Fixed- Versus Variable-Dose Prothrombin Complex Concentrate for the Emergent Reversal of Vitamin K Antagonists: A Systematic Review and Meta-Analysis.

OBJECTIVES: Four-factor prothrombin complex concentrate (4-PCC) is recommended for rapid reversal of vitamin K antagonists (VKAs) such as warfarin, yet optimal dosing remains uncertain. DATA SOURCES: A systematic review was conducted of PubMed, Embase, and Ovid MEDLINE (Wolters Kluwer) databases from January 2000 to August 2023 for clinical studies comparing fixed- vs. variable-dose 4-PCC for emergent VKA reversal with at least one reported clinical outcome. STUDY SELECTION: Abstracts and full texts were assessed independently and in duplicate by two reviewers. DATA EXTRACTION: Data were extracted independently and in duplicate by two reviewers using predefined extraction forms. DATA SYNTHESIS: The analysis comprised three randomized trials and 16 cohort studies comprising a total of 323 participants in randomized trials (161 in fixed dosage and 162 in variable dosage) and 1912 patients in cohort studies (858 in fixed-dose and 1054 in variable dose). Extracranial bleeding was the predominant indication, while intracranial hemorrhage varied. Overall, a fixed-dose regimen may be associated with a lower dose of 4-PCC and results in a reduction in 4-PCC administration time compared with a variable-dose regimen. A fixed-dose regimen also likely results in increased clinical hemostasis. While there is no clear difference between the two regimens in terms of achieving a goal international normalized ratio (INR) less than 2, a fixed-dose regimen is less likely to achieve a goal INR less than 1.5. High certainty evidence indicates that the fixed-dose regimen reduces both mortality and the occurrence of thromboembolic events. Additional subgroup analyses provides exploratory data to guide future studies. CONCLUSIONS: A fixed-dose regimen for 4-PCC administration provides benefits over a variable-dose regimen in terms of dose reduction, faster administration time, improved clinical hemostasis, and reduced mortality and thromboembolic events. Further studies are warranted to better refine the optimal fixed-dose regimen.

The Delphi Delirium Management Algorithms. A practical tool for clinicians, the result of a modified Delphi expert consensus approach.

Delirium is common in hospitalised patients, and there is currently no specific treatment. Identifying and treating underlying somatic causes of delirium is the first priority once delirium is diagnosed. Several international guidelines provide clinicians with an evidence-based approach to screening, diagnosis and symptomatic treatment. However, current guidelines do not offer a structured approach to identification of underlying causes. A panel of 37 internationally recognised delirium experts from diverse medical backgrounds worked together in a modified Delphi approach via an online platform. Consensus was reached after five voting rounds. The final product of this project is a set of three delirium management algorithms (the Delirium Delphi Algorithms), one for ward patients, one for patients after cardiac surgery and one for patients in the intensive care unit.

Magnesium and Hematoma Expansion in Intracerebral Hemorrhage: A FAST-MAG Randomized Trial Analysis.

BACKGROUND: Observational studies suggest that magnesium may have hemostatic effects. FAST-MAG (Field Administration of Stroke Therapy-Magnesium) was a pragmatic clinical trial of magnesium sulfate administered prehospital for acute clinical stroke syndromes and included patients with intracerebral hemorrhage. Exploratory secondary analysis by the treatment group found no reduction in hematoma expansion (HE) associated with magnesium treatment in intracerebral hemorrhage but did not consider serum magnesium levels achieved. We analyzed FAST-MAG intracerebral hemorrhage data for associations between serum magnesium level, HE, and early neurological deterioration, accounting for groupwise biases. METHODS: HE was defined as hematoma volume increase ≥3 mL within 24 hours and early neurological deterioration as ≥1-point Glasgow Coma Scale decline from arrival to hospital day 4. Comparing treatment and placebo groups confirmed biased availability of neuroimaging data. Therefore, HE and neurological deterioration were analyzed and stratified by treatment and placebo groups using univariate tests and adjusted logistic regression. RESULTS: Spontaneous intracerebral hemorrhage was present in 381 patients. Placebo patients had fewer serial neuroimaging studies available (123 [65.4%] versus 145 [75.1%]; P=0.038). Necessary data were available in 104 magnesium- and 85 placebo-treated patients (age, 64.9 [13.0] years; 67.7% male). In the magnesium group, higher magnesium level was associated with less HE (adjusted odds ratio, 0.64 per mg/dL [95% CI, 0.42-0.93]) and less neurological deterioration (adjusted odds ratio, 0.54 per mg/dL [95% CI, 0.33-0.82]). In the placebo group, magnesium level was not associated with either HE or neurological deterioration. CONCLUSIONS: Magnesium may exhibit a hemostatic effect that was only observable in the FAST-MAG magnesium treatment group. Equipoise should be maintained, and specific trials are needed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00059332.

