Evaluation of Liver Quality after Circulatory Death Versus Brain Death: A Comparative Preclinical Pig Model Study.

The current organ shortage in hepatic transplantation leads to increased use of marginal livers. New organ sources are needed, and deceased after circulatory death (DCD) donors present an interesting possibility. However, many unknown remains on these donors and their pathophysiology regarding ischemia reperfusion injury (IRI). Our hypothesis was that DCD combined with abdominal normothermic regional recirculation (ANOR) is not inferior to deceased after brain death (DBD) donors. We performed a mechanistic comparison between livers from DBD and DCD donors in a highly reproducible pig model, closely mimicking donor conditions encountered in the clinic. DCD donors were conditioned by ANOR. We determined that from the start of storage, pro-lesion pathways such as oxidative stress and cell death were induced in both donor types, but to a higher extent in DBD organs. Furthermore, pro-survival pathways, such as resistance to hypoxia and regeneration showed activation levels closer to healthy livers in DCD-ANOR rather than in DBD organs. These data highlight critical differences between DBD and DCD-ANOR livers, with an apparent superiority of DCD in terms of quality. This confirms our hypothesis and further confirms previously demonstrated benefits of ANOR. This encourages the expended use of DCD organs, particularly with ANOR preconditioning.

[Toward a customized preservation for each kidney graft?] / Vers une personnalisation de la conservation des greffons rénaux ?

The increased number of patients in waiting list for renal transplantation requires the establishment of recommendations regarding graft preservation techniques. The preservation method impacts graft function and survival particularly in case of extended criteria donors. Based on our experience, the aim of this review is to establish a decisional diagram to draw graft management to 5years in relation to donor type and graft quality. Novel biomarkers are necessary to evaluate graft quality. Nuclear magnetic resonance or transcriptomic analyses are promising. Thus, good quality organs will be preserved in static condition associated to hypothermia; while grafts from extended criteria donors need to be assessed early during dynamic perfusion through an evaluation of perfusion solution to discriminate: good organs, with acceptable risks without perfusion conditions modifications; tolerable risk grafts for which it will be recommended to use a supplementation of perfusion solution with oxygen or pharmacologic additives such as mitochondrion protectors or oxygen carriers; and elevated risks graft which will not be used. This diagram based on experimental data needs to be assessed in clinical trials but highlights the crucial role of kidney graft quality assessment for its management and placed dynamic perfusion preservation as the protocol of choice for extended criteria donors.

Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation.

In renal transplantation, live donor kidney grafts are associated with optimum success rates due to the shorter period of ischemia during the surgical procedure. The current shortage of donor organs for adult patients has caused a shift towards deceased donors, often with co-morbidity factors, whose organs are more sensitive to ischemia-reperfusion injury, which is unavoidable during transplantation. Donor management is pivotal to kidney graft survival through the control of the ischemia-reperfusion sequence, which is known to stimulate numerous deleterious or regenerative pathways. Although the key role of endothelial cells has been established, the complexity of the injury, associated with stimulation of different cell signaling pathways, such as unfolded protein response and cell death, prevents the definition of a unique therapeutic target. Preclinical transplant models in large animals are necessary to establish relationships and kinetics and have already contributed to the improvement of organ preservation. Therapeutic strategies using mesenchymal stem cells to induce allograft tolerance are promising advances in the treatment of the pediatric recipient in terms of reducing/withdrawing immunosuppressive therapy. In this review we focus on the different donor management strategies in kidney graft conditioning and on graft preservation consequences by highlighting the role of endothelial cells. We also propose strategies for preventing ischemia-reperfusion, such as cell therapy.

Interest of low-dose hydrocortisone therapy during brain-dead organ donor resuscitation: the CORTICOME study.

INTRODUCTION: Circulatory failure during brain death organ donor resuscitation is a problem that compromises recovery of organs. Combined administration of steroid, thyroxine and vasopressin has been proposed to optimize the management of brain deceased donors before recovery of organs. However the single administration of hydrocortisone has not been rigorously evaluated in any trial. METHODS: In this prospective multicenter cluster study, 259 subjects were included. Administration of low-dose steroids composed the steroid group (n = 102). RESULTS: Although there were more patients in the steroid group who received norepinephrine before brain death (80% vs. 66%: P = 0.03), mean dose of vasopressor administered after brain death was significantly lower than in the control group (1.18 ± 0.92 mg/H vs. 1.49 ± 1.29 mg/H: P = 0.03), duration of vasopressor support use was shorter (874 min vs. 1160 min: P < 0.0001) and norepinephrine weaning before aortic clamping was more frequent (33.8% vs. 9.5%: P < 0.0001). Using a survival approach, probability of norepinephrine weaning was significantly different between the two groups (P < 0.0001) with a probability of weaning 4.67 times higher in the steroid group than in the control group (95% CI: 2.30 - 9.49). CONCLUSIONS: Despite no observed benefits of the steroid administration on primary function recovery of transplanted grafts, administration of glucocorticoids should be a part of the resuscitation management of deceased donors with hemodynamic instability.

