Myths and methodologies: Assessment of dynamic cerebral autoregulation by the mean flow index.

The mean flow index-usually referred to as Mx-has been used for assessing dynamic cerebral autoregulation (dCA) for almost 30 years. However, concerns have arisen regarding methodological consistency, construct and criterion validity, and test-retest reliability. Methodological nuances, such as choice of input (cerebral perfusion pressure, invasive or non-invasive arterial pressure), pre-processing approach and artefact handling, significantly influence mean flow index values, and previous studies correlating mean flow index with other established dCA metrics are confounded by inherent methodological flaws like heteroscedasticity, while the mean flow index also fails to discriminate individuals with presumed intact versus impaired dCA (discriminatory validity), and its prognostic performance (predictive validity) across various conditions remains inconsistent. The test-retest reliability, both within and between days, is generally poor. At present, no single approach for data collection or pre-processing has proven superior for obtaining the mean flow index, and caution is advised in the further use of mean flow index-based measures for assessing dCA, as current evidence does not support their clinical application.

Test-retest reliability of transfer function analysis metrics for assessing dynamic cerebral autoregulation to spontaneous blood pressure oscillations.

Transfer function analysis (TFA) is a widely used method for assessing dynamic cerebral autoregulation in humans. In the present study, we assessed the test-retest reliability of established TFA metrics derived from spontaneous blood pressure oscillations and based on 5 min recordings. The TFA-based gain, phase and coherence in the low-frequency range (0.07-0.20 Hz) from 19 healthy volunteers, 37 patients with subarachnoid haemorrhage and 19 patients with sepsis were included. Reliability assessments included the smallest real difference (SRD) and the coefficient of variance for comparing consecutive 5 min recordings, temporally separated 5 min recordings and consecutive recordings with a minimal length of 10 min. In healthy volunteers, temporally separating the 5 min recordings led to a 0.38 (0.01-0.79) cm s-1 mmHg-1 higher SRD for gain (P = 0.032), and extending the duration of recordings did not affect the reliability. In subarachnoid haemorrhage, temporal separation led to a 0.85 (-0.13 to 1.93) cm s-1 mmHg-1 higher SRD (P = 0.047) and a 20 (-2 to 41)% higher coefficient of variance (P = 0.038) for gain, but neither metric was affected by extending the recording duration. In sepsis, temporal separation increased the SRD for phase by 94 (23-160)° (P = 0.006) but was unaffected by extending the recording. A recording duration of 8 min was required to achieve stable gain and normalized gain measures in healthy individuals, and even longer recordings were required in patients. In conclusion, a recording duration of 5 min appears insufficient for obtaining stable and reliable TFA metrics when based on spontaneous blood pressure oscillations, particularly in critically ill patients with subarachnoid haemorrhage and sepsis.

Major mistakes or errors in the use of trial sequential analysis in systematic reviews or meta-analyses - the METSA systematic review.

BACKGROUND: Systematic reviews and data synthesis of randomised clinical trials play a crucial role in clinical practice, research, and health policy. Trial sequential analysis can be used in systematic reviews to control type I and type II errors, but methodological errors including lack of protocols and transparency are cause for concern. We assessed the reporting of trial sequential analysis. METHODS: We searched Medline and the Cochrane Database of Systematic Reviews from 1 January 2018 to 31 December 2021 for systematic reviews and meta-analysis reports that include a trial sequential analysis. Only studies with at least two randomised clinical trials analysed in a forest plot and a trial sequential analysis were included. Two independent investigators assessed the studies. We evaluated protocolisation, reporting, and interpretation of the analyses, including their effect on any GRADE evaluation of imprecision. RESULTS: We included 270 systematic reviews and 274 meta-analysis reports and extracted data from 624 trial sequential analyses. Only 134/270 (50%) systematic reviews planned the trial sequential analysis in the protocol. For analyses on dichotomous outcomes, the proportion of events in the control group was missing in 181/439 (41%), relative risk reduction in 105/439 (24%), alpha in 30/439 (7%), beta in 128/439 (29%), and heterogeneity in 232/439 (53%). For analyses on continuous outcomes, the minimally relevant difference was missing in 125/185 (68%), variance (or standard deviation) in 144/185 (78%), alpha in 23/185 (12%), beta in 63/185 (34%), and heterogeneity in 105/185 (57%). Graphical illustration of the trial sequential analysis was present in 93% of the analyses, however, the Z-curve was wrongly displayed in 135/624 (22%) and 227/624 (36%) did not include futility boundaries. The overall transparency of all 624 analyses was very poor in 236 (38%) and poor in 173 (28%). CONCLUSIONS: The majority of trial sequential analyses are not transparent when preparing or presenting the required parameters, partly due to missing or poorly conducted protocols. This hampers interpretation, reproducibility, and validity. STUDY REGISTRATION: PROSPERO CRD42021273811.

