Exercise Reduces Cerebral Vasospasm After Aneurysm Subarachnoid Hemorrhage: A Retrospective Clinical Study and Correlation with Laboratory Investigation

Characteristic

Number (%)

Male

29 (36)

Female

51 (64)

Hunt and Hess grade

1 (1)

39 (49)

III

26 (32)

12 (15)

2 (2)

Fisher grade

4 (5)

21 (26)

3 + 4

23 (29)

24 (30)

Aneurysm location

Anterior circulation

58 (73)

Posterior circulation

13 (16)

Multiple

9 (11)

Treatment

Clip

29 (36)

Coil

51 (64)

All of the patients were managed by our standard SAH protocol that included nimodipine, continuous intravenous magnesium sulfate infusion, and simvastatin at the time of admission and enoxaparin after securing the aneurysm. All aneurysms were secured with either surgical clip ligation or endovascular embolization by the senior author (EMD) within 24 h of admission. Deep venous thrombosis (DVT) prophylaxis was initiated immediately after admission using lower extremity sequential compression devices.

Physical (PT) and occupational (OT) therapies were initiated within 24 h after the aneurysm was secured and patients were encouraged to ambulate with the nursing staff. The PT regimens were not standardized and activity was based on the functional ability of the patient. Functional ability and level of participation in therapy was divided into three categories: (1) Mild Exercise with Ambulation—ambulated whenever possible throughout the day plus participation in therapy sessions for 15–45 min daily, (2) Mild Exercise without Ambulation—out of bed and ambulation to chair only with participation in active range of motion (ROM) exercises, and (3) Non-Exercised Control—passive ROM exercises in all extremities and unable to participate in therapy sessions because of the severity of illness. Therapists and nurses would assist those who had difficulty with transferring out of bed, standing, and ROM exercises to ensure that they were exercised or had sufficient limb movement throughout the day.

For the purpose of statistical comparison, we categorized any patients from group 1 or 2 by the day they initiated active participation. Four groups were established: (1) initiation of active physical therapy before the vasospasm period (i.e., post-bleed day (PBD)-4), (2) initiation before PBD-10, (3) initiation before PBD-20, and (4) no active participation in physical therapy throughout the first 20 days of hospitalization.

Daily bedside transcranial Doppler studies were used to monitor for CV, and CT-angiography and CT-perfusion were performed at admission before the onset of CV as a reference and then on PBDs 4, 6, and 10 with some variation if CV was suspected clinically; PBD 14 was also included if severe CV was present on PBD 10 before discharging the patient to rehabilitation or home. Aggressive intraarterial spasmolytic therapy was provided with spasmolytic agents or balloon angioplasty in symptomatic cases resistant to a maximum of 1 hour of standard medical management. Complications occurring during hospitalization were noted on the basis of discharge diagnoses noted in the discharge summary as well as consultation notes from specialty services.

Data were analyzed using SPSS Version 17 (IBM Corporation, Armonk, NY, USA). Categorical variables were compared using Fisher Exact Tests. Multivariate analysis was performed using forward stepwise binary logistic regression with symptomatic CV as the dependent variable. Categorical variables tested in the model included (1) FG ≥ 3, (2) Hunt Hess Score (HHS) ≥ 3, (3) active exercise initiation, and (4) endovascular treatment. Odds ratios and their 95 % confidence intervals were reported. Two-sided probability values were considered statistically significant for all analyses if P < 0.05.

Rodent SAH Model of Early Mobilization

All procedures involving the use of animals were in accordance with the Guide for Care and Use of Laboratory Animals, US Department of Health and Human Services, and approved by the Committee for the Humane Use of Animals of the university. The double-injection SAH rodent model for induction of basilar artery CV described by us previously was used for this study [12]. Briefly, 18 male Sprague-Dawley rats ranging from 250–300 g (Taconic Farms, Germantown, NY, USA) were equally divided into four groups: (1) SAH Control—cisternal injections of normothermic (37 °C) normal saline (0.9 % NaCl) as a substitute for the blood injections and no exercise; (2) Exercised Control—SAH, no exercise; (3) Early Exercise—SAH plus mild exercise 24 h after injections; and (4) Late Exercise—SAH plus mild exercise 48 h after injection. These groups were established to mimic the early and late mild exercise regimens seen clinically. We implemented a mild exercise regimen that did not induce a severe stress response reported in the more intense exercise regimens to minimize confounding variables in the model [30, 39]. A treadmill (IITC Life Science model 801) was used to engage the rats in a mild exercise regimen. All rats were familiarized with, but not exercised on, the treadmill daily for 3 days before the first surgery to minimize the potential psychological stressor of a new environment at the time of experimentation. Exercised animals ran at 10 m/min for 20 min each day (200 m/day) for 4 consecutive days; non-exercised animals were placed on a static treadmill using the same time parameters. All subjects were killed 5 days after the second cisternal injection and the brain tissues were fixed for tissue slicing [12, 23].

