Very Early Mobilization in Stroke Patients Treated with Intravenous Recombinant Tissue Plasminogen Activator Scott M. Arnold, PT,* Maryane Dinkins, MS, PT,* Lesia H. Mooney, MSN, RN, CNRN,† William D. Freeman, MD,‡xjj Bhupendra Rawal, MS,{ Michael G. Heckman, MS,{ and Olivia A. Davis, OTD, OTR/L*
Background: There are limited prospective data on the relative safety of very early mobilization of stroke patients after intravenous recombinant tissue plasminogen activator (IV rtPA) in stroke patients. We hypothesized that very early patient mobilization within 24 hours after IV rtPA administration for acute ischemic stroke would be safe and feasible. Methods: The study was a prospective observational safety and feasibility study involving very early mobilization of stroke patients by physical therapy/occupational therapy within 24 hours after IV rtPA administration for treatment of ischemic stroke. A premobilization safety checklist was completed before mobilization to ensure hemodynamic stability. We assessed adverse safety events, including changes in patient symptoms, changes in vital signs, and bleeding complications. Results: Eighteen patients were enrolled in the study, and informed consent was obtained. One hundred percent of patients were evaluated with a premobilization safety checklist; 72.2% (13 of 18) were mobilized without any adverse event. Eighty-nine percent (42 of 47) of mobilization activities were tolerated without an adverse response. One patient was orthostatic, and 1 patient had transient worsening of hemiparesis. No patient had intracranial bleeding or permanent worsening of neurologic deficits. Conclusions: Very early mobilization within 24 hours of ischemic stroke for patients who receive IV rtPA appears to be relatively safe and feasible in most patients. Patients who are mobilized within 24 hours of IV rtPA require detailed neurologic and vital sign monitoring. Key Words: Early mobilization—intensive care unit—ischemic stroke—occupational therapy— physical therapy—recombinant tissue plasminogen activator. Ó 2015 by National Stroke Association
Introduction From the *Department of Rehabilitative Services; †Department of Nursing; ‡Department of Neurology; xDepartment of Critical Care; jjDivision of Neurosurgery; and {Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, Florida. Received September 5, 2014; revision received December 2, 2014; accepted January 4, 2015. This work was support by funds from the Mayo Clinic Clinical Research Subcommittee. The authors have no conflicts of interest to disclose. Address correspondence to Olivia A. Davis, OTD, OTR/L, Department of Rehabilitative Services, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.01.007
Patients with acute ischemic stroke (AIS) are routinely considered for thrombolytic intervention with intravenous recombinant tissue plasminogen activator (IV rtPA) in an effort to restore cerebral perfusion.1 Patients seeking treatment within 3-4.5 hours of onset of stroke symptoms with no evidence of cerebral hemorrhage on head computed tomography (CT) scan may be candidates for IV rtPA. Early rehabilitation efforts, including physical therapy (PT) and occupational therapy (OT), are generally recommended (level I evidence) after stroke but are not typically initiated within 24 hours after IV rtPA treatment.1 There are limited data regarding the safety of very early mobilization of post-AIS patients who receive
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2015: pp 1-6
1
S.M. ARNOLD ET AL.
2 2
IV rtPA. There is considerable variety among US hospitals regarding the timing of rehabilitation efforts for patients who have been treated with IV rtPA after stroke. Some hospitals routinely recommend bed rest for the first 24 hours after administration of IV rtPA, whereas others recommend bed rest for up to 48 hours. Some have no guidelines dictating when to initiate mobilization with this patient population. Despite the short half-life of tissue plasminogen activator (tPA), there remains a fear of mobilizing patients after treatment. tPA has a plasma half-life of less than 5 minutes, a terminal half-life of 72 minutes,3 and a plasma clearance of 380-570 mL/minute.4 Within 10 minutes of discontinuation of infusion, 80% of tPA is cleared from the circulating plasma.5 However, fibrinolytic effects can continue for several hours after administration. Cross-linked fibrin degradation products continue to rise for up to 12 hours after administration of IV rtPA indicating sustained fibrinolysis for this duration.6 A multivariate analysis of the National Institute of Neurological Disorders and Stroke IV rtPA trials found, in a total of 624 patients, that patients with severe neurologic deficits (defined as an National Institutes of Health Stroke Scale [NIHSS]7 .22), and patients aged older than 77 years were at greater risk for developing intracranial hemorrhage (ICH) after IV rtPA infusion.8 The most feared complication of IV rtPA use is ICH, which occurred in 6.4% of patients in the National Institute of Neurological Disorders and Stroke trials within 36 hours after receiving IV rtPA.8 A more recent study with a much larger subject pool (n 5 2639) found the symptomatic ICH rate to be 5.2%.9 The main concern related to the use of this drug is the fear of precipitating worsening intracranial or systemic bleeding by mobilizing stroke patients too soon; however, the effects of IV rtPA wear off in 6-8 hours, and most patients who develop intracranial bleeding do so within the first 12 hours.8 Most hospitals admit patients who have been treated with IV rtPA for AIS to the intensive care unit (ICU) given their need for frequent neurologic assessment and vital signs monitoring.1 The optimal timing of mobilization in IV rtPA–treated patients remains largely undefined. In contrast, the benefits of early mobilization, including expediting recovery, preventing deconditioning, and avoiding other undesirable complications of prolonged bed rest (eg, decubiti, venous thromboembolism, and paresis), are being demonstrated in other ICU patient populations. Studies show that earlier and more aggressive mobilization of surgical and medical ICU patients improves functional outcomes and potentially shortens ICU and hospital lengths of stay.10,11 We hypothesized that PT and OT would be safe in terms of major bleeding and other neurologic events when initiated within 24 hours after IV rtPA administration in patients with AIS.
Methods After institutional review board approval, a prospective study was conducted from June 2011 to July 2012, and formal patient consent was obtained. This study evaluated whether early mobilization, defined as mobilization between 13 and 24 hours after IV rtPA treatment of AIS, was well tolerated by patients. More specifically, the primary aim was to evaluate the safety of early patient mobilization within 24 hours after IV rtPA treatment of AIS by evaluating the proportion of patients who experienced an adverse response. Possible adverse responses included active bleeding, pallor, diaphoresis, heart rate greater than 100 bpm, systolic blood pressure (SBP) less than 90 mm Hg or greater than 180 mm Hg, diastolic blood pressure (DBP) greater than 105 mm Hg, orthostasis (defined as a reduction in SBP or mean arterial pressure [MAP] of 10 mm Hg or more after supine-to-sit transfer and/or a reduction in SBP or MAP of 20 mm Hg or more after sit-to-stand transfer), intense anxiety, pain, dizziness, syncope, and neurologic changes.
