Mobilization in the evening to prevent delirium: A pilot randomized trial

Background: Delirium is a common complication in patients in Intensive Care Units (ICU). Interventions such as mobilization are effective in the prevention and treatment of delirium, although this is usually completed during the daytime. Aim: The aim of this study was to assess the feasibility of mobilization in the evening to prevent and treat ICU patients from delirium by an additional mobility team over 2 weeks. Methods: The design was a pilot, multi-centre, randomized, controlled trial in four mixed ICUs over a period of 2 weeks. The mobility team consisted of trained nurses and physiotherapists. Patients in the intervention group were mobilized onto the edge of the bed or more between 21.00 and 23.00. Patients in the control group received usual care. The primary outcome parameter was the feasibility of were similar, with less delirium in the intervention group albeit not significant. With an association of Cramer's V = 0.237, a complete study reaching statistical significance would require at least 140 patients, last 6 weeks, and cost >30 000 € . Conclusions: In a mixed ICU population, mobilization in the evening was feasible in one-quarter of patients with a low rate of safety events. Future trials seem to be feasible and worth conducting.


| BACKGROUND
One of the most common complications patients experience in Intensive Care Units (ICU) is delirium 1 with incidences ranging between 20% and 89%. 2,3 Delirium is characterized by impaired attention and concentration, rapid onset and fluctuating course as well as flawed cognition, and is a direct result of one or more physical disorders, procedures, or medications. 4,5 The causes of a delirium are manifold and result from predisposing and triggering factors. [6][7][8][9] The consequences of delirium are an increased risk of prolonged duration of mechanical ventilation (MV) and length of stay, increased mortality, permanent cognitive damage, and institutionalization. 10 For the prevention and treatment of a delirium, non-pharmacological interventions, such as early mobilization, are recommended. 2,[10][11][12][13] Early mobilization is defined as interventions that support the patient through passive or active movement exercises, with the goal of maintaining or supporting patient mobility. 14 Previous studies of early mobilization during the day have been associated with a reduction in both the incidence and duration of delirium. [15][16][17] In order to maintain and achieve a normal day-and-night rhythm, mobilization is recommended during the day only, allowing bed rest at night. But in more than half of patients with delirium, there is a reversal of the day-and-night rhythm with more sleep hours during the day than at night or nocturnal exacerbation of symptoms. 18,19 There are several arguments for mobilization in the evening. First, mobilization may direct agitation, as often seen in patients with hyperactive or mixed type delirium, into controlled pathways. Second, mobilization in delirious patients may promote re-orientation and potentially normalize the homeostasis of neurotransmitters through verticalization. 6,20 Third, the physical exertion of mobilization may cause natural sleep to be achieved when patients are back in bed. 10 Mobilization of patients at night is not uncommon per se; indeed about a fifth to a quarter of out-of-bed mobilizations take place in the evening or at night, albeit unsystematically and for different reasons. 21,22 Conversely, mobilization in the evening may have an overexerting effect and it is not clear if this type of intervention is suitable in ICU patients. The aim of this study was to investigate the feasibility of mobilization in the evening to prevent and treat delirium in ICU patients by an additional mobility team over 2 weeks.

| METHODS
This was a pilot, multi-centre, randomized, controlled trial. The results of the study are reported in congruence with CONSORT criteria for pilot or feasibility randomized, controlled trials (Table S2). 23

| Setting
The study was conducted in four mixed ICUs within two university hospitals in Germany. All ICUs were general ICUs with mixed adult populations, covering 32 beds in total. A third hospital in the United Kingdom was originally planned for inclusion and collected data as part of wider service evaluation. Unfortunately, because of misunderstandings between the centres, local ethical approval was not in place What is known about the subject • Delirium is a common complication of critically ill patients.
• Non-pharmacological interventions such as mobilization may prevent delirium.
• Mobilization is recommended during the daytime.

