What does "brainstem death" mean? A review of international protocols.

PURPOSE: The term "brainstem death" is ambiguous; it can be used to refer either exclusively to loss of function of the brainstem or loss of function of the whole brain. We aimed to establish the term's intended meaning in national protocols for the determination of brain death/death by neurologic criteria (BD/DNC) from around the world. METHODS: Of 78 unique international protocols on determination of BD/DNC, we identified eight that referred exclusively to loss of function of the brainstem in the definition of death. Each protocol was reviewed to ascertain whether it 1) required assessment for loss of function of the whole brain, 2) required assessment only for loss of function of the brainstem, or 3) was ambiguous about whether loss of function of the higher brain was required to declare DNC. RESULTS: Of the eight protocols, two (25%) required assessment for loss of function of the whole brain, three (37.5%) only required assessment for loss of function of the brainstem, and three (37.5%) were ambiguous about whether loss of function of the higher brain was required to declare death. The overall agreement between raters was 94% (κ = 0.91). CONCLUSIONS: There is international variability in the intended meaning of the terms "brainstem death" and "whole brain death" resulting in ambiguity and potentially inaccurate or inconsistent diagnosis. Regardless of the nomenclature, we advocate for national protocols to be clear regarding any requirement for ancillary testing in cases of primary infratentorial brain injury who may fulfill clinical criteria for BD/DNC.

RéSUMé: OBJECTIF: Le terme « mort du tronc cérébral ¼ est ambigu; il peut être utilisé pour désigner soit la perte de fonction du tronc cérébral uniquement, soit la perte de fonction du cerveau entier. Nous avons cherché à établir la signification voulue du terme dans les protocoles nationaux utilisés pour la détermination de la mort cérébrale/du décès selon des critères neurologiques (MC/DCN) du monde entier. MéTHODE: Sur 78 protocoles internationaux uniques sur la détermination de la MC/DCN, nous en avons identifié huit qui faisaient exclusivement référence à la perte de fonction du tronc cérébral dans la définition de la mort. Chaque protocole a été examiné pour déterminer s'il 1) exigeait une évaluation de la perte de fonction du cerveau entier, 2) exigeait une évaluation uniquement pour la perte de fonction du tronc cérébral, ou 3) était ambigu quant à savoir si la perte de fonction du cerveau supérieur était requise pour déclarer un DCN. RéSULTATS: Sur les huit protocoles, deux (25 %) exigeaient une évaluation de la perte de fonction de l'ensemble du cerveau, trois (37,5 %) ne nécessitaient qu'une évaluation de la perte de fonction du tronc cérébral, et trois (37,5 %) étaient ambigus quant à savoir si la perte de fonction du cerveau supérieur était nécessaire pour déclarer le décès. L'accord global entre les évaluateurs était de 94 %, (κ = 0,91). CONCLUSION: Il existe une variabilité internationale quant au sens voulu des termes « mort du tronc cérébral ¼ et « mort cérébrale totale ¼ qui entraîne une ambiguïté et un diagnostic potentiellement inexact ou incohérent. Quelle que soit la nomenclature, nous préconisons que les protocoles nationaux soient clairs en ce qui concerne toute exigence d'examens auxiliaires dans les cas de lésion cérébrale infratentorielle primaire qui pourraient répondre aux critères cliniques de MC/DCN.

An in situ inferior vena cava ligation-stenosis model to study thrombin generation rates with flow.

BACKGROUND: Blood flow-induced shear stress affects platelet participation in coagulation and thrombin generation. We aimed to develop an in vivo model to characterize thrombin generation rates under flow. METHODS: An in situ inferior vena cava (IVC) ligation-stenosis model was established using C57BL/6 mice. Wild type C57BL/6 mice were fed normal chow diet for two weeks before experiments. On the day of experiments, mice were anesthetized, followed by an incision through the abdominal skin to expose the IVC, which was then ligated (followed by reperfusion through a stenosis for up to 2 h). IVC blood flow rate was monitored using a Transonic ultrasound flow meter. In sham animals, the IVC was exposed following the same procedure, but no ligation was applied. Thrombin generation following IVC ligation was estimated by measuring mouse plasma prothrombin fragment 1-2 concentration. Mouse plasma factor Va concentration was measured using phospholipids and a modified prothrombinase assay. Blood vessel histomorphology, vascular wall ICAM-1, von Willebrand Factor, tissue factor, and PECAM-1 expression were measured using immunofluorescence microscopy. RESULTS: IVC blood flow rate increased immediately following ligation and stenosis formation. Sizable clots formed in mouse IVC following ligation and stenosis formation. Both plasma factor Va and prothrombin fragment 1-2 concentration reduced significantly following IVC ligation/stenosis, while no changes were observed with ICAM-1, von Willebrand Factor, tissue factor and PECAM-1 expression. CONCLUSION: Clot formation was successful. However, the prothrombin-thrombin conversion rate constant in vivo cannot be determined as local thrombin and FVa concentration (at the injury site) cannot be accurately measured. Modification to the animal model is needed to further the investigation.