Patient Eligibility Criteria and Screening Eligible patients were aged 18 years or older, were treated for AIS with IV rtPA, and were able to actively engage in out-of-bed mobilization within 24 hours after tPA administration. Patients were excluded from the study if informed consent could not be obtained, the patient or caregiver refused the study, or the patient demonstrated hemodynamic instability. We defined hemodynamic instability as having a heart rate greater than 100 bpm and/or being hypotensive or hypertensive (SBP #90 mm Hg or $180 mm Hg; DBP $105 mm Hg). The alteplase manufacturer’s package insert recommends frequent monitoring and control of blood pressure (BP) during and after administration of IV rtPA.12 The American Heart Association and American Stroke Association recommend maintaining a BP of less than 180/105 mm Hg for 24 hours after IV rtPA administration.2 Within the study period, 287 patients were diagnosed with AIS at Mayo Clinic in Jacksonville, Florida, and IV rtPA was administered to 41 (14.3%) of these patients. Thirty patients formally consented to the study and underwent PT or OT evaluation and mobilization within 24 hours of initiation of IV rtPA treatment. The study patients later received diffusion-weighted magnetic resonance imaging at 24 hours to confirm ischemic stroke and to rule out hemorrhagic transformation. AIS was ruled out in 12 patients but was confirmed in the remaining 18 patients who were included in our final analysis.
Safety Monitoring A detailed safety checklist and a mobilization protocol were devised for patient monitoring following manufacturer safety information and the American Heart
MOBILIZATION WITHIN 24 HOURS OF THROMBOLYSIS 12
Association guidelines. This included monitoring heart rate and BP before, during, and after mobilization and inspections of percutaneous catheter insertion sites, arterial puncture sites, and wounds to verify the absence of active bleeding before and after mobilization. Patient mobilization was discontinued if a patient developed an adverse event or hemodynamic instability.
Very Early Mobilization Protocol Study patients received a protocol of very early mobilization while being monitored for adverse events. Mobilization was defined as the following rehabilitation procedures: having the patient (1) rise to sit on the side of the bed from the supine position; (2) stand at the side of the bed; (3) transfer from the bed to a bedside chair; and (4) ambulate. All activity events were evaluated by either a licensed physical or occupational therapist. Data were collected regarding patient demographics and stroke severity (age, gender, race, and NIHSS score), medication information, information related to early mobilization (heart rate; Barthel Index; pain rating; SBP and DBP while supine, sitting, and standing; intravenous line inspection results; degree of mobilization), and adverse outcomes related to mobilization as previously defined.
Statistical Analysis Numerical variables were summarized with the sample median, minimum, and maximum. Categorical variables were summarized with number and percentage. To evaluate the primary study aim of safety, we estimated the proportion of patients (and exact binomial 95% confidence interval [CI]) who experienced adverse responses, overall and individually. Statistical analyses were performed using SAS (version 9.2; SAS Institute, Inc., Cary, NC).
Results Eighteen patients were screened for early mobilization after treatment with IV rtPA from June 2011 to July 2012. Table 1. Demographic data on admission
Variables Patient characteristics Age (y) Gender (male) Race (white) NIHSS score Minor stroke (NIHSS ,7) Moderate stroke (NIHSS 7-15) Moderate/severe stroke (NIHSS .15)
Summary (n 5 18) 69 (35-89) 12 (66.7) 18 (100.0) 7 (38.9) 6 (33.3) 5 (27.8)
Abbreviation: NIHSS, National Institutes of Health Stroke Scale. The sample median (minimum-maximum) is given for numerical variables and number (%) is given for binary variables.
3
Patient demographic information is provided in Table 1. Median admission NIHSS was 12 (range, 1-23), and the most common NIHSS stroke severities were moderate stroke (44.4%) and minor stroke (38.9%). Median patient age was 69 years (range, 35-89). Twelve patients (66.7%) were men, and all patients (100%) were white. Medical histories were significant for myocardial infarction (10% of cases), stroke (10% of cases), transient ischemic attack (6.6% of cases), atrial fibrillation (23.3% of cases), hyperlipidemia (60% of cases), and hypertension (73.3% of cases). Of note, 1 subject had a history of cardiac arrest after a seizure, and 1 subject had a history of severe atherosclerotic cerebrovascular disease status after left middle cerebral artery (MCA) stent. Fifty percent of patients were nonsmokers, 33.3% of patients had a history of smoking, 6.6% were current smokers, and smoking history was unavailable for 10% of patients. Fifty percent of patients reported no current consumption of alcohol, 33.3% consumed alcohol rarely or occasionally, 3.3% reported daily alcohol consumption, and information about alcohol usage was unavailable for 13.3% of patients. Vital signs and patient symptom characteristics are shown in Table 2. While transferring from supine to sitting, 17 of 18 patients (94.4%) experienced no drop in SBP or MAP. In patients who moved from sitting to standing, 84.6% experienced no drop in SBP or MAP. All 18 study patients (100%; 95% CI, 81%-100%) were mobilized to sitting on the side of the bed, 13 (72%; 95% CI, 47%-90%) moved to standing at the side of the bed, 8 (44%; 95% CI, 22%-69%) moved out of the bed to a chair, and 8 (44%; 95% CI, 22%-69%) ambulated. The average onset of initiation of PT or OT evaluation was 19.4 hours, ranging from 13.1 to 23.8 hours after IV rtPA bolus. The average distance ambulated was 8 feet, ranging from 2 to 360 feet. Eighty-nine percent (42 of 47) of mobilization activities elicited no adverse response. Of the patients screened and mobilized, no serious adverse, permanent, or life-threating bleeding complications occurred. No patient experienced an active heart rate of greater than 100 bpm, bleeding, pallor, diaphoresis, intense anxiety, pain, syncope, intracranial bleeding, or permanent worsening of neurologic deficits. Five patients (28%; 95% CI, 10%-54%) experienced adverse responses related to early mobilization: orthostasis (n 5 3, 17%), DBP .105 mm Hg (n 5 1, 6%), dizziness (n 5 1, 6%), and neurologic signs (n 5 1, 6%; Table 3). One patient experienced both orthostasis and neurologic signs. Aside from the drops in BP, 1 patient had an increase in DBP to more than 105 mm Hg from a baseline of 93 mm Hg; 1 patient reported dizziness of unspecified duration after ambulating 20 feet with a 14-mm Hg drop in both SBP and DBP; and 1 patient experienced transient hemiparesis, which resolved without intervention within 5 minutes of returning to a supine position. The patient who had neurologic worsening had a right MCA-M1 occlusion
S.M. ARNOLD ET AL.