Relationship Between Socioeconomic Status and the Outcome of Lumbar Epidural Steroid Injections for Lumbar Radiculopathy.

OBJECTIVE: The aim of the study was to investigate the relationship between socioeconomic status and pain reduction from epidural steroid injections for lumbar radiculopathy. METHODS: The retrospective cohort consisted of patients undergoing epidural steroid injection for lumbar radiculopathy ( n = 544). Numeric Pain Rating Scale was measured at baseline and 2 wks after epidural steroid injection. Socioeconomic status was estimated using median family income in patients' ZIP code. Linear and mixed models examined demographic and clinical differences in pain before and after injection and whether family income moderated the effect. RESULTS: Majority of patients were White (72.4%), female (56.4%), engaged in physical activity (68.2%), and underwent unilateral, transforaminal epidural steroid injection (86.0% and 92.1%, respectively). Non-White patients and those who did not engage in physical activity had higher baseline pain ( P < 0.05). Lower socioeconomic status was associated with higher baseline pain (ß = 0.06 per $10,000, P = 0.01). Patients with lower socioeconomic status experienced larger improvement in pain after epidural steroid injection: -1.56 units for patients in the 10th percentile of family income versus -0.81 for 90th percentile. Being a current smoker was associated with higher pain (ß = 0.76, P = 0.03) and engaging in structured physical activity with less pain (ß = -0.07 P < 0.01). CONCLUSIONS: Lower socioeconomic status was independently associated with higher pain alleviation after controlling for other potentially influential demographics. Modifiable lifestyle factors may be a target of potential intervention.

Light at night in older age is associated with obesity, diabetes, and hypertension.

Light at night (LAN) has been associated with negative health consequences and metabolic risk factors. Little is known about the prevalence of LAN in older adults in the United States and its association with CVD risk factors. We tested the hypothesis that LAN in older age is associated with higher prevalence of individual CVD risk factors. Five hundred and fifty-two community-dwelling adults aged 63-84 years underwent an examination of CVD risk factor profiles and 7-day actigraphy recording for activity and light measures. Associations between actigraphy-measured LAN, defined as no light vs. light within the 5-hour nadir (L5), and CVD risk factors, including obesity, diabetes, hypertension, and hypercholesterolemia, were examined, after adjusting for age, sex, race, season of recording, and sleep variables. LAN exposure was associated with a higher prevalence of obesity (multivariable-adjusted odds ratio [OR] 1.82 [95% CI 1.26-2.65]), diabetes (OR 2.00 [1.19-3.43]), and hypertension (OR 1.74 [1.21-2.52]) but not with hypercholesterolemia. LAN was also associated with (1) later timing of lowest light exposure (L5-light) and lowest activity (L5-activity), (2) lower inter-daily stability and amplitude of light exposure and activity, and (3) higher wake after sleep onset. Habitual LAN in older age is associated with concurrent obesity, diabetes, and hypertension. Further research is needed to understand long-term effects of LAN on cardiometabolic risks.

Risk assessment of the acute stroke diagnostic process using failure modes, effects, and criticality analysis.

INTRODUCTION: To date, many emergency department (ED)-based quality improvement studies and interventions for acute stroke patients have focused on expediting time-sensitive treatments, particularly reducing door-to-needle time. However, prior to treatment, a diagnosis of stroke must be reached. The ED-based stroke diagnostic process has been understudied despite its importance in assuring high-quality and safe care. METHODS: We used a learning collaborative to conduct a failure modes, effects, and criticality analysis (FMECA) of the acute stroke diagnostic process at three health systems in Chicago, IL. Our FMECA was designed to prospectively identify, characterize, and rank order failures in the systems and processes of care that offer opportunities for redesign to improve stroke diagnostic accuracy. Multidisciplinary teams involved in stroke care at five different sites participated in moderated sessions to create an acute stroke diagnostic process map as well as identify failures and existing safeguards. For each failure, a risk priority number and criticality score were calculated. Failures were then ranked, with the highest scores representing the most critical failures to be targeted for redesign. RESULTS: A total of 28 steps were identified in the acute stroke diagnostic process. Iterative steps in the process include information gathering, clinical examination, interpretation of diagnostic test results, and reassessment. We found that failure to use existing screening scales to identify patients with large-vessel occlusions early on in their ED course ranked highest. Failure to obtain an accurate history of the index event, failure to suspect acute stroke in triage, and failure to use established stroke screening tools at ED arrival to identify potential stroke patients were also highly ranked. CONCLUSIONS: Our study results highlight the critical importance of upstream steps in the acute stroke diagnostic process, particularly the use of existing tools to identify stroke patients who may be eligible for time-sensitive treatments.

Optimizing Sleep and Circadian Health in the NeuroICU.

