The aim of this study was to test following hypothesis: ICU patients who perform gradual mobilization out-of-bed between 9:00 and 11:00 p.m., compared to patients who are treated by usual care, have a reduced duration of delirium. Further hypotheses are to prove the impact of the intervention on a lower incidence of delirium, duration of MV, length of stay in ICU and hospital. Furthermore, the trial was designed to test feasibility, estimation of effect size as well as recruitment rate to conduct future trials. This was an international, multicentre, randomized, controlled trial.
The study was approved by local ethics committees and registered in the German Register for Clinical Trials (DRKS00016859) at Feb. 26th 2019 (www.drks.de). The results of the study are reported in congruence with CONSORT criteria for randomized, controlled trials .
The study was conducted in five mixed ICUs within three university hospitals in two countries. All ICUs were general ICUs with mixed populations, covering 52 beds in total.
All patients were screened twice daily at 7:00 am and 3:00 p.m. for eligibility. The patients or their legal representatives gave their written informed consent.
In- and exclusion
Patients were included who fulfilled all following conditions: a) ≥ 18 years old, b) Richmond Agitation Sedation Score (RASS) ≥ -3 and were responsive, c) could be assessed for delirium, and d) were able to being mobilized out of bed due to local policies, and e) were expected to spend one night on ICU. Excluded were patients who had one or more of the following conditions: a) expectation of death within the next 72 h, 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 delirium (see Fig. 1).
The randomization was done in a 1:1 ratio by an independent researcher based on a query at www.randomizer.org; the group affiliation is coded in 1 = "intervention group", or 0 = "control group", the randomization was logged, archived and related to each patient.
The intervention of the early mobilization was provided by an additional mobilization team. Mobilization teams have been successfully used in other studies [16, 24]. Mobilization teams were recruited from the study centres and consisted of trained intensive care nurses and/or physiotherapists and could be complemented by medical professionals. Each mobilization team consisted of 2 persons. Each centre had a protocol for mobilization with similar criteria for conducting or withholding mobilization and safety criteria, based on literature [25–27]. The intervention began on day 1, or after patient’s consent and randomization. After consultation with the responsible physician and nurse, patients of the intervention group were approached between 9:00–11:00 p.m., 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, d) not available due to 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 . The duration of mobilization was at least 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 no longer existed, b) after three evenings, c) when the patient has been discharged from the ICU. The intervention has not been continued at secondary wards or units. The study was carried out in June to use the possible effect of dawn most efficiently .
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 individual judgement of nurses.
All data were extracted prospectively the patients’ charts by the study team or assigned employees. Data included socio-demographical (age, gender, admission diagnosis, co-morbidities, frailty ) and care specific data (categorized admission diagnosis, ventilation device, vigilance (Richmond Agitation Sedation Score; RASS), Pain (Numeric Rating Scale, Visual Analog Scala; NRS/VAS), Sequential Organ Failure Assessment, according to . Mobilizations were assessed using the ICU Mobility Scale, a valid, reliable scale ranging from 0=”no mobilization” over 3=”sitting on the edge of bed” to 10=”independent walking” . Due to the obvious character of the intervention, blinding was not feasible. The data collection ended at max. 28 days after admission.
Primary and secondary outcome parameters
Duration of a delirium has been assessed with the CAM-ICU as a valid, reliable instrument for delirious detection . The CAM-ICU has been routinely used and documented electronically by clinicians in the centres three times a day since several years. The duration of the delirium is counted in full days; the end of delirium is defined when patients were delirium-negative for 24 h or discharged. Patients had to be awake and delirium-assessable, or were ranked as unassessable. Secondary outcome parameters such as presence of delirium, duration of MV, length of stay in ICU and hospital, and mortality were collected and followed-up till day 28 after ICU admission. Based on the literature , phenotypes of delirium were determined by the physician in charge.
The feasibility of this RCT was tested by a) percentage of recruited patients, b) the rate of patients, actually receiving the intervention, and c) number of safety events (further divided in potential safety events (exceeding a priori defined safety limits, removal of lines or tubes, fall, Borg scale ≥ 7, stress pain ≥ 5), and safety events leading to consequences (withholding mobilization, re-insertion of lines or tubes, additional treatments) [33, 34].
Power-calculation und Financing
Previous studies were able to achieve a 30–50% reduction in delirium duration and incidence through early mobilization [15–17]. Assuming 5 ICUs with 52 beds, an average length of stay of 4 days and the inclusion of 60% of all patients, we calculated a total number of 109 patients should be included over a period of 2 weeks (intervention group: 55; control group: 55). With a delirium prevalence of 40% (n = 44) with a duration of 4 days +/- 2 days, a 50% reduction in delirium duration by the intervention and a two-sided significance level of p = 0.05, the study would have a power of 90% to test the hypothesis .
The study was funded by the Delirium Research Prize of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI) and the Philips company, and allowed us to finance several mobility teams in three centres during a study period of 14 days.
Collected variables are reported in frequency tables, means (M) and standard deviations (SD), or medians (MD) and quartiles (IQR), when appropriate. Mann-Whitney-U test, Fisher’s Exact Test or independent t-tests were used for the analysis of outcome parameters. Due to the confirmatory character of this study, a one-sided p < 0.05 was used to prove statistical significance. Based on the assumption, that the delirium-protective impact of early mobilization would last during the intervention period and one following day, an unplanned post-hoc analysis was added to analyse the presence of delirium, Absolute Risk Reduction (ARR) and Number Needed to Treat (NNT) during the first four days after inclusion.
The analysis was carried out using SPSS and validated by a statistician.