4
Table 2. Baseline patient characteristics before mobilization Variable
Table 3. Safety and adverse responses data during monitoring period
Summary (n 5 18)
Heart rate 78 (57, 91) Barthel Index 0-20 3 (16.7) 21-40 1 (5.6) 41-60 5 (27.8) 61-80 1 (5.6) 81-100 8 (44.4) Pain rating score 0 12 (70.6) 3 1 (5.9) 4 2 (11.8) 8 1 (5.9) 10 1 (5.9) Supine SBP 144 (104, 173) Supine DBP 79 (60, 94) Supine MAP 104 (73, 119) Sitting SBP 149 (111, 179) Sitting DBP 86 (58, 129) Sitting MAP 106 (84, 139) Drop in SBP or MAP while transferring from supine to sitting Drop of 10 1 (5.6) No drop 17 (94.4) Standing SBP 130 (91, 168) Standing DBP 85 (60, 100) Standing MAP 96 (73, 110) Drop in SBP or MAP while transferring from sitting to standing Drop of 20 2 (15.4) No drop 11 (84.6) INT inspection before clean, dry, 16 (88.9) intact INT inspection after clean, dry, 16 (88.9) intact Mobilization Sitting on side of bed 18 (100.0) Standing at side of bed 13 (72.2) Out of bed to chair 8 (44.4) Ambulation 8 (44.4) Number of feet ambulated 8 (2, 360) Time from IV rtPA bolus to 19.4 (13.1, 23.8) PT/OT initiation (h) Abbreviations: DBP, diastolic blood pressure; INT, IV site; IV rtPA, intravenous recombinant tissue plasminogen activator; MAP, mean arterial pressure; OT, occupational therapy; PT, physical therapy; SBP, systolic blood pressure. The sample median (minimum, maximum) is given for numerical variables and number (%) is given for categorical variables. Information was unavailable for the following variables: pain rating scores (n 5 1), standing SBP (n 5 5), standing DBP (n 5 5), standing MAP (n 5 5), and drop in SBP or MAP while transferring from sitting to standing (n 5 5).
Adverse response Any adverse response (including orthostasis) Any adverse response (excluding orthostasis) Individual adverse responses Orthostasis* DBP .105 Dizziness Heart rate .100 Neurologic signsy Active bleeding Pallor Diaphoresis Intense anxiety Pain Syncope
Number (%) of patients (n 5 18)
95% CI
5 (27.8)
9.7-53.5
3 (16.7)
3.6-41.4
3 (16.7) 1 (5.6) 1 (5.6) 0 (.0) 1 (5.6) 0 (.0) 0 (.0) 0 (.0) 0 (.0) 0 (.0) 0 (.0)
3.6-41.4 .1-27.3 .1-27.3 .0-18.5 .1-27.3 .0-18.5 .0-18.5 .0-18.5 .0-18.5 .0-18.5 .0-18.5
Abbreviations: CI, confidence interval; DBP, diastolic blood pressure; SBP, systolic blood pressure. *Orthostasis 5 10 mm Hg drop in SBP from supine to sitting or 20 mm Hg drop in SBP from sitting to standing. yTransient hemiparesis which resolved within 8 minutes of return to supine without intervention.
on CT angiogram imaging from a cardioembolic stroke from atrial fibrillation with an initial NIHSS of 13. She had a large mismatched area of the right MCA territory on perfusion-weighted imaging. She received IV rtPA an hour after onset and had marked clinical improvement about 12 hours after rtPA was administered. Her NIHSS went from 13 to 8, and 24 hours later, it was 0. During study mobilization, her supine BP was 156/61 mm Hg. Sitting BP was 159/63. Standing BP was 117/71 when she developed symptoms of new onset left upper extremity weakness. She was placed back in bed, head laid flat, and her symptoms resolved in less than 5 minutes. The doctor was contacted. Repeat supine BP was 151/65. She had no permanent residual symptoms and was later rehabilitated with PT and OT services without further incidents. Her episode was deemed because of impaired cerebral autoregulation because the rtPA had initially occluded her right MCA-M1 segment, which later recanalized. Also, the patient was mildly anemic (hemoglobin 10.1, normal .13) at the time and was later found to have iron deficiency anemia, which improved with iron supplementation (.1 month after discharge). No carotid occlusion was noted on carotid ultrasounds. The patient had a repeat CT angiogram and perfusion imaging, which
MOBILIZATION WITHIN 24 HOURS OF THROMBOLYSIS
showed recanalization of her right MCA-M1 thrombus with only some tiny areas of infarction within the basal ganglia and caudate. No hemorrhage occurred on imaging. She was later placed on warfarin after a few weeks of aspirin for stroke prevention (congestive heart failure, hypertension, age 5 75 years, diabetes mellitus, stroke scale of 3; 2 points for stroke and 1 point for hypertension). A closer look at the 5 patients who experienced any type of adverse response in our study is warranted. One patient (6%) experienced a DBP greater than 105 mm Hg with no accompanying symptoms. Of note, the patient’s DBP was 93 mm Hg before mobilization. Another patient reported ‘‘dizziness’’ with a corresponding 14 mm Hg decrease in both SBP and DBP after ambulating 20 feet. As dizziness was listed as an anticipated adverse response, mobilization was terminated. Complaints of dizziness alone, without conclusive evidence of orthostasis, may be an insufficient indicator of adverse response. One patient demonstrated transient neurologic worsening, including new onset of hemiparesis that resolved within several minutes of onset. The patient’s modified Rankin Scale several days after the stroke event was 2 (slight disability); this improved to 1 (no significant disability) by 30 days after ictus.
Discussion Recently, more literature has cited improved patient outcomes for patients who receive earlier, more aggressive mobilization and have indicated that such mobilization reduces complications, shortens ICU/hospital lengths of stay, and improves functional outcomes.10,11,13-16 Health care providers treating patients after tPA currently have limited evidence-based data to inform optimal initiation of safe patient mobilization1618 ; patient physical activity is often restricted19 despite the lack of specific clinical evidence to support this prolonged immobilization. Reasons for this immobilization are unclear. In one survey of stroke unit physicians and nurses, 85% reported fear of patient falls and 74% reported fear of worsening neurologic symptoms as factors influencing their decisions about early mobilization after IV rtPA.19 Often, orthostatic hypotension and the potential for resultant syncope are concerns related to patient mobilization into more upright postures. However, it has been suggested that upright positioning and mobilization after mild and moderate AIS do not lead to detrimental reductions in BP.20 Our study provides prospective observational data about the safety of patient mobilization within 24 hours after receiving tPA, which may provide a foundation for development of future treatment guidelines. Over 72% of patients tolerated mobilization within 24 hours after receiving tPA infusion without any adverse event or symptoms. Reported or observed adverse responses were mild, transient, and
5
non–life threatening. Study limitations include small sample size, lack of a control group, and no attempt to control for comorbidities. Several studies describe early stroke rehabilitative interventions, but few describe early mobilization initiated less than 24 hours after onset of stroke.21-24 One study examining the safety of early mobilization of patients experiencing any type of stroke is the A Very Early Rehabilitation Trial multiphase study. During its phase II safety and feasibility trial, investigators reported on 38 of 71 patients mobilized within 24 hours of stroke onset25; no significant differences in number, type, or severity of complications were seen between the early mobilization group and the standard care group.26 In another study, 156 patients with ischemic stroke were mobilized within 24 hours of symptom onset.24 Study authors concluded that no contraindications to early mobilization were identified. Furthermore, a significant rise in BP during early upright positioning (ie, sitting in bed with the head of bed at 70 and active standing) was independently associated with a favorable functional outcome 3 months after stroke (#1 on the modified Rankin Scale). Our study is the first, to our knowledge, to specifically address early mobilization of patients treated with tPA. Although underpowered to make generalizations, it offers a framework to build practice guidelines. Developing guidelines for optimal timing of mobilization will require larger studies. The ongoing A Very Early Rehabilitation Trial Phase III is expected to enroll approximately 380 patients treated with tPA, and approximately half of those patients are anticipated to be mobilized early. The authors of the present study welcome such larger studies to aid in the development of protocols guiding clinical decision making with this unique population.
