12 versus 24 hour bed rest after acute ischemic stroke thrombolysis

Abstract

Background:

The practice of ≥24 hours of bed rest after acute ischemic stroke thrombolysis is common among hospitals, but its value compared to shorter periods of bed rest is unknown.

Methods:

Consecutive adult patients with a diagnosis of ischemic stroke who had received intravenous thrombolysis treatment from 1/1/2010 until 4/13/2016, identified from the local ischemic stroke registry, were included. Standard practice bed rest for ≥24 hours, the protocol prior to 1/27/2014, was retrospectively compared with standard practice bed rest for ≥12 hours, the protocol after that date. The primary outcome was favorable discharge location (defined as home, home with services, or acute rehabilitation). Secondary outcome measures included incidence of pneumonia, NIHSS at discharge, and length of stay.

Results:

392 patients were identified (203 in the ≥24 hour group, 189 in the ≥12 hour group). There was no significant difference in favorable discharge outcome in the ≥24 hour bed rest protocol compared with the ≥12 hour bed rest protocol in multivariable logistic regression analysis (76.2% vs. 70.9%, adjusted OR 1.20 CI 0.71–2.03). Compared with the ≥24 hour bed rest group, pneumonia rates (8.3% versus 1.6%, adjusted OR 0.12 CI 0.03–0.55), median discharge NIHSS (3 versus 2, adjusted p=0.034), and mean length of stay (5.4 versus 3.5 days, adjusted p=0.006) were lower in the ≥12 hour bed rest group.

Conclusion:

Compared with ≥24 hour bed rest, ≥12 hour bed rest after acute ischemic stroke reperfusion therapy appeared to be similar. A non-inferiority randomized trial is needed to verify these findings.

Graphical Abstract

Introduction

Intravenous thrombolysis¹ and mechanical thrombectomy² are two of the most significant advances in the treatment of acute ischemic stroke over the last two decades. Up to 50% of patients receiving these interventions have substantial improvement in clinical outcome compared without these treatments. The practice of bed rest for ≥24 hours after reperfusion therapy became standard after the NINDS rt-PA trial.³ 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, level of evidence B-R (Randomized) recommendation.⁴ Arguments in favor of continued bed rest include increasing cerebral blood flow and avoidance of hypotension with an upright posture.^{5, 6} Arguments against bed rest include an increased risk of venous thromboembolism, aspiration pneumonia, and length of hospitalization. However, one study did not find a high rate of pneumonia with 0 degree head positioning for ≥24 hours.⁷

The goal of the study was to compare discharge outcomes among patients who had ≥24 hours versus ≥12 hours bed rest following acute ischemic stroke thrombolysis only. We hypothesized that at a protocol of ≥12 hours bed rest was not inferior to ≥24 hours bed rest following stroke thrombolysis. 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.

Methods

Study cohort and study design

The study was approved by the local institutional review board. Written consent was waived due to the before and after study design comparing local standard of care practices. Consecutive adult patients, age ≥18 years, with a diagnosis of ischemic stroke who had received intravenous thrombolysis treatment between January 1, 2010 and April 13, 2016 at a single comprehensive stroke center were included. Patients who underwent mechanical thrombectomy for large vessel occlusion and stroke mimics were excluded from this analysis. A prospectively collected database for quality improvement was used to identify patients. Standard practice was bed rest for ≥24 hours prior to January 27, 2014 (49 month observation period) and ≥12 hours thereafter (26 months observation period). Patients in the latter group had to have at least 12 hours of bed rest. There was no upper limit to the bed rest allowed in this group i.e. some patients may not have been mobilized by 24 hours because a therapy assessment could not be performed until that time e.g. patient had reperfusion treatment at 7 AM and the earliest the patient could be mobilized was at 7 PM but therapy evaluation could not be performed until the next morning. The decision to change bed rest from 24 hours to 12 hours was reviewed by a multidisciplinary meeting including physicians, nurses, physical therapists, and occupational therapists following review of existing scientific evidence regarding bed rest following stroke thrombolysis and logistical considerations. Based on literature review that did not demonstrate any significant scientific basis for 24 hour bed rest and that 12 hour bed rest was logistically not an increased challenge compared with 24 hour bed rest, the group unanimously approved the change to a ≥12 hour bed rest protocol.

