SUPPLEMENTARY APPENDIX
Feasibility and safety of early combined cognitive and physical therapy for critically ill medical and surgical patients: the Activity and Cognitive Therapy in ICU (ACT-ICU) trial.
N.E. Brummel MD, MSCI; T.D. Girard, MD, MSCI; E.W. Ely, MD, MPH; P.P. Pandharipande, MD, MSCI; A. Morandi, MD MPH; C.G. Hughes MD; E. Murphy, PT; B. Work OTR/L; B.T. Pun MSN, RN, ACNP; L. Boehm, MSN, RN, ACNS-BC; T.M. Gill, MD; R.S. Dittus, MD, MPH; J.C. Jackson, PsyD
Table of Contents:
1. Methods
- Cognitive therapy protocol
- Physical therapy protocol
- Imputation method for patients unable to complete outcome testing at hospital discharge.
2. Results
- Coordinated daily awakening and breathing trials
- Duration of physical therapy sessions
- Physical therapy milestones
- In-hospital clinical outcomes
- Cognitive and functional outcomes at hospital discharge
3. Tables
- Table S1 Daily coordinated awakening and breathing trials
b. Table S2 Sedative and analgesic medication exposure
- Table S3 Reasons cognitive therapy sessions not completed
- Table S4 Reasons for study withdrawal
- Table S5 In-hospital clinical outcomes
- Table S6 Hospital discharge cognitive and functional outcomes complete case analysis
- Table S7 Hospital discharge cognitive and functional outcomes imputed outcomes analysis
1. Methods
a. Cognitive Therapy Protocol. Cognitive exercises were provided to patients for two, 20-minute sessions separated by at least four hours. Prior to each assessment, the patient’s level of consciousness was determined using the Richmond Agitation-Sedation Scale (RASS). No intervention was given to patients who were stuporous or comatose (RASS -4 or -5). Patients who responded to voice but did not maintain wakefulness or sustain eye contact for more than 10 seconds (RASS -3 or -2) received an orientation exercise. A series of nine exercises were provided to patients who were alert (RASS -1 to +1). We emphasized providing cognitive stimulation and therefore, study staff provided assistance and hints as needed to help the patients through each exercise. Each session began with an orientation exercise and progressed as the patient was able until the 20-minute time limit was reached:
1) Orientation Exercise. Patients were asked 10 orientation questions. Five questions assessed orientation to time, including: the year, season, month, day of the week and today’s date. The next five questions assessed orientation to place: Which city, state, county, building and floor/unit of the hospital was the patient in at the current time. Questions answered incorrectly were repeated following all 10 orientation questions.
2) Digit Span-Forward. Patients were asked to repeat a sequence of numbers, beginning with a 4-digit sequence (e.g., 4-1-2-8) and progressing up to a 9-digit sequence (e.g., 6-1-4-2-9-3-5-7-8).
3) Matrix Puzzles. Patients were asked to choose the correct answer from a series of five answers that completed a matrix pattern.
4) Real World Exercises. Patients were asked to solve problems that might be encountered in everyday life outside of the hospital, such as reading a bus schedule, when to take medications, counting change and balancing a checkbook. For example: “Your starting balance in your check book is $365. You spend $70 at the grocery, $10 on your electric bill, $15 on your gas bill and $25 to buy a gift for a friend. How much do you have left in your account?”
5) Reverse Digit Span. Similar to the “Forward Digit Span” above, patients were read a sequence of numbers, however, in this exercise, patients were asked to repeat the sequence in reverse order it was read to them. For example, the patient was given the sequence 5-7-3, he or she would say, “3-7-5”. The exercise began with a 3-digit sequence and progressed to an 8-digit sequence.
6) Noun list recall. Patients were read a series of seven words and asked to repeat them in any order. For example: Dog, Car, Watch, Hand, Guitar, Knife, Zipper.
7) Paragraph/Story recall. Patients were read a story containing many details and asked to repeat it back to the study staff exactly as it was read to them. For example, “On March 14th, two cows escaped from their pasture through a hole in the fence and went onto a busy road. Three cars wrecked trying to avoid the cows. No one was injured. It was four hours before the cows were rounded up.”
8) Letter-Number Sequences. Patients were read a sequence of letters and numbers and asked to arrange them first in numerical order then alphabetical order. This exercise began with a series of 1 number and letter (e.g., “L, 2”, and the patient would reply, “2-L”) and progressed up to 4 numbers and 4 letters (e.g., “7, M, 2, T, 6, F, 1, Z, to which the patient would reply “1-2-6-7-F-M-T-Z”).
