Blood pressure variability at rest and during pressor challenges in patients with acute ischemic stroke.

INTRODUCTION: Patients with acute ischemic stroke (AIS) have elevated blood pressure (BP) variability (BPV) and reduced baroreflex sensitivity (BRS) at rest for several days after initial stroke symptoms. We aimed to assess BPV and BRS in AIS patients during pressor challenge maneuvers in the acute and subacute phases of stroke. Pressor challenge maneuvers simulate day-to-day activities and can predict the quality of life. METHODS: Continuous beat-to-beat BP and ECG in 15 AIS patients (mean age 69 ±â€…7.5 years) and 15 healthy controls (57 ±â€…16 years) were recorded at rest and during a 5-min rapid head positioning (RHP) paradigm. Patients were assessed within 24 h (acute phase) and 7 days (subacute phase) of stroke onset. Low frequency (LF) SBP power (measure of BPV), LF-α, and combined α-index (measure of BRS) were calculated from the recordings. RESULTS: In the acute phase, at rest, LF-SBP power was higher (P = 0.024) and α-index was lower (P = 0.006) in AIS patients than in healthy controls. There was no change in LF-SBP during RHP in the patients but in healthy controls, it increased significantly (P = 0.018). In the subacute phase, at rest, the alpha-index increased (P = 0.037) and LF-SBP decreased (P = 0.029) significantly in the AIS patients, however, there was still no rise in the LF-SBP power during RHP (P = 0.240). CONCLUSION: AIS patients have a high resting BPV. High resting BPV may be responsible for blunted BPV responses during pressor challenge maneuvers such as RHP, suggesting ongoing autonomic dysfunction and compromised quality of life.

Determinants of the dynamic cerebral critical closing pressure response to changes in mean arterial pressure.

Objective. Cerebral critical closing pressure (CrCP) represents the value of arterial blood pressure (BP) where cerebral blood flow (CBF) becomes zero. Its dynamic response to a step change in mean BP (MAP) has been shown to reflect CBF autoregulation, but robust methods for its estimation are lacking. We aim to improve the quality of estimates of the CrCP dynamic response.Approach. Retrospective analysis of 437 healthy subjects (aged 18-87 years, 218 males) baseline recordings with measurements of cerebral blood velocity in the middle cerebral artery (MCAv, transcranial Doppler), non-invasive arterial BP (Finometer) and end-tidal CO2(EtCO2, capnography). For each cardiac cycle CrCP was estimated from the instantaneous MCAv-BP relationship. Transfer function analysis of the MAP and MCAv (MAP-MCAv) and CrCP (MAP-CrCP) allowed estimation of the corresponding step responses (SR) to changes in MAP, with the output in MCAv (SRVMCAv) representing the autoregulation index (ARI), ranging from 0 to 9. Four main parameters were considered as potential determinants of the SRVCrCPtemporal pattern, including the coherence function, MAP spectral power and the reconstruction error for SRVMAP, from the other three separate SRs.Main results. The reconstruction error for SRVMAPwas the main determinant of SRVCrCPsignal quality, by removing the largest number of outliers (Grubbs test) compared to the other three parameters. SRVCrCPshowed highly significant (p< 0.001) changes with time, but its amplitude or temporal pattern was not influenced by sex or age. The main physiological determinants of SRVCrCPwere the ARI and the mean CrCP for the entire 5 min baseline period. The early phase (2-3 s) of SRVCrCPresponse was influenced by heart rate whereas the late phase (10-14 s) was influenced by diastolic BP.Significance. These results should allow better planning and quality of future research and clinical trials of novel metrics of CBF regulation.

Statistical Analysis Plan for the INTEnsive Ambulance-Delivered Blood Pressure Reduction in Hyper-ACute Stroke Trial.

INTRODUCTION: Recruitment is complete in the fourth INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4), a multicenter, prospective, randomized, open-label, blinded endpoint assessed trial of prehospital blood pressure (BP) lowering initiated in the ambulance for patients with a suspected acute stroke and elevated BP in China. According to the registered and published trial protocol and developed by the blinded trial Steering Committee and Operations team, this manuscript outlines a detailed statistical analysis plan for the trial prior to database lock. METHODS: Patients were randomized (1:1) to intensive (target systolic BP 130-140 mm Hg within 30 min) or guideline-recommended BP management (BP lowering only considered if systolic BP >220 mm Hg) group. Primary outcome is an ordinal analysis of the full range of scores on the modified Rankin scale at 90 days. A modified sample size of 2,320 was estimated to provide 90% power to detect a 22% reduction in the odds (common odds ratio of 0.78) of a worse functional outcome using ordinal logistic regression, on the assumption of 5% patients with missing outcome and 6% patients with a stroke mimic. CONCLUSION: The statistical analysis plan for the trial has been developed to ensure transparent, verifiable, and prespecified analysis and to avoid potential bias in the evaluation of the trial intervention.

Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Attitudes of cardiac rehabilitation and stroke teams towards integration of stroke survivors into adapted cardiac rehabilitation: A focus group study.

OBJECTIVE: To explore the attitudes and beliefs of cardiac rehabilitation and stroke teams towards adapted cardiac rehabilitation, and the broader topics of exercise, healthy lifestyles and health behaviour change, for people with mild-to-moderate severity stroke in the sub-acute phase of recovery. DESIGN: Qualitative focus group-based study. SETTING: Acute and community national health service trusts. PARTICIPANTS: Stroke and cardiac rehabilitation team members. INTERVENTION: Adapted cardiac rehabilitation. MAIN MEASURES: Focus groups. Thematic analysis was applied to the transcribed data. RESULTS: Overall, 57 health professionals participated in 12 focus groups. Positive impacts for teams and stroke survivors were identified particularly confidence. However, there were negatives, barriers and adaptations identified. In addition, there was a lack of knowledge for cardiac rehabilitation teams in relation to stroke survivors and stroke teams in relation to cardiac rehabilitation, exercise and healthy lifestyles. CONCLUSIONS: Cardiac rehabilitation and stroke staff attitudes to cardiac rehabilitation for stroke survivors showed a range of benefits, negatives, barriers and adaptations needed. Confidence and knowledge of the cardiac rehabilitation and stroke teams needs to be addressed. REGISTRATION: ISRCTN65957980.

A Multi-Parametric Approach for Characterising Cerebral Haemodynamics in Acute Ischaemic and Haemorrhagic Stroke.

BACKGROUND AND PURPOSE: Early differentiation between acute ischaemic (AIS) and haemorrhagic stroke (ICH), based on cerebral and peripheral hemodynamic parameters, would be advantageous to allow for pre-hospital interventions. In this preliminary study, we explored the potential of multiple parameters, including dynamic cerebral autoregulation, for phenotyping and differentiating each stroke sub-type. METHODS: Eighty patients were included with clinical stroke syndromes confirmed by computed tomography within 48 h of symptom onset. Continuous recordings of bilateral cerebral blood velocity (transcranial Doppler ultrasound), end-tidal CO2 (capnography), electrocardiogram (ECG), and arterial blood pressure (ABP, Finometer) were used to derive 67 cerebral and peripheral parameters. RESULTS: A total of 68 patients with AIS (mean age 66.8 ± SD 12.4 years) and 12 patients with ICH (67.8 ± 16.2 years) were included. The median ± SD NIHSS of the cohort was 5 ± 4.6. Statistically significant differences between AIS and ICH were observed for (i) an autoregulation index (ARI) that was higher in the unaffected hemisphere (UH) for ICH compared to AIS (5.9 ± 1.7 vs. 4.9 ± 1.8 p = 0.07); (ii) coherence function for both hemispheres in different frequency bands (AH, p < 0.01; UH p < 0.02); (iii) a baroreceptor sensitivity (BRS) for the low-frequency (LF) bands that was higher for AIS (6.7 ± 4.2 vs. 4.10 ± 2.13 ms/mmHg, p = 0.04) compared to ICH, and that the mean gain of the BRS in the LF range was higher in the AIS than in the ICH (5.8 ± 5.3 vs. 2.7 ± 1.8 ms/mmHg, p = 0.0005); (iv) Systolic and diastolic velocities of the affected hemisphere (AH) that were significantly higher in ICH than in AIS (82.5 ± 28.09 vs. 61.9 ± 18.9 cm/s), systolic velocity (p = 0.002), and diastolic velocity (p = 0.05). CONCLUSION: Further multivariate modelling might improve the ability of multiple parameters to discriminate between AIS and ICH and warrants future prospective studies of ultra-early classification (<4 h post symptom onset) of stroke sub-types.

