Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial

BackgroundTranexamic acid (TXA) reduces death due to bleeding after trauma and post-partum haemorrhage. The aim was to assess if tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral 6 haemorrhage (ICH). MethodsWe undertook an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage. Participants received 1g intravenous tranexamic acid bolus followed by an 8 hour 1g infusion, or matching placebo, within 8 hours of symptom onset. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale (mRS), using ordinal logistic regression, with adjustment for stratification and minimisation criteria. All analyses were performed on an intention to treat basis. This trial is registered as ISRCTN93732214.FindingsWe recruited 2,325 participants (TXA 1161, placebo 1164) from 124 hospitals in 12 countries between 2013 and 2017. Treatment groups were well balanced at baseline. The primary outcome was determined for 2307 (99·2%) participants. There was no statistically significant difference between the groups for the primary outcome of functional status at day 90 (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the TXA group (aOR 0·73, 95% CI 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (adjusted hazard ratio 0·92, 95% CI 0·77 to 1·10, p =0·37). There were fewer serious adverse events after TXA vs. placebo by days 2 (p=0·0272), 7 (p=0·0200) and 90 (p=0·0393).InterpretationThere was no significant difference in functional status 90 days after intracerebral haemorrhage with tranexamic acid, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect

Effects of dominant and non-dominant passive arm manoeuvres on the neurovascular coupling response.

PURPOSE: Models designed to study neurovascular coupling (NVC) describe a possible cerebral hemisphere dominance dependent on task completed and preference in handedness. We investigated whether passive arm manoeuvre performed with dominant (Dom-Arm) or non-dominant arm (ND-Arm) stimulated haemodynamic differences in either contralateral (Cont-H) or ipsilateral (Ipsil-H) cerebral hemisphere. METHODS: Healthy individuals lying in supine position, had measurements of beat-to-beat blood pressure (BP, mmHg), electrocardiogram (HR, bpm), end-tidal CO2 (etCO2, mmHg), and bilateral insonation of the middle cerebral arteries (MCA, cm s(-1)). Arm movement was performed for 60 s with passive flexion and extension of the elbow (1 Hz), before manoeuvre was repeated on other arm. Data were normalised and effect of treatment was analysed for differences between manoeuvres and within each time period. RESULTS: Seventeen (eight males) healthy volunteers, aged 56 ± 7 years, were studied. Dom-Arm and ND-Arm manoeuvres stimulated a comparable temporal response in peripheral and cerebral haemodynamic parameters between Cont-H and Ipsil-H. CONCLUSIONS: Both manoeuvres can be used to evoke similar bilateral MCA responses in assessing NVC. This finding should lead to more efficient protocols when using passive arm movement for NVC studies in healthy subjects

Managing high blood pressure during acute ischemic stroke and intracerebral hemorrhage.

PURPOSE OF REVIEW: Blood pressure (BP) elevations above premorbid levels are observed in at least 60% of acute ischemic and hemorrhagic stroke patients, within the first 24 h of symptom onset. A number of potential causes have been hypothesized, and high BP may be associated with poor stroke outcome. This review discusses management strategies of high BP in acute stroke, in the context of current guidelines. RECENT FINDINGS: Excessive BP elevation can impact acute stroke therapeutic strategies, particularly in modifying intervention safety and efficacy. Currently, guidance on BP management in acute ischemic stroke and intracerebral hemorrhage (ICH) exists in a limited number of specific clinical presentations, including spontaneous ICH and continuing versus stopping preexisting antihypertensive therapy. However, ongoing clinical trials will further investigate the safety and efficacy of urgent BP-lowering therapy for other indications. SUMMARY: There are clear national and international guidelines on BP lowering for specific indications, as well as ongoing clinical trials aiming to address common clinical scenarios in which the evidence-base is lacking and uncertain. This is specifically in important stroke subgroups previously excluded from trials, patients requiring mechanical thrombectomy and nonvitamin K antagonist-associated ICH reversal

Feasibility of Improving Cerebral Autoregulation in Acute Intracerebral Haemorrhage (BREATHE-ICH) study: a protocol for an experimental interventional study

