Intensive Care Med (2017) 43:171-183 1901 10.1007/300134-016-46120, SYSTEMATIC REVIEW The effects of active mobilisation on and rehabilitation in ICU on mortality and function: a systematic review Claire J. Tipping’, Meg Harrold*, Anne Holland?®, Lorena Romero”, Travis Nisbet? and Carol L. Hodgson!" (2016 spunger rag atin Hedlbargand EME Abstract Purpose: Early active mobilisation and rehabilitation in the intensive care unit (ICU) is being used to prevent the long-term functional consequences of critical lines. This review aimed to determine the effect of active mobilsa- tion and rehabiltation in the ICU on mortality function, mobility, muscle strength, quality of fe, days alive and out of hospital to 180 days, ICU and hospital lengths of stay, duration of mechanical ventilation and discharge destination, linking outcomes with the World Health Organization International Classification of function Framework ‘Methods: A PRISMA checklist-guided systematic review and meta-analysis of randomised and contralled clinical trials Results: Fourteen studies of varying qualty including a total of 1753 patients were reviewed. Active mobilisation and rehabilitation had no impact on short- or long-term mortality (p > 0.05). Meta-analysis showed that active mobilsa- tion and rehabiltation led to greater muscle strength (body function) at ICU discharge as measured using the Medical Research Council Surn Score (mean difference 862 points, 95% confidence interval (CI) 139~15.86), greater prob abilty of walking without assistance (activity limitation) at hospital discharge (odds ratio 2.13, 95% C! 1.19-3.83), and more days alive and out of hospital to day 180 (participation restriction} (mean difference 969, 95% Cl 17-176). There were na consistent effects on function, cualty of fe, ICU or hospital Iength of stay, duration of mechani ventilation or discharge destination, Conclusion: Active mobilisation and rehabilitation inthe ICU has no impact on short- and long-term mortalty, But may improve mobilty status, muscle strength and days alive and out of hospital to 180 days. Registration of protocol number: CRD42015029836 Keywords: Intensive care units, Critical illness, Early mobilty, Rehabilitation, Mortality Introduction Patients admitted to intensive care units (ICUs) often require multiple treatments that result in immobility and bed rest [I]. One of the consequences of bed rest in critically ill patients is profound muscle weakness, Corepondence cre hadgeoramonah eae "nus anand New Zaaand verve Cre Reetch Cee, Degartment a Eodemislogy ara revertve Madcine Monash Uns, Meboure I, Asal Ful srorintomatonsavlableat tend ofthe ace Q Springer termed ICU acquired weakness (ICU-AW) which occurs within 24 h and continues to progress [2]. ICU-AW is not yet fully understood, but is likely due to a combina- tion of muscle atrophy and inflammatory processes (3,4. Patients at ICU discharge have significant muscle weak- ness and decreased functional status [5] and it can take 1-2 yeats to reach peak functional recovery [6] and in some cases patients never fully recover [7]. There are many factors which may impact on func- tional recovery post critical illness, including premorbid health status (Le frailty [8], co-morbidities [9, 10] andm functional status) and factors occurring during critical illness (Le. medications provided, presence of sepsis [7], length of mechanical ventilation) [11] The use of mobilisation as an intervention to improve muscle strength and function in ICU patients is fea sible and safe, with very few adverse events recorded [12, 13]. A previous meta-analysis found that there was no significant association between mobilisation in the ICU and improvements in functional status, muscle strength, quality of life or healthcare utiliza- tion [14]. However mobility in the ICU was associated with improved walking ability compared to usual care at hospital discharge [14]. There have been several recently published randomised controlled trials (RCTs) that have not yet been included in a systematic review for meta-analysis, Because of the complexity of acute and critical illness itis possible that there may be adverse outcomes of reha- bilitation starting early in the ICU stay [15]. Although the mechanism by which rehabilitation in ICU might impact ‘on mortality and morbidity is not clear, it is important to establish whether rehabilitation during critical illness results in beneficial or harmful effects and whether it