Development of a preclinical model of donation after circulatory determination of death for translational application.

BACKGROUND: Extracorporeal membranous oxygenation is proposed for abdominal organ procurement from donation after circulatory determination of death (DCD). In France, the national Agency of Biomedicine supervises the procurement of kidneys from DCD, specifying the durations of tolerated warm and cold ischemia. However, no study has determined the optimal conditions of this technique. The aim of this work was to develop a preclinical model of DCD using abdominal normothermic oxygenated recirculation (ANOR). In short, our objectives are to characterize the mechanisms involved during ANOR and its impact on abdominal organs. METHODS: We used Large White pigs weighing between 45 and 55 kg. After 30 minutes of potassium-induced cardiac arrest, the descending thoracic aorta was clamped and ANOR set up between the inferior vena cava and the abdominal aorta for 4 hours. Hemodynamic, respiratory and biochemical parameters were collected. Blood gasometry and biochemistry analysis were performed during the ANOR procedure. RESULTS: Six ANOR procedures were performed. The surgical procedure is described and intraoperative parameters and biological data are presented. Pump flow rates were between 2.5 and 3 l/min. Hemodynamic, respiratory, and biochemical objectives were achieved under reproducible conditions. Interestingly, animals remained hemodynamically stable following the targeted protocol. Arterial pH was controlled, and natremia and renal function remained stable 4 hours after the procedure was started. Decreased hemoglobin and serum proteins levels, concomitant with increased lactate dehydrogenase activity, were observed as a consequence of the surgery. The serum potassium level was increased, owing to the extracorporeal circulation circuit. CONCLUSIONS: Our ANOR model is the closest to clinical conditions reported in the literature and will allow the study of the systemic and abdominal organ impact of this technique. The translational relevance of the pig will permit the determination of new biomarkers and protocols to improve DCD donor management.

Bilateral renal cortical necrosis with end-stage renal failure following envenoming by Proatheris superciliaris: a case report.

Acute bilateral renal cortical necrosis (BRCN) has been reported following envenoming by exotic venomous snakes. Proatheris superciliaris is a rare viper with restricted distribution in east Africa. Very little information is available on envenoming by this species. We herein describe the case of a 60-year-old professional wildlife photographer who was bitten on his thumb while photographing an adult specimen of P. superciliaris that he held at home in France. On admission, physical examination revealed severe hypertension and bruising with edema at the bite site. Within the following 24 h, he developed vomiting, diarrhea, acute lumbar pain and anuria. Laboratory tests showed acute kidney injury (serum creatinine 4.6 mg/dL), with thrombocytopenia, anemia and severe coagulopathy. Contrast-enhanced computed tomography scan revealed hypodense areas in the cortex of both kidneys consistent with diffuse BRCN. As no appropriate antivenom existed, only symptomatic care was given to the patient. Coagulation tests returned to normal within 48 h. The patient was placed on chronic hemodialysis, until he underwent successful kidney transplantation 18 months later. In developed countries, severe complications provoked by snake bites tend to be more frequent with the number of trendy exotic pets. Acute kidney injury, including BRCN, is a classic complication of viper bites. The present case of end-stage renal failure related to diffuse BRCN illustrates the potentially devastating effects of envenoming by P. superciliaris. Clinicians in developed countries should be informed about renal disorders and other potentially fatal complications of venomous snake bites and seek urgent expert advice for optimizing clinical management. Education and coaching of envenomed patients and exotic snake owners is mandatory to prevent dramatic accidents.

Gentamicin in hemodialyzed critical care patients: early dialysis after administration of a high dose should be considered.

