The gut microbiome in end-stage lung disease and lung transplantation.

Gut dysbiosis has been associated with impaired outcomes in liver and kidney transplant recipients, but the gut microbiome of lung transplant recipients has not been extensively explored. We assessed the gut microbiome in 64 fecal samples from end-stage lung disease patients before transplantation and 219 samples from lung transplant recipients after transplantation using metagenomic sequencing. To identify dysbiotic microbial signatures, we analyzed 243 fecal samples from age-, sex-, and BMI-matched healthy controls. By unsupervised clustering, we identified five groups of lung transplant recipients using different combinations of immunosuppressants and antibiotics and analyzed them in relation to the gut microbiome. Finally, we investigated the gut microbiome of lung transplant recipients in different chronic lung allograft dysfunction (CLAD) stages and longitudinal gut microbiome changes after transplantation. We found 108 species (58.1%) in end-stage lung disease patients and 139 species (74.7%) in lung transplant recipients that were differentially abundant compared with healthy controls, with several species exhibiting sharp longitudinal increases from before to after transplantation. Different combinations of immunosuppressants and antibiotics were associated with specific gut microbial signatures. We found that the gut microbiome of lung transplant recipients in CLAD stage 0 was more similar to healthy controls compared to those in CLAD stage 1. Finally, the gut microbial diversity of lung transplant recipients remained lower than the average gut microbial diversity of healthy controls up to more than 20 years post-transplantation. Gut dysbiosis, already present before lung transplantation was exacerbated following lung transplantation.IMPORTANCEThis study provides extensive insights into the gut microbiome of end-stage lung disease patients and lung transplant recipients, which warrants further investigation before the gut microbiome can be used for microbiome-targeted interventions that could improve the outcome of lung transplantation.

Ex Vivo Optimization of Donor Lungs with Inhaled Sevoflurane during Normothermic Ex Vivo Lung Perfusion (VITALISE): A Pilot and Feasibility Study in Sheep.

Volatile anesthetics have been shown in different studies to reduce ischemia reperfusion injury (IRI). Ex vivo lung perfusion (EVLP) facilitates graft evaluation, extends preservation time and potentially enables injury repair and improvement of lung quality. We hypothesized that ventilating lungs with sevoflurane during EVLP would reduce lung injury and improve lung function. We performed a pilot study to test this hypothesis in a slaughterhouse sheep DCD model. Lungs were harvested, flushed and stored on ice for 3 h, after which EVLP was performed for 4 h. Lungs were ventilated with either an FiO2 of 0.4 (EVLP, n = 5) or FiO2 of 0.4 plus sevoflurane at a 2% end-tidal concentration (Cet) (S-EVLP, n = 5). Perfusate, tissue samples and functional measurements were collected and analyzed. A steady state of the target Cet sevoflurane was reached with measurable concentrations in perfusate. Lungs in the S-EVLP group showed significantly better dynamic lung compliance than those in the EVLP group (p = 0.003). Oxygenation capacity was not different in treated lungs for delta partial oxygen pressure (PO2; +3.8 (-4.9/11.1) vs. -11.7 (-12.0/-3.2) kPa, p = 0.151), but there was a trend of a better PO2/FiO2 ratio (p = 0.054). Perfusate ASAT levels in S-EVLP were significantly reduced compared to the control group (198.1 ± 93.66 vs. 223.9 ± 105.7 IU/L, p = 0.02). We conclude that ventilating lungs with sevoflurane during EVLP is feasible and could be useful to improve graft function.

Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation.

