Effects of early mobilization (EM) in patients with noninvasive positive pressure ventilation (NIPPV) in Intensive Care Unit (ICU): a randomized controlled trial

Background Early mobilization (EM) may be an effective intervention for the promotion of rehabilitation in noninvasive positive pressure ventilation (NIPPV) patients. The aim of this study was to investigate the effects of EM in patients with NIPPV in Intensive Care Unit (ICU). Methods Participants were randomly allocated to the intervention group involving active and passive activities combined with routine treatments and the control group with routine treatments in this single-center, parallel-designed randomized controlled trial. Participants accepted initiative and passive activities following brought by medical and nursing team who were standardized training The primary outcomes were the incidence of ICU-AW, length of ICU stay, duration of ventilation and mortality. Results There were no adverse event in participants during EM. Compared with the control group, there was a signicantly lower length of ICU stay (m = 6.0 vs 7.8 days, respectively, P = 0.038), incidence of ICU-acquired weakness (n = 17.4% vs 50%, respectively, P = 0.026), duration of ventilation (m = 2.1 vs 4.0 days, respectively, P = 0.019) in the intervention group.


Introduction
Long-term bed rest or prolonged immobility can lead to serious complications in critically ill patients undergoing mechanical ventilation, such as ICU-acquired weakness (ICU-AW), cardiac circulatory system dysfunction, metobolic and mental disorders etc [3][4] . These complications not only prolong the duration of mechanical ventilation and ICU hospitalization, but also seriously impair the rehabilitation of patients' body functions [5][6][7] . As one of the most common complications, ICU-AW is clinically manifested by limb paralysis, muscle atrophy and di culty in ventilator weaning 8 . It has been reported that the incidence of ICU-AW among patients with mechanical ventilation could be 33%-82% [9][10] . ICU-AW also prolongs the time of ICU hospitalization, what's worse, it decreases the patient's life quality during 90 days after discharge 11 . Previous studies had followed up a queue of survivors of ARDS, nding that even 5 years after discharge, physical dysfunction failed to recover completely 5 . At present, no pharmacological therapy are recommended to prevent and treat ICU-AW 12 . The managements mainly focus on supportive care for patients. 13 Recently, it is suggested that long-term bed-rest, the traditional nursing mode, should be changed among mechanical ventilation patients. Meanwhile, early mobilization (EM) is recommended in many guidelines as a preferable method to promote the recovery. Even though EM is thought to be feasible and bene cial for mechanical ventilation patients in the ICU 14,15 , it is poorly de ned and previously only referred to early program of standing and walking training (rehabilitation) or simply moving patients' limbs, etc. 16 .
Many studies have shown the effectiveness of EM, as it not only helps patients regain muscle strength, especially inspiratory muscle, which leads to better physical function 17,18 , but also prolongs patients' ventilator-free time and increases their ability to ambulate and to conduct daily activities 19 . However, EM may also give rise to occasional side effects, such as increases of heart rate and respiratory rate and to minor adverse events, such as transient hypotension, oxygen desaturation, patient-ventilator asynchrony and agitation. Few studies reported that EM in AECOPD patients during hospitalization may increase the mortality and there are some risks and potential dangers such as unscheduled extubation 24 . The underlying cause may be that the critical conditions make these patients more vulnerable to accept EM. 24 .
Non-invasive ventilation provides an "intermediate" or "transitional" alternative of auxiliary ventilation between oxygen therapy and invasive ventilation, especially for respiratory failure in early stage or without emergent tracheal intubation indications 26 . Therefore, comparing with invasive ventilation patients, non-invasive ventilation patients may have better conditions and tolerance for EM, the safety of EM in non-invasive ventilation patients might be better. Moreover, interventions such as early and sustained mobilization may be key in deterring the progression to intubation and invasive mechanical ventilation in NIPPV patients. Hodgson 26 even emphasized the safety of EM among patients with mechanical ventilation, and gave some suggestions on the safety standards: it is necessary to organize a multidisciplinary treatment team to ensure the safety and effectiveness of EM.
Many studies have demonstrated the feasibility and safety of EM for invasive mechanical ventilation ICU patients 21 since EM can prevent ICU-AW by increasing the duration and level of active exercises and reducing the duration of ventilation and length of ICU stay 28 . However, few studies have reported whether EM has the similar effect for non-invasive ventilation population, especially NIPPV patients. To gure out this, we formed a multidisciplinary team including doctors, nurses and respiratory therapists in this study.
Meanwhile, we assessed the patients' conditions before EM to ensure the safety. This study aimed to investigate the feasibility and safety of EM in NIPPV patients and the effect of EM on the promotion of rehabilitation in patients with NIPPV in ICU. Therefore, we conducted a randomized controlled trail to investigate whether EM can prevent the ICU-AW, reduce the duration of (non-invasive) ventilation and the length of ICU stay, and improve the physical function among NIPPV patients.

