Primary graft dysfunction in heart transplantation: How to recognize it, when to institute extracorporeal membrane oxygenation, and outcomes

Abstract

Central MessagePrimary graft dysfunction (PGD) is the most common cause of mortality early after heart transplantation. Early implementation of venoarterial extracorporeal membrane oxygenation improves survival in severe PGD.See Commentary on page 134. Primary graft dysfunction (PGD) is the most common cause of mortality early after heart transplantation. Early implementation of venoarterial extracorporeal membrane oxygenation improves survival in severe PGD. See Commentary on page 134. Feature Editor's Introduction—Primary graft dysfunction (PGD) after orthotopic heart transplantation is the most common condition associated with mortality in the early postoperative period. Citing recent retrospective studies on the subject, Dr Hull and colleagues make the point that PGD is common, occurring in up to 30% of patients, with an associated 50% mortality if mechanical circulatory support (MCS) is required, which is the case in approximately one-half of cases. Recognizing that an understanding of the donor and recipient characteristics that increase the likelihood of PGD is the sine qua non for minimizing its occurrence, the authors have created a table that can easily serve as a “checklist” to use at the time of the donor offer to aid decision making. Furthermore, they emphasize the importance of grading PGD based on the 2014 International Society for Heart and Lung Transplantation consensus statement using the classifications mild, moderate, and severe. Differentiating mild from severe PGD is quite straightforward, but incorrectly assessing PGD as moderate (ie, able to be managed pharmacologically) as opposed to severe may delay more aggressive therapy and compromise outcomes. Among the several messages that the reader can glean from this article are (1) the importance of recognizing the onset of severe PGD, which mandates the immediate institution of MCS; (2) improved outcomes are associated with the early use of venoarterial extracorporeal membrane oxygenation (VA-ECMO), as opposed to temporary univentricular support; and (3) a delay in instituting MCS of even several hours significantly diminishes survival. The authors present interesting data suggesting that heart transplantation resulting from donation after cardiac death may in fact yield results comparable to donation after brain death, as long as there is liberal use of VA-ECMO in those experiencing PGD. The authors address virtually all of the basic clinical questions that arise in the management of PGD. Furthermore, and to our benefit, they provide a well-organized, well-referenced, and superbly written framework for postoperative care of these patients. Glenn J. R. Whitman, MD Primary graft dysfunction (PGD) is the leading cause of mortality early after cardiac transplantation.1Singh S.S.A. Dalzell J.R. Berry C. Al-Attar N. Primary graft dysfunction after heart transplantation: a thorn amongst the roses.Heart Fail Rev. 2019; 24: 805-820Crossref PubMed Scopus (33) Google Scholar Broadly, PGD is defined as single or biventricular allograft dysfunction that leads to hypotension from a reduced cardiac output that is insufficient to meet the circulatory demands of the recipient and occurs <24 hours post-transplantation. In 2014, the International Society for Heart and Lung Transplantation (ISHLT) published guidelines from a consensus conference that codified the definition, diagnosis, and management of PGD. These guidelines were based on input from 71 experts from 42 heart transplant centers worldwide.2Kobashigawa 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.J Heart Lung Transplant. 2014; 33: 327-340Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar Before the guidelines were established, each transplant centers used its own set of criteria to define PGD. These criteria varied by institution and often included such variables such as echocardiographic data, time after surgery, and need for mechanical circulatory (MCS) or inotropic support. The RADIAL score, based on right atrial pressure >10 mm Hg, recipient age >60 years, diabetes, inotrope dependence, donor age >30 years, and duration of ischemia >4 hours, was the only validated system available for predicting PGD.3Segovia J. Cosió M.D. Barceló J.M. Bueno M.G. Pavía P.G. Burgos R. et al.RADIAL: a novel primary graft failure risk score in heart transplantation.J Heart Lung Transplant. 2011; 30: 644-651Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar A higher RADIAL score corresponds to an increased incidence of PGD4Cosió Carmena M.D. Gómez Bueno M. Almenar L. Delgado J.F. Arizón J.M. González Vilchez F. et al.Primary graft failure after heart transplantation: characteristics in a contemporary cohort and performance of the RADIAL risk score.J Heart Lung Transplant. 