Conclusion Early mobilization in AIS patients after IV rtPA has the potential to reduce hospital and ICU lengths of stay, reduce overall hospital costs, and start an earlier, more aggressive poststroke rehabilitation process. Implementation of a very early patient mobilization program after IV rtPA represents a relatively low-cost, easily implementable intervention that many hospitals can consider.27 The underutilization of intravenous tPA may be due in part to fears of adverse events.28-30 The present study represents a step toward the establishment of safety data to minimize the fears of mobilization after tPA administration and the development of future protocols for mobilization earlier than 24 hours after IV rtPA administration for stroke.
References 1. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the
S.M. ARNOLD ET AL.
6
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
American Heart Association/American Stroke Association. Stroke 2013;44:870-947. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation 2007;115:e478-534. Genentech Inc. Cathflo Activase [Alteplase]. Available at: http://www.fda.gov/downloads/Drugs/Development ApprovalProcess/HowDrugsareDevelopedandApproved/ ApprovalApplications/TherapeuticBiologicApplications/ ucm088609.pdf; 2001. Accessed March 20, 2013. Genentech Inc. Activase [Alteplase]. Available at: http:// www.gene.com/download/pdf/activase_prescribing.pdf; 2011. Accessed March 20, 2013. Covill L, Ronnebaum J. Mobilization of patients status post acute ischemic stroke treated with tissue plasminogen activator: using the evidence for clinical decision making. Acute Care Perspectives 2008;17:7-9. Eisenberg PR, Sherman LA, Tiefenbrunn AJ, et al. Sustained fibrinolysis after administration of t-PA despite its short half-life in the circulation. Thromb Haemost 1987;57:35-40. Adams HP Jr, Davis PH, Leira EC, et al. Baseline NIH Stroke Scale score strongly predicts outcome after stroke: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology 1999;53:126-131. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333:1581-1587. Graham GD. Tissue plasminogen activator for acute ischemic stroke in clinical practice: a meta-analysis of safety data. Stroke 2003;34:2847-2850. Morris PE, Goad A, Thompson C, et al. Early intensive care unit mobility therapy in the treatment of acute respiratory failure. Crit Care Med 2008;36:2238-2243. Needham DM. Mobilizing patients in the intensive care unit: improving neuromuscular weakness and physical function. Jama 2008;300:1685-1690. Genentech Inc. Activase [Alteplase]. Available at: http:// www.gene.com/gene/products/information/cardiovas cular/activase/insert.jsp; 2005. Accessed March 20, 2013. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 2009;373:1874-1882. Bailey P, Thomsen GE, Spuhler VJ, et al. Early activity is feasible and safe in respiratory failure patients. Crit Care Med 2007;35:139-145. Sherman DG, Albers GW, Bladin C, et al. The efficacy and safety of enoxaparin versus unfractionated heparin for
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27. 28.
29.
30.
the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison. Lancet 2007;369:1347-1355. Cumming TB, Thrift AG, Collier JM, et al. Very early mobilization after stroke fast-tracks return to walking: further results from the phase II AVERT randomized controlled trial. Stroke 2011;42:153-158. Bernhardt J. Very early mobilization following acute stroke: controversies, the unknowns, and a way forward. Ann Indian Acad Neurol 2008;11:88-98. Bernhardt J, Cumming TB, Ha J. Response to letter by Freeman et al regarding article, ‘‘Very early mobilization after stroke fast-tracks return to walking: further results from the phase II AVERT randomized controlled trial’’. Stroke 2011;42:e585. Ha J, Churilov L, Linden T, et al. Bed rest or mobilization after rt-PA? A case-crossover study of factors influencing clinical decision making in stroke services. Int J Stroke 2013;8:172-179. Panayiotou B, Reid J, Fotherby M, et al. Orthostatic haemodynamic responses in acute stroke. Postgrad Med J 1999;75:213-218. Indredavik B, Loege AD, Rohweder G, et al. Early mobilisation of acute stroke patients is tolerated well, increases mean blood pressure and oxygen saturation and improves level of consciousness. Cerebrovasc Dis 2007;23:9. Gillick BT, Marshall WJ, Rheault W, et al. Mobility criteria for upright sitting with patients in the neuro/trauma intensive care unit: an analysis of length of stay and functional outcomes. Neurohospitalist 2011;1:172-177. Diserens K, Moreira T, Hirt L, et al. Early mobilization out of bed after ischaemic stroke reduces severe complications but not cerebral blood flow: a randomized controlled pilot trial. Clin Rehabil 2012;26:451-459. Aries MJ, Bakker DC, Stewart RE, et al. Exaggerated postural blood pressure rise is related to a favorable outcome in patients with acute ischemic stroke. Stroke 2012;43:92-96. Bernhardt J, Dewey H, Thrift A, et al. A very early rehabilitation trial for stroke (AVERT): phase II safety and feasibility. Stroke 2008;39:390-396. Sorbello D, Dewey HM, Churilov L, et al. Very early mobilisation and complications in the first 3 months after stroke: further results from phase II of A Very Early Rehabilitation Trial (AVERT). Cerebrovasc Dis 2009;28: 378-383. Bernhardt J, Indredavik B, Langhorne P. When should rehabilitation begin after stroke? Int J Stroke 2013;8:5-7. Liang BA, Lew R, Zivin JA. Review of tissue plasminogen activator, ischemic stroke, and potential legal issues. Arch Neurol 2008;65:1429-1433. Demaerschalk BM. Thrombolytic therapy for acute ischemic stroke: the likelihood of being helped versus harmed. Stroke 2007;38:2215-2216. Brown DL, Barsan WG, Lisabeth LD, et al. Survey of emergency physicians about recombinant tissue plasminogen activator for acute ischemic stroke. Ann Emerg Med 2005;46:56-60.
