Bilateral nephrectomy impairs cardiovascular function and cerebral perfusion in a rat model of acute hemodilutional anemia.

Anemia and renal failure are independent risk factors for perioperative stroke, prompting us to assess the combined impact of acute hemodilutional anemia and bilateral nephrectomy (2Nx) on microvascular brain Po2 (PBro2) in a rat model. Changes in PBro2 (phosphorescence quenching) and cardiac output (CO, echocardiography) were measured in different groups of anesthetized Sprague-Dawley rats (1.5% isoflurane, n = 5-8/group) randomized to Sham 2Nx or 2Nx and subsequently exposed to acute hemodilutional anemia (50% estimated blood volume exchange with 6% hydroxyethyl starch) or time-based controls (no hemodilution). Outcomes were assessed by ANOVA with significance assigned at P < 0.05. At baseline, 2Nx rats demonstrated reduced CO (49.9 ± 9.4 vs. 66.3 ± 19.3 mL/min; P = 0.014) and PBro2 (21.1 ± 2.9 vs. 32.4 ± 3.1 mmHg; P < 0.001) relative to Sham 2Nx rats. Following hemodilution, 2Nx rats demonstrated a further decrease in PBro2 (15.0 ± 6.3 mmHg, P = 0.022). Hemodiluted 2Nx rats did not demonstrate a comparable increase in CO after hemodilution compared with Sham 2Nx (74.8 ± 22.4 vs. 108.9 ± 18.8 mL/min, P = 0.003) that likely contributed to the observed reduction in PBro2. This impaired CO response was associated with reduced fractional shortening (33 ± 9 vs. 51 ± 5%) and increased left ventricular end-systolic volume (156 ± 51 vs. 72 ± 15 µL, P < 0.001) suggestive of systolic dysfunction. By contrast, hemodiluted Sham 2Nx animals demonstrated a robust increase in CO and preserved PBro2. These data support the hypothesis that the kidney plays a central role in maintaining cerebral perfusion and initiating the adaptive increase in CO required to optimize PBro2 during acute anemia.NEW & NOTEWORTHY This study has demonstrated that bilateral nephrectomy acutely impaired cardiac output (CO) and microvascular brain Po2 (PBro2), at baseline. Following acute hemodilution, nephrectomy prevented the adaptive increase in CO associated with acute hemodilution leading to a further reduction in PBro2, accentuating the degree of cerebral tissue hypoxia. These data support a role for the kidney in maintaining PBro2 and initiating the increase in CO that optimized brain perfusion during acute anemia.

Persistence is key: unresolved immune dysfunction is lethal in both COVID-19 and non-COVID-19 sepsis.

Introduction: Severe COVID-19 and non-COVID-19 pulmonary sepsis share pathophysiological, immunological, and clinical features, suggesting that severe COVID-19 is a form of viral sepsis. Our objective was to identify shared gene expression trajectories strongly associated with eventual mortality between severe COVID-19 patients and contemporaneous non-COVID-19 sepsis patients in the intensive care unit (ICU) for potential therapeutic implications. Methods: Whole blood was drawn from 20 COVID-19 patients and 22 non-COVID-19 adult sepsis patients at two timepoints: ICU admission and approximately a week later. RNA-Seq was performed on whole blood to identify differentially expressed genes and significantly enriched pathways. Using systems biology methods, drug candidates targeting key genes in the pathophysiology of COVID-19 and sepsis were identified. Results: When compared to survivors, non-survivors (irrespective of COVID-19 status) had 3.6-fold more "persistent" genes (genes that stayed up/downregulated at both timepoints) (4,289 vs. 1,186 genes); these included persistently downregulated genes in T-cell signaling and persistently upregulated genes in select innate immune and metabolic pathways, indicating unresolved immune dysfunction in non-survivors, while resolution of these processes occurred in survivors. These findings of persistence were further confirmed using two publicly available datasets of COVID-19 and sepsis patients. Systems biology methods identified multiple immunomodulatory drug candidates that could target this persistent immune dysfunction, which could be repurposed for possible therapeutic use in both COVID-19 and sepsis. Discussion: Transcriptional evidence of persistent immune dysfunction was associated with 28-day mortality in both COVID-19 and non-COVID-19 septic patients. These findings highlight the opportunity for mitigating common mechanisms of immune dysfunction with immunomodulatory therapies for both diseases.

Characterizing the profiles of patients with acute concussion versus prolonged post-concussion symptoms in Ontario.