Glycaemic control for patients with severe acute brain injury: Protocol for a systematic review.

BACKGROUND: Hyperglycaemia is common in patients with acute brain injury admitted to an intensive care unit (ICU). Many studies have found associations between development of hyperglycaemia and increased mortality in hospitalised patients. However, the optimal target for blood glucose control is unknown. We want to conduct a systematic review with meta-analysis and trial sequential analysis to explore the beneficial and harmful effects of restrictive versus liberal glucose control on patient outcomes in adults with severe acute brain injury. METHODS: We will systematically search medical databases including CENTRAL, Embase, MEDLINE and trial registries. We will search the following websites for ongoing or unpublished trials: http://www.controlled-trials.com/, http://www. CLINICALTRIALS: gov/, www.eudraCT.com, http://centerwatch.com/, The Cochrane Library's CENTRAL, PubMed, EMBASE, Science Citation Index Expanded and CINAHL. Two authors will independently review and select trials and extract data. We will include randomised trials comparing levels of glucose control in our analyses and observational studies will be included to address potential harms. The primary outcomes are defined as all-cause mortality, functional outcome and health-related quality of life. Secondary outcomes include serious adverse events including hypoglycaemia, length of ICU stay and duration of mechanical ventilation, and explorative outcomes including intracranial pressure and infection. Trial Sequential Analysis will be used to investigate the risk of type I error due to repetitive testing and to further explore imprecision. Quality of trials will be evaluated using the Cochrane Risk of Bias tool, and quality of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. DISCUSSION: The results of the systematic review will be disseminated through peer-reviewed publication. With the review, we hope to inform future randomised clinical trials and improve clinical practice.

Effect of controlled blood pressure increase on cerebral blood flow velocity and oxygenation in patients with subarachnoid haemorrhage.

BACKGROUND: Patients with aneurysmal subarachnoid haemorrhage (SAH) might have impaired cerebral autoregulation, that is, CBF - and thereby oxygen delivery - passively increase with an increase in CPP. This physiological study aimed to investigate the cerebral haemodynamic effects of controlled blood pressure increase in the early phase after SAH before any signs of delayed cerebral ischaemia (DCI) occurred. METHODS: The study was carried out within 5 days after ictus. Data were recorded at baseline and after 20 min of noradrenaline infusion to increase mean arterial blood pressure (MAP) by a maximum of 30 mmHg and to an absolute level of no more than 130 mmHg. The primary outcome was the difference in middle cerebral artery blood flow velocity (MCAv) measured by transcranial Doppler (TCD), while differences in intracranial pressure (ICP), brain tissue oxygen tension (PbtO2 ), and microdialysis markers of cerebral oxidative metabolism and cell injury were assessed as exploratory outcomes. Data were analysed using Wilcoxon signed-rank test with correction for multiplicity for the exploratory outcomes using the Benjamini-Hochberg correction. RESULTS: Thirty-six participants underwent the intervention 4 (median, IQR: 3-4.75) days after ictus. MAP was increased from 82 (IQR: 76-85) to 95 (IQR: 88-98) mmHg (p-value: <.001). MCAv remained stable (baseline, median 57, IQR: 46-70 cm/s; controlled blood pressure increase, median: 55, IQR: 48-71 cm/s; p-value: .054), whereas PbtO2 increased significantly (baseline, median: 24, 95%CI: 19-31 mmHg; controlled blood pressure increase, median: 27, 95%CI: 24-33 mmHg; p-value <.001). The remaining exploratory outcomes were unchanged. CONCLUSION: In this study of patients with SAH, MCAv was not significantly affected by a brief course of controlled blood pressure increase; despite this, PbtO2 increased. This suggests that autoregulation might not be impaired in these patients or other mechanisms could mediate the increase in brain oxygenation. Alternatively, a CBF increase did occur that, in turn, increased cerebral oxygenation, but was not detected by TCD. TRIAL REGISTRATION: clinicaltrials.gov (NCT03987139; 14 June 2019).

