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BACKGROUND AND PURPOSE: Cerebral infarction remains an important cause of death or disability in patients with aneurysmal subarachnoid hemorrhage (SAH). The prevalence, trends, and outcomes of cerebral infarction in patients with aneurysmal SAH at a national level are not known. METHODS: We identified the proportion of patients who develop cerebral infarction (ascertained using validated methodology) among patients with aneurysmal SAH and annual trends using the Nationwide Inpatient Sample (NIS) from 2016 to 2021. We analyzed the effect of cerebral infarction on in-hospital mortality, routine discharge without palliative care (based on discharge disposition), poor outcome defined by the NIS SAH outcome measure, and length and costs of hospitalization after adjusting for potential confounders. RESULTS: A total of 35,305 (53.6%) patients developed cerebral infarction among 65,840 patients with aneurysmal SAH over a 6-year period. There was a trend toward an increase in the proportion of patients who developed cerebral infarction from 51.5% in 2016 to 56.1% in 2021 (p trend p<.001). Routine discharge was significantly lower (30.5% vs. 37.8%, odds ratio [OR] 0.82, 95% confidence interval [CI] 0.75-0.89, p<.001), and poor outcome defined by NIS-SAH outcome measure was significantly higher among patients with cerebral infarction compared with those without cerebral infarction (67.4% vs. 59.3%, OR 1.29, 95% CI 1.18-1.40, p<.001). There was no difference in in-hospital mortality (13.0% vs. 13.6%, OR 0.94, 95% CI 0.85-1.05, p = .30). The length of stay (median 18 days [interquartile range [IQR] 13-25] vs. 14 days [IQR 9-20]), coefficient 3.04, 95% CI 2.44-3.52 and hospitalization cost (median $96,823 vs. $71,311, coefficient 22,320, 95% CI 20,053-24,587) were significantly higher among patients who developed cerebral infarction compared with those who did not develop cerebral infarction. CONCLUSIONS: Cerebral infarction was seen in 54% of the patients with a trend toward an increase in the affected proportion of patients with aneurysmal SAH. Patients with cerebral infarction had higher rates of adverse outcomes and required higher resources during hospitalization.
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BACKGROUND: Clinical practice recommendations guide healthcare decisions. This study aims to evaluate the strength and quality of evidence supporting the American Heart Association (AHA)/American Stroke Association (ASA) guidelines for aneurysmal subarachnoid hemorrhage (aSAH) and spontaneous intracerebral hemorrhage (ICH). METHODS: We reviewed the current AHA/ASA guidelines for aSAH and spontaneous ICH and compared with previous guidelines. Guidelines were classified based on the Class of recommendation (COR) and Level of evidence (LOE). COR signifies recommendation strength (COR 1: Strong; COR 2a: Moderate; COR 2b: Weak; COR 3: No Benefit/Harm), while LOE denotes evidence quality (LOE A: High-Quality; LOE B-NR: Moderate-Quality, Not Randomized; LOE B-R: Moderate-Quality, Randomized; LOE C-EO: Expert Opinion; LOE C-LD: Limited Data). RESULTS: For aSAH, we identified 84 recommendations across 15 guideline categories. Of these, 31% were classified as COR I, 30% as COR 2a, 17% as COR 2b, and 18% as COR 3. In terms of LOE, 7% were based on LOE A, 10% on LOE B-R, 65% on LOE B-NR, 14% on LOE C-LD, and 5% on LOE C-EO. Compared to previous guidelines, there was a 46% decrease in LOE A, a 45% increase in LOE B, and an 11% decrease in LOE C. For spontaneous ICH, 124 guidelines were identified across 31 guideline categories. Of these, 28% were COR I, 32% COR 2b, and 9% COR 3. For LOE, 4% were based on LOE A, 35% on LOE B-NR, and 42% on LOE C-LD. Compared to previous guidelines, there was a 78% decrease in LOE A, an 82% increase in LOE B, and a 14% increase in LOE C. This analysis highlights that less than a third of AHA/ASA guidelines are classified as the highest class of recommendation, with less than 10% based on the highest LOE. CONCLUSION: Less than a third of AHA/ASA guidelines on aSAH and spontaneous ICH are classified as the highest class of recommendation with less than 10% based on highest LOE. There appears to be a decrease in proportion of guidelines based on highest LOE in most recent guidelines.
