No Evidence of Progressive Proinflammatory Cytokine Storm in Brain-dead Organ Donors-A Time-course Analysis Using Clinical Samples.

BACKGROUND: Solid organ transplantation is a cost-effective treatment for end-stage organ failure. Organ donation after brain death is an important source of transplanted organs. Data are limited on the effects of brain injury or donor management on grafts. The consensus view has been that brain death creates a progressively proinflammatory environment. We aimed to investigate time-course changes across a range of cytokines in a donation after brain death cohort of donors who died of intracranial hemorrhage without any other systemic source of inflammation. METHODS: A donor cohort was defined using the UK Quality in Organ Donation biobank. Serum levels of proteins involved in proinflammatory and brain injury pathways (tumor necrosis factor-alpha, interleukin-6, complement C5a, neuron-specific enolase, and glial fibrillary acidic protein) were measured from admission to organ recovery. Moving median analysis was used to combine donor trajectories and delineate a time-course. RESULTS: A cohort of 27 donors with brain death duration between 10 and 30 h was created, with 24 donors contributing to the time-course analysis. We observed no increase in tumor necrosis factor-alpha or interleukin-6 throughout the donor management period. Neuronal injury marker and complement C5a remain high from admission to organ recovery, whereas glial fibrillary acidic protein rises around the confirmation of brain death. CONCLUSIONS: We found no evidence of a progressive rise of proinflammatory mediators with prolonged duration of brain death, questioning the hypothesis of a progressively proinflammatory environment. Furthermore, the proposed approach allows us to study chronological changes and identify biomarkers or target pathways when logistical or ethical considerations limit sample availability.

Isolation and primary culture of human abdominal aorta smooth muscle cells from brain-dead donors: an experimental model for vascular diseases.

Primary cell cultures are essential tools for elucidating the physiopathological mechanisms of the cardiovascular system. Therefore, a primary culture growth protocol of cardiovascular smooth muscle cells (VSMCs) obtained from human abdominal aortas was standardized. Ten abdominal aorta samples were obtained from patients diagnosed with brain death who were organ and tissue donors with family consent. After surgical ablation to capture the aorta, the aortic tissue was removed, immersed in a Custodiol® solution, and kept between 2 and 8 °C. In the laboratory, in a sterile environment, the tissue was fragmented and incubated in culture plates containing an enriched culture medium (DMEM/G/10% fetal bovine serum, L-glutamine, antibiotics and antifungals) and kept in an oven at 37 °C and 5% CO2. The aorta was removed after 24 h of incubation, and the culture medium was changed every six days for twenty days. Cell growth was confirmed through morphological analysis using an inverted optical microscope (Nikon®) and immunofluorescence for smooth muscle alpha-actin and nuclei. The development of the VSMCs was observed, and from the twelfth day, differentiation, long cytoplasmic projections, and adjacent cell connections occurred. On the twentieth day, the morphology of the VSMCs was confirmed by actin fiber immunofluorescence, which is a typical characteristic of VSMCs. The standardization allowed VSMC growth and the replicability of the in vitro test, providing a protocol that mimics natural physiological environments for a better understanding of the cardiovascular system. Its use is intended for investigation, tissue bioengineering, and pharmacological treatments.

Histological and clinical evaluation of discarded kidneys in a European cohort of deceased brain death donor kidneys of marginal quality.

BACKGROUND: Despite organ shortages, the discard rate of deceased donor kidneys is high. Risk factors for this trend warrant further study. METHODS: We investigated reasons for discard in a cohort of brain death donors with marginal kidneys and procurement biopsies. Paraffin embedded procurement biopsies were systematically reevaluated and graded for the purpose of the study. Assessment included percentage of global glomerulosclerosis, Banff Lesion scores and tubular epithelial damage. Donor-, transplant process-, perfusion quality-, histopathology-, and recipient-related parameters were compared between discarded and transplanted organs. RESULTS: Although most clinical characteristics were similar between donors whose kidneys were transplanted and those whose kidneys were procured but discarded, discarded kidneys were more likely to be from donors with hepatitis C, to have undergone wedge biopsies, to show changes of acute and chronic injury and to be deemed poor quality. Except for obvious anatomic abnormalities, kidneys were often discarded due to the findings of procurement biopsies. Donors of kidneys discarded for histologic reasons more often had hypertension, coronary artery disease, stroke, and increased serum creatinine. The reason for discard was unknown in 20% of cases. Discarded kidneys came from donors who appeared to be clinically similar to donors whose kidneys were utilized for transplant. CONCLUSION: A considerable proportion of discarded kidneys were of acceptable quality. The analysis of the outcome of every recovered organ could help to overcome this problem. Procurement biopsies more often lead to discard than to transplantation of recovered organs. Proper handling during allocation has to be determined.