Development of muscle contractures and spasticity during subacute rehabilitation after severe acquired brain injury: a prospective cohort study.

Objective: This study investigated the development of contractures, passive stiffness, and spasticity in the ankle joint in patients with severe acquired brain injury (ABI) from admission to rehabilitation unit until 1-year post-injury compared to healthy controls. Design: An observational longitudinal cohort study Methods and procedures: Nineteen patients (26 affected ankle joints) with severe ABI >17 years old and with paresis of a lower limb admitted to sub-acute neurorehabilitation were compared to 14 healthy controls (28 ankle joints). Passive and reflex-mediated ankle joint stiffness was obtained measuring torque, range of motion, velocity and acceleration of the ankle movements. Data was collected at inclusion, after 4-5 weeks, after 8-9 weeks and at 1-year follow-up. Outcomes and results: At admittance to rehabilitation range of motion and stiffness was significantly lower compared to controls. Range of motion decreased by one degree in three weeks and passive ankle joint stiffness increased significantly by 1% per week. More patients than controls had no stretch reflex. Conclusion: Patients with severe ABI show reduced mobility and increased passive stiffness despite less spasticity in the ankle joint compared to healthy controls. Research and clinical practice should therefore focus intensively on the prevention of contractures in the ankle joint. ISRCTN17910097.

Intravenous saline administration in patients with severe acquired brain injury and orthostatic intolerance for tilt-table mobilization.

PRIMARY OBJECTIVE: This study aimed to investigate the effect of intravenous saline administration on orthostatic hypotension (OH) during head up tilt (HUT) and the change in the renin-angiotensin-aldosterone system before and after HUT in patients with severe acquired brain injury (ABI). RESEARCH DESIGN: The study is designed as an observational study. METHODS AND PROCEDURES: Fourteen patients with ABI, low level of consciousness and OH were monitored before, during and after HUT with non-invasive beat-to-beat blood pressure measurement, and transcranial Doppler determination of middle cerebral artery blood flow velocity. Blood samples were collected before and after two HUT sessions separated by 1 hour and saline was administered in between. MAIN OUTCOMES AND RESULTS: Patients' ability to stand upright did not change after saline administration due to OH. The patients showed signs of reduced cerebral autoregulation at both HUT sessions. The patients had a significant lower level of renin and angiotensin II but not aldosterone. CONCLUSIONS: Patients with severe ABI and OH demonstrate no improvement in standing time with reduced plasma renin and angiotensin II after two HUT sessions and 1 hour fluid administration. Research focusing on the ability to retain fluid after bed rest is warranted.

Use of the EXOPULSE Mollii for severe ataxia in an adult male 4 months after cardiac arrest.

The EXOPULSE Mollii is designed to reduce spasticity through low-current electrical stimulation of major muscle groups. The effect on severe cerebellar ataxia has not been investigated. This case describes the use of the EXOPULSE Mollii in an adult male with severe cerebellar ataxia 4 months after cardiac arrest and ischaemic stroke. The patient used the suit in 15 of 19 possible sessions (78.9%). He improved in the sit-to-stand test, arm function test and 10 m walking test. He described improved visual focus, ability to speak and swallow. Improvements were maintained for 1 week after the last session. The EXOPULSE Mollii is relevant to consider in the early stages of inpatient rehabilitation for patients with severe ataxia, but further research is warranted.

Mapping physical activity patterns in hospitalised patients with moderate to severe acquired brain injury - MAP-ABI: Protocol for an observational study.

Introduction: The physical activity level in patients hospitalised for rehabilitation across multiple diagnoses is low. Moderate to severe acquired brain injury further reduces activity levels as impaired physical and cognitive functioning affect mobility independence. Therefore, supervised out-of-bed mobilisation and physical activity training are essential rehabilitation strategies. Few studies have measured the physical activity patterns in the early phases of rehabilitation after moderate to severe brain injury. Objectives: To map and quantify physical activity patterns in patients admitted to brain injury rehabilitation. Further, to investigate which factors are associated with activity and if the early physical activity level is associated with functional outcome at discharge. Methods: This observational study includes patients admitted to rehabilitation after moderate to severe acquired brain injury. Mobility and physical activity patterns are measured continuously during rehabilitation at two separate seven-day periods using a wearable activity tracker. Activity will be categorised into four levels and presented descriptively. Linear and logistic regression models will analyse associations between descriptive variables and activity levels. Discussion: This protocol describes an observational study investigating patients' mobility and physical activity patterns with moderate to severe acquired brain injury during in-hospital rehabilitation. The ability to increase the amount of mobilisation and physical activity in subgroups may have profound consequences on the rehabilitation outcome. Furthermore, data from this study may be used to inform a large variety of trials investigating physical rehabilitation interventions. (NCT05571462).