Introduction: Cerebral autoregulation (CA) is impaired in a multitude of neurological conditions. Increasingly, clinical studies are correlating the nature of this impairment with prognostic markers. In acute intracerebral haemorrhage (ICH), impairment of CA has been associated with worsening clinical outcomes including poorer Glasgow Coma Score and larger haematoma volume. Hypocapnia has been shown to improve CA despite concerns over hypoperfusion and consequent ischaemic risks, and it is therefore hypothesised that hypocapnia (via hyperventilation) in acute ICH may improve CA and consequently clinical outcome. BREATHE-ICH is a CA-targeted interventional study in acute ICH utilising a simple bedside hyperventilatory manoeuvre. Methods and Analysis: Patients with acute ICH within 48 hours of onset will be included. The experimental set-up measures cerebral blood flow (cerebral blood velocity, transcranial Doppler), blood pressure (Finometer) and end tidal carbon dioxide (capnography) at baseline, and in response to hypocapnia (-5 mm and -10 mm Hg below baseline) achieved via a 90 s hyperventilatory manoeuvre. Autoregulation is evaluated with transfer function analysis and autoregulatory index calculations. Important classical endpoints associated with this before and after interventional study include death and disability at 14 days and the proportion of recruited individuals able to comply with the full measurement protocol. Ethics and Dissemination: A favourable opinion was granted by the East Midlands-Nottingham 1 Research Ethics Committee (17/EM/0283). It is anticipated that the results of this study will be presented at national and international meetings, with reports being published in journals during late 2018. Trial registration number NCT03324321

Modelling the cerebral haemodynamic response in the physiological range of PaCO₂.

Objective Arterial CO2 (PaCO2) has a strong effect on cerebral blood flow (CBF), but its influence on CBF regulatory mechanisms and circulatory systemic variables has not been fully described over the entire physiological range of PaCO2. Approach CBF velocity (CBV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were measured in 45 healthy volunteers (19 male, mean age 37.5 years, range 21-71) at baseline, and in response to hypo- (-5mm Hg and -10mm Hg below baseline) and hypercapnia (5% and 8% CO2), applied in random order. Main Results CBV, cerebral dynamic autoregulation index (ARI), heart rate (HR), arterial blood pressure (ABP), critical closing pressure (CrCP) and resistance-area product (RAP) changed significantly (all p2 on the cerebral and systemic circulations. The four logistic model parameters describing each 'dose-response' curve were specific to each of the modelled variables (ANOVA p<0.0001). Significance The ability to model the CBV, ARI, HR, ABP, CrCP and RAP dependency of PaCO2 over its entire physiological range is a powerful tool for physiological and clinical studies, including the need to perform adjustments in disease populations with differing values of baseline PaCO2.

Feasibility of improving cerebral autoregulation in acute intracerebral hemorrhage (BREATHE-ICH) study: Results from an experimental interventional study.

BACKGROUND: Cerebral autoregulation is impaired in a multitude of neurological conditions. Increasingly, clinical studies are correlating the nature of this impairment with prognostic markers. In acute intracerebral hemorrhage, impairment of cerebral autoregulation has been associated with worsening clinical outcomes including poorer Glasgow Coma Score and larger hematoma volume. Hypocapnia has been shown to improve cerebral autoregulation despite concerns over hypoperfusion and consequent ischemic risks, and it is therefore hypothesized that hypocapnia (via hyperventilation) in acute intracerebral hemorrhage may improve cerebral autoregulation and consequently clinical outcome. AIMS: To assess the feasibility and acceptability of the first cerebral autoregulation-targeted intervention in acute intracerebral hemorrhage utilizing a simple bed-side hyperventilatory maneuver. METHODS: Twelve patients with acute intracerebral hemorrhage within 48 h of onset were enrolled. The experimental setup measured cerebral blood flow velocity (transcranial Doppler), blood pressure (Finometer), and end-tidal CO2 (EtCO2, capnography) at baseline, and in response to hypocapnia (-5 mmHg below baseline) achieved via a 90-s hyperventilatory maneuver. Cerebral autoregulation was evaluated with transfer function analysis and autoregulatory index calculations. RESULTS: We observed tolerance to the protocol in a cohort of mild (National Institutes of Health Scale 4) supratentorial intracerebral hemorrhage patients with small volume hematomas without intraventricular extension. Importantly, a significant difference was noted between ipsilateral autoregulatory index at baseline 4.8 (1.7) and autoregulatory index during hypocapnic intervention 7.0 (0.8) (p = 0.0004), reflecting improved cerebral autoregulation, though a dose-dependent effect of EtCO2 on autoregulatory index was not observed. CONCLUSIONS: In this small study, there was no observed effect on 14-day death and disability in recruited participants. This is the first report of improvement in cerebral autoregulation in acute intracerebral hemorrhage using a non-invasive interventional maneuver, through induction of hypocapnia via hyperventilation. ClinicalTrials.gov Identifier: NCT03324321 URL: https://clinicaltrials.gov/ct2/show/NCT03324321