Identifying vulnerability factors for developing persisting concussion symptoms is imperative for determining which patients may require specialized treatment. Using cross-sectional questionnaire data from an Ontario-wide observational concussion study, we compared patients with acute concussion (≤ 14 days) and prolonged post-concussion symptoms (PPCS) (≥ 90 days) on four factors of interest: sex, history of mental health disorders, history of headaches/migraines, and past concussions. Differences in profile between the two groups were also explored. 110 patients with acute concussion and 96 patients with PPCS were included in our study. The groups did not differ on the four factors of interest. Interestingly, both groups had greater proportions of females (acute concussion: 61.1% F; PPCS: 66.3% F). Patient profiles, however, differed wherein patients with PPCS were significantly older, more symptomatic, more likely to have been injured in a transportation-related incident, and more likely to live outside a Metropolitan city. These novel risk factors for persisting concussion symptoms require replication and highlight the need to re-evaluate previously identified risk factors as more and more concussions occur in non-athletes and different risk factors may be at play.

Evaluation of the association of factor XIII at hospital arrival and outcomes in a cohort of severely injured patients.

BACKGROUND: Severe traumatic bleeding depletes coagulation factor XIII (FXIII) and fibrinogen. However, the role of FXIII level in bleeding-related outcomes is unknown. OBJECTIVES: To evaluate the association between FXIII levels at hospital arrival and critical administration threshold (≥3 red blood cell units in 1 hour within the first 24 hours), bleeding-related outcomes, death, and baseline characteristics. METHODS: A retrospective cohort study was conducted in severely injured adult patients (Injury Severity Score of ≥22 or ≥2 red blood cell units transfused in 24 hours) admitted to a level 1 trauma center. Clinical and laboratory data were collected. Baseline FXIII antigen levels were measured in banked patient plasma. Multivariable logistic and linear regression models were used to estimate the association between FXIII levels, outcomes, and baseline characteristics. RESULTS: Three hundred sixty-four of 1730 subjects admitted during a 2-year period were analyzed. Median age was 44 years (IQR, 27-62 years), and median Injury Severity Score was 29 (IQR, 22-34). FXIII levels were not associated with critical administration threshold (odds ratio [OR], 1.06; 95% CI, 0.97-1.17) or death (OR, 0.98; 95% CI, 0.90-1.07). FXIII was associated with major bleeding (OR, 1.10; 95% CI, 1.02-1.2) and massive transfusion (OR, 1.25; 95% CI, 1.08-1.44). Lower baseline FXIII levels were associated with arrival from a referring hospital (FXIII level, -0.07 U/mL; 95% CI, -0.11 to -0.03), hemoglobin (FXIII level, -0.05 U/mL; 95% CI, -0.07 to -0.03), fibrinogen level (FXIII level, -0.05 U/mL; 95% CI, -0.08 to -0.02), and platelet count (FXIII level, -0.02 U/mL; 95% CI, -0.04 to -0.008). CONCLUSIONS: Baseline FXIII levels in severely injured patients were inconsistently associated with bleeding-related outcomes and mortality. However, their association with major bleeding warrants further investigation of the role of FXIII in massively transfused patients with trauma.

A brain-based definition of death and criteria for its determination after arrest of circulation or neurologic function in Canada: a 2023 clinical practice guideline.

This 2023 Clinical Practice Guideline provides the biomedical definition of death based on permanent cessation of brain function that applies to all persons, as well as recommendations for death determination by circulatory criteria for potential organ donors and death determination by neurologic criteria for all mechanically ventilated patients regardless of organ donation potential. This Guideline is endorsed by the Canadian Critical Care Society, the Canadian Medical Association, the Canadian Association of Critical Care Nurses, Canadian Anesthesiologists' Society, the Canadian Neurological Sciences Federation (representing the Canadian Neurological Society, Canadian Neurosurgical Society, Canadian Society of Clinical Neurophysiologists, Canadian Association of Child Neurology, Canadian Society of Neuroradiology, and Canadian Stroke Consortium), Canadian Blood Services, the Canadian Donation and Transplantation Research Program, the Canadian Association of Emergency Physicians, the Nurse Practitioners Association of Canada, and the Canadian Cardiovascular Critical Care Society.

RéSUMé: Ces Lignes directrices de pratique clinique 2023 Lignes directrices de pratique clinique dicale du décès basée sur l'arrêt permanent de la fonction cérébrale qui s'applique à toute personne, ainsi que des recommandations pour la détermination du décès par des critères circulatoires pour des donneurs d'organes potentiels et des recommandations pour la détermination du décès par des critères neurologiques pour tous les patients sous ventilation mécanique, indépendamment de leur potentiel de donneur d'organes. Les présentes Lignes directrices sont approuvées par la Société canadienne de soins intensifs, l'Association médicale canadienne, l'Association canadienne des infirmiers/infirmières en soins intensifs, la Société canadienne des anesthésiologistes, la Fédération des sciences neurologiques du Canada (représentant la Société canadienne de neurologie, la Société canadienne de neurochirurgie, la Société canadienne de neurophysiologie clinique, l'Association canadienne de neurologie pédiatrique, la Société canadienne de neuroradiologie et le Consortium neurovasculaire canadien), la Société canadienne du sang, le Programme de recherche en don et transplantation du Canada, l'Association canadienne des médecins d'urgence, l'Association des infirmières et infirmiers praticiens du Canada, et la Société canadienne de soins intensifs cardiovasculaires (CANCARE) et la Société canadienne de pédiatrie.

