Safety and Efficacy of Rehabilitation in Critically - A Systematic Review and Metaanalysis of Randomised
Controlled Trials
Systematic review registration number PROSPERO-CDR ID 132255
Petr Waldauf, Katerina Jiroutkova, Adela Krajcova, Tomas Urban, Frantisek Duska
∗Zudin Puthucheary
†2019-10-20 16:57:10
Report generated: 2019-10-20 16:57:10
Software: R version 3.6.1 (2019-07-05) + R Markdown
∗Dept. of Anaesthesia and Intensive Care, Charles University, 3^rd Faculty of Medicine and FNKV University Hospital, Prague, Czech Republic
†Queen Mary, University of London, London, United Kingdom
Contents
1 Selection of studies and data extraction (flow chart) 3
2 Studies included in quantitative synthesis (meta-analysis) 4
3 ICU mortality 5
4 End of study mortality 11
5 ICU LOS 16
5.1 ICU LOS without outlier (Fischer et al.) . . . 20
5.1.1 Risk of bias . . . 24
6 Hospital LOS 27 6.0.1 Risk of bias . . . 31
6.1 Hospital LOS without outlier (Fischer et al.) . . . 33
6.1.0.1 Risk of bias . . . 38
7 Duration of MV 40 7.1 Risk of bias . . . 44
8 Ventilator free days 47 8.1 Risk of bias . . . 50
9 SF-36 53 9.1 PCS (Physical Component Summary) . . . 53
9.2 PF NBS (Physical functioning) . . . 56
10 Metaregression / subgroup analysis 59 10.1 Descriptive analysis of covariates . . . 59
10.2 Meta-Analysis of Single Means / single proportions . . . 61
10.2.1 Average ICU LOS (without outlier: Fisher at al.) . . . 61
10.2.2 Average hospital LOS (without outlier: Fisher at al.) . . . 64
10.2.3 Average duration of mechanical ventiation . . . 66
10.2.4 Average age . . . 69
10.2.5 Average APACHE II . . . 72
10.2.6 ICU mortality . . . 75
10.2.7 End study mortality . . . 78
10.2.8 Percentage of males . . . 81
10.2.9 Sepsis ratio . . . 84
10.3 LOS . . . 87
10.3.1 Metaregression ICU LOS ~ Mean ICU LOS . . . 87
10.3.1.1 Metaregression ICU LOS ~ mean ICU LOS adjusted for ICU mortality, with- out the outlier Fischer et al. . . 91
10.3.1.2 Metaregression ICU LOS ~ Mean ICU LOS (<20 days) . . . 93
10.3.1.3 Metaregression ICU LOS <20 days ~ mean ICU LOS adjusted for ICU mor- tality, without the outlier Fischer et al. . . 95
10.3.1.4 Metaregression ICU LOS ~ Mean ICU LOS (>20 days) . . . 97
10.3.1.4.1 Metaregression ICU LOS ~ Mean ICU LOS (>20 days) without the outlier Fischer et al. . . 98
10.3.2 Metaregression ICU LOS ~ Mean hospital LOS . . . 101
10.3.2.1 Metaregression ICU LOS ~ Mean hospital LOS (<30 days) . . . 103
10.3.2.2 Metaregression ICU LOS ~ Mean hospital LOS (>=30 days) . . . 105
10.3.2.2.1 Metaregression ICU LOS ~ Mean hospital LOS (>=30 days) without the outlier (Fischer et al.) . . . 106
10.3.3 Metaregression ICU LOS ~ Mean Age . . . 109
10.3.4 Metaregression ICU LOS ~ ICU mortality . . . 112
10.3.4.1 Metaregression ICU LOS ~ ICU mortality without the outlier (França et al.) 115 10.3.5 Metaregression ICU LOS ~ Male/Female ratio . . . 118
10.3.6 Metaregression ICU LOS ~ average APACHE II score . . . 121
10.3.6.1 Subgroup analysis ICU LOS ~ APACHE II <= / > 20 . . . 122
10.3.7 Metaregression ICU LOS ~ sepsis ratio . . . 126
10.3.7.1 Metaregression ICU LOS ~ sepsis ratio (20-80%) . . . 128
10.3.8 Subgroup analysis ICU LOS ~ initiation of rehabilitation within 72 hrs in intervention group (without outlier: Fisher at al.) . . . 130
10.3.9 Subgroup analysis ICU LOS ~ Minimum intensity of RHB (frequency): 5 times/week in intervention group (without outlier: Fisher at al.) . . . 133
10.3.10 Metaregression ICU LOS ~ intensity of RHB (duration in min) in intervention group (without outlier: Fisher at al.) . . . 136
10.3.10.1 Metaregression ICU LOS ~ intensity of RHB (duration in min) in intervention group (<= 60 min) (without outlier: Fisher at al.) . . . 138
10.3.11 Metaregression ICU LOS ~ extra dose [min], ie. (duration I - duration C) * days delivered (without outlier: Fisher at al.) . . . 140
10.3.12 Metaregression ICU LOS ~ days of ICU stay before intervention started in intervention group (without outlier: Fisher at al.) . . . 142