Background: There are limited prospective data on the relative safety of very early mobilization of stroke patients after intravenous recombinant tissue plasminogen activator (IV rtPA) in stroke patients. We hypothesized that very early patient mobilization within 24 hours after IV rtPA administration for acute ischemic stroke would be safe and feasible. Methods: The study was a prospective observational safety and feasibility study involving very early mobilization of stroke patients by physical therapy/occupational therapy within 24 hours after IV rtPA administration for treatment of ischemic stroke. A premobilization safety checklist was completed before mobilization to ensure hemodynamic stability. We assessed adverse safety events, including changes in patient symptoms, changes in vital signs, and bleeding complications. Results: Eighteen patients were enrolled in the study, and informed consent was obtained. One hundred percent of patients were evaluated with a premobilization safety checklist; 72.2% (13 of 18) were mobilized without any adverse event. Eighty-nine percent (42 of 47) of mobilization activities were tolerated without an adverse response. One patient was orthostatic, and 1 patient had transient worsening of hemiparesis. No patient had intracranial bleeding or permanent worsening of neurologic deficits. Conclusions: Very early mobilization within 24 hours of ischemic stroke for patients who receive IV rtPA appears to be relatively safe and feasible in most patients. Patients who are mobilized within 24 hours of IV rtPA require detailed neurologic and vital sign monitoring. Key Words: Early mobilization—intensive care unit—ischemic stroke—occupational therapy— physical therapy—recombinant tissue plasminogen activator. Ó 2015 by National Stroke Association
Introduction From the *Department of Rehabilitative Services; †Department of Nursing; ‡Department of Neurology; xDepartment of Critical Care; jjDivision of Neurosurgery; and {Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, Florida. Received September 5, 2014; revision received December 2, 2014; accepted January 4, 2015. This work was support by funds from the Mayo Clinic Clinical Research Subcommittee. The authors have no conflicts of interest to disclose. Address correspondence to Olivia A. Davis, OTD, OTR/L, Department of Rehabilitative Services, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.01.007
Patients with acute ischemic stroke (AIS) are routinely considered for thrombolytic intervention with intravenous recombinant tissue plasminogen activator (IV rtPA) in an effort to restore cerebral perfusion.1 Patients seeking treatment within 3-4.5 hours of onset of stroke symptoms with no evidence of cerebral hemorrhage on head computed tomography (CT) scan may be candidates for IV rtPA. Early rehabilitation efforts, including physical therapy (PT) and occupational therapy (OT), are generally recommended (level I evidence) after stroke but are not typically initiated within 24 hours after IV rtPA treatment.1 There are limited data regarding the safety of very early mobilization of post-AIS patients who receive
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2015: pp 1-6
1
S.M. ARNOLD ET AL.
2 2
IV rtPA. There is considerable variety among US hospitals regarding the timing of rehabilitation efforts for patients who have been treated with IV rtPA after stroke. Some hospitals routinely recommend bed rest for the first 24 hours after administration of IV rtPA, whereas others recommend bed rest for up to 48 hours. Some have no guidelines dictating when to initiate mobilization with this patient population. Despite the short half-life of tissue plasminogen activator (tPA), there remains a fear of mobilizing patients after treatment. tPA has a plasma half-life of less than 5 minutes, a terminal half-life of 72 minutes,3 and a plasma clearance of 380-570 mL/minute.4 Within 10 minutes of discontinuation of infusion, 80% of tPA is cleared from the circulating plasma.5 However, fibrinolytic effects can continue for several hours after administration. Cross-linked fibrin degradation products continue to rise for up to 12 hours after administration of IV rtPA indicating sustained fibrinolysis for this duration.6 A multivariate analysis of the National Institute of Neurological Disorders and Stroke IV rtPA trials found, in a total of 624 patients, that patients with severe neurologic deficits (defined as an National Institutes of Health Stroke Scale [NIHSS]7 .22), and patients aged older than 77 years were at greater risk for developing intracranial hemorrhage (ICH) after IV rtPA infusion.8 The most feared complication of IV rtPA use is ICH, which occurred in 6.4% of patients in the National Institute of Neurological Disorders and Stroke trials within 36 hours after receiving IV rtPA.8 A more recent study with a much larger subject pool (n 5 2639) found the symptomatic ICH rate to be 5.2%.9 The main concern related to the use of this drug is the fear of precipitating worsening intracranial or systemic bleeding by mobilizing stroke patients too soon; however, the effects of IV rtPA wear off in 6-8 hours, and most patients who develop intracranial bleeding do so within the first 12 hours.8 Most hospitals admit patients who have been treated with IV rtPA for AIS to the intensive care unit (ICU) given their need for frequent neurologic assessment and vital signs monitoring.1 The optimal timing of mobilization in IV rtPA–treated patients remains largely undefined. In contrast, the benefits of early mobilization, including expediting recovery, preventing deconditioning, and avoiding other undesirable complications of prolonged bed rest (eg, decubiti, venous thromboembolism, and paresis), are being demonstrated in other ICU patient populations. Studies show that earlier and more aggressive mobilization of surgical and medical ICU patients improves functional outcomes and potentially shortens ICU and hospital lengths of stay.10,11 We hypothesized that PT and OT would be safe in terms of major bleeding and other neurologic events when initiated within 24 hours after IV rtPA administration in patients with AIS.
Methods After institutional review board approval, a prospective study was conducted from June 2011 to July 2012, and formal patient consent was obtained. This study evaluated whether early mobilization, defined as mobilization between 13 and 24 hours after IV rtPA treatment of AIS, was well tolerated by patients. More specifically, the primary aim was to evaluate the safety of early patient mobilization within 24 hours after IV rtPA treatment of AIS by evaluating the proportion of patients who experienced an adverse response. Possible adverse responses included active bleeding, pallor, diaphoresis, heart rate greater than 100 bpm, systolic blood pressure (SBP) less than 90 mm Hg or greater than 180 mm Hg, diastolic blood pressure (DBP) greater than 105 mm Hg, orthostasis (defined as a reduction in SBP or mean arterial pressure [MAP] of 10 mm Hg or more after supine-to-sit transfer and/or a reduction in SBP or MAP of 20 mm Hg or more after sit-to-stand transfer), intense anxiety, pain, dizziness, syncope, and neurologic changes.