Purpose of Review: This article introduces fundamental concepts in circadian biology and the neuroscience of sleep, reviews recent studies characterizing circadian rhythm and sleep disruption among critically ill patients and potentially links to functional outcomes, and draws upon existing literature to propose therapeutic strategies to mitigate those harms. Particular attention is given to patients with critical neurologic conditions and the unique environment of the neuro-intensive care unit. Recent Findings: Circadian rhythm disruption is widespread among critically ill patients and sleep time is reduced and abnormally fragmented. There is a strong association between the degree of arousal suppression observed at the bedside and the extent of circadian disruption at the system (e.g., melatonin concentration rhythms) and cellular levels (e.g., core clock gene transcription rhythms). There is a paucity of electrographically normal sleep, and rest-activity rhythms are severely disturbed. Common care interventions such as neurochecks introduce unique disruptions in neurologic patients. There are no pharmacologic interventions proven to normalize circadian rhythms or restore physiologically normal sleep. Instead, interventions are focused on reducing pharmacologic and environmental factors that perpetuate disruption. Summary: The intensive care environment introduces numerous potent disruptors to sleep and circadian rhythms. Direct neurologic injury and neuro-monitoring practices likely compound those factors to further derange circadian and sleep functions. In the absence of direct interventions to induce normalized rhythms and sleep, current therapy depends upon normalizing external stimuli.

Prothrombin Complex Concentrate for Emergent Reversal of Intracranial Hemorrhage in Patients with Ventricular Assist Devices.

BACKGROUND: Intracranial hemorrhage (ICH) is a devastating complication for patients with ventricular assist devices (VADs). The safety of emergent anticoagulation reversal with four-factor prothrombin complex concentrate (PCC) and optimal timing of anticoagulation resumption are not clear. In addition, lactate dehydrogenase (LDH) is used as a biomarker for thromboembolic risk, but its utility in guiding anticoagulation management after reversal with PCC has not be described. METHODS: We retrospectively reviewed a consecutive series of patients with VADs presenting with ICH between 2014 and 2020 who received four-factor PCC for rapid anticoagulation reversal. We collected the timing of PCC administration, timing of resumption of anticoagulation, survival, occurrence of thromboembolic events, and LDH levels throughout hospitalization. RESULTS: We identified 16 ICH events in 14 patients with VADs treated with rapid anticoagulation reversal using four-factor PCC (11 intraparenchymal, 4 subdural, 1 subarachnoid hemorrhage). PCC was administered at a mean of 3.3 ± 0.3 h after imaging diagnosis of ICH. Overall mortality was 63%. Survivors had higher presenting Glasgow Coma Scale (median 15, interquartile range [IQR] 15-15 versus 14, IQR 8-14.7, P = 0.041). In all six instances where the patient survived, anticoagulation was resumed on average 9.16 ± 1.62 days after reversal. There were no thromboembolic events prior to resumption of anticoagulation. Three events occurred after anticoagulation resumption and within 3 months of reversal: VAD thrombosis in a patient with thrombosis at the time of reversal, ischemic stroke, and readmission for elevated LDH in the setting of subtherapeutic international normalized ratio. CONCLUSIONS: Our limited series found no thromboembolic complications immediately following anticoagulation reversal with PCC prior to resumption of anticoagulation. LDH trends may be useful to monitor thromboembolic risk after reversal.

Early Seizures Are Predictive of Worse Health-Related Quality of Life at Follow-Up After Intracerebral Hemorrhage.

OBJECTIVES: Early seizures are a common complication of intracerebral hemorrhage, occurring in ~10% of patients. However, the independent effect of early seizures on patient outcomes, particularly health-related quality of life, is unclear. Without a potential benefit to patient outcomes, the widespread use (~40%) of prophylactic seizure medications has no reasonable chance of improving patient outcomes. We tested the hypothesis that health-related quality of life at follow-up is different between patients with and without early seizures (and secondarily, with nonconvulsive status epilepticus) after intracerebral hemorrhage. DESIGN: Patients with intracerebral hemorrhage were enrolled in an observational cohort study that prospectively collected clinical data and health-related quality of life at follow-up. SETTING: Academic medical center. PATIENTS: One-hundred thirty-three patients whose health-related quality of life was assessed 3 months after intracerebral hemorrhage onset. MEASUREMENTS AND MAIN RESULTS: Health-related quality of life was obtained at 3 months after intracerebral hemorrhage onset. T Scores of health-related quality of life were modeled with multivariable linear models accounting for severity with the intracerebral hemorrhage Score and hematoma location. Health-related quality of life was measured with National Institutes of Health Patient Reported Outcomes Measurement Information System/Neuroquality of life, expressed in T Scores (U.S. normal 50 ± 10). The modified Rankin Scale (a global measure) was a secondary outcome. There were 12 patients (9%) with early seizures. T Scores of health-related quality of life at follow-up were lower (worse) in patients with early seizure compared with patients without an early seizure (44 [32.75-51.85] vs 30.25 [18.9-39.15]; p = 0.04); results for other domains of health-related quality of life were similar. The association persisted in multivariable models. There was no association between early seizures and prophylactic seizure medications (p = 0.4). Results for patients with nonconvulsive status epilepticus were similar. There was no association between early seizures and the modified Rankin Scale at 3 months. CONCLUSIONS: Early seizures and nonconvulsive status epilepticus were associated with lower health-related quality of life at follow-up in survivors of intracerebral hemorrhage.