Normothermic regional perfusion (NRP) allows assessment of therapeutic interventions prior to donation after circulatory death transplantation. Sodium-3-hydroxybutyrate (3-OHB) increases cardiac output in heart failure patients and diminishes ischemia-reperfusion injury, presumably by improving mitochondrial metabolism. We investigated effects of 3-OHB on cardiac and mitochondrial function in transplanted hearts and in cardiac organoids. Donor pigs (n = 14) underwent circulatory death followed by NRP. Following static cold storage, hearts were transplanted into recipient pigs. 3-OHB or Ringer's acetate infusions were initiated during NRP and after transplantation. We evaluated hemodynamics and mitochondrial function. 3-OHB mediated effects on contractility, relaxation, calcium, and conduction were tested in cardiac organoids from human pluripotent stem cells. Following NRP, 3-OHB increased cardiac output (P < 0.0001) by increasing stroke volume (P = 0.006), dP/dt (P = 0.02) and reducing arterial elastance (P = 0.02). Following transplantation, infusion of 3-OHB maintained mitochondrial respiration (P = 0.009) but caused inotropy-resistant vasoplegia that prevented weaning. In cardiac organoids, 3-OHB increased contraction amplitude (P = 0.002) and shortened contraction duration (P = 0.013) without affecting calcium handling or conduction velocity. 3-OHB had beneficial cardiac effects and may have a potential to secure cardiac function during heart transplantation. Further studies are needed to optimize administration practice in donors and recipients and to validate the effect on mitochondrial function.

Disparities in donor heart acceptance between the USA and Europe: clinical implications.

BACKGROUND AND AIMS: Given limited evidence and lack of consensus on donor acceptance for heart transplant (HT), selection practices vary widely across HT centres in the USA. Similar variation likely exists on a broader scale-across countries and HT systems-but remains largely unexplored. This study characterized differences in heart donor populations and selection practices between the USA and Eurotransplant-a consortium of eight European countries-and their implications for system-wide outcomes. METHODS: Characteristics of adult reported heart donors and their utilization (the percentage of reported donors accepted for HT) were compared between Eurotransplant (n = 8714) and the USA (n = 60 882) from 2010 to 2020. Predictors of donor acceptance were identified using multivariable logistic regression. Additional analyses estimated the impact of achieving Eurotransplant-level utilization in the USA amongst donors of matched quality, using probability of acceptance as a marker of quality. RESULTS: Eurotransplant reported donors were older with more cardiovascular risk factors but with higher utilization than in the USA (70% vs. 44%). Donor age, smoking history, and diabetes mellitus predicted non-acceptance in the USA and, by a lesser magnitude, in Eurotransplant; donor obesity and hypertension predicted non-acceptance in the USA only. Achieving Eurotransplant-level utilization amongst the top 30%-50% of donors (by quality) would produce an additional 506-930 US HTs annually. CONCLUSIONS: Eurotransplant countries exhibit more liberal donor heart acceptance practices than the USA. Adopting similar acceptance practices could help alleviate the scarcity of donor hearts and reduce waitlist morbidity in the USA.

Near-infrared spectroscopy and processed electroencephalogram monitoring for predicting peri-operative stroke risk in cardiothoracic surgery: An observational cohort study.

