A Randomized Trial of an Intensive Physical Therapy Program for Patients with Acute Respiratory Failure.

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AJRCCM Articles in Press. Published on 10-December-2015 as 10.1164/rccm.201505-1039OC

A Randomized Trial of an Intensive Physical Therapy Program for Acute Respiratory Failure Patients Marc Moss, MD 1 Amy Nordon-Craft, PT, DSc 2 Dan Malone, PT, PhD 2 David Van Pelt, MD 3 Stephen K. Frankel, MD 4 Mary Laird Warner, MD 4 Wendy Kriekels, PT, DPT 2 Monica McNulty, M.S.5 Diane L. Fairclough, DrPH 5 Margaret Schenkman, PT, PhD 2

(1) Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO (2) Physical Therapy Program, University of Colorado School of Medicine, Aurora, CO (3) The Medical Center of Aurora, Aurora, CO (4) Division of Pulmonary Medicine, National Jewish Health, Denver, CO (5) Colorado Health Outcomes Group, University of Colorado School of Medicine, Aurora, CO

Corresponding author: Marc Moss, M.D. University of Colorado Denver Research 2, Box C272 12700 East 19th Ave. Aurora, CO 80045 Phone: 303-724-6079

Copyright © 2015 by the American Thoracic Society


Fax: 303-724-6042 Email: [email protected]

All nine authors meet the criteria for authorship based on the following four criteria: •Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND •Drafting the work or revising it critically for important intellectual content; AND •Final approval of the version to be published; AND •Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Support: NIH/NINR R01 NR011051 and NIH/NHLBI K24 HL 089223 (MM), Subject Category: Non-pulmonary Critical Care: (4.10) Running Title: Intensive Physical Therapy Trial Word count: abstract 259 ; Total manuscript: 4202 (Introduction: 418)

At a Glance Commentary: Early physical therapy programs may benefit patients with acute respiratory failure; however, the proper duration and intensity is currently unknown. We conducted a randomized controlled trial of 120 patients with acute respiratory failure and determined that an intensive physical therapy program did not improve long term physical functioning when compared to a standard of care physical therapy program.

Additional material has been submitted for the online supplement


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ABSTRACT: Rationale: Early physical therapy (PT) interventions may benefit patients with acute respiratory failure by preventing or attenuating neuromuscular weakness. However, the optimal dosage of these interventions is currently unknown. Objective: To determine whether an intensive PT program significantly improves long term physical functional performance when compared to a standard of care PT program. Methods: Patients who required mechanical ventilation for at least four days were eligible. Enrolled patients were randomized to receive PT for up to four weeks delivered in an intensive or standard of care manner. Physical functional performance was assessed at one, three, and six months in survivors who were not currently in an acute or long term care facility. The primary outcome was the Physical Functional Performance Test (PFP-10) score at one month. Measurements and Main Results: A total of 120 patients were enrolled from five hospitals. Patients in the intensive PT group received 12.4±6.5 sessions for a total of 408±261 minutes compared to only 6.1±3.8 sessions for 86±63 minutes in the standard of care group (p 0.05 for all three analyses).



Overall, 91 PT sessions were stopped early (on average 0.75 sessions per enrolled patient). The most common reasons were: patient fatigue (31%); patient requested to stop for other reasons (21%), inability to continue or cooperate with the session (17%), change in vital signs (13%), and other reasons (18%). There was no difference between the two groups in the frequency of stopping a PT session early (p = 0.79). There were only two adverse events associated with this clinical trial. One patient had a syncopal episode during a PT session, and another patient was readmitted to the hospital with polyarthralgia that was possibly related to PT interventions.

DISCUSSION: In a cohort of 120 critically ill patients with acute respiratory failure, an intensive PT program did not improve long term physical functioning when compared to a standard of care program. There were also no differences between the two study arms in regard to secondary outcomes including ICU and hospital free days. These findings are similar to the results of the only other previous PT intervention trial that included long term assessments of physical functioning. 25 Our study also confirms that patients who survive acute respiratory failure have severe and persistently diminished physical functioning.3;4 For example, a total PFP-10 score of 57 is an accepted threshold below which the probability of living independently is significantly reduced.47 The average total PFP-10 scores of our patients would predict that the majority would not be able to live independently at one, three, and six months after hospitalization. These reductions in physical functioning are all the more concerning because of the relatively young age of our patient population and that 100% were living independently at home prior to hospital admission. Intensive PT programs for critically ill patients are promising interventions that may improve patient-centered outcomes.48 Potential benefits of early and intensive PT interventions


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may include improved muscle strength, physical functioning, quality of life, reduced hospital and ICU length of stay, shorter duration of mechanical ventilation, and hospital costs.14;16;17 Based on the results of these primarily observational studies, an ICU culture shift has occurred with a focus on implementing PT interventions.19;49 Regardless of their potential benefits, routine implementation of PT interventions in the ICU remains low.50-52 During the first 14 days of mechanical ventilation, patients from Australian and New Zealand ICUs were observed over a total of 1,288 patient days.50 Even though these facilities had dedicated PT staffing, PT was performed on only 26% (n=209) of patient days. When treatment did occur, the maximum level of exercises occurred in bed (45% of sessions). Our study suggests that the implementation of an intensive PT program may not be indicated for all critically ill patients who require mechanical ventilation for at least four days. Much of the rationale for providing intensive PT has been based on shortening ICU and hospital length of stay, and therefore reducing hospital costs.53 Though PT is a relatively safe intervention, it is labor intensive.54 Therefore, studies are needed to identify those patients who may truly benefit from early and intensive PT, so that PT resources can be properly allocated. In addition, enrolling suitable patients that are most likely to benefit from PT would improve the conduct of future clinical trials. There are several potential reasons for the lack of benefit of our intensive PT program. First, like most studies of critical care patients, the patient population was fairly heterogeneous. At one, three, and six months, there was significant variability in the long term physical function status of our patients. During critical illness, there are multiple causes of acquired weakness and muscle injury. The cellular mechanisms responsible for deconditioning and critical illness polyneuromyopathy are also complex. As a result, there is inherent heterogeneity of patients with ICU-acquired weakness. An intensive PT program that targets specific patients, such as those with weakness due to deconditioning, may yield more positive treatment effects. Future research studies are needed that identify strategies to risk stratify patients for specific types of