Cerebral Hemodynamics in Mild Cognitive Impairment: A Systematic Review

BACKGROUND: The incidence of dementia is projected to rise over the coming decades, but with no sensitive diagnostic tests available. Vascular pathology precedes the deposition of amyloid and is an attractive early target. OBJECTIVE: The aim of this review was to investigate the use of cerebral hemodynamics and oxygenation as a novel biomarker for mild cognitive impairment (MCI), focusing on transcranial Doppler ultrasonography (TCD) and near-infrared spectroscopy (NIRS). METHODS: 2,698 articles were identified from Medline, Embase, PsychINFO, and Web of Science databases. 306 articles were screened and quality assessed independently by two reviewers; 26 met the inclusion criteria. Meta-analyses were performed for each marker with two or more studies and limited heterogeneity. RESULTS: Eleven studies were TCD, 8 NIRS, 5 magnetic resonance imaging, and 2 positron/single photon emission tomography. Meta-analyses showed reduced tissue oxygenation index, cerebral blood flow and velocity, with higher pulsatility index, phase and cerebrovascular resistance in MCI compared to controls. The majority of studies found reduced CO2 reactivity in MCI, with mixed findings in neuroactivation studies. CONCLUSION: Despite small sample sizes and heterogeneity, meta-analyses demonstrate clear abnormalities in cerebral hemodynamic and oxygenation parameters, even at an early stage of cognitive decline. Further work is required to investigate the use of cerebral hemodynamic and oxygenation parameters as a sensitive biomarker for dementia

Alternative representation of neural activation in multivariate models of neurovascular coupling in humans.