BACKGROUND: Stroke is a feared complication after cardiothoracic surgery, with an incidence of around 2 to 3%. Anaesthesia and postoperative sedation may obscure clinical symptoms of stroke and thus delay diagnosis and timely intervention. OBJECTIVES: The objective was to assess the value of intra-operative neuromonitoring and blood pressure monitoring for predicting the occurrence of peri-operative stroke within 3 days after cardiothoracic surgery. DESIGN: Single-centre retrospective observational cohort study. SETTING: Academic tertiary care medical centre. PATIENTS: All consecutive patients with cardiothoracic surgery and intra-operative neuromonitoring admitted postoperatively to the Intensive Care Unit (ICU) between 2008 and 2017. MAIN OUTCOME MEASURES: The primary endpoint was the occurrence of any stroke confirmed by brain imaging within 3 days postcardiothoracic surgery. Areas under the curve (AUC) of intra-operative mean arterial pressure (MAP), cerebral oxygen saturation (ScO 2 ) and bispectral index (BIS) below predefined thresholds were calculated, and the association with early stroke was tested using logistic regression analyses. RESULTS: A total of 2454 patients admitted to the ICU after cardiothoracic surgery had complete intra-operative data for ScO 2 , BIS and MAP and were included in the analysis. In 58 patients (2.4%), a stroke was confirmed. In univariate analysis, a larger AUC MAP<60 mmHg [odds ratio (OR) 1.43; 95% confidence interval (CI), 1.21 to 1.68) and larger AUC BIS<25 (OR 1.51; 95% CI, 1.24 to 1.83) were associated with the occurrence of postoperative stroke while ScO 2 less than 50% or greater than 20% reduction from individual baseline was not (OR 0.91; 95% CI, 0.50 to 1.67). After multivariable analysis, AUC BIS<25 (OR 1.45; 95% CI, 1.12 to 1.87) and longer duration of MAP less than 60 mmHg (OR 1.52; 95% CI, 1.02 to 2.27) remained independently associated with stroke occurrence. CONCLUSION: Cumulative intra-operative BIS values below 25 and longer duration of MAP below 60 mmHg were associated with the occurrence of peri-operative stroke within 3 days after cardiothoracic surgery. Prospective studies are warranted to evaluate a causal relationship between low BIS and stroke to establish whether avoiding intra-operative BIS values below 25 might reduce the incidence of peri-operative stroke.

Ex-situ oxygenated hypothermic machine perfusion in donation after circulatory death heart transplantation following either direct procurement or in-situ normothermic regional perfusion.

BACKGROUND: Heart transplantation in donation after circulatory death (DCD) relies on warm perfusion using either in situ normothermic regional perfusion (NRP) or ex situ normothermic machine perfusion. In this study, we explore an alternative: oxygenated hypothermic machine perfusion (HMP) using a novel clinically applicable perfusion system, which is compared to NRP with static cold storage (SCS). METHODS: In a porcine model, a DCD setting was simulated, followed by either (1) NRP and SCS (2) NRP and HMP with the XVIVO Heart preservation system or (3) direct procurement (DPP) and HMP. After preservation, heart transplantation (HTX) was performed. After weaning from cardiopulmonary bypass (CPB), biventricular function was assessed by admittance and Swan-Ganz catheters. RESULTS: Only transplanted hearts in the HMP groups showed significantly increased biventricular contractility (end-systole elastance) 2 hour post-CPB (left ventricle absolute change: NRP HMP: +1.8 ± 0.56, p = 0.047, DPP HMP: +1.5 ± 0.43, p = 0.045 and NRP SCS: +0.97 ± 0.47 mmHg/ml, p = 0.21; right ventricle absolute change: NRP HMP: +0.50 ± 0.12, p = 0.025, DPP HMP: +0.82 ± 0.23, p = 0.039 and NRP SCS: +0.28 ± 0.26, p = 0.52) while receiving significantly less dobutamine to maintain a cardiac output >4l/min compared to SCS. Diastolic function was preserved in all groups. Post-HTX, both HMP groups showed significantly less increments in plasma troponin T compared to SCS. CONCLUSION: In DCD HTX, increased biventricular contractility post-HTX was only observed in hearts preserved with HMP. In addition, the need for inotropic support and signs of myocardial damage were lower in the HMP groups. DCD HTX can be successfully performed using DPP followed by preservation with HMP in a preclinical setting.

Ventricular assist device implantation in a patient with systemic right ventricle and pectus excavatum.

Systemic right ventricular failure is a common finding in patients with transposition of the great arteries. Some of these patients require ventricular assist device implantation. We describe the feasibility of HeartMate 3 [Abbott, Illinois, United States] implantation in a patient with transposition of the great arteries, high human leukocyte antigen sensitization, and severe pectus excavatum using a two-stage approach. Learning objectives: 1.To notice the challenges faced while implanting HeartMate 3 [Abbott, Illinois, United States] in patients with congenital heart disease and anatomical limitations.2.To understand that despite the difficulties, HeartMate 3 implantation is possible, worthwhile, and sometimes the only choice in a patient with end-stage heart failure and congenital heart disease.