Results
From July, 2017 to March, 2019, our team screened 481 patients, 48 of them were nally enrolled and assigned randomly at 1:1 ratio to the intervention group and the control group.
During the study, 1 patient in the intervention group and 3 patients in the control group refused to join in further research and were considered to be "drop out". Moreover, another 3 patients in the control group were excluded after enrollment because two of them were respectively diagnosed with in uenza and tuberculosis; 1 patient was severely restricted to movements with aggravating heart failure. Eventually, 41 patients completed the whole procedure (23 participants in intervention group, 18 participants in control group).The trial pro le is presented in Fig. 1 (Fig. 1). Table 2 shows the baseline parameters and primary diseases of the study population ( Table 2). The average of APACHE II score, creatinue and leukocyte for the intervention group were 18, 58mmol/L, 7.9×10 9 /L respectively, while those of the control group were 16.3, 56.5mmol/L, 9.3×10 9 /L respectively. There was no signi cant difference in demographic data and primary diagnosis between the intervention and control groups (p > 0.05).
Compared with the control group, durations of ICU stay and ventilation were signi cantly shorter (p = 0.038, p = 0.019 respectively), and the incidence of ICU-acquired weakness was lower in the intervention group. Moreover, the increase of right or left hand-grip strength was signi cantly higher in intervention group than that of control group (p = 0.00, p = 0.047 respectively) ( Table 3). No adverse events were found during the study and 1 patient in the control group passed away because of respiratory failure caused by severe pneumonia. Statistically, there was no signi cant difference in ICU mortality (p = 0.439).

Discussion
In this study, alle th participants in the intervention group carried out EM personalized according to their physical tolerance. During the procedure, no adverse events such as falls or unplanned extubation occurred, and there was no signi cant difference in mortality between the two groups (p > 0.05). The results indicated that EM for patients with non-invasive positive pressure ventilation in ICU was safe under the conditions of this study.
EM may be an effective strategy to prevent ICU-acquired weakness, as it not only enhances muscle strength and prevents muscle atrophy, but also reduces oxidative stress and in ammation 38 . EM has a positive in uence on the recovery of muscle function and the reduction of the occurrence of ICU-AW. In this study, patients with non-invasive positive pressure ventilation were provided with EM including passive activities such as joint exion, abduction, rotation and turning over in bed, as well as initiative activities, such as grip strength training, upper limb strength training and bedside standing. We used MRC score to evaluate the occurrence of ICU-acquired weakness. The results of this study showed that the incidence of ICU-Acquired weakness and the duration of ICU stay in the intervention group were signi cantly lower than those in the control group (P = 0.026, P = 0.0038 respectively), the increase of left and right hand grip strength in the intervention group were signi cantly higher than that in the control group (P = 0.047, P = 0.00 respectively). It was con rmed that EM can reduce the occurrence of ICUacquired weakness, promote the recovery of muscle strength and shorten the length of ICU-stay in patients receiving NIPPV.
Ventilation is an effective treatment for respiratory failure, but it can also lead to diaphragmatic atrophy and contractile dysfunction, namely ventilation-related diaphragmatic dysfunction (VIDD). Animal experiments have shown that mechanical ventilation can cause diaphragm contraction dysfunction in mice in only 6 hours 39 .Some studies have shown that prolonged mechanical ventilation can lead to di culty in weaning and poor prognosis that will further restrict the activity of patients, thus further causing muscle (including diaphragm) atrophy, vicious circulation and aggravating ICU-Acquired weakness [40][41][42] . The results of this study showed that the duration of noninvasive ventilation in the EM intervention group was signi cantly lower than that in the control group (p = 0.019). The reason behind may be that EM prevented the occurrence of VIDD in patients with noninvasive ventilation. However, due to the lack of direct evaluation of diaphragm contraction function in this study, whether EM could prevent diaphragm atrophy and the occurrence of VIDD still needs further study.
This study promoted the recovery of physical function in patients with NIPPV in ICU through EM. But at present, there are many factors restricting the implement of EM such as the lack of breathing therapists and physiotherapists, inadequate muscle strength training equipment, lack of awareness of patients and medical staff towards EM and so on. In some extent, these factors limit the development of EM, which should be solved in the future. The results of this study showed that the EM can signi cantly improve the patient's body function and bene cial for them, we suggest that EM can be added to the routine management program for patients, especially for patients with better activities tolerance. Patients receiving NIPPV represent an understudied group. Studies have shown that the use of NIPPV can improve the physical activity in COPD patients [43][44][45] , therefore, early mobilization and NIPPV may have a synergistic positive effect on patients. Moreover, interventions such as early and sustained mobilization may be key in deterring the progression to intubation and mechanical ventilation, EM may also be an effective measure to improve the long-term prognosis of patients. Further investigation in this area can start from better intervention planning and longer follow-up to provide more valid evidence. The inclusion criteria of EM: (1) Patient ought to be aged 18 years or older; (2) Patient who has hospitalized in ICU received NIPPV for less than 48h; (3) The projected time of NIPPV was not less than 24h. (4) Patient ought to be conscious and cooperative.