9) Problem Solving Exercises. Patients were presented with a sequence of letters or numbers with portions of the sequence omitted. They were then asked to complete the sequence by recognizing the pattern of the missing components and filling in the missing letters or numbers (e.g., the sequence: 1-__- 3 - __ - 5 - __ - 7 - __ would be completed by filling in the missing even numbers, 1- 2 - 3 - 4 - 5 - 6 - 7 - 8).
b. Physical Therapy Protocol. Patients were screened for safety criteria prior to undergoing any physical therapy interventions. These criteria included:
1) Symptomatic drop in mean arterial pressure when not supine.
2) Heart rate <40 or >130 for ≥ 5 minutes.
3) Respiratory rate <5 or >40 for ≥5 minutes.
4) SpO2 < 88% for ≥5 minutes.
5) Systolic Blood Pressure >180 mmHg for ≥ 5 minutes.
6) Active GI bleeding.
7) Evidence of elevated intracranial pressure.
8) Evidence of myocardial ischemia in last 24 hours.
9) Actively undergoing a procedure
10) Inadequately secured airway device.
11) Agitation, as defined by RASS +2 to +4.
12) Presence of a femoral vascular device.
13) Increase in the dose of vasopressors in the last 2 hours.
14) Need for mechanical ventilation with FiO2 >0.6 and/or PEEP >10.
Additionally, if while receiving the physical therapy intervention, the patient developed any of the following, the intervention was immediately paused and the patient was placed in a resting position (e.g., seated in the chair, at the edge of the bed or supine in the bed). If these resolved within 5 minutes of rest, the protocol could resume based off the therapist’s clinical judgment.
1) Symptomatic drop in mean arterial pressure (e.g. dizziness, lightheadedness, syncope)
2) Heart rate <40, >130 beats/min
3) Respiratory rate <5, >40 breaths/min
4) Systolic blood pressure >180 mmHg
5) Pulse oximetry <88% for
6) Marked ventilator dysynchrony
7) Patient distress (nonverbal cues, gestures, physical combativeness)
Finally, if the patient developed a new arrhythmia, if there was concern for new myocardial ischemia, concern for the integrity of the patient’s airway, the patient’s airway became compromised, or if the patient fell to his or her knees, the therapy session was immediately terminated.
As with the cognitive therapy protocol, the physical therapy protocol was also based off a patient’s RASS assessment prior to initiation of the protocol. Comatose or stuporous patients (RASS -4 or -5) received passive range of motion of all major joints (e.g., fingers, wrists, elbows, shoulders, ankles, knees and hips). Patients who were aroused to voice (RASS –3 or –2) also received passive range of motion exercises and were placed in the sitting position in the bed for at least 20 minutes. Patients who were a RASS -1 to +1 progressed, as able, through active range of motion exercises of all major joints, bed mobility exercises (e.g., lateral rolling and supine to sit), dangling at the edge of the bed, postural re-training, balance exercises (such as reaching in and out of the base of support), activities of daily living training (eating/simulated eating, grooming, bathing, dressing and toileting), transferring from seated to standing and from bed to chair, reaching in and out of the base of support, mini-squats, marching, and ambulation (with or without assist devices).
c. Imputation method for patients unable to complete outcomes testing at hospital discharge. Within 72 hours of hospital discharge, we assessed cognitive and status using the Mini-Mental State Exam (MMSE), executive functioning using the Delis-Kaplan Executive Function System Tower test (Tower test) and functional status using the Timed-Up and Go test (TUG). A number of patients were unable to complete the entire assessment due to either cognitive impairment or physical disability. We present the cognitive and functional outcome results, therefore, in two formats: a complete case analysis including only the patients who were able to complete a given outcomes test and an imputation strategy where the patients who were unable to complete an outcome were assigned the worst possible score for the outcome measure. For patients unable to complete the Tower test or the TUG test, due to cognitive impairment (defined as an MMSE of less than 19 or inability to follow commands) or physical disability (defined as inability to ambulate without assistance of another person), we assigned patients a Tower score of 1 (worst possible score) and a TUG time of 150 seconds for the purposes of our discharge outcomes analysis.
2. RESULTS
a. Coordinated daily awakening and breathing trials. All three groups underwent equal percentages of daily spontaneous awakening trials and spontaneous breathing trials on days where the respective safety screens were passed. See Table S1.
b. Duration of physical therapy sessions. Physical therapy sessions delivered by the study physicians and/or nurses lasted 15.0 [10.0-20.0] minutes in both intervention groups and those conducted by study physical and occupational therapists lasted and 23.0 [16.0-26.0] and 23.0 [16.0-25.8] for the physical therapy only group and the cognitive plus physical therapy group, respectively.