Neuropathologic findings in a young woman 4 years following declaration of brain death: case analysis and literature review.

Brain death (death by neurologic criteria) is declared in 2% of all in-hospital deaths in the United States. Published neuropathology studies of individuals maintained on cardiorespiratory support are generally decades old, and notably include only 3 cases with long intervals between brain and "somatic" death (68 days, 101 days, 20 years). Here, we share our observations in a young woman supported for nearly 4½ years following declaration of brain death after oropharyngeal surgery. While limited by tissue availability and condition, we found evidence of at least partial perfusion of the superficial cerebral and cerebellar cortices by external carotid and vertebral arteries (via meningeal and posterior pharyngeal branches), characterized by focal cellular reaction and organization. Dural venous sinuses had thrombosis and recanalization, as well as iron deposition. In nonperfused brain areas, tissue "mummification," akin to that seen in certain postmortem conditions, including macerated stillbirths and saponification (adipocere formation), was identified, and are reviewed herein. Unfortunately, correlation with years-earlier clinical and radiographic observations was not possible. Nevertheless, we feel that our careful neuropathologic inspection of this case expands the understanding of the spectrum of human brain tissue alterations possible in a very rarely seen set of conditions.

Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes.

In brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys adversely impacting the quality of grafts. Here, we hypothesized that donation after brain death (DBD) kidneys undergo proteolytic processes that may deem grafts susceptible to posttransplant dysfunction. Using mass spectrometry and immunoblotting, we mapped degradation profiles of cytoskeletal proteins in deceased and living donor kidney biopsies. We found that key cytoskeletal proteins in DBD kidneys were proteolytically cleaved, generating peptide fragments, predominantly in grafts with suboptimal posttransplant function. Interestingly, α-actinin-4 and talin-1 proteolytic fragments were detected in brain death but not in circulatory death or living donor kidneys with similar donor characteristics. As talin-1 is a specific proteolytic target of calpain-1, we investigated a potential trigger of calpain activation and talin-1 degradation using human ex vivo precision-cut kidney slices and in vitro podocytes. Notably, we showed that activation of calpain-1 by transforming growth factor-ß generated proteolytic fragments of talin-1 that matched the degradation fragments detected in DBD preimplantation kidneys, also causing dysregulation of the actin cytoskeleton in human podocytes; events that were reversed by calpain-1 inhibition. Our data provide initial evidence that brain death donor kidneys are more susceptible to cytoskeletal protein degradation. Correlation to posttransplant outcomes may be established by future studies.

Brain and heart-specific death in cancer patients: Population-based study.

BACKGROUND: The occurrence of cardiovascular events is a major cause of death in patients with cancer. Small studies have documented a connection between specific brain alterations and autonomic cardiac dysfunctions, possibly resulting in a worse prognosis. We aimed to refine the knowledge of fatal cardiac events in patients with brain metastasis (BM). METHODS: We performed a Surveillance, Epidemiology, and End Results SEER registry-based investigation (timeline: 2010-2016) and extracted all the advanced patients who had experienced fatal cardiac outcomes. Populations were compared according to the presence or not BM. Kaplan-Meier (KM) methodology was used for survival analysis and a multivariate model was developed by adjusting for multiple possible confounders. RESULTS: Most related BM and cardiac death were observed at the site of lung cancer (81.4%). We extracted 3187 patients with lung cancer site, including 417 patients who had experienced fatal heart-specific with a history of BM, which is considered a BM group. The second group of heart-specific death included 2770 patients was stated as a non-BM group. Patients who had experienced heart-specific death in the BM group were predominately male, right side, upper site, and non-small type (62.11%, 54.92%, 51.56%, 69.78%), respectively. The survival outcomes between BM and the non- BM was significantly prominent (p = 0.003; median: 2 months vs. 3 months).The negative prognostic independent significance of heart-fatal events was confirmed after adjusting for multiple variables (HR = 0.76, CI = 0.68-84, p < 0.0001). The metastatic liver site was significantly associated with poorer survival rates (HR = 0.68; CI = 0.52-0.88, p = 0.005). We revealed a possible connection between the brain and heart functions. CONCLUSIONS: The prognosis of heart-specific death patients in BM is unfavorable compared to non-BM settings in lung cancer. We may be at the gates of a new field of neurocardiooncology.

