Intracerebral hemorrhage (ICH) results in a cascade of inflammatory cell activation with recruitment of peripheral leukocytes to the brain parenchyma and surrounding the hematoma. We hypothesized ...that in patients with ICH and intraventricular hemorrhage (IVH), a robust cerebrospinal fluid (CSF) inflammatory response occurs with leukocyte subtypes being affected by alteplase treatment and contributing to outcomes.
Serum and CSF cell counts from patients in the phase 3 Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III) trial were analyzed. CSF leukocytes were corrected for the presence of red blood cells. Trends in cell counts were plotted chronologically. Associations were evaluated between serum and CSF leukocyte subtypes and adjudicated functional outcome (modified Rankin Scale; mRS) at 30 and 180 days and bacterial infection according to treatment with intraventricular alteplase versus saline.
A total of 279 and 292 patients had ≥3 differential cell counts from serum and CSF, respectively. CSF leukocyte subtypes evolved during IVH resolution with a significantly augmented inflammatory response for all subtypes in alteplase- compared to saline-treated patients. CSF leukocyte subtypes were not associated with detrimental effect on functional outcomes in the full cohort, but all were associated with poor 30-day outcome in saline-treated patients with IVH volume ≥20 mL. Higher serum lymphocytes were associated with good functional outcomes (mRS 0-3) in the entire cohort and saline-treated but not alteplase-treated group. Conversely, increased serum neutrophil-to-lymphocyte ratio (NLR) in the entire cohort and saline group was associated with worse functional outcomes. Higher median serum lymphocytes were associated with the absence of infection at 7 days.
Aseptic CSF inflammation after IVH involves all leukocyte subtypes. Serum lymphocytes may be associated with better outcomes by mitigating infection. Alteplase augments the inflammatory response without affecting outcomes.
Introduction:
We investigated the effect of hematoma volume reduction with minimally invasive surgery (MIS) on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in patients with large ...spontaneous intracerebral hemorrhage (ICH).
Methods:
Post-hoc
analysis of the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE III) study, a clinical trial with blinded outcome assessments. The primary outcome was the proportion of ICP readings ≥20 and 30 mmHg, and CPP readings <70 and 60 mm Hg. Secondary outcomes included major disability (modified Rankin scale >3) and mortality at 30 and 365 days. We assessed the relationship between proportion of high ICP and low CPP events and MIS using binomial generalized linear models, and outcomes using multiple logistic regression.
Results:
Of 499 patients enrolled in MISTIE III, 72 patients had guideline based ICP monitors placed, 34 in the MIS group and 38 in control (no surgery) group. Threshold ICP and CPP events ≥20/ <70 mmHg occurred in 31 (43.1%) and 52 (72.2%) patients respectively. On adjusted analyses, proportion of ICP readings ≥20 and 30 mmHg were significantly lower in the MIS group vs. control group Odds Ratio (OR) 0.27, 95% Confidence Interval CI 0.11–0.63 (
p
= 0.002); OR = 0.18, 0.04–0.75,
p
= 0.02, respectively. Proportion of CPP readings <70 and 60 mm Hg were also significantly lower in MIS patients OR 0.31, 95% CI 0.15–0.63 (
p
= 0.001); OR 0.30, 95% CI 0.11–0.83 (
p
= 0.02), respectively. Higher proportions of CPP readings <70 and 60 mm were significantly associated with short term mortality (
p
= 0.04), and (
p
= 0.006), respectively. Long term mortality was significantly associated with higher proportion of time with ICP ≥ 20 (
p
= 0.04), ICP ≥ 30 (
p
= 0.04), and CPP <70 mmHg (
p
= 0.01).
Conclusion:
Our results are consistent with the hypothesis that surgical reduction of ICH volume decreases proportion of high ICP and low CPP events and that these variables are associated with short- and long-term mortality.