c. Physical Therapy Milestones
Patients in the physical therapy only group performed active range of motion exercises 1.0 [1.0-1.0] day after enrollment, sat at the edge of the bed (i.e., dangled legs) at 1.0 [1.0-2.0] days after enrollment, stood at 1.5 [1.0-2.2] days after enrollment and ambulated at least three feet at 2.0 [1.0-3.0] days after enrollment. The cognitive plus physical therapy group performed active range of motion exercises 1.0 [1.0-1.8] day after enrollment, sat at the edge of the bed (i.e., dangled legs) at 2.0 [1.0-4.0] days after enrollment, stood at 2.5 [1.2-4.0] days after enrollment and ambulated at least three feet at 3.0 [1.2-6.0] days after enrollment. Nearly two-thirds of patients in these intervention groups ambulated during the study, including 20% who ambulated while mechanically ventilated and 40% who ambulated while in the ICU. Patients in the intervention groups first ambulated 2.0 [1.0-4.0] days after enrollment.
d. In-hospital Clinical Outcomes. The three groups did not differ with regard to in- hospital outcomes, including the number delirium coma-free days during the first 30 days of the study, the number of ventilator-free days during the first 30 days of the study, ICU and hospital lengths of stay and in-hospital mortality (see Table S3).
e. Cognitive and Functional Outcomes at Hospital Discharge. We assessed at least one hospital discharge outcome in 12/16 (75%) patients in the usual care group, 14/16 (88%) in the physical therapy only group and 26/32 (81%) patients in the cognitive plus physical therapy group who were alive and not withdrawn from the study (overall assessment rate 84%). Of the 60 patients in the study at the time of hospital discharge, 42 completed the Tower test, 54 completed the MMSE and 29 completed the TUG test. Among patients who were unable to complete the Tower, 4 were delirious, 8 were cognitively impaired (with and MMSE of ≤ 19), 2 patients were physically disabled, 3 refused testing and 1 was discharged prior to completing discharge testing. While nearly all patients were able to complete the MMSE, 4 were unable to do so owing to delirium, 1 was unable due to physical weakness and 1 patient was discharged prior to being assessed. The 31 patients who did not complete the TUG test did so due to delirium (4), physical weakness (17), refusal (9) and discharge prior to testing (1). Following discharge, 11 patients did not complete the telephone interview portion of the discharge outcomes testing: 4 were unavailable, 3 refused one or more tests, 1 died and 1 was unable to follow commands and did not have a surrogate available. The results for each outcome test are presented in Table S5. Due to the number of patients who were unable to complete the full outcomes assessment, we therefore imputed results for the 8 patients who were unable to complete the Tower Test and for 17 patients unable to complete the TUG test. This analysis is presented in Table S6. Clinical outcomes did not differ between groups regardless of method used to analyze the results.
3. TABLES
Table S1. Median percentage of days where the safety screen for spontaneous awakening trials and for spontaneous breathing trials were passed and median percent of days where these trials were performed.
Usual Care(n= 22) / Physical Therapy Only
(n= 17) / Cognitive +
Physical Therapy
(n= 33)
% days of MV where SAT screen passed / 95% [71-100%] / 100% [67-100%] / 100% [75-100%]
% days of MV where SAT screen passed where SAT was performed / 100% [100-100%] / 100% [100-100%] / 100% [100-100%]
% days of MV where SBT screen passed / 0% [0-50%] / 67% [33-100%] / 33% [12-57%]
% days of MV where SBT screen passed where SBT was performed / 100% [50-100%] / 100% [100-100%] / 100% [100-100%]
MV, Mechanical Ventilation; SAT, Spontaneous Awakening Trial; SBT, Spontaneous Breathing Trial
N= number of patients in each group who were receiving mechanical ventilation at study enrollment
Data are Median [Interquartile Range]
Table S2. Sedative and analgesic medication exposure during study period
Usual Care(n=22) / Physical Therapy Only
(n=22) / Cognitive +
Physical Therapy
(n=43) / P
Benzodiazepines
n(%) / 12 (55%) / 14 (64%) / 21 (49%)
Daily dose (mg)a / 6.0 [2.5-11.2] / 2.9 [1.2-6.4] / 2.0 [1.1-10.4] / 0.46
Propofol
n(%) / 13 (59%) / 20 (91%) / 42 (98%)
Daily dose (mg) / 874 [217-1160] / 750 [133-1732] / 830 [280-1175] / 0.47
Dexmedetomidine
n(%) / 3 (14%) / 6 (27%) / 16 (37%)
Daily dose (mcg) / 404 [237-818] / 655 [417-950] / 531 [353-1220] / 0.83
Opiate
n(%) / 21 (95%) / 20 (91%) / 42 (98%)
Daily dose (mcg)b / 503 [283-1402] / 678 [344-1020] / 703 [245-1393] / 0.95
IQR, interquartile range; mg, milligrams; mcg, micrograms