Heart transplantation (HTx) remains the most successful long-term treatment for advanced chronic heart failure. Survival after cardiac transplantation has improved but primary graft dysfunction (PGD) remains a significant problem and the predominant cause of early mortality during the first month.1 In a previous UK study, the incidence of PGD was 32% using a study-specific definition comprising of severely impaired systolic function affecting 1 or both ventricles accompanied by hypotension, low cardiac output, and high filling pressures occurring in the first 72 hours (in the absence of hyper acute rejection and technical surgical factors, such as cardiac tamponade).2
However, comparative studies of the incidence and outcome of PGD have been hampered by the lack of an agreed definition until, in 2014, an international consensus statement was developed under the auspices of International Society for Heart and Lung Transplantation (ISHLT).
The consensus classified graft dysfunction as PGD or secondary graft dysfunction which had a discernible cause such as hyper-acute rejection, pulmonary hypertension, or surgical complications. PGD must be diagnosed within 24 hours of completion of surgery. PGD is divided into PGD-left ventricle and PGD-right ventricle. PGD-left ventricle is categorized into mild, moderate, or severe grades depending on the level of cardiac function and the extent of inotrope and mechanical support required. Risk factors for PGD include donor, recipient, and surgical procedural factors.3
In this study, we aimed to ascertain the incidence of PGD using the ISHLT criteria and examine preoperative donor and recipient characteristics as well as procedural risk factors for PGD in a study of an unselected national population of adult heart transplants.
MATERIALS AND METHODS
Inclusion Criteria
All first time orthotopic heart transplants in adults from donors after brainstem death.
From October 2012 to October 2015, 450 adult heart transplants which met our inclusion criteria were performed in the United Kingdom. Data were collected prospectively at the time of the heart transplant and incorporated into the UK Transplant database hosted by National Health Service Blood and Transplant. Data were retrospectively validated from case records for each of these patients and additional information necessary for the study was extracted from the clinical records by S.S. Patients with combined organ transplants were excluded from this study. Donor procurement was performed by the National Organ Retrieval Service with all but 1 center using 1 L of cold St Thomas solution (supplied by Martindale Pharmaceuticals, Romford, Essex, UK) followed by cold stage packed with surrounding ice during transportation. One center utilized the Organ Care System (OCS) (TransMedics Inc) and used Custodiol solution cardioplegia (supplied by Pharmapal Ltd, Elstree, Borehamwood, UK) at the beginning and end of the OCS run. A pulmonary artery catheter was inserted after the transplantation. If this was not possible, PGD was diagnosed using echocardiographic parameters as per Kobashigawa et al.3 Induction and maintenance immunosuppression were as per local hospital protocols.
PGD was defined using the 2014 ISHLT Consensus.3
The use of postoperative mechanical support was determined by individual surgeons.
Statistical Analysis
Continuous variables were described by mean and standard deviation or by median and interquartile range as appropriate. Categorical variables were expressed as number and proportion. Baseline characteristics were compared between PGD and non-PGD groups using Student t test and Mann-Whitney U test as appropriate and χ2 test or Fisher exact test for categorical variables. Variables with significance of P less than 0.1 in the unadjusted analysis were initially introduced as candidate variables in a multivariable logistic regression model for the probability of PGD and removed by stepwise backward elimination. Variables were retained in the model if they reduced the model deviance significantly (P < 0.05). This was done using a complete case data set to ensure appropriate comparison of nested models (however missing data were minimal due to interrogation of data at source). A further subgroup analysis was performed on just those with PGD using the same methodology to compare variables that predict the different severities of PGD as defined. Analysis was conducted in Minitab 17 Statistical Software (2010; Minitab, Inc.).
RESULTS
Four hundred fifty adults received heart transplants between October 1, 2012, and October 1, 2015. The mean age was 46.3 ± 13.5 years. Three hundred forty-eight (77.3%) of the recipients were men. During this period there were 10 donation after circulatory death (DCD) transplants and these were excluded from the study. There were also 3 patients who were retransplanted. Their second transplants were excluded from this study. 98.2% of patients had PA catheters inserted postoperatively. Preoperative, operative, and postoperative details of the PGD and non-PGD cohorts are shown in Table 1. The overall incidence of PGD was 36.2% (163 patients). There were 7 (16%) cases of secondary graft dysfunction. These were graft failure secondary to bleeding, hyperacute rejection, and elevated pulmonary pressures as defined by Kobashigawa et al.3 The phenotype and severity of PGD is shown in Figure 1.
