Alasdair Watson

a systematic review and meta-analysis of clinical trials of thyroid hormone administration to brain dead potential organ donors*

Objectives: To review all published clinical studies of thyroid hormone administration to brain-dead potential organ donors. Methods: A search of PubMed using multiple search terms retrieved 401 publications including 35 original reports describing administration of thyroid hormone to brain-dead potential organ donors. Detailed review of the 35 original reports led to identification of two additional publications not retrieved in the original search. The 37 original publications reported findings from 16 separate case series or retrospective audits and seven randomized controlled trials, four of which were placebo-controlled. Meta-analysis was restricted to the four placebo-controlled randomized controlled trials. Results: Whereas all case series and retrospective audits reported a beneficial effect of thyroid hormone administration, all seven randomized controlled trials reported no benefit of thyroid hormone administration either alone or in combination with other hormonal therapies. In four placebo-controlled trials including 209 donors, administration of thyroid hormone (n = 108) compared with placebo (n = 101) had no significant effect on donor cardiac index (pooled mean difference, 0.15 L/min/m2; 95% confidence interval –0.18 to 0.48). The major limitation of the case series and retrospective audits was the lack of consideration of uncontrolled variables that confound interpretation of the results. A limitation of the randomized controlled trials was that the proportion of donors who were hemodynamically unstable or marginal in other ways was too small to exclude a benefit of thyroid hormone in this subgroup. Conclusions: The findings of this systematic review do not support a role for routine administration of thyroid hormone in the brain-dead potential organ donor. Existing recommendations regarding the use of thyroid hormone in marginal donors are based on low-level evidence.

Primary Graft Failure after Heart Transplantation

Primary graft failure (PGF) is a devastating complication that occurs in the immediate postoperative period following heart transplantation. It manifests as severe ventricular dysfunction of the donor graft and carries significant mortality and morbidity. In the last decade, advances in pharmacological treatment and mechanical circulatory support have improved the outlook for heart transplant recipients who develop this complication. Despite these advances in treatment, PGF is still the leading cause of death in the first 30 days after transplantation. In todays climate of significant organ shortages and growing waiting lists, transplant units worldwide have increasingly utilised “marginal donors” to try and bridge the gap between “supply and demand.” One of the costs of this strategy has been an increased incidence of PGF. As the threat of PGF increases, the challenges of predicting and preventing its occurrence, as well as the identification of more effective treatment modalities, are vital areas of active research and development.

Enhanced preservation of the rat heart after prolonged hypothermic ischemia with erythropoietin-supplemented Celsior solution

BACKGROUND The cardioprotective efficacy of erythropoietin (EPO) has been widely documented in rodent models of acute coronary syndrome. We sought to evaluate its cardioprotective potential as an adjunct to Celsior cardioplegia in a rodent model of prolonged hypothermic global ischemia-reperfusion injury. METHODS Isolated working rat hearts were subjected to 6 or 10 hours of hypothermic ischemic storage in Celsior cardioplegic solution. Celsior was supplemented with EPO over a dose range of 0 to 5 units/ml, as well as with glyceryl trinitrate (0.1 mg/ml) and zoniporide (1 µmol/liter). Myocardial functional recovery was determined after 45 minutes of reperfusion, then left ventricular tissue was prepared for Western blotting. RESULTS The presence of EPO in Celsior dose-dependently improved recovery of myocardial function after 6 hours ischemic storage time (cardiac output recovery: 52.5 ± 11.3% vs 2.5 ± 0.4%; EPO: 5 units/ml vs 0 units/ml; p < 0.05). This functional benefit was associated with decreased lactate dehydrogenase released into coronary effluent and enhanced phosphorylation of STAT3, all of which were completely abrogated by pre-treatment with stattic, a selective inhibitor of STAT3 activation. When the ischemic storage time was extended to 10 hours, additive beneficial effects on myocardial function were seen when EPO was used in combination with the cardioprotective agents glyceryl trinitrate and zoniporide. CONCLUSIONS EPO has demonstrated cardioprotective efficacy in a rodent model of ischemia-reperfusion injury simulating cardiac allograft preservation, which appears to be mediated via activation of the SAFE cytoprotective signaling pathway.

Combining cariporide with glyceryl trinitrate optimizes cardiac preservation during porcine heart transplantation.

