Risk Factors for Severe Primary Graft Dysfunction in Infants Following Heart Transplant. Tajinder P. Singh, MD, MSc; Elizabeth L. Profita, MD; Peter Rycus, MPH; Ravi Thiagarajan, MD, MPH; Kimberlee Gauvreau, ScD; PMID: 34184543, PMCID: PMC8403271, DOI: 10.1161/JAHA.121.021082
Commentary from Dr. Manoj Gupta (New York City, NY, USA), chief section editor of Pediatric & Fetal Cardiology Journal Watch
Take Home Points:
- Infant heart transplant (HT) recipients are at higher risk of developing severe primary graft dysfunction (PGD) than older children. Severe PGD was identified in 7.8% of infant HT recipients in the United States during 1996 to 2015 with no significant change in incidence over time. Possible risk factors based on this study are recipient congenital heart disease, ECMO, or biventricular assist device support at transplant, recipient blood type AB, donor‐recipient weight ratio <0.9, and graft ischemic time ≥4 hours.
- Left ventricular assist device support at HT was not associated with increased risk of severe primary graft dysfunction. Hearts from donors with donor: recipient weight ratio <0.9 and with expected ischemic time ≥4 hours should be avoided in candidates with high‐risk recipient profile.
- Although some recipient‐level risk factors are nonmodifiable, avoiding modifiable risk factors may mitigate further risk in infants at high risk of developing severe PGD.
Based on a recent expert consensus statement endorsed by the International Society for Heart and Lung Transplantation, primary graft dysfunction (PGD) after heart transplant (HT) is defined as the development of left ventricular or biventricular systolic dysfunction within 24 hours of HT which is of primary cardiac origin and not secondary to causes such as acute rejection, pulmonary hypertension, or surgical complications. While HT recipients with milder forms of PGD may be managed with inotropes, those with severe PGD require mechanical circulatory support such as ventricular assist device or extracorporeal membrane oxygenation (ECMO).
Aim of the study:
The aim for the current study was to describe risk factors for developing severe PGD in US infants aged <1 year at HT during 1996 to 2015. Using the subject‐level variables of HT center, date of birth, and date of HT in the OPTN data and the date of initiating ECMO in the ELSO registry, we identified infants initiated on ECMO for cardiac support within 2 calendar days following HT. Exclusion criteria included infants at risk of secondary graft dysfunction, ie, those with a positive cross‐match attributable to the potential risk of acute antibody‐mediated rejection and those with pulmonary vascular resistance >6 wood units attributable to a risk of posttransplant acute right heart failure.
Incidence of Severe PGD
The overall incidence of severe PGD was 7.8% (95% CI, 6.6%‒9.2%). The incidence was 4% in infants with dilated cardiomyopathy, 10% in infants with CHD, 15% in those supported on ECMO or biventricular assist device (BIVAD) at HT, 2% in those supported on a left ventricular assist device (LVAD) and 21% in those supported on dialysis. A higher incidence of severe PGD was also noted in association with donor ischemic time ≥4 hours and with donor: recipient weight ratio <0.9 or >2.3 but not with donor left ventricular ejection fraction <0.45 or donor support using multiple inotropes.
The remaining 134 infants required veno‐arterial ECMO for cardiac support and thus met the criteria for severe PGD. Of these, 95 (71%) were initiated on ECMO support on the day of HT, 34 (25%) the following day, and 5 (4%) on the second posttransplant day. Their median age was 120 days, 52 (39%) were <90 days old, 42 (31%) were 91 to 180 days old and 40 (30%) were >180 days old. Cardiac diagnosis was CHD in 81% (46% with prior surgery, 35% unrepaired) and cardiomyopathy in 19%. A majority of patients with PGD (77%) were supported using a single ECMO run whereas 18% were supported using 2 ECMO runs. Median duration of ECMO support was 105 hours (interquartile range, 65−173 hours).
Independent Risk Factors for Severe PGD
Figure 2A illustrates the observed incidence of severe PGD with different combinations of recipient‐level risk factors if they received an HT using low‐risk donor criteria as defined by the multivariable model (donor: recipient weight ratio 0.9–2.3 and donor ischemic time <4 hours). The effect of a higher risk donor (either donor: recipient weight ratio <0.9 or ischemic time ≥4 hours) to corresponding recipient risk profiles is illustrated in Figure 2B, showing a disparate effect of higher risk donor on recipients with different risk profiles.
Death (or graft loss) before hospital discharge occurred in 42.5% of infants with PGD (55 deaths, 2 retransplants) and 8.8% of infants without severe PGD (P<0.001).
In this study, we identified severe PGD in 7.8% of infant HT recipients in the United States during 1996 to 2015 with no significant change in incidence over time when assessed in consecutive 5‐year periods. The finding that 3‐month survivors of severe PGD remained at increased risk of death or graft loss was surprising and not previously noted in the larger pediatric cohort. Infants are known to have worse first‐year survival after HT than older children but have the best conditional survival of all age‐groups if they survive the first posttransplant year.
Because LVAD support is being increasingly used to support infants awaiting HT, whether it is truly associated with lower incidence of severe PGD will be of high interest in future analyses of more recent recipients.
Severe PGD was identified in 7.8% of infant HT recipients in the United States during 1996 to 2015. The risk of developing severe PGD was heterogeneous, however, with independent recipient‐ and donor‐level risk factors identified in this study. Identifying and avoiding modifiable risk factors may mitigate further risk in infants at high risk of developing severe PGD.