Lowering blood pressure after acute intracerebral haemorrhage: protocol for a systematic review and meta-analysis using individual patient data from randomised controlled trials participating in the Blood Pressure in Acute Stroke Collaboration (BASC)

INTRODUCTION: Conflicting results from multiple randomised trials indicate that the methods and effects of blood pressure (BP) reduction after acute intracerebral haemorrhage (ICH) are complex. The Blood pressure in Acute Stroke Collaboration is an international collaboration, which aims to determine the optimal management of BP after acute stroke including ICH. METHODS AND ANALYSIS: A systematic review will be undertaken according to the Preferred Reporting Items for Systematic review and Meta-Analysis of Individual Participant Data (IPD) guideline. A search of Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE from inception will be conducted to identify randomised controlled trials of BP management in adults with acute spontaneous (non-traumatic) ICH enrolled within the first 7 days of symptom onset. Authors of studies that meet the inclusion criteria will be invited to share their IPD. The primary outcome will be functional outcome according to the modified Rankin Scale. Safety outcomes will be early neurological deterioration, symptomatic hypotension and serious adverse events. Secondary outcomes will include death and neuroradiological and haemodynamic variables. Meta-analyses of pooled IPD using the intention-to-treat dataset of included trials, including subgroup analyses to assess modification of the effects of BP lowering by time to treatment, treatment strategy and patient's demographic, clinical and prestroke neuroradiological characteristics. ETHICS AND DISSEMINATION: No new patient data will be collected nor is there any deviation from the original purposes of each study where ethical approvals were granted; therefore, further ethical approval is not required. Results will be reported in international peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42019141136

Blood Pressure Variability and Outcome in Acute Ischemic and Hemorrhagic Stroke: A Post-Hoc Analysis of the HeadPoST Study

The Head Positioning in Acute Stroke Trial (HeadPoST) is a pragmatic, international, cluster crossover randomized trial of 11,093 patients with acute stroke assigned to a lying-flat (0o) or sitting-up (head elevated ≥30o) position. This post-hoc analysis aimed to determine the association between BPV and outcomes for patients from a wide range of international clinical settings and how the association was modified by randomized head position. BPV was defined according to standard criteria with the key parameter considered the coefficient of variation (CV) of systolic BP (SBP) over 24 hours. Outcome was ordinal 90-day modified Rankin Scale (mRS) score. The association was analyzed by ordinal, logistic regression, hierarchical, mixed models with fixed intervention (lying-flat vs. sitting-up), and fixed period, random cluster, and random cluster-period, effects. 9,156 (8,324 AIS and 817 ICH; mean age 68.1 years; 39.2% women) were included in the analysis. CV of SBP had a significant linear association with unfavorable shift of mRS at 90 days (adjusted odds ratio [OR] 1.06, 95% confidence interval [CI] 1.02-1.11; P=0.01). There was no heterogeneity of the association by randomized head positioning. In addition, CV of diastolic BP (DBP) (1.08, 1.03-1.12; P=0.001) over 24 hours post stroke, was significantly associated with 3-month poor outcome. The association was more apparent in sitting-up position (1.12, 1.06-1.19) compared with lying-flat position (1.03, 0.98-1.09) (P interaction = 0.005). BPV was associated with adverse stroke outcome, the magnitude of the association was greater with sitting-up head positioning in terms of DBP variability

Latest developments in clinical stroke care

Stroke medicine has seen rapid developments in diagnosis and management, and consequently improved prognosis. Management of ischaemic stroke, in particular, has benefited from these advances. The approach to management has evolved from one of historical passivity to active intervention with time of the essence following stroke onset. The last decade has seen the comparative effectiveness of several pharmacological agents being tested, creating significant randomised controlled trial evidence to support the management of common clinical problems following acute stroke. While several of these interventions are widely available, some remain less accessible. This review will discuss the latest developments in clinical stroke medicine, based on a symposium presentation at the Royal College of Physicians of Edinburgh, and reference key randomised controlled trial evidence in an effort to provide a balanced perspective on our current understanding of acute ischaemic and haemorrhagic stroke