Neural stimulation leads to increases in cerebral blood flow (CBF), but simultaneous changes in covariates, such as arterial blood pressure (BP) and P a C O 2 , rule out the use of CBF changes as a reliable marker of neurovascular coupling (NVC) integrity. Healthy subjects performed repetitive (1 Hz) passive elbow flexion with their dominant arm for 60 s. CBF velocity (CBFV) was recorded bilaterally in the middle cerebral artery with transcranial Doppler, BP with the Finometer device, and end-tidal CO2 (EtCO2) with capnography. The simultaneous effects of neural stimulation, BP, and P a C O 2 on CBFV were expressed with a dynamic multivariate model, using BP, EtCO2, and stimulation [s(t)] as inputs. Two versions of s(t) were considered: a gate function [sG(t)] or an orthogonal decomposition [sO(t)] function. A separate CBFV step response was extracted from the model for each of the three inputs, providing estimates of dynamic cerebral autoregulation [CA; autoregulation index (ARI)], CO2 reactivity [vasomotor reactivity step response (VMRSR)], and NVC [stimulus step response (STIMSR)]. In 56 subjects, 224 model implementations produced excellent predictive CBFV correlation (median r = 0.995). Model-generated sO(t), for both dominant (DH) and nondominant (NDH) hemispheres, was highly significant during stimulation (<10-5) and was correlated with the CBFV change (r = 0.73, P = 0.0001). The sO(t) explained a greater fraction of CBFV variance (~50%) than sG(t) (44%, P = 0.002). Most CBFV step responses to the three inputs were physiologically plausible, with better agreement for the CBFV-BP step response yielding ARI values of 7.3 for both DH and NDH for sG(t), and 6.9 and 7.4 for sO(t), respectively. No differences between DH and NDH were observed for VMRSR or STIMSR. A new procedure is proposed to represent the contribution from other aspects of CBF regulation than BP and CO2 in response to sensorimotor stimulation, as a tool for integrated, noninvasive, assessment of the multiple influences of dynamic CA, CO2 reactivity, and NVC in humans.NEW & NOTEWORTHY A new approach was proposed to identify the separate contributions of stimulation, arterial blood pressure (BP), and arterial CO2 ( P a C O 2 ) to the cerebral blood flow (CBF) response observed in neurovascular coupling (NVC) studies in humans. Instead of adopting an empirical gate function to represent the stimulation input, a model-generated function is derived as part of the modeling process, providing a representation of the NVC response, independent of the contributions of BP or P a C O 2 . This new marker of NVC, together with the model-predicted outputs for the contributions of BP, P a C O 2 and stimulation, has considerable potential to both quantify and simultaneously integrate the separate mechanisms involved in CBF regulation, namely, cerebral autoregulation, CO2 reactivity and other contributions

Determining differences between critical closing pressure and resistance-area product: responses of the healthy young and old to hypocapnia.

Healthy ageing has been associated with lower cerebral blood flow velocities (CBFVs); however, the behaviour of hemodynamic parameters associated with cerebrovascular tone (critical closing pressure, CrCP) and cerebrovascular resistance (resistance-area product, RAP) remains unclear. Specifically, evidence supports ageing being associated with greater cerebrovascular tone and resistance during exercise with elevated CrCP and RAP in older individuals at rest and during exercise. Comprehensive hemodynamic assessment of CrCP and RAP during hyperventilation-induced hypocapnia in two distinct age groups (young ≤ 49 and old > 50) has not been described. CBFV in the middle cerebral artery (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were recorded in 104 healthy individuals (43 young [age 33.8 (9.3) years], 61 old [age 64.1 (8.5) years]) during a minimum of 60 s of metronome-driven hyperventilation-induced hypocapnia. Autoregulation index was calculated as a function of time, using a moving window autoregressive-moving average model. CBFV was reduced in response to age (p < 0.0001) and hypocapnia (p = 0.023) (young 57.3 (14.4) vs. 44.9 cm s-1 (11.1), old 51.7 (12.9) vs. 37.8 cm s-1 (9.6)). Critical closing pressure (CrCP) increased significantly in response to hypocapnia (young 37.6 (18.5) vs. 39.7 mmHg (16.0), old 33.9 (13.5) vs. 39.3 mmHg (11.4); p < 0.0001). Resistance-area product was increased in response to age (p = 0.001) and hypocapnia (p = 0.004) (young 1.02 (0.40) vs. 1.09 mmHg cm s-1 (11.07), old 1.16 (0.34) vs. 1.34 mmHg cm s-1 (0.39)). RAP and not CrCP mediates differences in cerebrovascular resistance responses to hypocapnia between the healthy young and old individuals

Is cerebral vasomotor reactivity impaired in Parkinson disease?

PURPOSE: The ability of a blood vessel to change diameter in response to a change in carbon dioxide concentration is often referred to as vasomotor reactivity. This study aimed to determine whether vasomotor reactivity is impaired in patients with idiopathic Parkinson's Disease in comparison to healthy controls. METHODS: Transcranial Doppler was used to measure cerebral blood flow velocity in the middle cerebral arteries at baseline and under hypocapnic conditions in 40 patients with idiopathic Parkinson's disease and 50 healthy controls. RESULTS/CONCLUSIONS: Vasomotor reactivity, assessed under hypocapnic conditions, is not impaired in patients with idiopathic Parkinson's Disease in comparison to healthy controls