The following baseline information was retrospectively collected from patient charts: age, sex, race, ethnicity, history of diabetes, hypertension, smoking, and prior stroke, time of stroke onset, time of arrival at hospital, NIH stroke scale score (NIHSS) prior to intravenous thrombolysis, times of intravenous thrombolysis bolus, initial physical therapy documentation of assessment, and initial occupational therapy documentation of assessment. Duration of initial physical and occupational therapy assessments were not recorded. Additionally, the type of physical and occupational therapy was not prescribed but an initial assessment typically consisted of movement as tolerated from the bed to a chair or to a standing position. Patients who were able to walk could participate in that activity if they were able. The duration of the initial assessment was less than 45 minutes and the amount of actual movement was estimated to be less than 15 minutes. Chest physiotherapy was not performed. Hospital outcomes that were collected included NIHSS at 8 hours, 24 hours, and discharge; occurrence of venous thromboembolism (defined as a clinical syndrome with imaging correlate); pneumonia (defined as a clinical diagnosis by the treating team); length of stay; and discharge disposition (home, acute rehabilitation facility, skilled nursing facility, hospice care, in-hospital death). Outcomes at three months and vessel recanalization status were not systematically collected prior to 2015 and were therefore not included in the analysis of this study. The primary outcome was favorable discharge location (defined as home, home with services, or acute rehabilitation). Secondary outcome measures were NIHSS at 24 hours, and discharge; length of hospital stay, venous thromboembolism, pneumonia, and readmission within 30 days. Symptomatic intracranial hemorrhage (defined as ≥4 points increase in the NIHSS with intracranial bleeding) was also compared between groups.

Statistical analysis

Comparison of baseline characteristics between ≥24 hour bed rest and ≥12 hour bed rest were performed using either the t-test for normally distributed continuous variables or the Wilcoxon rank sum test for non-normally distributed data, as determined by the Wilks-Shapiro test. Proportions were compared using a likelihood ratio chi-square test to better handle small proportions. Both unadjusted p-values, p-values (adjusted for age, sex, admission NIHSS, and tPA administration was performed) and adjusted odds ratios with 95% confidence intervals were calculated. The score statistic (and adjusted p-values) for van Elteren non-parametric test to compare non-normal continuous outcomes (NIHSS) between groups adjusted for the covariates sex, admission NIHSS, and tPA treatment was calculated.

We matched patients in the ≥24 hour protocol with patients in the ≥12 hour protocol using propensity score matching. The propensity score was calculated using a logistic model with ≥24 hour versus ≥12 hour bed rest assignment as the outcome and, as predictors, age, sex, admission NIHSS, tPA administration, and time to treatment. Matching was performed using the SAS macro gmatch from the Mayo Clinic. The propensity score was then added to the logistic model for the primary outcome to further adjust for any differences between the two groups.

We fit an interrupted time series to track change in the proportion of patients discharged to a favorable location (the primary outcome) on a month-to-month basis and noted substantial variability in the outcome on a month-to-month basis. Therefore, we collapsed the individual months into three-month intervals for this model. We used SAS statistical software to test for existence of autoregression (PROC AUTOREG), to test for seasonality and stationarity (PROC ARIMA), and to fit the final model (PROC AUTOREG).⁸ All analyses were performed using SAS Version 9.4 (SAS Institute Inc., Cary, NC).

Results:

From 1/1/2010 to 4/13/2016, 392 patients with acute ischemic stroke received intravenous thrombolysis, 203 patients in the ≥24 hour bed rest period (1/1/2010 to 1/27/2014) and 189 in the ≥12 hour bed rest period (1/28/2014 to 4/13/2016). Baseline demographics are summarized in Table 1. A history of prior stroke occurred significantly more often in the e12 hour treatment group. Mean time to documentation of initial physical and occupational therapy from symptom onset and treatment with thrombolysis was shorter in the ≥12 hour bed rest group, as was the proportion of patients having documentation within 24 hours (Table 1).