dif- fers for interventions commenced early or later during the ICU stay or in higher or lower doses. ‘The aims of this systematic review and meta-analy- sis were to determine the impact of active mobilisation and rehabilitation in the ICU on (1) patient mortality (measured at ICU discharge, hospital discharge, 3 and {6 months) compared to standard care; (2) patient's func- tional status, mobility status, muscle strength, quality of life, number of days alive and out of hospital to 180 days, duration of mechanical ventilation, ICU and hospital length of stay and discharge destination compared to standard care, Methods The PRISMA guidelines for systematic reviews and ‘meta-analysis [16] (Electronic Supplementary Material (ESM) 1, Table 1) and the Cochrane Handbook [17] were followed and the protocol was registered [18] Search strategy ‘A. comprehensive electronic search of MEDLINE, CINAHL, EMBASE, LILACS, Scopus and Web of Sci ence was undertaken, using a detailed search strategy (ESM 2, able 1). Clinical trials websites [19, 20] were also searched. All resources were searched from incep. ton to June 2016. The reference list of included articles and systematic reviews were searched for additional studies. Authors of eligible studies were contacted for clarification of methodology and results in the case of unpublished or missing data Inclusion and exclusion criteria Types of studies Studies were included if they were randomised or con- trolled clinical trials written in English, Type of patients Adult patients admitted to the ICU for greater than 24h, Interventions Active mobilisation and rehabilitation delivered in the ICU by any members of the ICU team, This could include any combination of active exercises in bed, bed mobility practice, progression of mobility from sitting, to standing and ambulation, tit table therapy or hoisting to a chais Studies were excluded if they investigated passive ther apies only, started rehabilitation after discharge from the ICU, ot were conducted in long-term weaning centres or rehabilitation facilities. Cycle ergometry and functional electrical muscle stimulation used as the sole rehabilita tion therapy were not included, as they do not involve the same complexities surrounding sedation and cardiovas- cular and respiratory stability that are encountered with out-of bed active exercise. Control For studies to be eligible the control group needed to be receiving standard physical therapy as determined by the treating centre during the ICU admission and standard medical and nursing care. Types of outcome measures ‘The primary outcome was mortality measured at hospi- tal discharge. The secondary outcomes were mortality at ICU discharge and 6 and 12 months after admission; functional status, mobility, muscle strength and quality of life and mood state at ICU discharge, hospital discharge and 6 and 12 months follow-up (ESM 2). Days alive and out of hospital to 180 days, length of stay (ICU and hos- pital), duration of mechanical ventilation and discharge destination were also included. Outcomes were catego- rised using the World Health Organization International Classification of Functioning, Disability and Health (WHO ICF) components into Body Functions (b1-8), Activity Limitation (d1-4) and Participation Restriction (45-9) [21]. Selection of studies Titles and abstracts were screened by two independent reviewers (CT, TN). Disagreements were resolved by consensus. Covidence was used to manage and review citations [22] The full text of eligible and uncertain refer ences were then reviewed (CT, TN), with a third reviewer (CH) asnecessary.ma Data extraction ‘A data extraction form was developed and piloted (CT). Data were extracted by two independent researchers. Disagreements were resolved using consensus, and by a third reviewer if necessary. Where the data extraction was unclear or required further detail, study authors ‘were contacted by email for clarification of results. One of the included studies [23] was co-authored by three of the authors on this paper; therefore two external inde. pendent reviewers completed data extraction and the risk of bias assessment. ‘Assessment of methodological quality, The studies were independently assessed by two research: cers for methodological quality using the Cochrane risk of bias tool [17]. This too! assesses seven domains of bias as high, low or unclear risk; selection, performance, detec: tion, attrition and reporting bias. Any