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TABLE 1: Preoperative characteristics of recipients
FIGURE 1: Distribution of primary graft dysfunction (PGD) according to severity. LV, left ventricle; RV, right ventricle.
We identified donor, recipient, and operative risk factors for PGD. Preoperative factors that were significantly associated with PGD in the unadjusted analysis were recipient diabetes mellitus, and female donor to male recipient sex mismatch (Table 1). There was no significant difference between the donor-recipient height and weight mismatch but the estimated left ventricle mass showed more downsizing of donor to recipient in the PGD cohort. Intraoperatively, implant time and bypass time were significantly longer in the PGD cohort (Table 2). Patients with PGD had increased transfusion of blood products (Table 3). Thirty-day mortality for patients with PGD was 31 (19%) versus 13 (4.5%) (P < 0.001). The 6-month mortality for patients with PGD was 52 (31.9%) versus 18 (6.3%) (P < 0.001). Comparing the PGD groups, there was a significantly higher 30-day mortality in the severe PGD-LV group versus moderate PGD-LV group 27 (30%) versus 4 (5%), respectively, P < 0.001).
TABLE 2: Preoperative characteristics of donors mismatch calculated as [(measure (recipient) − measure (donor)/measure (recipient)] × 100
TABLE 3: Postoperative details
The total extracorporeal time for the OCS subset was significantly longer than after cold storage (309.4 ± 88.4 minutes vs 100.3 ± 45.8 minutes; P < 0.001. However, the incidence of PGD was similar to the non-OCS cases (30.3% vs 37.2%, respectively) (P = 0.279). In a subgroup analysis of the OCS cases, extracorporeal time was significantly longer in the PGD group (344.9 ± 95 minutes vs 294.8 ± 81 minutes; P = 0.048).
The following variables were considered for a multivariable analysis of the probability of PGD in which 21 (5%) patients were excluded due to missing data.
Continuous variables: recipient age, donor age, explant time, implant time.
Categorical variables: recipient diabetes, recipient preoperative inotropes, recipient preoperative ventricular assist device (VAD)/extracorporeal membranous oxygenation (ECMO) support, female donor-male recipient mismatch, donor smoking history, OCS usage, recipient aetiology, donor cause of death, and recipient preoperative intra-aortic balloon pump (IABP) usage.
Bypass time and total blood were excluded from this analysis because these results may have arisen from PGD rather than being causative of it. Organ Care System use was not included because it occurred in a small surgeon-selected subset. The final model is shown in Table 4.
TABLE 4: Results of multivariable analysis for risk factors for PGD
In donors, the likelihood of PGD increased by 20% for each decade increment in donor age. A female donor/male recipient combination was 1.7 times more likely to develop PGD.
Recipients requiring preoperative mechanical circulatory support also conferred almost a twofold increase in likelihood of PGD. Diabetic recipients were more than twice likelier to develop PGD.
There was also 1% increase for each minute increment during implantation of the heart.
As an illustrative example, the absolute risk of developing PGD in an average donor (40-year-old) to an average recipient (nondiabetic, no preoperative mechanical circulatory support [MCS], implant time = 54 minutes, without female donor to male recipient sex mismatch) was 28.7%. This absolute risk increased to 45.1% if there was recipient diabetes or 41.9% if there was preoperative MCS. A female donor to male recipient increased the absolute risk to 41.2%.
The absolute PGD risk of advancing donor age in an average recipient is computed in Figure 2A. Figure 2B shows the effect of advancing implant time (minutes) in a 40-year old donor to an average recipient, who was not on any MCS support.
FIGURE 2: A, Probability of primary graft dysfunction with advancing donor age. B, Probability of primary graft dysfunction with increasing implant time.
A further subgroup logistic regression analysis was performed to identify risk factors for severe PGD versus mild/moderate PGD on the 163 patients who experienced some degree of PGD. The variables included for analysis were
Continuous variables: recipient age, donor age, explant time, implant time.
Categorical variables: recipient diabetes, recipient preoperative inotropes, recipient preoperative VAD/ECMO support, female donor-male recipient mismatch, donor smoking history, OCS usage, recipient aetiology, recipient resternotomy donor cause of death, and recipient preoperative IABP usage.
This subgroup analysis revealed implant time, female donor-male recipient sex mismatch and recipient resternotomy to be independent risk factors for severe PGD as opposed to mild or moderate PGD as seen in Table 5.