physical therapy and rehabilitation. Second, the sample size for this study meant that only large improvements could be detected in physical function. Future studies with a larger sample size may be indicated. Third, the duration of our PT program may not have been sufficient to improve physical functioning. Significant limitations in physical function performance persisted in many of these patients six months after hospital enrollment. It may be that patients require longer than one month of intensive PT. Though, patients enrolled in the recent RECOVER trial received prolonged post-ICU interventions and did not improve their long term physical recovery.55 Fourth, our study intervention was not continued for study patients transferred to another inpatient facility (e.g. Long Term Acute Care, sub-acute rehabilitation). In the United States, many patients recovering from critical illness are transferred to a long term acute care facility once they are medically stable.56 Half of the patients in our study were discharged to a location other than home. Physicians and other healthcare professionals who care for critically ill patients in acute care hospitals are not commonly involved in determining the physical therapy program after the patient is discharged to a long term care facility. The success of intensive PT program may be dependent on better integration with the care received in subsequent facilities. Fifth, we may not have started our intervention early enough. Patients in our study were eligible for enrollment after four days of mechanical ventilation, and received their first PT session on average eight days after the initiation of mechanical ventilation. In the Schweickert study, patients were eligible for enrollment if they had received mechanical ventilation for less than three days.26 Therefore, our patients initiated their PT program at a later time point when compared to the Schwieckert study.26 While the muscles are inflamed and undergoing proteolysis, early physical therapy may potentially be detrimental. The proper time to initiate physical therapy might be best informed through translational studies of muscle injury and repair. Sixth, it is possible that our intervention did not include the most beneficial components of PT. However, our intensive physical therapy program was based upon published models, and overall a higher percentage of our study patients (50%) were discharged to home when


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compared to the Schwieckert study (32%).26 Seventh, our lost to follow up rate can introduce biases that may affect the conclusion of our study. We did not review a national social security database to determine whether some of the lost to follow up may be related to death after hospital discharge. However, there does not appear to be significant participation bias as the one month PFP-10 scores were not different between the patients who followed up and did not follow up at three months. Regardless, there is always the concern of differential follow up in long term outcome studies. We also did not collect information regarding the home or outpatient administration of non-study related PT to the control subjects,. . Finally, it is possible that an intensive PT program truly does not yield better physical function when compared to a standard of care program. There are several strengths of this study. First, formal protocols were developed by physical therapists and critical care physicians for both the intensive PT and standard of care interventions. Second, the standard of care intervention was based upon national survey data of current practices for delivering PT to critically ill patients. 39 In addition, all of the sessions were provided by licensed physical therapists who attended formal training sessions prior to treating any study patients. In order to maintain treatment fidelity, the first several treatment sessions for each therapist were observed by one of the investigators who developed the protocol, and periodic reviews and co-treatments sessions were conducted with study investigators during the trial. Third, the results of the study may be more generalizable as patients were enrolled from both academic and community hospitals. Fourth, there was excellent separation in the amount and intensity of the intervention between the two arms of the study. Fifth, our primary outcome, the PFP-10 score (though labor intensive), is an excellent measure of actual physical performance. Self-report questionnaires measure different constructs than performance-based tests, such as the PFP-10.57 Schenkman and colleagues determined the PFP-10’s reliability and sensitivity to change in subjects that participated in a 12 week exercise program. 41 The



test-retest reliability of the PFP-10 was r = 0.93-0.98 for the total score and the individual domains, and the average total PFP-10 score increased by 16.5%. The change for the individual domains ranged from an increase in 20.4% for balance and coordination to 8.1% for upper-body flexibility. Finally, this study was conducted with extreme safety, as there were no increased adverse events in patients randomized to the intensive PT intervention group. In summary, this clinical trial demonstrates that an intensive PT program did not improve long term physical function performance when compared to a standard of care PT program. Future studies should consider determining characteristics that identify patients who require and could benefit from intensive PT, and identifying the specific components of PT that are beneficial to patients. Based on the long-term limitations in physical function, patients may also require more than a 28 day PT intervention. A larger multi-center trial that considers mortality as a measurable endpoint or a trial that enrolls a select cohort of acute respiratory failure patients that are more likely to benefit from PT may both be indicated to determine the efficacy of these interventions for patients recovering from critical illness. Finally, how occupational and speech therapy are delivered and integrated with PT also needs to be determined.


