Statistical analysis plan: Early mobilization by head-up tilt with stepping versus standard care after severe traumatic brain injury
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ABSTRACT: 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.
SUBMITTER: Riberholt C
PROVIDER: S-EPMC8628210 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Intensive rehabilitation of patients after severe traumatic brain injury aims to improve functional outcome. The effect of initiating rehabilitation in the early phase, in the form of head-up mobilization, is unclear. Objective: To assess whether early mobilization is feasible and safe in patients with traumatic brain injury admitted to a neurointensive care unit. Methods: This was a randomized parallel-group clinical trial, including patients with severe traumatic brain injury (Glasgow coma scale <11 and admission to the neurointensive care unit). The intervention consisted of daily mobilization on a tilt-table for 4 weeks. The control group received standard care. Outcomes were the number of included participants relative to all patients with traumatic brain injury who were approached for inclusion, the number of conducted mobilization sessions relative to all planned sessions, as well as adverse events and reactions. Information on clinical outcome was collected for exploratory purposes. Results: Thirty-eight participants were included (19 in each group), corresponding to 76% of all approached patients [95% confidence interval (CI) 63-86%]. In the intervention group, 74% [95% CI 52-89%] of planned sessions were carried out. There was no difference in the number of adverse events, serious adverse events, or adverse reactions between the groups. Conclusions: Early head-up mobilization is feasible in patients with severe traumatic brain injury. Larger randomized clinical trials are needed to explore potential benefits and harms of such an intervention. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT02924649]. Registered on 3rd October 2016.
| S-EPMC8079637 | biostudies-literature
Project description:BackgroundIntensive rehabilitation of patients with severe traumatic brain injury is generally applied in the subacute stages of the hospital stay. Few studies have assessed the association between early and intensive physical rehabilitation and functional outcomes. The aim of this trial is to assess the feasibility of an intensive physical rehabilitation intervention focusing on mobilisation to the upright position, starting as early as clinically possible versus standard care in the intensive care unit. The feasibility study is intended to inform a subsequent randomised clinical trial that will investigate benefits and harms of the intervention.MethodsThis randomised clinical feasibility trial with a follow-up period of 1 year will use blinded outcome assessors for the Coma Recovery Scale-Revised. A maximum of 60 patients admitted to the neurointensive care unit at Rigshospitalet, Denmark, with traumatic brain injury (age of at least 18 years), a low level of consciousness, and stable intracranial pressure will be included in the trial. Patients will be randomly assigned to experimental intervention versus standard care (1:1) stratified according to their Glasgow Coma Score. The intervention group will receive daily mobilisation in a tilt table with an integrated stepping device (ERIGO®). Feasibility is declared if more than 60% (the lower 95% confidence interval of the proportion) of eligible patients are included in the trial and more than 52% (the lower 95% confidence interval of the proportion) of patients in the intervention group receive more than 60% of the planned interventions. Safety is assessed by the occurrence of adverse events and adverse reactions. Exploratory clinical outcomes consist of cerebral haemodynamics (blood flow velocity and pressure autoregulation) and baroreceptor sensitivity in the early phase as well as functional outcomes (Coma Recovery Scale-Revised, Early Functional Ability scale, and Functional Independence Measure).DiscussionOur findings will inform a future, larger-scale randomised clinical trial on early mobilisation using a tilt table early after severe traumatic brain injury.Trial registrationClinicalTrials.gov identifier: NCT02924649 . Registered on 3 October 2016.
| S-EPMC6225708 | biostudies-literature
Project description: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.
| S-EPMC10116542 | biostudies-literature
Project description:Early mobilization is of importance for improving long-term outcome for patients after severe acquired brain injury. A limiting factor for early mobilization by head-up tilt is orthostatic intolerance. The purpose of the present study was to examine cerebral autoregulation in patients with severe acquired brain injury and a low level of consciousness. Fourteen patients with severe acquired brain injury and orthostatic intolerance and fifteen healthy volunteers were enrolled. Blood pressure was evaluated by pulse contour analysis, heart rate and RR-intervals were determined by electrocardiography, middle cerebral artery velocity was evaluated by transcranial Doppler, and near-infrared spectroscopy determined frontal lobe oxygenation in the supine position and during head-up tilt. Cerebral autoregulation was evaluated as the mean flow index calculated as the ratio between middle cerebral artery mean velocity and estimated cerebral perfusion pressure. Patients with acquired brain injury presented an increase in mean flow index during head-up tilt indicating impaired autoregulation (P < 0.001). Spectral analysis of heart rate variability in the frequency domain revealed lower magnitudes of ~0.1 Hz spectral power in patients compared to healthy controls suggesting baroreflex dysfunction. In conclusion, patients with severe acquired brain injury and orthostatic intolerance during head-up tilt have impaired cerebral autoregulation more than one month after brain injury.
