Induction Immunosuppression: Rationale and Options

In this episode, the CardioNerds (Dr. Natalie Tapaskar, Dr. Jenna Skowronski, and Dr. Shazli Khan) discuss the process of heart transplantation from the initial donor selection to the time a patient is discharged with Dr. Dave Kaczorowski and Dr. Jason Katz. We dissect a case where we understand criteria for donor selection, the differences between DBD and DCD organ donors, the choice of vasoactive agents in the post-operative period, complications such as cardiac tamponade, and the choice of immunosuppression in the immediate post-operative period. Most importantly, we highlight the importance of multi-disciplinary teams in the care of transplant patients. Audio editing for this episode was performed by CardioNerds Intern, Dr. Julia Marques Fernandes.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Pearls

1. When thinking about donor selection, you need to consider how much physiologic stress your recipient can tolerate, and this may guide your selection of “higher risk” or “lower risk” donors.  

2. The use of DCD donors has increased the potential donor pool and shortened waitlist times with very similar perioperative outcomes to DBD transplantation. 

3. Post-operative critical care management rests on a fundamental principle to apply as much inotropic/vasoactive therapy as needed to achieve some reasonable physiologic hemostasis, and then getting “the heck out of the way!” There are no standard regimens as practices vary across centers, but rest on providing adequate RV support, maintaining AV synchrony, and early resuscitation.  

4. The RV is fickle and doesn’t take a joke too well. RV dysfunction post-transplant is important to watch for, and it can be transient or require aggressive support. Don’t miss assessing for cardiac tamponade which can require surgical evacuation- “where there’s space, that space can be filled with fluid.”  

5. Induction immunosuppression post-transplant varies across centers, but some considerations for use may include (1) high sensitization of the patient, (2) high risk immunologic donor-recipient matching, and (3) recipient renal dysfunction to provide a calcineurin inhibitor (CNI) sparing regimen long term. 

6. Management of heart transplant patients is a multi-disciplinary effort that requires coordination amongst heart failure/transplant cardiologists, cardiac surgeons, anesthesiologists, pathology/immunologists and a slew of ancillary services. Without a dynamic and collaborative team, successful cardiac transplantation could not be possible. 

Notes

Notes: Notes drafted by Dr. Natalie Tapaskar 

What are the basic components of donor heart selection?

In practicality, it can be a very inexact science, but we use some basic selection criteria such as:

• (1) size matching
• (2) ischemic time
• (3) donor graft function
• (4) immunologic compatibility
• (5) age of the potential donor and recipient
• (6) severity of illness of the recipient
• (7) regional variation in donor availability

When thinking about accepting older donors (>50 years old), we ideally would screen for donor coronary disease and try to keep ischemic times as short as possible.

We may accept an older donor for a recipient who is highly sensitized, which leaves a smaller potential donor pool.

There is no clear consensus on size matching, but the predicted heart mass is most used. We are generally more comfortable oversizing than under-sizing donor hearts.

Serial echocardiography is important in potential donors as initially reduced ejection fractions can improve on repeat testing, and these organs should not be disregarded automatically.

For recipients who are more surgically complex, (i.e. multiple prior sternotomies or complex anatomy), it’s probably preferable to avoid older donors with some graft dysfunction and favor donors with shorter ischemic times.

What is the difference between DBD and DCD?

DBD is donation after brain death- these donors meet criteria for brain death.

Uniform Determination of Death Act 1980: the death of an individual is

• The irreversible cessation of circulatory and respiratory functions or
• The irreversible cessation of all functions of the entire brain, including those of the brain stem

DCD is donation after circulatory death- donation of the heart after confirming that circulatory function has irreversibly ceased.

Only donors in category 3 of the Maastricht Classification of DCD donors are considered for DCD donations: anticipated circulatory arrest (planned withdrawal of life-support treatment).

DCD hearts can be procured via direct procurement or normothermic regional perfusion (NRP). The basic difference is the way the hearts are assessed, either on an external circuit or in the donor body.

For the most complex recipient, DCD may not be utilized at some centers due to concern for higher rates of delayed graft function, but this is center specific and data is still evolving.

What are some features surgeons consider when procuring the donor heart?

Visual assessment of the donor heart is key in DBD or NRP cases. LV function may be hard to assess, but visually the RV can be inspected.

Palpation of the coronary arteries is important to assess any calcifications or abnormalities.

Ventricular arrhythmias at the time of procurement may be concerning.