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FIGURE 2: Total PFP-10 Scores in the Intensive PT and Standard of Care PT Patients


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TABLE 1: Patient Demographics

Gender (% male) Age (in years) APACHE II score Service Unit (% MICU) Pre-ICU location Emergency Department Standard Hospital Floor Service Other Primary Diagnosis ARDS Pneumonia Non-pulmonary sepsis Aspiration Post-operative COPD exacerbation Other Prior Residence Home Assessment after randomization Medical Research Council (MRC) scores* Hand grip strength (Kg-force)* Functional Independence Measure (FIM) bed mobility*

Intensive PT Patients (n=59) 61% 56 ± 14 17.9 ± 6.2 88%

Standard of Care PT Patients (n=61) 57% 49 ± 15 17.4 ± 5.6 90%

P-Value

63% 24% 13%

57% 31% 12%

0.54

32% 17% 22% 10% 2% 0% 17%

26% 31% 18% 7% 7% 5% 6%

100%

100%

1.0

33.8 ±13.4 (n=43) 10.0 ± 9.2 (n=30) 2.0 ± 1.2 (n=45)

38.0 ± 15.6 (n=43) 13.3 ± 10.6 (n=27) 2.3 ± 1.6 (n=43)

0.19

0.69 0.01 0.64 0.47

0.21

0.22 0.35

* = A normal Medical Research Council score is 60. ICU acquired weakness has been defined as a Medical Research Council score < 48. Depending on an individual’s age and gender, normal values for hand-grip strength range between 20-40 Kg-force. The Functional Independence Measure bed mobility survey is scored on a 1-7 scale with 1 meaning the patient needs total assistance to perform the bed mobility tasks and 7 means complete independence with no physical assistance or devices such as bed rails.



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TABLE 2: Implementation of Physical Therapy Programs Intensive PT Patients (n=59) 408 ± 261

Standard of Care PT Patients (n=61) 86 ± 63

P-Value

Total Number of Sessions ICU sessions Hospital ward sessions Outpatient sessions

12.4 ± 6.5 6.4 ± 5.3 6.2 ± 4.7 3.7 ± 2.8

6.1 ± 3.8 3.8 ± 2.4 3.8 ± 3.0 0

< 0.001 0.002 0.003

Average Duration of Individual Sessions (in minutes) ICU sessions Non-ICU sessions

39.4 ± 11.0

21.8 ± 3.5

< 0.001

31.3 ± 7.0 45.3 ± 13.4

21.0 ± 3.2 22.0 ± 4.8

< 0.001 < 0.001

40 47 49 43 52

7 34 36 9 49

33.8 ± 28.4 88.2 ± 80.1 77.8 ± 52.0 74.6 ± 64.2 175.2 ± 121.8

10 ± 7.9 37.2 ± 31.9 20.3 ± 15.1 18.0 ± 13.3 44.5 ± 34.5

< 0.001 < 0.001 < 0.001 < 0.001 < 0.001

431 353 32 13

222 182 0 0

< 0.001 < 0.001 < 0.001 < 0.001

Total Time in Physical Therapy (in minutes)

Number of Patients Receiving the Following Types of Physical Therapy Respiratory Exercises Supine Exercises Sitting Exercises Standing Exercises Functional Mobility Training Total Duration of Physical Therapy Time by Type of Therapy (in minutes) Respiratory Exercises Supine Exercises Sitting Exercises Standing Exercises Functional Mobility Training (including gait training) Total Number of Physical Therapy Sessions by Location ICU Hospital Ward Outpatient-home setting Outpatient-clinic setting

< 0.001

< 0.001


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TABLE 3: ICU Medication Duration and Average Daily Dosing Intensive PT Patients

Standard of Care PT Patients

Benzodiazepines Average Number of Days Average Hourly Dose in lorazepam equivalents (mgs)

(n=43) 6.0 ± 5.4 0.7 ± 1.1

(n=44) 6.5 ± 7.4 0.8 ± 1.4

0.71 0.81

Propofol Average Number of Days Average Hourly Dose (mgs)

(n=17) 3.4 ± 2.9 127 ± 110

(n=15) 4.7 ± 2.7 100 ± 78

0.21 0.43

Dexmedetomidine Average Number of Days Average Hourly Dose (mcgs)

(n=24) 4.0 ± 3.4 45 ± 27

(n=23) 4.8 ± 4.4 53 ± 43

0.48 0.43

Opiates Average Number of Days Average Hourly Dose in fentanyl equivalents (mcgs)

(n=47) 7.5 ± 6.9 74 ± 100

(n=49) 6.4 ± 7.0 82 ± 111

0.44 0.70

Neuromuscular Blocking Agents Average Number of Days

(n=7) 1.4 ± 0.8

(n=8) 1.0 ± 7.6

0.26


P-Value


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TABLE 4: PFP-10 and other Outcome Measures * Intensive PT Patients

