 2009;**138**:1425-1432

[37] Fukuhara S, Takeda K, Polanco AR, Takayama H, Naka Y. Prolonged continuous-flow left ventricular assist device suport and posttransplantation outcomes: A new challenge. The Journal of Thoracic and Cardiovascular Surgery. 2016;**151, 3**:872-880.e5. DOI: 10.1016/j. jtcvs.2015.10.024. Epub 2015 Oct 22

[38] Maltais S, Jaik NP, Feurer ID, Wigger MA, DiSalvo TG, Schlendorf KH, et al. Mechanical circulatory support and heart transplantation: Donor and recipient factors influencing graft survival. The Annals of Thoracic Surgery. 2013;**96**:1252-1258

[39] Yoshioka D, Li B, Takayama H, Garabn RA, Yopkata VK, Han J, et al. Outcomes of heart transplantation after bridge to-transplant strategy using various mechanical circulatory support devices. Interactive Cardiovascular and Thoracic Surgery. 2017;**25**:918-924. DOI: 10.1093/icvts/ivx201

*Heart Transplant after Mechanical Circulatory Support DOI: http://dx.doi.org/10.5772/intechopen.102589*

[40] Khush KK, Hsich E, Potena L, Cherikh WS, Chambers DC, Harhay MO, et al. International Society for Heart and Lung Transplantation: Thirty-eight adult heart transplantation report-2021; focus on recipient characteristics. The Journal of Heart and Lung Transplantation. 2021;**40**(10):1023-1072. DOI: 10.1016/j. healun.2021.07.022

[41] Chan JL, Kobashigawa JA, Aintablian TL, Dimbil SJ, Perry PA, Patel JK, et al. Characterizing predictors and severity of vasoplegia syndrome after heart transplantation. The Annals of Thoracic Surgery. 2018;**105**(3):770-777. DOI: 10.1016/j. athoracsur.2017.09.039. Epub 2017 Dec 28

[42] Clerkin KJ, Mancini DM, Stehlik J, Cherikh WS, Hund LH. Continuousflow mechanical circulatory support is not associated with early graft failure: An analysis of the International Society for Heart&lung transplantation registry. Clinical Transplantation. 2019;**33**(12):e13752. DOI: 10.1111/ctr.13752

[43] Shah P, Pagani FD, Desai SS, Rongione AJ, Maltais S, Haglund NA, et al. Outcomes of patients receiving temporary circulatory support before durable ventricular assist device. The Annals of Thoracic Surgery. 2017;**103**(1):106-112. DOI: 10.1016/j. athoracsurg.2016.06.002

[44] Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, et al. Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study group. The New England Journal of Medicine. 2001;**345**(20):1435-1443. DOI: 10.1056/ NEJMoa.012175

[45] Cogswell R, John R, Estep JD, Duval S, Tedford RJ, Pagani FD, et al. An early investigation of outcomes with the new 2018 donor heart allocation system in the United States. The Journal of Heart and Lung Transplantation. 2020;**39**(1):1- 4. DOI: doi.10.1016/j.healun.2019.11.002

#### **Chapter 6**

## The Role of Large Impella Devices in Temporary Mechanical Circulatory Support for Patients Undergoing Heart Transplantation

*Yukiharu Sugimura, Sebastian Bauer, Moritz Benjamin Immohr, Arash Mehdiani, Hug Aubin, Ralf Westenfeld, Udo Boeken, Artur Lichtenberg and Payam Akhyari*

#### **Abstract**

Large microaxial pump systems (Impella 5.0, or Impella 5.5; i.e., Impella 5+) (Abiomed Inc., Danvers, MA, USA) have gained increasing levels of attendance as valuable tools of mechanical circulatory support (MCS). Patients undergoing heart transplantation (HTX) often need temporary MCS in the perioperative course, either as a preoperative bridge or occasionally in the early post-transplant period. Here we present our experience using Impella 5+ support for patients designated to undergo HTX, describe technical aspects of implantation and removal, and further analyze factors influencing the overall patient outcome. Significant factors are discussed in front of the background of contemporary international literature, and current scientific questions are highlighted.

**Keywords:** cardiogenic shock, heart failure, Impella, heart transplantation, bridge to transplant, temporary mechanical circulatory support

#### **1. Introduction**

Impella (Abiomed Inc., Danvers, MA, USA) is a microaxial pump catheter inserted retrogradely into the left ventricle (LV) via the aortic valve to support antegrade blood flow from LV to the ascending aorta by the lifting force of rotation. Due to less invasive closed-chest application and convenient profile, Impella 5+ has attracted an increasing level of attention and widespread use to stabilize CS patients and to provide temporary mechanical circulatory support (MCS) combined with LV unloading.

Patients undergoing heart transplantation (HTX) often need large Impella 5+ as part of temporary mechanical circulatory support (tMCS) in the perioperative course, either as a preoperative bridge or occasionally in the early post-transplant period. However, despite some observational studies the evidence supporting this is yet limited, particularly in the specific cohort of patients awaiting HTX [1]. Therefore, we summarize the reported articles that focused on large Impella for a bridge to transplantation (BTT). Further, we present our experience using Impella 5+ support for patients undergoing HTX and further analyze factors influencing the overall patient outcome.