What this paper contributes
• In patients, who can be mobilized, mobilization in the evening can be delivered to most patients, is feasible, and safe without serious consequences.
• Mobilization in the evening may have an effect on prevention and duration of delirium.
• Future research should focus on a dose-response relationship of mobilization and delirium.
at the time of data collection, and therefore this centre was excluded from the trial.

| Population
All patients treated on the participating ICUs were screened twice daily at 7.00 and 15.00 for eligibility. After assessment of each eligible patient for capacity to consent, by the treating ICU physician, patients themselves or their legal representatives gave their written informed consent. Patients were included, irrespective of their status of being on MV or not, who fulfilled all following conditions: (a) ≥18 years old, (b) Richmond Agitation Sedation Score (RASS) ≥ À3 and were responsive, (c) could be assessed for delirium, and (d) were able to being mobilized out of bed according to local policies, and (e) were expected to spend at least one night in the ICU. Patients were excluded if they had one or more of the following conditions: (a) expectation of death within the next 72 hours, (b) no informed consent for the study, (c) pre-existing immobility, (d) contraindication against mobilization, (e) delirium already present before recruitment, (f) positive pregnancy test (routinely carried out in all patients of childbearing age upon admission to ICU), (g) delirium assessment not possible (coma, foreign language, aphasia, etc.), and (h) participation in a competitive study with the outcome of delirium ( Figure S1).

| Randomization
After inclusion, an independent researcher not involved in conducting this study randomized patients in a 1:1 ratio to the intervention or usual care group. Randomization was completed without blocks using a pseudo-random number generator based on a query at www. randomizer.org.

| Intervention
The early mobilization intervention was provided by an additional mobilization team. Mobilization teams have been successfully used in other studies. 16,24 The teams were made up of two people recruited from the study centres and consisted of trained intensive care nurses and/or physiotherapists and could be complemented by medical professionals. To ensure standardization of the intervention, each centre had a protocol for mobilization with similar criteria for conducting or withholding mobilization, with defined safety criteria based on the literature. [25][26][27] The intervention began on day 1, or after patient's consent and randomization. The time frame 21.00 to 23.00 was chosen because of the dusk at ca. 21:45 in June and practical reasons such as adaption to nurses' shift changeover and working routines in the evening. After consultation with the responsible physician and nurse, patients of the intervention group were approached between 21.00 and 23.00, informed, and mobilized after repeated verbal consent of the patients. The intervention was not delivered in cases where patients were (a) already sleeping and unresponsive to verbal questions, (b) refused the mobilization, (c) in pain, and (d) not available because of procedures. In shared rooms care was taken to ensure that fellow patients were not disturbed. The mobilization was carried out in compliance with the pre-defined safety criteria. The aim for a minimum mobility level was sitting on the edge of the bed, which, if tolerated, was progressed to standing, sitting out in a chair, or walking.
Additional soothing activities such as talking, hair combing, oral care, warm foot baths, back massage, or media use were offered. The duration of the mobilization depended on the tolerance and wishes of the patient. 28 The duration of mobilization was between a minimum of 3 minutes and a maximum of 2 hours. Mobilization was stopped at 23.00 and the patient was mobilized back to bed.
The intervention was carried out for three consecutive evenings; a patient may have therefore received the maximum of three interventions. The intervention was terminated if (a) inclusion criteria were no longer met, (b) after three evenings, and (c) when the patient was discharged from the ICU. The intervention was not continued at secondary wards or units. The study was carried out in a time frame of 2 weeks from June to July to use the possible effect of dusk most efficiently. 29

| Control group
Patients in the control group received usual care and were mobilized during the day by physiotherapists and nurses. If necessary, they received the same pharmacological treatment as patients in the intervention group, as per local policies. Patients in the control group could be mobilized during the evening, too, on the basis of nurses' clinical judgement.

