Rajamiyer V. Venkateswaran

The Proinflammatory Environment in Potential Heart and Lung Donors: Prevalence and Impact of Donor Management and Hormonal Therapy

Background. Brain stem death can elicit a potentially manipulable cardiotoxic proinflammatory cytokine response. We investigated the prevalence of this response, the impact of donor management with tri-iodothyronine (T3) and methylprednisolone (MP) administration, and the relationship of biomarkers to organ function and transplant suitability. Methods. In a prospective randomized double-blinded factorially designed study of T3 and MP therapy, we measured serum levels of interleukin-1 and -6 (IL-1 and IL-6), tumor necrosis factor-alpha (TNF-&agr;), C-reactive protein, and procalcitonin (PCT) levels in 79 potential heart or lung donors. Measurements were performed before and after 4 hr of algorithm-based donor management to optimize cardiorespiratory function and ±hormone treatment. Donors were assigned to receive T3, MP, both drugs, or placebo. Results. Initial IL-1 was elevated in 16% donors, IL-6 in 100%, TNF-&agr; in 28%, CRP in 98%, and PCT in 87%. Overall biomarker concentrations did not change between initial and later measurements and neither T3 nor MP effected any change. Both PCT (P =0.02) and TNF-&agr; (P =0.044) levels were higher in donor hearts with marginal hemodynamics at initial assessment. Higher PCT levels were related to worse cardiac index and right and left ventricular ejection fractions and a PCT level more than 2 ng·mL−1 may attenuate any improvement in cardiac index gained by donor management. No differences were observed between initially marginal and nonmarginal donor lungs. A PCT level less than or equal to 2 ng·mL−1 but not other biomarkers predicted transplant suitability following management. Conclusions. There is high prevalence of a proinflammatory environment in the organ donor that is not affected by tri-iodothyronine or MP therapy. High PCT and TNF-&agr; levels are associated with donor heart dysfunction.

Echocardiography in the Potential Heart Donor

Background. The relationship between echocardiographic left ventricular(LV) systolic function (E-function) and pulmonary artery catheter(PAC) assessment of hemodynamic function (H-function) in potential heart donors is ill defined. We investigated this and determined (a) whether optimization could improve abnormal E-function, (b) feasibility and usefulness of repeat transthoracic echocardiography (TTE), and (c) whether thyroid status and therapy affected E-function. Materials and Methods. Transthoracic E-function imaging was performed at baseline and 4 hr in potential donors (enrolled in a randomized controlled trial of tri-iodothyronine±methylprednisolone [MP] therapy) undergoing PAC-guided algorithmic optimization. Images were analyzed post hoc for LV wall thickness, ejection fraction, and Tei index. Results. The study comprised 66 donors. Both LV ejection fraction (LVEF) and LV-Tei correlated with cardiac index (CI; P<0.001), and LV Tei was most frequently measurable and repeatable(P=0.01). Normal LVEF independently predicted end-assessment H-functional suitability (odds ratio 1.05, 95% confidence interval 1.007–1.088 [P=0.021]) but had poor specificity. Initial subnormal E-function was identified in 29 of 66 of hearts, of which 58% (17/29) achieved H-function suitability criteria. In 52 hearts, repeat E-function assessment was possible. Nineteen of 52 had initially subnormal E-function, which improved in over half (53%). H-function could be manipulated to meet functional suitability criteria for transplant even without E-function change. Neither initial thyroid status nor hormonal therapy affected LV function. Conclusions. Echocardiography is possible in most potential heart donors. Normal E-function predicts hemodynamic suitability for transplantation but lacks specificity. More than 50% of hearts with subnormal E-function can attain hemodynamic transplantation criteria after donor management. Repeat echocardiography is feasible but has a limited role. Both initial echocardiography and PAC-guided management should be used routinely.

Trends in long-term mechanical circulatory support for advanced heart failure in the UK.

Heart transplantation (HTx) is limited by the scarcity of suitable donor hearts. Consequently, more patients with advanced heart failure require a ventricular assist device (VAD). We report UK activity, trends, and outcome for long‐term VAD support as a bridging therapy to HTx.

Measurement of extravascular lung water following human brain death; implications for lung donor assessment and transplantation

OBJECTIVES The measurement of extravascular lung water could aid the assessment and guide the management of potential lung donors following brain death. We therefore sought to validate a single indicator thermodilution extravascular lung water index (EVLWI-T) measurement using gravimetry and to assess the impact and clinical correlates of elevated EVLWI-T in potential lung donors and transplant recipients. METHODS In a prospective study, we measured serial EVLWI-T and haemodynamic and oxygenation data in 60 potential lung donors. To validate the EVLWI-T measurement, we measured in vivo thermodilution EVLWI (EVLWI-T) and gravimetric ex vivo EVLWI (EVLWI-G) in donor lungs rejected for transplant using the Holcroft and Trunkey modification of Pearces method. We assessed the clinical correlates of elevated lung water and measured interleukin-8 and hepatocyte growth factor in bronchoalveolar lavage (BAL) fluid. RESULTS The mean EVLWI-T (n = 60) was 9.7 (4.5) ml kg(-1), being >7-10 ml kg(-1) in 23/60 and >10 ml kg(-1) in 16/60 potential donors. Donor lungs with EVLWI >10 ml kg(-1) were more likely to be receiving norepinephrine (P = 0.04), have higher pulmonary capillary wedge pressures (P = 0.008), be unsuitable for transplantation (P = 0.007) and, if transplanted, have worse survival (P = 0.04). Lungs submitted to gravimetric analysis [n = 20 in 11 donors (9 double and 2 single)] had EVWLI-T of 10.8 (2.7) and EVLWI-G was 10.1 (2.5). There was a strong correlation between EVLW-T and EVLW-G (r = 0.7; P = 0.014), but EVLWI-T over-predicted the EVLWI-G by ≈ 1 ml kg(-1) (EVLW-T = 1.05 × EVLW-G). Cytokine levels in BAL fluid were elevated. CONCLUSIONS Elevated lung water is found in >50% of potential lung donors, predicts lung suitability for transplant and may adversely affect recipient outcome. Although EVLWI-T intrinsically overestimates gravimetric lung water, its measurement may aid the assessment of organ suitability. Lung water accumulation and the proinflammatory response may both be targets for modifying therapy.