Sodium–hydrogen exchange inhibitors, such as cariporide, are potent cardioprotective agents, however, safety concerns have been raised about intravenously (i.v.) administered cariporide in humans. The aim of this study was to develop a preservation strategy that maintained cariporides cardioprotective efficacy during heart transplantation while minimizing recipient exposure. We utilized a porcine model of orthotopic heart transplantation that incorporated donor brain death and 14 h static heart storage. Five groups were studied: control (CON), hearts stored in Celsior; CAR1, hearts stored in Celsior with donors and recipients receiving cariporide (2 mg/kg i.v.) prior to explantation and reperfusion, respectively; CAR2, hearts stored in Celsior supplemented with cariporide (10 μmol/L); GTN, hearts stored in Celsior supplemented with glyceryl trinitrate (GTN) (100 mg/L); and COMB, hearts stored in Celsior supplemented with cariporide (10 μmol/L) plus GTN (100 mg/L). A total of 5/5 CAR1 and 5/6 COMB recipients were weaned from cardiopulmonary bypass compared with 1/5 CON, 1/5 CAR2 and 0/5 GTN animals (p = 0.001). Hearts from the CAR1 and COMB groups demonstrated similar cardiac function and troponin release after transplantation. Supplementation of Celsior with cariporide plus GTN provided superior donor heart preservation to supplementation with either agent alone and equivalent preservation to that observed with systemic administration of cariporide to the donor and recipient.

A recombinant human neuregulin-1 peptide improves preservation of the rodent heart after prolonged hypothermic storage.

Background. Donor hearts are subjected to ischemia-reperfusion injury during transplantation. Recombinant human neuregulin (rhNRG)-1 peptide attenuates myocardial injury in various animal models of cardiomyopathy. Supplementing the organ-storage solution, Celsior (C), with glyceryl trinitrate (GTN) and cariporide improves cardiac preservation after hypothermic storage. We hypothesized that the addition of rhNRG-1 to C would improve cardiac preservation after hypothermic storage and provide incremental benefit in combination with GTN and cariporide. Methods. An isolated working rat heart model was used. To assess the effect of rhNRG-1, hearts were stored for 6 hr at 4°C in C±rhNRG-1 (14 nM). To assess the effect of using a combination of prosurvival kinase activators on cardiac preservation, the ischemic storage time was extended to 10 hr and hearts stored in C±rhNRG-1 (14 nM)±GTN (0.1 mg/mL)±Cariporide (10 &mgr;M). Hearts were subsequently reperfused, cardiac function remeasured, and tissue collected for protein analysis and immunohistochemistry. Optimal timing of rhNRG-1 administration was also assessed. Results. rhNRG-1 supplemented C improved functional recovery after 6 hr of storage (cardiac output recovery [mean±SEM]: control 1.4%±0.6%; rhNRG-1+C 21.1%±7.9%; P<0.05). After 10-hr storage, no improvement in functional recovery was observed with rhNRG-1, GTN, or cariporide alone; however, GTN combined with cariporide did improve recovery (P<0.01), which was further enhanced by the addition of rhNRG-1 (P<0.01). Functional improvements were accompanied by increased phosphorylation of Akt, ERK1/2, STAT3, and GSK-3&bgr; and reduced cleaved caspase-3 (P<0.01). Conclusions. rhNRG-1 given together with other activators of prosurvival pathways improves preservation of the rat heart and shows promise for increasing the cold-ischemic life of donor hearts in transplantation.

Critical role of the STAT3 pathway in the cardioprotective efficacy of zoniporide in a model of myocardial preservation - the rat isolated working heart.

Ischemia‐reperfusion injury plays an important role in the development of primary allograft failure after heart transplantation. Inhibition of the Na+/H+ exchanger is one of the most promising therapeutic strategies for treating ischemia‐reperfusion injury. Here we have characterized the cardioprotective efficacy of zoniporide and the underlying mechanisms in a model of myocardial preservation using rat isolated working hearts.

Pharmacological Conditioning of Brain Dead Donor Hearts with Erythropoietin and Glyceryl Trinitrate: Clinical Experience

Background: With the increasing success of heart transplantation, older and higher-risk donors and recipients are being accepted for transplantation. The risk of primary graft dysfunction (PGD) is thus increased. We investigated a ‘pharmacological conditioning’ strategy, where Celsior preservation solution supplemented with glyceryl trinitrate (GTN) and erythropoietin (EPO) was used for cardioplegia and hypothermic storage, and determined graft recovery and patient survival after cardiac transplantation.