Impact of COVID-19 social distancing measures on lung transplant recipients: decline in overall respiratory virus infections is associated with stabilisation of lung function.

BACKGROUND: Coronavirus disease 2019 (COVID-19) social distancing measures led to a dramatic decline in non-COVID-19 respiratory virus infections, providing a unique opportunity to study their impact on annual forced expiratory volume in 1 s (FEV1) decline, episodes of temporary drop in lung function (TDLF) suggestive of infection and chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTRs). METHODS: All FEV1 values of LTRs transplanted between 2009 and April 2020 at the University Medical Center Groningen (Groningen, The Netherlands) were included. Annual FEV1 change was estimated with separate estimates for pre-social distancing (2009-2020) and the year with social distancing measures (2020-2021). Patients were grouped by individual TDLF frequency (frequent/infrequent). Respiratory virus circulation was derived from weekly hospital-wide respiratory virus infection rates. Effect modification by TDLF frequency and respiratory virus circulation was assessed. CLAD and TDLF rates were analysed over time. RESULTS: 479 LTRs (12 775 FEV1 values) were included. Pre-social distancing annual change in FEV1 was -114 (95% CI -133- -94) mL, while during social distancing FEV1 did not decline: 5 (95% CI -38-48) mL (difference pre-social distancing versus during social distancing: p<0.001). The frequent TDLF subgroup showed faster annual FEV1 decline compared with the infrequent TDLF subgroup (-150 (95% CI -181- -120) versus -90 (95% CI -115- -65) mL; p=0.003). During social distancing, we found significantly lower odds for any TDLF (OR 0.53, 95% CI 0.33-0.85; p=0.008) and severe TDLF (OR 0.34, 0.16-0.71; p=0.005) as well as lower CLAD incidence (OR 0.53, 95% CI 0.27-1.02; p=0.060). Effect modification by respiratory virus circulation indicated a significant association between TDLF/CLAD and respiratory viruses. CONCLUSIONS: During COVID-19 social distancing the strong reduction in respiratory virus circulation coincided with markedly less FEV1 decline, fewer episodes of TDLF and possibly less CLAD. Effect modification by respiratory virus circulation suggests an important role for respiratory viruses in lung function decline in LTRs.

Conservative initial postoperative anticoagulation strategy after HeartMate 3 left ventricular assist device implantation.

INTRODUCTION: Although anticoagulation therapy is mandated after implantation of a left ventricular assist device (LVAD), postoperative bleedings and reoperations occur relatively frequently and are associated with worse outcomes. We evaluated the use of a conservative postoperative anticoagulation protocol in patients implanted with a HeartMate 3 (HM3) LVAD. METHODS: In a single-centre retrospective analysis of postoperative outcomes after HM3 LVAD implantation, a standard (old) anticoagulation protocol (i.e. early, full-dose anticoagulation with low-molecular weight heparin and overlapping vitamin K antagonist) was compared with a new conservative anticoagulation protocol (i.e. slow initiation of vitamin K antagonists without overlapping heparin). Main outcomes were changes in international normalised ratio (INR), lactate dehydrogenase (LDH), bleeding and/or tamponade events requiring reoperation, length of stay and adverse events. RESULTS: In total, 73 patients (48 in old vs 25 in new protocol group) were evaluated. Mean age was 56 years (standard deviation 13) and most patients (78%) were males. Changes in INR and LDH in the first 14 days were similar in both groups (p = 0.50 and p = 0.997 for interaction, respectively). Number of bleeding/tamponade events requiring reoperation was lower in the new than in the old protocol group (4% vs 33%, p = 0.005). Postoperative 30-day mortality was similar, and we observed no thromboembolic events. Median (25th-75th percentiles) total length of postoperative hospital stay (27 (25-41) vs 21 (19-27) days, p < 0.001) and length of intensive care unit stay (5 (2-9) vs 2 (2-5) days, p = 0.022) were significantly shorter in the new protocol group. CONCLUSION: These retrospective data suggest that conservative slow initiation of anticoagulation therapy after HM3 LVAD implantation is associated with less bleeding/tamponade events requiring reoperation, a similar safety profile and a shorter duration of stay than the currently advised standard anticoagulation protocol.