other potential bias can also be reported [17] Data synthesis and analysis ‘Meta-analysis was performed using Review Manager 5.3, (RevMan 5.3) Dichotomous variables were presented as relative risks or odds ratios, whilst continuous variables were expressed as mean differences between groups and associated confidence intervals (CD. Data that were presented non-parametrically were assessed for suitability for conversion to parametric statis- tics toallow for meta-analysis [17]. The dala were converted by replacing the median with mean, and the standard deviation (SD) was calculated by dividing the interquar- tile range by 1.35. The skew was then assessed by calculat- ing the ratio of mean/SD. A ratio less than 2 demonstrates some skew, and ess than 1 demonstrates strong evidence of skewed deviation and data was not converted (24) Meta-analysis was performed when data were pre- sented for the same outcome at the sime time point, providing the studies were clinically and statistically homogenous. Clinial heterogeneity was determined by reviewing the setting, participants, intervention and con- trol therapies and statistically by assessing the /* value 17], P values were interpreted as 0-40% might not be important, 30-60% may represent moderate heterogene- 50-90% may represent substantial heterogeneity and 75-10% considerable heterogeneity [17]. As a result of the high level of heterogeneity across al studies, random effects methods were used forall meta-analysis Subgroup analyses were undertaken for all outcomes, where able, in two predefined subgroups: + Early active mobilisation and rehabilitation defined as commencing <3 days of admission, compared to Tate starting after the first 3 days of ICU admission + High dose of rehabilitation defined as completing over 30 min of active rehabilitation daily, compared to those receiving less than 30 min daily Subgroups were determined on the basis of the positive results of trials commencing rehabilitation early [12] and preliminary data on inflammatory changes in early reha bilitation [25] and from the results of high dosage reha bilitation studies [15]. ‘A post hoc analysis was completed to determine if methodological quality was a cause for the statist cal heterogeneity observed in the meta-analysis, This is described in detail in ESM 2. Results Study selection The search of ll databases resulted in 8380 articles, of which 13 studies of active mobilisation and rehabilitation in the ICU were included (Fig 1) [12, 23, 25-35]. There were five studies identified from clinical tials registries; one of these studies was completed prior to publication of this systematic review and therefore was inluded [36] (ESM 2, Table?) No further articles were found from hand searches. (ne study [12] was published in two reports, one for inpatient hospital data [12] and another for the long-term follow-up 37] and both were reported in Fig. 2 risk of bias assessment. Risk of bias assessment The risk of bias assessment is outlined in Fig. 2. Three studies were of low quality with four or five sources of bias (28, 31, 32}, two studies were controlled clinical trials and therefore had a high risk of bias for many of the eri- teria (29, 35], four studies were of moderate quality with three sources of bias [25, 33, 34, 36], and the remaining studies had minimal sources of bias (12, 23, 26, 27, 30} Patients In total, 1753 patients were represented across the 14 stud ies (880 intervention and 873 control). They represented a range of medical, surgical and trauma patients, recruited in nine different countries and across 25 sites. Patient demo- trophies are presented in Table 1 and details ofthe study centres and further patients demographics in ESM 2, ‘Table 3. The patients in the intervention and control groups ineach study were similar at baseline, except fortwo studies ‘where the intervention patients were significantly older [23 30) and had poorer muscle strength and bed mobility on enrolment; however this difference was not significant [30 Intervention therapy Details of the therapies received are outlined in Table 1, Commencement of the intervention ranged from 1 tom4 2580 cond rom date fh postemnoval of kplets Toh 119 seords exci bt sere tie wast 36 fillet aces 2 cor exch bse fl ext lst review | Pssst ty it nuts TT] eet TW anises tak @ [aes st Review ace only Wrong study desi ‘Wrong interven (2) Tales inca ‘Wren otras qantitalie ana sta Conference astact wih fl Sls) resus pubis else