#### **2. ECMELLA strategy for a bridge to candidacy**

Impella 5+ plays a significant role as part of tMCS in patients considered eligible for a bridge to candidacy. In crash and burn patients suffering from acute cardiogenic shock or refractory decompensated heart failure, physicians are faced with four clinical therapy choices: (1) conservative therapy with adequate inotrope support, (2) tMCS using va-ECMO implantation, (3) tMCS by Impella implantation, and (4) the combination of the latter two represented by so-called ECMELLA concept.

Traditionally, va-ECMO is preferred as the first choice of tMCS for acute or sustained CS, e.g., in the setting of cardiopulmonary resuscitation (CPR), because of its convenience, rapid initiation effect, and stable mode of action. Moreover, patients can be not only supported hemodynamically but also regarding the respiratory situation. However, va-ECMO does not unload the left ventricle (LV), and by increasing the afterload, it may lead to LV congestion, pulmonary edema, and secondary right ventricular (RV) failure. To compensate for these limitations of va-ECMO, a large microaxial pump catheter, i.e., Impella 5+, maybe additionally administrated to obtain the concept of "ECMELLA" support. Herein, Impella enables to provide antegrade flow and unload LV to reduce myocardial oxygen consumption and increase coronary perfusion, which leads to improving pulmonary congestion [2]. Simultaneous use of Impella with va-ECMO contributes to a shift of LV pressure-volume loops to the left, which is particularly effective when a larger microaxial pump is used. This is supported by a simulation study, in which a 23% decrease in end-diastolic LV volume and a 41% decrease in pulmonary capillary wedge pressure has been demonstrated [3].

Regarding the superiority of clinical outcomes of ECMELLA over va-ECMO, a recent meta-analysis sheds new light on patient outcomes [4]. A total of 425 patients (only va-ECMO (n = 312 (73.4%)) and ECMELLA (n = 113 (26.6%)) arising from five retrospective observational comparative studies were selected for this analysis [5–9]. Although most of ECMELLA cohorts received "small" Impella, i.e., (Impella CP or Impella 2.5; n = 95 (84.1%), Impella 5.0; n = 18 (15.9%)), study results prompted the authors to suggest that ECMELLA strategy might contribute to lower mortality with a reasonable potential to improve the hemodynamic status and promote bridge to recovery or to the next therapy, i.e., pMCS or HTX. Further observational/meta-analysis studies support this hypothesis [10–12]. Further, the multicenter cohort study "STOP-SHOCK" shows a 21% reduction in 30-day mortality in propensity-score matched patients with LV unloading by Impella (thereof n = 14 with Impella 5.0; (5.5%)) despite a higher rate of bleeding or ischemic complications *versus* controls with ECMO alone (n = 255 per each group) [13]. At present, although no randomized, controlled trial exists, we can conclude that a growing body of evidence may favor the effectiveness of ECMELLA strategy on clinical outcomes. As far as timing of Impella implantation under va-ECMO is concerned, "STOP-SHOCK" has indicated that early LV unloading, i.e., before or within 2 hours after va-ECMO initiation, was associated with lower 30-day mortality (hazard ratio 0.76, P = 0.03). In contrast, delayed LV unloading, i.e., >2 hours post va-ECMO, revealed no significant effect of LV venting on 30-day mortality according to subanalysis. In another prospective observational study termed

*The Role of Large Impella Devices in Temporary Mechanical Circulatory Support for Patients… DOI: http://dx.doi.org/10.5772/intechopen.101680*

"HACURE" from Hannover in Germany, the efficacy and safety of early MCS escalation therapy, i.e., ECMELLA has been evaluated. Although the authors did not specify the exact time window between the first MCS device and the implementation of the second MCS device, the study showed a reasonable survival rate (survival on MCS 61%, at 30 days 49%, 6 months 40%) and acceptable safety (hemolysis in 55%, major TIMI bleeding in 1%, limb ischemia in 9%) [14]. In summary, ECMELLA strategy involving an early initiation of LV unloading with large Impella under va-ECMO is a promising approach for better clinical outcomes, and this strategy may contribute to improved progression to the next therapy step beyond "bridge to candidacy", i.e., "bridge to pMCS" or "bridge to transplant."

#### **3. Role for a bridge to pMCS/HTX strategy**

In fact, how many Impella 5+ patients could be successfully bridged to pMCS/HTX? A comprehensive search of the database "Pubmed" up to September 20, 2021 in English has been conducted. Studies that focused on clinical outcomes inclusive transition to pMCS/HTX in consecutive series of adult patients (>18 years) with CS utilizing a large Impella system, i.e., Impella 5+, were included. Case reports were excluded. In the interest of comparable results, studies that did not mention the size of applied Impella were also excluded. Some studies contained patients with various sizes of Impella or with other LV unloading systems. These were also excluded because of a small cohort of large Impella systems and mixed effects. Finally, a total of 6 observational studies were signed up (**Table 1**) [15–20].

