12 versus 24-hour Bed Rest after Acute Ischemic Stroke Reperfusion Therapy Brian Silver, MD, Tariq Hamid, MD; Muhib Khan, MD; Mario DiNapoli, MD; Reza Behrouz, DO; Gustavo Saposnik, MD; Jo-Ann Sarafin, RNP; Susan Martin, OT; Majaz Moonis, MD; Nils Henninger, MD, PhD; Richard Goddeau, MD; Adalia Jun-O’Connell, MD; Shawna M Cutting, MD, MS; Ali Saad, MD; Shadi Yaghi, MD; Wiley Hall, MD; Susanne Muehlschlegel, MD, MPH; Raphael Carandang, MD; Marcey Osgood, DO; Bradford B. Thompson, MD; Corey R Fehnel, MD; Linda C. Wendell, MD; N. Stevenson Potter, MD; James M Gilchrist, MD; Bruce Barton, PhD

Disclosures Salary: UMassMemorial Medical Center, University of Massachusetts Medical School, Joint Commission (surveyor) Consultant fees: Women’s Health Initiative, Medicolegal malpractice review Honoraria: Ebix publishing, MedLink, Medscape

Background The practice of bed rest for ≥24 hours after reperfusion therapy became standard after the NINDS rt-PA trial. Yet, the optimal timing of mobilization in these patients is unknown. Current guidelines recommend against high-dose, very early mobilization within 24 hours of stroke onset as a class III recommendation.

Hypothesis We hypothesized that at a protocol of ≥12 hours bed rest was not inferior to ≥24 hours bed rest following stroke reperfusion therapy. Secondary hypotheses were that rates of pneumonia, venous thromboembolism, and lengths of stay would be reduced in patients in the ≥12 hours bed rest group.

Goals The goal of the study was to compare discharge outcomes among patients who had ≥24 hours bed rest following acute ischemic stroke reperfusion therapy with ≥12 hours bed rest.

Design Single center Retrospective Before and after (January 27, 2014) Consecutive patients Adjustments for age, sex, admission NIHSS, time to treatment Analyses separated by 1) intravenous thrombolysis only patients, and 2) thrombectomy patients with or without intravenous thrombolysis

Thrombolysis Only patients Overall (N = 392) ≥24 hour bed rest group (N = 203) ≥12 hour bed rest group (N = 189) P Age (years), mean + SD 71.7 + 15.6 71.8 + 15.5 71.5 + 15.9 0.87 Sex (% female) 208 (52.1) 106 (48.0) 102 (54.3) 0.65 Race (% white) 330 (84.2) 172 (84.3) 158 (84.0) 0.94 Race (% black) 31 (7.9) 17 (8.3) 14 (7.4) 0.75 Ethnicity (% Hispanic) 29 (7.4) 14 (6.9) 15 (8.0) 0.67 History of hypertension (%) 293 (74.7) 155 (76.0) 138 (73.4) 0.56 History of prior stroke (%) 94 (24.0) 40 (19.6) 54 (28.7) 0.03 History of atrial fibrillation (%) 104 (26.5) 53 (26.0) 51 (27.1) 0.80 History of diabetes (%) 96 (24.5) 50 (24.5) 46 (24.5) 0.99 History of smoking (%) 125 (31.9) 63 (30.9) 62 (33.0) 0.66 History of coronary artery disease (%) 92 (23.5) 54 (26.5) 38 (20.2) 0.14

Thrombolysis Only patients   Overall (N = 392) ≥24 hour bed rest group (N = 203) ≥12 hour bed rest group (N = 189) P Median admission NIHSS (IQR) 7 (4-13) 8 (5-13) 7 (4-11) 1.0 Mean time to tPA from symptom onset, minutes +SD 146 ± 95 155 + 110 137 + 74 0.06 Mean time to physical therapy documentation from symptom onset, hours + SD 50 ± 57 59 + 72 41 + 30 0.003 Patients with physical therapy documentation < 24 hours from symptom onset (%) 47 (15.4) 5 (3.1) 42 (28.8) <0.0001 Mean time to physical therapy documentationfrom first thrombolysis bolus or groin puncture (hours) 49 ± 57 57 + 72 39 + 30 Patients with physical therapy documentation < 24 hours from first thrombolysis bolus or groin puncture (%) 58 (19.0) 6 (3.8) 52 (35.6)

Thrombolysis Only patients Outcome measure ≥24 hour bed rest group (N = 203) ≥12 hour bed rest group (N = 189) P value Unadjusted* P-Value Adjusted** Odds Ratio†(95% CI) Diff:12-24 hr (95% CI) Primary outcome   Favorable discharge¹ (%) 144 (70.9%) 144 (76.2%) 0.24 0.50 OR: 1.20 (0.71: 2.03) Secondary outcomes Median NIHSS at 24 hours (IQR) 4.5 (2-8) 3 (1-7.5) 0.003 0.008†† Median NIHSS at discharge (IQR) 3 (1-7) 2 (0-5) 0.004 0.034†† Mean length of stay (days + SD) 5.4 ± 8.8 3.5  ±  2.7 0.006 Diff: -1.07 (-3.22: -0.53) Medical Complications Venous thromboembolism (%) 3 (1.5) 1 (0.5) 0.34 0.31 OR: 0.30 (0.03: 3.06) Pneumonia (%) 17 (8.3) 3 (1.6) 0.001 OR: 0.12 (0.03: 0.55) Readmission within 30 days (%) 21 (10.3) 10 (5.3) 0.06 0.054 OR: 0.46 (0.21: 1.01) ¹Favorable outcome: discharge to home, home with services, or acute rehabilitation. * P-values from likelihood ratio chi-square test for proportions, from standard two-sample two-sided t-test for normally distributed means, and from Wilcoxon rank sum test for non-normally distributed variables. ** Adjusted for age (continuous), sex (m/f), admission NIHSS (continuous), tPA received (yes/no: including bolus for endovascular treated patients), endovascular treatment (yes/no), and time to treatment (tPA or time to groin puncture, whichever is first). For medical complications, endovascular treatment could not be used in adjustment due to convergence failure. † Odds ratio for 12 hours relative to 24 hours (OR < 1.0 indicates 12 hour outcome lower than 24 hour outcome); difference for 12 – 24 hour outcome (difference < 0.0 indicates 12 hour outcome lower than 24 hour outcome) †† Adjusted p-value for van Elteren non-parametric test to compare non-normal continuous outcomes (NIHSS) between assigned bedtime adjusted for covariates: sex, NIHSS at admission. Resulting score statistic not presented.