Lower beta cell yield from donor pancreases after controlled circulatory death prevented by shortening acirculatory warm ischemia time and by using IGL-1 cold preservation solution.

Organs from donors after controlled circulatory death (DCD III) exhibit a higher risk for graft dysfunction due to an initial period of warm ischemia. This procurement condition can also affect the yield of beta cells in islet isolates from donor pancreases, and hence their use for transplantation. The present study uses data collected and generated by our Beta Cell Bank to compare the number of beta cells in isolates from DCD III (n = 141) with that from donors after brain death (DBD, n = 609), before and after culture, and examines the influence of donor and procurement variables. Beta cell number per DCD III-organ was significantly lower (58 x 106 versus 84 x 106 beta cells per DBD-organ; p < 0.001) but their purity (24% insulin positive cells) and insulin content (17 µg / 106 beta cells in DCD III-organs versus 19 µg / 106 beta cells in DBD-organs) were similar. Beta cell number correlated negatively with duration of acirculatory warm ischemia time above 10 min; for shorter acirculatory warm ischemia time, DCD III-organs did not exhibit a lower beta cell yield (74 x 106 beta cells). Use of Institut Georges Lopez-1 cold preservation solution instead of University of Wisconsin solution or histidine-tryptophan-ketoglutarate also protected against the loss in beta cell yield from DCD III-organs (86 x 106 for IGL-1 versus 54 x 106 and 65 x 106 beta cells respectively, p = 0.042). Multivariate analysis indicates that both limitation of acirculatory warm ischemia time and use of IGL-1 prevent the reduced beta cell yield in islet cell isolates from DCD III-organs.

Validation of the factors influencing family consent for organ donation in the UK.

Between 2013 and 2019, there was an increase in the consent rate for organ donation in the UK from 61% to 67%, but this remains lower than many European countries. Data on all family approaches (16,896) for donation in UK intensive care units or emergency departments between April 2014 and March 2019 were extracted from the referral records and the national potential donor audit held by NHS Blood and Transplant. Complete data were available for 15,465 approaches. Consent for donation after brain death was significantly higher than for donation after circulatory death, 70% (4260/6060) vs. 60% (5645/9405), (OR 1.58, 95%CI 1.47-1.69). Patient ethnicity, religious beliefs, sex and socio-economic status, and knowledge of a patient's donation decision were strongly associated with consent (p < 0.001). These factors should be addressed by medium- to long-term strategies to increase community interventions, encouraging family discussions regarding donation decisions and increasing registration on the organ donor register. The most readily modifiable factor was the involvement of an organ donation specialist nurse at all stages leading up to the approach and the approach itself. If no organ donation specialist nurse was present, the consent rates were significantly lower for donation after brain death (OR 0.31, 95%CI 0.23-0.42) and donation after cardiac death (OR 0.26, 95%CI 0.22-0.31) compared with if a collaborative approach was employed. Other modifiable factors that significantly improved consent rates included less than six relatives present during the formal approach; the time from intensive care unit admission to the approach (less for donation after brain death, more for donation after cardiac death); family not witnessing neurological death tests; and the relationship of the primary consenter to the patient. These modifiable factors should be taken into consideration when planning the best bespoke approach to an individual family to discuss the option of organ donation as an end-of-life care choice for the patient.

Compromised right ventricular contractility in an ovine model of heart transplantation following 24 h donor brain stem death.