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A priori estimation of sample size and subject accrual in multi-site, time-to-event clinical trials is often challenging. Such trials are powered based on the number of events needed to detect a clinically significant difference. Sample size based on number of events relates to the expected duration of observation time for each subject. Temporal patterns in site initiation and subject enrollment ultimately affect when subjects can be accrued into the study. Lag times are common as the site start-up process optimizes, resulting in delays that may curtail observational follow-up and therefore undermine power. The proposed method introduces a Program Evaluation and Review Technique (PERT) model into the sample size estimation which accounts for the lag in site start-up. Additionally, a PERT model is introduced into a Poisson-Gamma subject accrual model to predict the quantity of study sites needed. The introduction of the PERT model provides greater flexibility in both a priori power assessment and planning the number of sites, as it specifically allows for the inclusion of anticipated delays in site start-up time. This model results in minimal power loss even when PERT distribution inputs are misspecified compared to the traditional assumption of simultaneous start-up for all sites. Together these updated formulations for sample size and subject accrual models offer an improved method for designing a multi-site time-to-event clinical trial that accounts for a flexible site start-up process.
Subject(s)
Sample Size , Humans , Program Evaluation , Time FactorsABSTRACT
The Glasgow outcome scale-extended (GOS-E), an ordinal scale measure, is often selected as the endpoint for clinical trials of traumatic brain injury (TBI). Traditionally, GOS-E is analyzed as a fixed dichotomy with favorable outcome defined as GOS-E ≥ 5 and unfavorable outcome as GOS-E < 5. More recent studies have defined favorable vs unfavorable outcome utilizing a sliding dichotomy of the GOS-E that defines a favorable outcome as better than a subject's predicted prognosis at baseline. Both dichotomous approaches result in loss of statistical and clinical information. To improve on power, Yeatts et al proposed a sliding scoring of the GOS-E as the distance from the cutoff for favorable/unfavorable outcomes, and therefore used more information found in the original GOS-E to estimate the probability of favorable outcome. We used data from a published TBI trial to explore the ramifications to trial operating characteristics by analyzing the sliding scoring of the GOS-E as either dichotomous, continuous, or ordinal. We illustrated a connection between the ordinal data and time-to-event (TTE) data to allow use of Bayesian software that utilizes TTE-based modeling. The simulation results showed that the continuous method with continuity correction offers higher power and lower mean squared error for estimating the probability of favorable outcome compared to the dichotomous method, and similar power but higher precision compared to the ordinal method. Therefore, we recommended that future severe TBI clinical trials consider analyzing the sliding scoring of the GOS-E endpoint as continuous with continuity correction.
Subject(s)
Brain Injuries, Traumatic , Humans , Bayes Theorem , Brain Injuries, Traumatic/therapy , Glasgow Outcome Scale , Probability , Prognosis , Clinical Trials as TopicABSTRACT
From 2016 to 2021, the National Institutes of Health Stroke Trials Network funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke initiated ten multicenter randomized controlled clinical trials. Optimal subject randomization designs are demanded with 4 critical properties: (1) protection of treatment assignment randomness, (2) achievement of the desired treatment allocation ratio, (3) balancing of baseline covariates, and (4) ease of implementation. For acute stroke trials, it is necessary to minimize the time between eligibility assessment and treatment initiation. This article reviews the randomization designs for 3 trials currently enrolling in Stroke Trials Network funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke, the SATURN (Statins in Intracerebral Hemorrhage Trial), the MOST (Multiarm Optimization of Stroke Thrombolysis Trial), and the FASTEST (Recombinant Factor VIIa for Hemorrhagic Stroke Trial). Randomization methods utilized in these trials include minimal sufficient balance, block urn design, big stick design, and step-forward randomization. Their advantages and limitations are reviewed and compared with traditional stratified permuted block design and minimization.