Patient Eligibility Criteria and Screening Eligible patients were aged 18 years or older, were treated for AIS with IV rtPA, and were able to actively engage in out-of-bed mobilization within 24 hours after tPA administration. Patients were excluded from the study if informed consent could not be obtained, the patient or caregiver refused the study, or the patient demonstrated hemodynamic instability. We defined hemodynamic instability as having a heart rate greater than 100 bpm and/or being hypotensive or hypertensive (SBP #90 mm Hg or $180 mm Hg; DBP $105 mm Hg). The alteplase manufacturer’s package insert recommends frequent monitoring and control of blood pressure (BP) during and after administration of IV rtPA.12 The American Heart Association and American Stroke Association recommend maintaining a BP of less than 180/105 mm Hg for 24 hours after IV rtPA administration.2 Within the study period, 287 patients were diagnosed with AIS at Mayo Clinic in Jacksonville, Florida, and IV rtPA was administered to 41 (14.3%) of these patients. Thirty patients formally consented to the study and underwent PT or OT evaluation and mobilization within 24 hours of initiation of IV rtPA treatment. The study patients later received diffusion-weighted magnetic resonance imaging at 24 hours to confirm ischemic stroke and to rule out hemorrhagic transformation. AIS was ruled out in 12 patients but was confirmed in the remaining 18 patients who were included in our final analysis.
Safety Monitoring A detailed safety checklist and a mobilization protocol were devised for patient monitoring following manufacturer safety information and the American Heart
MOBILIZATION WITHIN 24 HOURS OF THROMBOLYSIS 12
Association guidelines. This included monitoring heart rate and BP before, during, and after mobilization and inspections of percutaneous catheter insertion sites, arterial puncture sites, and wounds to verify the absence of active bleeding before and after mobilization. Patient mobilization was discontinued if a patient developed an adverse event or hemodynamic instability.
Very Early Mobilization Protocol Study patients received a protocol of very early mobilization while being monitored for adverse events. Mobilization was defined as the following rehabilitation procedures: having the patient (1) rise to sit on the side of the bed from the supine position; (2) stand at the side of the bed; (3) transfer from the bed to a bedside chair; and (4) ambulate. All activity events were evaluated by either a licensed physical or occupational therapist. Data were collected regarding patient demographics and stroke severity (age, gender, race, and NIHSS score), medication information, information related to early mobilization (heart rate; Barthel Index; pain rating; SBP and DBP while supine, sitting, and standing; intravenous line inspection results; degree of mobilization), and adverse outcomes related to mobilization as previously defined.
Statistical Analysis Numerical variables were summarized with the sample median, minimum, and maximum. Categorical variables were summarized with number and percentage. To evaluate the primary study aim of safety, we estimated the proportion of patients (and exact binomial 95% confidence interval [CI]) who experienced adverse responses, overall and individually. Statistical analyses were performed using SAS (version 9.2; SAS Institute, Inc., Cary, NC).
Results Eighteen patients were screened for early mobilization after treatment with IV rtPA from June 2011 to July 2012. Table 1. Demographic data on admission
Variables Patient characteristics Age (y) Gender (male) Race (white) NIHSS score Minor stroke (NIHSS ,7) Moderate stroke (NIHSS 7-15) Moderate/severe stroke (NIHSS .15)
Summary (n 5 18) 69 (35-89) 12 (66.7) 18 (100.0) 7 (38.9) 6 (33.3) 5 (27.8)
Abbreviation: NIHSS, National Institutes of Health Stroke Scale. The sample median (minimum-maximum) is given for numerical variables and number (%) is given for binary variables.
3
Patient demographic information is provided in Table 1. Median admission NIHSS was 12 (range, 1-23), and the most common NIHSS stroke severities were moderate stroke (44.4%) and minor stroke (38.9%). Median patient age was 69 years (range, 35-89). Twelve patients (66.7%) were men, and all patients (100%) were white. Medical histories were significant for myocardial infarction (10% of cases), stroke (10% of cases), transient ischemic attack (6.6% of cases), atrial fibrillation (23.3% of cases), hyperlipidemia (60% of cases), and hypertension (73.3% of cases). Of note, 1 subject had a history of cardiac arrest after a seizure, and 1 subject had a history of severe atherosclerotic cerebrovascular disease status after left middle cerebral artery (MCA) stent. Fifty percent of patients were nonsmokers, 33.3% of patients had a history of smoking, 6.6% were current smokers, and smoking history was unavailable for 10% of patients. Fifty percent of patients reported no current consumption of alcohol, 33.3% consumed alcohol rarely or occasionally, 3.3% reported daily alcohol consumption, and information about alcohol usage was unavailable for 13.3% of patients. Vital signs and patient symptom characteristics are shown in Table 2. While transferring from supine to sitting, 17 of 18 patients (94.4%) experienced no drop in SBP or MAP. In patients who moved from sitting to standing, 84.6% experienced no drop in SBP or MAP. All 18 study patients (100%; 95% CI, 81%-100%) were mobilized to sitting on the side of the bed, 13 (72%; 95% CI, 47%-90%) moved to standing at the side of the bed, 8 (44%; 95% CI, 22%-69%) moved out of the bed to a chair, and 8 (44%; 95% CI, 22%-69%) ambulated. The average onset of initiation of PT or OT evaluation was 19.4 hours, ranging from 13.1 to 23.8 hours after IV rtPA bolus. The average distance ambulated was 8 feet, ranging from 2 to 360 feet. Eighty-nine percent (42 of 47) of mobilization activities elicited no adverse response. Of the patients screened and mobilized, no serious adverse, permanent, or life-threating bleeding complications occurred. No patient experienced an active heart rate of greater than 100 bpm, bleeding, pallor, diaphoresis, intense anxiety, pain, syncope, intracranial bleeding, or permanent worsening of neurologic deficits. Five patients (28%; 95% CI, 10%-54%) experienced adverse responses related to early mobilization: orthostasis (n 5 3, 17%), DBP .105 mm Hg (n 5 1, 6%), dizziness (n 5 1, 6%), and neurologic signs (n 5 1, 6%; Table 3). One patient experienced both orthostasis and neurologic signs. Aside from the drops in BP, 1 patient had an increase in DBP to more than 105 mm Hg from a baseline of 93 mm Hg; 1 patient reported dizziness of unspecified duration after ambulating 20 feet with a 14-mm Hg drop in both SBP and DBP; and 1 patient experienced transient hemiparesis, which resolved without intervention within 5 minutes of returning to a supine position. The patient who had neurologic worsening had a right MCA-M1 occlusion
S.M. ARNOLD ET AL.
