American Journal of Respiratory and Critical Care Medicine

To the Editor:

Increasing numbers of patients are both being admitted to intensive care and surviving critical illness. As mortality from critical illness decreases, survivorship has become a major public health issue: In survivors, return-to-work rates are low, and older patients and those with preceding poor functional state need an increased level of care, resulting in care facility and rehabilitation discharges (1).

In a single-center randomized control trial of 104 patients, a multimodal intervention of physical and occupational therapy initiated at 1.5 versus 7.4 days postintubation resulted in a higher return to functional independence in the intervention group (2). Subsequent multicenter trials of physical rehabilitation are yet to reproduce such results. The PRaCTICaL (Pragmatic Randomised, Controlled Trial of Intensive Care Postdischarge Review Clinics in Improving Longer-term Outcomes from Critical Illness) study from the United Kingdom showed no difference in health-related quality of life (3) at 12 months, and a 12-center Australian study of post–intensive care unit (ICU) rehabilitation did not demonstrate a recovery effect from exercise intervention (4). More recently, a single-center study of intensive rehabilitation from intensive care through to outpatient classes published a further negative result (5).

Repeated negative trials mandate questioning with regard to the effectiveness of the intervention, compliance with delivery, and the assessment endpoints (6). Further, the characteristics of the recruited population and their projected trajectory of recovery based on their pre-ICU functional status may be important (7, 8). No study to date has used pre-ICU comorbidity status as an inclusion criterion or examined this as a factor influencing the trajectory of recovery and outcome, despite recent publications hypothesizing that these factors may be influential (7, 8).

We performed a secondary analysis of the previously published exercise intervention study by Denehy and colleagues (5), stratifying patients by preexisting chronic disease and attempting to correct for interindividual variation in functional disability. The aims were to examine the functional exercise capacity data over the course of 12 months, using the 6-minute-walk test (6MWT) between intervention and control participants in two subgroups (previously healthy and those with at least one documented comorbidity at admission); and to calculate sample sizes on the basis of these subgrouped data.

We reexamined data from the previously published single-center, assessor-blinded, randomized controlled trial of 150 participants randomly assigned to receive usual care or intensive exercises in the ICU and the ward and as outpatients. Function was evaluated using absolute difference data from the 6MWT, the Timed Up and Go Test, and the Short Form 36 Health Survey. No significant differences were found for any outcomes at 3, 6, or 12 months after ICU discharge, although exploratory analyses identified a significant change over time in 6MWT between groups. For this new analysis, participant data were stratified by the presence or absence of chronic disease from the original database (see Tables E2 and E3 in the online supplement). Two analyses were undertaken to compare the percentage change in the 6MWT distance between those with no documented chronic disease pre-ICU and chronic disease subgroups of the original sample (the definition for chronic disease was that participants had at least one disease coded as earlier). We present only 6MWT data.

Significant intersubject variability exists in physical performance (see Figure E1); this is likely to be augmented by the global functional impairment after critical illness (9, 10). Furthermore, no true baseline 6MWT could be performed for comparisons; to address this, data were reanalyzed, using percentage change from ICU discharge performance (11, 12). The 6MWT is a standardized performance-based test of functional exercise capacity and is important because it most closely represents activities of daily living (13, 14). It is also the most widely used test for physical function in critically ill patients across the continuum of care (4, 15), and for these reasons, it was chosen as the primary outcome in the original trial.

Of the 150 patients, reanalysis was performed in those who survived to ICU discharge and were able to perform a 6MWT. These 113 patients were stratified into presence (n = 84) or absence (n = 29) of chronic disease, and between-group differences were tested separately in these subcohorts. No differences in characteristics were found between the control and intervention groups in each subgroup (see Table E1), although as expected, the healthy and chronic disease subgroups displayed significant differences in age and sex (see Table E1).

In the cohort of healthy subjects, there was no significant improvement in the 6MWT interventional group versus control (81.5% [95% confidence interval (CI), 31.1%–131.7%] versus 62.2% [95% CI, 24.3%–100%]; P = 0.280) at hospital discharge, but between-group differences existed at 3 months and were maintained at 12 months (272.5% [95% CI, 155.2%–389.7%] versus 126.0% (95% CI, 19.1%–232.9%]; P = 0.008; Table 1; Figure 1).

Table 1. Change in 6-Minute-Walk Test Expressed as Percentage Change from Intensive Care Unit Discharge

 ICUdHospd3 mo6 mo12 mo
No chronic disease     
 Control subjects     
  n151512128
  Mean (95% CI)062.2 (24.3–100)115.5 (49.3–181.8)93.5 (7.7–179.8)126.0 (19.1–232.9)
 Exercise     
  n1414989
  Mean (95% CI)081.5 (31.1–131.7)235.7 (156.7–314.8)216.3 (108.1–324.5)272.5 (155.2–389.7)
P value 0.2800.026*0.026*0.008*
Chronic disease     
 Control subjects     
  n4140363126
  Mean (95% CI)058.9 (30.2–87.6)132.5 (102.5–162.5)132.8 (93.9–171.7)168.3 (123.3–213.3)
 Exercise     
  n4342363430
  Mean (95% CI)083.9 (55.8–112.0)185.2 (141.9–228.4)200.0 (152.4–247.6)217.7 (165.3–270.0)
P value 0.2130.0590.027*0.047*

Definition of abbreviations: CI = confidence interval; Hospd = hospital discharge; ICUd = intensive care unit discharge.