Long-term outcome and bridging success of patients evaluated and bridged to lung transplantation on the ICU.

BACKGROUND: Evaluating and bridging patients to lung transplantation (LTx) on the intensive care unit (ICU) remains controversial, especially without a previous waitlist status. Long term outcome data after LTx from ICU remains scarce. We compared long-term survival and development of chronic lung allograft dysfunction (CLAD) in elective and LTx from ICU, with or without previous waitlist status. METHODS: Patients transplanted between 2004 and 2018 in 2 large academic Dutch institutes were included. Long-term survival and development of CLAD was compared in patients who received an elective LTx (ELTx), those bridged and transplanted from the ICU with a previous listing status (BTT), and in patients urgently evaluated and bridged on ICU (EBTT). RESULTS: A total of 582 patients underwent a LTx, 70 (12%) from ICU, 39 BTT and 31 EBTT. Patients transplanted from ICU were younger than ELTx (46 vs 51 years) and were bridged with mechanical ventilation (n = 42 (60%)), extra corporeal membrane oxygenation (n = 28 (40%)), or both (n = 21/28). Bridging success was 48% in the BTT group and 72% in the EBTT group. Patients bridged to LTx on ICU had similar 1 and 5 year survival (86.8% and 78.4%) compared to elective LTx (86.8% and 71.9%). This was not different between the BTT and EBTT group. 5 year CLAD free survival was not different in patients transplanted from ICU vs ELTx. CONCLUSION: Patients bridged to LTx on the ICU with and without prior listing status had excellent short and long-term patient and graft outcomes, and was similar to patients electively transplanted.

Oxygenated machine perfusion at room temperature as an alternative for static cold storage in porcine donor hearts.

BACKGROUND: There is a continued interest in ex situ heart perfusion as an alternative strategy for donor heart preservation. We hypothesize that oxygenated machine perfusion of donor hearts at a temperature that avoids both normothermia and deep hypothermia offers adequate and safe preservation. METHODS: Cardioplegia-arrested porcine donor hearts were randomly assigned to six hours of preservation using cold storage (CS, n = 5) or machine perfusion using an oxygenated acellular perfusate at 21°C (MP, n = 5). Subsequently, all grafts were evaluated using the Langendorff method for 120 min. Metabolic parameters and histology were analyzed. Systolic function was assessed by contractility and elastance. Diastolic function was assessed by lusitropy and stiffness. RESULTS: For both groups, in vivo baseline and post-Langendorff biopsies were comparable, as were lactate difference and myocardial oxygen consumption. Injury markers gradually increased and were comparable. Significant weight gain was seen in MP (p = 0.008). Diastolic function was not impaired in MP, and lusitropy was superior from 30 min up to 90 min of reperfusion. Contractility was superior in MP during the first hour of evaluation. CONCLUSION: We conclude that the initial functional outcome of MP-preserved hearts was transiently superior compared to CS, with no histological injury post-Langendorff. Our machine perfusion strategy could offer feasible and safe storage of hearts prior to transplantation. Future studies are warranted for further optimization.

Early Thromboembolic Stroke Risk of Postoperative Atrial Fibrillation Following Cardiac Surgery.