Thrombectomy Patients (with/without tPA)   Overall (N = 193) ≥24 hour bed rest group (N = 59) ≥12 hour bed rest group (N = 134) P Age (years), mean + SD 72.2 + 16.0 71.9 + 16.1 72.4 + 16.0 0.85 Sex (% female) 95 (49.2) 22 (37.3) 73 (54.5) 0.03 Race (% white) 156 (80.8) 49 (83.1) 107 (79.9) 0.60 Race (% black) 17 (8.8) 4 (6.8) 13 (9.7) 0.50 Ethnicity (% Hispanic) 8 (4.2) 5 (8.5) 3 (2.2) 0.06 History of hypertension (%) 136 (70.5) 42 (71.2) 94 (70.2) 0.88 History of prior stroke (%) 35 (18.1) 7 (11.9) 28 (20.9) 0.12 History of atrial fibrillation (%) 64 (33.2) 16 (27.1) 48 (35.8) 0.23 History of diabetes (%) 41 (21.2) 11 (18.6) 30 (22.4) 0.55 History of smoking (%) 51 (26.4) 17 (28.8) 34 (25.4) 0.62 History of coronary artery disease (%) 47 (24.4) 13 (22.0)

Thrombectomy Patients (with/without tPA)   Overall (N = 193) ≥24 hour bed rest group (N = 59) ≥12 hour bed rest group (N = 134) P* Median admission NIHSS (IQR) 18 (12-23) 18 (14-23) 17 (12-22) 1.0 Received tPA (%) 172 (89.1) 59 (100.0) 113 (84.3) <0.0001 Mean time to groin puncture from symptom onset, minutes ± SD 168 ± 94 160 ± 107 171 ± 87 0.45 Mean time to physical therapy documentation from symptom onset, hours + SD 47 ± 43 78 + 65 38 + 21 0.0002 Patients with physical therapy documentation < 24 hours from symptom onset (%) 34 (22.5) 1 (2.3) 33 (30.8) Mean time to physical therapy documentation from first thrombolysis bolus or groin puncture (hours) 76 + 65 35 + 21 0.0001 Patients with physical therapy documentation < 24 hours from first thrombolysis bolus or groin puncture (%) 45 (29.8) 44 (41.1)

Thrombectomy Patients (with/without tPA) Outcome measure ≥24 hour bed rest group (N =59) ≥12 hour bed rest group (N = 134) P value Unadjusted* P-Value Adjusted** Odds Ratio†(95% CI) Diff:12-24 hr (95% CI) Primary outcome   Favorable discharge¹ (%) 32 (54.2) 92 (68.7) 0.056 0.14 OR: 1.73 (0.84: 3.56) Secondary outcomes Median NIHSS at 24 hours (IQR) 12 (7-18) 8 (4-14) 0.013 0.024†† Median NIHSS at discharge (IQR) 8 (4-14) 4 (2-9) 0.004 0.036†† Mean length of stay (days + SD) 7.5 ± 6.1 3.9 ± 3.3 <0.0001 Diff: -3.45 (-4.82: -2.03) Medical Complications Venous thromboembolism (%) 1 (1.7) 0 (0.0) 0.12 0.31 -- Pneumonia (%) 8 (13.6) 5 (3.7) 0.017 0.030 OR: 0.27 (0.08: 0.88) Readmission within 30 days (%) 6 (10.2) 3 (2.2) 0.022 OR: 0.16 (0.04: 0.72) ¹Favorable outcome: discharge to home, home with services, or acute rehabilitation. * P-values from likelihood ratio chi-square test for proportions, from standard two-sample two-sided t-test for normally distributed means, and from Wilcoxon rank sum test for non-normally distributed variables. ** Adjusted for age (continuous), sex (m/f), admission NIHSS (continuous), tPA received (yes/no: including bolus for endovascular treated patients), endovascular treatment (yes/no), and time to treatment (tPA or time to groin puncture, whichever is first). For medical complications, endovascular treatment could not be used in adjustment due to convergence failure. † Odds ratio for 12 hours relative to 24 hours (OR < 1.0 indicates 12 hour outcome lower than 24 hour outcome); difference for 12 – 24 hour outcome (difference < 0.0 indicates 12 hour outcome lower than 24 hour outcome) †† Adjusted p-value for van Elteren non-parametric test to compare non-normal continuous outcomes (NIHSS) between assigned bedtime adjusted for covariates: sex, NIHSS at admission. Resulting score statistic not presented.

Conclusions Compared with ≥24 hour bed rest, ≥12 hour bed rest after acute ischemic stroke reperfusion therapy appeared to be safe and may be associated with reduced neurological deficit at discharge, shorter length-of-stay, and reduced rates of readmission within 30 days. A randomized trial is needed to verify these findings.