10.3.12.1 Metaregression ICU LOS ~ days of ICU stay before intervention started in intervention group (<10 days) (without outlier: Fisher at al.) . . . 145
10.3.12.2 Metaregression ICU LOS ~ days of ICU stay before intervention started in intervention group (<20 days) (without outlier: Fisher at al.) . . . 148
10.3.13 Metaregression ICU LOS ~ days of exercise in intervention group (without outlier: Fisher at al.) . . . 151
10.3.13.1 Metaregression ICU LOS ~ days of exercise in intervention group (<10 days)
(without outlier: Fisher at al.) . . . 154
10.3.14 Subgroup analysis ICU LOS ~ type of analysis (all analysed vs survivors only) (without outlier: Fisher at al.) . . . 156
10.3.14.1 Subgroup analysis ICU LOS ~ type of analysis (all analysed vs survivors only), average ICU LOS < 20 days (without outlier: Fisher at al.) . . . 159
10.4 End study mortality . . . 162
10.4.1 Metaregression End study mortality ~ Mean ICU LOS (without outlier: Fisher at al.) 162 10.4.1.1 Metaregression End study mortality ~ Mean ICU LOS (< 30 days) (without outlier: Fisher at al.) . . . 165
10.4.2 Metaregression End study mortality ~ average APACHE II score . . . 167
10.4.2.1 Subgroup analysis End study mortality ~ APACHE II <= / > 20 . . . 169
10.5 Hospital LOS . . . 172
10.5.1 Metaregression Hospital LOS ~ Mean ICU LOS . . . 172
10.5.1.1 Metaregression ICU LOS ~ Mean ICU LOS (<20 days) . . . 174
10.5.2 Metaregression Hospital LOS ~ Mean hospital LOS . . . 176
10.5.3 Metaregression Hospital LOS ~ Mean Age . . . 178
10.5.4 Metaregression hospital LOS ~ average APACHE II score . . . 180
10.5.4.1 Subgroup analysis Hospital LOS ~ APACHE II <= / > 20 . . . 182
10.6 Duration of MV . . . 184
10.6.1 Metaregression duration of MV ~ average APACHE II score . . . 184
10.6.1.1 Subgroup analysis Duration of mechanical ventilation ~ APACHE II <= / > 20 . . . 186
10.6.2 Metaregression duration of mechanical ventilation ~ mean duration of mechanical ven- tilation . . . 189
10.6.2.1 Metaregression duration of mechanical ventilation ~ mean duration of me- chanical ventilation adjusted for ICU mortality . . . 192
10.6.2.2 Metaregression duration of mechanical ventilation ~ mean duration of me- chanical ventilation (<15 days) . . . 194
10.6.2.3 Metaregression duration of mechanical ventilation ~ mean duration of me- chanical ventilation (<15 days) adjusted for ICU mortality . . . 196
10.6.3 Subgroup analysis MV duration ~ type of analysis (all analysed vs survivors only) . . 198
11 Risk of bias 201 11.1 Individual studies Risk of bias . . . 201
12 Figure 2 205
13 Figure 3 206
14 Figure 4 207
15 Appendix 209 15.1 R session info . . . 210
16 References 211
1 Selection of studies and data extraction (flow chart)
Identification
Screening
Eligibility
Included
Records after duplicates removed
(n=4377) Records excluded
(n=4165)
Records screened
(n=212) Records excluded (n=144)
Full-text articles assessed for eligibility
(n=68)
Full-text articles excluded, with reasons (n=25) Not randomised n=4
Cross-over design n=1 Limb exercise only n=3 Only non-clinical outcomes n=4
Chest physio only n=1 Sit out only n=1 Passive tilting only n=1 Intervention unclear n=1 Post-ICU phase intervention n=4
Protocol only n=3 Before-after study n=1
NMES vs vibration n=1
Studies included in qualitative synthesis (n=43)
Records identified through database searching
total (n=3844) PubMed (n=1041) CENTRAL (n=2320) MEDLINE (n=483)
Additional records identified through other sources
(n=1986) PEDro (n=818) SciELO + LILACS (n=90) Web of Science (n=1015)
ICTRP (n=63)
Records identified upon search update
(n=6)
Studies included in quantitative synthesis (meta-analysis) (n=43)
n=9 for cycling n=14 for NMES n=20 for PPR
Figure 1: Selection of studies and data extraction (flow chart)
2 Studies included in quantitative synthesis (meta-analysis)
Table 1: Used studies
ID ID1 Group Trial name Journal Year
1 1 Cycling Burtin et al. Crit Care Med 2009
