Acute kidney injury is a known clinical risk factor for delirium, an acute cognitive dysfunction that is commonly encountered in the critically ill population. In this comprehensive review of ...clinical and basic research studies, we detail the epidemiology, clinical implications, pathogenesis, and management strategies of patients with acute kidney injury-associated delirium. Specifically addressed are the pathological roles of endogenous toxin or drug accumulation, acute kidney injury-mediated neuroinflammation, and acute kidney injury-associated volume overload as discrete potential biological mechanisms of the condition. The optimization of clinical contributors and normalization of renal function are reviewed as pragmatic management strategies in addition to potential and emerging therapeutic approaches.
Objective
To create a multidimensional tool to prognosticate long‐term functional, cognitive, and quality of life outcomes after spontaneous subarachnoid hemorrhage (SAH) using data up to 48 hours ...after admission.
Methods
Data were prospectively collected for 1,619 consecutive patients enrolled in the SAH outcome project July 1996 to March 2014. Linear models (LMs) were applied to identify factors associated with outcome in 1,526 patients with complete data. Twelve‐month functional, cognitive, and quality of life outcomes were measured using the modified Rankin scale (mRS), Telephone Interview for Cognitive Status, and Sickness Impact Profile. Based on the LM residuals, we constructed the FRESH score (Functional Recovery Expected after Subarachnoid Hemorrhage). Score performance, discrimination, and internal validity were tested using the area under the receiver operating characteristic curve (AUC), Nagelkerke and Cox/Snell R2, and bootstrapping. For external validation, we used a control population of SAH patients from the CONSCIOUS‐1 study (n = 413).
Results
The FRESH score was composed of Hunt & Hess and APACHE‐II physiologic scores on admission, age, and aneurysmal rebleed within 48 hours. Separate scores to prognosticate 1‐year cognition (FRESH‐cog) and quality of life (FRESH‐quol) were developed controlling for education and premorbid disability. Poor functional outcome (mRS = 4–6) for score levels 1 through 9 respectively was present in 3, 6, 12, 38, 61, 83, 92, 98, and 100% at 1‐year follow‐up. Performance of FRESH (AUC = 0.90), FRESH‐cog (AUC = 0.80), and FRESH‐quol (AUC = 0.78) was high. External validation of our cohort using mRS as endpoint showed satisfactory results (AUC = 0.77). To allow for convenient score calculation, we built a smartphone app available for free download.
Interpretation
FRESH is the first clinical tool to prognosticate long‐term outcome after spontaneous SAH in a multidimensional manner. Ann Neurol 2016;80:46–58
COVID-19 is a severe infectious disease that has claimed >150,000 lives and infected millions in the United States thus far, especially the elderly population. Emerging evidence has shown the virus ...to cause hemorrhagic and immunologic responses, which impact all organs, including lungs, kidneys, and the brain, as well as extremities. SARS-CoV-2 also affects patients', families', and society's mental health at large. There is growing evidence of re-infection in some patients. The goal of this paper is to provide a comprehensive review of SARS-CoV-2-induced disease, its mechanism of infection, diagnostics, therapeutics, and treatment strategies, while also focusing on less attended aspects by previous studies, including nutritional support, psychological, and rehabilitation of the pandemic and its management. We performed a systematic review of >1,000 articles and included 425 references from online databases, including, PubMed, Google Scholar, and California Baptist University's library. COVID-19 patients go through acute respiratory distress syndrome, cytokine storm, acute hypercoagulable state, and autonomic dysfunction, which must be managed by a multidisciplinary team including nursing, nutrition, and rehabilitation. The elderly population and those who are suffering from Alzheimer's disease and dementia related illnesses seem to be at the higher risk. There are 28 vaccines under development, and new treatment strategies/protocols are being investigated. The future management for COVID-19 should include B-cell and T-cell immunotherapy in combination with emerging prophylaxis. The mental health and illness aspect of COVID-19 are among the most important side effects of this pandemic which requires a national plan for prevention, diagnosis and treatment.