Standard of Care PT Patients

P-Value

Total PFP-10 scores 1 month 3 months 6 months

19.0 ± 3.7 30.7 ± 3.8 39.5 ± 3.9

20.9 ± 4.1 36.8 ± 4.3 44.0 ± 4.0

0.73 0.29 0.43

Upper Body Strength PFP-10 scores 1 month 3 months 6 months

19.5 ± 4.0 30.1 ± 4.2 40.3 ± 4.5

22.6 ± 4.6 38.5 ± 4.8 47.2 ± 4.6

0.61 0.19 0.29

Upper Body Flexibility PFP-10 scores 1 month 3 months 6 months

31.8 ± 5.6 50.4 ± 5.3 61.1 ± 4.3

30.6 ± 5.5 50.1 ± 5.2 63.6 ± 4.7

0.87 0.97 0.69

Lower Body Strength PFP-10 scores 1 month 3 months 6 months

14.5 ± 3.1 23.9 ± 3.4 30.4 ± 3.9

17.6 ± 3.6 31.0 ± 4.0 36.6 ± 3.8

0.52 0.18 0.26

Balance & Coordination PFP-10 scores 1 month 3 months 6 months

20.7 ± 4.2 30.9 ± 3.8 40.0 ± 3.9

20.7 ± 4.0 37.2 ± 4.4 43.8 ± 4.1

0.77 0.28 0.51

Endurance PFP-10 scores 1 month 3 months 6 months

19.0 ± 3.7 30.8 ± 3.8 39.9 ± 3.9

20.8 ± 4.1 37.1 ± 4.4 43.9 ± 4.1

0.74 0.28 0.49

28 day ICU-free days 13 [3-18] 11 [4-18] 0.69 ICU length of stay (in days) 15 [10-25] 16 [10-24] 0.69 Mechanical ventilation duration (in days) 10 [7-18] 10 [7-19] 0.89 28 day Hospital-free days 7 [0-12] 7 [0-14] 0.97 Hospital length of stay (in days) 21 [16-32] 21 [14-38] 0.97 Discharged to Home 51% (25/49) 49% (27/56) 0.84 90 day institution free days 61 [39-73] 56 [33-75] 0.87 180 day institution free days 151 [129-163] 146 [123-165] 0.89 * PFP-10 scores are presented as mean ± standard error of the mean. The PFP-10 total and component scores are scored from 0-100 with higher scores indicating better function. Scores vary with age. For non-disabled adults ages 35-54, average total PFP-10 scores range from 70.9-73.9. Other outcome measures are presented as median and 25-75% quartiles.


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On-Line Supplement:

A Randomized Trial of an Intensive Physical Therapy Program for Acute Respiratory Failure Patients Marc Moss, MD 1 Amy Nordon-Craft, PT, DSc 2 Dan Malone, PT, PhD 2 David Van Pelt, MD 3 Steve Frankel, MD 4 Mary Laird Warner, MD 4 Wendy Kriekels, PT, DPT 2 Monica McNulty, M.S.5 Diane L. Fairclough, DrPH 5 Margaret Schenkman, PT, PhD 2

(1) Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO (2) Physical Therapy Program, University of Colorado School of Medicine, Aurora, CO (3) The Medical Center of Aurora, Aurora, CO (4) Division of Pulmonary Medicine, National Jewish Health, Denver, CO (5) Colorado Health Outcomes Group, University of Colorado School of Medicine, Aurora, CO



Methods: Exclusion Criteria: The following exclusion criteria have been include in this study primarily for potential safety concerns regarding the performance of the intensive physical therapy program.1 Patients were excluded for the following reasons: myocardial infarction within the last 3 weeks, presence of signs or symptoms of unstable angina or history of unstable arrhythmias; acute dissecting aortic aneurysm; pulmonary embolism within the last six weeks; severe aortic stenosis; significant language barrier that would limit the ability to participate in the physical therapy program; currently living > 45 miles from the University of Colorado Hospital; unlikely to survive 6 months, severe physical or cognitive impairment that would impair participation in physical therapy, and patient or physician declined. Informed Consent Process and Definition of Awakening: After patients met the inclusion criteria and did not met any of the exclusion criteria, surrogates were approached about possible enrollment into the study. Enrolled patients were then followed until the time of awakening. Awakening and comprehension was determined based upon the response of the patient to five commands (“open/close your eyes,” “look at me,” “open your mouth and stick out your tongue,” “nod your head,” and “raise your eyebrows when I have counted to five”).2 The first day that the patient responded to at least three of these orders on two consecutive evaluations at a 6-hour interval was referred to as “awakening”. On the first day of awakening, patients were randomized to receive either a four week intensive physical therapy program or a four week standard of care protocol. When patients achieved decisional capacity, they were then re-consented for continued enrollment in the study. Medical Research Council (MRC) score determination: Twelve muscle groups in upper (wrist extension, elbow flexion, and shoulder abduction) and lower extremities (dorsiflexion of the foot, knee extension, hip flexion) were tested.3 Each muscle group can be scored from 1 = no muscle


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activity to 5 = normal strength. Therefore a maximum Medical Research Council (MRC) score would be 60. Hand grip strength can be quantified by measuring the amount of static force that the hand can squeeze around a dynamometer. Subjects were positioned as close to sitting upright with their elbows at 90° as possible. Hand grip strength is a reliable measurement when standardized methods and calibrated equipment are used. Depending on an individual’s age and gender, normal values for hand-grip strength range between 20-40 Kg-force 4-7. The Functional Independence Measure (FIM) Bed Mobility Survey is scored on a one to seven scale. One means the patient needs total assistance to perform the task and seven means complete independence with no physical assistance or devices such as bed rails 8.

Inpatient component of the intensive physical therapy protocol: Our intensive physical therapy program consisted of five specific components as described below. a) Techniques for proper breathing during exercise and activities: Exercises designed to facilitate timing, efficiency, and effectiveness of breathing including: inspiratory muscle training (i.e. diaphragmatic controlled breathing) and segmental breathing training. Patients will be taught to utilize the diaphragm effectively. For this purpose the physical therapist places his or her hands over the diaphragm and applies pressure inward as the patient breathes out. The patient is taught to integrate diaphragmatic breathing into demanding postures and activities. Segmental breathing requires the physical therapist to place his or her hands over the lateral and posterior chest and apply pressure inward as the patient breathes out. b) Therapeutic Exercises using different Therabands™: An individual exercise program will be initiated for all patients based on their ability to perform 6-8 repetition maximums for the upper