2 2 Cycling Coutinho et al. Fisioter Pesqui 2016
3 3 Cycling Frazzitta et al. PloS One 2016
4 4 Cycling Machado et al. J Bras Pneumol 2017
5 5 Cycling França et al. Clinics 2017
6 6 Cycling Eggmann et al. Trials, PLoS One 2018
7 7 Cycling Fossat et al. JAMA 2018
8 8 Cycling Hickmann Crit Care Med 2018
9 9 Cycling Kho et al. BMJ Open Respiratory Research 2019
10 1 NMES Zanotti et al. Chest 2003
11 2 NMES Gerovasili et al. Crit Care 2009
12 3 NMES Routsi et al. Crit Care 2012
13 4 NMES Abu-Khaber et al. Alexandria J Med 2013
14 5 NMES Kho et al. J Crit Care 2015
15 6 NMES Goll et al. Intensive Care Med Exp. 2015
16 7 NMES Kurtoglu et al. Turk J Phys Med Rehab 2015
17 8 NMES Fischer et al. Crit Care 2016
18 9 NMES Shen et al. Int J Geront 2017
19 10 NMES Acqua et al. J Rehabil Med 2017
20 11 NMES Cerqueira et al. Medicine 2018
21 12 NMES Santos et al. Physiotherapy Theory and Practice 2018 22 13 NMES Koutsioumpa et al. Critical Care Techniques 2018
23 14 NMES Shaolin et al. Chin Crit Care Med 2019
24 1 PPR Nava et al. Arch Phys Med Rehabil 1998
25 2 PPR Schweickert et al. Lancet 2009
26 3 PPR Chen S et al. J Formos Med Assoc 2011
27 4 PPR Dantas et al. Rev Bras Ter Intensiva 2012
28 5 PPR Chen YH et al. Respir Care 2012
29 6 PPR Denehy et al. Crit Care 2013
30 7 PPR Dong et al. World J Emerg Med 2014
31 8 PPR Yosef-Brauner et al. Clin Respir J 2014
32 9 PPR Brummel et al. Intensive Care Med 2014
33 10 PPR Kayambu et al. Intensive Care Med 2015
34 11 PPR Morris et al. JAMA 2016
35 12 PPR Dong et al. Int Heart J 2016
36 13 PPR Moss et al. Crit Care Med 2016
37 14 PPR Hodgson et al. Crit Care Med 2016
38 15 PPR Schaller et al. Lancet 2016
39 16 PPR Maffei et al. Arch Phys Med Rehabil 2017
40 17 PPR Wright et al. Thorax 2018
41 18 PPR McWilliams et al. J Crit Care 2018
42 19 PPR Winkelman et al. Biol Res Nurs 2018
43 20 PPR Amundadottir at al. European Journal of Physiotherapy 2019
3 ICU mortality
Descriptive statistics
Table 2: Descritive statistics: ICU mortality, all studies
parameter n mean sd p25 median p75 min max
c_cases 41 6.7 8.2 1 4 8 0 40
c_noncases 41 34.0 32.3 15 20 43 4 132
t_cases 41 6.9 7.9 2 4 9 0 33
t_noncases 41 34.9 31.8 15 26 45 2 132
Table 3: Descritive statistics: ICU mortality, Cycling
parameter n mean sd p25 median p75 min max
c_cases 9 7.8 6.8 4 7 9 1 24
c_noncases 9 32.2 39.4 9 19 38 4 130
t_cases 9 9.2 9.5 4 7 9 2 33
t_noncases 9 32.4 37.7 8 22 34 2 125
Table 4: Descritive statistics: ICU mortality, NMES
parameter n mean sd p25 median p75 min max
c_cases 12 5.5 6.7 0.8 3.0 6.5 0 22
c_noncases 12 23.7 16.8 11.8 18.5 28.8 7 60
t_cases 12 5.2 7.9 1.0 3.0 4.5 0 28
t_noncases 12 23.0 15.1 12.8 17.0 28.5 8 58
Table 5: Descritive statistics: ICU mortality, PPR
parameter n mean sd p25 median p75 min max
c_cases 20 7.0 9.6 1.0 3.5 7.2 0 40
c_noncases 20 41.1 35.5 16.8 25.5 51.2 9 132
t_cases 20 6.8 7.2 1.5 5.0 10.5 0 26
t_noncases 20 43.1 35.2 19.5 29.5 49.5 9 132
Forest plot Odds ratio
Number of studies combined: k = 36
OR 95%-CI z p-value
Random effects model 1.0229 [0.8417; 1.2432] 0.23 0.8196 Quantifying heterogeneity:
tau^2 = 0; H = 1.00 [1.00; 1.16]; I^2 = 0.0% [0.0%; 26.1%]
Quantifying residual heterogeneity:
tau^2 = 0; H = 1.00 [1.00; 1.19]; I^2 = 0.0% [0.0%; 28.9%]
Test of heterogeneity:
Q d.f. p-value 29.44 35 0.7334
Results for subgroups (random effects model):
k OR 95%-CI Q tau^2 I^2
Cycling 9 1.1843 [0.8160; 1.7188] 6.93 0 0.0%
NMES 10 1.0450 [0.6855; 1.5932] 7.61 0 0.0%
PPR 17 0.9374 [0.7137; 1.2311] 13.89 0 0.0%
Test for subgroup differences (random effects model):
Q d.f. p-value Between groups 1.00 2 0.6070 Within groups 28.44 33 0.6938 Details on meta-analytical method:
- Inverse variance method
- DerSimonian-Laird estimator for tau^2 (assuming common tau^2 in subgroups) - Continuity correction of 0.5 in studies with zero cell frequencies
Study
Random effects model
Heterogeneity: I2 = 0%, τ2 = 0, p = 0.73 Residual heterogeneity: I2 = 0%, τ2 = 0, p = 0.69 Cycling
NMES
PPR