Participants
The exclusive criteria of EM: (1) GCS score was not less than or equal to 12; (2) Patient who was unable to move or be moved; (3) Patient who has received non-invasive positive pressure ventilation for more than 48h 28 ; (4) Patient who had an incurable disease was projected six-month mortality rate more than or equal to50%; (5) Patient who has received invasive mechanical ventilation before NIPPV; (6) Patient who cannot be up to the standard of EM; (7) Patient who was suffering from severe contagious diseases.
Patients in the medical ICU were screened daily to identify adults (≥ 18 years of age) who had been on mechanical ventilation for less than 72 h, were expected to continue for at least 24 h, and who met criteria for baseline functional independence. A participant's daily screening results appear one item in the exclusive criteria of EM, the participant would be excluded. An adverse event emerges, the trial would be stopped.

Sample size
This study is a pilot study to establish the feasibility and safety and to support our future study about EM in NIPPV patients. According to Hodgson's previous feasibility studies in severely ill ICU patients 1 , a minimum of 20 patients assigned to per group was deemed necessary to avoid the occasional loss of follow-up and facilitate meaningful assessment of feasibility and safety.

Procedures
Generated by computer, random numbers were randomly assigned in a 1:1 ratio to the intervention group and the control group. We used the random envelope method to put the plan of the intervention group and the control group into a light-proof envelop coded in order. It was given to investigators after sealed. When the eligible patient showed up, investigators coded the patient as the order of random numbers (ascending sequence), and then opened the corresponding envelope, and took measures according to the plan shown in the envelope. It included 24 cases of the intervention group (EM combined with standard treatment and nursing measures of ICU) and 24 cases of the control group (standard treatment and nursing measures of ICU). The total number of participants was 48. Blinding was conducted in patients and the researchers who performed the measures.
Before each intervention, the researchers would comprehensively assess the patient's condition including the following items 29,30 , (1)blood pressure increases or decreases suddenly with mean arterial blood pressure lower than 65mmHg or higher than 110mmHg; (2)heart rate (HR) ≥ 130 beats/min or ≤ 50 beats/min; (3) respiratory rate (RR) ≤ 8 times/min or ≥ 40 times/min (4) pulse oxygen saturation (SPO 2 ) ≤ 90% (5) patients' discomfort which fails them to accept intervention any more (6) clinical manifestations or signs of cardiopulmonary distress (7)severe adverse events including falling out of bed, unexpected pulling out of tuber, sudden coma, malignant arrhythmia, ischemia myocardial, acute respiratory distress (ARDS), etc. Once any of these items occurred, the EM of the intervention group would be suspended. While during each implementation, researchers would closely monitor the changes of various indicators for the participants to ensure the safety.
In order to improve the muscle strength of participants to prevent ICU-acquired weakness, participants accepted initiative and passive activities following brought by medical and nursing team who were standardized training. Before those activities, patients were required to test their grip strength by grippers.
As the de nition of EM still needs further evidence to underpinned 16 , in this study EM comprises of passive and initiative activities, moving patients' limbs and sitting them out of bed 28,31,32 , these were sequential steps and the intervention providers had been trained in consistency. Passive activities 28, 32-36 : In the begin, the intervention providers exed and extended the patient's ngers for 30 times each hand, secondly rotated the wrist clockwise, and promoted elbow exion and extension, thirdly, completed abduction and exion of each shoulder, and then promoted internal rotation and external rotation of each shoulder. Besides, from the distal end of lower extremity, providers helped