BACKGROUND: Heart failure is an inexorably progressive disease with a high mortality, for which heart transplantation (HTx) remains the gold standard treatment. Currently, donor hearts are primarily derived from patients following brain stem death (BSD). BSD causes activation of the sympathetic nervous system, increases endothelin levels, and triggers significant inflammation that together with potential myocardial injury associated with the transplant procedure, may affect contractility of the donor heart. We examined peri-transplant myocardial catecholamine sensitivity and cardiac contractility post-BSD and transplantation in a clinically relevant ovine model. METHODS: Donor sheep underwent BSD (BSD, n = 5) or sham (no BSD) procedures (SHAM, n = 4) and were monitored for 24h prior to heart procurement. Orthotopic HTx was performed on a separate group of donor animals following 24h of BSD (BSD-Tx, n = 6) or SHAM injury (SH-Tx, n = 5). The healthy recipient heart was used as a control (HC, n = 11). A cumulative concentration-effect curve to (-)-noradrenaline (NA) was established using left (LV) and right ventricular (RV) trabeculae to determine ß1-adrenoceptor mediated potency (-logEC50 [(-)-noradrenaline] M) and maximal contractility (Emax). RESULTS: Our data showed reduced basal and maximal (-)-noradrenaline induced contractility of the RV (but not LV) following BSD as well as HTx, regardless of whether the donor heart was exposed to BSD or SHAM. The potency of (-)-noradrenaline was lower in left and right ventricles for BSD-Tx and SH-Tx compared to HC. CONCLUSION: These studies show that the combination of BSD and transplantation are likely to impair contractility of the donor heart, particularly for the RV. For the donor heart, this contractile dysfunction appears to be independent of changes to ß1-adrenoceptor sensitivity. However, altered ß1-adrenoceptor signalling is likely to be involved in post-HTx contractile dysfunction.

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.

Bacterial Pneumonia in Brain-Dead Patients: Clinical Features and Impact on Lung Suitability for Donation.

OBJECTIVES: To appraise the epidemiological features of bacterial pneumonia and its impact on lung suitability for donation in brain-dead patients managed with protective ventilatory settings. DESIGN: Retrospective observational study. SETTING: Six ICUs from two university-affiliated hospitals. PATIENTS: Brain-dead adult patients managed in the participating ICUs over a 4-year period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 231 included patients, 145 (62.8%) were classified as ideal or extended-criteria potential lung donors at ICU admission and the remaining 86 patients having baseline contraindication for donation. Culture-proven aspiration pneumonia and early-onset ventilator-associated pneumonia occurred in 54 patients (23.4%) and 15 patients (6.5%), respectively (overall pneumonia incidence, 29.9%). Staphylococcus aureus and Enterobacterales were the most common pathogens. Using mixed-effects Cox proportional hazard models, age (adjusted hazard ratio, 0.98; 95% CI [0.96-0.99]), anoxic brain injury (3.55 [1.2-10.5]), aspiration (2.29 [1.22-4.29]), and not receiving antimicrobial agents at day 1 (3.56 [1.94-6.53]) were identified as independent predictors of pneumonia occurrence in the whole study population. Analyses restricted to potential lung donors yielded similar results. Pneumonia was associated with a postadmission decrease in the PaO2/FIO2 ratio and lower values at brain death, in the whole study population (estimated marginal mean, 294 [264-323] vs 365 [346-385] mm Hg in uninfected patients; p = 0.0005) as in potential lung donors (299 [248-350] vs 379 [350-408] mm Hg; p = 0.04; linear mixed models). Lungs were eventually retrieved in 31 patients (34.4%) among the 90 potential lung donors with at least one other organ harvested (pneumonia prevalence in lung donors (9.7%) vs nondonors (49.2%); p = 0.0002). CONCLUSIONS: Pneumonia occurs in one-third of brain-dead patients and appears as the main reason for lung nonharvesting in those presenting as potential lung donors. The initiation of antimicrobial prophylaxis upon the first day of the ICU stay in comatose patients with severe brain injury could enlarge the pool of actual lung donors.

Laser interstitial thermal therapy for in-field recurrence of brain metastasis after stereotactic radiosurgery: does treatment with LITT prevent a neurologic death?