Anticoagulation Therapy is Associated with Increased Access-related Wound Infections after Hemodialysis Access Creation.

BACKGROUND: The effect of anticoagulation therapy (AC) on hemodialysis access patency and related complications is not well defined. Patients on long-term or chronic AC due to their underlying comorbid conditions may be particularly susceptible to access-related bleeding and complications from repetitive cannulation. Our goal is to assess the effect of anticoagulation therapy on outcomes after access creation. METHODS: The Vascular Quality Initiative (VQI) database was queried for patients undergoing arteriovenous fistula (AVF) or graft (AVG) placement, from 2011 to 2019. Only patients with data on post-procedural AC status were included. Anticoagulation use was defined as patients on warfarin, dabigatran, or rivaroxaban after access creation at postoperative follow up. Demographic and procedural details were analyzed. Wound infection and patency rates at six months were assessed. Binomial logistic regression analysis was performed to assess the association of anticoagulation use with these outcomes. RESULTS: A total of 27,757 patients underwent access creation, with the majority undergoing AVF creation (78.8%). The average age was 61.4 years and 55.3% were male. 12.9% of patients were on postoperative AC. The wound infection rate was 2.3- 3.8% in the no AC and AC cohorts, respectively (P < 0.001). At six months follow-up, patency was 85.7- 84.3% in the no AC and AC cohorts, respectively (P = 0.044). Expectedly, grafts had lower patency rates compared to AVF; those within the no AC cohort had a patency of 83.0% compared to 81.2 % in those on AC (P = 0.106). On multivariable analysis, anticoagulation use was associated with a higher risk of wound infections (odds ratio [OR] 1.513, 95% confidence interval [CI] 1.160-1.973, P = 0.002). AC use did not significantly affect access patency. CONCLUSION: Anticoagulation therapy was associated with a higher rate of wound infections but did not affect short-term access patency within six-months. These patients warrant close surveillance of their access for signs of infection. Furthermore, long-term implications of anticoagulation needs further evaluation.

Barriers to the Use of Neurologic Criteria to Declare Death in Africa.

There are varying medical, legal, social, religious and philosophical perspectives about the distinction between life and death. Death can be declared using cardiopulmonary or neurologic criteria throughout much of the world. After solicitation of brain death/death by neurologic criteria (BD/DNC) protocols from contacts around the world, we found that the percentage of countries with BD/DNC protocols is much lower in Africa than other developing regions. We performed an informal review of the literature to identify barriers to declaration of BD/DNC in Africa. We found that there are numerous medical, legal, social and religious barriers to the creation of BD/DNC protocols in Africa including 1) limited number of healthcare facilities, critical care resources and clinicians with relevant expertise; 2) absence of a political and legal framework codifying death; and 3) cultural and religious perspectives that present ideological conflict with the idea of BD/DNC, in particular, and between traditional and Western medicine, in general. Because there are a number of unique barriers to the creation of BD/DNC protocols in Africa, it remains to be seen how the World Brain Death Project, which is intended to create minimum standards for BD/DNC around the world, will impact BD/DNC determination in Africa.

Ancillary Testing for Determination of Death by Neurologic Criteria Around the World.

OBJECTIVE: We sought to identify similarities and differences in the diagnostic requirements for ancillary testing for determination of brain death/death by neurologic criteria (BD/DNC) around the world. METHODS: We reviewed diagnostic requirements for ancillary testing for BD/DNC in 78 unique official national BD/DNC protocols obtained from contacts worldwide between January 2018 and April 2019. RESULTS: Details provided on the performance and interpretation of ancillary tests for determination of BD/DNC were variably provided and inconsistent. Approximately half of all protocols that included each ancillary test provided details about study performance: 63% of protocols that included conventional cerebral angiography, 55% of protocols that included electroencephalography, 50% of protocols that included somatosensory evoked potentials, 48% of protocols that included transcranial Doppler ultrasonography, 43% of protocols that included nuclear medicine flow study and 41% of protocols that included brainstem auditory evoked potentials. Similarly, about half of all protocols that included each ancillary test provided details about study interpretation: 66% of protocols that included electroencephalography, 59% of protocols that included brainstem auditory evoked potentials, 56% of protocols that included somatosensory evoked potentials, 55% of protocols that included transcranial Doppler ultrasonography, 52% of protocols that included conventional cerebral angiography and 49% of protocols that included nuclear medicine flow study. INTERPRETATION: Diagnostic requirements for ancillary testing in BD/DNC determination vary around the world. We hope that the World Brain Death Project will improve worldwide consensus on the diagnostic requirements for ancillary testing in BD/DNC, both for performance and interpretation.