Severe COVID-19 and non-COVID-19 severe sepsis converge transcriptionally after a week in the intensive care unit, indicating common disease mechanisms.

Introduction: Severe COVID-19 and non-COVID-19 pulmonary sepsis share pathophysiological, immunological, and clinical features. To what extent they share mechanistically-based gene expression trajectories throughout hospitalization was unknown. Our objective was to compare gene expression trajectories between severe COVID-19 patients and contemporaneous non-COVID-19 severe sepsis patients in the intensive care unit (ICU). Methods: In this prospective single-center observational cohort study, whole blood was drawn from 20 COVID-19 patients and 22 non-COVID-19 adult sepsis patients at two timepoints: ICU admission and approximately a week later. RNA-Seq was performed on whole blood to identify differentially expressed genes and significantly enriched pathways. Results: At ICU admission, despite COVID-19 patients being almost clinically indistinguishable from non-COVID-19 sepsis patients, COVID-19 patients had 1,215 differentially expressed genes compared to non-COVID-19 sepsis patients. After one week in the ICU, the number of differentially expressed genes dropped to just 9 genes. This drop coincided with decreased expression of antiviral genes and relatively increased expression of heme metabolism genes over time in COVID-19 patients, eventually reaching expression levels seen in non-COVID-19 sepsis patients. Both groups also had similar underlying immune dysfunction, with upregulation of immune processes such as "Interleukin-1 signaling" and "Interleukin-6/JAK/STAT3 signaling" throughout disease compared to healthy controls. Discussion: Early on, COVID-19 patients had elevated antiviral responses and suppressed heme metabolism processes compared to non-COVID-19 severe sepsis patients, although both had similar underlying immune dysfunction. However, after one week in the ICU, these diseases became indistinguishable on a gene expression level. These findings highlight the importance of early antiviral treatment for COVID-19, the potential for heme-related therapeutics, and consideration of immunomodulatory therapies for both diseases to treat shared immune dysfunction.

Importance of assessing biomarkers and physiological parameters of anemia-induced tissue hypoxia in the perioperative period

Abstract Anemia is associated with increased risk of Acute Kidney Injury (AKI), stroke and mortality in perioperative patients. We sought to understand the mechanism(s) by assessing the integrative physiological responses to anemia (kidney, brain), the degrees of anemia-induced tissue hypoxia, and associated biomarkers and physiological parameters. Experimental measurements demonstrate a linear relationship between blood Oxygen Content (CaO2) and renal microvascular PO2 (y = 0.30x + 6.9, r2= 0.75), demonstrating that renal hypoxia is proportional to the degree of anemia. This defines the kidney as a potential oxygen sensor during anemia. Further evidence of renal oxygen sensing is demonstrated by proportional increase in serum Erythropoietin (EPO) during anemia (y = 93.806*10−0.02, r2= 0.82). This data implicates systemic EPO levels as a biomarker of anemia-induced renal tissue hypoxia. By contrast, cerebral Oxygen Delivery (DO2) is defended by a profound proportional increase in Cerebral Blood Flow (CBF), minimizing tissue hypoxia in the brain, until more severe levels of anemia occur. We hypothesize that the kidney experiences profound early anemia-induced tissue hypoxia which contributes to adaptive mechanisms to preserve cerebral perfusion. At severe levels of anemia, renal hypoxia intensifies, and cerebral hypoxia occurs, possibly contributing to the mechanism(s) of AKI and stroke when adaptive mechanisms to preserve organ perfusion are overwhelmed. Clinical methods to detect renal tissue hypoxia (an early warning signal) and cerebral hypoxia (a later consequence of severe anemia) may inform clinical practice and support the assessment of clinical biomarkers (i.e., EPO) and physiological parameters (i.e., urinary PO2) of anemia-induced tissue hypoxia. This information may direct targeted treatment strategies to prevent adverse outcomes associated with anemia.

Altered connectivity of default mode and executive control networks among female patients with persistent post-concussion symptoms.