The Effect of Tranexamic Acid on Neurosurgical Intervention in Spontaneous Intracerebral Hematoma: Data From 121 Surgically Treated Participants From the Tranexamic Acid in IntraCerebral Hemorrhage-2 Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: An important proportion of patients with spontaneous intracerebral hemorrhage (ICH) undergo neurosurgical intervention to reduce mass effect from large hematomas and control the complications of bleeding, including hematoma expansion and hydrocephalus. The Tranexamic acid (TXA) for hyperacute primary IntraCerebral Hemorrhage (TICH-2) trial demonstrated that tranexamic acid (TXA) reduces the risk of hematoma expansion. We hypothesized that TXA would reduce the frequency of surgery (primary outcome) and improve functional outcome at 90 days in surgically treated patients in the TICH-2 data set. METHODS: Participants enrolled in TICH-2 were randomized to placebo or TXA. Participants randomized to either TXA or placebo were analyzed for whether they received neurosurgery within 7 days and their characteristics, outcomes, hematoma volumes (HVs) were compared. Characteristics and outcomes of participants who received surgery were also compared with those who did not. RESULTS: Neurosurgery was performed in 5.2% of participants (121/2325), including craniotomy (57%), hematoma drainage (33%), and external ventricular drainage (21%). The number of patients receiving surgery who received TXA vs placebo were similar at 4.9% (57/1153) and 5.5% (64/1163), respectively (odds ratio [OR] 0.893; 95% CI 0.619-1.289; P-value = .545). TXA did not improve outcome compared with placebo in either surgically treated participants (OR 0.79; 95% CI 0.30-2.09; P = .64) or those undergoing hematoma evacuation by drainage or craniotomy (OR 1.19 95% 0.51-2.78; P-value = .69). Postoperative HV was not reduced by TXA (mean difference -8.97 95% CI -23.77, 5.82; P-value = .45). CONCLUSION: TXA was not associated with less neurosurgical intervention, reduced HV, or improved outcomes after surgery.

Predictors of Early versus Delayed Neurological Deterioration after Thrombolysis for Ischemic Stroke.

INTRODUCTION: We aimed to determine predictors of early (END) and delayed neurological deterioration (DND) and their association with the functional outcome in patients with acute ischemic stroke (AIS) who participated in the international Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: END and DND (without END) were defined as scores of a ≥2-point increase on the National Institutes of Health Stroke Scale (NIHSS) or a ≥1-point decrease on the Glasgow coma scale or death, from baseline to 24 h and 24-72 h, respectively. Multivariable logistic regression models were used to determine independent predictors of END and DND and their association with 90-day outcomes (dichotomous scores on the modified Rankin scale [mRS] of 2-6 vs. 0-1 and 3-6 vs. 0-2 and death). RESULTS: Of 4,496 patients, 871 (19.4%) and 302 (8.4%) patients experienced END and DND, respectively. Higher baseline NIHSS score, older age, large-artery occlusion due to significant atheroma, cardioembolic stroke subtype, hemorrhagic infarction and parenchymatous hematoma within 24 h were all independent predictors for both END (all p ≤ 0.01) and DND (all p ≤ 0.024). Moreover, higher baseline systolic blood pressure (BP) (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.02-1.12), higher diastolic BP variability within 24 h (OR 1.07, 95% CI 1.04-1.09), patients from Asia (OR 1.25, 95% CI 1.03-1.52) were the only independent predictors for END. However, Asian ethnicity was negatively associated with DND (OR 0.64, 95% CI 0.47-0.86). Hemorrhagic infarction and parenchymatous hematoma within 24 h were the key predictors of END across all stroke subtypes. END and DND were all associated with a poor functional outcome at 90 days (all p < 0.001). CONCLUSION: We identified overlapping and unique demographic and clinical predictors of END and DND after thrombolysis for AIS. Both END and DND predict unfavorable outcomes at 90 days.

Physiological Variability during Prehospital Stroke Care: Which Monitoring and Interventions Are Used?

Prehospital care is a fundamental component of stroke care that predominantly focuses on shortening the time between diagnosis and reaching definitive stroke management. With growing evidence of the physiological parameters affecting long-term patient outcomes, prehospital clinicians need to consider the balance between rapid transfer and increased physiological-parameter monitoring and intervention. This systematic review explores the existing literature on prehospital physiological monitoring and intervention to modify these parameters in stroke patients. The systematic review was registered on PROSPERO (CRD42022308991) and conducted across four databases with citation cascading. Based on the identified inclusion and exclusion criteria, 19 studies were retained for this review. The studies were classified into two themes: physiological-monitoring intervention and pharmacological-therapy intervention. A total of 14 included studies explored prehospital physiological monitoring. Elevated blood pressure was associated with increased hematoma volume in intracerebral hemorrhage and, in some reports, with increased rates of early neurological deterioration and prehospital neurological deterioration. A reduction in prehospital heart rate variability was associated with unfavorable clinical outcomes. Further, five of the included records investigated the delivery of pharmacological therapy in the prehospital environment for patients presenting with acute stroke. BP-lowering interventions were successfully demonstrated through three trials; however, evidence of their benefit to clinical outcomes is limited. Two studies investigating the use of oxygen and magnesium sulfate as neuroprotective agents did not demonstrate an improvement in patient's outcomes. This systematic review highlights the absence of continuous physiological parameter monitoring, investigates fundamental physiological parameters, and provides recommendations for future work, with the aim of improving stroke patient outcomes.

