The Relationship Between Manifestation of Diabetes Insipidus and Estimated Glomerular Filtration Rate in Brain Death.

OBJECTIVES: Systematic reviews have revealed that up to 50% of patients with brain death have residual hypothalamic/pituitary activity based on the absence of central diabetes insipidus (DI). We hypothesized that different degrees of renal dysfunction may impact the presence of DI in patients with brain death. DESIGN: Single-center prospective data collection. SETTING: ICUs in a tertiary academic hospital. PATIENTS: All adult patients declared brain dead over 12 years. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: DI was diagnosed by polyuria, low urine specific gravity, and increasing serum sodium, measured in close proximity. Renal function was assessed by the estimated glomerular filtration rate (eGFR), calculated using the simplified modification of diet in renal disease equation. Analysis was completed in 192 of 234 patients with brain death after excluding those with missing data, those younger than 18 years and those on vasopressin infusions. One hundred twenty-two patients (63.5%) developed DI and 70 patients (36.5%) did not. The proportion of DI decreased significantly with decreasing eGFR: for eGFR greater than 60 mL/min, DI was present in 77.2%; for eGFR 15-60 mL/min, DI was present in 54.5%; for eGFR 14.9-9.8 mL/min, DI was present in 32%; none of the 14 patients with eGFR less than or equal to 9.7 mL/min ever experienced DI ( p < 0.001). Using logistic regression, for every 10 mL/min decrease in eGFR, the odds of DI decreased 0.83 times (95% CI, 0.76-0.90, p < 0.001). CONCLUSIONS: Renal dysfunction significantly impacts DI's clinical manifestation in brain death. We report that patients who experience brain death with severe renal dysfunction may not develop clinical signs of DI.

Comparison of 1 vs 2 Brain Death Examinations on Time to Death Pronouncement and Organ Donation: A 12-Year Single Center Experience.

OBJECTIVE: To fill the evidence gap on the value of a single brain death (SBD) or dual brain death (DBD) examination by providing data on irreversibility of brain function, organ donation consent, and transplantation. METHODS: Twelve-year tertiary hospital and organ procurement organization data on brain death (BD) were combined and outcomes, including consent rate for organ donation and organs recovered and transplanted after SBD and DBD, were compared after multiple adjustments for covariates. RESULTS: A total of 266 patients were declared BD, 122 after SBD and 144 after DBD. Time from event to BD declaration was longer by an average of 20.9 hours after DBD (p = 0.003). Seventy-five (73%) families of patients with SBD and 86 (72%) with DBD consented for organ donation (p = 0.79). The number of BD examinations was not a predictor for consent. No patient regained brain function during the periods following BD. Patients with SBD were more likely to have at least 1 lung transplanted (p = 0.031). The number of organs transplanted was associated with the number of examinations (ß coefficient [95% confidence interval] -0.5 [-0.97 to -0.02]; p = 0.044), along with age (for 5-year increase, -0.36 [-0.43 to -0.29]; p < 0.001) and PaO2 level (for 10 mm Hg increase, 0.026 [0.008-0.044]; p = 0.005) and decreased as the elapsed time to BD declaration increased (p = 0.019). CONCLUSIONS: A single neurologic examination to determine BD is sufficient in patients with nonanoxic catastrophic brain injuries. A second examination is without additional yield in this group and its delay reduces the number of organs transplanted.

Factors that affect consent rate for organ donation after brain death: A 12-year registry.

OBJECTIVE: To account for factors affecting family approach and consent for organ donation after brain death (BD). MATERIAL AND METHODS: A prospective cohort study in a large, tertiary, urban hospital, where we reviewed the database of all brain-dead patients between January 2006 and December 2017 cross-matched with local organ procurement organization (OPO) records. RESULTS: Two-hundred sixty-six brain-dead patients were included (55% African Americans (AAs)). Two-hundred twenty-two were approached for donation. The reason for not approaching families was medical exclusion due to cancer or multi-organ failure. Patient demographics or religion were not associated with approaching families. Lower creatinine level was the only independent factor associated with higher approach. Consent rate for organ donation was 72.5%. Consent was significantly higher in Caucasians (89% vs 62% for AAs), younger patients (46.7 vs 52.5 years old), in patients with lower creatinine at time of death (1.7 vs 2.4 mg/dL), patients for whom apnea testing was completed (92% vs 80%) and patients with diabetes insipidus (DI) (72% vs 54%). There was no significant relationship between consent and patient gender, admission diagnosis, number of examinations or completion of a confirmatory test. In a logistic regression model, only AA race independently predicted consent for donation (odds, 95% CI, 0.27, 0.12-0.57 p < .001). In a different model, apnea test completion was an additional independent predictor (3.66, 1.28-10.5 p = .015). CONCLUSIONS: Approaching families for organ donation consent was associated with medical suitability only and not with demographic or religious characteristics. AAs were 3.7 times less likely to consent for organ donation than non-AAs. Completion of apnea testing was associated with higher consent rates, an observation that needs to be explored in future studies documenting the effect on bedside family presence during this test.