Donor cardiac troponin-I: a biochemical surrogate of heart function

OBJECTIVE Cardiac troponin-I (cTnI) levels in the potential heart transplant donor may be a marker of heart dysfunction and predictive of recipient outcome. We studied the prevalence of cTnI elevation, its association with heart function and usability and its relationship with the time duration from coning. METHODS In a prospective study, cTnI measurement, Swan-Ganz catheterisation and transthoracic echocardiography were performed at initial assessment in 79 potential heart donors (mean age 43 +/- 13.1 years). All donors were then managed according to a strict algorithm to optimise cardiac function, some receiving hormonal therapy as part of a randomised trial. Donor heart suitability for transplantation was assessed after 7 h of management. The association of cTnI with initial functional indices was assessed and outcome compared for donors categorised according to cTnI level < or = 1 microg l(-1) or >1 microg l(-1). RESULTS Serum cTnI levels negatively correlated with initial cardiac index (CI) (p = 0.003), right (p < 0.001) and left ventricular ejection fraction (p = 0.001) and positively with LV Tei index (p = 0.003). Serum cTnI was >1 microg l(-1) in 29/79 donors. Higher CVP (10 +/- 5.1 vs 7.9 +/- 2.9; p = 0.026) and PAWP (12 +/- 5.4 vs 8.1 +/- 3.1; p = 0.002), lower cardiac index (2.7 +/- 1.1 vs 3.6 +/- 0.9; p = 0.001) and fractional shortening (p < 0.01) and worse wall motion score index (p < 0.01) were observed in the cTnI >1 microg l(-1) group. CTnI and functional markers correlated with the time duration from coning. CONCLUSION The donor cTnI level represents a biochemical surrogate of functional donor heart assessment. High cTnI is associated with worse donor heart function and may act as a prompt for detailed assessment and optimisation.

Early donor management increases the retrieval rate of hearts for transplantation in marginal donors

OBJECTIVES Organ donations continue to fall, failing to meet the clinical requirements for heart transplantation. Furthermore, the pathophysiology of brain stem death including hormonal and inflammatory changes may lead to significant donor heart injury. Early donor management may potentially alleviate these changes and therefore increase the number of available hearts for transplantation. We aimed to investigate whether early management of borderline donors can increase the heart retrieval rate. METHODS Between September 2011 and February 2013, we performed early donor management of 26 potential heart donors in the intensive care units of the respective donor hospitals. At the time of referral donors were considered as borderline based on high-dose inotrope requirements, history of hypertension and cardiopulmonary resuscitation. Our management protocol included insertion of a pulmonary artery catheter and performance of cardiac output studies, weaning noradrenaline and commencing arginine vasopressin, and administration of tri-iodothyronine, methylprednisolone and insulin. Our primary end-point was donor heart acceptance, depending collectively on the results of cardiac output studies, cardiac contractility and coronary artery patency at the time of retrieval operation. RESULTS We retrieved 14 (56%) borderline hearts after donor management (Group A) with a 30-day survival rate of 86%. Twelve (44%) organs were declined due to poor heart function (n=8; 66.7%; P<0.001) and/or palpable coronary artery disease (n=4; 33.3%; P=0.018) (Group B). The mean age of Groups A and B was 42.77 and 47.78 years, respectively (P=0.19). Most of the female donors, i.e. 10 (83%), were declined, and only 4 (27%) were accepted (P=0.005). Majority of patients in both groups (Group A: 71.4%; n=10; and Group B: 66.7%; n=8) were on high-dose noradrenaline (>0.08 μg kg(-1) min(-2)) at the time of donor offer. Group A had a mean cardiac output of 6.29 and 3.09 l/min for Group B (P=0.01). A positive smoking history was present in 28.6% (n=4) and 33.5% (n=4) in Groups A and B, respectively (P=0.793). Cardiopulmonary resuscitation was performed on 3 (21.4%) patients in Group A and 2 (16.7%) in Group B (P=0.759). A history of hypertension was present in 7.1% (n=1) of the Group A and 33.3% (n=4) of the Group B donors. CONCLUSIONS In our study, we were able to retrieve more than half of the potential heart donors as a result of early active donor management without impacting on the post-transplant recipient outcome. Early active donor management may assist in increasing the number of heart transplantations, thus warranting further investigation.