OBJECTIVE: To examine the roles of the default mode network (DMN) and executive control network (ECN) in prolonged recovery after mild traumatic brain injury (mTBI), and relationships with indices of white matter microstructural injury. METHODS: Seventeen mTBI patients with persistent symptoms were imaged an average of 21.5 months post-injury, along with 23 healthy controls. Resting-state functional magnetic resonance imaging (rs-fMRI) was used to evaluate functional connectivity (FC) of the DMN and ECN. Diffusion tensor imaging (DTI) quantified fractional anisotropy, along with mean, axial and radial diffusivity of white matter tracts. RESULTS: Compared to controls, patients with mTBI had increased functional connectivity of the DMN and ECN to brain regions implicated in salience and frontoparietal networks, and increased white matter diffusivity within the cerebrum and brainstem. Among the patients, FC was correlated with better neurocognitive test scores, while diffusivity was correlated with more severe self-reported symptoms. The FC and diffusivity values within abnormal brain regions were not significantly correlated. CONCLUSION: For female mTBI patients with prolonged symptoms, hyper-connectivity may represent a compensatory response that helps to mitigate the effects of mTBI on cognition. These effects are unrelated to indices of microstructural injury, which are correlated with symptom severity, suggesting that rs-fMRI and DTI may capture distinct aspects of pathophysiology.

Importance of assessing biomarkers and physiological parameters of anemia-induced tissue hypoxia in the perioperative period.

Anemia is associated with increased risk of Acute Kidney Injury (AKI), stroke and mortality in perioperative patients. We sought to understand the mechanism(s) by assessing the integrative physiological responses to anemia (kidney, brain), the degrees of anemia-induced tissue hypoxia, and associated biomarkers and physiological parameters. Experimental measurements demonstrate a linear relationship between blood Oxygen Content (CaO2) and renal microvascular PO2 (y = 0.30x + 6.9, r2 = 0.75), demonstrating that renal hypoxia is proportional to the degree of anemia. This defines the kidney as a potential oxygen sensor during anemia. Further evidence of renal oxygen sensing is demonstrated by proportional increase in serum Erythropoietin (EPO) during anemia (y = 93.806*10-0.02, r2 = 0.82). This data implicates systemic EPO levels as a biomarker of anemia-induced renal tissue hypoxia. By contrast, cerebral Oxygen Delivery (DO2) is defended by a profound proportional increase in Cerebral Blood Flow (CBF), minimizing tissue hypoxia in the brain, until more severe levels of anemia occur. We hypothesize that the kidney experiences profound early anemia-induced tissue hypoxia which contributes to adaptive mechanisms to preserve cerebral perfusion. At severe levels of anemia, renal hypoxia intensifies, and cerebral hypoxia occurs, possibly contributing to the mechanism(s) of AKI and stroke when adaptive mechanisms to preserve organ perfusion are overwhelmed. Clinical methods to detect renal tissue hypoxia (an early warning signal) and cerebral hypoxia (a later consequence of severe anemia) may inform clinical practice and support the assessment of clinical biomarkers (i.e., EPO) and physiological parameters (i.e., urinary PO2) of anemia-induced tissue hypoxia. This information may direct targeted treatment strategies to prevent adverse outcomes associated with anemia.

Size-dependent shape distributions of platinum nanoparticles.

While it is well established that nanoparticle shape can depend on equilibrium thermodynamics or growth kinetics, recent computational work has suggested the importance of thermal energy in controlling the distribution of shapes in populations of nanoparticles. Here, we used transmission electron microscopy to characterize the shapes of bare platinum nanoparticles and observed a strong dependence of shape distribution on particle size. Specifically, the smallest nanoparticles (<2.5 nm) had a truncated octahedral shape, bound by 〈111〉 and 〈100〉 facets, as predicted by lowest-energy thermodynamics. However, as particle size increased, the higher-energy 〈110〉 facets became increasingly common, leading to a large population of non-equilibrium truncated cuboctahedra. The observed trends were explained by combining atomistic simulations (both molecular dynamics and an empirical square-root bond-cutting model) with Boltzmann statistics. Overall, this study demonstrates experimentally how thermal energy leads to shape variation in populations of metal nanoparticles, and reveals the dependence of shape distributions on particle size. The prevalence of non-equilibrium facets has implications for metal nanoparticles applications from catalysis to solar energy.

Origin of Pressure-Dependent Adhesion in Nanoscale Contacts.

The adhesion between nanoscale components has been shown to increase with applied load, contradicting well-established mechanics models. Here, we use in situ transmission electron microscopy and atomistic simulations to reveal the underlying mechanism for this increase as a change in the mode of separation. Analyzing 135 nanoscale adhesion tests on technologically relevant materials of anatase TiO2, silicon, and diamond, we demonstrate a transition from fracture-controlled to strength-controlled separation. When fracture models are incorrectly applied, they yield a 7-fold increase in apparent work of adhesion; however, we show that the true work of adhesion is unchanged with loading. Instead, the nanoscale adhesion is governed by the product of adhesive strength and contact area; the pressure dependence of adhesion arises because contact area increases with applied load. By revealing the mechanism of separation for loaded nanoscale contacts, these findings provide guidance for tailoring adhesion in applications from nanoprobe-based manufacturing to nanoparticle catalysts.