Optimization of risk stratification for anticoagulation-associated intracerebral hemorrhage: net risk estimation.

BACKGROUND: Every anticoagulation decision has in inherent risk of hemorrhage; intracerebral hemorrhage (ICH) is the most devastating hemorrhagic complication. We examined whether combining ischemic and hemorrhagic stroke risk in individual patients might provide a meaningful paradigm for risk stratification. METHODS: We enrolled consecutive patients with anticoagulation-associated ICH in 15 tertiary centers in the USA, Europe and Asia between 2015 and 2017. Each patient was assigned baseline ischemic stroke and hemorrhage risk based on their CHA2DS2-VASc and HAS-BLED scores. We computed a net risk by subtracting hemorrhagic from ischemic risk. If the sum was positive the patient was assigned a "Favorable" indication for anticoagulation; if negative, "Unfavorable". RESULTS: We enrolled 357 patients [59% men, median age 76 (68-82) years]. 31% used non-vitamin K antagonist (NOAC). 191 (53.5%) patients had a favorable indication for anticoagulation prior to their ICH; 166 (46.5%) unfavorable. Those with unfavorable indication were younger [72 (66-80) vs 78 (73-84) years, p = 0.001], with lower CHA2DS2-VASc score [3(3-4) vs 5(4-6), p < 0.001]. Those with favorable indication had a significantly higher prevalence of most cardiovascular risk factors and were more likely to use a NOAC (35% vs 25%, p = 0.045). Both groups had similar prevalence of hypertension and chronic kidney disease. CONCLUSIONS: In this anticoagulation-associated ICH cohort, baseline hemorrhagic risk exceeded ischemic risk in approximately 50%, highlighting the importance of careful consideration of risk/benefit ratio prior to anticoagulation decisions. The remaining 50% suffered an ICH despite excess baseline ischemic risk, stressing the need for biomarkers to allow more precise estimation of hemorrhagic complication risk.

Tales of a department: how the COVID-19 pandemic transformed Detroit's Henry Ford Hospital, Department of Neurology-part I: the surge.

The COVID-19 pandemic has reshaped the way healthcare systems operate around the world. The major hurdles faced have been availability of personal protective equipment, intensive care unit beds, ventilators, treatments and medical personnel. Detroit, Michigan has been an epidemic 'hotspot' in the USA with Wayne County among the hardest hit counties in the nation. The Department of Neurology at Henry Ford Hospital, in the heart of Detroit, has responded effectively to the pandemic by altering many aspects of its operations. The rapid engagement of the department and enhanced utilisation of teleneurology were two of the pivotal elements in the successful response to the pandemic. In this review, we describe the transformation our department has undergone, as it relates to its infrastructure redesigning, coverage restructuring, redeployment strategies, medical education adaptations and novel research initiatives.

Microbleed prevalence and burden in anticoagulant-associated intracerebral bleed.

Prior studies suggest an association between Vitamin K antagonists (VKA) and cerebral microbleeds (CMBs); less is known about nonvitamin K oral anticoagulants (NOACs). In this observational study we describe CMB profiles in a multicenter cohort of 89 anticoagulation-related intracerebral hemorrhage (ICH) patients. CMB prevalence was 51% (52% in VKA-ICH, 48% in NOAC-ICH). NOAC-ICH patients had lower median CMB count [2(IQR:1-3) vs. 7(4-11); P < 0.001]; ≥5 CMBs were less prevalent in NOAC-ICH (4% vs. 31%, P = 0.006). This inverse association between NOAC exposure and high CMB count persisted in multivariable logistic regression models adjusting for potential confounders (OR 0.10, 95%CI: 0.01-0.83; P = 0.034).

Clinical Outcomes and Neuroimaging Profiles in Nondisabled Patients With Anticoagulant-Related Intracerebral Hemorrhage.