Recent preclinical studies demonstrate a direct pathological role for the interleukin-6 (IL-6) pathway in mediating structural and functional delirium-like phenotypes in animal models of acute lung ...injury. Tocilizumab, an IL-6 pathway inhibitor, has shown reduced duration of ventilator dependency and mortality in critically ill patients with COVID-19. In this study, we test the hypothesis that tocilizumab is associated with reduced delirium/coma prevalence in critically ill patients with COVID-19. 253 patients were included in the study cohort, 69 in the tocilizumab group and 184 in the historical control group who did not receive tocilizumab. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) with a positive score indicating delirium. Coma was defined as a Richmond Agitation-Sedation Scale score of - 4 or - 5. Tocilizumab was associated with significantly greater number of days alive without delirium/coma (tocilizumab 7 days (IQR: 3-9 days) vs control 3 days (IQR: 1-8 days); p < 0.001). These results remained significant after adjusting for age, sex, sepsis, Charlson Comorbidity Index, Sequential Organ Failure Assessment score, and median daily dose of analgesics/sedatives (
= 0.671, p = 0.010). There were no significant differences in mortality (
= - 0.204, p = 0.561), ventilator duration (
= 0.016, p = 0.956), and ICU or hospital length of stay (
= - 0.134, p = 0.603;
= 0.003, p = 0.991, respectively). Tocilizumab use was associated with significantly increased number of days without delirium/coma. Confirmation of these findings in randomized prospective studies may inform a novel paradigm of pharmacological amelioration of delirium/coma during critical illness.
Urinary tract infection (UTI) is frequently implicated as a precipitant of delirium, which refers to an acute confusional state that is associated with high mortality, increased length of stay, and ...long-term cognitive decline. The pathogenesis of delirium is thought to involve cytokine-mediated neuronal dysfunction of the frontal cortex and hippocampus. We hypothesized that systemic IL-6 inhibition would mitigate delirium-like phenotypes in a mouse model of UTI.
C57/BL6 mice were randomized to either: (1) non-UTI control, (2) UTI, and (3) UTI + anti-IL-6 antibody. UTI was induced by transurethral inoculation of 1 × 10
Escherichia coli. Frontal cortex and hippocampus-mediated behaviors were evaluated using functional testing and corresponding structural changes were evaluated via quantification of neuronal cleaved caspase-3 (CC3) by immunohistochemistry and western blot. IL-6 in the brain and plasma were evaluated using immunohistochemistry, ELISA, and RT-PCR.
Compared to non-UTI control mice, mice with UTI demonstrated significantly greater impairments in frontal and hippocampus-mediated behaviors, specifically increased thigmotaxis in Open Field (p < 0.05) and reduced spontaneous alternations in Y-maze (p < 0.01), while treatment of UTI mice with systemic anti-IL-6 fully reversed these functional impairments. These behavioral impairments correlated with frontal and hippocampal neuronal CC3 changes, with significantly increased frontal and hippocampal CC3 in UTI mice compared to non-UTI controls (p < 0.0001), and full reversal of UTI-induced CC3 neuronal changes following treatment with systemic anti-IL-6 antibody (p < 0.0001). Plasma IL-6 was significantly elevated in UTI mice compared to non-UTI controls (p < 0.01) and there were positive and significant correlations between plasma IL-6 and frontal CC3 (r
= 0.5087/p = 0.0028) and frontal IL-6 and CC3 (r
= 0.2653, p < 0.0001).
These data provide evidence for a role for IL-6 in mediating delirium-like phenotypes in a mouse model of UTI. These findings provide pre-clinical justification for clinical investigations of IL-6 inhibitors to treat UTI-induced delirium.
Objective
The modified Rankin Scale is a functional outcome measure that disproportionately represents motor deficits. We hypothesize that among physicians who most commonly use the modified Rankin ...Scale to counsel patients on neurological treatment options, personal perception of acceptable or optimal outcome may be discordant with those described in clinical trials.
Methods
A three-question anonymous voluntary survey was emailed to academic and community practicing neurologists and board-eligible or board-certified neurology fellows inquiring about their personal perception of a better quality of life between two choices featuring clinical scenarios that would qualify as modified Rankin Scale 2 and 4 disability outcome scores.
Results
Sixty-nine percent of participants were 30–45 years old, 24% were 45–60 years old, and 7% were over 60 years old. Most responders were general neurologists (31.3%). The remaining responders represented multiple subspecialties including neurocritical care, vascular neurology, neurohospitalist medicine, neuromuscular neurology, neurophysiology, child neurology, neuro-oncology, headache, neuroimmunology, movement disorders, and palliative care medicine. Forty-four of 45 neurologists (97.7%) stated they would choose needing a wheelchair if still able to function at their cognitive baseline at work (p < 0.000001). One responder preferred to get around without assistance, despite new cognitive symptoms that would preclude them from working as a physician.
Conclusions
The modified Rankin Scale may not adequately represent preferred outcomes among neurology specialists, particularly with respect to cognitive symptoms. Future studies are needed to characterize long-term cognitive outcomes in patients with acute stroke-related conditions.