TABLE 5: Results of multivariable analysis for risk factors for severe PGD
DISCUSSION
This study is the first national study of PGD in an unselected population of adult heart transplants using the ISHLT consensus definition. The main findings were, first, a high overall incidence of PGD and, second, a significant increase in perioperative mortality in the PGD group. Third, the risk factor analysis identifies not only donor and recipient factors but also potentially modifiable procedural risk factors, such as surgical implant time and use of blood products. Finally, the use of the OCS allowed an extension of the extracorporeal time for the donor heart with a similar incidence of PGD. Nevertheless, increasing extracorporeal time in the OCS group was associated with an increase in PGD, indicating that any protection afforded by OCS was relative, not absolute.
Incidence of PGD
There was a relatively high incidence of PGD (36.2%) in this cohort. This finding is similar to that reported by Dronavalli et al2 which reported an incidence of about 32%. The changing patient demographics with increasing use of pretransplant mechanical circulatory support and increased utilization of marginal donors could be a contributory factors as donor age and preoperative MCS usage were independent risk factors for PGD.4 Dronavalli et al also mentioned the lack of echocardiographic criteria which reduced the sensitivity of diagnosing PGD in the previous study. There were more severe PGD-LV patients (18%) and moderate PGD-LV (16%) than mild PGD-LV (1%) and PGD-RV (1%). These findings were similar findings noted in a single-center series by Sabatino et al.5 Most of their patients were classified as severe PGD (65%) followed by moderate (12%) and mild (0%; P < 0.01). The low rates of mild PGD-LV could be as a result of earlier intervention by physicians and surgeons by increasing the inotropic treatment in response to a low cardiac output state to the point where the inotrope score will meet the ISHLT definition of moderate PGD-LV. The clinical significance of the mild PGD-LV group is uncertain because there was no 30-day mortality in this group.
PGD-related Mortality
The 30-day mortality in our cohort was lower than the previous study (19% vs 37%) and in other studies.6-8 The lack of a standardized definition previously also potentially resulted in more conservative definitions of PGD which was the need for instituting MCS. This could also explain the improved mortality figures due to the inclusion of inotrope dependence as part of the definition. The improved 30-day survival could also be a result of improvements in recognition and treatment of PGD. Short-term PGD-related mortality rates in our cohort was also similar to that described by Squiers et al9 from a high volume center in the United States. They had a 30-day mortality rate of 25% in the moderate/severe PGD group. Sabatino et al5 also reported similar mortality rates in their cohort (37% in-hospital mortality). However, the mortality rate at 6 months remains high in the PGD cohort (31.9% vs 6.3%). There is a paucity of data regarding longer-term outcomes after PGD. Kim et al10 retrospectively reviewed a single center cohort of patients and noted that moderate and severe PGD-LV patients had worse long-term outcomes. Given the large proportion of moderate and severe PGD-LV patients in our cohort, further studies may be needed to evaluate longer-term outcomes of PGD survivors versus non-PGD patients.
Risk Factors
The increased incidence of PGD reported is multifactorial. It highlights several vascular risk factors that may shed light on the etiology of PGD. Increasing donor age and recipient diabetes were both independent risk factors in our cohort and have identified in previous studies before the ISHLT definition.8
Donor age was a significant risk factor for both PGD and severe PGD in the subgroup analysis. This finding was also noted by Russo et al11 during interrogation of the United Network for Organ Sharing (UNOS) database. They concluded that the effect of ischemic time on survival after HTx is dependent on donor age, with greater tolerance for prolonged ischemic times among grafts from younger donors.
Ischemic time was subdivided into warm and cold ischemic time in our cohort.12 Warm ischemic time was defined as the explant time + the implant time. The implant time was found to be a strong predictor of PGD. Marasco et al13 retrospectively reviewed 206 patients over a period of around 10 years (June 2001–November 2010). Their definition of warm ischemic time included the implant time. They found that poorer survival with a warm ischemia time longer than 80 minutes compared with warm ischemia time group less than 60 minutes. Donor age was once again an independent predictor of outcome in this cohort.