How do we identify the crashing traumatic brain injury patient - the intensivist's view.

PURPOSE OF REVIEW: Over 40% of patients with severe traumatic brain injury (TBI) show clinically significant neurological worsening within the acute admission period. This review addresses the importance of identifying the crashing TBI patient, the difficulties appreciating clinical neurological deterioration in the comatose patient and how neuromonitoring may provide continuous real-time ancillary information to detect physiologic worsening. RECENT FINDINGS: The latest editions of the Brain Trauma Foundation's Guidelines omitted management algorithms for adult patients with severe TBI. Subsequently, three consensus-based management algorithms were published using a Delphi method approach to provide a bridge between the evidence-based guidelines and integration of the individual treatment modalities at the bedside. These consensus statements highlight the serious situation of critical deterioration requiring emergent evaluation and guidance on sedation holds to obtain a neurological examination while balancing the potential risks of inducing a stress response. SUMMARY: One of the central tenets of neurocritical care is to detect the brain in trouble. The first and most fundamental neurological monitoring tool is the clinical exam. Ancillary neuromonitoring data may provide early physiologic biomarkers to help anticipate, prevent or halt secondary brain injury processes. Future research should seek to understand how data integration and visualization technologies may reduce the cognitive workload to improve timely detection of neurological deterioration.

Renal microvascular oxygen tension during hyperoxia and acute hemodilution assessed by phosphorescence quenching and excitation with blue and red light.

PURPOSE: The kidney plays a central physiologic role as an oxygen sensor. Nevertheless, the direct mechanism by which this occurs is incompletely understood. We measured renal microvascular partial pressure of oxygen (PkO2) to determine the impact of clinically relevant conditions that acutely change PkO2 including hyperoxia and hemodilution. METHODS: We utilized two-wavelength excitation (red and blue spectrum) of the intravascular phosphorescent oxygen sensitive probe Oxyphor PdG4 to measure renal tissue PO2 in anesthetized rats (2% isoflurane, n = 6) under two conditions of altered arterial blood oxygen content (CaO2): 1) hyperoxia (fractional inspired oxygen 21%, 30%, and 50%) and 2) acute hemodilutional anemia (baseline, 25% and 50% acute hemodilution). The mean arterial blood pressure (MAP), rectal temperature, arterial blood gases (ABGs), and chemistry (radiometer) were measured under each condition. Blue and red light enabled measurement of PkO2 in the superficial renal cortex and deeper cortical and medullary tissue, respectively. RESULTS: PkO2 was higher in the superficial renal cortex (~ 60 mmHg, blue light) relative to the deeper renal cortex and outer medulla (~ 45 mmHg, red light). Hyperoxia resulted in a proportional increase in PkO2 values while hemodilution decreased microvascular PkO2 in a linear manner in both superficial and deeper regions of the kidney. In both cases (blue and red light), PkO2 correlated with CaO2 but not with MAP. CONCLUSION: The observed linear relationship between CaO2 and PkO2 shows the biological function of the kidney as a quantitative sensor of anemic hypoxia and hyperoxia. A better understanding of the impact of changes in PkO2 may inform clinical practices to improve renal oxygen delivery and prevent acute kidney injury.

RéSUMé: OBJECTIF: Les reins jouent un rôle physiologique central en tant que détecteurs d'oxygène. Cependant, le mécanisme direct de ce rôle n'est pas complètement compris. Nous avons mesuré la pression partielle d'oxygène microvasculaire rénal (PkO2) afin de déterminer l'impact de conditions pertinentes d'un point de vue clinique qui modifient de façon aiguë la PkO2, y compris l'hyperoxie et l'hémodilution. MéTHODE: Nous avons utilisé l'excitation à deux longueurs d'onde (spectres rouge et bleu) de la sonde phosphorescente, sensible à l'oxygène, intravasculaire Oxyphor PdG4 afin de mesurer la PO2 dans le tissu rénal de rats sous anesthésie (isoflurane 2 %, n = 6) dans deux conditions de contenu en oxygène du sang artériel (CaO2) altéré : 1) hyperoxie (fraction d'oxygène inspiré 21 %, 30 % et 50 %) et 2) anémie par hémodilution aiguë (valeurs de base, hémodilution aiguë 25 % et 50 %). La tension artérielle moyenne (TAM), la température rectale, les gaz sanguins artériels et la chimie (radiomètre) ont été mesurés dans chacune des conditions. Les lumières bleue et rouge ont permis de mesurer la PkO2 dans le cortex rénal superficiel et les tissus cortical et médullaire plus profonds, respectivement. RéSULTATS: La PkO2 était plus élevée dans le cortex rénal superficiel (~ 60 mmHg, lumière bleue) comparativement au cortex rénal plus profond et à la zone médullaire extérieure (~ 45 mmHg, lumière rouge). L'hyperoxie a entraîné une augmentation proportionnelle des valeurs de PkO2, alors que l'hémodilution a diminué la PkO2 microvasculaire de façon linéaire tant dans les régions rénales superficielles que plus profondes. Dans les deux cas (lumières bleue et rouge), la PkO2 était corrélée au CaO2 mais pas à la TAM. CONCLUSION: La relation linéaire observée entre le CaO2 et la PkO2 montre la fonction biologique du rein en tant que détecteur quantitatif de l'hypoxie anémique et de l'hyperoxie. Une meilleure compréhension de l'impact des changements de la PkO2 pourrait guider les pratiques cliniques afin d'améliorer la distribution d'oxygène aux reins et prévenir l'insuffisance rénale aiguë.