Because the patient cohort of each study was heterogeneous, e.g., proportion of ECMELLA patients varying between 10 and 74%, the mortality rate of each study also differed (23.5–50%). However, patients who were successfully weaned from Impella 5+ were 13.1–38.2% of total patients. On the other hand, 16–61% of patients were successfully bridged to pMCS/HTX. Of note, patients who were successfully bridged to pMCS/HTX obtained favorable clinical outcomes. Strikingly, almost all patients who underwent HTX survived until discharge. Seese *et al.* reported that 24% (n = 57) of all patients on the waiting list for HTX being on Impella 5.0 support (n = 236) finally experienced HTX, in whom post-transplant survival rate was excellent as 96.5% at 30-day, 93.8% at 90-day, and 90.3% at 1-year follow-up [19]. Despite no information of simultaneous use of va-ECMO (ECMELLA), Lima *et al.* also reported that 75% of patients in the bridge to pMCS/HTX group treated with Impella 5.0 were successfully transferred to subsequent therapy (left ventricular assist device (LVAD) or HTX), and survival rate at discharge was 93% (HTX) and 87% (LVAD) in these groups, respectively [21].

As a study for the superior function of preconditioning of Impella 5+ for direct bridging to HTX, Nordan *et al.* performed a retrospective analysis comparing MCS by Impella with IABP support. In this study, all patients were supported with either "solo" LV unloading (most of all; Impella 5.0) or IABP. They observed that the post-transplant survival rate is comparable between Impella-bridged patients and IABP-bridged patients despite higher operative risk in Impella-bridged patients.

In summary, although there are no randomized comparative studies about clinical outcomes between groups with and without Impella 5+ in CS patients and we cannot make definitive statements in this field yet, we suppose that large Impella systems most likely offer a valuable contribution to preconditioning of CS patients and to



*Overview and outcomes of large Impella with a focus on the transition to pMCS/HTX.*

*The Role of Large Impella Devices in Temporary Mechanical Circulatory Support for Patients… DOI: http://dx.doi.org/10.5772/intechopen.101680*

bridging strategies to pMCS/HTX, and furthermore, these strategies are associated with excellent postoperative clinical outcome.

#### **4. Expected role for a bridge to recovery in post-transplant phase**

After HTX, comprehensive therapy is required for recovery. We sometimes encounter life-threatening complications. Primary graft dysfunction (PGD) is one of the critical complications and might occur in 2-28% of patients in the acute phase after HTX [22]. In PGD, mortality is reported to be as high as up to 85% [22]. The primary clinical manifestation of PGD is LV failure, which is affected by various factors, e.g., age and ischemic time of donor, acute rejection [23, 24]. Thus, most patients require MCS, e.g., va-ECMO support or temporary ventricular assist device (VAD) in PGD. A recent study has indicated that va-ECMO initiation due to "early graft failure," defined as the need of va-ECMO within the first 24-hours post-HTX, might be associated with a worse survival rate at 1 year (36%) and 5 years (28%) when compared to outcome in patients without early graft failure [25]. On the other hand, as far as temporary extracorporeal centrifugal VAD, i.e., CentriMag (Levitronix, LLC, Waltham, MA, USA) is concerned, a retrospective study of CentriMag utilization in the setting of PGD in 34 post-HTX patients reported that CentriMag support contributed to the salvage of 32% patients with severe PGD (survival rate at 30 days; 50%, at 1 year; 32%) [26].

The efficacy of Impella is theoretically comparable to that of CentriMag when used as a temporary VAD. Because of its convenient use, Impella will be the preferred system for the management of PGD. However, no studies have been yet reported, to the best of our knowledge. We suppose that Impella certainly must have been used as a bridge to recovery tool in the early post-HTX phase in clinical practice. Due to limited cases of PGD, no robust data have been published so far. More studies are warranted to evaluate the role of standard and primary utilization of Impella for PGD.

#### **5. Our experience**

#### **5.1 Background**

At our institute, Impella 5+ has been utilized since November 2018. We reported our initial experience with the first 50 consecutive cases treated with Impella 5+, in which patients were enrolled in the observation period between November 2018 and August 2020 [15]. However, meanwhile more patients have been treated with Impella 5+ at our institution. In front of this background, we would like to discuss the clinical role and the clinical outcomes of Impella 5+ in the setting of a bridge to HTX. As described, reports on the role of Impella 5+ in the context of the bridge to HTX are still scarce. Thus, we designed a single-center observational retrospective study to identify the clinical outcome of large Impella-bridged HTX and to elucidate the usefulness of the large Impella system as a temporary MCS in a larger patient cohort.

#### **5.2 Study population**

At our institute from November 2018 up to September 2021, a total of 102 Impella 5+ were utilized for MCS in 89 patients. Finally, pMCS implantation or HTX were

#### **Figure 1.**

*Flow chart of the study population for analysis. BTT, bridge to transplant; DT, destination therapy; HTX, heart transplantation; LVAD, left ventricular assist device.*


*Data documented as n (%) or mean ± standard deviation. COPD, chronic obstructive pulmonary disease; CPR, cardiopulmonary resuscitation; DCM, dilatative cardiomyopathy; ICM, ischemic cardiomyopathy; PCI, percutaneous coronary intervention; va-ECMO, venous–arterial extracorporeal membrane oxygenation.*

#### **Table 2.**

*Baseline clinical characteristics.*

performed in 12 of them (13.5%), in whom 11 patients were directly bridged to pMCS/HTX under Impella 5+ support, whereas 1 patient underwent HTX after successfully weaning of Impella 5 at the current admission.