Subject(s)
National Institute of Neurological Disorders and Stroke (U.S.) , Stroke , Humans , Cerebral Hemorrhage/therapy , Multicenter Studies as Topic , National Institutes of Health (U.S.) , Random Allocation , Stroke/drug therapy , United States , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: We sought to compare outcomes for infants with tetralogy of Fallot with pulmonary atresia (TOF/PA) and confluent pulmonary arteries who underwent staged or primary complete surgical repair. METHODS: This retrospective study included infants undergoing initial surgical intervention between 0 and 60 days of age with TOF/PA without aortopulmonary collaterals from 2009 to 2018 at 20 centers. The primary outcome was days alive and out of the hospital in the first year of life (DAOH365). Secondary outcomes were mortality at 1 year of age and a composite major complication outcome. Multivariable modeling with generalized estimating equations were used to compare outcomes between groups. RESULTS: Of 221 subjects, 142 underwent staged repair and 79 underwent primary complete repair. There was no significant difference in median DAOH365 between the staged and primary repair groups (317 days [interquartile range, 278-336] vs 338 days [interquartile range, 314-348], respectively; adjusted P = .13). Nine staged repair patients (7%) died in the first year of life vs 5 primary repair patients (6%; adjusted odds ratio, 1.00; 95% CI, 0.25-3.95). At least 1 major complication occurred in 37% of patients who underwent staged repair vs 41% of patients who underwent primary complete repair (P = .75), largely driven by the need for unplanned cardiac reinterventions. CONCLUSIONS: For infants with TOF/PA with confluent pulmonary arteries, a surgical strategy of staged or primary complete repair resulted in statistically similar DAOH365, early mortality, and morbidity.
Subject(s)
Cardiac Surgical Procedures , Pulmonary Atresia , Tetralogy of Fallot , Infant , Humans , Tetralogy of Fallot/complications , Retrospective Studies , Cardiac Surgical Procedures/methods , Treatment Outcome , Pulmonary Artery/surgery , Pulmonary Artery/abnormalitiesABSTRACT
BACKGROUND: We performed this meta-analysis of randomized clinical trials to compare the outcomes in patients treated with endovascular thrombectomy who receive prior intravenous thrombolysis with those who do not receive such treatment. Recently, one randomized trial reported outcomes to address this issue, so timely update of meta-analysis is needed to determine the value of administering intravenous thrombolysis before endovascular thrombectomy. MATERIALS AND METHODS: Four randomized clinical trials are included in our meta-analysis. We calculated pooled odds ratios and 95% CIs using random-effects models. The primary efficacy endpoint was a favorable outcome defined by a modified Rankin Scale score of 0 (no symptoms), 1 (no significant disability), or 2 (slight disability) at 90 days post-randomization. Secondary endpoints analyzed were any intracerebral hemorrhage, symptomatic intracerebral hemorrhage, and mortality. RESULTS: Of the 1633 patients randomized, the proportion of patients who achieved a favorable outcome was similar between endovascular thrombectomy alone and combined approach with intravenous thrombolysis and endovascular thrombectomy (1631 patients analyzed; odds ratio 1.02; CI 0.84-1.25; p = 0.83). Risk of any intracerebral hemorrhage was significantly lower among those randomized to endovascular thrombectomy alone (1633 patients analyzed; odds ratio 0.75; CI 0.57-0.99; p = 0.04). Rates of symptomatic intracerebral hemorrhage (p = 0.36) and mortality (p = 0.62) were not significantly different between the two groups. CONCLUSIONS: Compared with endovascular thrombectomy preceded by intravenous thrombolysis, endovascular thrombectomy resulted in similar rates of favorable outcome with a lower rate of intracerebral hemorrhage. A large phase 3 trial is required to conclusively demonstrate equivalency of both approaches to guide future practice.