Determination of Brain Death/Death by Neurologic Criteria: The World Brain Death Project.

IMPORTANCE: There are inconsistencies in concept, criteria, practice, and documentation of brain death/death by neurologic criteria (BD/DNC) both internationally and within countries. OBJECTIVE: To formulate a consensus statement of recommendations on determination of BD/DNC based on review of the literature and expert opinion of a large multidisciplinary, international panel. PROCESS: Relevant international professional societies were recruited to develop recommendations regarding determination of BD/DNC. Literature searches of the Cochrane, Embase, and MEDLINE databases included January 1, 1992, through April 2020 identified pertinent articles for review. Because of the lack of high-quality data from randomized clinical trials or large observational studies, recommendations were formulated based on consensus of contributors and medical societies that represented relevant disciplines, including critical care, neurology, and neurosurgery. EVIDENCE SYNTHESIS: Based on review of the literature and consensus from a large multidisciplinary, international panel, minimum clinical criteria needed to determine BD/DNC in various circumstances were developed. RECOMMENDATIONS: Prior to evaluating a patient for BD/DNC, the patient should have an established neurologic diagnosis that can lead to the complete and irreversible loss of all brain function, and conditions that may confound the clinical examination and diseases that may mimic BD/DNC should be excluded. Determination of BD/DNC can be done with a clinical examination that demonstrates coma, brainstem areflexia, and apnea. This is seen when (1) there is no evidence of arousal or awareness to maximal external stimulation, including noxious visual, auditory, and tactile stimulation; (2) pupils are fixed in a midsize or dilated position and are nonreactive to light; (3) corneal, oculocephalic, and oculovestibular reflexes are absent; (4) there is no facial movement to noxious stimulation; (5) the gag reflex is absent to bilateral posterior pharyngeal stimulation; (6) the cough reflex is absent to deep tracheal suctioning; (7) there is no brain-mediated motor response to noxious stimulation of the limbs; and (8) spontaneous respirations are not observed when apnea test targets reach pH <7.30 and Paco2 ≥60 mm Hg. If the clinical examination cannot be completed, ancillary testing may be considered with blood flow studies or electrophysiologic testing. Special consideration is needed for children, for persons receiving extracorporeal membrane oxygenation, and for those receiving therapeutic hypothermia, as well as for factors such as religious, societal, and cultural perspectives; legal requirements; and resource availability. CONCLUSIONS AND RELEVANCE: This report provides recommendations for the minimum clinical standards for determination of brain death/death by neurologic criteria in adults and children with clear guidance for various clinical circumstances. The recommendations have widespread international society endorsement and can serve to guide professional societies and countries in the revision or development of protocols and procedures for determination of brain death/death by neurologic criteria, leading to greater consistency within and between countries.

When to transfuse your acute care patient? A narrative review of the risk of anemia and red blood cell transfusion based on clinical trial outcomes.

This narrative review critically evaluates the evidence for risk of anemia and red blood cell (RBC) transfusion. For this purpose, it assesses large prospective randomized-controlled trials (RCTs) in medical, surgical, and critical care patient populations in which the impact of specific hemoglobin transfusion thresholds are compared. In these trials, the risks of anemia relative to those of RBC transfusion are assessed. The results of published systematic reviews and meta-analyses are also discussed. Lastly, recommendations for patient blood management and treatment of anemia are explored. The main conclusion of this review emphasizes that the decision to transfuse RBCs is complex and depends on the interaction between multiple factors including the balance between the risk of anemia and the risk of RBC transfusion, existing patient comorbidities, and medical and surgical exposures. The transfusion thresholds recommended by current guidelines vary for medical and surgical patient populations. Guidelines suggesting specific transfusion thresholds for different patient populations should be viewed as a starting point for making an informed decision about RBC transfusion. Alternatives to transfusion (i.e., patient blood management), biomarkers of anemia-induced tissue hypoxia, and transfusion alternatives should continue to be evaluated in large RCTs, with the goal of improving event-free survival in critically ill and perioperative patients.