*The Role of Large Impella Devices in Temporary Mechanical Circulatory Support for Patients… DOI: http://dx.doi.org/10.5772/intechopen.101680*

LVAD implantation as primary pMCS was performed in 8 patients whose therapy concept was "BTT" for 7 patients and "destination therapy (DT)" for 1 patient because of his advanced age (76 years old).

Direct HTX were performed in 4 patients (primary HTX; n = 3, secondly HTX; n = 1). Further, HTX following LVAD after Impella 5+ support was also performed in 5 patients, who build up 62.5% of patients who underwent LVAD implantation as primary tMCS after Impella 5+ support. Thus, a total of 9 patients (10.1%) underwent HTX after Impella 5+ support (**Figure 1**).

#### **5.3 Patients characteristics**

**Table 2** shows baseline clinical characteristics of 11 patients (BTT n = 7, direct HTX n = 4), without 1 DT patient. The most common underlying disease for Impella implantation was ischemic cardiomyopathy (ICM) (n = 7, 63.6%), followed by dilated cardiomyopathy (DCM; n = 2, 18.2%). Three patients were post-CPR, and a combination of va-ECMO plus Impella, referred to as 'ECMELLA' was administrated in 7 patients (63.6%). In all eleven cases, implantation of Impella 5 was performed via the right subclavian artery.

#### **5.4 Clinical outcomes**

**Table 3** shows the clinical course of MCS in 11 patients successfully bridged to pMCS/HTX. Impella 5+ support time was 17.4 ± 15.6 days (median 12 days) for bridge to pMCS/HTX in 11 patients. It means that patients underwent either LVAD implantation or HTX on average after 17.4 days following Impella 5+ initiation.


*ECMELLA, venous–arterial extracorporeal membrane oxygenation+Impella; ex, explantation; HTX, heart transplantation; LVAD, left ventricular assist device; pMCS, permanent mechanical circulatory support; tRVAD, temporary right ventricular assist device; va-ECMO, venous–arterial extracorporeal membrane oxygenation; −, not applicable; (HTX), indirect HTX.*

#### **Table 3.**

*Clinical course in 11 patients successfully bridged to pMCS/HTX.*

In 5 of 7 ECMELLA patients, va-ECMO explanation was performed before pMCS/HTX, of whom 1 patient required a temporary right ventricular assist device (tRVAD). As described, 1 patient underwent HTX after successful weaning of Impella 5 at the same admission (patient 4).

Among LVAD patients (n = 7), simultaneous tRVAD was required in 4 patients for postoperative management.

All 11 patients survived the first 30 days after pMCS/HTX operations. However, 2 patients (patients 9, 11) died of septic shock (after 129 days, 122 days, respectively) after HTX. The latter patient was after secondly HTX due to heart transplant rejection.

As far as complications of Impella 5+, a re-implantation of Impella 5+ was necessary total in 3 patients due to (1) Impella thrombosis (n = 2), and (2) Impella dislocation (n = 1). Additionally, Impella dislocation occurred in one more patient. The patient (Patient 10. in **Table 3**) was directly implanted LVAD.

#### **6. Conclusion**

Our experience shows (1) successful transition to pMCS/HTX of 13.5% (n = 12/89), (2) 30 days survival after bridging to pMCS/HTX of 100%, (3) HTX of 10.1% (n = 9/89), and (4) 30 days survival rate of 100% and in-hospital mortality of 22.2% (n = 2/9) after HTX.

According to already published articles, a large Impella system seems to contribute to preconditioning of CS patients not only for a bridge to pMCS/HTX but also for the excellent postoperative clinical outcome. This hypothesis is supported by 100% posttransplant 30 days survival rate in patients who underwent HTX on Impella 5+ in our study. Using Impella 5+ the majority of patients with ECMELLA due to CS could be successfully weaned from va-ECMO before pMCS/HTX installation. This fact also indicates favorable clinical outcomes of Impella 5+ in CS patients awaiting HTX. However, patient selection and choice of size and timing of Impella support remain the subject of future studies for bridging strategies to pMCS/HTX. As a caution, Impella dysfunction due to thrombosis or dislocation of the pump could occur with the long-term utilization of Impella 5+ for bridge to pMCS/HTX.

#### **Acknowledgements**

We gratefully acknowledge the work of the members of the heart failure team at the University Hospital Duesseldorf.

#### **Conflict of interest**

The authors declare no conflict of interest.