4
Table 2. Baseline patient characteristics before mobilization Variable
Table 3. Safety and adverse responses data during monitoring period
Summary (n 5 18)
Heart rate 78 (57, 91) Barthel Index 0-20 3 (16.7) 21-40 1 (5.6) 41-60 5 (27.8) 61-80 1 (5.6) 81-100 8 (44.4) Pain rating score 0 12 (70.6) 3 1 (5.9) 4 2 (11.8) 8 1 (5.9) 10 1 (5.9) Supine SBP 144 (104, 173) Supine DBP 79 (60, 94) Supine MAP 104 (73, 119) Sitting SBP 149 (111, 179) Sitting DBP 86 (58, 129) Sitting MAP 106 (84, 139) Drop in SBP or MAP while transferring from supine to sitting Drop of 10 1 (5.6) No drop 17 (94.4) Standing SBP 130 (91, 168) Standing DBP 85 (60, 100) Standing MAP 96 (73, 110) Drop in SBP or MAP while transferring from sitting to standing Drop of 20 2 (15.4) No drop 11 (84.6) INT inspection before clean, dry, 16 (88.9) intact INT inspection after clean, dry, 16 (88.9) intact Mobilization Sitting on side of bed 18 (100.0) Standing at side of bed 13 (72.2) Out of bed to chair 8 (44.4) Ambulation 8 (44.4) Number of feet ambulated 8 (2, 360) Time from IV rtPA bolus to 19.4 (13.1, 23.8) PT/OT initiation (h) Abbreviations: DBP, diastolic blood pressure; INT, IV site; IV rtPA, intravenous recombinant tissue plasminogen activator; MAP, mean arterial pressure; OT, occupational therapy; PT, physical therapy; SBP, systolic blood pressure. The sample median (minimum, maximum) is given for numerical variables and number (%) is given for categorical variables. Information was unavailable for the following variables: pain rating scores (n 5 1), standing SBP (n 5 5), standing DBP (n 5 5), standing MAP (n 5 5), and drop in SBP or MAP while transferring from sitting to standing (n 5 5).
Adverse response Any adverse response (including orthostasis) Any adverse response (excluding orthostasis) Individual adverse responses Orthostasis* DBP .105 Dizziness Heart rate .100 Neurologic signsy Active bleeding Pallor Diaphoresis Intense anxiety Pain Syncope
Number (%) of patients (n 5 18)
95% CI
5 (27.8)
9.7-53.5
3 (16.7)
3.6-41.4
3 (16.7) 1 (5.6) 1 (5.6) 0 (.0) 1 (5.6) 0 (.0) 0 (.0) 0 (.0) 0 (.0) 0 (.0) 0 (.0)
3.6-41.4 .1-27.3 .1-27.3 .0-18.5 .1-27.3 .0-18.5 .0-18.5 .0-18.5 .0-18.5 .0-18.5 .0-18.5
Abbreviations: CI, confidence interval; DBP, diastolic blood pressure; SBP, systolic blood pressure. *Orthostasis 5 10 mm Hg drop in SBP from supine to sitting or 20 mm Hg drop in SBP from sitting to standing. yTransient hemiparesis which resolved within 8 minutes of return to supine without intervention.
on CT angiogram imaging from a cardioembolic stroke from atrial fibrillation with an initial NIHSS of 13. She had a large mismatched area of the right MCA territory on perfusion-weighted imaging. She received IV rtPA an hour after onset and had marked clinical improvement about 12 hours after rtPA was administered. Her NIHSS went from 13 to 8, and 24 hours later, it was 0. During study mobilization, her supine BP was 156/61 mm Hg. Sitting BP was 159/63. Standing BP was 117/71 when she developed symptoms of new onset left upper extremity weakness. She was placed back in bed, head laid flat, and her symptoms resolved in less than 5 minutes. The doctor was contacted. Repeat supine BP was 151/65. She had no permanent residual symptoms and was later rehabilitated with PT and OT services without further incidents. Her episode was deemed because of impaired cerebral autoregulation because the rtPA had initially occluded her right MCA-M1 segment, which later recanalized. Also, the patient was mildly anemic (hemoglobin 10.1, normal .13) at the time and was later found to have iron deficiency anemia, which improved with iron supplementation (.1 month after discharge). No carotid occlusion was noted on carotid ultrasounds. The patient had a repeat CT angiogram and perfusion imaging, which
MOBILIZATION WITHIN 24 HOURS OF THROMBOLYSIS
showed recanalization of her right MCA-M1 thrombus with only some tiny areas of infarction within the basal ganglia and caudate. No hemorrhage occurred on imaging. She was later placed on warfarin after a few weeks of aspirin for stroke prevention (congestive heart failure, hypertension, age 5 75 years, diabetes mellitus, stroke scale of 3; 2 points for stroke and 1 point for hypertension). A closer look at the 5 patients who experienced any type of adverse response in our study is warranted. One patient (6%) experienced a DBP greater than 105 mm Hg with no accompanying symptoms. Of note, the patient’s DBP was 93 mm Hg before mobilization. Another patient reported ‘‘dizziness’’ with a corresponding 14 mm Hg decrease in both SBP and DBP after ambulating 20 feet. As dizziness was listed as an anticipated adverse response, mobilization was terminated. Complaints of dizziness alone, without conclusive evidence of orthostasis, may be an insufficient indicator of adverse response. One patient demonstrated transient neurologic worsening, including new onset of hemiparesis that resolved within several minutes of onset. The patient’s modified Rankin Scale several days after the stroke event was 2 (slight disability); this improved to 1 (no significant disability) by 30 days after ictus.
Discussion Recently, more literature has cited improved patient outcomes for patients who receive earlier, more aggressive mobilization and have indicated that such mobilization reduces complications, shortens ICU/hospital lengths of stay, and improves functional outcomes.10,11,13-16 Health care providers treating patients after tPA currently have limited evidence-based data to inform optimal initiation of safe patient mobilization1618 ; patient physical activity is often restricted19 despite the lack of specific clinical evidence to support this prolonged immobilization. Reasons for this immobilization are unclear. In one survey of stroke unit physicians and nurses, 85% reported fear of patient falls and 74% reported fear of worsening neurologic symptoms as factors influencing their decisions about early mobilization after IV rtPA.19 Often, orthostatic hypotension and the potential for resultant syncope are concerns related to patient mobilization into more upright postures. However, it has been suggested that upright positioning and mobilization after mild and moderate AIS do not lead to detrimental reductions in BP.20 Our study provides prospective observational data about the safety of patient mobilization within 24 hours after receiving tPA, which may provide a foundation for development of future treatment guidelines. Over 72% of patients tolerated mobilization within 24 hours after receiving tPA infusion without any adverse event or symptoms. Reported or observed adverse responses were mild, transient, and
5
non–life threatening. Study limitations include small sample size, lack of a control group, and no attempt to control for comorbidities. Several studies describe early stroke rehabilitative interventions, but few describe early mobilization initiated less than 24 hours after onset of stroke.21-24 One study examining the safety of early mobilization of patients experiencing any type of stroke is the A Very Early Rehabilitation Trial multiphase study. During its phase II safety and feasibility trial, investigators reported on 38 of 71 patients mobilized within 24 hours of stroke onset25; no significant differences in number, type, or severity of complications were seen between the early mobilization group and the standard care group.26 In another study, 156 patients with ischemic stroke were mobilized within 24 hours of symptom onset.24 Study authors concluded that no contraindications to early mobilization were identified. Furthermore, a significant rise in BP during early upright positioning (ie, sitting in bed with the head of bed at 70 and active standing) was independently associated with a favorable functional outcome 3 months after stroke (#1 on the modified Rankin Scale). Our study is the first, to our knowledge, to specifically address early mobilization of patients treated with tPA. Although underpowered to make generalizations, it offers a framework to build practice guidelines. Developing guidelines for optimal timing of mobilization will require larger studies. The ongoing A Very Early Rehabilitation Trial Phase III is expected to enroll approximately 380 patients treated with tPA, and approximately half of those patients are anticipated to be mobilized early. The authors of the present study welcome such larger studies to aid in the development of protocols guiding clinical decision making with this unique population.