Random effects model
Random effects model
Random effects model
Heterogeneity: I2 = 0%, τ2 = 0, p = 0.54
Heterogeneity: I2 = 0%, τ2 = 0, p = 0.57
Heterogeneity: I2 = 0%, τ2 = 0, p = 0.61 Coutinho et al. 2016
Machado et al. 2017 França et al. 2017 Burtin et al. 2009 Eggmann et al. 2018 Fossat et al. 2018 Frazzitta et al. 2016 Hickmann 2018 Kho et al. 2019
Zanotti et al. 2003 Gerovasili et al. 2009 Routsi et al. 2012 Abu−Khaber et al. 2013 Kho et al. 2015 Fischer et al. 2016 Shen et al. 2017 Cerqueira et al. 2018 Kurtoglu et al. 2015 Acqua et al. 2017 Santos et al. 2018 Koutsioumpa et al. 2018
Nava et al. 1998 Chen S et al. 2011 Dantas et al. 2012 Dong et al. 2014
Yosef−Brauner et al. 2014 Brummel et al. 2014 Morris et al. 2016 Dong et al. 2016 Moss et al. 2016 Maffei et al. 2017 Wright et al. 2018 McWilliams et al. 2018 Winkelman et al. 2018 Schweickert et al. 2009 Hodgson et al. 2016 Schaller et al. 2016 Chen YH et al. 2012 Denehy et al. 2013 Kayambu et al. 2015 Amundadottir at al. 2019
Events
6 4 7 11 9 33 2 2 9
0 6 28 4 3 1 2 1 0 3 3 12
12 2 12 0 0 6 18 2 10 0 26 7 4 9 2 17 0 6 3 0
Total
1713 375
339
999 14 26 9 45 58 158 20 9 36
12 24 68 40 16 27 18 59 15 11 11 38
60 20 26 30 9 22 150 53 59 20 150 52 25 49 29 104 12 74 26 29 Experimental
Events
2 7 6 7 10 24 1 4 9
0 5 22 6 1 3 0 3 0 3 8 15
4 2 19 0 0 6 18 3 6 0 40 7 1 14 1 8 3 6 1 1
Total
1672 360
350
962 11 23 10 45 57 154 20 10 30
12 25 72 40 18 27 7 63 15 14 15 42
20 19 33 30 9 22 150 53 61 20 158 50 29 55 21 96 15 76 24 21 Control
0.1 0.2 0.5 1 2 5 10
Odds Ratio
Favours experimental Favours control OR
1.02 1.18
1.05
0.94 3.38 0.42 2.33 1.76 0.86 1.43 2.11 0.43 0.78
1.33 1.59 0.63 3.92 0.31 2.27 0.34 1.38 0.33 0.83
1.00 0.94 0.63
1.00 1.00 0.65 1.87 0.62 0.96 5.33 0.66 1.48 2.15 0.14 1.03 3.00 0.23
95%−CI
[0.84; 1.24]
[0.82; 1.72]
[0.69; 1.59]
[0.71; 1.23]
[0.52; 21.73]
[0.10; 1.66]
[0.31; 17.54]
[0.61; 5.04]
[0.32; 2.31]
[0.80; 2.55]
[0.18; 25.35]
[0.06; 3.22]
[0.26; 2.30]
[0.35; 5.13]
[0.79; 3.19]
[0.16; 2.43]
[0.36; 42.20]
[0.03; 3.16]
[0.10; 53.39]
[0.03; 3.41]
[0.22; 8.67]
[0.06; 1.74]
[0.33; 2.11]
[0.28; 3.54]
[0.12; 7.48]
[0.22; 1.78]
[0.27; 3.77]
[0.50; 2.01]
[0.10; 4.08]
[0.63; 5.52]
[0.36; 1.08]
[0.31; 2.95]
[0.55; 51.27]
[0.26; 1.69]
[0.13; 17.50]
[0.88; 5.24]
[0.01; 3.06]
[0.32; 3.35]
[0.29; 31.01]
[0.01; 5.97]
Weight
100.0%
27.4%
21.4%
51.2%
1.1%
2.0%
0.9%
3.4%
3.9%
11.3%
0.6%
0.9%
3.2%
0.0%
2.1%
7.8%
2.1%
0.7%
0.7%
0.4%
0.7%
0.0%
1.1%
1.4%
4.4%
2.4%
0.9%
3.6%
0.0%
0.0%
2.2%
7.8%
1.1%
3.2%
0.0%
12.4%
3.0%
0.7%
4.3%
0.6%
4.8%
0.4%
2.7%
0.7%
0.4%
Risk difference
Study
Random effects model
Heterogeneity: I2 = 0%, τ2 = 0, p = 0.76 Residual heterogeneity: I2 = 0%, τ2 = 0, p = 0.74 Cycling
NMES
PPR
Random effects model
Random effects model
Random effects model
Heterogeneity: I2 = 0%, τ2 = 0, p = 0.52
Heterogeneity: I2 = 0%, τ2 = 0, p = 0.65
Heterogeneity: I2 = 0%, τ2 = 0, p = 0.64 Coutinho et al. 2016
Machado et al. 2017 França et al. 2017 Burtin et al. 2009 Eggmann et al. 2018 Fossat et al. 2018 Frazzitta et al. 2016 Hickmann 2018 Kho et al. 2019
Zanotti et al. 2003 Gerovasili et al. 2009 Routsi et al. 2012 Abu−Khaber et al. 2013 Kho et al. 2015 Fischer et al. 2016 Shen et al. 2017 Cerqueira et al. 2018 Kurtoglu et al. 2015 Acqua et al. 2017 Santos et al. 2018 Koutsioumpa et al. 2018
Nava et al. 1998 Chen S et al. 2011 Dantas et al. 2012 Dong et al. 2014
Yosef−Brauner et al. 2014 Brummel et al. 2014 Morris et al. 2016 Dong et al. 2016 Moss et al. 2016 Maffei et al. 2017 Wright et al. 2018 McWilliams et al. 2018 Winkelman et al. 2018 Schweickert et al. 2009 Hodgson et al. 2016 Schaller et al. 2016 Chen YH et al. 2012 Denehy et al. 2013 Kayambu et al. 2015 Amundadottir at al. 2019
Events
6 4 7 11 9 33 2 2 9
0 6 28 4 3 1 2 1 0 3 3 12
12 2 12 0 0 6 18 2 10 0 26 7 4 9 2 17 0 6 3 0
Total
1713 375
339
999 14 26 9 45 58 158 20 9 36
12 24 68 40 16 27 18 59 15 11 11 38
60 20 26 30 9 22 150 53 59 20 150 52 25 49 29 104 12 74 26 29 Experimental
Events