Interplay of Diabetes Mellitus and End-Stage Renal Disease in Open Revascularization for Chronic Limb-Threatening Ischemia.

BACKGROUND: Chronic limb-threatening ischemia (CLTI) in patients with end-stage renal disease (ESRD) confers a significant survival disadvantage and is associated with a high major amputation rate. Moreover, diabetes mellitus (DM) is an independent risk factor for developing CLTI. However, the interplay between end-stage renal disease (ESRD) and DM on outcomes after peripheral revascularization for CLTI is not well established. Our goal was to assess the effect of DM on outcomes after an infrainguinal bypass for CLTI in patients with ESRD. METHODS: Using the Vascular Quality Initiative dataset from January 2003 to March 2020, records for all primary infrainguinal bypasses for CLTI in patients with ESRD were included for analysis. One-year and perioperative outcomes of all-cause mortality, reintervention, amputation-free survival (AFS), and major adverse limb event (MALE) were compared for patients with DM versus those without DM. RESULTS: Of a total of 1,058 patients (66% male) with ESRD, 726 (69%) patients had DM, and 332 patients did not have DM. The DM group was younger (median age, 65 years vs. 68 years; P = 0.002), with higher proportions of obesity (body-mass index>30 kg/m2; 34% vs. 19%; P < 0.001) and current smokers (26% vs. 19%; P = 0.013). The DM group presented more frequently with tissue loss (76% vs. 66%; P < 0.001). A distal bypass anastomosis to tibial vessels was more frequently performed in the DM group compared to the non-DM group (57% vs. 45%; P < 0.001). DM was independently associated with higher perioperative MALE (OR 1.34; 95% CI, 1.06-1.68; P = 0.013), without increased risks of loss of primary patency and composite outcomes of amputation or death. On the mean follow-up of 11.4 ± 5.5 months, DM patients had a significantly higher rate of one-year MALEs (43% vs. 32%; P = 0.001). However, the one-year primary patency and AFS did not differ significantly. After adjusting for confounders, the risk-adjusted hazards for MALE (HR 1.34; 95% CI, 1.06-1.68; P = 0.013) were significantly increased in patients with DM. However, DM was not associated with increased risk of AFS (HR 1.16; 95% CI, 0.91-1.47; P = 0.238), or loss of primary patency (HR 1.04; 95% CI, 0.79-1.37; P = 0.767). CONCLUSIONS: DM and ESRD each independently predict early and late major adverse limb events after an infrainguinal bypass in patients presenting with CLTI. However, in the presence of ESRD, DM may increase perioperative adverse events but does not influence primary patency and AFS at one year. The risk profile associated with ESRD appears to supersede that of DM, with no additive effect.

Lung-derived HMGB1 is detrimental for vascular remodeling of metabolically imbalanced arterial macrophages.

Pulmonary disease increases the risk of developing abdominal aortic aneurysms (AAA). However, the mechanism underlying the pathological dialogue between the lungs and aorta is undefined. Here, we find that inflicting acute lung injury (ALI) to mice doubles their incidence of AAA and accelerates macrophage-driven proteolytic damage of the aortic wall. ALI-induced HMGB1 leaks and is captured by arterial macrophages thereby altering their mitochondrial metabolism through RIPK3. RIPK3 promotes mitochondrial fission leading to elevated oxidative stress via DRP1. This triggers MMP12 to lyse arterial matrix, thereby stimulating AAA. Administration of recombinant HMGB1 to WT, but not Ripk3-/- mice, recapitulates ALI-induced proteolytic collapse of arterial architecture. Deletion of RIPK3 in myeloid cells, DRP1 or MMP12 suppression in ALI-inflicted mice repress arterial stress and brake MMP12 release by transmural macrophages thereby maintaining a strengthened arterial framework refractory to AAA. Our results establish an inter-organ circuitry that alerts arterial macrophages to regulate vascular remodeling.