*The Role of Large Impella Devices in Temporary Mechanical Circulatory Support for Patients… DOI: http://dx.doi.org/10.5772/intechopen.101680*

#### **Author details**

Yukiharu Sugimura1 , Sebastian Bauer1 , Moritz Benjamin Immohr1 , Arash Mehdiani1 , Hug Aubin1 , Ralf Westenfeld2 , Udo Boeken1 , Artur Lichtenberg1 and Payam Akhyari1 \*

1 Department of Cardiac Surgery and Research Group for Experimental Surgery, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Hospital, Düsseldorf, Germany

2 Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany,

\*Address all correspondence to: Payam.Akhyari@med.uni-duesseldorf.de

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Wernly B, Bhatt DL, Thiele H, Jung C. Impella in cardiogenic shock: Is it time to hit the break? Shock. 2021;**55**(5):693-694

[2] Donker DW, Brodie D, Henriques JPS, Broome M. Left ventricular unloading during veno-arterial ECMO: A review of percutaneous and surgical unloading interventions. Perfusion. 2019;**34**(2):98-105

[3] Donker DW, Brodie D, Henriques JPS, Broome M. Left ventricular unloading during veno-arterial ECMO: A simulation study. ASAIO Journal. 2019;**65**(1):11-20

[4] Vallabhajosyula S, O'Horo JC, Antharam P, Ananthaneni S, Vallabhajosyula S, Stulak JM, et al. Venoarterial extracorporeal membrane oxygenation with concomitant impella versus venoarterial extracorporeal membrane oxygenation for cardiogenic shock. ASAIO Journal. 2020;**66**(5):497-503

[5] Patel SM, Lipinski J, Al-Kindi SG, Patel T, Saric P, Li J, et al. Simultaneous venoarterial extracorporeal membrane oxygenation and percutaneous left ventricular decompression therapy with impella is associated with improved outcomes in refractory cardiogenic shock. ASAIO Journal. 2019;**65**(1):21-28

[6] Akanni OJ, Takeda K, Truby LK, Kurlansky PA, Chiuzan C, Han J, et al. EC-VAD: Combined use of extracorporeal membrane oxygenation and percutaneous microaxial pump left ventricular assist device. ASAIO Journal. 2019;**65**(3):219-226

[7] Mourad M, Gaudard P, De La Arena P, Eliet J, Zeroual N, Rouviere P, et al. Circulatory support with

extracorporeal membrane oxygenation and/or impella for cardiogenic shock during myocardial infarction. ASAIO Journal. 2018;**64**(6):708-714

[8] Tepper S, Masood MF, Baltazar Garcia M, Pisani M, Ewald GA, Lasala JM, et al. Left ventricular unloading by impella device versus surgical vent during extracorporeal life support. The Annals of Thoracic Surgery. 2017;**104**(3):861-867

[9] Pappalardo F, Schulte C, Pieri M, Schrage B, Contri R, Soeffker G, et al. Concomitant implantation of Impella((R)) on top of veno-arterial extracorporeal membrane oxygenation may improve survival of patients with cardiogenic shock. European Journal of Heart Failure. 2017;**19**(3):404-412

[10] Grajeda Silvestri ER, Pino JE, Donath E, Torres P, Chait R, Ghumman W. Impella to unload the left ventricle in patients undergoing venoarterial extracorporeal membrane oxygenation for cardiogenic shock: A systematic review and metaanalysis. Journal of Cardiac Surgery. 2020;**35**(6):1237-1242

[11] Russo JJ, Aleksova N,

Pitcher I, Couture E, Parlow S, Faraz M, et al. Left ventricular unloading during extracorporeal membrane oxygenation in patients with cardiogenic shock. Journal of the American College of Cardiology. 2019;**73**(6):654-662

[12] Schrage B, Burkhoff D, Rubsamen N, Becher PM, Schwarzl M, Bernhardt A, et al. Unloading of the left ventricle during venoarterial extracorporeal membrane oxygenation therapy in cardiogenic shock. JACC Heart Failure. 2018;**6**(12):1035-1043

*The Role of Large Impella Devices in Temporary Mechanical Circulatory Support for Patients… DOI: http://dx.doi.org/10.5772/intechopen.101680*

[13] Schrage B, Becher PM, Bernhardt A, Bezerra H, Blankenberg S, Brunner S, et al. Left ventricular unloading is associated with lower mortality in patients with cardiogenic shock treated with venoarterial extracorporeal membrane oxygenation: Results from an international, Multicenter Cohort Study. Circulation. 2020;**142**(22):2095-2106

[14] Tongers J, Sieweke JT, Kuhn C, Napp LC, Flierl U, Rontgen P, et al. Early escalation of mechanical circulatory support stabilizes and potentially rescues patients in refractory cardiogenic shock. Circulation. Heart Failure. 2020;**13**(3):e005853

[15] Sugimura Y, Katahira S, Immohr MB, Sipahi NF, Mehdiani A, Assmann A, et al. Initial experience covering 50 consecutive cases of large Impella implantation at a single heart centre. ESC Heart Fail. 2021. DOI:10.1002/ehf2.13594

[16] Nelson DW, Sundararajan S, Klein E, Joyce LD, Durham LA, Joyce DL, et al. Sustained use of the impella 5.0 heart pump enables bridge to clinical decisions in 34 patients. Texas Heart Institute Journal. 2021;**48**(3):e207260