| S-EPMC4864314 | biostudies-literature
Project description:The hypothesis that cerebrovascular autoregulation was not impaired during head-up tilt (HUT) that followed brief exposures to varying degrees of prior head-down tilt (HDT) was tested in 10 healthy young men and women. Cerebral mean flow velocity (MFV) and cardiovascular responses were measured in transitions to a 60-s period of 75° HUT that followed supine rest (control) or 15 s HDT at -10°, -25°, and -55°. During HDT, heart rate (HR) was reduced for -25° and -55°, and cardiac output was lower at -55° HDT. MFV increased during -10° HDT, but not in the other conditions even though blood pressure at the middle cerebral artery (BPMCA) increased. On the transition to HUT, HR increased only for -55° condition, but stroke volume and cardiac output transiently increased for -25° and -55°. Total peripheral resistance index decreased in proportion to the magnitude of HDT and recovered over the first 20 s of HUT. MFV was significantly less in all HDT conditions compared with the control in the first 5-s period of HUT, but it recovered quickly. An autoregulation correction index derived from MFV recovery relative to BPMCA decline revealed a delay in the first 5 s for prior HDT compared with control but then a rapid increase to briefly exceed control after -55° HDT. This study showed that cerebrovascular autoregulation is modified by but not impaired by brief HDT prior to HUT and that cerebral MFV recovered quickly and more rapidly than arterial blood pressure to protect against cerebral hypoperfusion and potential syncope.
| S-EPMC4451294 | biostudies-literature
Project description:BackgroundHUTT test is used in evaluation of syncope. Isoprenaline and isosorbide dinitrate are used to increase the sensitivity of the test. These drugs act by different mechanisms. We aimed to compare the results of isoprenaline with isosorbide dinitrate.Methods and resultsWe studied 198 subjects referred for HUTT to our institute; those above the age of 35 years were not included in our study, because isoprenaline was not used commonly above this age; thus, only 90 subjects were analyzed. We found that isosorbide dinitrate resulted in more HUTT-positive results than isoprenaline by absolute risk difference of 26%; relative risk for positive isoprenaline was 60%, confidence interval 0.38-0.93, and P value of 0.03. There was no difference in frequency of types of responses, i.e. Type 1, Type 2, and Type 3 between passive testing, isosorbide dinitrate, and isoprenaline, confidence interval 1.53-2.02, and P value 0.71. Time to get positive response was highest for passive testing followed by ISO and ISDN; the mean was 16.85±7.00min, 9.85±5.84min, and 7.00±3.35min, respectively. Statistically, ISDN versus ISO time to get positive response was not significant; P value was 0.074 and 95% confidence interval was -0.28 to 5.98.ConclusionsIsosorbide dinitrate yields more positive HUTT than isoprenaline. The frequencies of type of responses are not different between passive testing, isosorbide dinitrate, and isoprenaline. There is no difference in time taken for positive response between isosorbide dinitrate and isoprenaline. In comparison to isosorbide dinitrate and isoprenaline, passive testing showed longest time for positive response.
| S-EPMC5319004 | biostudies-literature
Project description:The incidence of syncope exhibits a daily pattern with more occurrences in the morning, possibly as a result of influences from the endogenous circadian system and/or the daily pattern of behavioral/emotional stimuli. This study tested the hypothesis that the circadian system modulates cardiovascular responses to postural stress, leading to increased susceptibility to syncope at specific times of day.Twelve subjects underwent a 13-day in-laboratory protocol in which subjects' sleep-wake cycles were adjusted to 20 hours for 12 cycles. A 15-minute tilt-table test (60° head-up) was performed ?4.5 hours after scheduled awakening in each cycle so that 12 tests in each subject were distributed evenly across the circadian cycle. Of 144 tests, signs/symptoms of presyncope were observed in 21 tests in 6 subjects. These presyncope events displayed a clear circadian rhythm (P=0.028) with almost all cases (17/21) occurring in the half of the circadian cycle corresponding to the biological night (10:30 pm to 10:30 am). Significant circadian rhythms were also observed in hemodynamic and autonomic function markers (blood pressure, heart rate, epinephrine, norepinephrine, and indices of cardiac vagal tone) that may underlie the circadian rhythm of presyncope susceptibility.The circadian system affects cardiovascular responses to postural stress, resulting in greater susceptibility to presyncope during the night. This finding suggests that night-shift workers and people with disrupted sleep at night may have greater risk of syncope as a result of their exposure to postural stress during the biological night.