Diet-induced ketosis in adult patients with subacute acquired brain injury: a feasibility study.

Background: Research in animal models on cerebral metabolism after brain injury highlights the potential benefits of ketosis in reducing secondary brain injury, but studies in humans are lacking. Aim: This study aimed to examine if a 6-week ketogenic diet intervention with added medium-chain triglycerides (MCT) was feasible in adult patients with acquired brain injury in the subacute phase, whether ketosis could be achieved and maintained, and to what extent serious adverse reactions, adverse reactions, serious adverse events, and adverse events occured. Methods: Patients ≥18 years of age diagnosed with subacute acquired brain injury and an expectation of hospitalisation ≥6 weeks were included in the intervention group. Patients not included in the intervention group were included in a standard care reference group. The intervention consisted of a ketogenic diet supplemented with MCT to obtain a plasma concentration of ß-hydroxybutyrate (BHB) ≥0.5 mmol/L. Patients who were enterally fed were given KetoCal® 2.5:1 LQ MCT Multi Fiber (Nutricia A/S, Allerød, Denmark), supplemented with Liquigen® (Nutricia A/S, Allerød, Denmark). Patients consuming oral nutrition were given KetoCal® 2.5:1 LQ MCT Multi Fiber supplemented with Liquigen®, in addition to ketogenic meals. Results: During a 13-week inclusion period, 12 of 13 eligible patients (92% [95% CI: 67% to 99%]) were included in the intervention group, and 17 of 18 excluded patients (94% [95% CI: 74% to 99%]) were included in the reference group. Eight patients (67%) completed the 6-week intervention. It took a median of 1 day to achieve ketosis from starting a 100% MCT ketogenic diet, and it was maintained for 97% of the intervention period after ketosis was obtained. There were no serious adverse reactions to the MCT ketogenic diet, and patients experienced adverse reactions not considered serious in 9.5% of days with the intervention. The MCT ketogenic diet was accepted by patients on all intervention days, and in the two patients transitioning from enteral feeding to oral intake, there were no complications related to transitioning. Conclusion: Intervention with MCT ketogenic diet is feasible and tolerated for 6 weeks in hospitalised adult patients with subacute acquired brain injury. Randomised controlled trials are needed to assess the benefits and harms of the MCT ketogenic diet and the effect on patients' recovery.Clinical trial registration: ClinicalTrials.gov, identifier [NCT04308577].

Autonomic response to early head-up tilt in patients with severe traumatic brain injury: Analysis from a randomized feasibility trial.

Patients with severe traumatic brain injury (TBI) may have autonomic dysfunction, one manifestation of which is orthostatic intolerance. This potentially impairs physical rehabilitation. However, the exact mechanisms remain elusive. In 30 patients participating in a trial of early tilt training versus standard care and 15 healthy volunteers, 5-min electrocardiography was recorded in the supine position and during 70° head-up tilt. Heart rate variability was analyzed by the low- and high-frequency (LF and HF) power, the LF-HF ratio, the total power, the ratio of the standard deviation of normal-to-normal intervals (SDNN), the root mean square of successive differences (RMSSD), the detrended fluctuations, and sample entropy. In patients in the upright compared to the supine position, SDNN (p < 0.001), RMSSD (p < 0.001), and total power (p = 0.004) all decreased, while the remaining variables were unchanged; no long-term differences in heart rate variability in the supine position were found between early tilt training and standard care. In the healthy volunteers, all measures besides SDNN and total power changed significantly between supine and upright position. In patients with severe TBI compared to healthy volunteers, several measures of heart rate variability changed differentially during mobilization from the supine to the upright position.

Major mistakes and errors in the use of Trial Sequential Analysis in systematic reviews or meta-analyses - protocol for a systematic review.