Brain metastasis (BM) affects up to one-third of adults with cancer and carries a historically bleak prognosis. Despite advances in stereotactic radiosurgery (SRS), rates of in-field recurrence (IFR) after SRS range from 10 to 25%. High rates of neurologic death have been reported after SRS failure, particularly for recurrences deep in the brain and surgically inaccessible. Laser interstitial thermal therapy (LITT) is an emerging option in this setting, but its ability to prevent a neurologic death is unknown. In this study, we investigate the causes of death among patients with BM who undergo LITT for IFR after SRS. We conducted a single institution retrospective case series of patients with BM who underwent LITT for IFR after SRS. Clinical and demographic data were collected via chart review. The primary endpoint was cause of death. Between 2010 and 2018, 70 patients with BM underwent LITT for IFR after SRS. Median follow-up after LITT was 12.0 months. At analysis, 49 patients died; a cause was determined in 44. Death was neurologic in 20 patients and non-neurologic in 24. The 24-month cumulative incidence of neurologic and non-neurologic death was 35.1% and 38.6%, respectively. Etiologies of neurologic death included local recurrence (n = 7), recovery failure (n = 7), distant progression (n = 5), and other (n = 1). Among our patient population, LITT provided the ability to stabilize neurologic disease in up to 2/3 of patients. For IFR after SRS, LITT may represent a reasonable treatment strategy for select patients. Additional work is necessary to determine the extent to which LITT can prevent neurologic death after recurrence of BM.

Expanding pancreas donor pool by evaluation of unallocated organs after brain death: Study protocol clinical trial (SPIRIT Compliant).

BACKGROUND: Pancreas graft quality directly affects morbidity and mortality rates after pancreas transplantation (PTx). The criteria for pancreas graft allocation are restricted, which has decreased the number of available organs. Suitable pancreatic allografts are selected based on donor demographics, medical history, and the transplant surgeon's assessment of organ quality during procurement. Quality is assessed based on macroscopic appearance, which is biased by individual experience and personal skills. Therefore, we aim to assess the histopathological quality of unallocated pancreas organs to determine how many unallocated organs are potentially of suitable quality for PTx. METHODS AND ANALYSIS: This is a multicenter cross-sectional explorative study. The demographic data and medical history of donor and cause of rejection of the allocation of graft will be recorded. Organs of included donors will be explanted and macroscopic features such as weight, color, size, and stiffness will be recorded by 2 independent transplant surgeons. A tissue sample of the organ will be fixed for further microscopic assessments. Histopathologic assessments will be performed as soon as a biopsy can be obtained. We will evaluate up to 100 pancreata in this study. RESULT: This study will evaluate the histopathological quality of unallocated pancreas organs from brain-dead donors to determine how many of these unallocated organs were potentially suitable for transplantation based on a histopathologic evaluation of organ quality. CONCLUSION: The comprehensive findings of this study could help to increase the pancreas graft pool, overcome organ shortage, reduce the waiting time, and also increase the number of PTx in the future. Registration number: ClinicalTrials.gov: NCT04127266.

Endoplasmic reticulum stress induces liver cells apoptosis after brain death by suppressing the phosphorylation of protein phosphatase 2A.

The present study aimed to investigate whether brain death (BD) induces the activation of endoplasmic reticulum stress (ERS) and protein phosphatase 2A (PP2A), and reveal the possible association with BD­induced liver cell apoptosis. A total of 30 healthy adult male Sprague­Dawley rats were randomized into three groups: Sham­operated group (S), BD group and 4­phenylbutyric acid group (BD + 4­PBA), with 10 rats in each group. All rats were anesthetized. The model of BD was established by inflating a balloon catheter that was placed into the extradural space after anesthesia. 4­PBA was administered via an intraperitoneal injection when the BD model was established. Anesthesia of the S group of rats was maintained for 6 h. Liver tissues were harvested after 6 h of BD. HE staining was used to evaluate the damage of liver. Terminal deoxynucleotidyl transferase­mediated 2'­deoxyuridine 5'­triphosphate nick­end labeling staining was used to observe the apoptosis of liver cells. Activation of ERS and PP2A was examined by western blotting and immunohistochemical staining. We reported that the apoptosis of liver cells after BD was significantly promoted than in the S group. Activation of ERS and PP2A was induced in the BD group when compared with S group. Phosphorylation of PP2A was suppressed in BD group. Application of 4­PBA decreased the activation of ERS and apoptosis rate compared with the BD group. In addition, activation of PP2A in the BD + 4­PBA group was decreased due to the reduction of PP2A phosphorylation compared with the BD group, but the levels were higher than in the S group. (P<0.05). In summary, our results indicated that BD induced ERS, then activated PP2A by suppressing the phosphorylation of PP2A, resulting in the apoptosis of liver cells.