Table 1:

Baseline demographics for all, ≥ 24 hour, and ≥ 12 hour bed rest 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
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 documentation from first thrombolysis bolus (hours)	49 ± 57	57 ± 72	39 ± 30	0.003
Patients with physical therapy documentation < 24 hours from first thrombolysis bolus (%)	58 (19.0)	6 (3.8)	52 (35.6)	<0.0001
Mean time to occupational therapy documentation from symptom onset (hours ± SD)	51 ± 57	60 ± 72	42 ± 31	<0.0001
Patients with occupational therapy documentation < 24 hours from symptom onset (%)	40 (13.1)	3 (1.9)	37 (25.3)	<0.0001
Mean time to occupational therapy documentation from first thrombolysis bolus (hours ± SD)	49 ± 57	58 ± 72	40 ± 31	<0.0001
Patients with occupational therapy documentation < 24 hours from first thrombolysis bolus (%)	58 (19.0)	6 (3.8)	52 (35.6)	<0.0001

^*P value comparison between ≥24 hour and ≥12 hour bed rest groups.

With respect to the primary outcome measure, there was no significant difference in favorable outcome between the ≥12 hour and ≥24 hour bedrest groups (76.2% vs. 70.9%, adjusted OR 1.20, 95% CI 0.71–2.03) (Table 2). Adjustment by adding the propensity score did not affect this outcome.

Table 2:

Primary and secondary outcomes

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	0.004	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	0.006	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), and time to tPA treatment.

^†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, and NIHSS at admission. Resulting score statistic not presented.

Secondary outcome measure analysis showed significantly lower median NIHSS scores at 24 hours and discharge, rates of pneumonia, and mean lengths of stay in the ≥12 hour bed rest group (Table 2). No significant difference was seen in the rate of venous thromboembolism or readmission within 30 days. Symptomatic intracranial hemorrhage rates were not significantly different (7.2% versus 4.6% in the ≥24 hour and ≥12 hour bed rest groups respectively, p=0.17).

Discussion:

The present 6-year study comprising almost 400 patients with acute ischemic stroke undergoing thrombolysis showed no significant difference in discharge outcomes among patients who had at ≥12 hour bed rest compared to patients who had ≥24 hour bed rest. Modified Rankin scale or Glasgow outcome scale scores would have been preferable to the discharge location. At the time these data were collected, modified Rankin scales were collected at discharge or at 3 months less than 10% of the time. We chose to select an outcome measure, that, while not validated, was consistently collected. Discharge outcomes, however, did correlate well with 3 month modified Rankin scale scores in one study.⁹ In addition, decreased pneumonia rates, more favorable discharge NIHSS scores and reduced lengths of stay were observed in the ≥12 hour bed rest group. That the improvement in NIHSS scores was greater in the 12 hour bed rest group at 24 hours and discharge despite similar baseline scores and may be due to a variety of possible factors such as reduced rates of pneumonia as seen in this study. In future studies, volumetric analyses of infarct volumes at 24 hours should also be studied to evaluate additional potential mechanisms (e.g. suggestive of improved perfusion). We believe the difference in pneumonia rates was due to avoidance of a prolonged flat position but this would need to further investigated in a prospective study. We do not collect information on the percent of patients who required ventilator support but this could be analyzed in a future study. No statistically significant differences were seen in the rates of venous thromboembolism, readmission, and symptomatic intracranial hemorrhage, though there was a trend towards reduced readmissions in the 12 hour group We did not collect reasons for readmission but this should be focus of future studies. These results remained unchanged after propensity score matching.

Previously, the powerful effect of stroke unit care was, in part, thought to be due to early mobilization of patients.^{10, 11} Avoidance of medical complications¹² and adverse effects on multiple body systems were also thought to be potential reasons for success. In pilot studies, early and intensive mobilization was associated with improved outcomes among stroke patients.^{13, 14} However, the AVERT study, which compared early, higher intensity, mobilization with usual care found an increased risk or poor outcomes among patients who were assigned higher intensity early mobilization.¹⁵ In that study, early mobilization patients were treated at a median of 18.5 hours after stroke onset with a median of 31 minutes of therapy daily. Usual care patients were treated at a median of 22.4 hours after stroke with a median of 10 minutes therapy daily. Our study differs from AVERT in that the ≥12 hour bed rest group had documentation of physical therapy at a mean of a 38 hours after stroke, with approximately 25% of patients having documentation within 24 hours of onset, and no obvious adverse outcome. The findings in the current study suggests that there may be an opportunity for better defining optimal timing of therapy services.¹⁵ We hypothesize that between the ranges of no mobilization and high intensity mobilization, as investigated in the AVERT trial, there may be benefit of intermediate mobilization with respect to patients with respect to reduced rates of pneumonia, 90 day modified Rankin scale outcomes, and lengths of stay. Duration and dosing of therapy should be the focus of a future study. An additional finding from the AVERT study, which was that cognitive outcomes were not influenced by early, intense therapy¹⁶ and should also be a focus of future studies.