*P < 0.05, using two-way repeated measures of analysis of variance.

In the cohort of patients with preexisting chronic disease, significant differences were found between groups at 6 months and were maintained at 12 months (217.7% [95% CI, 165.3%–270%] vs. 168.3% (95% CI, 123.3%–213.3%]; P = 0.047; Table 1, Figure 1).

For pre-ICU healthy participants with no documented chronic diseases, a difference in 6MWT of 50% was obtained between groups at 3 months. Using an α of 0.05 and a β of 0.90 and a two-way repeated measures of analysis of variance, a sample size of 14 patients in each group would be needed when measuring the 6MWT as the outcome of interest at 3 months (16). In the cohort of patients with preexisting chronic disease, using a difference between groups of 28% at 3 months (α, 0.05; β, 0.90), 36 patients would be required in each group.

Muscle wasting occurs rapidly in critical illness (17) and is consistently cited as the greatest contributor to this functional impairment post-ICU (15). Further, patients perceive reduced function as their greatest limitation up to 1 year from ICU discharge (15). Given the level 1 evidence for pulmonary, heart failure, and cardiac rehabilitation (11, 18), the failure of exercise interventional trials in the ICU to produce positive results is puzzling.

The interesting result from this analysis is the trajectory of improvement shown in the two subgroups. Although the “healthy” groups are small sample sizes, the results raise questions about stratification variables to use in future randomized controlled trials. Both intervention and control groups had an upward trajectory to 12 months in the chronic disease group, but the control group that received standard care in the “healthy” ICU subgroup did not. Most improvement was evident in the first 3 months in all groups, perhaps reflecting both acute improvement with time and that the exercise intervention was completed in 2 to 3 months in intervention groups.

This secondary analysis suggests that previously healthy patients respond well to rehabilitation and that significant gains in short periods may be made (7). Furthermore, patients with preexisting chronic disease may require targeted rehabilitation, which should be mapped to their premorbid functional status.

The response to exercise between intensive care discharge and hospital discharge was associated with improvement at 12 months (r2 = 0.25; P < 0.001). Percentage change in 6MWT by 3 months was highly predictive of change at 12 months (r2 = 0.72; P < 0.001; see Figure E2)

By stratifying cohorts by the presence or absence of chronic disease states, as well as addressing interindividual variation by using relative responses to rehabilitation or usual care, our reanalyzed data have the additional benefit of reducing sample sizes with significant implications for future trial design.

Although the power calculations suggest the original study was adequately powered to detect a difference in the chronic disease population, the post hoc nature of this analysis precludes definitive conclusions. A further limitation exists in our definitions of chronic disease, or more specifically, baseline cohort stratification, as within a single comorbid diagnosis a wide spectrum of functional status may be seen as in chronic obstructive pulmonary disease. With an increasing medically complex and aging population, a priori assessments of pre-ICU functional status for cohort allocation are needed for prospective trials (7). The best measures and definition of comorbid disease to use remain unclear, as does the prioritization of comorbid conditions and severity versus global functional status as the primary stratification variable. This needs to be addressed in future prospective studies, as the effects of addressing functional heterogeneity seem powerful.

In future randomized controlled trials of interventions to improve outcomes in critical illness survivors, preexisting disease heterogeneity should be addressed by subgroup stratification, and interindividual variation in functional capacity can be minimized with data analyzed using percentage differences.

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8. Iwashyna TJ, Netzer G, Langa KM, Cigolle C. Spurious inferences about long-term outcomes: the case of severe sepsis and geriatric conditions. Am J Respir Crit Care Med 2012;185:835841.
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12. Puhan MA, Mador MJ, Held U, Goldstein R, Guyatt GH, Schünemann HJ. Interpretation of treatment changes in 6-minute walk distance in patients with COPD. Eur Respir J 2008;32:637643.
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15. Herridge MS, Cheung AM, Tansey CM, Matte-Martyn A, Diaz-Granados N, Al-Saidi F, Cooper AB, Guest CB, Mazer CD, Mehta S, et al.; Canadian Critical Care Trials Group. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003;348:683693.
16. Dobson AJ, Gebski VJ. Sample sizes for comparing two independent proportions using the continuity-corrected arc sine transformation. Statistican 1986;35:5153.
17. Puthucheary ZA, Rawal J, McPhail M, Connolly B, Ratnayake G, Chan P, Hopkinson NS, Phadke R, Dew T, Sidhu PS, et al. Acute skeletal muscle wasting in critical illness. JAMA 2013;310:15911600.
18. Leon AS, Franklin BA, Costa F, Balady GJ, Berra KA, Stewart KJ, Thompson PD, Williams MA, Lauer MS; American Heart Association; Council on Clinical Cardiology (Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention); Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity); American association of Cardiovascular and Pulmonary Rehabilitation. Cardiac rehabilitation and secondary prevention of coronary heart disease: an American Heart Association scientific statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity), in collaboration with the American association of Cardiovascular and Pulmonary Rehabilitation. Circulation 2005;111:369376.

Author Contributions: Concept and design: Z.A.P. and L.D.; data collection: L.D.; analysis and interpretation: Z.A.P. and L.D.; and manuscript drafting and revision: Z.A.P. and L.D.

The original randomized controlled trial was completed with funds from the National Health and Medical Research Council (grant 454717), the Physiotherapy Research Foundation, the Austin Hospital Medical Research Foundation, and the Australian and New Zealand Intensive Care Society.

This letter has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Author disclosures are available with the text of this letter at www.atsjournals.org.

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