Emerging evidence in the delivery of stroke thrombolysis

Intravenous Thrombolysis (IVT) significantly increases the chance of functional independence post-stroke, and an improved understanding of delivery has ensured better safety and clinical outcomes. Despite this, there remain several aspects of IVT delivery that are yet to be clarified including: the role of new thrombolytic agents; treatment strategies for stroke with unknown onset time, including wake-up stroke; and the role of an intensive peri-thrombolysis BP target. Tenecteplase is an emerging IVT agent that has preferential characteristics yet to be fully examined in larger studies of AIS patients or sub-groups including ‘wake-up’ stroke. We await the results of on-going trials to ensure continuing optimisation of IVT delivery

Sex differences in cerebral haemodynamics across the physiological range of PaCO2

OBJECTIVE: Cerebral blood flow (CBF) is influenced by changes in arterial CO2 (PaCO2). Recently, cerebral haemodynamic parameters were demonstrated to follow a four parameter logistic curve offering simultaneous assessment of dCA and CO2 vasoreactivity. However, the effects of sex on cerebral haemodynamics have yet to be described over a wide range of PaCO2. APPROACH: CBF velocity (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were measured in healthy volunteers at baseline, and in response to hypo- (-5 mmHg and  -10 mmHg below baseline) and hypercapnia (5% and 8% CO2), applied in random order. MAIN RESULTS: Forty-five subjects (19 male, 26 female, mean age 37.5 years) showed significant differences between males and females in CBFV (50.9  ±  10.4 versus 61.5  ±  12.3 cm · s-1, p  =  0.004), EtCO2 (39.2  ±  2.8 versus 36.9  ±  3.0 mmHg, p  =  0.005), RAP (1.16  ±  0.23 versus 0.94  ±  0.40 mmHg cm · s-1, p  =  0.005) and systolic BP (125.2  ±  8.0 versus 114.6  ±  12.4 mmHg, p  =  0.0372), respectively. Significant differences between sexes were observed in the four logistic parameters: y min, y max, k (exponential coefficient) and x (EtCO2 level) across the haemodynamic variables. Significant differences included the CBFV-EtCO2 and ARI-EtCO2 relationship; ARImin (p  =  0.036) and CBFVmax (p  =  0.001), respectively. Furthermore, significant differences were observed for both CrCPmin (p  =  0.045) and CrCPmax (p  =  0.005) and RAPmin (p  <  0.001) and RAPmax (p  <  0.001). SIGNIFICANCE: This is the first study to examine sex individually within the context of a multi-level CO2 protocol. The demonstration that the logistic curve parameters are influenced by sex, highlights the need to take into account sex differences between participants in both physiological and clinical studies

Dynamic cerebral autoregulation measurement using rapid changes in head positioning: experiences in acute ischemic stroke and healthy control populations

The ideal technique for dynamic cerebral autoregulation (dCA) assessment in critically ill patients should provide considerable variability in blood pressure (BP) but without the need for patient cooperation. We proposed using rapid head positioning (RHP) over spontaneous BP fluctuations for dCA assessment in patients with acute ischemic stroke (AIS). Cerebral blood velocity (transcranial Doppler), beat-to-beat BP (Finometer), and end-tidal CO2 (capnography) were recorded during 5-min baseline and RHP in 16 controls (8 women and 8 men, mean age: 57 ± 16 yr) and 15 patients with AIS (7 women and 8 men, mean age: 69 ± 8 yr) at two (12 ± 8 days) and three visits (13.3 ± 6.9 h, 4.8 ± 3.2 days, and 93.9 ± 11.5 days from the symptom onset), respectively. All participants were able to complete the RHP protocol without difficulty. Compared with controls, patients with AIS were hypocapnic (all visits, P < 0.0024) and hypertensive ( visit 1, P = 0.011), although BP gradually reduced after the acute phase. RHP demonstrated greater beat-to-beat BP variability (BPV) in controls ( visits 1 and 2, P < 0.001) but not in patients with AIS at any visit. Compared with controls, a reduced autoregulation index (ARI) was demonstrated in patients with AIS, at visit 2 for the baseline recording but not at other visits or during RHP. The area under the receiver-operating curve was 0.53 and 0.54 for baseline and RHP, respectively. The RHP paradigm required minimal patient cooperation and could be considered a feasible alternative for assessing dCA, mainly in conditions leading to increased BPV. The lack of BPV increase in AIS with RHP deserves further investigation. NEW & NOTEWORTHY This study used rapid head positioning (RHP) to enhance blood pressure (BP) variability (BPV) to improve BP signal-to-noise ratio and reliability of dynamic cerebral autoregulation (dCA). RHP was well accepted by controls and acute ischemic stroke (AIS); the increased BPV induced in controls was not observed in AIS, suggesting BPV at rest was already elevated. RHP did not improve detection of impaired CA in AIS; further work is needed to understand the different responses observed