BACKGROUND: Adequately conducted systematic reviews with meta-analyses are considered the highest level of evidence and thus directly defines many clinical guidelines. However, the risks of type I and II errors in meta-analyses are substantial. Trial Sequential Analysis is a method for controlling these risks. Erroneous use of the method might lead to research waste or misleading conclusions. METHODS: The current protocol describes a systematic review aimed to identify common and major mistakes and errors in the use of Trial Sequential Analysis by evaluating published systematic reviews and meta-analyses that include this method. We plan to include all studies using Trial Sequential Analysis published from January 2018 to January 2022, an estimated 400 to 600 publications. We will search Medical Literature Analysis and Retrieval System Online and the Cochrane Database of Systematic Reviews, including studies with all types of participants, interventions, and outcomes. Two independent reviewers will screen titles and abstracts, include relevant full text articles, extract data from the studies into a predefined checklist, and evaluate the methodological quality of the study using the AMSTAR 2, assessing the methodological quality of the systematic reviews. DISCUSSION: This protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P). The identified mistakes and errors will be published in peer reviewed articles and form the basis of a reviewed guideline for the use of Trial Sequential Analysis. Appropriately controlling for type I and II errors might reduce research waste and improve quality and precision of the evidence that clinical guidelines are based upon.

Diagnostic and prognostic performance of Mxa and transfer function analysis-based dynamic cerebral autoregulation metrics.

Dynamic cerebral autoregulation is often assessed by continuously recorded arterial blood pressure (ABP) and transcranial Doppler-derived mean cerebral blood flow velocity followed by analysis in the time and frequency domain, respectively. Sequential correlation (in the time domain, yielding e.g., the measure mean flow index, Mxa) and transfer function analysis (TFA) (in the frequency domain, yielding, e.g., normalised and non-normalised gain as well as phase in the low frequency domain) are commonly used approaches. This study investigated the diagnostic and prognostic performance of these metrics. We included recordings from 48 healthy volunteers, 19 patients with sepsis, 36 with traumatic brain injury (TBI), and 14 patients admitted to a neurorehabilitation unit. The diagnostic (between healthy volunteers and patients) and prognostic performance (to predict death or poor functional outcome) of Mxa and the TFA measures were assessed by area under the receiver-operating characteristic (AUROC) curves. AUROC curves generally indicated that the measures were 'no better than chance' (AUROC ∼0.5) both for distinguishing between healthy volunteers and patient groups, and for predicting outcomes in our cohort. No metric emerged as superior for distinguishing between healthy volunteers and different patient groups, for assessing the effect of interventions, or for predicting mortality or functional outcome.

Reliability of non-invasive arterial blood pressure measurement in patients with aneurysmal subarachnoid haemorrhage.

Objective. Invasively measured arterial blood pressure (ABP) is associated with complications, while non-invasively measured ABP is generally considered risk-free. This study aimed to investigate the reliability of non-invasive ABP measured using finger-cuff volume-clamp device compared to invasive ABP measured by an arterial catheter in patients with aneurysmal subarachnoid haemorrhage (SAH).Approach. In 30 patients admitted for neurointensive care with SAH, invasive and non-invasive ABP were recorded simultaneously. Reliability was assessed for mean, diastolic and systolic ABP separately using intraclass correlation coefficient (ICC) agreement for each full period and each 3 s average.Main results.A median of 3 (IQR: 2-3) periods were included for each participant. The full periods (n = 81) showed an ICC of 0.34 (95% CI: 0.14-0.52), 0.31 (95% CI: 0.10-0.49), and 0.20 (95% CI: 0.00-0.39) for mean, diastolic, and systolic ABP, respectively. Three-second averages (n = 33 786) for mean (ICC: 0.35; 95% CI: 0.33-0.36), diastolic (ICC: 0.25; 95% CI: 0.25-0.28), and systolic ABP (ICC: 0.26; 95% CI: 0.18-0.33) yielded similar findings. Pearson's correlation coefficient showed anR2of 0.15 (p < 0.001), 0.15 (p < 0.001), 0.06 (p = 0.027) for mean, diastolic and systolic ABP, respectively.Significance.In patients with SAH, non-invasive measurement of ABP using the widely used Nano system from Finapres Medical Systems-a finger-cuff volume-clamp device (Finapres, Chennai, India) showed poor reliability and therefore cannot be used interchangeably with invasively measured ABP.

Reliability of cerebral autoregulation using different measures of perfusion pressure in patients with subarachnoid hemorrhage.