OBJECTIVE: The authors aimed to study the association between postoperative atrial fibrillation (POAF) and thromboembolic stroke and to determine risk factors for thromboembolic stroke after cardiac surgery. DESIGN: The authors performed a secondary analysis from a randomized controlled trial (GRIP-COMPASS). The patients with thromboembolic stroke were compared with those without thromboembolic stroke, and the difference in the incidence of POAF between these groups was assessed. Odds ratios (OR) were calculated using logistic regression analyses. Brain imaging was studied for the occurrence of thromboembolic stroke during hospital admission, and POAF was monitored for seven days. To assess which characteristics were associated with occurrence of thromboembolic stroke, stepwise backward regression analysis was performed. PARTICIPANTS: All adult consecutive cardiac surgery patients admitted postoperatively to the intensive care unit. SETTING: Academic tertiary care medical center. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 910 patients included in this study, 26 patients (2.9%) had a thromboembolic stroke during hospital admission. The incidence of POAF during the first seven days after cardiac surgery in those with thromboembolic stroke was 65%, compared with 39% in those without thromboembolic stroke: adjusted OR 3.01 (95% confidence interval, 1.13-8.00). POAF, a history of peripheral vascular disease, a higher EuroSCORE, and a longer duration of surgery were associated with thromboembolic stroke. CONCLUSIONS: POAF within seven days after cardiac surgery was associated with a three-fold increased risk for a thromboembolic stroke during hospital admission. Expeditious treatment of POAF may, therefore, reduce early stroke risk after cardiac surgery.

Potential of Donation After Unexpected Circulatory Death Programs Defined by Their Demographic Characteristics.

BACKGROUND: Donation after unexpected circulatory death (uDCD) donors are often suggested to increase the number of donor organs. In 2014, a uDCD protocol was implemented in three transplant centers in the Netherlands which unfortunately did not result in additional transplantations. This study was initiated to identify demographic factors influencing the potential success of uDCD programs. METHODS: Dutch resuscitation databases covering various demographic regions were analyzed for potential donors. The databases were compared with the uDCD implementation project and successful uDCD programs in Spain, France, and Russia. RESULTS: The resuscitation databases showed that 61% of all resuscitated patients were transferred to an emergency department. Age selection reduced this uDCD potential to 46% with only patients aged 18-65 years deemed eligible. Of these patients, 27% died in the emergency department. The urban region of Amsterdam showed the largest potential in absolute numbers (52 patients/y). Comparison with the uDCD implementation project showed large similarities in the percentage of potential donors; however, in absolute numbers, it showed a much smaller potential. Calculation of the potential per million persons and the extrapolation of the potential based on the international experience revealed the largest potential in urban regions. CONCLUSIONS: Implementation of a uDCD program should not only be based on the number of potential donors calculated from resuscitation databases. They show promising potential uDCD percentages for large rural regions and small urban regions; however, actual numbers per hospital are low, leading to insufficient exposure rates. It is, therefore, recommendable to limit uDCD programs to large urban regions.

A translational rat model for ex vivo lung perfusion of pre-injured lungs after brain death.

The process of brain death (BD) detrimentally affects donor lung quality. Ex vivo lung perfusion (EVLP) is a technique originally designed to evaluate marginal donor lungs. Nowadays, its potential as a treatment platform to repair damaged donor lungs is increasingly studied in experimental models. Rat models for EVLP have been described in literature before, yet the pathophysiology of BD was not included in these protocols and prolonged perfusion over 3 hours without anti-inflammatory additives was not achieved. We aimed to establish a model for prolonged EVLP of rat lungs from brain-dead donors, to provide a reliable platform for future experimental studies. Rat lungs were randomly assigned to one of four experimental groups (n = 7/group): 1) healthy, directly procured lungs, 2) lungs procured from rats subjected to 3 hours of BD and 1 hour cold storage (CS), 3) healthy, directly procured lungs subjected to 6 hours EVLP and 4), lungs procured from rats subjected to 3 hours of BD, 1 hour CS and 6 hours EVLP. Lungs from brain-dead rats showed deteriorated ventilation parameters and augmented lung damage when compared to healthy controls, in accordance with the pathophysiology of BD. Subsequent ex vivo perfusion for 6 hours was achieved, both for lungs of healthy donor rats as for pre-injured donor lungs from brain-dead rats. The worsened quality of lungs from brain-dead donors was evident during EVLP as well, as corroborated by deteriorated ventilation performance, increased lactate production and augmented inflammatory status during EVLP. In conclusion, we established a stable model for prolonged EVLP of pre-injured lungs from brain-dead donor rats. In this report we describe tips and pitfalls in the establishment of the rat EVLP model, to enhance reproducibility by other researchers.