and lower extremities, and will be performed with resistance bands for each major muscle group. Initially patients will start will the least resistant band (tan colored). When patients are able to complete the 3 sets of 6-8 repetitions with proper form and no excessive signs or symptoms of fatigue, they will progress to the next higher band in terms of resistance. The different levels of resistance are as follows: Tan, Yellow, Red, Green, Blue, Black, Silver, and Gold. These exercises will initially be performed in the supine position and, when the patient is able they will be performed in the sitting position. The second phase of therapeutic exercises will begin when the patient is able to perform 3 sets of 10 repetitions with the Gold bands. They will begin to perform strengthening exercises standing, including mini squats, squats, step-ups with a 6 inch block, side step-ups with a 6 inch block, and gait training by ambulating over level surfaces. They will increase their distance by 25% each session if possible. c) Exercises designed to improve trunk mobility and strength: Postural control is the ability to maintain body position for stability and orientation. Training of postural control will begin once an individual is able to sit independently. The therapist facilitates and challenges the postural muscles (i.e. reaching for objects within and outside base of support). To strengthen the muscles, the therapist uses alternating isometric contractions against resistance at the shoulders and the pelvis in sitting and standing. Once the patient has attained static postural control, dynamic activities will be integrated, first in sitting (e.g., reaching for objects within and outside the base of support) and then in standing (e.g. retrieving objects from the floor and reaching outside base of support). These activities will progress as the patient’s physical and functional status allows. d) Functional mobility retraining including bed mobility, transfers, gait and balance: Functional mobility retraining assists patients in regaining their ability to coordinate different muscle groups, improve their balance, and perform activities of daily living. The initial phase of functional mobility will begin with 3 sets of 10 repetitions of axial mobility activities including: moving of the


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lower extremities in a side to side motion while in a supine position, moving the arms in a purposeful reaching motion, and rolling their body from side to side while in a supine position. The second phase of functional mobility will include moving from a supine to sitting position, and moving from a sitting to a standing position from different heights (raised bed, lowered bed to the height of a standard chair, and lowered bed to the height of a standard toilet). Next, the therapist would initiate gait training with the patient using the least restrictive assistive device. The amount of assistance would be decreased and the ambulation distance would be progressed as the patient tolerates. The final phase of therapy will begin when patients are able to stand without assistance and will include postural control and balance activities (carrying objects while walking, stopping and changing direction, and stepping over objects while walking). e) Range of motion and positioning: Range of motion (ROM) is the maximal movement available at a joint. The joint excursion is influenced by the joint and soft tissue structures surrounding the joints. Full ROM can be maintained by utilizing passive ROM (i.e. moving a body segment through its unrestricted available ROM by an external force), or active ROM where the person uses muscular contractions to move the body segment through available ROM. The session will include passive ROM for the upper and lower extremities in supine position and will progress to active ROM in the supine and sitting positions.

Outpatient Component of the Intensive Physical Therapy Protocol: Once a participant is discharged from the hospital, physical therapy will continue either in the home or in an outpatient exercise facility associated with our research facilities. This outpatient program will be continued three days a week to complete a total of four weeks of therapy. The outpatient program will be a continuation of the five components as outlined above. Criteria for discharge



from the intensive physical therapy program included the ability to independently perform all functional activities such as bed mobility, sit to stand transfers, and walking with good form and no excessive fatigue over level and un-level surfaces including stairs if needed in home.

Inpatient Component of the Standard of Care Protocol: The standard of care physical therapy protocol was based on the results of a national survey.9 Similar to the intensive physical therapy program, patients randomized to standard of care protocol will receive their intervention for a total of 4 weeks. Inpatient component of the standard of care physical therapy protocol: Patients would perform 10 minutes functional training, 10 minutes therapeutic exercise and therapeutic exercises including passive range of motion progressing to active range of motion as noted above. Patients were seen 3 times per week for a goal duration of 20 minutes in the intensive care unit and on the floor.

Outpatient Component of the Standard of Care Protocol: Once patients are discharged from the hospital, they will receive an educational pamphlet including information on the importance of daily exercise. Patients will be encouraged to initiate their own exercise program. No formal outpatient therapy program with a physical therapist will included for patients that are randomized to this arm of the study. To avoid the occurrence of attention bias for patients randomized to this arm of the study, they will receive telephone calls three days a week to answer any questions and to ensure that they are functioning properly. Again, the combined length of the inpatient and outpatient components for the standard of care arm of this study will be a total of 4 weeks.


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Safety criteria and stopping rules: Vital signs will be recorded on all patients while performing their physical therapy sessions. We adapted the following stopping criteria for an individual physical therapy or standard of care session based on published guidelines.1;10;11 If a patient meets any of the criteria prior to the beginning of their daily session, the session will be postponed until later that day, or the next day. a) Development of chest pain during the session. b) Development of severe shortness of breath during session. c) Development of light headedness during the session. d) Increase in HR >140 bpm or 20 bpm above baseline during the session. e) Blood pressure > 200/110, a SBP drop of >20mmHg below baseline during the session, or BP < 90/40

Treatment Fidelity: Before the start of the clinical trial, treating physical therapists selected to be either a treatment or control therapist. All treating therapists in both groups received extensive training with one of the study physical therapists (DM or AN-C). This training involved multiple one hour long sessions, multiple co-treatment sessions with one of the study physical therapists. Each treating physical therapist was allowed to perform study-related sessions only after they were observed to properly perform the entire study protocol by a study physical therapist. The first several treatment sessions for each therapist were also observed by one of the study physical therapists. Subsequently, the study physical therapists visited each site once a year and provided a study overview including an hour presentation that highlighted inclusion/exclusion criteria and randomization. The study physical therapists also provided an overview of the control and intervention arms and discussed the outpatient testing (1, 3, 6 month follow up). In addition, one of the study investigators (MM) also performed separate inservices at the each of the hospitals on an annual basis. Finally, one of our study physical



therapists also attended and co-treated with every control and intervention physical therapist at least two-three times a year. The study physical therapists also worked with an observed outcome tester and performed our primary and secondary outcome measures two to three times a year. After each treatment or outcome sessions, the study physical therapists provided feedback regarding protocol compliance as necessary. Finally, we created a fidelity check list of the treatment and control interventions. Treatment and control physical therapists sessions were evaluated on an occasional and “un-announced” basis. The check list included review of patient safety eligibility criteria to receive a PT session, components of PT interventions provided to control and intervention patients, and evaluation of the amount of time that should be provided to a patient.