RéSUMé: Ce compte rendu narratif évalue de façon critique les données probantes concernant le risque de l'anémie et de la transfusion d'érythrocytes. Pour ce faire, nous avons évalué des études randomisées contrôlées (ERC) prospectives de grande envergure réalisées auprès de populations de patients médicaux, chirurgicaux et de soins intensifs dans lesquelles l'impact de seuils spécifiques de transfusion d'hémoglobine est comparé. Dans ces études, les risques de l'anémie sont comparés aux risques de la transfusion d'érythrocytes. Les résultats des comptes rendus systématiques et méta-analyses publiés sont également présentés. Enfin, les recommandations concernant la gestion du sang des patients et le traitement de l'anémie sont explorées. La conclusion principale de ce compte rendu souligne que la décision de transfuser des érythrocytes est complexe et dépend de l'interaction de plusieurs facteurs, notamment de l'équilibre entre le risque de l'anémie et le risque de la transfusion d'érythrocytes, les comorbidités existantes du patient, et les risques médicaux et chirurgicaux. Les seuils de transfusion recommandés par les directives actuelles sont différents pour les populations de patients médicaux et chirurgicaux. Les directives proposant des seuils de transfusion spécifiques en fonction des différentes populations de patients devraient être considérées comme point de départ pour prendre une décision informée concernant la transfusion d'érythrocytes. Les alternatives à la transfusion (c.-à-d. la gestion du sang des patients), les biomarqueurs d'une hypoxie tissulaire induite par l'anémie et les alternatives à la transfusion devraient continuer à être évalués dans des ERC d'envergure, avec pour but l'amélioration de la survie sans complication des patients en état critique et périopératoires.

Building organizational compassion among teams delivering end-of-life care in the intensive care unit: The 3 Wishes Project.

BACKGROUND: The 3 Wishes Project is a semistructured program that improves the quality of care for patients dying in the intensive care unit by eliciting and implementing wishes. This simple intervention honors the legacy of patients and eases family grief, forging human connections between family members and clinicians. AIM: To examine how the 3 Wishes Project enables collective patterns of compassion between patients, families, clinicians, and managerial leaders in the intensive care unit. DESIGN: Using a qualitative descriptive approach, interviews and focus groups were used to collect data from family members of dying patients, clinicians, and institutional leaders. Unconstrained directed qualitative content analysis was performed using Organizational Compassion as the analytic framework. SETTING/PARTICIPANTS: Four North American intensive care units, participants were 74 family members of dying patients, 72 frontline clinicians, and 20 managerial leaders. RESULTS: The policies and processes of the 3 Wishes Project exemplify organizational compassion by supporting individuals in the intensive care unit to collectively notice, feel, and respond to suffering. As an intervention that enables and empowers clinicians to engage in acts of kindness to enhance end-of-life care, the 3 Wishes Project is particularly well situated to encourage collective responses to suffering and promote compassion between patients, family members, and clinicians. CONCLUSIONS: Examining the 3 Wishes Project through the lens of organizational compassion reveals the potential of this program to cultivate the capacity for people to collectively notice, feel, and respond to suffering. Our data document multidirectional demonstrations of compassion between clinicians and family members, forging the type of human connections that may foster resilience.

Renal tissue Po2 sensing during acute hemodilution is dependent on the diluent.

Sensing changes in blood oxygen content ([Formula: see text]) is an important physiological role of the kidney; however, the mechanism(s) by which the kidneys sense and respond to changes in [Formula: see text] are incompletely understood. Accurate measurements of kidney tissue oxygen tension ([Formula: see text]) may increase our understanding of renal oxygen-sensing mechanisms and could inform decisions regarding the optimal fluid for intravascular volume resuscitation to maintain renal perfusion. In some clinical settings, starch solution may be nephrotoxic, possibly due to inadequacy of tissue oxygen delivery. We hypothesized that hemodilution with starch colloid solutions would reduce [Formula: see text] to a more severe degree than other diluents. Anesthetized Sprague-Dawley rats (n = 77) were randomized to undergo hemodilution with either colloid (6% hydroxyethyl starch or 5% albumin), crystalloid (0.9% saline), or a sham procedure (control) (n = 13-18 rats/group). Data were analyzed by ANOVA with significance assigned at P < 0.05. After hemodilution, mean arterial pressure (MAP) decreased marginally in all groups, while hemoglobin (Hb) and [Formula: see text] decreased in proportion to the degree of hemodilution. Cardiac output was maintained in all groups after hemodilution. [Formula: see text] decreased in proportion to the reduction in Hb in all treatment groups. At comparably reduced Hb, and maintained arterial oxygen values, hemodilution with starch resulted in larger decreases in [Formula: see text] relative to animals hemodiluted with albumin or saline (P < 0.008). Renal medullary erythropoietin (EPO) mRNA levels increased more prominently, relative to other hypoxia-regulated molecules (GLUT-1, GAPDH, and VEGF). Our data demonstrate that the kidney acts as a biosensor of reduced [Formula: see text] following hemodilution and that [Formula: see text] may provide a quantitative signal for renal cellular responsiveness to acute anemia. Evidence of a more severe reduction in [Formula: see text] following hemodilution with starch colloid solution suggests that tissue hypoxia may contribute to starch induced renal toxicity.

