Six-minute walk distance after critical illness: a systematic review and meta-analysis

Abstract

Background and Objectives:

Impaired physical functioning is common and long lasting after an intensive care (ICU) admission. The six-minute walk test (6MWT) is a validated and widely used test of functional capacity. This systematic review synthesises existing data in order to: (1) evaluate six-minute walk distance (6MWD) in metres over longitudinal follow-up after critical illness, (2) compare 6MWD between acute respiratory distress syndrome (ARDS) versus non-ARDS survivors, and (3) evaluate patient- and ICU-related factors associated with 6MWD.

Data Sources:

Five databases (PubMed, EMBASE, Cumulative Index of Nursing and Allied Health literature, PsychINFO, and Cochrane Controlled Trials Registry) were searched to identify studies reporting 6MWT after hospital discharge in survivors from general (i.e., non-speciality) ICUs. The last search was run on 14 February 2018. Databases were accessed via Johns Hopkins University Library.

Data Extraction and Synthesis:

Pooled mean 6MWD were reported, with separate linear random effects models used to evaluate associations of 6MWD with ARDS status, and patient- and ICU-related variables. Twenty-six eligible articles on 16 unique participant groups were included. The pooled mean (95% CI) 6MWD results at 3 and 12-months post discharge were: 361 [321-401] and 436 [391-481] metres, respectively. There was a significant increase in 6MWD at 12 months compared to 3 months (p=0.017). In ARDS versus non-ARDS survivors, the mean (95% CI) 6MWD difference over 3-, 6-, and 12-month follow-up was 73 [13-133] meters lower. Female sex and pre-existing comorbidity also were significantly associated with lower 6MWD, with ICU-related variables having no consistent associations.

Conclusions:

Compared to initial assessment at 3 months, significant improvement in 6MWD was reported at 12 months. Female sex, pre-existing comorbidity, and ARDS (vs. non-ARDS) were associated with lower 6MWT results. Such factors warrant consideration in the design of clinical research studies and in the interpretation of patient status using the 6MWT.

INTRODUCTION

Survivorship after critical illness is frequently associated with significant long-term morbidity in terms of physical, cognitive and/or mental health outcomes [1, 2]. Within physical impairments, reduction in exercise capacity is an important issue that negatively impacts survivors’ health-related quality of life (HRQoL) and subsequent healthcare utilisation [2, 3]. The six-minute walk test (6MWT) is a widely used measure of functional exercise capacity. In survivors of critical illness, the 6MWT has established clinimetric properties in terms of validity and responsiveness, including a minimal clinically important difference of 20-30 meters [4].

The objectives of this systematic review and meta-analysis are to synthesise existing data to: (1) evaluate mean six-minute walk distance (6MWD) over longitudinal follow-up during the first 5 years after critical illness, (2) compare 6MWD between acute respiratory distress syndrome (ARDS) versus non-ARDS survivors, and (3) evaluate patient- and Intensive care unit (ICU)-related factors associated with 6MWD.

METHODS

The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [5] were followed. An initial scoping review has been published [6], and the protocol for this review was registered on PROSPERO (CRD42018102066).

Eligibility Criteria

Studies, which included patients who had been admitted through an ICU and evaluated 6MWT after hospital discharge, were eligible for inclusion in this systematic review. In studies, which involved >50% of their cohort from a specialised ICU such as transplant, trauma, cardiac surgery or neurology were excluded from this systematic review. Complete eligibility criteria are outlined in Table 1.