Primary Outcome Variable: The PFP-10 is a test of capacity to perform household activities. The PFP-10 consists of a spectrum of activities (from low to high effort) that become progressively more difficult. The activities are: carrying a pan of water, putting on and taking off a jacket, reaching for a sponge, sweeping the floor, transferring laundry, picking up four scarves, carrying groceries, going from sitting to standing from a floor position, climbing stairs, and a six minute walk. The activities were constructed so that it is difficult to reach a maximum or minimum limit; and therefore avoid ceiling and floor effects. The total and individual scores for the PFP-10 range from 0-100, are based on the performance of older adults without specific disorders, are calculated using time to complete individual tasks and weight carried, and are determined from the results of one or more activities. The total and individual scores are generated using a syntax algorithm for the SPSS version 11.1 statistical package. This algorithm takes into account the time / weight carried for each task as appropriate and was determined during test development. In Table E1, we have included normative data for the PFP-10.


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Secondary Outcome Variables: The Timed Up and Go Test (TUG): The Timed Up and Go Test evaluates a subject’s ability to rise from a chair, walk three meters, turn, and return to the sitting position 12. The Timed Up and Go Test is administered in less than two minutes and has been used to predict falls in community dwelling elderly individuals, individuals with hip fracture, and amyotrophic lateral sclerosis patients 13;14. The Timed Up and Go Test has been used to determine response to interventions in Parkinson’s disease and other neuromuscular diseases. Interrater and intrarater reliability for the Timed Up and Go Test is 0.99. The Timed Up and Go Test has been validated against the Berg Balance Scale (r=-0.72), gait speed (r=-0.55), and the Barthel Index (r=-0.51) 12

. For community-dwelling elderly individuals, Timed Up and Go Test times of greater than 14

seconds correlates to increased fall risk with sensitivity (87%) and specificity (87%) for identifying individuals who fall 12. Times of 60 years) a cutoff



point of 14.2 seconds reflects a 87% sensitivity and a 84% specificity for balance dysfunction 21. For individuals younger than 60 years old the cutoff point of 10 seconds has a sensitivity of 87% and specificity of 84% for predicting balance dysfunction 21. The Medical Outcomes Study 36-Item Short Form Health Survey, Standard Form (SF-36): The SF-36 is a brief, 36-item, generic health-related quality of life questionnaire that has been used in a variety of patient populations 22. The results are grouped into domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. Score range from 0 to 100 with a higher score indicating a better health-related quality of life. A 5-point change in the SF-36 has been determined to be a clinically meaningful difference 22. It takes approximately 5 minutes to complete the SF-36. The questionnaire has been reported to be reliable and valid in a wide range of acute and chronic diseases (including survivors of acute respiratory failure and ICU admission) and shown to be responsive to small but important changes in quality of life 22-25. The SF-36 was found to have a high internal reliability with an α coefficient of Cronbach of 0.91 for the entire questionnaire 23. Calculation of Institution Free Days: Patients were followed throughout the course of their hospitalization and (if necessary) their subsequent long term care. After hospital or long term care discharge, patients were considered to be institution free. Institution days was calculated as the sum of the hospital length of stay and (if necessary) the long term acute care length of stay. This number was then subtracted from 90 or180 to calculate 90 or 18 day institution free days. We had only 1 patient for whom we are missing LOS data, and therefore we could not calculate their institution days Categorization of Study Patients regarding Outcome Assessments: Patients were considered to be unable to complete their PFP outcome assessments if they were either still in the hospital or in a long term care facility. They would have been unable to complete the primary


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outcome assessment (PFP-10), and therefore were assigned a PFP-10 score of zero. The patients categorized as “lost to follow up” were individuals who we attempted to contact on numerous occasions but they did not respond to us. They were not included in the primary analysis. Patients who were dead at the time of the outcome assessment were also not included in the analysis.

In regard to the secondary outcome measures of physical function performance (Timed Up and Go Test, Berg Balance Scale, and the Five Times Sit to Stand Test), assessments were conducted at the same time as their PFP assessment. There were two patients that were still in the acute care hospital at the time of their follow up assessments (one at one month and another at three months) that were able to perform these measures. These two assessments were included in the analysis. Patients who had been discharged to a long term care facility were classified as missing data for these secondary outcome measures of physical function performance.

Post-hoc subgroup analyses: When present, the following diagnoses were considered a preexisting co-morbidity: diabetes, cirrhosis, cancer, renal failure requiring dialysis, HIV positivity, and organ transplantation 26. Study participants were also stratified into age tertiles. The cut-off values for the age tertiles were: < 47 years; ≥ 47 years and ≤ 59 years, and > 59 years.

RESULTS: Ten of the 120 study patients were transferred into one of the five enrolling hospitals. Nine of the ten patients were transferred to one of the five enrolling hospitals on the day of admission to the outside hospital. The remaining patient was transferred two days after admission to the outside hospital.



