Janice Collier

A very early rehabilitation trial for stroke (AVERT) phase II safety and feasibility

Background and Purpose— Very early rehabilitation, with an emphasis on mobilization, may contribute to improved outcomes after stroke. We hypothesized that a very early rehabilitation protocol would be safe and feasible. Methods— We performed a randomized, controlled trial with blinded outcome assessment. Patients at <24 hours after stroke were recruited from 2 Melbourne metropolitan stroke units. Patients were randomly assigned to receive standard care (SC) or SC plus very early mobilization (VEM) until discharge or 14 days (whichever was sooner). The primary safety outcome was the number of deaths at 3 months. The primary feasibility outcome was a higher “dose” of mobilization achieved in VEM. Secondary safety outcomes included adverse events (including falls and early neurologic deterioration), compliance with physiologic monitoring criteria, and patient fatigue after interventions. Secondary feasibility outcomes included “contamination” of standard care. Results— Overall, 18% of patients screened were suitable for recruitment. Seventy-one patients were recruited and randomized, with 2 dropouts by 12 months. The majority experienced ischemic strokes (87%). The group mean±SD age was 74.7±12.5 years, and 58% (n=41) had a National Institutes of Health Stroke Scale score >7. There was no significant difference in the number of deaths between groups (SC, 3 of 33; VEM, 8 of 38; P=0.20). Almost all deaths occurred in patients with severe stroke. Secondary safety outcomes were similar between groups. The intervention protocol was successfully delivered, achieving VEM dose targets (double SC, P=0.003) and faster time to first mobilization (P<0.001). Conclusions— VEM of patients within 24 hours of acute stroke appears safe and feasible. Intervention efficacy and cost-effectiveness are currently being tested in a large randomized, controlled trial.

Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): a randomised controlled trial.

BACKGROUND Early mobilisation after stroke is thought to contribute to the effects of stroke-unit care; however, the intervention is poorly defined and not underpinned by strong evidence. We aimed to compare the effectiveness of frequent, higher dose, very early mobilisation with usual care after stroke. METHODS We did this parallel-group, single-blind, randomised controlled trial at 56 acute stroke units in five countries. Patients (aged ≥18 years) with ischaemic or haemorrhagic stroke, first or recurrent, who met physiological criteria were randomly assigned (1:1), via a web-based computer generated block randomisation procedure (block size of six), to receive usual stroke-unit care alone or very early mobilisation in addition to usual care. Treatment with recombinant tissue plasminogen activator was allowed. Randomisation was stratified by study site and stroke severity. Patients, outcome assessors, and investigators involved in trial and data management were masked to treatment allocation. The primary outcome was a favourable outcome 3 months after stroke, defined as a modified Rankin Scale score of 0-2. We did analysis on an intention-to-treat basis. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12606000185561. FINDINGS Between July 18, 2006, and Oct 16, 2014, we randomly assigned 2104 patients to receive either very early mobilisation (n=1054) or usual care (n=1050); 2083 (99%) patients were included in the 3 month follow-up assessment. 965 (92%) patients were mobilised within 24 h in the very early mobilisation group compared with 623 (59%) patients in the usual care group. Fewer patients in the very early mobilisation group had a favourable outcome than those in the usual care group (n=480 [46%] vs n=525 [50%]; adjusted odds ratio [OR] 0·73, 95% CI 0·59-0·90; p=0·004). 88 (8%) patients died in the very early mobilisation group compared with 72 (7%) patients in the usual care group (OR 1·34, 95% CI 0·93-1·93, p=0·113). 201 (19%) patients in the very early mobilisation group and 208 (20%) of those in the usual care group had a non-fatal serious adverse event, with no reduction in immobility-related complications with very early mobilisation. INTERPRETATION First mobilisation took place within 24 h for most patients in this trial. The higher dose, very early mobilisation protocol was associated with a reduction in the odds of a favourable outcome at 3 months. Early mobilisation after stroke is recommended in many clinical practice guidelines worldwide, and our findings should affect clinical practice by refining present guidelines; however, clinical recommendations should be informed by future analyses of dose-response associations. FUNDING National Health and Medical Research Council, Singapore Health, Chest Heart and Stroke Scotland, Northern Ireland Chest Heart and Stroke, UK Stroke Association, National Institute of Health Research.