Table 1:

Eligibility criteria for studies in the systematic review

Characteristics	Inclusion	Exclusion
Study design	• Quantitative studies including RCTs, pseudo-RCTs, cohort studies, case-control studies, case series and cross-sectional studies	• Studies without original participant data (such as reviews, editorials, clinical guidelines)
Participants	• > 20 Adult ICU survivors	• (>50%) of study population <16 years of age • (>50%) of study population was a specialized patient cohort (such as neurological, cardiac surgery, transplantation, or trauma intensive care unit)
Exposure	• ICU admission
Outcomes	• 6MWT after hospital discharge	• Outcomes only assessed in the hospital setting
Publication	• Peer reviewed	• Published prior to 1970 • Conference abstracts or dissertations

Abbreviations: RCT, randomized controlled trial; ICU: intensive care unit; <, less than; >, more than; %, percentage; 6MWT, six-minute walk test.

Information Sources and Search Strategy

Prior to conducting this review, the Cochrane Library and Database of Abstract of Review of Effectiveness (DARE) were searched to ensure a similar systematic review had not been published. Five electronic databases (PubMed, EMBASE, Cumulative Index of Nursing and Allied Health literature, PsychINFO, and Cochrane Controlled Trials Registry) were searched using a systematic, comprehensive and reproducible search strategy (Figure 1, ETable 1). The last search was run on 14 February 2018. Databases were accessed via the Johns Hopkins University Library. The search strategy was broadly focused to identify publications evaluating patient outcomes (including evaluation of physical functioning) after hospital discharge in survivors of critical illness. A combination of keywords and controlled vocabulary for ‘intensive care’ combined with ‘outcome assessment’ and ‘follow-up’ were adopted. Identified articles were evaluated for the purposes of this systematic review specifically focused on 6MWT after hospital discharge. Additional references were identified by manually cross-referencing the reference lists of all included articles.

Figure 1: PRISMA flow diagram of study selection process.

Abbreviations: CINAHL, Cumulative Index to Nursing and Allied Health Literature; EMBASE, the Excerpta Medica Database.

Study Selection

All papers identified by the search strategy were screened in duplicate by title and abstract and then by full text articles in duplicate using DistillerSR^® (2014 Evidence Partners, Ottawa, Canada). Disagreement regarding eligibility was resolved by consensus.

Data Collection Process and Data Items

A standardized data collection form was developed and used to extract data from the included studies by two trained reviewers (SRN, KN) and a third independent reviewer cross-checked the extracted data (SP). To avoid double counting data, multiple reports on the same patient cohort were identified by comparing papers with similar author names, sample sizes, participant demographics and outcomes. Authors of eligible studies were contacted for any required clarifications and additional study data available (e.g. mean/median 6MWD).

Data items were extracted by two independent reviewers (SRN, KN) for each eligible article, with any conflicts resolved by consensus. The data items extracted included author, country and year published, participant demographics, severity of illness, ICU and hospital length of stay (LOS), 6MWT methodology, time-points of assessment and sample size at each 6MWT assessment, mean and standard deviation of 6MWD, and any factors associated with 6MWD. Only 1 of the included studies reported conducting 2 walk attempts for each assessment, all others did not indicate whether 1 or 2 walk attempts were conducted for each assessment. We used analyses from the first follow-up assessment after hospital discharge for studies with longitudinal evaluations of risk factors and recorded risk factor associations from multivariable regressions when available.

Risk of bias of individual studies

Two independent trained reviewers (SRN, KN) evaluated the risk of bias of each publication using the Cochrane Risk of Bias Methodology for randomised controlled trials (RCTs)[7] and the adapted Newcastle-Ottawa Quality Assessment[8] for observational studies. Risk of bias evaluation was not considered in the eligibility criteria for this systematic review.

