Association of physical restraint requirement with unfavorable neurologic outcomes in subarachnoid hemorrhage

Background The association between physical restraint requirement and neurological outcome in patients with subarachnoid hemorrhage (SAH) has not been fully examined. The aim of this study was to examine the association between physical restraint and neurological outcomes in patients with SAH. A single-center, retrospective study was conducted on patients with acute phase SAH treated for >72 h in the intensive care unit from 2014 to 2020. Patients were divided into three groups based on the amount of time required for physical restraint during the rst 24–72 h after admission: no (cid:0) intermittent (cid:0) and continuous use of physical restraint. Unfavorable neurologic outcome, assessed using the modied Rankin scale upon hospital discharge, has been considered as primary end-point.

Therefore, this study aimed to examine the association between physical restraint requirement and neurological outcome in patients with SAH.

Study design and setting
This single-center, retrospective study was conducted at the Kagawa University Hospital, a 613-bed teaching institution with an 8-bed intensive care unit (ICU) managed by a neurointensivist. Medical records were reviewed with the approval of the institutional review board (approval number: 2020-053) and in accordance with the ethical standards established in the 1964 Declaration of Helsinki and its later amendments. The requirement for patient consent was waived due to the retrospective nature of the study.

Study participants and inclusion criteria
We included patients aged ≥18 years who were consecutively admitted to the ICU between July 1, 2014, and July 31, 2020, with a con rmed diagnosis of aneurysmal SAH. Patients who met the following inclusion criteria were included: acute phase of SAH treated for >72 h in the ICU. Exclusion criteria were patients who were not performed treatment (coil or clip) for aneurysmal SAH, patients provided with comfort care only or patients admitted to the ICU for <72 h. Additionally, those with Hunt and Kosnik (H & K) grade 5, or Richmond Agitation-Sedation Scale (RASS) -5 or neuromuscular blockade use during the rst 24-72 h after admission were excluded.
General management of SAH in the ICU All patients were managed in accordance with Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage by the American Heart Association/American Stroke Association (8). In addition to the general intensive care, all patients were monitored for clinical deterioration or cerebral infarction development due to delayed cerebral ischemia (DCI). Fever was treated aggressively with acetaminophen, nonsteroidal anti-in ammatory medications, or cooling devices.

Analgosedation management
A meeting was held every morning and evening, and the depth of sedation was determined in patients undergoing mechanical ventilation. The depth of sedation was assessed using the RASS (9, 10). If increased intracranial pressure was noted or highly suspected, deep sedation targeting a RASS score of −5 with neuromuscular blockade was initiated as needed. The minimum amount of sedatives, such as propofol, midazolam, or dexmedetomidine (DEX), which were necessary to prevent ventilator dyssynchrony and patient discomfort, were used. Analgesics, including acetaminophen, nonsteroidal antiin ammatory medications, and fentanyl, were administered as required. Each physician was responsible for the choice of sedatives. Duration of physical restraint was determined during the rst 24-72 h after admission because various treatment strategies (emergency surgical operation or angiography with general anesthesia, deep sedation followed by treatment operation in the next day, computed tomography followed by treatment and so on), were initiated for the rst 24 hours; therefore, this phase was excluded in the current study.
Continuous physical restraint was de ned as the patients who required continuous physical restraint during the rst 24-72 h after admission. Intermittent physical restraint was de ned as the patients who required any physical restraint during the rst 24-72 h after admission.

Outcome measures
Unfavorable neurologic outcome was considered as the primary end-point, which was assessed using the mRS upon hospital discharge (12). mRS is a global disability measurement tool and comprises seven outcome categories: no symptoms at all, no signi cant disability, slight disability, moderate disability, moderately severe disability, severe disability, and death. All patients with SAH were examined in real time using mRS upon hospital discharge and listed their medical records. The neurologic outcome was de ned as unfavorable when the mRS score was 3-6 and as favorable when the mRS score was 0-2. The secondary outcome was the occurrence of delirium evaluated by ICU nurses.

Statistical analysis
To obtain the association between physical restraint in the acute phase and neurological outcomes, patients were divided into three groups based on the amount of time required for physical restraint during the rst 24-72 h after admission: no intermittent and continuous use of physical restraint Demographic factors and baseline characteristics were summarized using descriptive statistics. The groups were compared using Kruskal-Wallis test or Mann-Whitney U-test, and categorical comparisons were drawn using the Fisher's exact test or chi-square test, as deemed appropriate. Univariate and multivariate analyses were performed to explore independent factors that predicted the unfavorable neurologic outcomes. Covariates of age (>65 years), H & K grade, treatment modality (coil or clip), and physical restraint were included in the multivariable analysis. The Cochran-Armitage trend test was used to examine the trend between physical restraint during the rst 24-72 h after admission and incidence of delirium during the rst 48-72 h after admission. Subgroup analysis was performed on patients with RASS of ≥ −2 and Hunt & Kosnik grade of 1-3. We also repeated the analysis using different de nitions of physical restraint during the rst 24-72 h after admission as a continuous variable. Statistical analyses were performed using the JMP version 12 statistical software (SAS Institute, Cary, NC, USA). A two-sided p-value < 0.05 was considered statistically signi cant for all analyses. Missing data were not replaced or estimated.