Machine Perfusion of Donation After Circulatory Death Liver and Lungs Before Combined Liver-lung Transplantation.

Shortage of deceased donor organs for transplantation has led to the increased use of organs from donation after circulatory death (DCD) donors. There are currently no reports describing outcomes after multiorgan transplantation with DCD livers. The use of DCD organs for multiorgan transplantation can be enhanced if the detrimental effects of prolonged cold ischemia and subsequent ischemia-reperfusion injury are overcome. We present a case in which the liver and lungs of a DCD donor were preserved using ex situ machine perfusion for combined liver-lung transplantation. The recipient was a 19-year-old male patient requiring bilateral lung transplantation for severe progressive pleural parenchymal fibroelastosis and portal hypertension with portal vein thrombosis. The donor liver was preserved with dual hypothermic oxygenated machine perfusion, whereas the lungs were perfused using ex vivo lung perfusion. With ex vivo lung perfusion, total preservation time of right and left lung reached 17 and 21 h, respectively. Now, 2 y after transplantation, liver function is normal and lung function is improving. To conclude, we suggest that combined transplantation of DCD liver and lungs is feasible when cold ischemia is reduced with ex situ machine perfusion preservation.

Donor Heart Preservation with Hydrogen Sulfide: A Systematic Review and Meta-Analysis.

Preclinical studies have shown that postconditioning with hydrogen sulfide (H2S) exerts cardioprotective effects against myocardial ischemia-reperfusion injury (IRI). The aim of this study was to appraise the current evidence of the cardioprotective effects of H2S against IRI in order to explore the future implementation of H2S in clinical cardiac transplantation. The current literature on H2S postconditioning in the setting of global myocardial ischemia was systematically reviewed and analyzed, performing meta-analyses. A literature search of the electronic databases Medline, Embase and Cinahl identified 1835 studies that were subjected to our pre-defined inclusion criteria. Sixteen studies were considered eligible for inclusion. Postconditioning with H2S showed significant robust effects with regard to limiting infarct size (standardized mean difference (SMD) = -4.12, 95% CI [-5.53--2.71], p < 0.00001). Furthermore, H2S postconditioning consistently resulted in a significantly lower release of cardiac injury markers, lower levels of oxidative stress and improved cardiac function. Postconditioning with slow-releasing H2S donors offers a valuable opportunity for novel therapies within cardiac preservation for transplantation. Before clinical implication, studies evaluating the long-term effects of H2S treatment and effects of H2S treatment in large animal studies are warranted.

Ex Situ Perfusion of Hearts Donated After Euthanasia: A Promising Contribution to Heart Transplantation.

Organ donation after euthanasia is performed in an increasing number of countries. In this donation after circulatory death procedure, it has not been possible to donate the heart. Recent literature, however, reports positive results of heart donation after circulatory death. Therefore, patients who donate organs following euthanasia might be suitable candidates for heart donation. We want to confirm this assumption by sharing the results of 2 cases of heart donation following euthanasia with ex situ subnormothermic heart preservation. Our aim is to raise awareness of the potential of heart donation following euthanasia for both clinical transplantation and research. METHODS: The data of 2 consecutive heart donations following euthanasia were collected prospectively. Informed consent was obtained from the patients themselves for heart donation for research purposes. An acellular oxygenated subnormothermic machine perfusion strategy was used to preserve both donor hearts. Subsequently, the hearts were evaluated on a normothermic perfusion machine using a balloon in the left ventricle. RESULTS: Heart donation following euthanasia was feasible without significant changes in existing retrieval protocols. Duration of machine perfusion preservation was 408 and 432 minutes, for heart 1 and 2, respectively. For heart 1, developed pressure (Pdev) was 119 mm Hg, maximal rate of pressure rise (dP/dtmax), and fall (dP/dtmin) were 1524 mm Hg/s and -1057 mm Hg/s, respectively. For heart 2, Pdev was 142 mm Hg, dP/dtmax was 1098 mm Hg/s, and dP/dtmin was -802 mm Hg/s. CONCLUSIONS: Hearts donated following euthanasia are highly valuable for research purposes and can have sufficient quality to be transplanted. With the implementation of ex situ heart perfusion, patients who are to donate their organs following euthanasia should also be able to donate their hearts. The complex combination of euthanasia and heart donation is ethically sound and surgically feasible and can contribute to shortening the heart transplant waiting list.