2 7 6 7 10 24 1 4 9
0 5 22 6 1 3 0 3 0 3 8 15
4 2 19 0 0 6 18 3 6 0 40 7 1 14 1 8 3 6 1 1
Total
1672 360
350
962 11 23 10 45 57 154 20 10 30
12 25 72 40 18 27 7 63 15 14 15 42
20 19 33 30 9 22 150 53 61 20 158 50 29 55 21 96 15 76 24 21 Control
−0.6 −0.4 −0.2 0 0.2 0.4 Risk Difference
Favours experimental Favours control RD
0.00 0.03
−0.01
−0.00 0.25
−0.15 0.18 0.09
−0.02 0.05 0.05
−0.18
−0.05
0.00 0.05 0.11
−0.05 0.13
−0.07 0.11
−0.03 0.00 0.06
−0.26
−0.04
0.00
−0.01
−0.11 0.00 0.00 0.00 0.00
−0.02 0.07 0.00
−0.08
−0.01 0.13
−0.07 0.02 0.08
−0.20 0.00 0.07
−0.05
95%−CI
[−0.02; 0.02]
[−0.03; 0.08]
[−0.05; 0.03]
[−0.03; 0.02]
[−0.10; 0.59]
[−0.38; 0.08]
[−0.23; 0.59]
[−0.08; 0.25]
[−0.16; 0.12]
[−0.03; 0.14]
[−0.11; 0.21]
[−0.59; 0.23]
[−0.27; 0.17]
[−0.15; 0.15]
[−0.18; 0.28]
[−0.05; 0.26]
[−0.19; 0.09]
[−0.09; 0.35]
[−0.21; 0.06]
[−0.12; 0.34]
[−0.09; 0.03]
[−0.12; 0.12]
[−0.28; 0.40]
[−0.63; 0.10]
[−0.25; 0.17]
[−0.20; 0.20]
[−0.20; 0.19]
[−0.37; 0.14]
[−0.06; 0.06]
[−0.19; 0.19]
[−0.26; 0.26]
[−0.07; 0.07]
[−0.10; 0.06]
[−0.05; 0.19]
[−0.09; 0.09]
[−0.17; 0.01]
[−0.14; 0.13]
[−0.03; 0.28]
[−0.23; 0.09]
[−0.11; 0.15]
[−0.01; 0.17]
[−0.43; 0.03]
[−0.08; 0.09]
[−0.07; 0.22]
[−0.16; 0.07]
Weight
100.0%
12.8%
24.1%
63.0%
0.3%
0.7%
0.2%
1.5%
2.1%
5.4%
1.5%
0.2%
0.8%
1.8%
0.7%
1.6%
1.9%
0.8%
2.1%
0.8%
10.2%
2.7%
0.3%
0.3%
0.9%
1.0%
1.1%
0.6%
10.0%
1.1%
0.6%
7.3%
6.1%
2.7%
4.6%
4.8%
2.2%
1.6%
1.6%
2.3%
4.9%
0.8%
5.2%
1.8%
3.0%
Figure 2: Forest plot: ICU mortality (risk difference)
Funnel plots
0.1 0.5 2.0 5.0
1.21.00.80.60.40.20.0
Odds ratio, Cycling
Standard Error
0.05 0.20 1.00 5.00 20.00
1.51.00.50.0
Odds ratio, NMES
Standard Error
0.05 0.20 1.00 5.00 20.00
1.51.00.50.0
Odds ratio, PPR
Standard Error
Figure 3: Funnel plots: ICU mortality
[1] "P values of Eager's test for each group:"
$Cycling [1] 0.8406415
$NMES
[1] 0.3981985
$PPR[1] 0.5341783
0.05 0.10 0.20 0.50 1.00 2.00 5.00 10.00 20.00
1.51.00.50.0
Odds ratio
Standard Error
0.1 > p > 0.05 0.05 > p > 0.01
< 0.01
Figure 4: Funnel plots: ICU mortality
[1] "P values of Eager's test for all studies:"
[1] 0.918305
4 End of study mortality
Descriptive statistics
Table 6: Descritive statistics: End study mortality, all studies
parameter n mean sd p25 median p75 min max
c_cases 38 9.7 11.3 3.0 6.0 14.0 0 56
c_noncases 38 31.9 30.2 13.2 20.0 40.2 4 122
t_cases 38 9.4 10.8 2.2 6.0 11.8 0 43
t_noncases 38 33.2 29.2 13.2 25.5 40.0 2 117
Table 7: Descritive statistics: End study mortality, Cycling
parameter n mean sd p25 median p75 min max
c_cases 9 10.1 8.8 6 7 11 4 32
c_noncases 9 29.9 37.2 6 16 38 4 122
t_cases 9 10.4 12.4 4 7 11 2 42
t_noncases 9 31.2 34.8 12 22 34 2 116
Table 8: Descritive statistics: End study mortality, NMES
parameter n mean sd p25 median p75 min max
c_cases 11 5.9 6.8 2.5 3 7.0 0 22
c_noncases 11 23.6 17.9 11.5 15 30.5 5 60
t_cases 11 5.5 8.2 1.0 3 4.5 0 28
t_noncases 11 23.2 15.9 12.5 15 31.0 8 58
Table 9: Descritive statistics: End study mortality, PPR
parameter n mean sd p25 median p75 min max
c_cases 18 11.9 14.0 2.2 7.5 14.8 0 56
c_noncases 18 37.9 32.5 16.8 23.5 51.5 4 117
t_cases 18 11.2 11.3 3.2 9.0 12.8 0 43
t_noncases 18 40.3 31.8 18.5 27.5 48.8 11 117
Forest plot Odds ratio
Number of studies combined: k = 35
OR 95%-CI z p-value
Random effects model 0.9387 [0.7871; 1.1193] -0.70 0.4809 Quantifying heterogeneity:
tau^2 = 0; H = 1.00 [1.00; 1.26]; I^2 = 0.0% [0.0%; 37.1%]
Quantifying residual heterogeneity:
tau^2 = 0.0108; H = 1.02 [1.00; 1.20]; I^2 = 3.4% [0.0%; 30.8%]
Test of heterogeneity:
Q d.f. p-value 33.36 34 0.4989
Results for subgroups (random effects model):
k OR 95%-CI Q tau^2 I^2
Cycling 9 0.9852 [0.6885; 1.4099] 10.88 0.0108 26.5%
NMES 9 0.9520 [0.6123; 1.4800] 5.95 0.0108 0.0%
PPR 17 0.9081 [0.7122; 1.1579] 16.29 0.0108 1.8%
Test for subgroup differences (random effects model):
Q d.f. p-value Between groups 0.14 2 0.9307 Within groups 33.12 32 0.4125 Details on meta-analytical method:
- Inverse variance method
