Vamsidhar B. Dronavalli

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.

Incidence and outcome of Levitronix CentriMag support as rescue therapy for early cardiac allograft failure: a United Kingdom national study

OBJECTIVE Primary graft failure is the most common cause of mortality early after heart transplantation. The availability of relatively low-cost short-term mechanical support devices has altered the management of primary graft failure but there are few data on clinical outcome. Here, we describe the UK experience with Levitronix CentriMag support following heart transplantation across multiple centres. METHODS Data for all adult heart transplants and all CentriMag devices used within 30 days of heart transplantation in the UK between November 2003 and July 2008 were collected. Transplant characteristics were compared for those who did and did not receive CentriMag support, and device outcomes and survival rates were summarised. RESULTS A total of 572 heart transplants were performed in this period. As many as 38 patients (6.6%) were implanted with CentriMag devices for primary graft failure. Four patients received extracorporeal membrane oxygenation concurrently and were excluded from further analysis. There were no significant differences in transplant characteristics between the patients who received CentriMag support and those who did not. Twelve patients were explanted; nine survived but three died shortly afterwards. Five underwent acute retransplantation; two survived and three died. Seventeen patients died on support. The 30-day and 1-year survival rates were 50% (95% confidence interval (CI) 32-65%) and 32% (95% CI 18-48%), respectively. Patients who previously had a bridge-to-transplant ventricular assist device (VAD) had significantly better survival than those who did not (1-year survival 71% vs 22%, p = 0.029). CONCLUSIONS Primary graft failure remains an important early complication of heart transplantation. Levitronix CentriMag support led to the salvage of 32% of patients with severe allograft failure.

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.

Chronic Kidney Disease After Nonrenal Solid Organ Transplantation: A Histological Assessment and Utility of Chronic Allograft Damage Index Scoring

Background. It is proposed that chronic calcineurin inhibitor (CNI) nephrotoxicity has a central role in chronic kidney disease after nonrenal solid organ transplantation (NRSOT), although there are little data on renal histology in this setting. The aim of this study was to assess the histological features and renal outcomes of a cohort of patients with chronic kidney disease after NRSOT. Methods. Renal biopsies of 62 NRSOT recipients were evaluated for histological diagnoses. Biopsies were graded for chronic allograft damage index parameters and for arteriolar hyalinosis. The sum of all chronic allograft damage index parameters and arteriolar hyalinosis scores was called chronic damage index. Results. The biopsies were performed at a median of 4 (range: 0.3–15.9) years after NRSOT and at serum creatinine of 318±17.7 &mgr;mol/L (mean±standard deviation). Twenty-two (35.5%) biopsies showed predominant features of chronic CNI nephrotoxicity, 27 (43.5%) predominant features of hypertensive nephropathy, and 12 (19.3%) an alternative primary renal pathology. Twenty-four (38.7%) patients had progression to end-stage renal disease, at a median of 1.5 (0–10.1) years after biopsy and 6.9 (0.3–19.2) years after NRSOT. The risk of renal progression was associated with in situ damage measured by chronic damage index. Conclusions. Although CNI nephrotoxicity is an important cause of renal failure after NRSOT, many patients do not have overt histological evidence of CNI toxicity. Quantitative parameters of chronic damage can stratify renal prognosis.

Assessment of the Potential Heart Donor: A Role for Biomarkers?

Demand for donor hearts exceeds supply, and a significant number of patients die while awaiting transplantation. Within the pool of currently unused potential donor hearts, a proportion may be suitable for transplantation but are declined due to anticipated poor function. Despite current assessment methods, in some donor hearts accepted for transplantation early graft failure develops in the recipient. Current methods of assessment are inadequate, and there is a potential for biomarkers to improve identification of satisfactory hearts for transplantation or hearts destined to fail in the recipient. Biomarkers are routinely used to diagnose and risk-stratify myocardial infarction, acute coronary syndromes, and heart failure. Some of these might facilitate donor heart assessment. Cardiac troponins, cytokines, inflammatory markers, natriuretic peptides, and intracellular proteins may each have discriminant value. This review details the current status of biomarkers in the assessment of donor hearts.