Conclusion Early mobilization in AIS patients after IV rtPA has the potential to reduce hospital and ICU lengths of stay, reduce overall hospital costs, and start an earlier, more aggressive poststroke rehabilitation process. Implementation of a very early patient mobilization program after IV rtPA represents a relatively low-cost, easily implementable intervention that many hospitals can consider.27 The underutilization of intravenous tPA may be due in part to fears of adverse events.28-30 The present study represents a step toward the establishment of safety data to minimize the fears of mobilization after tPA administration and the development of future protocols for mobilization earlier than 24 hours after IV rtPA administration for stroke.
References 1. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the
S.M. ARNOLD ET AL.
6
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
American Heart Association/American Stroke Association. Stroke 2013;44:870-947. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation 2007;115:e478-534. Genentech Inc. Cathflo Activase [Alteplase]. Available at: http://www.fda.gov/downloads/Drugs/Development ApprovalProcess/HowDrugsareDevelopedandApproved/ ApprovalApplications/TherapeuticBiologicApplications/ ucm088609.pdf; 2001. Accessed March 20, 2013. Genentech Inc. Activase [Alteplase]. Available at: http:// www.gene.com/download/pdf/activase_prescribing.pdf; 2011. Accessed March 20, 2013. Covill L, Ronnebaum J. Mobilization of patients status post acute ischemic stroke treated with tissue plasminogen activator: using the evidence for clinical decision making. Acute Care Perspectives 2008;17:7-9. Eisenberg PR, Sherman LA, Tiefenbrunn AJ, et al. Sustained fibrinolysis after administration of t-PA despite its short half-life in the circulation. Thromb Haemost 1987;57:35-40. Adams HP Jr, Davis PH, Leira EC, et al. Baseline NIH Stroke Scale score strongly predicts outcome after stroke: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology 1999;53:126-131. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333:1581-1587. Graham GD. Tissue plasminogen activator for acute ischemic stroke in clinical practice: a meta-analysis of safety data. Stroke 2003;34:2847-2850. Morris PE, Goad A, Thompson C, et al. Early intensive care unit mobility therapy in the treatment of acute respiratory failure. Crit Care Med 2008;36:2238-2243. Needham DM. Mobilizing patients in the intensive care unit: improving neuromuscular weakness and physical function. Jama 2008;300:1685-1690. Genentech Inc. Activase [Alteplase]. Available at: http:// www.gene.com/gene/products/information/cardiovas cular/activase/insert.jsp; 2005. Accessed March 20, 2013. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 2009;373:1874-1882. Bailey P, Thomsen GE, Spuhler VJ, et al. Early activity is feasible and safe in respiratory failure patients. Crit Care Med 2007;35:139-145. Sherman DG, Albers GW, Bladin C, et al. The efficacy and safety of enoxaparin versus unfractionated heparin for
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27. 28.
29.
30.
the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison. Lancet 2007;369:1347-1355. Cumming TB, Thrift AG, Collier JM, et al. Very early mobilization after stroke fast-tracks return to walking: further results from the phase II AVERT randomized controlled trial. Stroke 2011;42:153-158. Bernhardt J. Very early mobilization following acute stroke: controversies, the unknowns, and a way forward. Ann Indian Acad Neurol 2008;11:88-98. Bernhardt J, Cumming TB, Ha J. Response to letter by Freeman et al regarding article, ‘‘Very early mobilization after stroke fast-tracks return to walking: further results from the phase II AVERT randomized controlled trial’’. Stroke 2011;42:e585. Ha J, Churilov L, Linden T, et al. Bed rest or mobilization after rt-PA? A case-crossover study of factors influencing clinical decision making in stroke services. Int J Stroke 2013;8:172-179. Panayiotou B, Reid J, Fotherby M, et al. Orthostatic haemodynamic responses in acute stroke. Postgrad Med J 1999;75:213-218. Indredavik B, Loege AD, Rohweder G, et al. Early mobilisation of acute stroke patients is tolerated well, increases mean blood pressure and oxygen saturation and improves level of consciousness. Cerebrovasc Dis 2007;23:9. Gillick BT, Marshall WJ, Rheault W, et al. Mobility criteria for upright sitting with patients in the neuro/trauma intensive care unit: an analysis of length of stay and functional outcomes. Neurohospitalist 2011;1:172-177. Diserens K, Moreira T, Hirt L, et al. Early mobilization out of bed after ischaemic stroke reduces severe complications but not cerebral blood flow: a randomized controlled pilot trial. Clin Rehabil 2012;26:451-459. Aries MJ, Bakker DC, Stewart RE, et al. Exaggerated postural blood pressure rise is related to a favorable outcome in patients with acute ischemic stroke. Stroke 2012;43:92-96. Bernhardt J, Dewey H, Thrift A, et al. A very early rehabilitation trial for stroke (AVERT): phase II safety and feasibility. Stroke 2008;39:390-396. Sorbello D, Dewey HM, Churilov L, et al. Very early mobilisation and complications in the first 3 months after stroke: further results from phase II of A Very Early Rehabilitation Trial (AVERT). Cerebrovasc Dis 2009;28: 378-383. Bernhardt J, Indredavik B, Langhorne P. When should rehabilitation begin after stroke? Int J Stroke 2013;8:5-7. Liang BA, Lew R, Zivin JA. Review of tissue plasminogen activator, ischemic stroke, and potential legal issues. Arch Neurol 2008;65:1429-1433. Demaerschalk BM. Thrombolytic therapy for acute ischemic stroke: the likelihood of being helped versus harmed. Stroke 2007;38:2215-2216. Brown DL, Barsan WG, Lisabeth LD, et al. Survey of emergency physicians about recombinant tissue plasminogen activator for acute ischemic stroke. Ann Emerg Med 2005;46:56-60.