Abstract Objective Higher hemoglobin A1c (HbA1c ) is associated with lower cognitive function in type 2 diabetes. To determine whether associations persist at lower levels of dysglycemia in patients ...who have established cardiovascular disease, cognitive performance was assessed in the Targeting INflammation Using SALsalate in CardioVascular Disease (TINSAL-CVD) trial. Methods The age-adjusted relationships between HbA1c and cognitive performance measured by the Mini-Mental State Examination, Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Trail Making Test, and Categorical Verbal Fluency were assessed in 226 men with metabolic syndrome and established stable coronary artery disease. Results Of the participants, 61.5% had normoglycemia, 20.8% had impaired fasting glucose, and 17.7% had type 2 diabetes. HbA1c was associated with cognitive function tests of Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Trail Making Test, and Categorical Verbal Fluency (all P < .02), but not the Mini-Mental State Examination. In an age-adjusted model, a 1% (11 mmol/mol) higher HbA1c value was associated with a 5.9 lower Digit Symbol Substitution Test score (95% confidence interval CI, −9.58 to −2.21; P < .0001); a 2.44 lower Rey Auditory Verbal Learning Test score (95% CI, −4.00 to −0.87; P < .0001); a 15.6 higher Trail Making Test score (95% CI, 5.73 to 25.6; P < .0001); and a 3.71 lower Categorical Verbal Fluency score (95% CI, −6.41 to −1.01; P < .02). In a multivariate model adjusting for age, education, and cardiovascular covariates, HbA1c remained associated with cognitive function tests of Rey Auditory Verbal Learning Test ( R 2 = 0.27, P < .0001), Trail Making Test ( R 2 = 0.18, P < .0001), and Categorical Verbal Fluency ( R 2 = 0.20, P < .0001), although association with the Digit Symbol Substitution Test was reduced. Conclusions Higher HbA1c is associated with lower cognitive function performance scores across multiple domain tests in men with metabolic syndrome and coronary artery disease. Future studies may demonstrate whether glucose lowering within the normative range improves cognitive health.
BackgroundMinimally invasive surgery (MIS) for spontaneous supratentorial intracerebral haemorrhage (ICH) is controversial but may be beneficial if end-of-treatment (EOT) haematoma volume is reduced ...to ≤15 mL. We explored whether MRI findings of cerebral small vessel disease (CSVD) modify the effect of MIS on long-term outcomes.MethodsPrespecified blinded subgroup analysis of 288 subjects with qualified imaging sequences from the phase 3 Minimally Invasive Surgery Plus Alteplase for Intracerebral Haemorrhage Evacuation (MISTIE) trial. We tested for heterogeneity in the effects of MIS and MIS+EOT volume ≤15 mL on the trial’s primary outcome of good versus poor function at 1 year by the presence of single CSVD features and CSVD scores using multivariable models.ResultsOf 499 patients enrolled in MISTIE III, 288 patients had MRI, 149 (51.7%) randomised to MIS and 139 (48.3%) to standard medical care (SMC). Median (IQR) ICH volume was 42 (30–53) mL. In the full MRI cohort, there was no statistically significant heterogeneity in the effects of MIS versus SMC on 1-year outcomes by any specific CSVD feature or by CSVD scores (all Pinteraction >0.05). In 94 MIS patients with EOT ICH volume ≤15 mL, significant reduction in odds of poor outcome was found with cerebral amyloid angiopathy score <2 (OR, 0.14 (0.05–0.42); Pinteraction=0.006), absence of lacunes (OR, 0.37 (0.18–0.80); Pinteraction=0.02) and absence of severe white matter hyperintensities (WMHs) (OR, 0.22 (0.08–0.58); Pinteraction=0.03).ConclusionsFollowing successful haematoma reduction by MIS, we found significantly lower odds of poor functional outcome with lower total burden of CSVD in addition to absence of lacunes and severe WMHs. CSVD features may have utility for prognostication and patient selection in clinical trials of MIS.
Abstract only Introduction: Clinical trial outcomes such as the modified Rankin score (mRS) are heavily influenced by mobility. We examined if mobility impairment and functional disability influenced ...long-term overall health evaluation by survivors of intracerebral and intraventricular hemorrhage (ICH/IVH). Methods: We pooled data from MISTIE-III and CLEAR-III trials. ICH/IVH survivors performed a protocolized direct valuation of their overall health using time trade-off utility (TTO-U) at 6 months post-ictus. TTO-U asks responders to consider trading years off their current disability-stricken state in exchange for perfect health. TTO-U index ranges from 0-1, with lower scores indicating greater years traded off and poorer valuation of overall health. TTO-U scores were dichotomized as good (>=0.7) and poor (<0.7). Associations between functional outcomes, European quality of life 5 dimensions (EQ-5D) and poor TTO-U at 6-months were assessed in multivariable logistic regression. A mediation analysis evaluated if mobility impairment and persistent poor mRS (mRS4-5) mediated associations between significant covariates and poor TTO-U at 6-months. Results: Of 773 survivors at 6-months, 442 (57%) patients with median (IQR) mRS of 3 (3-4) reported median (IQR) TTO-U of 1 (0.7-1); 332 patients had good and 110 had poor TTO-U. In multivariable logistic regression, moderate to severe anxiety/depression and problems with selfcare (dressing/washing) were independently associated with poor valuation of overall health, but mobility impairment and poor functional outcome were not. In mediation analyses, mobility impairment and poor mRS (4-5) at 6-months did not mediate the effect of persistent anxiety/depression (controlled direct effect (CDE), 1.79 1.10-2.89; natural indirect effect (NIE) of mobility, 0.93 0.58-1.49, p=0.75; NIE of mRS, 1.00 0.91-1.10, p=0.96) and selfcare deficits (CDE, 4.85 2.13-11.05; NIE of mobility, 0.72 0.42-1.26; NIE of mRS, 1.04 0.78-1.39) on long-term valuation of health state. Conclusions: Long-term valuation of overall health in survivors after severe ICH/IVH was influenced by persistent dependence in caring for self and mood dysfunction. Mobility impairment and mRS did not mediate these associations.