The cisternal double-injection SAH model specifically induces basilar artery CV; thus, we chose to analyze the brainstem for the injury marker, inducible nitric oxide synthase (iNOS) [3, 32]. Briefly, brainstem sections were incubated with primary iNOS antibody (Santa Cruz), rinsed in phosphate-buffered saline (PBS), and then incubated in 10 % normal donkey serum (NDS). Tissue was then incubated for 2 h with primary iNOS antibody (1:50 dilution). After primary antibody incubation, sections were washed in PBS and incubated with the secondary antibody Alexa Fluor 594 anti-rabbit (1:400 dilution). These sections were washed and incubated in Hoechst (1:1000 dilution) for nuclear staining. Sections were washed and cover slipped with Vectashield Mounting Media. Antibody fluorescence was visualized with a Nikon TE2000-U fluorescent microscope at 20×. Images were photographed using SPOT Advance imaging software. Photographs of brainstem tissue adjacent to the basilar artery were used to quantify iNOS-positive cells (20×). Fluorescing cells were counted in a predetermined rectangular section of brainstem tissue. These data were collected and statistical comparison between the groups was performed using Analysis of Variance (ANOVA) followed by Fisher’s Protected Least Significant Difference (PLSD) or Tukey/Kramer post hoc test. A probability of (P < 0.05) was considered statistically significant.

Results

Eighty SAH patients met criteria to be included in this study and were all managed according to the standard SAH protocol described above. The mean age was 56.0 years with a female predominance (64 %), and the majority presented with a good to mildly impaired neurological examination (HHS of 2 or 3) and severe SAH (FG 3, 3 + 4). 51 patients (64 %) were treated with coil embolization and the rest were surgically clipped (Table 1). There was no difference in HHS (P = 0.645) or FG (P = 0.335) between surgically and endovascular treated patients, but as would be expected, there was a statistically significant difference in HHS (P = 0.003) between FG’s. Of those with a FG ≥ 3, 57 % also had a HHS ≥ 3, in comparison to only 8 % of those with a FG < 3. Twenty-two patients from the mild exercise groups were able to ambulate or participate in active ROM therapy prior to PBD-4, an additional 20 patients began active therapy before PBD-10, and 9 patients began before PBD-20. The remaining 29 patients received passive ROM during the first 20 days of hospitalization (Table 2).

Table 2

Patient characteristics and outcome comparison by the timing of active physical therapy

	Day of active exercise initiation
	≤3 (n = 22)	4–9 (n = 20)	10–19 (n = 9)	≥20/none (n = 29)	P
Male	6 (27.3 %)	9 (45.0 %)	5 (55.6 %)	9 (31.0 %)	0.366
Hunt-Hess ≥ 3	7 (31.8 %)	7 (35.0 %)	4 (44.4 %)	22 (75.9 %)	0.005^a
Fisher grade ≥ 3	19 (86.4 %)	14 (70.0 %)	9 (100 %)	26 (89.7 %)	0.179
Endovascular aneurysm securement	18 (81.8 %)	12 (60.0 %)	6 (66.7 %)	15 (51.7 %)	0.158
Symptomatic cerebral vasospasm	3 (13.6 %)	7 (35.0 %)	4 (44.4 %)	16 (55.2 %)	0.019^b
Radiographic cerebral vasospasm	14 (63.6 %)	11 (55.0 %)	6 (66.7 %)	18 (62.1 %)	0.917
Complications	8 (36.4 %)	9 (45.0 %)	5 (55.6 %)	12 (41.4 %)	0.795
Discharge disposition
Home	17 (77.3 %)	10 (50.0 %)	4 (44.4 %)	8 (27.6 %)	0.005^c
Rehabilitation	3 (13.6 %)	9 (45.0 %)	5 (55.6 %)	12 (41.4 %)	0.050^d
Deceased	2 (9.1 %)	1 (5.0 %)	0 (0 %)	9 (31.0 %)	0.035^e

^a≤3 versus ≥20, P = 0.002; 4–9 versus ≥20, P = 0.007

^b≤3 versus ≥20, P = 0.003

^c≤3 versus ≥20, P = 0.001

^d≤3 versus 4–9, P = 0.040; ≤3 versus 10–19, P = 0.027

^e4–9 versus ≥20, P = 0.007

Forty-seven patients (59 %) developed asymptomatic radiographic CV and 30 (38 %) developed symptomatic CV. Symptomatic CV was higher in patients presenting with FG 3, 3 + 4, and 4 (P = 0.048), consistent with previous reports (2–4, 8–9, 12). Mild exercise before PBD-4 significantly lowered the incidence of symptomatic CV compared with patients who were not exercised (13.6 % vs 55.2 %, respectively; P = 0.003). Patients who only received passive ROM therapy had a greater incidence of severe HHS in comparison with patients who began active therapy before PBD-10 (P = 0.007) (Table 2). There was no difference in the incidence of FG ≥3 between groups (P = 0.179).

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