The role of recipient diabetes as a predictor of PGD was evident in our study as it was in the RADIAL study. The UK Prospective Diabetes Study trial established a link between microvascular complications and glycemic control.14 In recipients with diabetes, there may be a combination of direct glucose-mediated endothelial damage, oxidative stress from superoxide overproduction, and production of advanced glycation end-products, which may result in changes in endothelial permeability, excessive vascular protein deposition, and altered blood flow.15 In a recent meta-analysis, diabetes mellitus was an independent predictor of 1-year mortality postheart transplant.16 They attributed this to the summative increased hazard for comorbidities of diabetes at time of transplant which was also noted by Russo et al.17 In a subgroup analysis, diabetic recipients with well-controlled diabetes had similar survivals to nondiabetic patients. Interrogation of the UNOS database by Taghavi et al18 revealed that of 20,348 patients undergoing orthotopic HTx, 496 (2.4%) received hearts from diabetic donors. The diabetic donors were likelier to be females and older. The recipients of diabetic hearts were also older. However, on multivariable analysis of subgroups, neither insulin-dependent diabetes (1.173; 95% confidence interval, 0.884-1.444; P = 0.268) nor duration of diabetes for more than 5 years (hazard ratio, 1.239; 95% confidence interval, 0.914-1.016; P = 0.167) were risk factors once the groups had been matched. A similar finding was noted by Smits et al19 in a European cohort.
The odds ratio for severe PGD was double that of mild/moderate PGD in female donor—male recipient sex mismatched patients in our study. It has also been identified as a risk in several previous studies. Jalowiec et al20 conducted a study on early outcomes after HTx in sex-mismatched patients. Seventy-four of 347 patients received a heart from an opposite sex. They concluded that sex-mismatched heart transplant recipients had more complications due to rejection and higher resource utilization due to more rehospitalization during the first postoperative year as compared with sex-matched recipients. Stehlik et al21 published similar findings with female donor-male recipients having a higher risk of posttransplant death. Some have postulated the relative differences between the size (body surface area) or weight mismatch between female donor and male recipient, citing a smaller female donor heart being unable to sustain the demands of a larger male patient although there was no significant size mismatch (>20%) noted in our cohort.22,23
Recipient resternotomy was identified as a risk factor for developing severe PGD in our subgroup analysis. Patients with previous sternotomies develop adhesions which complicate the surgical dissection thereby prolonging the explantation period and bypass time. They are also at an increased risk of infections.24 This may further exaggerate the inflammatory response explaining the need for increased support postoperatively. Analysis of the UNOS database revealed an increased risk of all cause mortality in patients with resternotomies.24
OCS
It is widely believed that an important factor in the pathogenesis of PGD is acute ischemia-reperfusion injury. The donor heart is exposed to variable blood pressures, hypothermic storage, warm ischemia and finally reperfusion. The role of the OCS in reducing the impact of this has not been studied. A multivariable analysis has not been done here owing to the relatively small number of OCS transplants during the study period (n = 66). However, in the unadjusted analysis, length of time on the OCS machine was a strong predictor of PGD. One hypothesis for this phenomenon is the lack of metabolic and excretory functions within the OCS circuit to sustain the metabolically active heart within the machine. The mean extracorporeal time of hearts on the OCS was significantly longer than cold storage with similar PGD rates. Garcia-Saez et al25 reported improved short-term outcomes from the use of the OCS in extended criteria donors. The OCS may have a role in improving logistical limitations of organ procurement. The ex vivo perfusion of the heart allows evaluation of extended criteria allografts prior to implantation. It also reduces functional ischemia by means of continuous oxygenation and perfusion which may be importance in higher-risk recipients who are on MCS. Nevertheless, a randomized study of a larger cohort of donors is needed to establish any benefit of the OCS in reducing PGD.
Size Mismatch
The height and weight profiles of donors and recipients in our cohort were not significantly different in both groups. This could be due to careful donor selection and matching process to ensure accurate sizing of the cardiac allograft for the recipient. Height mismatch and weight mismatch were negligible in our cohort. However, a composite of the 2 measurements to calculate the estimated LV mass showed a higher proportion of downsizing in the PGD cohort. We used the following equation which has been published and validated in the literature.26
where α = 6.82 for women and 8.25 for men
However, this was not a significant finding on multivariable analysis. This could be due to the coefficient weightage which may reflect the potential downsizing in a female donor to male recipient sex mismatch using this equation. The equation is also limited because there is no correlation with other confounders of LV mass, such as ethnicity, history of cardiovascular disease, and valvular heart disease. Size mismatching has been noted in other studies.5,9,27,28 Transplanted hearts are denervated and thus rely on increased stroke volume to augment workload.29 Consistent increments of stroke volume results in increasing filling pressure. Smaller hearts are also prone to tachycardia to meet the demands of the previously larger sized heart which is mediated by catecholamine release.30,31 Tachycardia may worsen episodes of myocardial ischemia and significantly increases the production of oxygen free radicals by increased metabolic demand.32 These results in immune infiltration and activation, potentially causing acute or chronic rejection.