Acute neuropsychiatric impairments occur in over 70% of patients with acute lung injury. Mechanical ventilation is a well-known precipitant of acute lung injury and is strongly associated with the ...development of acute delirium and anxiety phenotypes. In prior studies, we demonstrated that IL-6 mediates neuropathological changes in the frontal cortex and hippocampus of animals with mechanical ventilation-induced brain injury; however, the effect of systemic IL-6 inhibition on structural and functional acute neuropsychiatric phenotypes is not known. We hypothesized that a murine model of mechanical ventilation-induced acute lung injury (VILI) would induce neural injury to the amygdala and hippocampus, brain regions that are implicated in diverse neuropsychiatric conditions, and corresponding delirium- and anxiety-like functional impairments. Furthermore, we hypothesized that these structural and functional changes would reverse with systemic IL-6 inhibition. VILI was induced using high tidal volume (35 cc/kg) mechanical ventilation. Cleaved caspase-3 (CC3) expression was quantified as a neural injury marker and found to be significantly increased in the VILI group compared to spontaneously breathing or anesthetized and mechanically ventilated mice with 10 cc/kg tidal volume. VILI mice treated with systemic IL-6 inhibition had significantly reduced amygdalar and hippocampal CC3 expression compared to saline-treated animals and demonstrated amelioration in acute neuropsychiatric behaviors in open field, elevated plus maze, and Y-maze tests. Overall, these data provide evidence of a pathogenic role of systemic IL-6 in mediating structural and functional acute neuropsychiatric symptoms in VILI and provide preclinical justification to assess IL-6 inhibition as a potential intervention to ameliorate acute neuropsychiatric phenotypes following VILI.
Urinary tract infections (UTIs) are common and frequently precipitate delirium-like states. Advanced age coincident with the postmenopausal period is a risk factor for delirium following UTIs. We ...previously demonstrated a pathological role for interleukin-6 (IL-6) in mediating delirium-like phenotypes in a murine model of UTI. Estrogen has been implicated in reducing peripheral IL-6 expression, but it is unknown whether the increased susceptibility of postmenopausal females to developing delirium concomitant with UTIs reflects diminished effects of circulating estrogen. Here, we tested this hypothesis in a mouse model of UTI. Female C57BL/6J mice were oophorectomized, UTIs induced by transurethral inoculation of E. coli, and treated with 17β-estradiol. Delirium-like behaviors were evaluated prior to and following UTI and 17β-estradiol treatment. Compared to controls, mice treated with 17β-estradiol had less neuronal injury, improved delirium-like behaviors, and less plasma and frontal cortex IL-6. In vitro studies further showed that 17β-estradiol may also directly mediate neuronal protection, suggesting pleiotropic mechanisms of 17β-estradiol-mediated neuroprotection. In summary, we demonstrate a beneficial role for 17β-estradiol in ameliorating acute UTI-induced structural and functional delirium-like phenotypes. These findings provide pre-clinical justification for 17β-estradiol as a therapeutic target to ameliorate delirium following UTI.
Background
Mechanical ventilation is frequently performed in patients with ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). In this study, we used statewide ...administrative claims data to examine the rates of use, associated conditions, and in-hospital mortality rates for mechanically ventilated stroke patients.
Methods
We used statewide administrative claims data from three states and
ICD
-
9
-
CM
codes to identify patients admitted with stroke and those who received mechanical ventilation and tracheostomy. Descriptive statistics and exact 95 % confidence intervals were used to report rates of mechanical ventilation, tracheostomy, and in-hospital mortality. Logistic regression analysis was performed to identify conditions associated with mechanical ventilation based on previously described risk factors.
Results
798,255 hospital admissions for stroke were identified. 12.5 % of these patients underwent mechanical ventilation. This rate varied by stroke type: 7.9 % for IS, 29.9 % for ICH, and 38.5 % for SAH. Increased age was associated with a decreased risk of receiving mechanical ventilation (RR per decade, 0.91). Of stroke patients who underwent mechanical ventilation, 16.3 % received a tracheostomy. Mechanical ventilation was more likely to occur in association with status epilepticus (RR, 5.1), pneumonia (RR, 4.9), sepsis (RR, 3.6), and hydrocephalus (RR, 3.3). In-hospital mortality rate for mechanically ventilated stroke patients was 52.7 % (46.8 % for IS, 61.0 % for ICH, and 54.6 % for SAH).
Conclusions
In this large population-based sample, over half of mechanically ventilated stroke patients died in the hospital despite the fact that younger patients were more likely to receive mechanical ventilation. Future studies are indicated to elucidate mechanical ventilation strategies to optimize long-term outcomes after severe stroke.
PDF