Rest-activity rhythm disturbance in liver cirrhosis and association with cognitive impairment.

Cognitive impairment and disturbed sleep-wake rhythms are disabling complications of liver cirrhosis, yet there is limited understanding of how they are related. We tested the hypothesis that alterations of sleep, rest-activity, and light exposure patterns are associated with worse cognition in cirrhosis. A total of 54 ambulatory adult patients with cirrhosis and 41 age-/gender-matched healthy controls wore wrist actigraphy for rest-activity and light measurements and completed Patient-Reported Outcomes Measurement Information System sleep instruments for self-reported sleep quality. We used standard nonparametric descriptors to characterize rest-activity and light patterns, and wake after sleep onset and sleep efficiency to assess objective sleep quality. The NIH Toolbox cognition battery was used for objective cognitive evaluation using T-scores from a demographically adjusted population reference. Spearman's correlation and multivariable models were used to explore associations between measures of cognition, sleep, rest-activity, and light. Cognition was significantly impaired in cirrhosis patients. Sleep quality was worse in cirrhosis patients by subjective and objective measures compared with controls. Cirrhosis patients exhibited fragmented and dampened rest-activity rhythms, lower daytime and higher nighttime light exposure compared with controls. Worse working memory and processing speed was associated with lower daytime activity level, higher rest-activity fragmentation, lower day-to-day stability, and greater nocturnal light exposure. No association was found between cognition and sleep quality. Rest-activity fragmentation and abnormal light exposure patterns are common in patients with liver disease and are associated with the severity of cognitive impairment. Further research is needed to investigate the effects of timed bright light and exercise intervention on cognitive function in patients with liver disease.

Identifying Modifiable Predictors of Patient Outcomes After Intracerebral Hemorrhage with Machine Learning.

BACKGROUND/OBJECTIVE: Demonstrating a benefit of acute treatment to patients with intracerebral hemorrhage (ICH) requires identifying which patients have a potentially modifiable outcome, where treatment could favorably shift a patient's expected outcome. A decision rule for which patients have a modifiable outcome could improve the targeting of treatments. We sought to determine which patients with ICH have a modifiable outcome. METHODS: Patients with ICH were prospectively identified at two institutions. Data on hematoma volumes, medication histories, and other variables of interest were collected. ICH outcomes were evaluated using the modified Rankin Scale (mRS), assessed at 14 days and 3 months after ICH, with "good outcome" defined as 0-3 (independence or better) and "poor outcome" defined as 4-6 (dependence or worse). Supervised machine learning models identified the best predictors of good versus poor outcomes at Institution 1. Models were validated using repeated fivefold cross-validation as well as testing on the entirely independent sample at Institution 2. Model fit was assessed with area under the ROC curve (AUC). RESULTS: Model performance at Institution 1 was strong for both 14-day (AUC of 0.79 [0.77, 0.81] for decision tree, 0.85 [0.84, 0.87] for random forest) and 3 month (AUC of 0.75 [0.73, 0.77] for decision tree, 0.82 [0.80, 0.84] for random forest) outcomes. Independent predictors of functional outcome selected by the algorithms as important included hematoma volume at hospital admission, hematoma expansion, intraventricular hemorrhage, overall ICH Score, and Glasgow Coma Scale. Hematoma expansion was the only potentially modifiable independent predictor of outcome and was compatible with "good" or "poor" outcome in a subset of patients with low hematoma volumes, good Glasgow Coma scale and premorbid modified Rankin Scale scores. Models trained on harmonized data also predicted patient outcomes well at Institution 2 using decision tree (AUC 0.69 [0.63, 0.75]) and random forests (AUC 0.78 [0.72, 0.84]). CONCLUSIONS: Patient outcomes are predictable to a high level in patients with ICH, and hematoma expansion is the sole-modifiable predictor of these outcomes across two outcome types and modeling approaches. According to decision tree analyses predicting outcome at 3 months, patients with a high Glasgow Coma Scale score, less than 44.5 mL hematoma volume at admission, and relatively low premorbid modified Rankin Score in particular have a modifiable outcome and appear to be candidates for future interventions to improve outcomes after ICH.