2013; 32: 1187-1195Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar and in-hospital death among PGD patients.5Sabatino M. Vitale G. Manfredini V. Masetti M. Borgese L. Maria Raffa G. et al.Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: epidemiology, risk factors, and outcomes.J Heart Lung Transplant. 2017; 36: 1217-1225Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar In this Expert Opinion, we focus on data generated after publication of the consensus guidelines, which were essential to (1) standardize the definition of PGD across transplant centers, (2) allow for a systemized comparison of independent reports on PGD risk factors, management, and outcomes among centers; and (3) promote the forward momentum of interventions for PGD and its scientific study. The ISHLT consensus guidelines distinguish between PGD and secondary graft dysfunction, with the latter being attributed to a discernible cause such as hyperacute rejection, pulmonary hypertension, a surgical complication or a systemic issue, such as sepsis. PGD is further classified as left ventricular (L-PGD) or right ventricular (R-PGD). L-PGD includes biventricular dysfunction and is graded as mild, moderate, or severe based on the extent of inotropic or mechanical support needed to maintain cardiac function (Table 1).2Kobashigawa 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.J Heart Lung Transplant. 2014; 33: 327-340Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar With a standardized definition of PGD established, the diagnosis of this disease phenomenon and an understanding of its risk factors (Table 2) and incidence are possible (Table 3; Figure 1).Table 1Definitions of PGD: type and gradeTypes of early graft dysfunction (diagnosis made with imaging and hemodynamic data, not pathologic information) PGD:Incidence 3%-30%Occurs within the first 24 h of surgery and is not due to a discernible secondary cause SGD:Results from a discernible cause of graft dysfunction:-Hyperacute rejection-Pulmonary hypertension-Surgical complication-SepsisTypes of PGD L-PGD: includes left ventricular and biventricular dysfunctionR-PGD: isolated right ventricular dysfunction, diagnosed based on the following:-Need for RVAD, or-RAP > 15 mm Hg, PCWP < 15 mm Hg, CI < 2 L/min/m2 and TPG < 15 mm Hg or PA systolic pressure < 50 mm HgGrade of L-PGD based on severity MildLVEF ≤ 40% or >1 h of CI < 2 L/min/m2, RAP > 15 mm Hg, and PCWP > 20 mm Hg, on low-dose inotropes ModerateMild + MAP < 70 mm Hg for >1 h and high-dose inotropes or requirement for IABP SevereNeed for MCS other than IABP:-VA-ECMO-LVAD or biVADEarly graft dysfunction can be classified as either PGD or SGD. In 2014, PGD was further defined by ventricular involvement and severity by the International Society for Heart and Lung Transplantation, from which this table is adapted.2Kobashigawa 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.J Heart Lung Transplant. 2014; 33: 327-340Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar PGD, Primary graft dysfunction; SGD, secondary graft dysfunction; L-PGD, left ventricular primary graft dysfunction; R-PGD, right ventricular primary graft dysfunction; RVAD, right ventricular assist device; RAP, right atrial pressure; PCWP, pulmonary capillary wedge pressure; CI, cardiac index; TPG, transpulmonary gradient; PA, pulmonary artery; LVEF, left ventricular ejection fraction; MAP, mean arterial pressure; IABP, intra-aortic balloon pump; MCS, mechanical circulatory support; VA-ECMO, venoarterial extracorporeal membrane oxygenation; LVAD, left ventricular assist device; biVAD, biventricular assist device. Open table in a new tab Table 2Risk factors for PGDRecipientDonorPerioperative and procedural-Age and weight-Comorbidities-MCS or mechanical ventilation-Reoperation, retransplantation, or multiorgan transplant-Pulmonary vascular resistance∗Pulmonary hypertension is a cause of secondary graft dysfunction, but even within accepted ranges of pulmonary artery pressures for heart transplantation, lower pulmonary resistance is associated with decreased risk of PGD-Sensitized or infected recipient-Congenital heart disease-Older age-Cause of death (trauma)-Duration of downtime-Decreased cardiac function, valvular disease, LVH, or CAD-Requirement for inotropic or hemodynamic support-Comorbidities or sepsis-Drug abuse-Laboratory tests: hormones, troponins, sodium-Graft preservation strategy-Ischemic time-Sex mismatch-Size mismatch-Transfusion requirement-Emergent transplant-Transplant team experienceMCS, Mechanical circulatory support; LVH, left ventricular hypertrophy; CAD, coronary artery disease.∗ Pulmonary hypertension is a cause of secondary graft dysfunction, but even within accepted ranges of pulmonary artery pressures for heart transplantation, lower pulmonary resistance is associated with decreased risk of PGD Open table in a new tab Table 3Management of PGD and expected outcomesManagement of PGD PretransplantationMinimize risk factors in donor–recipient match PosttransplantationEarly recognition and diagnosisInotropes and pulmonary vasodilatorsMechanical circulatory support (VA-ECMO > VAD, early initiation)Outcomes in PGD5Sabatino M. Vitale G. Manfredini V. Masetti M. Borgese L. Maria Raffa G. et al.Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: epidemiology, risk factors, and outcomes.J Heart Lung Transplant. 2017; 36: 1217-1225Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar,6Jacob S. Lima B. Gonzalez-Stawinski G.V. El-Sayed et membrane oxygenation as a therapy for with severe primary graft dysfunction after heart Transplant. 2019; 33: PubMed Scopus Google Scholar mortality or mortality or mortality or retransplantation, MCS with improved early in the of in PGD based on of and PGD with associated mortality for each as by an of the after publication of the 2014 International Society for Heart and Lung Transplantation 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.J Heart Lung Transplant. 2014; 33: 327-340Abstract Full Text Full Text PDF PubMed Scopus (346) Google M. Vitale G. Manfredini V. Masetti M. Borgese L. Maria Raffa G. et al.Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: epidemiology, risk factors, and outcomes.J Heart Lung Transplant. 2017; 36: 1217-1225Abstract Full Text Full Text PDF PubMed Scopus (48) Google S. Lima B. Gonzalez-Stawinski G.V. El-Sayed et membrane oxygenation as a therapy for with severe primary graft dysfunction after heart Transplant. 2019; 33: PubMed Scopus Google A. M. A. et al.Primary graft dysfunction after heart transplantation: and associated risk Transplant. PubMed Scopus Google Scholar PGD, Primary graft dysfunction; VA-ECMO, venoarterial extracorporeal membrane oxygenation; VAD, ventricular assist device; MCS, mechanical circulatory support. Open table in a new tab Early graft dysfunction can be classified as either PGD or SGD. In 2014, PGD was further defined by ventricular involvement and severity by the International Society for Heart and Lung Transplantation, from which this table is adapted.2Kobashigawa 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.J Heart Lung Transplant. 2014; 33: 327-340Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar PGD, Primary graft dysfunction; SGD, secondary graft dysfunction; L-PGD, left ventricular primary graft dysfunction; R-PGD, right ventricular primary graft dysfunction; RVAD, right ventricular assist device; RAP, right atrial pressure; PCWP, pulmonary capillary wedge pressure; CI, cardiac index; TPG, transpulmonary gradient; PA, pulmonary artery; LVEF, left ventricular ejection fraction; MAP, mean arterial pressure; IABP, intra-aortic balloon pump; MCS, mechanical circulatory support; VA-ECMO, venoarterial extracorporeal membrane oxygenation; LVAD, left ventricular assist device; biVAD, biventricular assist device. MCS, Mechanical circulatory support; LVH, left ventricular hypertrophy; CAD, coronary artery A of in PGD based on of and PGD with associated mortality for each as by an of the after publication of the 2014 International Society for Heart and Lung Transplantation 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.J Heart Lung Transplant. 2014; 33: 327-340Abstract Full Text Full Text PDF PubMed Scopus (346) Google M. Vitale G. Manfredini V. Masetti M. Borgese L. Maria Raffa G. et al.Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: epidemiology, risk factors, and outcomes.J Heart Lung Transplant. 2017; 36: 1217-1225Abstract Full Text Full Text PDF PubMed Scopus (48) Google S. Lima B. Gonzalez-Stawinski G.V. El-Sayed et membrane oxygenation as a therapy for with severe primary graft dysfunction after heart Transplant. 2019; 33: PubMed Scopus Google A. M. A. et al.Primary graft dysfunction after heart transplantation: and associated risk Transplant. PubMed Scopus Google Scholar PGD, Primary graft dysfunction; VA-ECMO, venoarterial extracorporeal membrane oxygenation; VAD, ventricular assist device; MCS, mechanical circulatory support. the ISHLT guidelines have in of which we In and M. Vitale G. Manfredini V. Masetti M. Borgese L. Maria Raffa G. et al.Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: epidemiology, risk factors, and outcomes.J Heart Lung Transplant. 2017; 36: 1217-1225Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar that in heart transplantation between and the ISHLT criteria for PGD mild, moderate, The biventricular L-PGD, which was associated with a significantly with isolated ventricular the of PGD was associated with a significantly higher risk of death or the need for with graft function < which at an incidence of in severe PGD, in moderate PGD, and in mild M. Vitale G. Manfredini V. Masetti M. Borgese L. Maria Raffa G. et al.Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: epidemiology, risk factors, and outcomes.J Heart Lung Transplant. 