Key considerations in the procurement process:

• (1) Ensuring the heart remains decompressed at all times and doesn’t become distended
• (2) adequate cardioplegia delivery
• (3) aorta is cross-clamped properly all the way across the vessel
• (4) avoiding injury to adjacent structures during procurement

What hemodynamic parameters should we monitor and what vasoactive agents are used peri-heart transplant?

There is no consensus regarding vasoactive agent use post-transplant and practice varies across institutions. Some commonly seen regimens may include:

• (1) AAI pacing around 110 bpm to support RV function and preserve AV synchrony
• (2) inotropic agents such as epinephrine and dobutamine to support RV function
• (3) pulmonary vasodilators such as inhaled nitric oxide to optimize RV afterload

Early post-transplant patients tend to have low cardiac filling pressures and require preload monitoring and resuscitation initially.

Slow weaning of inotropes as the patient shows signs of stable graft function and hemodynamics.

RV dysfunction may manifest as elevated central venous pressure with low cardiac index or hypotension with reducing urine output.

Optimize inotropic support, volume status, metabolic status (acidosis and hypoxia), afterload (pulmonary hypertension), and assess for cardiac tamponade.

Tamponade requires urgent take-back to the operating room to evacuate material.

Refractory RV failure requires mechanical circulatory support, with early consideration of VA-ECMO. Isolated RV MCS may be used in the right clinical context.

Why do pericardial effusions/cardiac tamponade happen after transplant?

They are not uncommon after transplant and can be due to:

• Inherent size differences between the donor and recipient (i.e. if the donor heart is much smaller than the recipient’s original heart)
• Bleeding from suture lines and anastomoses, pacing wires, and cannulation sites

Depending on the hemodynamic stability of the patient and the location of the effusion, these effusions may require urgent return to the OR for drainage/clot evacuation via reopening the sternotomy, mini thoracotomy, and possible pericardial windows.

What are the basics of immunosuppression post-transplant?

Induction immunosuppression is variably used and is center-specific.

Considerations for using induction therapy may include:

• (1) high sensitization of the patient
• (2) younger patients or multiparous women with theoretically more robust immune systems
• (3) crossing of recipient antibodies with donor antigens
• (3) renal function to provide a CNI sparing regimen long term

Some considerations for avoiding induction may include:

• (1) older age of the recipient
• (2) underlying comorbid conditions such as infections or frailty of the recipient

What are expected activity restrictions post-transplant?

Sternal precautions are important to maintain sternal wire integrity. Generally avoiding lifting >10 pounds in the first 4-12 weeks, no driving usually in the first 4 weeks, monitoring for signs and symptoms of wound infections, and optimizing nutrition and physical activity.

Cardiac rehabilitation is incredibly important as soon as feasible.

References

1. Kharawala A , Nagraj S , Seo J , et al. Donation after circulatory death heart transplant: current state and future directions. Circ: Heart Failure. 2024;17(7). doi: 10.1161/circheartfailure.124.011678 
2. Copeland H, Knezevic I, Baran DA, et al. Donor heart selection: Evidence-based guidelines for providers. The Journal of Heart and Lung Transplantation. 2023;42(1):7-29. doi:10.1016/j.healun.2022.08.030 
3. Moayedifar R, Shudo Y, Kawabori M, et al. Recipient Outcomes With Extended Criteria Donors Using Advanced Heart Preservation: An Analysis of the GUARDIAN-Heart Registry. J Heart Lung Transplant. 2024;43(4):673-680. doi:10.1016/j.healun.2023.12.013 
4. Kharawala A, Nagraj S, Seo J, et al. Donation After Circulatory Death Heart Transplant: Current State and Future Directions. Circ Heart Fail. 2024;17(7):e011678. doi:10.1161/CIRCHEARTFAILURE.124.011678 
5. Copeland H, Hayanga JWA, Neyrinck A, et al. Donor heart and lung procurement: A consensus statement. J Heart Lung Transplant. 2020;39(6):501-517. doi:10.1016/j.healun.2020.03.020 
6. Velleca A, Shullo MA, Dhital K, et al. The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2023;42(5):e1-e141. doi:10.1016/j.healun.2022.10.015 
7. Sicim H, Tam WSV, Tang PC. Primary graft dysfunction in heart transplantation: the challenge to survival. J Cardiothorac Surg. 2024;19(1):313. doi:10.1186/s13019-024-02816-6