Consequently, undersized hearts are shown to undergo pathological cardiac hypertrophy, which may cause fibrosis.33,34 Fibrosis of myocardium and conduction fibers are likely to increase the risk of arrhythmias which may be misconstrued as rejection.35
Bypass Time and Blood Transfusion
Patients with PGD in our cohort had a significantly longer bypass time. We considered that this may have been due to the need to institute further treatment by means of insertion of IABP or institution of mechanical circulatory support. However, prolonged bypass time in itself is an independent predictor of morbidity and mortality in general cardiac surgery.36,37
The mechanism of injury from cardiopulmonary bypass and ischemic-reperfusion of the myocardium is similar; both producing a systemic inflammatory response syndrome. They result in a hyperdynamic circulatory state due to the vasoplegia reducing vascular resistance, platelet and coagulation factor dysfunction, inflammatory pathway activation triggered by leucocytes and endothelial cells and finally cytokine release and formation of oxygen free radicals.38 Prolonged cardiopulmonary bypass also increases transfusion requirement.39 Our PGD cohort had higher blood transfusion requirements compared to the non-PGD cohort. This could once again be a response to the vasoplegic state caused by the systemic inflammatory response syndrome effect from either prolonged bypass time or PGD itself. Blood transfusion in general cardiac surgery is associated with both infection and ischemic postoperative morbidity, increased hospital stay, increased early and late mortality, and increased hospital costs.40,41 In animal models, stored red blood cells have implicated in causing organ hypoxia.42 Blood transfusion also increases pulmonary vascular resistance thereby affecting right ventricular ejection, without improving systemic or regional oxygen utilization.43
Given these findings, blood transfusion and cardiopulmonary bypass time may both contribute to the worsening of the ischemic injury caused by PGD.
Treatment of PGD
Treatment of PGD is primarily supportive. As the definition of PGD is based on the treatment modality, mild and moderate PGD-LV is primarily inotropic support. Moderate PGD-LV is also treated with implantation of IABP. Escalation from this usually requires ECMO. Most cases of severe PGD-LV involve failure to wean from bypass, necessitating the institution of ECMO or short-term VAD support. PGD-RV is initially treated with inotropic support, including agents such as milrinone to promote pulmonary vasodilation. A right ventricular assist device is cited if right heart failure persists.3 Because of the shortage of organs and the increasing waiting list, retransplantation is rarely done (3 in this study period).
Limitations
This was a retrospective analysis of prospectively collated national data. This study design is advantageous because the risk factors were recorded before the occurrence of the outcome (PGD). This is important because it allows the temporal sequence of risk factors and outcomes to be assessed. Selection bias was also minimized by including all adults with heart-only transplants during the study period. However, as an observational study, only association and not causation can be inferred from the results. Other unrecorded factors may have affected the outcome.44
As the data collected were from different hospitals, variations in practice were unaccounted for. This included postoperative immunosuppression regimes, choice of inotropes, myocardial preservation methods and MCS experience with some centers having a greater proportion of patients on LVADs. We relied on both PAC measurements and echocardiography for defining PGD in patients without devices where possible. Some patients did not have pulmonary capillary wedge pressure readings and then we were reliant on echocardiographic criteria and vice versa.
The ISHLT consensus definition relies on the use of mechanical circulatory support to define the more severe forms of PGD. The use of mechanical circulatory support was decided by individual surgeons, and this is a potential weakness of the consensus definition. However, the national multicenter nature of this study is likely to have mitigated this problem.
We performed an exploratory analysis of transplants performed on the OCS device but were unable to perform a multivariable analysis because of the limited number of cases and events.
CONCLUSION
Primary graft dysfunction remains a significant risk factor for early mortality in heart transplant recipients. The standardized definition allows early diagnosis and recognition of this condition. There are several donor, recipient, and procedural risk factors that may be contributory to the pathogenesis of PGD that should be considered for predicting outcomes. Further studies are warranted to establish the long-term outcomes of PGD using the current definition.
ACKNOWLEDGMENTS
The authors wish to acknowledge the help and support of all the transplant centers across the United Kingdom for their contributions to this study.
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