[17] Bernhardt AM, Potapov E, Schibilsky D, Ruhparwar A, Tschope C, Spillmann F, et al. First in man evaluation of a novel circulatory support device: Early experience with the Impella 5.5 after CE mark approval in Germany. The Journal of Heart and Lung Transplantation. 2021;**40**(8):850-855

[18] Tarabichi S, Ikegami H, Russo MJ, Lee LY, Lemaire A. The role of the axillary Impella 5.0 device on patients with acute cardiogenic shock. Journal of Cardiothoracic Surgery. 2020;**15**(1):218

[19] Seese L, Hickey G, Keebler ME, Mathier MA, Sultan I, Gleason TG, et al. Direct bridging to cardiac transplantation with the surgically implanted Impella 5.0 device. Clinical Transplantation. 2020;**34**(3):e13818

[20] Chung JS, Emerson D, Ramzy D, Akhmerov A, Megna D, Esmailian F, et al. A new paradigm in mechanical circulatory support: 100-patient experience. The Annals of Thoracic Surgery. 2020;**109**(5):1370-1377

[21] Lima B, Kale P, Gonzalez-Stawinski GV, Kuiper JJ, Carey S, Hall SA. Effectiveness and safety of the impella 5.0 as a bridge to cardiac transplantation or durable left ventricular assist device. The American Journal of Cardiology. 2016;**117**(10):1622-1628

[22] Kobashigawa J, Zuckermann A, Macdonald P, Leprince P, Esmailian F, Luu M, et al. Report from a consensus conference on primary graft dysfunction after cardiac transplantation. The Journal of Heart and Lung Transplantation. 2014;**33**(4):327-340

[23] Russo MJ, Chen JM, Sorabella RA, Martens TP, Garrido M, Davies RR, et al. The effect of ischemic time on survival after heart transplantation varies by donor age: an analysis of the United Network for organ sharing database. The Journal of Thoracic and Cardiovascular Surgery. 2007;**133**(2):554-559

[24] Del Rizzo DF, Menkis AH, Pflugfelder PW, Novick RJ, McKenzie FN, Boyd WD, et al. The role of donor age and ischemic time on survival following orthotopic heart transplantation. The Journal of Heart and Lung Transplantation. 1999;**18**(4):310-319

[25] Loforte A, Fiorentino M, Murana G, Gliozzi G, Cavalli GG, Mariani C, et al. Mechanically supported early graft failure after heart transplantation.

Transplantation Proceedings. 2021;**53**(1): 311-317

[26] Thomas HL, Dronavalli VB, Parameshwar J, Bonser RS, Banner NR. Steering group of the UKCTA. Incidence and outcome of Levitronix CentriMag support as rescue therapy for early cardiac allograft failure: A United Kingdom national study. European Journal of Cardio-Thoracic Surgery. 2011;**40**(6):1348-1354

### Section 3

## Heart Transplantation in Pediatrics

### **Chapter 7** Pediatric Heart Transplantation

### *Estela Azeka*

#### **Abstract**

Despite advances in medical management, patients submitted for heart transplantation procedures still are at risk to development of complications. This chapter will discuss some specific topics of pediatric heart transplantation, focusing on perioperative care: (i) recipient management, (ii) donor evaluation, (iii) immunosuppression, (iv) early postoperative management, (v) complications, and (vi) conclusions.

**Keywords:** heart transplantation, child, complications, immunosuppression, management, perioperative period, heart failure, mechanical circulatory support, pediatric

#### **1. Introduction**

Heart transplantation (HT) has been the therapeutic option for patients with complex congenital heart disease and cardiomyopathies with heart failure (HF) refractory to conventional treatment [1–4].

Despite advances in molecular biology, immunosuppressive drug therapy, the knowledge of the potential complications that may occur after the procedure are essential to improve the quality of life of patients and their survival.

In this chapter we will discuss:


#### **2. Recipient management**

The main types of pediatric heart diseases considered for heart transplantation are [1]:


The clinical manifestations of heart failure in children vary according to age of the patient and severity of disease. In infants, the most common signs and symptoms are poor weight gain, tachypnea and diaphoresis during feeding and fatigability. Young children may present abdominal pain, vomiting, nausea, poor appetite, fatigability,

**Figure 1.** *Chest X-ray showing enlargement cardiac área in a child with dilated cardiomyopathy.*

**Figure 2.** *Echocardiogram showing enlargement of left ventricle chamber in a child with dilated cardiomyopathy.*


**Table 1.**

*Specific topics for evaluation.*

recurrent cough and failure to thrive. In adolescents, abdominal pain, anorexia, exercise intolerance, dyspnea, oedema or syncope may be found. Nowadays, heart failure in children can be classified and categorize of the stage and severity by the modified NYHA, stages of heart failure infants and children and recommended therapy (stage A, B, C and D), modified Ross classification and by INTERMACS, which can help in decision making. The INTERMACS classification was initially developed to consider the patient for mechanical circulatory support [5–8]. Pediatric patients with stage D heart failure are listed for heart transplantation [1, 6].