Subject(s)
Brain Ischemia , Endovascular Procedures , Stroke , Humans , Stroke/surgery , Stroke/etiology , Brain Ischemia/surgery , Treatment Outcome , Endovascular Procedures/methods , Randomized Controlled Trials as Topic , Thrombectomy/methods , Thrombolytic Therapy/methods , Cerebral Hemorrhage/therapy , Fibrinolytic Agents/therapeutic useABSTRACT
BACKGROUND: Cilostazol, a phosphodiesterase III inhibitor, appears to be a promising agent for preventing cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage. Here, the authors perform a systematic review and meta-analysis to quantitatively assess the effects of cilostazol on brain structural and functional outcomes in animal models of cerebral ischemia and subarachnoid hemorrhage-induced cerebral vasospasm. METHODS: By using the PRISMA guidelines, a search of the PubMed, Scopus, and Web of Science was conducted to identify relevant studies. Study quality of each included study for both systematic reviews were scored by using an adapted 15-item checklist from the Collaborative Approach to Meta-Analysis of Animal Data from Experimental Studies. We calculated a standardized mean difference as effect size for each comparison. For each outcome, comparisons were combined by using random-effects modeling to account for heterogeneity, with a restricted maximum likelihood estimate of between-study variance. RESULTS: A total of 22 (median [Q1, Q3] quality score of 7 [5, 8]) and 6 (median [Q1, Q3] quality score of 6 [6, 6]) studies were identified for cerebral ischemia and subarachnoid hemorrhage-induced cerebral vasospasm, respectively. Cilostazol significantly reduced the infarct volume in cerebral ischemia models with a pooled standardized mean difference estimate of - 0.88 (95% confidence interval [CI] [- 1.07 to - 0.70], p < 0.0001). Cilostazol significantly reduced neurofunctional deficits in cerebral ischemia models with a pooled standardized mean difference estimate of - 0.66 (95% CI [- 1.06 to - 0.28], p < 0.0001). Cilostazol significantly improved the basilar artery diameter in subarachnoid hemorrhage-induced cerebral vasospasm with a pooled standardized mean difference estimate of 2.30 (95% CI [0.94 to 3.67], p = 0.001). Cilostazol also significantly improved the basilar artery cross-section area with a pooled standardized mean estimate of 1.88 (95% CI [0.33 to 3.43], p < 0.05). Overall, there was between-study heterogeneity and asymmetry in the funnel plot observed in all comparisons. CONCLUSIONS: Published animal data support the overall efficacy of cilostazol in reducing infarct volume and neurofunctional deficits in cerebral ischemia models and cerebral vasospasm in subarachnoid hemorrhage models.
Subject(s)
Brain Ischemia , Subarachnoid Hemorrhage , Vasospasm, Intracranial , Animals , Cilostazol/pharmacology , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/drug therapy , Vasospasm, Intracranial/drug therapy , Vasospasm, Intracranial/etiology , Likelihood Functions , Cerebral Infarction , Brain Ischemia/drug therapy , Brain Ischemia/etiology , Models, AnimalABSTRACT
BACKGROUND: On the basis of increased mortality associated with hyperchloremia among critically ill patients, we investigated the effect of occurrence of early hyperchloremia on death or disability at 90 days in patients with intracerebral hemorrhage (ICH). METHODS: We analyzed the data from Antihypertensive Treatment of Cerebral Hemorrhage 2 trial, which recruited patients with spontaneous ICH within 4.5 h of symptom onset. Patients with increased serum chloride levels (110 mmol/L or greater) at either baseline or 24, 48, or 72 h after randomization were identified. We further graded hyperchloremia into one occurrence or two or more occurrences within the first 72 h. Two logistic regression analyses were performed to determine the effects of hyperchloremia on (1) death within 90 days and (2) death or disability at 90 days after adjustment for potential confounders. RESULTS: Among the total of 1,000 patients analyzed, hyperchloremia within 72 h was seen in 114 patients with one occurrence and in 154 patients with two or more occurrences. Patients with one occurrence of hyperchloremia (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.1-5.5) and those with two or more occurrences (OR 2.6, 95% CI 1.3-5.0) had significantly higher odds of death within 90 days after adjustment for age, race and ethnicity, National Institutes of Health Stroke Scale score strata, hematoma volume, presence or absence of intraventricular hemorrhage, cigarette smoking, previous stroke, and maximum hourly dose of nicardipine. Patients with two or more occurrences of hyperchloremia (OR 3.4, 95% CI 2.1-5.6) had significantly higher odds of death or disability at 90 days compared with patients without hyperchloremia after adjustment for the abovementioned potential confounders. CONCLUSIONS: The independent association between hyperchloremia and death or disability at 90 days suggests that avoidance of hyperchloremia may reduce the observed death or disability in patients with ICH. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01176565.