Very Early Mobilization After Stroke Fast-Tracks Return to Walking Further Results From the Phase II AVERT Randomized Controlled Trial

Background and Purpose— Regaining functional independence is an important goal for people who have experienced stroke. We hypothesized that introducing earlier and more intensive out-of-bed activity after stroke would reduce time to unassisted walking and improve independence in activities of daily living. Methods— A Very Early Rehabilitation Trial (AVERT) was a phase II randomized controlled trial. Patients with confirmed stroke (infarct or hemorrhage) admitted <24 hours after stroke and who met physiological safety criteria were eligible. Patients randomized to the very early and intensive mobilization group were mobilized within 24 hours of stroke and at regular intervals thereafter. Control patients received standard stroke unit care. The primary outcome for this analysis was the number of days required to return to walking 50 m unassisted. Secondary outcomes were the Barthel Index and Rivermead Motor Assessment at 3 and 12 months after stroke. Results— Seventy-one stroke patients with a mean age of 74.7 years were recruited from 2 hospitals. Adjusted Cox regression indicated that very early and intensive mobilization group patients returned to walking significantly faster than did standard stroke unit care controls (P=0.032; median 3.5 vs 7.0 days). Multivariable regression revealed that exposure to very early and intensive mobilization was independently associated with good functional outcome on the Barthel Index at 3 months (P=0.008) and on the Rivermead Motor Assessment at 3 (P=0.050) and 12 (P=0.024) months. Conclusions— Earlier and more intensive mobilization after stroke may fast-track return to unassisted walking and improve functional recovery. Clinical Trial Registration— This trial was not registered because enrollment began before July 2005.

Little Therapy, Little Physical Activity : Rehabilitation Within the First 14 Days of Organized Stroke Unit Care

OBJECTIVE To examine rehabilitation interventions and resulting physical activity patterns of patients managed in acute stroke units to help inform development of a randomized controlled trial of very early rehabilitation. DESIGN An open observational study of patient activity and therapist report of patient interventions. A survey of stroke unit resources. METHODS Patients less than 14 days post-stroke from 5 metropolitan stroke units were observed over 2 consecutive weekdays at 10-minute intervals between 08.00 h and 17.00 h. Physical activity, location and person(s) present were ascertained at each observation. Therapists completed treatment records. Senior staff completed stroke unit surveys. RESULTS Patients after stroke (n=58) were with therapists 5.2% of the observed day. Few patients (17.1%) received daily therapy by more than one therapist. When patients received therapy, average session times were 24 minutes of physiotherapy, 23 minutes of occupational therapy and 33 minutes of speech pathology. The more time that family members were present, the longer the treatment time. Four to 11 min of upper-limb therapy was provided. Muscle weakness and left hemiparesis were associated with less upper-limb activity. CONCLUSION These acute stroke care units were resourced according to recommended staff-patient ratios. Patients received little therapy and had low levels of physical activity.

Constraints on the kinetic, kinematic and spatiotemporal parameters of gait in Parkinson's disease

Abstract The characteristic slow, short stepped, shuffling walking pattern in Parkinsons disease (PD) results from a combination of constraints on locomotor control imposed by neurotransmitter imbalance. Previous research on the pathogenesis of gait disorders in PD has been confined to descriptions of changes in spatiotemporal parameters of the footstep pattern in response to antiparkinsonian medication and attentional strategies. By analysing the changes that occur in kinematics and kinetics with systematic manipulations of dopaminergic status and attention, a fuller understanding of the primary determinants of gait dysfunction in PD can be obtained. We illustrate this point with a case history on a 71 year old hypokinetic woman with PD who demonstrated normalisation of key kinematic and spatiotemporal variables of gait when provided with visual cues at peak-dose of the medication cycle, despite persistent abnormalities in gait kinetics. PsycINFO classification : 2330; 3297; 2520