Dynamic cerebral autoregulation to spontaneous fluctuations in cerebral perfusion pressure (CPP) is often assessed by transcranial Doppler (TCD) in the time domain, yielding primarily the mean flow index (Mx), or in the frequency domain using transfer function analysis (TFA), yielding gain and phase. For both domains, the measurement of blood pressure is critical. This study assessed the inter-method reliability of dynamic cerebral autoregulation using three different methods of pressure measurement. In 39 patients with aneurysmal subarachnoid hemorrhage, non-invasive arterial blood pressure (ABP), invasive ABP (measured in the radial artery) and CPP were recorded simultaneously with TCD. Intraclass correlation coefficient (ICC) was used to quantify reliability. Mx was higher when calculated using invasive ABP (0.39; 95% confidence interval [95% CI]: 0.33; 0.44) compared to non-invasive ABP, and CPP. The overall ICC showed poor to good reliability (0.65; 95% CI: 0.11; 0.84; n = 69). In the low frequency domain, the comparison between invasively measured ABP and CPP showed good to excellent (normalized gain, ICC: 0.87, 95CI: 0.81; 0.91; n = 96; non-normalized gain: 0.89, 95% CI: 0.84; 0.92; n = 96) and moderate to good reliability (phase, ICC: 0.69, 95% CI: 0.55; 0.79; n = 96), respectively. Different methods for pressure measurement in the assessment of dynamic cerebral autoregulation yield different results and cannot be used interchangeably.

Reliability and validity of the mean flow index (Mx) for assessing cerebral autoregulation in humans: A systematic review of the methodology.

Cerebral autoregulation is a complex mechanism that serves to keep cerebral blood flow relatively constant within a wide range of cerebral perfusion pressures. The mean flow index (Mx) is one of several methods to assess dynamic cerebral autoregulation, but its reliability and validity have never been assessed systematically. The purpose of the present systematic review was to evaluate the methodology, reliability and validity of Mx.Based on 128 studies, we found inconsistency in the pre-processing of the recordings and the methods for calculation of Mx. The reliability in terms of repeatability and reproducibility ranged from poor to excellent, with optimal repeatability when comparing overlapping recordings. The discriminatory ability varied depending on the patient populations; in general, those with acute brain injury exhibited a higher Mx than healthy volunteers. The prognostic ability in terms of functional outcome and mortality ranged from chance result to moderate accuracy.Since the methodology was inconsistent between studies, resulting in varying reliability and validity estimates, the results were difficult to compare. The optimal method for deriving Mx is currently unknown.

Mobilising patients with severe acquired brain injury in intensive care (MAWERIC) - Protocol for a randomised cross-over trial.

INTRODUCTION: In the early phase after severe brain injury, patients are often bedridden in an attempt to control intracranial homeostasis; however, prolonged immobilisation may trigger complications. There is limited knowledge about the physiological effects of mobilisation in this early phase. OBJECTIVE: To investigate changes in brain tissue oxygen tension when patients are mobilised using a Sara Combilizer® in the early phase after severe brain injury, in a randomised cross-over design. METHODS: Patients with traumatic brain injury, subarachnoid haemorrhage or intracranial haematoma, will be randomised to early mobilisation or rest (no mobilisation = control) on the first day that the patient is deemed to be fit for mobilisation, and the opposite on the next day. On both days, patients will undergo continuous multimodal monitoring measuring brain tissue oxygen tension (primary outcome), invasive blood pressure, heart rate, middle cerebral artery blood flow velocity by transcranial Doppler ultrasound, intracranial pressure, and microdialysis markers of cerebral oxidative metabolism. DISCUSSION: Intensive care unit patients with acute brain injury are frequently immobilised in the early phase after the ictus. The optimal timing and intensity of mobilisation is unknown. The present study attempts to establish if early mobilisation is safe with respect to intracranial homeostasis. Protocol version 1.1. Date: 19.02.2022. Ethical registration: H-21002728; approved on August 11, 2021. GDPR registration: P-2021 - 105; approved on February 10, 2021. CLINICALTRIALS: govidentifier:NCT05038930; approved on September 8, 2021. Electronic case report file: REDCap-database; created on August 13, 2021.

Reliability of the mean flow index (Mx) for assessing cerebral autoregulation in healthy volunteers.