Subject(s)
Nicardipine , Stroke , Antihypertensive Agents/therapeutic use , Cerebral Hemorrhage , Chlorides/therapeutic use , Humans , Nicardipine/therapeutic useABSTRACT
PURPOSE: Vaccinations are reported at the state level, but services are delivered at the county level through health departments (HD). This research contributes statistical models to predict county level HPV vaccination. METHODS: Using a cross sectional study design, secondary data were analyzed for the years 2016-2018 for all counties of GA. Study population was male and female adolescents aged 13-17 who received the tetanus, diphtheria and pertussis (Tdap) vaccine. The number of administered HPV vaccine doses and HPV vaccination coverage rate were modeled using indicators of HD clinic access, age, sex, race/ethnicity, socioeconomic status, education, median household income, health insurance, and urban/rural residence. RESULTS: By county the number of administered HPV vaccine doses showed a statistically significant positive association with indicators of HD clinic access: public transit and the number of HD private clinics. HPV vaccination coverage showed a statistically significant negative association with White race and rural residency. CONCLUSION: Examining Tdap vaccinated adolescents conservatively predicted HPV vaccination and controlled for multiple confounders such as vaccination ineligibility, vaccine exemption, and vaccine opposition. Within this population, public health professionals and clinicians could use these statistical models to target HPV vaccination efforts among non-Hispanic whites and rural communities at the county level.
Subject(s)
Diphtheria , Papillomavirus Infections , Papillomavirus Vaccines , Tetanus , Whooping Cough , Adolescent , Cross-Sectional Studies , Female , Georgia , Humans , Male , Papillomavirus Infections/prevention & control , Papillomavirus Vaccines/therapeutic use , Vaccination , Whooping Cough/prevention & controlABSTRACT
OBJECTIVE: To characterize counties in GA by quantifying administered doses of the HPV and Tdap vaccines collected by the state health department immunization registry and indicators of Health Department (HD) clinic access. METHODS: Using a cross sectional study design, secondary data were collected from public health data sources for the years 2016 to 2018 for 159 counties of Georgia. The study population was male and female adolescents aged 13-17. The number of administered HPV and Tdap vaccine doses were modeled in relation to number of private and public HD clinics, number of HD clinics registered in the VFC program and the availability of public transportation using Poisson regression, negative binomial regression, and Bayesian spatial analysis. RESULTS: Choropleth maps showed similar clustering patterns between administered doses of the HPV vaccine and Tdap vaccine and increased counts of administered vaccine doses in counties with both public and private clinics. Administered doses of HPV and Tdap vaccines were found to exhibit spatial dependence across counties. Accounting for spatial dependence, the availability of public transit had a significant positive effect on administered HPV vaccine doses, while the number of private HD clinics had a significant positive effect on administered Tdap vaccine doses. CONCLUSIONS: Maps at the county level show vaccination variability, clustering patterns and provide additional insights on the access to health care. Bayesian spatial models are needed to accurately identify and estimate factors associated with administering doses of the HPV and Tdap vaccines. Future work is needed to further examine the utilization of HPV vaccination services among urban groupings.