where (8) Not yet completed cx published) 8 days after admission to the ICU. Therapy was pro- vided at least daily in the intervention groups and ranged from an average of 15 to 31 min of therapy per day. Fur- ther details of timing and duration of the interventions delivered in the studies are outlined in ESM 2, Table 3. Eleven studies used a protocol to guide the intervention therapies (23, 26, 27, 29-36], whilst the other three indi vidual tailored therapy to each patient [12, 25, 28]. Pro gression of exercise was determined by sedation [25, 26, 34], strength (30-32, 35], fatigue [33], level of mobility (IMS [38)) [23], function [27] or a combination of these factors [36]. One study aimed to exercise patients at an intensity of 3-5 on the modified Borg scale whilst in the ICU [27], whilst another aimed for 12-13 on the Borg scale [32] ‘One study had two intervention arms, namely physical therapy alone and physical therapy combined with cogni- tive therapy [26]; results from the cognitive therapy group were not included. Five of the studies had little detail regarding the timing of the intervention [31, 32, 34-36] and seven studies had litle detail regarding duration of intervention (28, 31~36] and therefore, despite attempts to contact the corresponding authors, were not included in the subgroup analyses. A post hoc analysis was com- pleted to investigate whether methodological quality was a cause for the detected statistical heterogeneity across the studies. These results are outlined in ESM 2 Control therapy ‘There was large variation in the standard therapy pro- vided in the control groups. The control group in six studies received daily therapy as part of standard care (23, 25, 27, 31, 32, 35]. This mainly involved passive or active asisted range of motion and was individually tai lored. The other eight studies received therapy one to three times a week, with limited resources (12,26, 28-30, 33, 34, 36]. One study reported that physical therapy was not routinely provided in patients mechanically vent Iated for less than 2 weeks [12]. Effects of intervention Mortality All studies reported mortality at one or more time points (Fig. 3). One study reported the p value only and there: fore could not be included in the meta-analysis [29]. As not all centres used central death registries to report ‘mortality, no assumptions were made for the patients who were not followed up at 6 months, Mortality was eal culated by the number of patients at risk and therefore at 6 months was influenced by the number of patients who withdrew or were lost to follow-up. In a pooled analysis no significant difference was found in mortality at any time point (Fig. 3). Subgroup analysis showed that early mobilisation and high dose rehabilitation had no signi cant effect on mortality (ESM 2, Table 4). Measures of body function Five of the studies reported three different measures of body functions at relevant time points 12, 23, 25, 31, 32] (ESM 2, Table 5). Four studies reported MRC-SS at ICU discharge (23, 25, 31, 32}; however, raw results for cone study were unable to be obtained and could not be included in the meta-analysis [31]. Analysis of the three studies demonstrated an improvement in. mus- le strength favouring rehabilitation in the ICU (pooled mean difference (MD) 8.62, 95% CI 1.39-15.86, p = 0.02,Ws E : é 2 ing of outcome assessment frumme! 2014 Dantas 2011 Dewey 2013 Bona 2014 bong 2016 E e e @ e e Hanekom 2012 @ e e e e e e e e Hodgson 2016 ayarnbu 2015; Moms 208 Moms 2016 Moss 2016 ‘Schaller 2016 ‘Schwoicker 2009 Woe 2019 © | © | | @[e |e (0 |e) @[@]O| ©] @|@ serene recoring veportng bias) HOOOOOOOOOOOOUUiw @| 0/0/00 /O | 2 /O|O| 2| 0/00 S/O omens i a e e e 2 ® e e e e o e e e e e © 0 0'0'0 0'0 002/02 |e/2/0% Oe eee ee ee ees /\e\2/e" Yosetrauner2015| @ Fig. 2 Fskof bia assessment fe denotes high rik elon unclear ‘kand given low rk. Vary se deta quen regarding ne thorny received inthe cotta group Ne detais given regorcing the duration ane Iniensty of he therapy “stores conta, herefore could be Some added ias “Heath rete quality of ife outcome dows not account for non-sunvos 73%, three studies, nm = 120) [23, 25, 32]. When one study of high risk of bias was removed the f decreased to 0% and the result was stl significant (ESM 2, Fig. 1). ‘Three studies reported strength using the hand-held dynamometer at ICU discharge [12, 31, 34]; however, the aw values could not be obtained for one study [31] and the data