Statistical Analyses

The pooled mean 6MWD results were calculated as described herein. Two 2-month studies [9, 10] were pooled with the other 3-month studies; one 7-month study[10] was pooled with the 6-month studies; otherwise, follow-up times in eligible studies were 3, 6, 12, 24, 36, 48 and 60 months. For studies with only median and interquartile range for 6MWD and/or age, for purposes of meta-analysis the mean and standard deviation were estimated using existing methods[11]. Treatment groups or patient groups within a study at the same follow-up time were tested for statistical differences using t-tests or generalized linear models. Mean and 95% confidence intervals were estimated using a linear random effects model with a random intercept for study. The estimates were tested across follow-up time. A separate, similar linear regression model, with a random intercept, was used to compare the ARDS vs. non-ARDS patient cohorts, and effect modification by time point on this comparison was also assessed. This regression model was limited to 3, 6, and 12-month follow up time points due to small sample sizes in later follow-up time points. The regression model was also used to evaluate if the study mean 6MWD varied as a function of the following four patient characteristics reported by the eligible studies: age, percent of male patients, mean body mass index (BMI), and percent of patients with one or more comorbidity. We selected four pre-ICU patient characteristics that we hypothesized may be associated with 6MWD. To avoid over-fitting regression models, four separate models were constructed for each of the four characteristics; in each model, the patient characteristic was centered for ease of interpretation. Statistical significance was defined as p<0.05. SAS^® version 9.4 (2013, Cary, NC) was used to conduct all analyses.

RESULTS

Description of search and study characteristics

The search of five electronic databases resulted in 26 articles on 16 unique participant groups (Figure 1), including 8 RCTs. The 8 RCTs predominantly focused on evaluating of rehabilitation interventions, with 2 reporting a significant difference in 6MWD (ETable 2). The remaining studies were observational follow-up studies (without intervention). Geographic origin varied across the 16 unique participant groups including: North America (n=4/16, 25%); United Kingdom (n=4/16, 25%); Europe (n=3/16, 19%), Australia (n=2/16, 12.5%); South America (n=2/16, 12.5%) and Asia (n=1/16, 6%). Baseline demographics are described in ETable 2. A total of 1,755 unique patients were enrolled across the 16 studies. Seven studies specifically examined survivors of ARDS and the other nine were not specifically focused on ARDS ICU survivors. The maximum follow-up period was 60 months, with two studies, [2, 12] reporting a follow-up period of 60 months and one study having a maximum of 48-60 month follow-up (not differentiated as to whether it was 48 or 60 month follow-up and thus, grouped with 48 month studies) [13]. Six of 16 studies (37.5%) had a maximum follow-up period of 12 months (ETable 2).

Risk of bias within studies

Risk of bias was reported for each article (n=26). Among the eight articles reporting on RCTs randomisation and allocation concealment were adequate with low risk of bias. Double blinding was achieved in three studies, [14–16] with the majority lacking adequate blinding of participants (ETable 3). Among the observational studies, nine of 19 (47%) had adequate follow up (ETable 4).

Mean 6MWD and longitudinal change in 6MWD over 60 months after critical illness

Individual study data on mean (SD) or median [IQR] 6MWD and the predicted 6MWD, if available, are summarized in Table 2. The pooled mean (95% CI) 6MWD was 361 meters (321, 401) at 3 months with significantly greater pooled values reported at 12 months: 436 meters (391, 481) (p = 0.017, Figure 2). The mean 6MWD of 361 meters at 3 months; 436 meters at 12 months and 411 meters by 60 months are below population norms [17–19]. For 24- to 60-month follow-up timepoints there was only data able to be pooled from 2-3 studies (total N = 157 to 203, Figure 2) compared with 12-month follow-up (N = 649-828 across 9-11 studies, Figure 2). Forest plots for individual papers across all time-points are provided in the online supplementary material (EFigure 1a–g).