N-terminal pro-brain-type natriuretic peptide: a biochemical surrogate of cardiac function in the potential heart donor,

OBJECTIVES N-terminal pro-B-type natriuretic peptide (NT-proBNP) is elevated in subarachnoid haemorrhage, brainstem death (BSD) and heart failure. We examined the relationship between NT-proBNP and cardiac functional status after BSD and left ventricular (LV) BNP precursor gene expression. METHODS We assayed NT-proBNP in the serum of potential heart donors investigated with pulmonary artery flotation catheters, transthoracic echocardiography and cardiac troponin (cTn) I and T. After 6.9 h of optimisation, haemodynamic studies were repeated to determine haemodynamic functional suitability for transplantation. Median (interquartile range (IQR)) NT-proBNP levels are reported according to initially measured dichotomised pulmonary capillary wedge pressure (PCWP), cardiac index (CI), indexed cardiac power output (CPOi), left ventricular ejection fraction (LVEF), wall motion score (WMS), extravascular lung water index (EVLWI), cTnT and cTnI and end-management functional suitability. LV biopsies were snap-frozen, mRNA extracted and reverse-transcribed, allowing performance of Taqman real-time polymerase chain reaction assays of mRNA-BNP precursor. RESULTS There were 79 subjects. Median NT-proBNP was 121 pg ml(-1) (range 5-4139) and levels correlated with time from coning (p<0.01, r=-0.379). Higher NT-proBNP was found in donors with PCWP >14 mmHg; 504 (120-1544) versus 101 (38-285); p=0.01; CI <2.4 l min(-1) m(-2) 410 (123-1511) versus 95 (37-264); p=0.001; CPOi <0.5 Wm(-2) 256 (78-694) versus 105 (37-315); p=0.02; LVEF <50% 231 (75-499) versus 72 (36-177); p=0.04; WMS >2; 343 (80-673) versus 99 (37-236); p=0.01; cTnT >0.1 microg ml(-1) 499 (127-967) versus 80 (36-173); p<0.001 and cTnI >1 mg ml(-1) 410 (97-684) versus 88 (36-190); p<0.01 and in hearts functionally unsuitable at end-optimisation; 189 (74-522) versus 85 (39-243); p=0.02. Hearts functionally suitable for transplantation expressed significantly less mRNA encoding for BNP precursor (0.19-fold; p=0.01). CONCLUSION During or after BSD, NT-proBNP is released and the heart is a likely source. Higher NT-proBNP levels are associated with donor heart dysfunction and a failure to achieve haemodynamic functional suitability criteria. This supports the hypothesis that biomarkers, including NT-proBNP, may be useful in donor heart assessment.

Primary Cardiac Allograft Dysfunction-Validation of a Clinical Definition

Background Heart transplantation is an established treatment for advanced heart failure. Primary allograft dysfunction (PGD) is reported in up to 40% of transplants and is associated with a poor outcome. Methods As part of Heart Evaluation and Retrieval for Transplantation study, an investigation of the assessment of donor hearts for transplantation, we proposed a clinical definition for cardiac PGD comprising severely impaired systolic function affecting one 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). Here, we examine the prospective application of this definition to 290 heart transplants. We compared the clinical outcome of PGD and non-PGD cases. Results Ninety-four of 290 transplants developed PGD (32.4%). Inotrope use (score) was higher in the PGD group at 24, 48, and 72 hours after transplantation (P < 0.01). In the PGD group, there was a greater requirement for, intra-aortic balloon pump (50% vs 15%, P < 0.01), mechanical support (27% vs 0%, P < 0.01), and renal replacement therapy (61% vs 26%, P < 0.01). Intensive care stay was longer for recipients with PGD (median 14 vs 5 days, P < 0.01) and early mortality was higher (37% vs 4% at 30 days, 42% vs 8% at 1 year, P < 0.01). Conclusions In conclusion, our definition of PGD could be applied in a national multicenter study, and the cases it defined had more frequent complications and higher mortality.

Failure to exclude a saccular arch aneurysm during hybrid repair: arch replacement without cerebral circulatory arrest.

Thoracic endovascular aortic reconstruction (TEVAR) is increasingly used in the management of descending aortic pathology including aneurysms, dissections and transaction. When treating aortic arch pathology, hybrid procedures have been devised, in which major supra-aortic arteries are translocated using a variety of techniques. Such hybrid procedures offer an attractive alternative to open arch procedures in frail elderly patients in whom the risks of open repair are considerable. We describe a surgical bail-out procedure which was used during a hybrid aortic arch replacement when endovascular aneurysm exclusion could not be achieved.