Subject(s)
Diphtheria-Tetanus-acellular Pertussis Vaccines , Papillomavirus Infections , Papillomavirus Vaccines , Adolescent , Bayes Theorem , Cross-Sectional Studies , Female , Georgia , Humans , Male , Papillomavirus Infections/prevention & control , VaccinationABSTRACT
OBJECTIVE: The aim of this study was to better define the shape of association between the degree ("magnitude") of early (< 1 h) reduction in systolic blood pressure (SBP) and outcomes in patients with acute intracerebral hemorrhage (ICH) through pooled analysis of the second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) and second Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-II) datasets. METHODS: Association of the continuous magnitude of SBP reduction described using cubic splines and an ordinal measure of the functional outcome on the modified Rankin scale (mRS) scores at 90 days were analyzed in generalized linear mixed models. Models were adjusted for achieved (mean) and variability (standard deviation, SD) of SBP between 1 and 24 h, various baseline covariates, and trial as a random effect. RESULTS: Among 3796 patients (mean age 63.1 (SD = 13.0) years; female 37.4%), with a mean magnitude (< 1 h) of SBP reduction of 28.5 (22.8) mmHg, those with larger magnitude were more often non-Asian and female, had higher baseline SBP, received multiple blood pressure (BP) lowering agents, and achieved lower SBP levels in 1-24 h. Compared to those patients with no SBP reduction within 1 h (reference), the adjusted odds of unfavorable functional outcome, according to a shift in mRS scores, were lower for SBP reductions up to 60 mmHg with an inflection point between 32 and 46 mmHg, but significantly higher for SBP reductions > 70 mmHg. Similar J-shape associations were evident across various time epochs across 24 h and consistent according to baseline hematoma volume and SBP and history of hypertension. INTERPRETATION: A moderate degree of rapid SBP lowering is associated with improved functional outcome after ICH, but large SBP reductions over 1 h (e.g. from > 200 to target < 140 mmHg) were associated with reduction, or reversal, of any such benefit.
Subject(s)
Hypertension , Stroke , Humans , Female , Middle Aged , Blood Pressure , Cerebral Hemorrhage/complications , Cerebral Hemorrhage/therapy , Hematoma , Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Treatment OutcomeABSTRACT
BACKGROUND: Neurodevelopmental impairment is an important consequence for survivors of surgery for critical congenital heart disease. This study sought to determine whether intraoperative methylprednisolone during neonatal cardiac surgery is associated with neurodevelopmental outcomes at 12 months of age and to identify early prognostic variables associated with neurodevelopmental outcomes. METHODS: We performed a planned secondary analysis of a 2-center, double-blind, randomized, placebo-controlled trial of intraoperative methylprednisolone in neonates undergoing cardiac surgery. A brain injury biomarker was measured during surgery. Bayley Scales of Infant and Toddler Development-III (BSID-III) were performed at 12 months of age. Two-sample t tests and generalized linear models were used. RESULTS: There were 129 participants (n = 61 methylprednisolone; n = 68 placebo). There were no significant differences in BSID-III scores and brain injury biomarker levels between treatment groups. Participants who underwent a palliative (versus corrective) procedure had lower mean BSID-III cognitive (101 ± 15 versus 106 ± 14; P = .03) and motor scores (85 ± 18 versus 94 ± 16; P < .01). Longer ventilation time was associated with lower motor scores. Longer cardiac intensive care unit stay was associated with lower cognitive, language, and motor scores. Cardiopulmonary bypass time, aortic cross-clamp time, and deep hypothermic circulatory arrest were not associated with BSID-III scores. CONCLUSIONS: Neurodevelopmental outcomes were not associated with intraoperative methylprednisolone or intraoperative variables. Participants who underwent a neonatal palliative (versus corrective) procedure had longer cardiac intensive care unit stays and worse neurodevelopmental outcomes at 1 year. This work suggests that interventions focused solely on the operative period may not be associated with a long-term neurodevelopmental benefit.
Subject(s)
Brain Injuries , Cardiac Surgical Procedures , Neurodevelopmental Disorders , Biomarkers , Cardiac Surgical Procedures/adverse effects , Humans , Infant , Infant, Newborn , Methylprednisolone/therapeutic use , Neurodevelopmental Disorders/epidemiology , Neurodevelopmental Disorders/etiology , PrognosisABSTRACT
BACKGROUND: With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial. METHODS: We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110-139 mm Hg versus 140-179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days. RESULTS: Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume > 30 cm3 was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00-5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71-1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90 days, compared with patients without lesions. CONCLUSIONS: Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565 ).