- DerSimonian-Laird estimator for tau^2 (assuming common tau^2 in subgroups) - Continuity correction of 0.5 in studies with zero cell frequencies
Study
Random effects model
Heterogeneity: I2 = 0%, τ2 = 0, p = 0.50
Residual heterogeneity: I2 = 3%, τ2 = 0.0108, p = 0.41 Cycling
NMES
PPR
Random effects model
Random effects model
Random effects model
Heterogeneity: I2 = 26%, τ2 = 0.0108, p = 0.21
Heterogeneity: I2 = 0%, τ2 = 0.0108, p = 0.65
Heterogeneity: I2 = 2%, τ2 = 0.0108, p = 0.43 Coutinho et al. 2016
Machado et al. 2017 França et al. 2017 Burtin et al. 2009 Eggmann et al. 2018 Fossat et al. 2018 Frazzitta et al. 2016 Hickmann 2018 Kho et al. 2019
Zanotti et al. 2003 Routsi et al. 2012 Abu−Khaber et al. 2013 Kho et al. 2015 Fischer et al. 2016 Shen et al. 2017 Cerqueira et al. 2018 Kurtoglu et al. 2015 Acqua et al. 2017 Dos Santos et al. 2018 Koutsioumpa et al. 2018
Nava et al. 1998 Chen S et al. 2011 Dantas et al. 2012 Dong et al. 2014 Brummel et al. 2014 Morris et al. 2016 Moss et al. 2016 Maffei et al. 2017 Wright et al. 2018 McWilliams et al. 2018 Winkelman et al. 2018 Schweickert et al. 2009 Hodgson et al. 2016 Schaller et al. 2016 Chen YH et al. 2012 Denehy et al. 2013 Kayambu et al. 2015 Amundadottir at al. 2019
Events
2 4 7 11 10 42 5 2 11
0 28 4 3 1 5 1 0 3 3 12
12 9 12 2 7 33 10 0 43 14 4 9 2 21 0 13 8 3
Total
1617 375
315
927 14 26 9 45 58 158 20 9 36
12 68 40 16 27 18 59 15 11 11 38
60 20 26 30 22 150 59 20 150 52 25 49 29 104 12 64 26 29 Experimental
Events
6 7 6 7 14 32 4 4 11
0 22 6 3 3 2 3 0 3 8 15
4 14 19 3 9 33 6 0 56 13 1 14 1 15 3 19 2 2
Total
1582 360
325
897 11 23 10 45 57 154 20 10 30
12 72 40 18 27 7 63 15 14 15 42
20 18 33 30 22 150 61 20 158 50 29 55 21 96 15 76 22 21 Control
0.1 0.2 0.5 1 2 5 10
Odds Ratio
Favours experimental Favours control End study mortality
OR
0.94 0.99
0.95
0.91 0.14 0.42 2.33 1.76 0.64 1.38 1.33 0.43 0.76
1.59 0.63 1.15 0.31 0.96 0.34 1.38 0.33 0.83
1.00 0.23 0.63 0.64 0.67 1.00 1.87 0.73 1.05 5.33 0.66 1.48 1.37 0.14 0.76 4.44 1.10
95%−CI
[0.79; 1.12]
[0.69; 1.41]
[0.61; 1.48]
[0.71; 1.16]
[0.02; 0.94]
[0.10; 1.66]
[0.31; 17.54]
[0.61; 5.04]
[0.26; 1.59]
[0.82; 2.33]
[0.30; 5.93]
[0.06; 3.22]
[0.27; 2.12]
[0.79; 3.19]
[0.16; 2.43]
[0.20; 6.74]
[0.03; 3.16]
[0.14; 6.67]
[0.03; 3.41]
[0.22; 8.67]
[0.06; 1.74]
[0.33; 2.11]
[0.28; 3.54]
[0.06; 0.97]
[0.22; 1.78]
[0.10; 4.15]
[0.20; 2.32]
[0.58; 1.73]
[0.63; 5.52]
[0.45; 1.18]
[0.43; 2.53]
[0.55; 51.27]
[0.26; 1.69]
[0.13; 17.50]
[0.66; 2.83]
[0.01; 3.06]
[0.34; 1.70]
[0.83; 23.73]
[0.17; 7.22]
Weight
100.0%
26.1%
16.7%
57.3%
0.8%
1.6%
0.8%
2.8%
3.7%
11.2%
1.4%
0.8%
2.9%
0.0%
6.4%
1.7%
1.0%
0.6%
0.8%
0.6%
0.0%
0.9%
1.1%
3.6%
1.9%
1.5%
2.9%
0.9%
2.0%
10.4%
2.6%
0.0%
13.4%
4.0%
0.6%
3.5%
0.5%
5.8%
0.3%
4.8%
1.1%
0.9%
Figure 5: Forest plot: End study mortality (odds ratio)
Risk difference
Study
Random effects model
Heterogeneity: I2 = 4%, τ2 = 0.0003, p = 0.39 Residual heterogeneity: I2 = 8%, τ2 = 0.0006, p = 0.33 Cycling
NMES
PPR
Random effects model
Random effects model
Random effects model
Heterogeneity: I2 = 34%, τ2 = 0.0006, p = 0.14
Heterogeneity: I2 = 0%, τ2 = 0.0006, p = 0.86
Heterogeneity: I2 = 17%, τ2 = 0.0006, p = 0.25 Coutinho et al. 2016
Machado et al. 2017 França et al. 2017 Burtin et al. 2009 Eggmann et al. 2018 Fossat et al. 2018 Frazzitta et al. 2016 Hickmann 2018 Kho et al. 2019
Zanotti et al. 2003 Routsi et al. 2012 Abu−Khaber et al. 2013 Kho et al. 2015 Fischer et al. 2016 Shen et al. 2017 Cerqueira et al. 2018 Kurtoglu et al. 2015 Acqua et al. 2017 Dos Santos et al. 2018 Koutsioumpa et al. 2018
Nava et al. 1998 Chen S et al. 2011 Dantas et al. 2012 Dong et al. 2014 Brummel et al. 2014 Morris et al. 2016 Moss et al. 2016 Maffei et al. 2017 Wright et al. 2018 McWilliams et al. 2018 Winkelman et al. 2018 Schweickert et al. 2009 Hodgson et al. 2016 Schaller et al. 2016 Chen YH et al. 2012 Denehy et al. 2013 Kayambu et al. 2015 Amundadottir at al. 2019
Events
2 4 7 11 10 42 5 2 11