Post-transplant inotrope score is associated with clinical outcomes after adult heart transplantation.

BACKGROUND: Inotrope score has been proposed as a marker of clinical outcome after adult heart transplantation (HTx) but is rarely used in practice. METHODS: Inotrope score during the first 48 h after HTx was calculated in 81 patients as: dopamine + dobutamine + amrinone + milrinone (dose × 15) + epinephrine (dose × 100) + norepinephrine (dose × 100) + enoximone + isoprenaline (dose × 100), with each drug in µg/kg/min. Determinants of inotrope score were identified with linear regression. Cox regression was used to determine the association of inotrope score with mortality. RESULTS: The mean recipient age was 52 ± 11 years, and 32 (39.5%) patients were female. Determinants of inotrope score were preoperative C-reactive protein, serum urea, congenital heart disease, and donor cardiac arrest (R2  = .30). Inotrope score was associated with 5-year mortality, independent of recipient age and gender (HR 1.03, 95% CI 1.00-1.07). This association was attenuated when adjusting for female-to-male transplant and ischemia time. Inotrope score was also strongly associated with continuous veno-venous hemofiltration (OR 1.07, 95% CI 1.03-1.12). CONCLUSION: High inotrope score post-HTx was observed in recipient congenital heart disease and was associated with a higher risk of mortality and acute kidney injury.

Methylprednisolone Treatment in Brain Death-Induced Lung Inflammation-A Dose Comparative Study in Rats.

Background: The process of brain death (BD) leads to a pro-inflammatory state of the donor lung, which deteriorates its quality. In an attempt to preserve lung quality, methylprednisolone is widely recommended in donor lung management. However, clinical treatment doses vary and the dose-effect relation of methylprednisolone on BD-induced lung inflammation remains unknown. The aim of this study was to investigate the effect of three different doses methylprednisolone on the BD-induced inflammatory response. Methods: BD was induced in rats by inflation of a Fogarty balloon catheter in the epidural space. After 60 min of BD, saline or methylprednisolone (low dose (5 mg/kg), intermediate dose (12.5 mg/kg) or high dose (22.5 mg/kg)) was administered intravenously. The lungs were procured and processed after 4 h of BD. Inflammatory gene expressions were analyzed by RT-qPCR and influx of neutrophils and macrophages were quantified with immunohistochemical staining. Results: Methylprednisolone treatment reduced neutrophil chemotaxis as demonstrated by lower IL-8-like CINC-1 and E-selectin levels, which was most evident in rats treated with intermediate and high doses methylprednisolone. Macrophage chemotaxis was attenuated in all methylprednisolone treated rats, as corroborated by lower MCP-1 levels compared to saline treated rats. Thereby, all doses methylprednisolone reduced TNF-α, IL-6 and IL-1ß tissue levels. In addition, intermediate and high doses methylprednisolone induced a protective anti-inflammatory response, as reflected by upregulated IL-10 expression when compared to saline treated brain-dead rats. Conclusion: We showed that intermediate and high doses methylprednisolone share most potential to target BD-induced lung inflammation in rats. Considering possible side effects of high doses methylprednisolone, we conclude from this study that an intermediate dose of 12.5 mg/kg methylprednisolone is the optimal treatment dose for BD-induced lung inflammation in rats, which reduces the pro-inflammatory state and additionally promotes a protective, anti-inflammatory response.