Table 2:

Six- Minute Walk Distance (6MWD) by study

Author year, location	Patient population	Follow-up (in months)	N at follow-up	Mean±SD or Median [IQR] 6MWD (m)	Predicted 6MWD (%)
Wright 2018, United Kingdom [31]	ICU	3	32I,27S	293 [124-444]I, 255 [120-337]S	NR
		6	28,25	374 [203-435], 321 [197-400]	NR
Wang 2017, China [32]	ARDS	12	24E	531±84	81±13
			48N	495±90	78±13
Viana 2017, Brazil [33]	ICU	3	20	273±126	NR
Dinglas 2016, United States [14]	ARDS	6	52	377± 145	65±24
		12	42	415 ± 154	71±23
Das Neves 2015, Argentina [34]	ICU	3	59	434± 181	63±22
		6	56	437 ± 166	116 ±176
		12	57	481 ± 143	93 ±117
Connolly 2015, United Kingdom [35]	ICU	3	30	362 ± 146.9	NR
Jones 2015, United Kingdom [15]	ICU	3	72	310±151	NR
Fan 2014, United States1 [12, 30]	ARDS	3	99	320±138	53±22
		6	117	338±128	57±21
		12	115	355±138	60±22
		24	112	371±151	63±25
		36	92	402±125	70 [58-82]
		48	98	401±123	70 [56-82]
		60	103	399±122	71 [59-83]
Needham 2014, United States2 [29, 36]	ARDS	6	158	368±139	64±22
		12	149	388±159	67±26
Denehy 2013, Australia3 [13, 16, 37, 38]	ICU	3	100	383±143	78.7±26.9
		6	89	398±161	72.5±27.4
		12	79	422±154	78.7±26.9
		48-60	48	508±118	70
Chiumello 2012, Italy [39]	ARDS	12	13	375 [335-445]	71a; 73b
			13	400 [350-450]
Elliott 2011, Australia4 [10, 40, 41]	ICU	2	155	400 ± 167
		7	145	435 ± 157
Herridge 2011, Canada5 [2, 28, 42, 43]	ARDS	3	80	281 [55-454]	49
		6	78	396 [244-250]	64
		12	81	422 [277-510]	66
		24	64	416 [285-496]	68
		36	65	418 [311-474]	67
		48	57	406 [314-488]	71
		60	54	436 [324-512]	76
Masclans 2011, Spain [44]	ARDS	6	38	368±69	60-65
Schandl 2011, Sweden [45]	ICU	3	52	512±144	NR
		6	42	533±150
		12	28	568±121
McWiliams 2009, United Kingdom [9]	ICU	2	38	424±111	NR

Abbreviations: ARDS, acute respiratory distress syndrome; ICU, intensive care unit; I, Intensive rehabilitation group; S, Standard rehabilitation group; E, ECMO group; N, non-ECMO group; 6MWD, six-minute walk distance; n, number; NR, not reported; SD, standard deviation; IQR, interquartile range; %, percentage.

Figure 2: Mean Six minute Walk Distance and 95% Confidence Interval across Months 3-60.

Legend Descriptor: This figure demonstrates the pooled mean and 95% CI for 6MWD over 3 - 60 month follow-up for survivors of critical illness. Pooled data at each follow up time-point ranging from 6 - 60 months were compared to the initial assessment at 3 months to determine if there was a significant change. There was a significant increase in 6MWD at 12 and 48 months compared to 3 months (p=0.017, and p=0.028 respectively).

Six-Minute walk test results for ARDS vs. non-ARDS studies

In this a priori analysis comparing ARDS vs non-ARDS studies over 3, 6, and 12-month follow-up assessments, the mean 6MWD was 73 meters (95% CI 13,133, p=0.019) lower in ARDS vs. non-ARDS. This difference was stable over 3, 6, and 12-month follow-up time points (i.e., time did not modify the association between ARDS status and 6MWD; p=0.948). The mean and 95% CI of 6MWD for ARDS vs. non-ARDS studies are plotted in eFigure2.

Risk factors associated with impairments in physical functioning

Of the four patient characteristics (i.e., age, sex, BMI and comorbidities) separately evaluated for associations with 6MWD, percent male and percent with one or more comorbidity were significantly associated with 6MWD (Table 3). A 10% increase in the percentage of males in the study was associated with a 50 meter (95% CI: 20, 79, p=0.002) greater mean 6MWD, and a 10% increase in the percentage of patients with one or more comorbidity in the study was associated with a 35 meter (95% CI: −66, −5, p=0.046) lower mean 6MWD (Table 3).