2017; 36: 1217-1225Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar was in severe PGD. the with severe PGD with venoarterial extracorporeal membrane oxygenation retransplantation, and 20 were from M. Vitale G. Manfredini V. Masetti M. Borgese L. Maria Raffa G. et al.Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: epidemiology, risk factors, and outcomes.J Heart Lung Transplant. 2017; 36: 1217-1225Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar In a by and colleagues in F. M. J. S. et of the International Society for Heart and Lung Transplantation primary graft dysfunction in heart transplantation.J Heart Lung Transplant. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar the incidence of L-PGD in heart transplant as defined by the ISHLT guidelines was mild, moderate, and and there was a between mortality and moderate and severe L-PGD, with a mortality of in severe PGD. In a and A. M. A. et al.Primary graft dysfunction after heart transplantation: and associated risk Transplant. PubMed Scopus Google Scholar a incidence in PGD of with significantly higher mortality in with PGD with with early graft function these reports that approximately to 30% of heart transplant of PGD, and that with more severe PGD outcomes. donor and recipient risk factors can be used to the of PGD and donor–recipient that survival (Table factors more associated with from severe PGD of donor and recipient ischemia recipient diabetes, and M. Vitale G. Manfredini V. Masetti M. Borgese L. Maria Raffa G. et al.Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: epidemiology, risk factors, and outcomes.J Heart Lung Transplant. 2017; 36: 1217-1225Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar donor ischemia and higher right atrial pressure as risk factors for the of A. M. A. et al.Primary graft dysfunction after heart transplantation: and associated risk Transplant. PubMed Scopus Google Scholar PGD, and is of clinical importance the significantly there is a of on the and of PGD in heart transplantation. to the of the is a of all its extent and severity can be by such factors as donor and that the and severity of PGD (Table all cardiac are to not all PGD. PGD is severe is a of PGD in recent by in Before the and implementation of MCS, severe PGD was associated with survival with management inotropes and to lower pulmonary vascular resistance (Table these are used in transplantation independent of the of PGD and are not The of MCS is to the cardiac allograft from occurs at the time failure from a for MCS in PGD temporary single and biventricular assist as as VA-ECMO, with the latter being used with increased to outcomes and of either at the of the transplant due to to from or in a more due to allograft failure early A published in outcomes in severe PGD with the use of VA-ECMO with heart transplant severe PGD MCS, an and were for a and significantly higher of and support time on mortality was and not significantly between the 2 the to from MCS due to graft was in the VA-ECMO in which support was more in the and left ventricular was not B. J. et outcomes from extracorporeal membrane oxygenation ventricular assist temporary support of primary graft dysfunction in heart Heart Lung Transplant. 2017; 36: Full Text Full Text PDF PubMed Scopus Google Scholar of VA-ECMO in PGD be ventricular an with the for and vascular and N. The of vascular on survival of on venoarterial extracorporeal membrane Full Text Full Text PDF PubMed Scopus Google B. of venoarterial extracorporeal membrane oxygenation and of in Google Scholar for PGD are not from those used in for A single and that and not M. M. G. P. et of or extracorporeal membrane oxygenation in and 2019; Full Text Full Text PDF PubMed Scopus Google Scholar and with survival between the in the A. M. N. V. et and outcomes of with extracorporeal membrane oxygenation for Full Text Full Text PDF PubMed Scopus Google Scholar Central can be using the for in our from the can be an Central VA-ECMO may more cardiac the is in the right an is needed in patients, we use the right pulmonary or of the left with the latter the left atrial is to the can be an or with the used more and with between and and the for with VA-ECMO are the of this Expert and are in in the Expert R. G. M. Raffa G. et consensus on extracorporeal support in Full Text Full Text PDF PubMed Scopus Google Scholar The management of in on VA-ECMO in the transplantation is is to in the right artery and on on VA-ECMO The is and a is to hours and output is The is to time if the output at and is after 24 VA-ECMO in to and in these more such as a or may be for support in and postoperative heart transplant 2017; PubMed Scopus Google Scholar the duration of support in severe PGD ranges between to with duration of support predicting and increased et membrane oxygenation to failure after heart transplantation: a PubMed Scopus Google Scholar of support in heart transplant can be of and and and are not from those in on for other than PGD. publication of the ISHLT guidelines, the of in PGD was A by and C. S. A. et membrane