Predestinating Role of Cardiac Ganglia on Heart Life Expectancy in Rabbits After Brain Death Following Subarachnoid Hemorrhage: An Experimental Study.

BACKGROUND: Cardiac ganglia are rechargeable batteries of the heart. The essential role of cardiac ganglia on cardiac life expectancy has not been examined following brain death. The aim of this study was to determine cardiac ganglia numbers and neuron density following subarachnoid hemorrhage (SAH). METHODS: Twenty-five hybrid rabbits were grouped as control (n = 5), sham (n = 5), and SAH (n = 15). The SAH groups' animals were subjected to injections of lethal dose of 2.00 cc autologous blood into their cisterna magna until linear EEG was obtained. The hearts of all animals were extracted following intracardiac formalin injection and examined. Cardiac ganglia and normal/degenerated neuron densities of cardiac neurons were recorded. RESULTS: The mean volume of normal neuron density of ganglia was 6.980 ± 830/mm3, and the degenerated neuron density of ganglia was 3 ± 1/mm3 in the control group, 6134 ± 712/mm3; 23 ± 9/mm3 in the sham group, 3456 ± 589; 1161 ± 72/mm3 in the surviving group; and 1734 ± 341/mm3, 4259 ± 865/mm3 in the dead animals in the SAH group. The algebraic results of heart work capacity (Wh) were estimated as 1375 ± 210 Wh in the control group, 1036 ± 225 in the sham group, 800 ± 110 Wh in the surviving group, and < 100 ± 20 in the dead animals in the SAH group. Degenerated cardiac neuron density/Wh correlation is statistically meaningful between the dead in the SAH group versus the SAH-surviving, sham, and control groups (P < .0005). CONCLUSIONS: Normal cardiac ganglia numbers and/or cardiac ganglia neuron density may be related to cardiac survival following brain death after subarachnoid hemorrhage.

Practice Variability in Determination of Death by Neurologic Criteria for Adult Patients.

In 2010, the American Academy of Neurology (AAN) published updated official guidelines for specific practices involved in the determination of death by neurologic criteria for adult patients, otherwise known as brain death. Most states, however, do not have laws mandating the standard adoption of the AAN guidelines. The responsibilities for creating and implementing brain death determination policies thus falls on individual hospitals. As a result, significant variability in practice exists between hospitals and even between providers. This review highlights the ways in which and the extent to which adult brain death determination varies across the US, while also making the case that such persistent levels of heterogeneity call for improvements in standardizing training in brain death determination.

Brain Death Criteria: Medical Dogma and Outliers.

The diagnosis of brain death (BD) is legally and medically accepted. Recently, several high-profile cases have led to discussions regarding the integrity of current criteria, and many physiologic problems have been identified to support the necessity for their reevaluation. These include a global variability of the criteria, the suggestion of a clinical "hierarchy," and the resultant approximation of BD. Further ambiguity has been exposed through case reports of reversible BD, and an inconsistent understanding from physicians who are viewed as experts in this domain. Meeting BD criteria clearly does not equate to a physiologic "death" of the brain, and a greater community perspective should be considered as the dialogue moves forward.

Oxygen and brain death; back from the brink.