Results
Among 129 patients with SAH who were admitted to the ICU, 119 met the inclusion criteria. Among those who met the inclusion criteria, 18 were excluded due to H & K grade 5 or RASS-5 without analgosedation or neuromuscular blockade use during the rst 24-72 h after admission. The remaining 101 patients were ultimately included for analyses ( Figure 1). Association between physical restraint and sedative and antipsychotic medication use Among three groups, a signi cant difference was observed in propofol and DEX use ( Table 2). Regarding the evaluation of RASS score, the difference in maximum and minimum RASS score, agitated state (RASS ≥ 1), and deep sedation (RASS score ≤ −3) were also signi cant among the three groups. Differences in antipsychotic medications use were not signi cant (  Table 4).

Discussion
In this study, continuous use of physical restraint during the rst 24-72 h after admission was found to be more signi cantly associated with unfavorable neurological outcomes at discharge than no physical restraint in patients with SAH. Continuous use of physical restraint during the rst 24-72 h after admission was also associated with the occurrence of delirium during the rst 48-72 h ICU stay.
A recent study performed by Classen et al. demonstrated that a longer duration of agitation in the acute setting may be associated with more favorable outcomes in patients with SAH with RASS score > 0(6). This result seemed to be inconsistent with the results of the current study. Moreover, even in the subgroup analysis limited to patients with RASS ≥ − 2 during the rst 24-72 h after admission in the current study, the stronger conclusion that continuous use of physical restraint during the rst 24-72 h after admission was more signi cantly associated with unfavorable neurological outcomes than no physical restraint was obtained. However, because agitation was not evaluated directly in the current study, the discrepancy between two studies could not be con rmed precisely.
The increasing exposure of patients to potentially harmful sedative and antipsychotic medications can be reduced with the use of physical restraint (13); however, sedative drug use such as midazolam and propofol was paralleled to physical restraint in this study. In neurocritically ill patients, delirium was independently associated with worse neurological outcome (7,14), and continuous use of physical restraint was associated with the occurrence of delirium in the acute phase in this study. Thus, continuous use of physical restraint during the rst 24-72 h after admission was considered to be more associated with unfavorable neurological outcomes. Another hypothesis could be that although signi cant difference was not observed, patients with no physical restraint had a shorter ventilation period compared to two physical restraint groups. Thus, more patients with good consciousness levels after initial treatment might have been included in no physical restraint group.
Although physical restraint was the exposure not the intervention in the current study, the hypothesis that continuous use of physical restraint during the rst 24-72 h after admission was more signi cantly associated with unfavorable neurological outcomes than no physical restraint might be generated. In addition, our subgroup analysis results suggested that its association in patients with non-severe SAH (H&K grade 1-3) were stronger. However, application of physical restraint is closely associated with sedative and antipsychotic medication use (15)(16)(17). Moreover, no RCT has explored the safety and e cacy of physical restraint use in critically ill adult patients(1). Thus, further study to explore the safety and e cacy of physical restraint for patients with SAH will be required. In the study, establishing appropriate outcomes such as biomarker, (S100β, NSE)(18), post-aSAH syndrome (19), and harmful sedative and antipsychotic medication use to prevent self-extubation, tube dislodgement, and/or medical device removal may be required.
This study has several limitations that should be addressed. First, this was a retrospective single-center study with a small sample size; hence, the possibility selection bias and uncontrolled confounding factors should be considered. Also, some patients received unrecorded physical restraint might have been categorized as no physical restraint group. Second, physical restraint criteria were not established. Third, details of devices in physical restraint were not examined due to the small sample size. Finally, as the primary end-point was unfavorable neurological outcome at hospital discharge, differences in the time of evaluation may have affected the results.

Conclusions
This study found that continuous use of physical restraint during the rst 24-72 h after admission was signi cantly more associated with unfavorable neurological outcomes than no physical restraint at discharge in patients with SAH. This study was approved by the institutional review board of the Kagawa University Hospital (approval number: 2020-053). The requirement for patient consent was waived due to the retrospective nature of the study.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
None.
Authors' contributions Drs. Akiyama and Inoue contributed equally to this work. TH takes responsibility for the paper as a whole. All authors read and approved the nal manuscript.