Individual Patient Data Meta-Analysis of Dynamic Cerebral Autoregulation and Functional Outcome After Ischemic Stroke.

BACKGROUND: The relationship between dynamic cerebral autoregulation (dCA) and functional outcome after acute ischemic stroke (AIS) is unclear. Previous studies are limited by small sample sizes and heterogeneity. METHODS: We performed a 1-stage individual patient data meta-analysis to investigate associations between dCA and functional outcome after AIS. Participating centers were identified through a systematic search of the literature and direct invitation. We included centers with dCA data within 1 year of AIS in adults aged over 18 years, excluding intracerebral or subarachnoid hemorrhage. Data were obtained on phase, gain, coherence, and autoregulation index derived from transfer function analysis at low-frequency and very low-frequency bands. Cerebral blood velocity, arterial pressure, end-tidal carbon dioxide, heart rate, stroke severity and sub-type, and comorbidities were collected where available. Data were grouped into 4 time points after AIS: <24 hours, 24 to 72 hours, 4 to 7 days, and >3 months. The modified Rankin Scale assessed functional outcome at 3 months. Modified Rankin Scale was analyzed as both dichotomized (0 to 2 versus 3 to 6) and ordinal (modified Rankin Scale scores, 0-6) outcomes. Univariable and multivariable analyses were conducted to identify significant relationships between dCA parameters, comorbidities, and outcomes, for each time point using generalized linear (dichotomized outcome), or cumulative link (ordinal outcome) mixed models. The participating center was modeled as a random intercept to generate odds ratios with 95% CIs. RESULTS: The sample included 384 individuals (35% women) from 7 centers, aged 66.3±13.7 years, with predominantly nonlacunar stroke (n=348, 69%). In the affected hemisphere, higher phase at very low-frequency predicted better outcome (dichotomized modified Rankin Scale) at <24 (crude odds ratios, 2.17 [95% CI, 1.47-3.19]; P<0.001) hours, 24-72 (crude odds ratios, 1.95 [95% CI, 1.21-3.13]; P=0.006) hours, and phase at low-frequency predicted outcome at 3 (crude odds ratios, 3.03 [95% CI, 1.10-8.33]; P=0.032) months. These results remained after covariate adjustment. CONCLUSIONS: Greater transfer function analysis-derived phase was associated with improved functional outcome at 3 months after AIS. dCA parameters in the early phase of AIS may help to predict functional outcome.

Implementation of low-intensity thrombolysis monitoring care in routine practice: process evaluation of the Optimal Post rtPA-IV Monitoring in Acute Ischemic Stroke (OPTIMISTmain) study in the United States.

INTRODUCTION: The ongoing OPTIMISTmain study, an international, multicenter, stepped-wedge cluster randomized trial, aims to determine effectiveness and safety of low-intensity versus standard monitoring in thrombolysis-treated patients with mild-to-moderate acute ischemic stroke (AIS). An embedded process evaluation explored integration and impact of the intervention on care processes at participating US sites. METHODS: A mixed-methods approach with quantitative and qualitative data were collected between September 2021 and November 2022. Implementer surveys were undertaken at pre- and post-intervention phases to understand the perceptions of low-intensity monitoring strategy. A sample of stroke care nurses were invited to participate in semi-structured interviews at an early stage of post-intervention. Qualitative data were analyzed deductively using the normalization process theory; quantitative data were tabulated. RESULTS: Interviews with 21 nurses at 8 hospitals have shown low-intensity monitoring was well accepted, as there were less time constraints and reduced workload for each patient. There were initial safety concerns over missing deteriorating patients and difficulties in changing established routines. Proper training, education, and communication, and changing the habits and culture of care, were key elements to successfully adopting the new monitoring care into routine practice. Similar results were found in the post-intervention survey (42 nurses from 13 hospitals). Nurses reported time being freed up to provide patient education (56%), daily living care (50%), early mobilization (26%), mood/cognition assessment (44%), and other aspects (i.e. communication, family support). CONCLUSIONS: Low-intensity monitoring for patients with mild-to-moderate acute ischemic stroke, facilitated by appropriate education and organizational support, appears feasible and acceptable at US hospitals.