There are some important topics [1] to be addressed at the moment to evaluate a pediatric recipient for heart transplantation (**Table 1**):

1.The clinical status of patient: if the patient is in the intensive care unit receiving drugs with continuous infusions such as phosphodiesterase 3 (PDE3) inhibitors (milrinone) or epinephrine and anti-congestive medications; if the patient is with ventricular assist device or if the patient is at outpatient clinics.

The clinical status will determine if the patient is in priority or not for heart transplantation when listed;

	- Pre-transplant specific assessments are in **Table 1**. They are performed according to the patient's history and clinical conditions.
	- Laboratory tests for initial evaluation for heart transplantation are in **Table 2**. HLA antibody level greater than 70% is considered high and may compromise short- and medium-term survival outcomes after transplantation.
	- The assessment of the multidisciplinary team is fundamental for the success of long-term follow-up. The multidisciplinary team including nurse, psychologist, social worker, physiotherapist, dentist and nutritionist provides information about the patient as well as the family's suitability for the transplant procedure. Psychosocial support is vital when the child becomes a candidate for heart transplantation, as there is a need to restructure the family routine as a result of outpatient follow-up.

Mechanical circulatory support has been an option for children with refractory heart failure.

ECMO in children should be considered to provide adequate systemic perfusion and oxygenation for myocardial recovery after cardiopulmonary bypass or in patients as a bridge for heart transplantation and considered for long-term mechanical circulatory support (MCS). The use of ventricular assist device (VAD) has been increased for bridge to heart transplantation, decision or destination. The type of VAD depends on the weight, body superface área and pulmonary hypertension. In general, infants


#### **Table 2.**

*Pre-transplant specific cardiac assessment.*


#### **Table 3.**

*Laboratory tests for initial evaluation of heart transplantation.*

are candidates for paracorporeal MCS and adolescents for implanted ones. The prevalence of children waiting for heart transplantation with MCS has been increased in the last years (**Table 3**).

#### **3. Donor assessment**

The potential donor must be evaluated in relation to the recipient. The topics for donor evaluation in children are in **Table 4**. Pre-existing cardiac anomalies such as coronary artery disease, valve anomalies, left ventricular hypertrophy, donor cardiac function, donor-recipient size matching should be addressed before accepting the potential donor.


#### **Table 4.** *Donor evaluation.*

Recently, ISHLT Pediatric Consensus (DOAM) describes the principal recommendations for acceptance of the pediatric donor [9].

Donation after Circulatory Death (DCD) should be performed in centres with experience in marginal donor hearts, perioperative mechanical support, the use of ex-situ organ perfusion devices for preservation and transportation.

ABO-incompatible heart transplant procedure has been performed in children in some centres with results similar to ABO compatible due to the scarcity of donors.

#### **4. Immunosuppression**

Immunosuppression regimens are generally defined according to the period of transplantation and the presence of rejection [10, 11]:


Induction therapy can be defined as prophylactic immunosuppressive therapy in the perioperative period, usually with cytolytic agents, to reduce the incidence of early rejection (**Table 5**). Nowadays, the use of induction therapy has increased and is not associated with an increase in infection and malignancy [12].

Different classes of drugs are used for initial and maintenance immunosuppression in children.

The most used initial regimens are composed of the association of corticosteroids, calcineurin inhibitors and antiproliferative agents (**Table 5**).

The use of tacrolimus as a calcineurin inhibitor and the replacement of Azathioprine as an antiproliferative agent with mycophenolate is the current trend in most centres worldwide.


#### **Table 5.**

*Most common immunosuppression drugs.*


#### **Table 6.**

*Monitoring in Early post-operative care.*

Proliferation signal inhibitors (everolimus and sirolimus) are used in renal failure, graft vascular disease and lymphoproliferative disease in combination with a calcineurin inhibitor or in monotherapy (**Table 5**).

In children, it is important to address the avoidance of steroids as maintenance drug therapy due to failure to adequate height development.

#### **5. Perioperative management**

Perioperative management consists of some topics that are listed in **Table 6** [11–16].

#### **6. Complications**

In perioperative period, the main complications of transplantation can be inherent to transplantation, such as early graft dysfunction, right ventricular dysfunction,


**Table 7.** *Topics of perioperative care.*


#### **Table 8.**

*Methods for rejection diagnosis.*

hyperacute rejection as well as due to the immunosuppressive medication itself: infection, systemic arterial hypertension and renal failure (**Tables 7** and **8**). In the late postoperative period, coronary allograft vasculopathy, tumour, primary graft dysfunction are some causes of long-term complications.

Rejection has been reported as the main cause of death after transplantation. The diagnosis of rejection is made by a combination of clinical signs and symptoms, non-invasive tests and/or endomyocardial biopsy, using the International Society of Cardiac and Lung Transplantation (ISHLT) criteria [14]. Several noninvasive methods have been reported such as echocardiography, cardiac magnetic resonance, electrocardiogram, Gallium-67 as well as biomarkers of injury or immunoreactivity such as BNP, troponin and donor-specific antibodies (DSA) for rejection surveillance in pediatric heart transplantation. These non-invasive methods have been described as high degree of specificity and low sensitivity and are useful for identifying those without rejection episodes. Therefore, endomyocardial biopsy is still the gold standard for rejection although there are risks related to the procedure such as venous occlusion, radiation and perforation.