BACKGROUND: Mean flow index (Mxa) for evaluating dynamic cerebral autoregulation is derived using varying approaches for calculation, which may explain that the reliability ranges from poor to excellent. The comparability, repeatability, stability, and internal consistency of approaches have not previously been assessed. METHODS: We included 60 recordings from resting healthy volunteers and calculated Mxa using four different approaches: three without overlapping calculations, using intervals for averaging wave-form data (blocks) of 3, 6, and 10 s, and correlation periods (epochs) of 60, 240, and 300 s (3-60-F, 6-240-F, and 10-300-F); and one using 10-second blocks, 300 s epochs, and overlaps of 60 s (10-300-60). The comparability between the approaches was assessed using Student's t test, intraclass correlation coefficients (ICC), and Bland-Altman plot. RESULTS: Overall, 3-60-F resulted in a higher Mxa than the other indices (p < 0.001, for all). The reliability when comparing all the approaches ranged from moderate to good (ICC: 0.68; 95%CI: 0.59-0.84), which was primarily due to similarities between 10-300-F and 10-300-60 (ICC: 0.94; 95%CI: 0.86-0.98). The reliability when comparing the first and last half was poor for 10-300-F and ranged from poor to moderate for the other approaches. Additional random artifacts resulted in poor reliability for 10-300-F, while the other approaches were more stable. CONCLUSIONS: Mxa in general has a low sensitivity to artifacts, but otherwise seems highly dependent on the approach, with a repeatability that is moderate at best. The varying accuracy and precision renders Mxa unreliable for classifying impaired cerebral autoregulation when using healthy adults for comparison.

Statistical analysis plan: Early mobilization by head-up tilt with stepping versus standard care after severe traumatic brain injury.

BACKGROUND: Early mobilization on a tilt table with stepping versus standard care may be beneficial for patients with severe brain injury, but data from randomized clinical trials are lacking. This detailed statistical analysis plan describes the analyses of data collected in a randomized clinical feasibility trial for early mobilization by head-up tilt with stepping versus standard care after severe traumatic brain injury. METHODS: Primary feasibility outcomes are the proportion of included participants who were randomized out of all screened patients; the proportion of participants allocated to the experimental intervention who received at least 60% of the planned exercise sessions; and safety outcomes such as adverse events and reactions and serious adverse events and reactions. Exploratory clinical outcomes are suspected unexpected serious adverse reactions; and functional outcomes as assessed by the Coma Recovery Scale-Revised at four weeks; Early Functional Ability Scale and Functional Independence Measure at three months. The description includes the statistical analysis plan, including the use of multiple imputations and Trial Sequential Analysis.

Scoping review to identify and map non-pharmacological, non-surgical treatments for dysphagia following moderate-to-severe acquired brain injury.

INTRODUCTION: Dysphagia is a common and critical consequence of acquired brain injury (ABI) and can cause severe complications. Dysphagia rehabilitation is transforming from mainly compensatory strategies to the retraining of swallowing function using principles from neuroscience. However, there are no studies that map interventions available to retrain swallowing function in patients with moderate-to-severe ABI. OBJECTIVE: To systematically map the accessible research literature to answer the research question: Which non-surgical, non-pharmacological interventions are used in the treatment of dysphagia in patients with moderate and severe ABI in the acute and subacute phase? DESIGN: Scoping review based on the methodology of Arksey and O'Malley and methodological advancement by Levac et al. DATA SOURCES: MEDLINE, Embase, Cochrane Library, CINAHL, PsycINFO, Web of Science, OTseeker, speechBITE and PEDro were searched up until 14 March 2021. ELIGIBILITY CRITERIA: All studies reporting rehabilitative interventions within 6 months of injury for patients with moderate-to-severe ABI and dysphagia were included. DATA EXTRACTION AND SYNTHESIS: Data was extracted by two independent reviewers and studies were categorised based on treatment modality. RESULTS: A total of 21 396 records were retrieved, and a final of 26 studies were included. Interventions were categorised into cortical or non-cortical stimulation of the swallowing network. Cortical stimulation interventions were repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation. Non-cortical were complex swallowing interventions, neuromuscular electrical stimulation, pharyngeal electrical stimulation (PES), sensory stimulation, strengthening exercises and respiratory muscle training. CONCLUSION: This scoping review provides an overview of rehabilitative dysphagia interventions for patients with moderate and severe ABI, predominantly due to stroke, in the acute and subacute phase. Positive tendencies towards beneficial effects were found for rTMS, complex swallowing interventions, PES and cervical strengthening. Future studies could benefit from clear reporting of patient diagnosis and disease severity, the use of more standardised treatment protocols or algorithms and fewer but standardised outcome measures to enable comparison of effects across studies and interventions.