Influence of Time to Achieve Target Systolic Blood Pressure on Outcome After Intracerebral Hemorrhage: The Blood Pressure in Acute Stroke Collaboration.

OBJECTIVE: To investigate whether an earlier time to achieving and maintaining systolic blood pressure (SBP) at 120 to 140 mm Hg is associated with favorable outcomes in a cohort of patients with acute intracerebral hemorrhage. METHODS: We pooled individual patient data from randomized controlled trials registered in the Blood Pressure in Acute Stroke Collaboration. Time was defined as time form symptom onset plus the time (hour) to first achieve and subsequently maintain SBP at 120 to 140 mm Hg over 24 hours. The primary outcome was functional status measured by the modified Rankin Scale at 90 to 180 days. A generalized linear mixed models was used, with adjustment for covariables and trial as a random effect. RESULTS: A total of 5761 patients (mean age, 64.0 [SD, 13.0], 2120 [36.8%] females) were included in analyses. Earlier SBP control was associated with better functional outcomes (modified Rankin Scale score, 3-6; odds ratio, 0.98 [95% CI, 0.97-0.99]) and a significant lower risk of hematoma expansion (0.98, 0.96-1.00). This association was stronger in patients with bigger baseline hematoma volume (>10 mL) compared with those with baseline hematoma volume ≤10 mL (0.006 for interaction). Earlier SBP control was not associated with cardiac or renal adverse events. CONCLUSIONS: Our study confirms a clear time relation between early versus later SBP control (120-140 mm Hg) and outcomes in the one-third of patients with intracerebral hemorrhage who attained sustained SBP levels within this range. These data provide further support for the value of early recognition, rapid transport, and prompt initiation of treatment of patients with intracerebral hemorrhage.

Do maternal haemodynamics have a causal influence on treatment for gestational diabetes?

BACKGROUND: Arterial stiffening is believed to contribute to the worsening of insulin resistance, and factors which are associated with needing pharmacological treatment of gestational diabetes (GDM), such as maternal obesity or advanced age, are associated with impaired cardiovascular adaptation to pregnancy. In this observational study, we aimed to investigate causal relationships between maternal haemodynamics and treatment requirement amongst women with GDM. METHODS: We assessed maternal haemodynamics in women with GDM, comparing those who remained on dietary treatment with those who required pharmacological management. Maternal haemodynamics were assessed using the Arteriograph® (TensioMed Ltd, Budapest, Hungary) and the NICOM® non-invasive bio-reactance method (Cheetah Medical, Portland, Oregon, USA). A graphical causal inference technique was used for statistical analysis. RESULTS: 120 women with GDM were included in the analysis. Maternal booking BMI was identified as having a causative influence on treatment requirement, with each unit increase in BMI increasing the odds of needing metformin and/or insulin therapy by 12% [OR 1.12 (1.02 - 1.22)]. The raw values of maternal heart rate (87.6 ± 11.7 vs. 92.9 ± 11.90 bpm, p = 0.014) and PWV (7.8 ± 1.04 vs. 8.4 ± 1.61 m/s, p = 0.029) were both significantly higher amongst the women requiring pharmacological management, though these relationships did not remain significant in causal logistic regression. CONCLUSIONS: Maternal BMI at booking has a causal, rather than simply associational, relationship on the need for pharmacological treatment of GDM. No significant causal relationships were found between maternal haemodynamics and the need for pharmacological treatment.

This observational study is the first to examine relationships between maternal haemodynamics and treatment requirement for gestational diabetes (GDM). This is also the first study to demonstrate a causative, rather than simply associational, relationship between maternal body mass index (BMI) and the need for pharmacological treatment of GDM, with each unit increase in BMI increasing the odds of needing metformin and/or insulin therapy by 12%. Maternal heart rate and pulse wave velocity were significantly higher among women with GDM requiring pharmacological management, but this finding did not remain significant in logistic regression analysis, and no causative relationships between maternal hemodynamics and treatment requirement were identified. Our findings highlight the importance of pre- and peri-conception weight control, but do not support a role for measurement of maternal hemodynamics in the prediction of women who are likely to require pharmacological management of GDM.