0 28 4 3 1 5 1 0 3 3 12
12 9 12 2 7 33 10 0 43 14 4 9 2 21 0 13 8 3
Total
1617 375
315
927 14 26 9 45 58 158 20 9 36
12 68 40 16 27 18 59 15 11 11 38
60 20 26 30 22 150 59 20 150 52 25 49 29 104 12 64 26 29 Experimental
Events
6 7 6 7 14 32 4 4 11
0 22 6 3 3 2 3 0 3 8 15
4 14 19 3 9 33 6 0 56 13 1 14 1 15 3 19 2 2
Total
1582 360
325
897 11 23 10 45 57 154 20 10 30
12 72 40 18 27 7 63 15 14 15 42
20 18 33 30 22 150 61 20 158 50 29 55 21 96 15 76 22 21 Control
−0.6 −0.4 −0.2 0 0.2 0.4 Risk Difference
Favours experimental Favours control End study mortality
RD
−0.01
−0.00
−0.02
−0.00
−0.40
−0.15 0.18 0.09
−0.07 0.06 0.05
−0.18
−0.06
0.00 0.11
−0.05 0.02
−0.07
−0.01
−0.03 0.00 0.06
−0.26
−0.04
0.00
−0.33
−0.11
−0.03
−0.09 0.00 0.07 0.00
−0.07 0.01 0.13
−0.07 0.02 0.05
−0.20
−0.05 0.22 0.01
95%−CI
[−0.03; 0.02]
[−0.07; 0.06]
[−0.07; 0.03]
[−0.04; 0.03]
[−0.75; −0.06]
[−0.38; 0.08]
[−0.23; 0.59]
[−0.08; 0.25]
[−0.22; 0.07]
[−0.04; 0.15]
[−0.21; 0.31]
[−0.59; 0.23]
[−0.29; 0.17]
[−0.15; 0.15]
[−0.05; 0.26]
[−0.19; 0.09]
[−0.24; 0.28]
[−0.21; 0.06]
[−0.40; 0.39]
[−0.09; 0.03]
[−0.12; 0.12]
[−0.28; 0.40]
[−0.63; 0.10]
[−0.25; 0.17]
[−0.20; 0.20]
[−0.62; −0.04]
[−0.37; 0.14]
[−0.17; 0.11]
[−0.37; 0.19]
[−0.09; 0.09]
[−0.05; 0.19]
[−0.09; 0.09]
[−0.17; 0.04]
[−0.16; 0.18]
[−0.03; 0.28]
[−0.23; 0.09]
[−0.11; 0.15]
[−0.06; 0.15]
[−0.43; 0.03]
[−0.19; 0.09]
[ 0.00; 0.43]
[−0.16; 0.18]
Weight
100.0%
15.8%
31.7%
52.5%
0.5%
1.1%
0.4%
2.2%
2.7%
6.3%
0.9%
0.4%
1.2%
2.7%
2.4%
2.9%
0.9%
3.1%
0.4%
12.8%
4.0%
0.5%
0.5%
1.4%
1.5%
0.7%
0.9%
3.1%
0.8%
6.4%
4.0%
6.6%
5.3%
2.1%
2.4%
2.4%
3.5%
5.1%
1.2%
3.1%
1.3%
2.2%
Figure 6: Forest plot: End study mortality (risk difference)
Funnel plots
0.2 0.5 1.0 2.0 5.0
1.00.80.60.40.20.0
Odds ratio, Cycling
Standard Error
0.1 0.2 0.5 1.0 2.0 5.0 10.0
1.21.00.80.60.40.20.0
Odds ratio, NMES
Standard Error
0.05 0.20 0.50 2.00 5.00 20.00
1.51.00.50.0
Odds ratio, PPR
Standard Error
Figure 7: Funnel plots: ICU mortality
[1] "P values of Eager's test for each group:"
$Cycling [1] 0.175371
$NMES
[1] 0.04451462
$PPR[1] 0.7021767
0.05 0.10 0.20 0.50 1.00 2.00 5.00 10.00 20.00
1.51.00.50.0
Odds ratio
Standard Error
0.1 > p > 0.05 0.05 > p > 0.01
< 0.01
Figure 8: Funnel plots: ICU mortality
[1] "P values of Eager's test for all studies:"
[1] 0.2287411
5 ICU LOS
Descriptive statistics
Table 10: Descritive statistics: ICU LOS, all studies
parameter n mean sd p25 median p75 min max
c_mean 32 19.4 15.1 10.3 15.6 20.5 2.7 74.3
c_n 32 36.4 36.1 15.8 23.0 37.5 10.0 158.0
c_sd 32 12.2 11.3 5.1 9.5 13.5 0.5 52.6
t_mean 32 16.6 11.4 9.6 13.2 20.2 2.6 51.8
t_n 32 37.2 35.8 14.8 26.5 40.8 9.0 150.0
t_sd 32 9.9 6.9 4.1 8.3 14.4 0.5 32.2
Table 11: Descritive statistics: ICU LOS, Cycling
parameter n mean sd p25 median p75 min max
c_mean 8 16.2 7.9 9.5 17.2 22.5 4.8 25.1
c_n 8 23.2 16.7 10.8 16.0 31.5 10.0 57.0
c_sd 8 10.5 4.3 7.6 10.2 12.0 4.7 18.7
t_mean 8 18.1 10.7 10.0 17.8 21.5 6.3 38.8
t_n 8 24.2 16.8 12.8 18.5 32.2 9.0 58.0
t_sd 8 12.4 5.1 12.0 14.2 15.2 2.6 17.1
Table 12: Descritive statistics: ICU LOS, NMES
parameter n mean sd p25 median p75 min max
c_mean 8 26.5 23.5 13.3 18.0 32.3 2.7 74.3
c_n 8 23.8 10.7 14.8 22.5 30.0 12.0 42.0
c_sd 8 14.1 17.0 2.6 9.3 17.6 0.5 52.6
t_mean 8 18.7 15.9 9.6 12.2 24.1 2.6 51.8
t_n 8 21.0 9.9 11.8 21.0 27.0 11.0 38.0
t_sd 8 6.6 6.1 2.3 4.5 8.9 0.5 17.0
Table 13: Descritive statistics: ICU LOS, PPR
parameter n mean sd p25 median p75 min max
c_mean 16 17.4 12.3 11.7 15.3 18.2 4.6 56.9
c_n 16 49.3 46.4 20.8 26.5 56.5 14.0 158.0
c_sd 16 12.1 10.9 5.0 9.7 12.9 2.9 45.6
t_mean 16 14.8 9.4 10.1 12.8 14.7 4.3 38.1
t_n 16 51.7 45.0 24.2 29.5 59.2 9.0 150.0
t_sd 16 10.3 7.7 4.5 8.3 12.1 3.2 32.2
controltreatment
0 20 40 60
0.00 0.01 0.02 0.03
0.00 0.01 0.02 0.03
mean
density
group
Cycling NMES PPR
Forest plot
Number of studies combined: k = 32
MD 95%-CI z p-value
Random effects model -1.2157 [-2.4475; 0.0160] -1.93 0.0531 Quantifying heterogeneity:
tau^2 = 6.4615; H = 2.65 [2.29; 3.07]; I^2 = 85.8% [80.9%; 89.4%]
Quantifying residual heterogeneity:
tau^2 = 6.7132; H = 2.38 [2.03; 2.79]; I^2 = 82.3% [75.6%; 87.2%]
Test of heterogeneity:
Q d.f. p-value 217.64 31 < 0.0001
Results for subgroups (random effects model):
k MD 95%-CI Q tau^2 I^2
Cycling 8 1.2148 [-1.7077; 4.1374] 9.34 6.7132 25.0%
NMES 8 -1.2338 [-3.7387; 1.2710] 91.13 6.7132 92.3%
PPR 16 -1.9860 [-3.6409; -0.3310] 63.65 6.7132 76.4%
Test for subgroup differences (random effects model):
Q d.f. p-value Between groups 3.49 2 0.1747
Within groups 164.11 29 < 0.0001 Details on meta-analytical method:
- Inverse variance method
- DerSimonian-Laird estimator for tau^2 (assuming common tau^2 in subgroups)
Study
Random effects model
Heterogeneity: I2 = 86%, τ2 = 6.4615, p < 0.01 Residual heterogeneity: I2 = 82%, τ2 = 6.7132, p < 0.01 Cycling
NMES
PPR
Random effects model
Random effects model
Random effects model
Heterogeneity: I2 = 25%, τ2 = 6.7132, p = 0.23
Heterogeneity: I2 = 92%, τ2 = 6.7132, p < 0.01
Heterogeneity: I2 = 76%, τ2 = 6.7132, p < 0.01 Coutinho et al. 2016
Machado et al. 2017 França et al. 2017 Burtin et al. 2009 Eggmann et al. 2018 Frazzitta et al. 2016 Hickmann 2018 Kho et al. 2019
Zanotti et al. 2003 Kho et al. 2015 Fischer et al. 2016 Cerqueira et al. 2018 Acqua et al. 2017 Dos Santos et al. 2018 Koutsioumpa et al. 2018 Shaolin et al. 2019
Nava et al. 1998 Dong et al. 2014 Yosef−Brauner et al. 2014 Brummel et al. 2014 Morris et al. 2016 Dong et al. 2016 Moss et al. 2016 Maffei et al. 2017 Wright et al. 2018 Winkelman et al. 2018 Schweickert et al. 2009 Hodgson et al. 2016 Schaller et al. 2016 Chen YH et al. 2012 Kayambu et al. 2015 Amundadottir at al. 2019
Total
1189 194
168
827 14 22 9 31 58 15 9 36
12 16 27 26 11 11 38 27
60 30 9 22 150 53 59 20 150 25 49 29 104 12 26 29
Mean
20.1 20.0 6.3 25.7 7.5 38.8 10.8 15.5
51.8 22.0 10.7 2.6 10.0 13.8 30.5 8.3
38.1 12.7 13.0 4.3 8.5 11.7 16.7 12.0 14.0 13.4 7.9 10.7 5.3 35.4 20.3 13.5
SD
15.1 14.3 2.6 17.1 6.3 15.7 14.2 13.9
14.7 17.0 5.0 0.5 4.0 6.9 2.2 2.4
14.3 4.1 4.6 3.9 7.5 3.2 11.4 15.7 9.7 8.0 6.6 8.6 3.8 21.9 32.2 8.7 Experimental
Total
1165 186
190
789 11 16 10 36 57 16 10 30
12 18 27 33 14 15 42 29
20 14 30 22 150 53 61 20 158 29 55 21 96 15 24 21
Mean
20.1 21.7 4.8 25.0 8.6 25.1 9.8 14.3
47.4 20.0 74.3 2.7 16.0 14.2 27.3 10.4
33.2 15.2 18.1 4.6 8.3 18.3 16.7 14.3 15.3 18.8 9.0 12.7 8.3 56.9 15.8 13.7
SD
9.3 18.7 4.7 13.1 7.7 11.2 7.4 11.6
19.2 17.0 52.6 0.5 9.0 9.7 2.5 2.6
11.7 4.5 3.1 2.9 6.7 4.2 10.6 20.0 11.2 14.5 5.2 8.7 6.0 45.6 26.0 12.3 Control
−20 −10 0 10 20
Mean Difference
Favours experimental Favours control ICU LOS
MD
−1.22 1.21
−1.23
−1.99 0.00
−1.67 1.50 0.67
−1.17 13.70 1.03 1.17
4.40 2.00
−63.67
−0.09
−6.00
−0.40 3.19
−2.11
4.90
−2.50
−5.11
−0.23 0.17
−6.60 0.00
−2.30
−1.33
−5.36
−1.10
−2.00
−3.00
−21.50 4.50
−0.23
95%−CI
[ −2.45; 0.02]
[ −1.71; 4.14]
[ −3.74; 1.27]
[ −3.64; −0.33]
[ −9.63; 9.63]
[−12.60; 9.26]
[ −1.90; 4.90]
[ −6.72; 8.06]
[ −3.74; 1.41]
[ 4.04; 23.36]
[ −9.31; 11.37]
[ −4.98; 7.31]
[ −9.28; 18.08]
[ −9.45; 13.45]
[−83.59; −43.74]
[ −0.36; 0.18]
[−11.27; −0.73]
[ −6.78; 5.98]
[ 2.15; 4.23]
[ −3.41; −0.81]
[ −1.38; 11.18]
[ −5.28; 0.28]
[ −8.31; −1.91]
[ −2.27; 1.80]
[ −1.44; 1.78]
[ −8.02; −5.18]
[ −3.95; 3.95]
[−13.44; 8.84]
[ −3.68; 1.01]
[−11.48; 0.76]
[ −3.41; 1.21]
[ −6.87; 2.87]
[ −4.40; −1.60]
[−47.69; 4.69]
[−11.66; 20.66]
[ −6.39; 5.92]
Weight
100.0%
18.1%
24.9%
57.0%
1.3%
1.1%
4.2%
1.9%
4.8%
1.3%
1.2%
2.4%
0.7%
1.0%
0.4%
6.1%
2.9%
2.3%
5.9%
5.7%
2.4%
4.7%
4.3%
5.2%
5.5%
5.7%
3.8%
1.0%
5.0%
2.4%
5.0%
3.1%
5.7%
0.2%
0.5%
2.4%
Figure 9: Forest plot: ICU LOS
Funnel plots
−10 −5 0 5 10 15
543210
Mean difference
Standard Error
−60 −40 −20 0 20
1086420
Mean difference
Standard Error
−30 −20 −10 0 10 20
121086420
Mean difference
Standard Error
Figure 10: Funnel plots: ICU LOS
[1] "P values of Eager's test for each group:"
$Cycling [1] 0.2534403
$NMES
[1] 0.5602923
$PPR[1] 0.4970562
−60 −40 −20 0 20
128<