oxygenation temporary support for early graft failure after cardiac Google Scholar survival with in graft dysfunction within hours of transplantation. was of in management, of in those with a VAD, and 50% of in those with C. S. A. et membrane oxygenation temporary support for early graft failure after cardiac Google Scholar in-hospital mortality was significantly higher in early graft dysfunction, survival was not significantly in from VA-ECMO with those not early graft A that recipient age >60 and MCS as as donor characteristics mean as the cause of death, ejection and were of severe C. M. R. et risk factors for primary graft failure temporary membrane oxygenation support after cardiac transplantation in 2011; Google Scholar In that the of and survival to were and with PGD, those with PGD significantly survival at and but survival was not significantly in the were from C. M. R. et risk factors for primary graft failure temporary membrane oxygenation support after cardiac transplantation in 2011; Google Scholar contemporary studies that have used the ISHLT guidelines to PGD and its severity to support the use of VA-ECMO in severe PGD. A of a heart transplant between and that severe PGD S. Lima B. Gonzalez-Stawinski G.V. El-Sayed et membrane oxygenation as a therapy for with severe primary graft dysfunction after heart Transplant. 2019; 33: PubMed Scopus Google Scholar these patients, were from VA-ECMO and to S. Lima B. Gonzalez-Stawinski G.V. El-Sayed et membrane oxygenation as a therapy for with severe primary graft dysfunction after heart Transplant. 2019; 33: PubMed Scopus Google Scholar The improved survival in with severe PGD managed with VA-ECMO the of there is an time to severe PGD and support. A recent this in of heart transplant severe PGD between and The were with institution of VA-ECMO, with a mean time of hours hours after transplantation, in the in-hospital mortality in care of or the of survival improved in the as on which a lower risk of mortality in the these that early VA-ECMO improved in heart transplant with severe PGD the risk of S. P. S. et membrane oxygenation for primary graft dysfunction after heart 2019; Full Text Full Text PDF PubMed Scopus Google Scholar The of early institution of VA-ECMO was in reports the ISHLT guidelines, of and survival to in with severe PGD with early institution of J. of the and of support as therapy for early cardiac allograft a 2011; Google M. V. A. A. A. et membrane oxygenation in primary graft failure after heart Full Text Full Text PDF PubMed Scopus Google Scholar the made in understanding and PGD in recent years, questions in the of cardiac transplantation of MCS is in mild PGD but is in severe PGD. moderate PGD a and further is needed to institution of MCS, VA-ECMO, a in this the recent increase in the use of and donor may of the incidence of PGD and a secondary increase in the incidence of PGD with donor cardiac and MCS can be most in the of these are for study. a published in that that were for transplantation to coronary artery disease, dysfunction, or and a inotropic requirement not an increased incidence of PGD, mortality was significantly B. B. et cardiac not have increased primary graft dysfunction in Google Scholar Furthermore, as the use of donor after circulatory death which results in a set of to the donor due to increased time but independent of the in donor after death the incidence of PGD and its management in need to be A. S. Heart transplantation from donation after circulatory PubMed Scopus Google Scholar there is a of data at PGD in but in and S. A. R. M. J. S. et after heart transplantation from donation after death Heart Lung Transplant. 2017; 36: Full Text Full Text PDF PubMed Scopus Google Scholar in or survival between and independent of the and in the need for MCS to support the In a more recent by and A. M. S. J. L. et of donation after circulatory death heart transplantation in 2019; PubMed Scopus Google Scholar of of VA-ECMO to of and were diagnosed with severe PGD. The duration of VA-ECMO was 2 the to biventricular function at post-transplantation. These the importance of early VA-ECMO in PGD and that comparable outcomes of PGD in and heart In in heart transplantation in the that have increased survival and management of and rejection, the incidence of PGD at to PGD is the leading cause of early mortality after heart transplantation to and donor and transplantation more common to address the the of PGD increased recent M. Vitale G. Manfredini V. Masetti M. Borgese L. Maria Raffa G. et al.Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: epidemiology, risk factors, and outcomes.J Heart Lung Transplant. 2017; 36: 1217-1225Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar for the of PGD are essential as the VA-ECMO, with early is a of of severe PGD. improves survival in this and further to define and at an in the of and survival in with PGD. 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