Determination of Brain Death/Death by Neurologic Criteria in Countries in Asia and the Pacific.

BACKGROUND AND PURPOSE: We sought to 1) identify countries in Asia and the Pacific that have protocols for the determination of brain death/death by neurologic criteria (BD/DNC) and 2) review the similarities and differences of these protocols in different countries. METHODS: Between January 2018 and April 2019, we attempted to communicate with contacts in the 57 countries in Asia and the Pacific to determine if they had official national BD/DNC protocols. We reviewed and compared the identified protocols. RESULTS: We identified contacts for 40 (70%) of the 57 countries in Asia and the Pacific, and successfully communicated with 37 of them (93% of countries with contacts identified, 65% of countries in Asia and the Pacific). We found that 24 of the 37 countries had BD/DNC protocols. Two (13%) of the 16 protocols that provided a definition of death referred to brainstem death. Kazakhstan and Israel required only 1 examination to declare BD/DNC, while 10 (71%) of the other 14 protocols required 2 examinations separated by 6-48 hours. The prerequisites, clinical examination, apnea testing procedure, and indications for/selection of ancillary tests varied. Ancillary testing was required for all determinations of BD/DNC in five (21%) countries. Thirteen (54%) of the protocols included information about the time of death, while 12 (50%) of them provided instructions about discontinuation of organ support. CONCLUSIONS: The protocols for conducting a BD/DNC determination vary markedly among countries in Asia and the Pacific. Since it is optimal to have internationally and intranationally consistent BD/DNC protocols, efforts should be made to harmonize protocols both within this region and worldwide.

Determination of death by neurologic criteria in Latin American and Caribbean countries.

OBJECTIVES: We sought to (1) identify the countries in the Latin America/Caribbean Group of the United Nations (GRULAC) that have protocols for brain death/death by neurologic criteria (BD/DNC) and (2) review the similarities and differences between these protocols. MATERIALS AND METHODS: Between January 2018 and April 2019, we obtained and reviewed BD/DNC protocols from countries in GRULAC. RESULTS: We communicated with contacts in 30/33 countries in GRULAC (91 % of countries) and found that 16 (53 % of countries with contacts, 48 % of Latin American/Caribbean countries) had BD/DNC protocols. Of the 13 protocols that provided a definition of death, 10 (77 %) referred to whole brain death. The number of exams/examiners, prerequisites for BD/DNC, and descriptions of the clinical assessment and apnea test were inconsistent among protocols. Although Brazil and Panama required an ancillary test, the indications for ancillary testing, and the types of accepted ancillary tests, varied by country. CONCLUSION: BD/DNC determination protocols in the countries in GRULAC are inconsistent. Acknowledging the fact that there are diverse cultural, legal and religious perspectives on death, and human and technological resources differ by region, we recommend that attempts be made to harmonize protocols on BD/DNC both regionally and worldwide.

Determination of death by neurologic criteria around the world.

OBJECTIVE: To identify similarities and differences in protocols on determination of brain death/death by neurologic criteria (BD/DNC) around the world. METHODS: We collected and reviewed official national BD/DNC protocols from contacts around the world between January 2018 and April 2019. RESULTS: We communicated with contacts in 136 countries and found that 83 (61% of countries with contacts identified, 42% of the world) had BD/DNC protocols, 78 of which were unique. Protocols addressed the following prerequisites and provided differing instructions: drug clearance (64, 82%), temperature (61, 78%), laboratory values (56, 72%), observation period (37, 47%), and blood pressure (34, 44%). Protocols did not consistently identify the same components for the clinical examination of brain death; 70 (90%) included coma, 70 (90%) included the pupillary reflex, 68 (87%) included the corneal reflex, 67 (86%) included the oculovestibular reflex, 64 (82%) included the gag reflex, 62 (79%) included the cough reflex, 58 (74%) included the oculocephalic reflex, 37 (47%) included noxious stimulation to the face, and 22 (28%) included noxious stimulation to the limbs. Apnea testing was mentioned in 71 (91%) protocols; there was variability in the technique and target across protocols. Ancillary testing was included as a requirement for all determinations of BD/DNC in 22 (28%) protocols. CONCLUSIONS: There is considerable variability in BD/DNC determination protocols around the world. Medical standards for death should be the same everywhere. We recommend that a worldwide consensus be reached on the minimum standards for BD/DNC.