#### **6.1 Rejection treatment**

Treatment of rejection should be directed towards the underlying aetiology, as well as the severity of the condition based on clinical, laboratory and pathological findings.

#### **6.2 Acute cellular rejection**


#### **6.3 Humoral rejection**

It includes the same schemes used to treat cell rejection, with high doses of corticosteroids and lymphocytolytic agents. Additionally, intravenous immunoglobulin

#### **Figure 3.**

*Cellular rejection: a focus of inflammatory infiltrate with cellular aggression and architectural distortion in acute cellular rejection grade 2R.*

#### **Figure 4.**

*Humoral rejection: interstitial edema and endothelial swelling of capillaries in antibody-mediated rejection. Note also the presence of mononuclear cells inside capillaries.*

and plasmapheresis to remove circulating antibodies and specific therapies to target B cells (cyclophosphamide, mycophenolate and rituximab) can be used (**Figure 4**).

#### **7. Conclusions**

Heart transplantation is an option for refractory heart failure in children with cardiomyopathies and complex heart diseases. It is a highly complex clinical-surgical therapy that involves a specialized multidisciplinary team so that child care can be performed successfully. Nowadays, the Pediatric Heart Transplantation Society

(PHTS) has developed a database where clinical trials and robust research have been performed for the best care of this fragile pediatric population.

### **Acknowledgements**

Dr. Luiz Benvenuti from the Pathology Department for the pictures of rejection.

#### **Author details**

Estela Azeka

Pediatric Cardiology and Adults with Congenital Heart Disease Unit, Instituto do Coração (InCor) HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

\*Address all correspondence to: estela\_azeka9@hotmail.com; estela.azeka@hc.fm.usp.br

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Kirk R, Dipchand AI, Rosenthal DN, et al. The International Society for Heart and Lung Transplantation Guidelines for the management of pediatric heart failure: Executive summary. The Journal of Heart and Lung Transplantation. 2014;**33**(9):888-909

[2] Lipshultz SE, Law YM, Asante-Korang A, et al. Cardiomyopathy in children: Classification and diagnosis: A scientific statement from the American Heart Association. Circulation. 2019;**140**. CIR000682

[3] Law YM, Lal AK, Chen S, et al. Diagnosis and management of myocarditis in children: A Scientific Statement from the American Heart Association. Circulation. 2021;**144**(6):e123-e135

[4] Roeleveld PP, Axelrod DM, Klugman D, et al. Hypoplastic left heart syndrome: From fetus to fontan. Cardiology in the Young. 2018;**28**(11):1275-1288

[5] Ross RD. The Rossclassification for heart failure in children after 25 years: A review and an age-stratified revision. Pediatric Cardiology. 2012;**33**(8):1295- 1300. DOI: 10.1007/s00246-012-0306-8

[6] Rosenthal D, Chrisant MR, Edens E, et al. International Society for Heart and Lung Transplantation: Practice guidelines for management of heart failure in children. The Journal of Heart and Lung Transplantation. 2004;**23**:1313-1333

[7] Morales DLS, Rossano JW, VanderPluym C, et al. Third Annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) Report: Preimplant Characteristics and Outcomes. The

Annals of Thoracic Surgery. 2019; **107**(4):993-1004

[8] Baumgartner H, DeBacker J, Babu-Narayan SV, et al. 2020 ESC guidelines for the management ofadult congenital heart disease. European Heart Journal. 2020;**00**:1-83

[9] Kirk R, Dipchand AI, Davies RR, et al. ISHLT consensus statement on donor organ acceptability and management in pediatric heart transplantation. The Journal of Heart and Lung Transplantation. 2020;**39**(4):331-341

[10] Daly KP. Contemporary transplantation immunosuppression: Balancing on the immunosuppression seesaw. Pediatric Transplantation;**13**:52

[11] Azeka E, Auler JO Jr, Marcial MB, et al. Heart transplantation in children: Clinical outcome during the early postoperative period. Pediatric Transplantation. 2005;**9**(4):491-497

[12] Gajarski R, Blume ED, Urschel S, et al. Infection and malignancy after pediatric heart transplantation: The role of induction therapy. The Journal of Heart and Lung Transplantation. 2011;**30**(3):299-308

[13] Mowers KL, Simpson KE, Gazit AZ, et al. Moderate-severe primary graft dysfunction after pediatric heart transplantation. Pediatric Transplantation. 2019;**23**(2):e13340

[14] Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. The Journal of Heart and Lung Transplantation. 2005;**24**(11): 1710-1720

[15] Dipchand AI, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: Seventeenth official pediatric heart transplantation report--2014; focus theme: Retransplantation. The Journal of Heart and Lung Transplantation. 2014;**33**(10):985-995

[16] L'Huillier AG, Dipchand AI, Ng VL, et al. Posttransplant lymphoproliferative disorder in pediatric patients: Survival rates according to primary sites of occurrence and a proposed clinical categorization. American Journal of Transplantation. 2019

Section 4