NEW FINDINGS: • What is the topic of this review? To explore the unique evolutionary origins of the human brain and critically appraise its energy budget, including limits of oxygen and glucose deprivation during anoxia and ischaemia. • What advances does it highlight? The brain appears to be more resilient to substrate depletion than traditionally thought, highlighting greater resilience and an underappreciated capacity for functional recovery. ABSTRACT: The human brain has evolved into an unusually large, complex and metabolically expensive organ that relies entirely on a continuous supply of O2 and glucose. It has traditionally been assumed that its exorbitant energy budget, combined with little to no energy reserves, renders it especially vulnerable to anoxia and ischaemia, with substrate depletion and progression towards cell death largely irreversible and rapid. However, new and exciting evidence suggests that neurons can survive for longer than previously thought, highlighting an unexpected resilience and underappreciated capacity for functional recovery that has changed the way we think about brain cell death. Nature has the potential to unlock some of the mysteries underlying ischaemic survival, with select vertebrates having solved the problem of anoxia-hypoxia tolerance over millions of years of evolution. Better understanding of their survival strategies, including remarkable adaptations in brain physiology and redox homeostasis, might help to identify new therapeutic targets for human diseases characterized by O2 deprivation, ischaemia-reperfusion injury and ageing.

Impact of Secondary Insults in Brain Death After Traumatic Brain Injury.

In addition to primary injury in severe head trauma, secondary systemic insults that aggravate the brain injury may result in fatal neurologic outcome. We aim to evaluate the correlation between brain death and secondary systemic insults in 100 patients with severe traumatic brain injury (TBI) admitted to the intensive care unit. We collected data on hypotension and hypoxemia at the time of admission to intensive care unit and data on hypotension, hypoxemia, hypocarbia, hypercarbia, shock, anemia, hyperglycemia, and hyperthermia within the first 24 hours. In addition, we recorded the category of TBI according to computed tomography findings. Twenty-six patients (26%) who developed brain death were significantly younger than survivors. Early hypotension (odds ratio [OR], 10.24; 95% confidence interval [CI], 3.64-28.78; P = .000) and early shock (OR, 8.31; 95% CI, 2.65-26.01; P = .000) were significantly more frequent among brain-death patients. The most featured factor that independently predicted the development of brain death in patients with severe TBI was the existence of hypotension (B-2.74; 95% CI, 0.016-0.252; P = .000). The most common type of injury among brain death patients was a surgically evacuated mass lesion. Although all critical care principles are applied to prevent secondary systemic brain insults, when brain death occurs, the prevention of hypotension will become significant in preserving organs in better condition for procurement.

EGF-GH Axis in Rat Steatotic and Non-steatotic Liver Transplantation From Brain-dead Donors.

BACKGROUND: We evaluated the potential dysfunction caused by changes in growth hormone (GH) levels after brain death (BD), and the effects of modulating GH through exogenous epidermal growth factor (EGF) in steatotic and nonsteatotic grafts. METHODS: Steatotic and nonsteatotic grafts from non-BD and BD rat donors were cold stored for 6 hours and transplanted to live rats. Administration of GH and EGF and their underlying mechanisms were characterized in recipients of steatotic and nonsteatotic grafts from BD donors maintained normotensive during the 6 hours before donation. Circulating and hepatic GH and EGF levels, hepatic damage, and regeneration parameters were evaluated. Recipient survival was monitored for 14 days. Somatostatin, ghrelin, and GH-releasing hormones that regulate GH secretion from the anterior pituitary were determined. The survival signaling pathway phosphoinositide-3-kinase/protein kinase B that regulates inflammation (suppressors of cytokine signaling, high-mobility group protein B1, oxidative stress, and neutrophil accumulation) was evaluated. RESULTS: BD reduced circulating GH and increased GH levels only in steatotic livers. GH administration exacerbated adverse BD-associated effects in both types of graft. Exogenous EGF reduced GH in steatotic livers, thus activating cell proliferation and survival signaling pathways, ultimately reducing injury and inflammation. However, EGF increased GH in nonsteatotic grafts, which exacerbated damage. The benefits of EGF for steatotic grafts were associated with increased levels of somatostatin, a GH inhibitor, whereas the deleterious effect on nonsteatotic grafts was exerted through increased amounts of ghrelin, a GH stimulator. CONCLUSIONS: GH treatment is not appropriate in rat liver transplant from BD donors, whereas EGF (throughout GH inhibition) protects only in steatotic grafts.