Depression of dynamic cerebral autoregulation during neural activation: The role of responders and non-responders.

Neurovascular coupling (NVC) interaction with dynamic cerebral autoregulation (dCA) remains unclear. We investigated the effect of task complexity and duration on the interaction with dCA. Sixteen healthy participants (31.6 ± 11.6 years) performed verbal fluency (naming-words (NW)) and serial subtraction (SS) paradigms, of varying complexity, at durations of 05, 30 and 60 s. The autoregulation index (ARI), was estimated from the bilateral middle cerebral artery blood velocity (MCAv) step response, calculated by transfer function analysis (TFA), for each paradigm during unstimulated (2 min) and neuroactivated (1 min) segments. Intraclass correlation (ICC) and coefficient of variation (CV) determined reproducibility for two visits and objective criteria were applied to classify responders (R) and non-responders (NoR) to task-induced MCAv increase. ICC values demonstrated fair reproducibility in all tasks. ARI decreased in right (RH) and left (LH) hemispheres, irrespective of paradigm complexity and duration (p < 0.0001). Bilateral ARI estimates were significantly decreased during NW for the R group only (p < 0.0001) but were reduced in both R (p < 0.0001) and NoR (p = 0.03) groups for SS tasks compared with baseline. The reproducible attenuation of dCA efficiency due to paradigm-induced NVC response, its interaction, and different behaviour in R and NoR, warrant further research in different physiological and clinical conditions.

Intensive blood pressure lowering and renal function in ischemic stroke patients: secondary analysis of ENCHANTED trial.

BACKGROUND: Renal failure is a major safety concern of intensive systolic blood pressure (SBP) lowering. We aimed to determine the effect of this treatment on early change in renal function in participants of the international Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: Post-hoc analysis of the ENCHANTED BP-arm in which thrombolyzed patients with acute ischemic stroke (AIS) were randomized to intensive (target 130-140 mm Hg within 1 h) or guideline-recommended (target <180 mm Hg) management within 6 h of symptom onset. Primary outcome is early change in renal function, defined by a difference in estimated glomerular filtration rate (∆eGFR = 24 h - baseline eGFR), analyzed using linear regression with adjustment for clinical variables. Key SBP parameters were attained (mean), variability (standard deviation [SD]) and magnitude of reduction within 24 h. RESULTS: Of 2151 participants (mean age 66.9 years; 38% female) included with available baseline eGFR, there were significant differences in attained 144.3±10.2 vs 149.8±12.0 [5.5 mm Hg]; P<0.0001), variation (15.1±5.4 vs 14.0±5.6 mm Hg; P<0.0001) and magnitude of reduction (44.6±16.2 vs 38.7±17.6 mm Hg; P<0.0001) in SBP within 24 hours. 1718 (79.9%) participants with complete follow-up eGFR were included in the primary analysis, and there was no significant difference in ∆eGFR (adjusted mean difference -1.10, 95% confidence interval [CI] -3.14 to -0.94; P=0.29) between the intensive and guideline groups, respectively. The neutral effect on ∆eGFR was consistent in patients with different baseline eGFR stages and in sensitivity analysis after multiple imputation for missing follow-up eGFR. SBP variability was significantly associated with decreasing ∆eGFR (per 5 mm Hg increase by category: adjusted mean difference -1.35, 95%CI -2.43 to -0.28; P for trend=0.01). CONCLUSIONS: Intensive SBP lowering with a target of 130-140 mm Hg had no impact on early renal function in thrombolyzed AIS patients. Wide SBP variability was associated with a larger decline in eGFR. CLINICAL TRIAL REGISTRATION: ENCHANTED is registered at ClinicalTrials.gov (NCT01422616).

Prehospital transdermal glyceryl trinitrate for ultra-acute ischaemic stroke: data from the RIGHT-2 randomised sham-controlled ambulance trial.