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Project description:BackgroundThe Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial aims to determine whether the administration of erythropoietin to patients with moderate or severe traumatic brain injury improves patient-centred outcomes.MethodsEPO-TBI is a multicentre, blinded, randomised, parallel groups, placebo-controlled, phase III superiority trial of erythropoietin in ICU patients with traumatic brain injury conducted in Australia and New Zealand, Saudi Arabia and Europe; 606 critically ill patients aged 15 to 65 years with moderate or severe acute traumatic brain injury will be enrolled. Trial patients will receive either 40,000 IU erythropoietin or placebo by subcutaneous injection administered weekly for up to three doses during their ICU admission. The primary outcome measure is the proportion of unfavourable neurological outcomes, comprising death or severe disability, observed at 6 months following randomisation utilizing the Extended Glasgow Outcome Scale. Secondary outcomes, also assessed at 6 months following randomisation, include the probability of an equal or greater Extended Glasgow Outcome Scale level, mortality, the proportions of patients with proximal deep venous thrombosis or with composite thrombotic vascular events, as well as assessment of quality of life and cost-effectiveness. The planned sample size will allow 90% power to detect a reduction from 50% to 36% in unfavourable neurological outcomes at a two-sided alpha of 0.05.DiscussionA detailed analysis plan has been developed for EPO-TBI that is consistent with international guidelines. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses. Application of this statistical analysis plan to the forthcoming EPO-TBI trial will facilitate unbiased analyses of these important clinical data.Trial registrationAustralian New Zealand Clinical Trials Registry: ACTRN12609000827235 (22 September 2009). ClinicalTrials.gov: NCT00987454 (29 September 2009). European Drug Regulatory Authorities Clinical Trials: 2011-005235-22 (18 January 2012).
| S-EPMC4414377 | biostudies-literature
Project description:BackgroundHead-up tilt testing (HUTT), a well-established tool in the diagnosis of vasovagal syncope, is time-consuming, and every provoked vasovagal reaction may result in consolidating the reflex mechanism. Therefore, identification of parameters that could shorten the duration of HUTT and prevent fainting is desirable. Quantitative complexity theory (QCT) may provide holistic information on the cardiovascular reaction in HUTT. The aim of the present article was to evaluate the prognostic value of complexity in comparison with traditional haemodynamic parameters (HR and BP) in predicting the HUTT outcome.MethodsEighty-one healthy volunteers (74 men; mean age: 37.8 years) were included in this retrospective analysis of data collected within the project realized in Department of Cardiology and Internal Diseases, Military Institute of Medicine between January 2012 and October 2014. The subjects underwent HUTT, with beat-to-beat haemodynamic monitoring with a Niccomo™. The chosen haemodynamic parameters (including BP, HR, stroke volume, cardiac output, systemic vascular resistance) have been used in complexity analysis.ResultsHUTT was positive in 54 (66.7%) study participants. The values of complexity were already higher in fainting subjects than those were in nonfainting ones 300 s before HUTT termination (HUTT_end), with a significant upward trend starting 150 s before (pre)syncope. An area under the curve (AUC) over 0.700 was observed for complexity from 120 s before HUTT_end, with a sensitivity of 63% and specificity of 78% at this time point. The prognostic value of complexity was superior to that of the HR and mean arterial pressure (MAP).ConclusionsComplexity has been shown to be a sensitive marker of cardiovascular haemodynamic response to orthostatic stress and proved to be superior over HR and BP in predicting HUTT outcomes.
| S-EPMC8486546 | biostudies-literature
Project description:BACKGROUND:Electrocardiography (ECG) and the head-up tilt test (HUTT) are vital in clinical work-up in children with vasovagal syncope (VVS). Ventricular repolarization parameters (QT) measured during the HUTT can be indicative of electrical instability; however, these parameters are not frequently assessed. This study aimed to investigate if ventricular repolarization parameters measured during the HUTT could be indicative of future ventricular arrhythmias in children with syncope. METHODS:The shape and amplitude of the T-wave and parameters of the repolarization period (QT, QTpeak, Tpeak-Tend) were evaluated in a resting ECG performed on the first day of hospitalization and in ECGs performed during three phases of the HUTT. RESULTS:In the after-tilt phase of the HUTT, 19/30 children displayed a change in T-wave morphology. QTc was significantly longer in VVS I compared to that in VVS II patients, but not in the controls (p = 0.092). CONCLUSIONS:We need further follow-up studies to establish the clinical importance of abnormal dynamics of the repolarization period in children with VVS and negative HUTT. Therefore, children with abnormal T-wave refraction and prolonged duration of the TpTe should remain under the care of a cardiological outpatient.
| S-EPMC7143898 | biostudies-literature