Background and Purpose- The aim of this study was to prospectively validate our prior findings of smaller hematoma volume and lesser neurological deficit in nonvitamin K oral anticoagulant (NOAC) compared with Vitamin K antagonist (VKA)-related intracerebral hemorrhage (ICH). Methods- Prospective 12-month observational study in 15 tertiary stroke centers in the United States, Europe, and Asia. Consecutive patients with premorbid modified Rankin Scale score of <2 with acute nontraumatic anticoagulant-related ICH divided into 2 groups according to the type of anticoagulant: NOAC versus VKA. We recorded baseline ICH volume, significant hematoma expansion (absolute [12.5 mL] or relative [>33%] increase), neurological severity measured by National Institutes of Health Stroke Scale score, 90-day mortality, and functional status (modified Rankin Scale score). Results- Our cohort comprised 196 patients, 62 NOAC related (mean age, 75.0±11.4 years; 54.8% men) and 134 VKA related (mean age, 72.3±10.5; 73.1% men). There were no differences in vascular comorbidities, antiplatelet, and statin use; NOAC-related ICH patients had lower median baseline hematoma volume (13.8 [2.5-37.6] versus 19.5 [6.6-52.0] mL; P=0.026) and were less likely to have severe neurological deficits (National Institutes of Health Stroke Scale score of >10 points) on admission (37% versus 55.3%, P=0.025). VKA-ICH were more likely to have significant hematoma expansion (37.4% versus 17%, P=0.008). NOAC pretreatment was independently associated with smaller baseline hematoma volume (standardized linear regression coefficient:-0.415 [95% CI, -0.780 to -0.051]) resulting in lower likelihood of severe neurological deficit (odds ratio, 0.44; 95% CI, 0.22-0.85) in multivariable-adjusted models. Conclusions- Patients with NOAC-related ICH have smaller baseline hematoma volumes and lower odds of severe neurological deficit compared with VKA-related ICH. These findings are important for practicing clinicians making anticoagulation choices.

Direct oral anticoagulant- vs vitamin K antagonist-related nontraumatic intracerebral hemorrhage.

OBJECTIVE: To compare the neuroimaging profile and clinical outcomes among patients with intracerebral hemorrhage (ICH) related to use of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF). METHODS: We evaluated consecutive patients with NVAF with nontraumatic, anticoagulant-related ICH admitted at 13 tertiary stroke care centers over a 12-month period. We also performed a systematic review and meta-analysis of eligible observational studies reporting baseline characteristics and outcomes among patients with VKA- or DOAC-related ICH. RESULTS: We prospectively evaluated 161 patients with anticoagulation-related ICH (mean age 75.6 ± 9.8 years, 57.8% men, median admission NIH Stroke Scale [NIHSSadm] score 13 points, interquartile range 6-21). DOAC-related (n = 47) and VKA-related (n = 114) ICH did not differ in demographics, vascular risk factors, HAS-BLED and CHA2DS2-VASc scores, and antiplatelet pretreatment except for a higher prevalence of chronic kidney disease in VKA-related ICH. Patients with DOAC-related ICH had lower median NIHSSadm scores (8 [3-14] vs 15 [7-25] points, p = 0.003), median baseline hematoma volume (12.8 [4-40] vs 24.3 [11-58.8] cm3, p = 0.007), and median ICH score (1 [0-2] vs 2 [1-3] points, p = 0.049). Severe ICH (>2 points) was less prevalent in DOAC-related ICH (17.0% vs 36.8%, p = 0.013). In multivariable analyses, DOAC-related ICH was independently associated with lower baseline hematoma volume (p = 0.006), lower NIHSSadm scores (p = 0.022), and lower likelihood of severe ICH (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.13-0.87, p = 0.025). In meta-analysis of eligible studies, DOAC-related ICH was associated with lower baseline hematoma volumes on admission CT (standardized mean difference = -0.57, 95% CI -1.02 to -0.12, p = 0.010) and lower in-hospital mortality rates (OR = 0.44, 95% CI 0.21-0.91, p = 0.030). CONCLUSIONS: DOAC-related ICH is associated with smaller baseline hematoma volume and lesser neurologic deficit at hospital admission compared to VKA-related ICH.

Primary Posterior Fossa Lesions and Preserved Supratentorial Cerebral Blood Flow: Implications for Brain Death Determination.