| Data collection
All data were extracted prospectively from the patients' charts by the study team or assigned employees. Data included socio-demographic (age, gender, admission diagnosis, co-morbidities, frailty 30 ) and care specific data (categorized admission diagnosis, ventilation device, vigilance (Richmond Agitation Sedation Score; RASS), Pain (Numeric Rating Scale, Visual Analogue Scale; NRS/VAS), Sequential Organ Failure Assessment (SOFA), according to Devlin et al. 1 Mobilizations were assessed using the ICU Mobility Scale, a valid, reliable scale ranging from 0="no mobilization" to 3="sitting on the edge of bed" to 10="independent walking." 31 Because of the obvious character of the intervention, blinding was not feasible. The data collection ended at a maximum of 28 days after admission.

| Primary and secondary outcome parameters
The primary outcome of this study was to test the feasibility of mobilization in the evening. Feasibility measures of the intervention included percentage of recruited patients (recruitment rate), the number of patients actually receiving the intervention (delivery rate), and the number of safety events (safety rate). Potential safety events were defined as exceeding a priori defined safety limits, removal of lines or tubes, falls, Borg Rating of Perceived Exertion scale ≥7, 28 stress pain ≥5 (as measured by Numeric Rating Scale from 0 to 10, 10 indicating maximum pain), and safety events leading to consequences, e.g. withholding mobilization, re-insertion of lines or tubes, additional treatments. 32 Secondary outcome parameters included a reduction in duration and incidence of delirium, duration of MV, length of ICU and hospital stay, mortality, and a power calculation for a full trial. Duration of delirium was assessed with the Confusion Assessment Method for the ICU (CAM-ICU) as a valid, reliable instrument for delirious detection.
The duration of delirium was counted in full days; with the end of delirium defined when patients were delirium-negative for 24 hours or discharged. Patients had to be awake and delirium-assessable or were ranked as un-assessable. Other parameters such as incidence of delirium, phenotypes of delirium, 9 duration of MV, length of stay in ICU and hospital, and mortality were collected and followed-up till day 28 after ICU admission.

| Financing
Because of the pilot character of this study, we report no power calculation, but a calculation of financing the additional mobility teams.
We assumed that the trial would need three mobility teams for four ICUs in two centres (in one centre, two ICU were smaller and were served by one team). Each team consisted of two clinicians, giving six clinicians per evening in total. Additionally, we recruited one clinician in each centre as reserve. Each clinician received 100€ excl. Taxes per evening, and clinicians in reserve received 50€, leading to costs of 700 € per evening. A research grant covered 10.000€, allowing us to finance three teams over the time frame of 2 weeks and additional days (in case patients were recruited at the last study day and needed another 2 days for receiving the complete, 3 days intervention), resulting in 11.200€. The costs above the grant were covered by the department.  Table 2). The median level of mobilization in the evening was 4="standing in front of bed" (IQR 3 = "sitting on the edge of bed" till 6="marching on spot"). During the mobilization, 122 activities in total were delivered, mostly talks (n = 53, 98.1%) ( Table 2).

| Statistical analysis
In terms of safety, mobilization was well tolerated in most cases (n = 45, 83.3%). In patients with unwanted safety events, deviation of systolic blood pressure > 20% was the most common event (n = 4, 7.4%). Consequences of safety events appeared in 12.9% of mobilizations, mostly stopping mobilization (n = 4, 7.4%). No patient required reÀ/insertions of lines or tubes, or cardiopulmonary resuscitation (Table 3).  Table 4). Phenotypes of delirium did not differ between both groups (Table S1).
Based on these results, we calculated in a point biserial model the required number of patients in a multi-centre trial, including 32 beds would be at least n = 140, using a power of 80% and a double-sided P = .05. Estimating the same recruitment and delivery rate, the duration of a RCT would last for 6 weeks with costs of at least 33 600€.