Different strategies to initiate and maintain hyperventilation: their effect on continuous estimates of dynamic cerebral autoregulation

OBJECTIVE: Capnography is a key monitoring intervention in several neurologically vulnerable clinical states. Cerebral autoregulation (CA) describes the ability of the cerebrovascular system to maintain a near constant cerebral blood flow throughout fluctuations in systemic arterial blood pressure, with the partial pressure of arterial carbon dioxide known to directly influence CA. Previous work has demonstrated dysautoregulation lasting around 30 s prior to the anticipated augmentation of hyperventilation-associated hypocapnia. In order assess to potential benefit of hypocapnic interventions in an acute stroke setting, minimisation of dysregulation is paramount. APPROACH: Hyperventilation strategies to induce and maintain hypocapnia were performed in 61 healthy participants, effects on temporal estimates of dynamic cerebral autoregulation (autoregulation index, ARI) were assessed to validate the most effective strategy for inducing and maintaining hypocapnia. MAIN RESULTS: The extent of initial decrease was significantly smaller in the continuous metronome strategy compared to the delayed metronome and voluntary strategies (▵ARI 0.33  ±  1.18, 2.80  ±  3.33 and 3.69  ±  2.79 respectively, p   <  0.017). SIGNIFICANCE: The use of a continuous metronome to induce hypocapnia rather than the sudden inception of an auditory stimulus appears to reduce the initial decrease in autoregulatory capacity seen in previous studies. Dysautoregulation can be minimised by continuous metronome use during hyperventilation-induced hypocapnia. This advancement in understanding of the behaviour of CA during hypocapnia permits safer delivery of CA targeted interventions, particularly in neurologically vulnerable patient populations

Inter-subject analysis of transfer function coherence in studies of dynamic cerebral autoregulation

Objective: The gain and phase of the arterial blood pressure (BP)-cerebral blood flow velocity (CBFV) relationship, assessed by transfer function analysis (TFA), are widely used dynamic cerebral autoregulation (CA) metrics, but their reliability depend on the statistical significance of the magnitude squared coherence (MSC) function. We tested a new approach, based on inter-subject data, to estimate the confidence limits of MSC. Approach: Five minute beat-to-beat time series of mean arterial BP (MAP, Finometer) and CBFV (transcranial Doppler) were used for intra-subject (MAP and CBFV from same subject) and inter-subject (BP and CBFV swapped between subjects) estimates of MSC. The 95% confidence limit of MSC was obtained by non-parametric methods for the cases of single frequency harmonics in the range [0.02-0.50 Hz], and also from the mean value of all possible frequency intervals in this range. Main results: Intra-subject estimates of MSC were obtained from 100 healthy subjects (48 female, age range: 21-82 years old) allowing calculation of 9,900 inter-subject estimates, with 95% confidence limits in excellent agreement with classical values derived from surrogate random data. Confidence limits of MSC, derived from mean values, decreased asymptotically to around 0.16 with the increasing number of harmonics averaged. Significance: Replacing estimates of MSC at a single frequency harmonic by the mean calculated over the range [0.02-0.30 Hz] could lead to more robust studies of dynamic CA with greater acceptance of recordings, an important consideration in clinical studies where measurements tend to be more susceptible to noise and artefacts.