Gentamicin is a widely used antibiotic in the intensive care unit (ICU). Its dosage is difficult to adapt to hemodialyzed ICU patients. The FDA-approved regimen consists of the administration of 1 to 1.7 mg/kg of gentamicin at the end of each dialysis session. Better pharmacokinetic management could be obtained if gentamicin were administered just before the dialysis session. We performed Monte Carlo simulations (MCS) to determine the best gentamicin pharmacokinetic profile (high peak and low trough concentrations). Then, 6 mg/kg of gentamicin was infused into 10 ICU patients over a period of 30 min. A 4-h-long hemodialysis session was started 30 min after the end of the infusion. Pharmacokinetic samples were regularly collected over 24 h. A one-compartment model with zero-order input and first-order elimination was developed in Nonmem version VI to analyze patients' measured gentamicin concentration-versus-time profiles. Finally, additional MCS were performed to compare the regimen chosen with the FDA-approved gentamicin regimen. High peak concentrations (C(max), 31.8 ± 16.8 mg/liter) were achieved. The estimated C(24) and C(48) values (concentrations 24 and 48 h, respectively, after the beginning of the infusion) were 4.1 ± 2.3 and 1.8 ± 1.2 mg/liter, respectively. The volume of distribution was 0.21 ± 0.06 liter/kg. MCS confirmed that the dosing regimen chosen achieved the target C(max) whereas the FDA-approved regimen did not (31.0 ± 10.9 versus 8.8 ± 3.1 mg · liter(-1)). Moreover, the C(24) values were similar while the AUC(0-24) values were moderately increased (190.8 ± 65.0 versus 135 ± 42.2 mg · h · liter(-1)). Therefore, administration of 6 mg/kg of gentamicin before hemodialysis to critically ill patients achieves a high C(max) and an acceptable AUC, maximizing pharmacokinetic/pharmacodynamic endpoints.

A pair analysis of the delayed graft function in kidney recipient: the critical role of the donor.

PURPOSE: The aim of this study was to analyze the importance of donor factors and especially the potential role of hemodynamic management in regard to delayed graft function in paired kidney recipient patients after renal transplantation and to analyze the urine of organ donors by proton-nuclear magnetic resonance spectroscopy to identify urine markers potentially correlated with delayed graft function in recipient patients. METHODS: A prospective multicenter epidemiologic study was conducted. A logistic regression model taking into account paired data was used. RESULTS: Data from 72 donors and the 144 corresponding paired recipients were analyzed. Univariate analysis showed that age of donor, previous history of tobacco, ischemic cause of brain death, norepinephrine infusion, and recipient age were the risk factors for delayed graft function. After adjusting for correlated outcome data and controlling for other potential prognostic factors, 3 variables remained significantly associated with outcome: donor age (odds ratio [OR], 10.7), hemodynamic status (OR, 0.167), and hydroxyl-ethyl starch infusion (OR, 0.135). Proton-nuclear magnetic resonance analysis evidenced 3 metabolites of interest in donors (trimethylamine-N-oxide, citrate, and lactate). However, these peaks were not correlated the clinical parameters in donors. CONCLUSIONS: Paired analysis of kidney transplantation emphasizes the important role of factor donor associated with delayed graft function in recipient. Thus, a particular attention should be paid to the hemodynamic management of donor.

Validation of an algorithm based on direct examination of specimens in suspected ventilator-associated pneumonia.

BACKGROUND: The management of suspected ventilator-associated pneumonia (VAP) is traditionally based on either a clinical or a "bacteriological" approach. Direct examination of specimens may provide a valuable help to both approaches. OBJECTIVE: The objective was to test an algorithm for the management of suspected pneumonia based on severity criteria and Gram stains of specimens, including early treatment of patients with a positive Gram stain of a protected telescoping catheter specimen and awaiting culture results in patients with either Gram stains of endotracheal aspirate and protected specimen both being negative, or only positive endotracheal aspirate (EA), except in the presence of the severity criteria. METHODS: Observational study including 76 first episodes of suspected pneumonia in 4 units. We assessed the rates of correctly diagnosed episodes and of those treated empirically (i.e., ultimately confirmed pneumonia), or appropriately not receiving such therapy (non-confirmed pneumonia), based on protected specimen culture results. RESULTS: When adhered to, the algorithm allowed early appropriate management in 80% of patients, including 83% of those with confirmed pneumonia, and 74% of those without confirmed infection. The rate of appropriately managed episodes using this algorithm was significantly higher than that using a strategy based on the modified clinical pulmonary infection score (CPIS) alone (80 vs. 50%, p<0.001). The empiric regimen was adequate in 86% of confirmed episodes. CONCLUSION: A strategy based on severity criteria and Gram stain examination of respiratory tract specimens allows correct identification and appropriate management of more than 80% of mechanically ventilated patients who need or do not need therapy for suspected pneumonia.