BackgroundStereotactic thrombolysis reduces intracerebral haemorrhage (ICH) volume in patients with spontaneous ICH. Whether intrahaematomal alteplase administration is associated with a change in ...intraventricular haemorrhage volume (deltaIVH) and functional outcomes is unknown.MethodsPost hoc secondary analysis of the Minimally Invasive Surgery plus Alteplase for Intracerebral Hemorrhage Evacuation Phase III (MISTIE-III) trial in patients with IVH on the stability CT scan. Exposure was minimally invasive surgery plus alteplase (MIS+alteplase). Primary outcome was deltaIVH defined as IVH volume on end-of-treatment CT minus IVH volume on stability CT scan. Secondary outcomes were favourable functional outcome (modified Rankin Scale 0–3) and mortality at 365 days. We assessed the relationship between MIS+alteplase and deltaIVH in the primary analysis using multivariable linear regression, and between deltaIVH and functional outcomes in secondary analyses using multiple logistic regression.ResultsOf 499 patients in MISTIE-III, 310 (62.1%) had IVH on stability scans; mean age (SD) was 61.2±12.3 years. A total of 146 (47.1%) received the MISTIE procedure and 164 (52.9%) standard medical care (SMC) only. The MIS+alteplase group had a greater mean reduction in IVH volume compared with the SMC group (deltaIVH: −2.35 (5.30) mL vs −1.15 (2.96) mL, p=0.02). While IVH volume decreased significantly in both treatment groups, in the primary analysis, MIS+alteplase was associated with greater deltaIVH in multivariable linear regression analysis adjusted for potential confounders (β −0.80; 95% CI −1.37 to −0.22, p=0.007). Secondary analysis demonstrated no associations between IVH reduction and functional outcomes (adjusted OR (aOR) for poor outcome 1.02; 95% CI 0.96 to 1.08, p=0.61; aOR for mortality 0.99; 95% CI 0.92 to 1.06, p=0.77).ConclusionsAlteplase delivered into the ICH in MISTIE-III subjects with IVH was associated with a small reduction in IVH volume. This reduction did not translate into a significant benefit in mortality or functional outcomes at 365 days.Trial registration numberNCT01827046.
IMPORTANCE: Patients who survive severe intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) typically have poor functional outcome in the short term and understanding of future ...recovery is limited. OBJECTIVE: To describe 1-year recovery trajectories among ICH and IVH survivors with initial severe disability and assess the association of hospital events with long-term recovery. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis pooled all individual patient data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 trial (CLEAR-III) and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE-III) phase 3 trial in multiple centers across the US, Canada, Europe, and Asia. Patients were enrolled from August 1, 2010, to September 30, 2018, with a follow-up duration of 1 year. Of 999 enrolled patients, 724 survived with a day 30 modified Rankin Scale score (mRS) of 4 to 5 after excluding 13 participants with missing day 30 mRS. An additional 9 patients were excluded because of missing 1-year mRS. The final pooled cohort included 715 patients (71.6%) with day 30 mRS 4 to 5. Data were analyzed from July 2019 to January 2022. EXPOSURES: CLEAR-III participants randomized to intraventricular alteplase vs placebo. MISTIE-III participants randomized to stereotactic thrombolysis of hematoma vs standard medical care. MAIN OUTCOMES AND MEASURES: Primary outcome was 1-year mRS. Patients were dichotomized into good outcome at 1 year (mRS 0 to 3) vs poor outcome at 1 year (mRS 4 to 6). Multivariable logistic regression models assessed associations between prospectively adjudicated hospital events and 1-year good outcome after adjusting for demographic characteristics, ICH and IVH severity, and trial cohort. RESULTS: Of 715 survivors, 417 (58%) were male, and the overall mean (SD) age was 60.3 (11.7) years. Overall, 174 participants (24.3%) were Black, 491 (68.6%) were White, and 49 (6.9%) were of other races (including Asian, Native American, and Pacific Islander, consolidated owing to small numbers); 98 (13.7%) were of Hispanic ethnicity. By 1 year, 129 participants (18%) had died and 308 (43%) had achieved mRS 0 to 3. In adjusted models for the combined cohort, diabetes (adjusted odds ratio aOR, 0.50; 95% CI, 0.26-0.96), National Institutes of Health Stroke Scale (aOR, 0.93; 95% CI, 0.90-0.96), severe leukoaraiosis (aOR, 0.30; 95% CI, 0.16-0.54), pineal gland shift (aOR, 0.87; 95% CI, 0.76-0.99), acute ischemic stroke (aOR, 0.44; 95% CI, 