| DISCUSSION
This pilot, multi-centre, randomized, controlled trial including n = 46 patients on mixed ICUs demonstrated mobilization in the evening by an additional mobility team to be feasible. One-quarter of all patients could be recruited, and the intervention could be delivered to threequarters of included patients. The incidence of safety events was low, without any serious consequences. The intervention reduced incidence and duration of delirium but did not reduce length of MV or days in ICU and hospital.
The trial was feasible in terms of recruitment, provision, and safety. Nevertheless, recruitment was not sufficient, as two-thirds of patients could not be included. We underestimated the impact of some aspects. Organizational changes increased the ratio of patients with a short stay. Some patients refused to consent, which is common in ICU rehabilitation studies. 34 The complete intervention, mobilization during three evenings in a row, could be delivered only to the half of the patients. This refusal of rehab because of fatigue, pain, or sleepiness appears in up to 70% of critical care patients, and may reduce effect size. 34 The research grant, which financed the whole trial, covered 2 weeks of extra mobility teams. Retrospectively, we probably overestimated the need for mobility teams, and found that one team of two clinicians instead of two teams with four staff members was sufficient to mobilize patients on three ICUs. Also, as a number of patients reported feeling tired or were already asleep at the time of intervention, the study may have benefitted from using different time frames, such as 7 to 10 PM, which might be as feasible. While studies including early mobilization and rehabilitation in critically ill patients achieved a reduction in delirium duration or incidence, [15][16][17] other studies with similar interventions did not. [35][36][37] A recent meta-analysis found promising data for the prevention of delirium, but not for the reduction of duration of an existing delirium. 38 Our data suggest a reduction in the duration of delirium, but this is hypothesis generating at its best: how does mobilization reduce delirium? What is the impact of verticalization, gravity, muscle activity, increased metabolism, or re-activation of cerebral locomotionprogrammes on brain dysfunction? 6 Is there a dose-response relationship for delirium similar to that seen in physical rehabilitation, 39 but also in delirium? And is mobilization best used as a stand-alone intervention or as part of a care bundle? Although additional re-orientation strategies were included in our protocol, this predominantly consisted of talking with the patient (98%) or back massage (72%). Anecdotally, we observed a reduction in delirium severity by mobilizing agitated patients, but delirium severity was not systematically assessed. Specific delirium phenotypes 9 could not be identified and as such it is unclear which may benefit most from mobilization. It would also be reasonable to consider that mobilization has the potential to worsen delirium, which is caused by shock and reduced cerebral perfusion, 40 but may improve a delirium caused by sedation, hypoxia, or metabolic disturbances. 5 Mobilization in the evening may also reduce delirium contributing factors such as immobility, sleep disorders or hormonal misbalance, and others. 5 Another hypothesis is that early mobilization improves brain functionality. 41 Future trials may benefit from providing a more structured approach to re-orientation in combination with evening mobilization and evaluate the effect of mobilization on the severity of delirium.

| CONCLUSIONS
In mixed ICU patients, a study of mobilization in the evening to prevent and treat delirium is feasible. The intervention can be delivered to three of four occasions, while exceptions happen in a few cases because of examinations, patients' refusal, or other reasons. The intervention appears to be safe. Mobilization shows signs of beneficial effects on preventing and treating delirium, but more research is needed to prove further hypotheses, such as a dose-response relationship between mobilization and delirium. We estimate that a trial reaching statistical significance would require three times the number of patients, study duration, and costs, compared with this pilot study.

ACKNOWLEDGEMENTS
We are thankful for the German Society of Critical Care Medicine and Co. Philips, which financed the pilot study. This work is funded by the Delirium Research Prize of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI) and the Philips company. Both entities did not have any influence in designing, conducting, analysing, interpreting, or writing the study.
Open access funding enabled and organized by Projekt DEAL.

PATIENT CONSENT
All patients or their legal representatives gave written consent to use their data for research.

ETHIC APPROVAL AND REGISTRATION
The study was approved by local ethics committees and registered in the German Register for Clinical Trials (DRKS00016859) on 26 February 2019 (www.drks.de). The results of the study are reported in congruence with CONSORT criteria for pilot, randomized, controlled trials.

DATA AVAILABILITY STATEMENT
Data are available on reasonable request.