An Enriched Environment Improves Sensorimotor Function Post-Ischemic Stroke

Objective. An enriched environment (EE) refers to conditions that facilitate or enhance sensory, cognitive, motor, and social stimulation relative to standard (laboratory) conditions. Despite numerous published studies investigating this concept in animal stroke models, there is still debate around its efficacy. The authors performed a systematic review and meta-analysis to determine the efficacy of an EE on neurobehavioral scores, learning, infarct size, and mortality in animal models of ischemic stroke. Methods. Systematic review of controlled studies of the use of an EE in experimental stroke was conducted. Data extracted were analyzed using weighted mean difference meta-analysis. For pooled tests of neurobehavioral scores, a random effects standardized method was used. Results. Animals recovering in an EE poststroke had mean neurobehavioral scores 0.9 standard deviations (95% confidence interval [CI] = 0.5-1.3; P < .001) above the mean scores of animals recovering in standard conditions and showed a trend toward improvement in learning (25.1% improvement; 95% CI = 3.7-46.6; P = .02). There was no significant increase in death. Animals exposed to an EE had 8.0% larger infarcts than control animals (95% CI = 1.8-14.1; P = .015). Conclusions. The results indicate significant improvements in sensorimotor function with EE poststroke but suggest a small increase in infarct volume. Clarification of the underlying mechanisms requires further study but should not overshadow the observed functional improvements and their application to clinical trials during stroke rehabilitation.

A very early rehabilitation trial (AVERT)

Inthedevelopedworld,oneinfourmenandoneinfivewomencan expect to suffer a stroke if they live to 85 years (1). Strokeresults in both premature death and disability however, incontrast tocoronaryheartdiseaseand cancer,its major burdenis chronicdisability rather than death (2). We know that strokepatients who have received organised multidisciplinary care inaStrokeCareUnit(SCU)environmenthavereducedmortalityand dependency (3). However, it is uncertain which compo-nents of the SCU management strategies are responsible forimproved outcomes. The strongest evidence for the benefit ofstarting mobilisation as early as possible after stroke comesfrom a post hoc analysis of the Norwegian randomized trial ofSCU vs. general medical ward care and using discharge at sixweeks as a surrogate outcome measure (4). Patients managedin the SCU (and receiving very early mobilisation, hereafterknown as VEM) were 64% less likely to be dead or disabled.Of the factors that distinguished stroke unit from generalmedical care, VEM was found to be the strongest predictor ofimprovedoutcometogetherwithbetter bloodpressurecontrol(5).Thisanalysis indicatedthatVEMmayaccountforas muchas 78% of the SCU benefit. Starting mobilisation (i.e. sittingout of bed, standing and walking) very early after stroke andcontinuing it at frequent intervals until discharge, may reducethe levelofdisabilityexperienced by strokepatients and reducethe number of patients requiring nursing home care (5).Although preliminary, the evidence from these studies hasprompted the inclusion of early mobilisation in acute strokecare best practice guidelines both in Australia (6) and inter-nationally (7). As there is only a low level of evidence tosupporttheseguidelinesthereisanobviousneedtoconductaninterventional trial of early mobilisation to determine whetherearly mobilisation of stroke patients is safe, improves out-comes and is cost effective. In order to do this we havecommenced A Very Early Rehabilitation Trial (AVERT). Ouris to determine the efficacy and cost effectiveness of this earlyintervention.AVERT differs from many previous rehabilitation trials on anumber of levels. First, it has been designed to mirror otheracute interventional trials of stroke such as thrombolysis andneuroprotection. This design objective was imperative giventhe frequently poor methodological quality of rehabilitationtrials. Second, AVERT is a large, multicentre randomisedcontrolled trial, adequately powered to detect a benefit ofsimilar magnitude to other proven interventions, with broadinclusion criteria to be assured that the result is generalisable.Finally, a detailed economic evaluation is included to allow acost effectiveness assessment to be made to assist in healthplanning and to allow comparison with other proven inter-ventions. If positivethese features should helpdrivechanges inclinical practice.The trial design is a randomised controlled trial of VEM(intervention) vs. standard care (control), with blinded assess-ment of outcome and intention-to-treat analysis.The hypothesis is that VEM of stroke patients (in addi-tion to standard care), compared with standard care alonewill:reduce death and disability at 3-month post stroke,reduce the number and severity of complications experi-enced by stroke patients,result in better quality of life at 12 months, andbe cost-effective.The study includes patients over 18 years with confirmedstroke admitted to hospital within 24h of onset of strokesymptoms. Patients must be rouseable. Patients who aremoderately to severely disabled before stroke (modified Ran-kin Scale (8) 42) will be excluded. In addition, we will excludethoseshowingrapidearlydeteriorationofsymptoms,orwithaconcurrent diagnosis of rapidly deteriorating disease (e.g.terminal cancer). Patients with unstable coronary or othermedical conditions that would impose hazard to the patientwill also be excluded. Physiological variables (e.g. heart rate,blood pressure, O