0.21-0.94), gastrostomy (aOR, 0.30; 95% CI, 0.17-0.50), and persistent hydrocephalus by day 30 (aOR, 0.37; 95% CI, 0.14-0.98) were associated with lack of recovery. Resolution of ICH (aOR, 1.82; 95% CI, 1.08-3.04) and IVH (aOR, 2.19; 95% CI, 1.02-4.68) by day 30 were associated with recovery to good outcome. In the CLEAR-III model, cerebral perfusion pressure less than 60 mm Hg (aOR, 0.30; 95% CI, 0.13-0.71), sepsis (aOR, 0.05; 95% CI, 0.00-0.80), and prolonged mechanical ventilation (aOR, 0.96; 95% CI, 0.92-1.00 per day), and in MISTIE-III, need for intracranial pressure monitoring (aOR, 0.35; 95% CI, 0.12-0.98), were additional factors associated with poor outcome. Thirty-day event-based models strongly predicted 1-year outcome (area under the receiver operating characteristic curve AUC, 0.87; 95% CI, 0.83–0.90), with significantly improved discrimination over models using baseline severity factors alone (AUC, 0.76; 95% CI, 0.71-0.80; P < .001). CONCLUSIONS AND RELEVANCE: Among survivors of severe ICH and IVH with initial poor functional outcome, more than 40% recovered to good outcome by 1 year. Hospital events were strongly associated with long-term functional recovery and may be potential targets for intervention. Avoiding early pessimistic prognostication and delaying prognostication until after treatment may improve ability to predict future recovery.
...we urge caution in the combination of proxy responses and patient responses or in the isolated use of proxy reports to precisely characterize patient status until the sources of biases are fully ...understood. Health-related quality of life should be reported by those experiencing the life lived. ...this is possible for patients with acute neurologic injury, who are unable to report their perspective, stating the limitations of data obtained from proxy reports and the impact of biases in any analysis is critical to the interpretation and use of such proxy data. Using and understanding the patient’s perspective may provide a more accurate representation of the potential value of recovery following brain injury and may allow for an informed shared decision-making process during the acute phase of injury that incorporates patients’ perspectives of their long-term health-related quality of life.
Abstract only Introduction: Intracerebral hemorrhage (ICH) management guidelines recommend maintaining intracranial pressure (ICP) <20 and cerebral perfusion pressure (CPP) between 50-70 mmHg. We did ...subgroup analyses of MISTIE III trial to explore whether minimally invasive surgery (MIS) improves ICP or CPP and whether thresholds are associated with long term outcomes. Methods: MISTIE III was a randomized clinical trial including 499 patients with spontaneous ICH randomized to MIS+Alteplase or standard medical care (SMC). Primary outcomes were any threshold event of ICP >20 and CPP <60/70 mmHg. Secondary outcomes were poor modified Rankin Scale at one year and mortality at 30/365 days. We used multivariable models to investigate factors associated with ICP/CPP events and outcomes. Results: Of 72 patients with ICP monitored for median 92 (72-96) hours, 31 (43.1%) had at least one ICP reading >20 and 52/35 (72.2/34.7%) had at least one CPP reading <70/60 mmHg. Lower intraventricular hemorrhage volume and SMC group were associated with having any ICP threshold event >20 and CPP event <70 mmHg whereas CPP<60 mmHg was associated with end of treatment (EOT) ICH volume, hydrocephalus on diagnostic CT and no prior antiplatelet agent use. On adjusted analyses, percentage of ICP readings >20 were significantly less likely in patients undergoing MIS vs SMC (Coefficient -0.79, 95% Confidence Interval CI (-)1.46-(-)0.11; p=0.02). Percentage of CPP readings <70 were significantly less frequent in MIS group (Coefficient -1.59 (-)2.58-(-)0.59; p=0.002). Patients who underwent successful MIS with EOT ICH volume <15mL also had significantly lower percentage of readings at ICP<20 (p=0.02), and CPP<70 (p=0.05). Lower percentage of CPP readings <60 mmHg was independently associated with lower mortality at 30 and 365 days (p=0.02 and 0.04) and CPP <70 was associated with lower one-year mortality (p=0.04). There were no significant associations with one-year functional outcome. Conclusion: Elevated ICP and inadequate CPP are not infrequent during ICP monitoring for large ICH. Burden of low CPP events predict higher short and long term mortality, but not functional outcomes. CPP may be more significant than ICP. MIS appears to mitigate ICP and CPP threshold events.
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