Inhibiting α5 Subunit-Containing γ-Aminobutyric Acid Type A Receptors Attenuates Cognitive Deficits After Traumatic Brain Injury.

OBJECTIVES: Cognitive deficits after traumatic brain injury are a leading cause of disability worldwide, yet no effective pharmacologic treatments exist to improve cognition. Traumatic brain injury increases proinflammatory cytokines, which trigger excess function of α5 subunit-containing γ-aminobutyric acid type A receptors. In several models of brain injury, drugs that inhibit α5 subunit-containing γ-aminobutyric acid type A receptor function improve cognitive performance. Thus, we postulated that inhibiting α5 subunit-containing γ-aminobutyric acid type A receptors would improve cognitive performance after traumatic brain injury. In addition, because traumatic brain injury reduces long-term potentiation in the hippocampus, a cellular correlate of memory, we studied whether inhibition of α5 subunit-containing γ-aminobutyric acid type A receptors attenuated deficits in long-term potentiation after traumatic brain injury. DESIGN: Experimental animal study. SETTING: Research laboratory. SUBJECTS: Adult male mice and hippocampal brain slices. INTERVENTIONS: Anesthetized mice were subjected to traumatic brain injury with a closed-head, free-weight drop method. One week later, the mice were treated with L-655,708 (0.5 mg/kg), an inhibitor that is selective for α5 subunit-containing γ-aminobutyric acid type A receptors, 30 minutes before undergoing behavioral testing. Problem-solving abilities were assessed using the puzzle box assay, and memory performance was studied with novel object recognition and object place recognition assays. In addition, hippocampal slices were prepared 1 week after traumatic brain injury, and long-term potentiation was studied using field recordings in the cornu Ammonis 1 region of slices that were perfused with L-655,708 (100 nM). MEASUREMENTS AND MAIN RESULTS: Traumatic brain injury increased the time required to solve difficult but not simple tasks in the puzzle box assay and impaired memory in the novel object recognition and object place recognition assays. L-655,708 improved both problem solving and memory in the traumatic brain injury mice. Traumatic brain injury reduced long-term potentiation in the hippocampal slices, and L-655,708 attenuated this reduction. CONCLUSIONS: Pharmacologic inhibition of α5 subunit-containing γ-aminobutyric acid type A receptors attenuated cognitive deficits after traumatic brain injury and enhanced synaptic plasticity in hippocampal slices. Collectively, these results suggest that α5 subunit-containing γ-aminobutyric acid type A receptors are novel targets for pharmacologic treatment of traumatic brain injury-induced persistent cognitive deficits.

Remote ischemic conditioning improves outcome independent of anesthetic effects following shockwave-induced traumatic brain injury.

Traumatic brain injury due to primary blast exposure is a major cause of ongoing neurological and psychological impairment in soldiers and civilians. Animal and human evidence suggests that low-level blast exposure is capable of inducing white matter injury and behavioural deficits. There are currently no effective therapies to treat the underlying suspected pathophysiology of low-level primary blast or concussion. Remote ischemic conditioning (RIC) has been shown to have cardiac, renal and neuro-protective effects in response to brief cycles of ischemia. Here we examined the effects of RIC in two models of blast injury. We used a model of low-level primary blast in rats to evaluate the effects of RIC neurofilament expression. We subsequently used a model of traumatic brain injury in adult zebrafish using pulsed high intensity focused ultrasound (pHIFU) to evaluate the effects of RIC on behavioural outcome and apoptosis in a post-traumatic setting. In blast exposed rats, RIC pretreatment modulated NF200 expression suggesting an innate biological buffering effect. In zebrafish, behavioural deficits and apoptosis due to pHIFU-induced brain injury were reduced following administration of serum derived from RIC rats. The results in the zebrafish model demonstrate the humoral effects of RIC independent of anesthetic effects that were observed in the rat model of injury. Our results indicate that RIC is effective in improving outcome following modeled brain trauma in pre- and post-injury paradigms. The results suggest a potential role for innate biological systems in the protection against pathophysiological processes associated with impairment following shockwave induced trauma.