One of the major concerns surrounding early mobilization is the impact on cerebral blood flow to the brain and the effect of reduced flow on collateral blood supply.⁵ Change of head position from 0 to 30 degrees can reduce cerebral blood flow by approximately 15%.¹⁷ Mean flow velocities may also change in response to head positioning,¹¹ but the clinical meaningfulness of these changes is uncertain. Further, the responses may be variable with paradoxical increases in cerebral blood flow with increasing head of bed angle.¹⁷ In some circumstances, a provocative maneuver may selectively identify patients at risk for clinical deterioration.⁶ The international multicenter Head Position in Acute Stroke Trial (HeadPoST) randomly assigned acute stroke patients to a 0 degree head position versus a 30 degree head position for 24 hours after acute stroke to determine whether there is a differential shift in the modified Rankin scale score at 90 days.¹⁸ There was no difference in the primary outcome between groups. An additional substudy of 92 patients in the HeadPost study found no difference in mean cerebral blood flow velocity.¹⁹ One concern about the study is that the population included predominantly patients with low to moderate NIHSS scores, leaving open the question as to whether patients with higher NIHSS scores might benefit from ≥24 hour 0 degree head positioning.

A 2012 Centers for Disease Control and Prevention report on stroke in the United States found an average length of stay of 5.3 days during 2009, which was not significantly different from an average length of stay of 5.4 days in 1999.²⁰ Hospitalization costs for ischemic stroke in 2006–2008 were approximately $19,000.²¹ If the findings of reduced length of stay in our study are replicated in a non-inferiority randomized trial, there could be a substantial cost reduction for ischemic stroke admissions.

There are several limitations to this study. First, the comparison groups were not during concurrent time periods thus introducing the possibility of other factors which may have played a role in the differences seen. For example, economic pressure on hospitals to shorten length of stay could have been a factor explaining some of the findings. Second, patients were not randomly assigned to different durations of bed rest, which could have introduced treatment biases leading to different outcomes. Third, the origin of patients i.e. whether they came from a home or were living in a supervised setting was not recorded so return to pre-stroke living situation could not be calculated. Fourth, the definition of poor discharge outcome to include skilled nursing facility may not accurately reflect the ultimate 3-month outcome of patients since many patients are not eligible for acute rehabilitation at the time of hospital discharge but may still improve while at skilled nursing facility. Fifth, the duration of therapy assessments was not measured, so that the actual amount of physical and occupational therapy assessment was not known. Modern technologies such as actigraphs²² may be useful for determining patient movement during the initial and subsequent course of hospital stay, but further refinement of the technique is required.²³ Sixth, three-month outcomes were not collected in this study because they were not systematically collected prior to 2014. Seventh, this was a single center study and the results may not be generalizable to other hospitals with different stroke pathways. Eighth, the maximum NIHSS scores were low in this study, which was a function of the exclusion criteria. Specifically, patients being excluded who received thrombectomy and these patients have higher NIHSS scores. Lastly, there may have been residual confounders not accounted for in this analysis.

Despite the limitations, our findings suggest possibly similar discharge clinical outcomes among patients with ≥12 hour bed rest compared to those with ≥24 hour bed rest with significant reductions in pneumonia rates, discharge NIHSS scores, and lengths of stay. A multi-center non-inferiority randomized trial would be required to definitively determine shortened bed rest following thrombolysis is reasonable.

• This single center, retrospective study of 392 consecutive patients who received intravenous thrombolysis found that those who had bed rest for 12 hours had no statistically different discharge outcome compared to those who had bedrest for the standard 24 hours

• Rates of pneumonia and mean length of stay were significantly lower, and the improvement in NIHSS scores was significantly better, in the 12 hour group compared with the 24 hour group

• There was a trend towards reduced readmissions at 30 days in the 12 hour group compared with the 24 hour group.