Table 3:

Exploration of patient characteristics using linear random effects model, which may affect six-minute walk distance

Individual patient characteristic	Mean Change in 6MWD (meters) (95% CI)	p-value
Mean age (per 10 years)	0.2 (−27, 27)	0.988
Percent male (per 10 percent)	50 (20, 79)	0.002
Mean body mass index (per 1 unit)	−3 (14, −7)	0.550
Percent of patients with 1 or more comorbidities prior to ICU admission (per 10 percent)	−35 (−66, −5)	0.046

The 6MWD mean and 95% confidence intervals were estimated using a linear random effects model with a random intercept for study. The estimates were tested across follow-up time. This model was extended to determine if the study mean 6MWD varied as a function of the following patient characteristics reported by the eligible studies: age, percent of male patients, mean body mass index (BMI), and percent of patients with one or more comorbidities. Due to the limited availability of these patient characteristics variables, four separate models were constructed for each of the four characteristics; in each model the patient characteristic was centered for ease of interpretation. This table provides data on the estimated change in study mean 6MWD per unit change in variable explored. It is based on available data in the eligible studies, regression model with ‘age’ and with ‘percent male’ have data for all follow-up times. Regression models with ‘body mass index’ and ‘percent 1 or more comorbidities’ have data from 3, 6 and 12 month follow-up times.

Among ICU factors evaluated for associations with 6MWD, the majority of studies did not report associations with 6MWD for severity of illness or ICU LOS, neuromuscular blockers, and duration of mechanical ventilation. In four studies that evaluated systemic corticosteroid use, two reported no association and two reported lower 6MWD (Table 4).

Table 4:

Summary of Unadjusted Association of Six-Minute Walk Distance (6MWD) with ICU Factors

ICU Factors	No. of distinct studies	Association with (6MWD)	Assessment timepoint
			3-month	6-month	12-month	24-month	36-month	48-month	60-month
Severity of illness (APACHE II score)	5	Negative None	[12, 28] [16]	[12] [28, 29]	[12] [28, 29]	[12]	[12]	[12]	[12] [2]
ICU length of stay (days)	4	Negative None	[28] [16] [12]	[12, 28, 29]	[12, 28, 29]	[12]	[12]	[12]	[12, 2]
Neuromuscular blocker	3	Negative None	[28]	[28] [29]	[28, 29]				[2]
Mechanical ventilation duration (days)	4	Negative None	[12, 28] [16]	[12] [28, 29]	[12] [28, 29]	[12]	[12]	[12]	[12] [2]
Systemic corticosteroid	3	Negative None	[28] [12, 30]	[28, 29] [12, 30]	[29] [12, 30], [28]	[12, 30]	[12]	[12]	[12, 2]

Abbreviations: ICU:intensive care unit; No: number;

^aSymbols used in table across time-points:

Negative association : i.e. worse walk results (statistically significant), numbers in square brackets are citation numbers

No association : no statistically significant association, numbers in square brackets are citation numbers

DISCUSSION:

This systematic review and meta-analysis synthesized data on impairments in physical functioning, as measured using the 6MWT, in ICU survivors after hospital discharge. Pooled data evaluating the longitudinal changes in 6MWT results demonstrated a significant increase at 12- month time points compared to initial assessment at 3 months. Female sex, presence of pre-existing comorbidity and ARDS were each associated with lower 6MWD results. The effect of sex on 6MWT performance is well recognised (and expected) as evident by this characteristic being included in regression equations to predict 6MWT performance from healthy populations [17, 18]. Only 5 of the 26 studies looked at associations between ICU factors (e.g. severity of illness and organ failure, neuromuscular blockers, systemic corticosteroids, durations of mechanical ventilation and ICU stay) and 6MWT performance – therefore it is not possible to draw definitive conclusions from the available data.