BACKGROUND: The effect of transdermal glyceryl trinitrate (GTN, a nitrovasodilator) on clinical outcome when administered before hospital admission in suspected stroke patients is unclear. Here, we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2). METHODS: RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4 hours of onset. The primary outcome was a shift in scores on the modified Rankin scale (mRS) at day 90. Secondary outcomes included death; a global analysis (Wei-Lachin test) containing Barthel Index, EuroQol-5D, mRS, telephone interview for cognitive status-modified and Zung depression scale; and neuroimaging-determined 'brain frailty' markers. Data were reported as n (%), mean (SD), median [IQR], adjusted common OR (acOR), mean difference or Mann-Whitney difference (MWD) with 95% CI. RESULTS: 597 of 1149 (52%) patients had a final diagnosis of ischaemic stroke; age 75 (12) years, premorbid mRS>2 107 (18%), Glasgow Coma Scale 14 (2) and time from onset to randomisation 67 [45, 108] min. Neuroimaging 'brain frailty' was common: median score 2 [2, 3] (range 0-3). At day 90, GTN did not influence the primary outcome (acOR for increased disability 1.15, 95% CI 0.85 to 1.54), death or global analysis (MWD 0.00, 95% CI -0.10 to 0.09). In subgroup analyses, there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1 hour of symptom onset and in those with more severe stroke. CONCLUSIONS: In patients who had an ischaemic stroke, ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital trials.

Optimum Baseline Clinical Severity Scale Cut Points for Prognosticating Intracerebral Hemorrhage: INTERACT Studies.

BACKGROUND: The optimal cut point of baseline National Institutes of Health Stroke Scale (NIHSS) and Glasgow Coma Scale scores for prognosticating acute intracerebral hemorrhage (ICH) is unknown. METHODS: Secondary analyses of participant data are from the INTERACT (Intensive Blood Pressure Reduction in Acute Intracerebral Hemorrhage Trials) 1 and 2 studies. Receiver operating characteristic analyses were used to compare the predictive performance of baseline NIHSS and Glasgow Coma Scale scores, ICH score, and max-ICH score. Optimal cut points for predicting 90-day clinical outcomes (death or major disability [defined as modified Rankin Scale scores 3-6], major disability [defined as modified Rankin Scale scores 3-5], and death alone) were determined using the Youden index. Logistic regression models were adjusted for age, sex, hematoma volume, and other known risk factors for poor prognosis. We validated our findings in the INTERACT1 database. RESULTS: There were 2829 INTERACT2 patients (age, 63.5±12.9 years; male, 62.9%; ICH volume, 10.96 [5.77-19.49] mL) included in the main analyses. The baseline NIHSS score (area under the curve, 0.796) had better prognostic utility for predicting death or major disability than the Glasgow Coma Scale score (area under the curve, 0.650) and ICH score (area under the curve, 0.674) and was comparable to max-ICH score (area under the curve, 0.789). Similar findings were observed when assessing the outcome of major disability. A cut point of 10 on baseline NIHSS optimally (sensitivity, 77.5%; specificity, 69.2%) predicted death or major disability (adjusted odds ratio, 4.50 [95% CI, 3.60-5.63]). The baseline NIHSS cut points that optimally predicted major disability and death alone were 10 and 12, respectively. The predictive effect of NIHSS≥10 for poor functional outcomes was consistent in all subgroups including age and baseline hematoma volume. Results were consistent when analyzed in the independent INTERACT1 validation database. CONCLUSIONS: In patients with mild-to-moderate ICH, a baseline NIHSS score of ≥10 was optimal for predicting poor outcomes at 90 days. Prediction based on baseline NIHSS is better than baseline Glasgow Coma Scale score. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00226096 and NCT00716079.

The effect of hypercapnia on the directional sensitivity of dynamic cerebral autoregulation and the influence of age and sex.

The cerebral circulation responds differently to increases in mean arterial pressure (MAP), compared to reductions in MAP. We tested the hypothesis that this directional sensitivity is reduced by hypercapnia. Retrospective analysis of 104 healthy subjects (46 male (44%), age range 19-74 years), with five minute recordings of middle cerebral blood velocity (MCAv, transcranial Doppler), non-invasive MAP (Finometer) and end-tidal CO2 (capnography) at rest, during both poikilocapnia and hypercapnia (5% CO2 breathing in air) produced MCAv step responses allowing estimation of the classical Autoregulation Index (ARIORIG), and corresponding values for both positive (ARI+D) and negative (ARI-D) changes in MAP. Hypercapnia led to marked reductions in ARIORIG, ARI+D and ARI-D (p < 0.0001, all cases). Females had a lower value of ARIORIG compared to males (p = 0.030) at poikilocapnia (4.44 ± 1.74 vs 4.74 ± 1.48) and hypercapnia (2.44 ± 1.93 vs 3.33 ± 1.61). The strength of directional sensitivity (ARI+D-ARI-D) was not influenced by hypercapnia (p = 0.46), sex (p = 0.76) or age (p = 0.61). During poikilocapnia, ARI+D decreased with age in females (p = 0.027), but not in males. Directional sensitivity was not affected by hypercapnia, suggesting that its origins are more likely to be inherent to the mechanics of vascular smooth muscle than to myogenic pathways.