A total of 26 treatment or control sessions were formally observed through the study: 7 initial evaluations that would determine at what level of PT the patient should be started, 12 intervention sessions, and 7 control treatments. Based upon these evaluations, overall compliance with all elements of the protocol was greater than 92%. As mentioned in the Methods section, patients who were still hospitalized or in a long term care facility were considered to be unable to perform the PFP. Therefore, they were assigned a PFP score of zero. Table E2 displays the number of patient who were unable to perform the PFP by treatment group and time point. To examine the potential effects of participation bias, we performed a secondary analysis comparing the total PFP score at one month between those who were lost to follow up at 3 months and those who were not lost to follow up at 3 months. There were a total of 11 patients who were lost to follow up at 3 months that had performed the PFP at one month. There were a total of 55 patients who were not lost to follow up at 3 months who had performed the PFP at one month. There were no significant differences in the PFP scores between the two groups (24.46±26.90 (not lost) vs. 30.90±31.75 (lost); p 0.54). Though the sample size is small, it does not appear that patients most distress by the physical function impairments were preferentially more likely to become lost to follow up. Subgroup analyses: In total, 56 patients (47% of the 120 enrolled subjects) had at least one preexisting comorbidity. The distribution of comorbidities is displayed in the Table E3. In both the patients with and without a pre-existing comorbidity, there were no differences in the effect of the intensive intervention group on the PFP-10 scores at one, three, or six months (see Table E4 and Figure E1). Patients were also divided into age tertiles (< 47 years, 47-59 years, and > 59 years). There appeared to be no significant differences in the effect of the intervention upon PFP-10 scores in any of the three age tertiles (Table E5). However in the youngest age tertile,


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the standard of care patients has a significantly better PFP-10 score when compared to the intensive treatment group (49.3 ± 6.1 vs. 19.4 ± 10.1, p = 0.01)



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Table E1: Normative Data for the PFP-10 (adapted from Hearty et al) 27

35-44 years

45-54 years

55-64 years

65-74 years

75-85 years

(n=26)

(n-23)

(n=21)

(n=33)

(n=39)

Total Score

73.9 ± 11.5

70.9 ± 11.4

63.2 ± 10.4

58.7 ± 12.5

48.2 ± 11.2

Upper Body Strength

74.7 ± 15.0

73.6 ± 14.2

64.0 ± 13.3

56.5 ± 13.2

46.9 ± 9.8

Upper Body Flexibility

84.8 ± 7.1

82.7 ± 6.6

74.1 ± 14.1

58.9 ± 14.4

51.8 ± 12.9

Lower Body Strength

72.7 ± 15.9

67.6 ± 13.4

59.2 ± 13.3

58.1 ± 14.2

45.1 ± 13.3

Balance and Coordination

67.5 ± 11.9

63.8 ± 12.8

58.7 ± 12.0

54.7 ± 14.7

44.7 ± 13.3

Endurance

75.7 ± 10.1

72.7 ± 12.3

65.0 ± 10.5

65.1 ± 15.7

52.2 ± 14.3



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Table E2: Patients with PFP score of zero due to prolonged hospitalization or long term care admission Intensive PT group

Standard of Care PT group

1 month:

21/41

29/48

3 month:

5/34

10/39

6 month:

1/28

3/27



Table E3: Distribution of Co-Morbidities in Enrolled Study Participants* Co-Morbidity Diabetes Cirrhosis Cancer Renal Failure HIV Positive Organ Transplantation

Distribution 27/120 (23%) 16/120 (13%) 11/120 (9%) 8/120 (7%) 4/120 (3%) 8/120 (7%)

* = Patients could have more than one co-morbidity. Overall, 42 study participants had one comorbidity, 11 had two co-morbidities, 2 had three co-morbidities, and one patient had four comorbidities (diabetes, cirrhosis, cancer , and renal failure)


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Table E4: Total PFP-10 data stratified by treatment group and pre-existing comorbidities * Intensive PT

Standard of Care PT

+ comorbidity

+ comorbidity

1 month:

23.6 ± 5.7

8.2 ± 6.1

3 month:

31.1 ± 6.3

6 month:

42.8 ± 6.2

P value

P value

Intensive PT

Standard of Care PT

- comorbidity

- comorbidity

0.07

14.5 ± 5.6

27.9 ± 4.6

0.07

33.5 ± 6.5

0.80

29.1 ± 5.9

39.2 ± 5.0

0.19

38.7 ± 6.4

0.65

36.5 ± 5.5

47.8 ± 5.0

0.13

* = Data presented as mean and standard error of the mean



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Table E5: Treatment effect on PFP-10 data by age tertiles* Intensive PT group


P value

1 month:

15.7 ± 8.5

33.3 ± 5.8

0.09

3 month:

19.4 ± 10.1

49.3 ± 6.1

0.01

6 month:

49.2 ± 9.1

58.4 ± 5.8

0.40

1 month:

26.5 ± 6.3

15.0 ± 6.4

0.20

3 month:

40.6 ± 6.3

28.5 ± 6.5

0.18

6 month:

51.0 ± 5.6

39.0 ± 5.9

0.15

1 month:

12.9 ± 6.4

9.4 ± 7.0

0.71

3 month:

24.1 ± 6.5

29.0 ± 7.5

0.62

6 month:

24.8 ± 5.8

30.9 ± 6.7

0.50

Age: < 47 years

Age: 47-59 years

Age: > 59 years

* = Data presented as mean and standard error of the mean



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Table E6: Secondary Outcome Measures of Physical Function * Intensive PT group


P value

15.6 ± 13.2

15.2 ± 13.8

0.9

(n=21)

(n=19)

13.3 ± 8.1

13.3 ± 12.4

(n=27)

(n=30)

14.2 ± 9.6

11.1 ± 7.6

(n=27)

(n=24)

40.7 ± 24.4

47.3 ± 13.7

(n=21)

(n=19)