patient complete rotation of ankle joint clockwise, exion and extension of knee joint to promote blood circulation of limbs, and improve muscle strength. In the end, providers would assist patients to turn over in bed. Initiative activities [32][33][34][35] : In the begin, soft elastic balls were applied for patients to enhance their hand grip strength at an average speed of 30 times per minute, and then they were required to lift 1 kg dumbbell at an average speed of 25 times per minute to exercise upper arm strength. Thirdly, participants completed the lower extremity initiative activity including rotation of ankle joint clockwise, exion and extension of knee joint 10 times each per minute to improve muscle strength. At last, patients would be asked to sit by the bed without any support for 10-20 minutes according to their tolerance degree of the activity. In the intervention group, participants carried out all the activities twice a day, 30 minutes each time (Table 1). Except for EM, participants in the control group received the same level of clinical care as the intervention group (standard of care).
During the procedure of the trial, each participant in the intervention group was equally distributed with the same duration of those activities even though the intensity of each item of those activities depended on patients' tolerance levels and their physical condition assessment. In order to prevent adverse events in the course of the trial, the relevant knowledge and skills for the researchers would be assessed regularly, and the operation of EM would be regularly examined. If any adverse events occur to the subjects, any activities must be suspended immediately and handled promptly according to the doctor's instructions.

Variables and measures
As for the primary outcome, it consisted of e cacy indicators and safety indication of EM implementing. E cacy indicators include: (1) occurrence of ICU acquired weakness (ICU-AW) (2) the length of ICU stay (3) duration of NIPPV; Safety indicators include ICU mortality rate and occurrence of adverse events. The secondary outcome was the growth value of hand-grip strength. The calculation method was to subtract the grip strength at discharge from the grip strength at admission.
The occurrence of ICU-Acquired weakness is evaluated by MRC muscle strength score, which means the muscle strength of limbs would be comprehensively evaluated. ICU-acquired weakness was diagnosed when the muscle strength score is lower than 48 credits and also lower than the patient's credits assessed before each intervention patient had in the group 37 , researchers would observe and record the vital signs and indicators to monitor the process of patient's conditions consistently. All the outcomes were measured by medical personnel.

Ethics Statement
This was a single-center, parallel-designed randomized controlled trial in the respiratory intensive care unit (RICU) of the First A liated Hospital of Chongqing Medical University (Chongqing, China). The research plan and informed consent submitted in this project complied with the medical ethics principles and the requirements of the Helsinki Declaration. The research design based with science evidence does not bring unnecessary risks to the participants, and maximum protection had been given to ensure the safety and privacy of the subjects. The trial was approved by the Ethics Committee of the First A liated Hospital of Chongqing Medical University (Document No. 2018-015).

Statistical analysis
We utilized SPSS software (version 19.0) to analyze the data. Continuous variables were described as mean and standard deviation or as median (interquartile range). Kolmogorov-Smirnov test was used for testing the normality of distribution unpaired. Normally distributed variables were compared by independent Student's t tests. All statistical tests were two-sided, and signi cance was determined at the 0.05 probability level and non-normally variables were compared by Wilcoxon, Mann-Whitney U tests. We used the χ² test to compare categorical variables between the intervention group and control group.  Tables   Table 1. The exercises (interventions) that the intervention group received.