from one study was severely skewed and was not appropriate for conversion to mean and SD [12]. No other meta-analyses were appropriate. ‘Measures of activity imitation Nine studies reported 14 different measures of acti ity limitations (ESM, Table 6) (12, 23, 25-27, 30, 31, 34, 36]. Two studies reported ability to walk independently at hospital discharge [12, 29]. One study presented the information graphically [12]; therefore the nume cal results were gathered from a previous systema review [Id]. In a pooled analysis, patients in the reha- bilitation group had a higher probability of mobilising without assistance at hospital discharge (OR 2.13, 95% CI 1.19-3.83, p = 0.01, F = O%, two studies, m = 188), Three studies reported the PFIT at ICU discharge. Pooled analysis demonstrated no significant difference between the intervention and control group (MP —0.19, 95% CI 0.69 to 0.32, P = 0%, three studies, m = 207) (23, 25, 27]. There were no differences between groups for any of the subgroup analysis (23, 25,27] (ESM 2, Table ). ‘Two studies report TUG at hospital discharge [26, 27] and two studies at 6 months (27, 30}. The data from one of the studies at hospital discharge was highly skewed [26] and not appropriate for meta-analysis. The pooled analysis at 6 months showed no difference between the rehabilitation and standard care groups (MD 0.11, 95% CI =5.96 to 6.19, P = 66%, two studies, = 146) [27, 30]. No subgroup analysis or other meta-analysis could be performed. Measures of participation restriction Nine studies reported 13 different measures of participa tion restriction at the time points of interested for this review (ESM 2, Table 7) [12, 23, 25-27, 29, 30, 34 36]. Four studies reported the SF-36 at 6 months [25, 27, 30, Ss however, one study only reported physical function and the physical and mental component score [34]. One study reported non-parametric results which were con- verted to mean and standard deviation for meta-analysis [07, 30) ‘the pooled analysis ofthe four studies showed no significant difference between the intervention and control groups (ESM 2, Table 8) (25, 27, 30, 34]. In the social functioning domain, when one study of high tsk of bias was removed the / value decreased to 0%. There was no change in the /* when separating by methodological quality in the other three domains (ESM 2, Table 8). 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Five studies reported days alive and out of hospital to {6 months [23, 25, 29, 30, 37]. A pooled analysis of the five studies showed a significant mean difference favouring ae rehabilitation group (MD 9.63, 95% CI 1.68-17.57, 02, P= 0, five studies, = 509). However the data from one ofthe studies was highly skewed and required conversion to mean and SD to allow meta-analysis [25) ‘herefore a pooled analysis was also completed for the remaining four studies, demonstrating a significant MD ‘of 9.69 (Fig. 4) favouring the rehabilitation group [23, 29, 30, 37]. No subgroup differences were identified (Fig. 4) Length of toy, mechanical ventilation duration ‘and discharge destination ‘The individual results of each study are outlined in TSM 2, Table 8. Because the majority ofthe length of stay and duration of mechanical ventilation data were signif icantly skewed, a meta-analysis was not able to be per- formed. Several studies did not report LOS for survivors and non-survivors separately, thereby introducing bias [23, 25-27, 29, 30, 32-34, 36), Two studies had no deaths in ICU and reported significantly shorter ICU length of stay in the rehabilitation group compared to the standard, care group (FSM Table 9) [28,31] No difference was found in the pooled analysis of dis- charge destination (proportion of patients discharged home, OR 1.35, 95% Cl 098-187, p = 0.07 F = 40%,180 “eo 8 2 vam sunne = a ee = ose Somes etal = ae saree ect 22238 Tet ear tsrnces 0 Fig. slot for daysalve and to 180 cays eight studies, = 1255) [12, 23, 26, 27, 30, 34-36], The subgroup analysis showed no difference in proportion of patients discharged home (ESM 2, Table 4). ‘Adverse events One serious adverse events was reported (desaturation less than 80%) [12] Six studies reported adverse events an Hopkinson N5, Pak Dew, Sih 2 ello Seymour, Ailey {lsat 8 Lima Mads LI, Smith KRowleson Rene, ashame Haridge SO, rar N Montgomery HE 013) cat tll tmusce waxing ncrteallines AMA ¥@(5)7591-T600 1610017 jira 20"3278481 3. 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