The mean 6MWD of 361 meters at 3 months; 436 meters at 12 months and 411 meters by 60 months are below population norms [17–19]. Results from 24- to 60-month follow-up (Figure 2) must be interpreted with caution as data from only 2-3 studies (total N = 157 to 203) could be pooled compared with 12-month follow-up (N = 649-828 across 9-11 studies). Within our analysis, males vs. females walked significantly longer distances (mean difference: 50 meters; 95% CI: 20, 79), consistent with population norms [17, 19]. In other populations, comorbidities are also associated with lower 6MWD results, similar to our findings [20, 21]. Interestingly, included studies evaluating patients with ARDS versus all other non-ARDS ICU studies had consistently lower 6MWD, with a mean difference of 73-meters (95% CI: 13, 133) that is almost twice the minimal important difference for ICU survivors [4]. This difference may be an underestimation as the non-ARDS studies may have included ARDS patients, and thus likely having a lower point-estimate of 6MWD compared to a purely non-ARDS cohort. Acute respiratory distress syndrome significantly impacts on the functioning of the respiratory system. Similarly in individuals with chronic obstructive pulmonary disease who have active symptoms such as dyspnoea there is evidence of poorer 6MWT performance [22]. More research is required to understand the etiology and mechanisms for reduced 6MWD in ARDS survivors to better understand if this finding is related to reduced respiratory reserve, impaired lower limb strength, and/or potential impact on other issues affecting performance. An understanding of the etiology and mechanisms for reduced 6MWD in ARDS survivors may assist in identifying the most optimal targeted intervention(s) to improve physical functioning for the ARDS survivors.

There were no consistent negative associations between ICU factors such as severity of illness, organ failure, neuromuscular blockers, systemic corticosteroids, duration of mechanical ventilation and ICU/hospital stay) on post-discharge 6MWD. Given this lack of definitive association, it may be difficult to predict, based on ICU factors alone, which ICU survivors will have the greatest impairments in long-term physical functioning. Our findings (which are consistent with prior literature) [23–25] highlight the importance of considering pre-ICU factors such as sex, with women normally having shorter 6MWD than men, and comorbidities which are related to poorer 6MWT performance.

This study followed a robust protocol that was registered and incorporated duplicate screening and data extraction. However there are potential limitations. First, this review only focused on physical functioning as measured using the 6MWT. It is important to recognise that there are a wide range of different physical functioning instruments utilized in ICU survivorship studies [6, 26]; in fact, heterogeneity of such instruments has created challenges in synthesizing the literature [6]. Among performance-based physical functioning measures, the 6MWT received the greatest level of support in the ImproveLTO international consensus process (www.ImproveLTO.com), but did not reach the a priori threshold for inclusion in a minimum core outcome measurement set due to participants’ concerns about the feasibility of mandating an in-person performance-based test for large-scale multi-centered studies [27]. Second, all studies were included in this review regardless of risk of bias. Hence, results should be interpreted with caution. Finally, although we attempted to identify all potentially relevant studies, it is possible that potentially eligible studies may have been omitted.

CONCLUSIONS:

In this meta-analysis of studies evaluating 6MWD after hospital discharge in ICU survivors, compared to initial assessment at 3-month follow-up, significant improvement was detected at 12- and 48-month time points. Studies evaluating ARDS survivors (versus general ICU population) and survivors with greater baseline comorbidity had worse 6MWD, but ICU-related factors were not consistently associated with 6MWD values.

Abbreviations List:

ARDS

acute respiratory distress syndrome

BMI

body mass index

DARE

Database of abstract of review of effectiveness

HRQoL

Health-related quality of life

ICU

intensive care unit

LOS

length of stay

PRISMA

Preferred Reporting Items for systematic reviews and meta-analyses

RCT

randomised controlled trial

6MWD

six-minute walk distance

6MWT

six-minute walk test

95%CI

95% confidence interval