Subject(s)
Antihypertensive Agents , Cerebral Hemorrhage , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Blood Pressure/physiology , Cerebral Hemorrhage/complications , Humans , Middle Aged , Nicardipine/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: We evaluated the effect of persistent hyperglycemia on outcomes in 1000 patients with intracerebral hemorrhage enrolled within 4.5 hours of symptom onset. METHODS: We defined moderate and severe hyperglycemia based on serum glucose levels ≥140 mg/dL-<180 and ≥180 mg/dL, respectively, measured at baseline, 24, 48, and 72 hours. Persistent hyperglycemia was defined by 2 consecutive (24 hours apart) serum glucose levels. We evaluated the relationship between moderate and severe hyperglycemia and death or disability (defined by modified Rankin Scale score of 4-6) at 90 days in the overall cohort and in groups defined by preexisting diabetes. RESULTS: In the multivariate analysis, both moderate (odds ratio, 1.8 [95% CI, 1.1-2.8]) and severe (odds ratio, 1.8 [95% CI, 1.2-2.7]) hyperglycemia were associated with higher 90-day death or disability after adjusting for Glasgow Coma Scale score, hematoma volume, presence or absence of intraventricular hemorrhage, hyperlipidemia, cigarette smoking, and hypertension (no interaction between hyperglycemia and preexisting diabetes, P=0.996). Among the patients without preexisting diabetes, both moderate (odds ratio, 1.8 [95% CI, 1.0-3.2]) and severe (odds ratio, 2.0 [95% CI, 1.1-3.7]) hyperglycemia were associated with 90-day death or disability after adjusting for above mentioned potential confounders. Among the patients with preexisting diabetes, moderate and severe hyperglycemia were not associated with 90-day death or disability. CONCLUSIONS: Persistent hyperglycemia, either moderate or severe, increased the risk of death or disability in nondiabetic patients with intracerebral hemorrhage. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01176565.
Subject(s)
Diabetes Mellitus , Hyperglycemia , Cerebral Hemorrhage/diagnosis , Diabetes Mellitus/epidemiology , Glucose , Hematoma , Humans , Hyperglycemia/complicationsABSTRACT
Aim: Missing data cause problems through decreasing sample size and the potential for introducing bias. We tested four missing data methods on the Sequential Organ Failure Assessment (SOFA) score, an intensive care research severity adjuster. Methods: Simulation study using 2015-2017 electronic health record data, where the complete dataset was sampled, missing SOFA score elements imposed and performance examined of four missing data methods - complete case analysis, median imputation, zero imputation (recommended by SOFA score creators) and multiple imputation (MI) - on the outcome of in-hospital mortality. Results: MI performed well, whereas other methods introduced varying amounts of bias or decreased sample size. Conclusion: We recommend using MI in analyses where SOFA score component values are missing in administrative data research.
Subject(s)
Electronic Health Records , Organ Dysfunction Scores , Humans , Intensive Care Units , Monte Carlo Method , Retrospective StudiesABSTRACT
One of the challenges in bringing new therapeutic agents (since nimodipine) in for the treatment of cerebral ischemia associated with aneurysmal subarachnoid hemorrhage (aSAH) is the incongruence in therapeutic benefit observed between phase II and subsequent phase III clinical trials. Therefore, identifying areas for improvement in the methodology and interpretation of results is necessary to increase the value of phase II trials. We performed a systematic review of phase II trials that continued into phase III trials, evaluating a therapeutic agent for the treatment of cerebral ischemia associated with aSAH. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for systematic reviews, and review was based on a peer-reviewed protocol (International Prospective Register of Systematic Reviews no. 222965). A total of nine phase III trials involving 7,088 patients were performed based on eight phase II trials involving 1558 patients. The following therapeutic agents were evaluated in the selected phase II and phase III trials: intravenous tirilazad, intravenous nicardipine, intravenous clazosentan, intravenous magnesium, oral statins, and intraventricular nimodipine. Shortcomings in several design elements of the phase II aSAH trials were identified that may explain the incongruence between phase II and phase III trial results. We suggest the consideration of the following strategies to improve phase II design: increased focus on the selection of surrogate markers of efficacy, selection of the optimal dose and timing of intervention, adjustment for exaggerated estimate of treatment effect in sample size calculations, use of prespecified go/no-go criteria using futility design, use of multicenter design, enrichment of the study population, use of concurrent control or placebo group, and use of innovative trial designs such as seamless phase II to III design. Modifying the design of phase II trials on the basis of lessons learned from previous phase II and phase III trial combinations is necessary to plan more effective phase III trials.