The Short-Term Effects of Remote Ischaemic Conditioning on Cerebral Haemodynamics and Cerebral Autoregulation in Healthy Individuals

Remote Ischaemic conditioning (RIC), where brief cycles of ischaemia and reperfusion are applied to the limbs, may improve neurological outcome in acute stroke and reduce recurrent stroke. The short-term effect of RIC on the regulation of cerebral blood flow (CBF), one possible mechanism for these benefits, was investigated. Healthy participants underwent 5-minute recordings in beat-to-beat blood pressure (BP), electrocardiogram (heart rate, HR), end-tidal CO2 and cerebral blood flow velocity (CBFV) with transcranial Doppler insonation of the middle cerebral arteries, before and after four cycles of RIC using 5-min inflation of bilateral thigh cuffs followed by 5-min deflation. Mean values were calculated together with estimates for cerebrovascular resistance, transfer function analysis (TFA) and autoregulation index (ARI). Twenty-five individuals (10 male), aged 28 ± 11 years, had increases in mean and diastolic BP after RIC (113 ± 13 vs. 116 ± 13, p = 0.046; 74 ± 8 vs. 76 ± 9 mmHg, p = 0.03; respectively). Systolic and mean CBFV decreased after RIC (94.5 ± 17.7 vs. 90.0 ± 15.5, p = 0.001; 63.9 ± 11.1 vs. 62.2 ± 10.5 cm s–1, p = 0.02; respectively), as well as pulsatility index (0.77 ± 0.11 vs 0.73 ± 0.11, p = 0.001). No changes occurred in ARI. TFA showed changes in very low frequency range with significantly increased power oscillations (BP and CBFV) and reduction in phase shift (1.04 ± 0.35 vs. 0.76 ± 0.34 radians, p < 0.01). RIC using bilateral thigh cuffs achieved short-term changes to the cerebrovascular and cardiovascular systems. Further evidence is required to establish the effects in a stroke population

Reproducibility of task activation using the Addenbrooke's cognitive examination in healthy controls: A functional Transcranial Doppler ultrasonography study

Introduction Cerebral blood flow velocity (CBFv) changes occurring with cognitive stimulation can be measured by Transcranial Doppler ultrasonography (TCD). The aim of this study was to assess the reproducibility of CBFv changes to the Addenbrooke's cognitive examination (ACE-III). New method 13 volunteers underwent bilateral TCD (middle cerebral artery), continuous heart rate (HR, 3-lead ECG, Finometer), beat-to-beat mean arterial pressure (MAP, Finometer), and end-tidal CO2 (ETCO2, capnography). After 5 min baseline, all ACE-III tasks were performed in 3 domains (A/B/C). Data presented are population CBFv peak normalised changes and area under the curve (AUC). Statistical analysis was by 2-way repeated measures (ANOVA), intra-class correlation coefficient (ICC), standard error of measurement (SEM) and coefficient of variation (CV). Results 12 bilateral data sets were obtained (10 right hand dominant, 6 female). Baseline parameters (MAP, HR, ETCO2) did not differ between visits. All tasks increased CBFv. Only domain A on AUC analysis differed significantly on ANOVA, and one task on post hoc testing (p < 0.05). ICC values were poor (<0.4) for most tasks, but 3 tasks produced more consistent results on AUC and peak CBFv analysis (range ICC: 0.15–0.73, peak CV: 16.2–56.1(%), AUC CV: 23.2–60.2(%), peak SEM: 2.5–6.0 (%), AUC SEM: 21.8–135.8 (%*s). Comparison with existing methods This is the first study to examine reproducibility of CBFv changes to a complete cognitive assessment tool. Conclusions Reproducibility of CBFv measurements to the ACE-III was variable. AUC may provide more reliable estimates than peak CBFv responses. These data need validating in patient populations