BACKGROUND: Patients with primary posterior fossa catastrophic lesions may clinically meet brain death criteria, but may retain supratentorial brain function or blood flow. These patients could be declared brain-dead in the United Kingdom (UK), but not in the United States of America (USA). We report the outcome of adult patients with primary posterior fossa lesions without concurrent major supratentorial injury. METHODS: Henry Ford Hospital database was reviewed over a period of 88 months in order to identify all adult patients with isolated brainstem or posterior fossa lesions. We excluded patients with concurrent significant supratentorial pathology potentially confounding the clinical brain death examination. One more patient from a different hospital meeting these criteria was also included. RESULTS: Three patients out of 161 met inclusion criteria (1.9% of all brain deaths during this period). With the addition of a fourth patient from another hospital, 4 patients were analyzed. All four patients had catastrophic brainstem and cerebellar injuries meeting the clinical criteria of brain death with positive apnea test in the UK. All had preserved supratentorial blood flow, which after a period of 2 h to 6 days disappeared on repeat testing, allowing declaration of brain death by US criteria in all four. One patient became an organ donor. CONCLUSIONS: Patients with primary posterior fossa catastrophic lesions, who clinically seem to be brain-dead, evolve from retaining to losing supratentorial blood flow. If absent cerebral blood flow is used as an additional criterion for the declaration of death by neurological criteria, these patients are not different than those who become brain death due to supratentorial lesions.

PAMAM dendrimer-based multifunctional conjugate for cancer therapy: synthesis, characterization, and functionality.

Poly(amidoamine) (PAMAM) dendrimer-based multifunctional cancer therapeutic conjugates have been designed and synthesized. The primary amino groups on the surface of the generation 5 (G5) PAMAM dendrimer were neutralized through partial acetylation, providing enhanced solubility of the dendrimer (in conjugation of FITC (fluorescein isothiocyanate)) and preventing nonspecific targeting interactions (in vitro and in vivo) during delivery. The functional molecules fluorescein isothiocyanate (FITC, an imaging agent), folic acid (FA, targets overexpressed folate receptors on specific cancer cells), and paclitaxel (taxol, a chemotherapeutic drug) were conjugated to the remaining nonacetylated primary amino groups. The appropriate control dendrimer conjugates have been synthesized as well. Characterization of the G5 PAMAM dendrimer and its nanosize conjugates, including the molecular weight and number of primary amine groups, has been determined by multiple analytical methods such as gel permeation chromatography (GPC), nuclear magnetic resonance spectroscopy (NMR), potentiometric titration, high-performance liquid chromatography (HPLC), and UV spectroscopy. These multifunctional dendrimer conjugates have been tested in vitro for targeted delivery of chemotherapeutic and imaging agents to specific cancer cells. We present here the synthesis, characterization, and functionality of these dendrimer conjugates.

Poly(amidoamine) dendrimer-based multifunctional engineered nanodevice for cancer therapy.

Multifunctional cancer therapeutic nanodevices have been designed and synthesized using the poly(amidoamine) (PAMAM) dendrimer as a carrier. Partial acetylation of the generation 5 (G5) PAMAM dendrimer was utilized to neutralize a fraction of the primary amino groups, provide enhanced solubility of the dendrimer during the conjugation reaction of fluorescein isothiocyanate (FITC) (in dimethyl sulfoxide (DMSO)), and prevent nonspecific targeting interactions (in vitro and in vivo) during delivery. The remaining nonacetylated primary amino groups were utilized for conjugation of the functional molecules fluorescein isothiocyanate (FITC, an imaging agent), folic acid (FA, targets overexpressed folate receptors on specific cancer cells), and methotrexate (MTX, chemotherapeutic drug). The appropriate control nanodevices have been synthesized as well. The G5 PAMAM dendrimer molecular weight and number of primary amino groups were determined by gel permeation chromatography (GPC) and potentiometric titration for stoichiometric design of ensuing conjugation reactions. Additionally, dendrimer conjugates were characterized by multiple analytical methods including GPC, nuclear magnetic resonance spectroscopy (NMR), high performance liquid chromatography (HPLC), and UV spectroscopy. The fully characterized nanodevices can be used for the targeted delivery of chemotherapeutic and imaging agents to specific cancer cells. Here, we present a more extensive investigation of our previously reported synthesis of this material with improvements directed toward scale-up synthesis and clinical trials (Pharm. Res. 2002, 19 (9), 1310-1316).