Subject(s)
Brain Ischemia , Subarachnoid Hemorrhage , Vasospasm, Intracranial , Brain Ischemia/complications , Brain Ischemia/drug therapy , Cerebral Infarction/complications , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Humans , Multicenter Studies as Topic , Nicardipine/therapeutic use , Nimodipine/therapeutic use , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/drug therapy , Treatment Outcome , Vasospasm, Intracranial/complications , Vasospasm, Intracranial/etiologyABSTRACT
BACKGROUND: Hematoma volume in chronic subdural hematoma (CSDH) may predict neurologic deterioration and need for surgical evacuation. Several computer software-assisted methods exist for accurate volume measurements of intracerebral hemorrhage, but no reliable method has been identified for measurement of CSDH volume. METHODS: A total of 30 consecutive patients with CSDH from 2018-2019 admitted to our institution were selected. The noncontrast computed tomography head studies were reviewed by 2 residents. The region of interest method on a Horos Open Source Medical Image Viewer (version 3.3.6) was utilized for volume measurement by each resident (resident-1 and resident-2) independently. Resident-1 repeated the protocol on the same studies 1 month later. We calculated the intra- and interobserver reliability of hematoma volume measurements using the Bland-Altman method. RESULTS: Mean age of the patients was 79 years (range, 50-92 years). For interobserver analysis, resident-1 mean hematoma volume was 85.46 cm3 (range, 6.40-178.63 cm3) and was 87.15 cm3 (range, 8.79-165.97 cm3) for resident-2. The Bland-Altman coefficient of variation was 13.15% (range, 0.07%-46.29%, 97% within the limits of acceptance). For intraobserver analysis, the initial average volume measured by resident-1 was 85.46 cm3 (range, 6.40-178.63 cm3) and subsequent was 95.26 cm3 (range, 10.48-182.99 cm3). The Bland-Altman coefficient of variation was 13.76% (range, 0.81%-48.34%, 97% within the limits of acceptance). CONCLUSIONS: We are reporting inter- and intraobserver reliability for a novel volumetric analysis of CSDH volume using Horos Medical Image Viewer region of interest generated volume calculation. This method is accurate and efficient and could have important clinical and research implications for risk stratification.
Subject(s)
Hematoma, Subdural, Chronic/diagnostic imaging , Aged , Aged, 80 and over , Automation , Female , Humans , Image Processing, Computer-Assisted , Male , Middle Aged , Observer Variation , Reproducibility of Results , Retrospective Studies , Risk Assessment , Tomography, X-Ray ComputedABSTRACT
An amendment to this paper has been published and can be accessed via the original article.
ABSTRACT
BACKGROUND: Monitoring and reporting of drug safety during a clinical trial is essential to its success. More recent attention to drug safety has encouraged statistical methods development for monitoring and detecting potential safety signals. This paper investigates the potential impact of the process of the blinded investigator identifying a potential safety signal, which should be further investigated by the Data and Safety Monitoring Board with an unblinded safety data analysis. METHODS: In this paper, two-stage Bayesian hierarchical models are proposed for safety signal detection following a pre-specified set of interim analyses that are applied to efficacy. At stage 1, a hierarchical blinded model uses blinded safety data to detect a potential safety signal and at stage 2, a hierarchical logistic model is applied to confirm the signal with unblinded safety data. RESULTS: Any interim safety monitoring analysis is usually scheduled via negotiation between the trial sponsor and the Data and Safety Monitoring Board. The proposed safety monitoring process starts once 53 subjects have been enrolled into an eight-arm phase II clinical trial for the first interim analysis. Operating characteristics describing the performance of this proposed workflow are investigated using simulations based on the different scenarios. CONCLUSIONS: The two-stage Bayesian safety procedure in this paper provides a statistical view to monitor safety during the clinical trials. The proposed two-stage monitoring model has an excellent accuracy of detecting and flagging a potential safety signal at stage 1, and with the most important feature that further action at stage 2 could confirm the safety issue.