Prespecified dose-response analysis for A Very Early Rehabilitation Trial (AVERT)

Objective: Our prespecified dose-response analyses of A Very Early Rehabilitation Trial (AVERT) aim to provide practical guidance for clinicians on the timing, frequency, and amount of mobilization following acute stroke. Methods: Eligible patients were aged ≥18 years, had confirmed first (or recurrent) stroke, and were admitted to a stroke unit within 24 hours of stroke onset. Patients were randomized to receive very early and frequent mobilization, commencing within 24 hours, or usual care. We used regression analyses and Classification and Regression Trees (CART) to investigate the effect of timing and dose of mobilization on efficacy and safety outcomes, irrespective of assigned treatment group. Results: A total of 2,104 patients were enrolled, of whom 2,083 (99.0%) were followed up at 3 months. We found a consistent pattern of improved odds of favorable outcome in efficacy and safety outcomes with increased daily frequency of out-of-bed sessions (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.09 to 1.18, p < 0.001), keeping time to first mobilization and mobilization amount constant. Increased amount (minutes per day) of mobilization reduced the odds of a good outcome (OR 0.94, 95% CI 0.91 to 0.97, p < 0.001). Session frequency was the most important variable in the CART analysis, after prognostic variables age and baseline stroke severity. Conclusion: These data suggest that shorter, more frequent mobilization early after acute stroke is associated with greater odds of favorable outcome at 3 months when controlling for age and stroke severity. Classification of evidence: This study provides Class III evidence that shorter, more frequent early mobilization improves the chance of regaining independence after stroke.

Very early mobilisation and complications in the first 3 months after stroke: further results from phase II of A Very Early Rehabilitation Trial (AVERT).

Background: Interventions that may reduce the number and severity of potentially harmful post-stroke complications are desirable. This study explored whether very early and frequent mobilisation (VEM) affected complication type (immobility/stroke related), number and severity. Methods: Secondary analysis from phase II, randomised controlled trial. Patients admitted within 24 h of stroke, whose physiological parameters fell within set limits, were randomised to either VEM, commencing <24 h, or standard care. Complications to 3 months were recorded by a blinded assessor and classified by a neurologist. Analysis was intention to treat. Results: Seventy-one patients were recruited (standard care 33; VEM 38).There were no significant group differences in the number, type or severity of complications by 3 months, and most patients (81.6%) experienced one or more complications. Falls were common, while depression was absent. The multivariate analysis showed older age (OR 1.10, 95% CI: 1.02–1.18, p = 0.009) and longer length of stay (OR 1.18, 95% CI: 1.06–1.32, p = 0.002) were associated with experiencing an immobility-related complication. Conclusion: Interventions that promote recovery and reduce complications may consequently reduce length of stay. The larger phase III trial currently underway may shed light on whether increasing mobilisation reduces complications after stroke.

The effect of very early mobilisation after stroke on psychological well-being.

OBJECTIVE The immobility common to patients after acute stroke has the potential to increase negative mood symptoms. We evaluated the effect of very early mobilization after stroke on levels of depression, anxiety and irritability. DESIGN AVERT is a randomized controlled trial; patients in the very early mobilization group receive mobilization earlier (within 24 h of stroke) and more frequently than patients in the standard care group. PATIENTS Seventy-one patients with confirmed stroke were included. METHODS Patients were assessed on the Irritability, Depression and Anxiety (IDA) scale at multiple time-points. RESULTS At 7 days, very early mobilization patients were less depressed (z=2.51, p=0.012) and marginally less anxious (z=1.79, p=0.073) than standard care patients (Mann-Whitney test). Classifying IDA scores as normal or depressed, and using backward stepwise multivariable logistic regression, very early mobilization was associated with a reduced likelihood of depression at 7 days (odds ratio 0.14, 95% confidence interval 0.03-0.61; p=0.009). CONCLUSION Very early mobilization may reduce depressive symptoms in stroke patients at 7 days post-stroke.