Update on the INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4): progress and baseline features in 2053 participants.

BACKGROUND AND AIMS: Uncertainty persists over the effects of blood pressure (BP) lowering in acute stroke. The INTEnsive ambulance-delivered blood pressure Reduction in hyper-Acute stroke Trial (INTERACT4) aims to determine efficacy and safety of hyperacute intensive BP lowering in patients with suspected acute stroke. Given concerns over the safety of this treatment in the pre-hospital setting, particularly in relation to patients with intracerebral hemorrhage, we provide an update on progress of the study and profile of participants to date. METHODS: INTERACT4 is an ongoing multicentre, ambulance-delivered, randomized, open-label, blinded endpoint trial of pre-hospital BP lowering in patients with suspected acute stroke and elevated BP in China. Patients are randomized via a mobile phone digital system to intensive (target systolic BP [SBP] <140mmHg within 30 min) or guideline-recommended BP management. Primary outcome is an ordinal analysis of the full range of scores on the modified Rankin scale scores at 90 days. RESULTS: Between March 2020 and April 2023, 2053 patients (mean age 70 years, female 39%) were recruited with a mean BP 178/98 mmHg in whom 45% have a diagnosis of primary intracerebral hemorrhage upon arrival at hospital. At the time of presentation to hospital, the mean SBP was 160 and 170mmHg in the intensive and control groups (Δ10 mmHg), respectively. The independent data and safety monitoring board has not identified any safety concerns and recommended continuation of the trial. The sample size was reduced from 3116 to 2320 after meetings in August 2022 as the stroke mimic rate was persistently lower than initially estimated (6% vs 30%). The study is expected to be completed in late 2023 and the results announced in May 2024. CONCLUSIONS: INTERACT4 is on track to provide reliable evidence of the effectiveness of ambulance-delivered intensive BP lowering in patients with suspected acute stroke. TRIAL REGISTRATION: ClinicalTrials.gov NCT03790800 ; registered on 2 January 2019. Chinese Trial Registry ChCTR1900020534 , registered on 7 January 2019.

The main Optimal Post rTpa-Iv Monitoring in Ischemic Stroke Trial (OPTIMISTmain): protocol for a pragmatic, stepped wedge, cluster randomized controlled trial.

Introduction Careful monitoring of patients who receive intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) is resource-intensive, and potentially less relevant in those with mild degrees of neurological impairment who are at low-risk of symptomatic intracerebral hemorrhage (sICH) and other complications. \ Methods OPTIMISTmain is an international, multicenter, prospective, stepped wedge, cluster randomized, blinded outcome assessed trial aims to determine whether a less-intensity monitoring protocol is at least as effective, safe and efficient as standard post-IVT monitoring in patients with mild deficits post-AIS. Clinically-stable adult patients with mild AIS (defined by a NIHSS <10) who do not require intensive care within 2 hours post-IVT are recruited at hospitals in Australia, Chile, China, Malaysia, Mexico, UK, US and Vietnam. An average of 15 patients recruited per period (overall 60 patient participants) at 120 sites for a total of 7200 IVT-treated AIS patients will provide 90% power (one-sided α 0.025). The initiation of eligible hospitals is based on a rolling process whenever ready, stratified by country. Hospitals are randomly allocated using permuted blocks into 3 sequences of implementation, stratified by country and the projected number of patients to be recruited over 12 months. These sequences have four periods that dictate the order in which they are to switch from control (usual care) to intervention (implementation of low intensity monitoring protocol) to different clusters of patients in a stepped manner. Compared to standard monitoring, the low-intensity monitoring protocol includes assessments of neurological and vital signs every 15 minutes for 2 hours, 2 hourly (versus every 30 minutes) for 8 hours, and 4 hourly (versus every 1 hour) until 24 hours, post-IVT. The primary outcome measure is functional recovery, defined by the modified Rankin scale (mRS) at 90 days, a seven-point ordinal scale (0 [no residual symptom] to 6 [death]). Secondary outcomes include death or dependency, length of hospital stay, and health-related quality of life, sICH and serious adverse events. Conclusion OPTIMISTmain will provide Level I evidence for the safety and effectiveness of a low-intensity post-IVT monitoring protocol in patients with mild severity of AIS.