45.6 ± 13.6

51.3 ± 7.9

(n=27)

(n=30)

51.1 ± 6.9

51.1 ± 6.9

(n=27)

(n=24)

11.9 ± 8.6

15.8 ± 13.8

(n=21)

(n=19)

11.9 ± 8.3

13.2 ± 8.2

(n=27)

(n=30)

11.9 ± 6.4

11.3 ± 7.0

(n=27)

(n=24)

Timed Up and Go Outcome 1 month:

3 month:

6 month:

1.0

0.15

Berg Balance Scale 1 month:

3 month:

6 month:

0.21

0.06

0.98

Five Times Sit to Stand 1 month:

3 month:

6 month:

* = Data presented as mean and standard deviation


0.19

0.54

0.72


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Table E7: Secondary Outcome Measures of Health Related Quality of Life* Intensive PT group


P value

35 [20-50]

50 [30-80]

0.15

(n=21)

(n=19)

52.5 [37.5-85]

62.5 [40-75]

(n=28)

(n=30)

57.5 [ 35-85]

80 [60-100]

(n=26)

(n=24)

0 [0-0]

0 [0-0]

(n=21)

(n=19)

0 [0-75]

0 [0-75]

(n=28)

(n=30)

62.5 [25-100]

12.5 [0-75]

(n=26)

(n=24)

35 [32.5-67.5]

42.5 [22.5-80]

(n=21)

(n=19)

51.3 [33.8-90]

57.5 [45-80]

(n=28)

(n=30)

57.5 [ 45-90]

57.5 [45-77.5]

(n=26)

(n=23)

45 [30-65]

60 [45-70]

(n=21)

(n=19)

57.5 [37.5-72.5]

55 [40-65]

SF-36 Physical Function 1 month:

3 month:

6 month:

0.96

0.66

SF-36 Physical Role Function 1 month:

3 month:

6 month:

0.91

0.86

0.07

SF-36 Pain 1 month:

3 month:

6 month:

0.61

0.41

0.81

SF-36 General Health 1 month:

3 month:


0.18

0.49

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6 month:

(n=28)

(n=30)

52.5 [40-75]

55 [37.5-72.5]

(n=26)

(n=24)

68 [56-76]

64 [56-76]

(n=21)

(n=19)

74 [66-84]

72 [60-80]

(n=28)

(n=30)

74 [64-92]

64 [48-88]

(n=26)

(n=23)

66.7 [0-100]

66.7 [0-66.7]

(n=21)

(n=19)

66.7 [0-100]

100 [33.3-100]

(n=28)

(n=30)

10 [66.7-100]

66.7 [0-100]

(n=26)

(n=23)

50 [25-75]

37.5 [25-50]

(n=21)

(n=19)

65.7 [53.1-87.5]

68.8 [50-75]

(n=28)

(n=30)

68.8 [50-87.5]

75 [56.3-87.5]

(n=26)

(n=23)

35 [30-55]

50 [40-60]

(n=21)

(n=19)

55 [47.5-65]

50 [40-60]

0.84

SF-36 Emotional Well Being 1 month:

3 month:

6 month:

0.74

0.32

0.17

SF-36 Emotional Role Functioning 1 month:

3 month:

6 month:

0.52

0.71

0.22

SF-36 Social Functioning 1 month:

3 month:

6 month:

0.36

0.66

0.19

SF-36 Energy/Fatigue 1 month:

3 month:


0.11

0.36


6 month:

(n=28)

(n=30)

50 [40-70]

50 [40-65]

(n=26)

(n=23)

25 [0-50]

25 [0-50]

(n=21)

(n=19)

37.5 [0-75]

25 [0-75]

(n=28)

(n=30)

50 [25-100]

37.5 [25-75]

(n=26)

(n=24)

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0.36

SF-36 Health Change 1 month:

3 month:

6 month:

* = Data presented as median and 25-75% quartiles.


0.65

0.43

0.19


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FIGURE E1: PFP-10 scores stratifed by treatment and pre-existing co-morbidity


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Determinants of immediate survival among chronic respiratory insufficiency patients admitted to an intensive care unit for acute respiratory failure. A prospective multicenter study. The French Task Group for Acute Respiratory Failure in Chronic Respiratory insufficiency.

Inclusion of trigger point dry needling in a multimodal physical therapy program for postoperative shoulder pain: a randomized clinical trial.

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Clinical Impact and Cost-Effectiveness of an Education Program for PD Patients: A Randomized Controlled Trial.

Manual therapy compared with physical therapy in patients with non-specific neck pain: a randomized controlled trial.

A randomized trial of prophylactic palifermin on gastrointestinal toxicity after intensive induction therapy for acute myeloid leukaemia.

Reply: Is an Earlier and More Intensive Physical Therapy Program Better?

Management of Acute Respiratory Failure in Patients With Hematological Malignancy.

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Physical activity program for patients with dementia and their relative caregivers: randomized clinical trial in Primary Health Care (AFISDEMyF study).

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A Case of Biotinidase Deficiency in an Adult with Respiratory Failure in the Intensive Care Unit.

A 12-Words-for-Life-Nurturing Exercise Program as an Alternative Therapy for Cervical Spondylosis: A Randomized Controlled Trial.

A randomized controlled trial of an online self-management program for adults with arthritis pain.

An intensive physiotherapy program improves mobility for trauma patients.

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Remote ischemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischemic stroke: a randomized trial.

Corticosteroids for Pneumocystis carinii pneumonia with acute respiratory failure. Experience with rescue therapy.

High-flow nasal cannula oxygen therapy versus noninvasive ventilation in immunocompromised patients with acute respiratory failure: an observational cohort study.