Efficacy and Safety of a Multicomponent Physical Therapy Program in Mechanically Ventilated Patient With Sepsis

Study Overview
=================
Brief Summary
-----------------
Despite of a remarkable decrease in overall mortality has been achieved following the International Guidelines for Management of Sepsis and Septic Shock since 2004,the short-and long-term outcomes remain poor in critically ill sepsis patients who had experienced prolonged ventilation in the Intensive Care Unit (ICU). The reason could be due to some subsequent complications developed in the ICU rather than original disease, e.g., ICU-acquired weakness (ICUAW), delirium, diaphragmatic dysfunction (DD) and acute gastrointestinal (GI) injury, which are still not fully recognized or dealt with in a majority of ICU settings across China. This study is aimed to examine whether a multi-component physical therapy (PT) program against these lethal ICU-related complications could reduce ICU 28-day mortality, improve independent functional status and 1-year survival in this subset of patients.

Detailed Description
-----------------
The study is a prospective, multi-center, assessor-blinded, randomized controlled trial and will be conducted in 9 medical ICUs at 7 tertiary hospitals in Southern China. Mechanically ventilated septic patient admitted into ICU will be screened for eligibility into the study. When medically stable, patients randomize into the intervention group will receive a multi-component PT. The PT program is designed to counteract ICUAW, delirium, DD and acute GI injury, and consists of 5 consecutive sessions including positioning, extremities muscle strength training, respiratory muscle strength training, neuromuscular electrical stimulation (NMES) and gut rehabilitation. Each PT session will last for 30 minutes and be provided once daily, 5 days per week, and tailored for each individual subject. PT intervention will continue throughout patient's ICU stay or the primary endpoint is reached. The primary outcome will be the ICU 28-day all-cause mortality, and the secondary outcome measures, e.g., incidences or duration of ICUAW, delirium, DD and acute GI injury, mechanical ventilation outcomes (ventilator dependence, ventilator-free days), adverse events, restoration to independent functional status and long-term survival, will be assessed at preset time points of interviews during periods of treatment and 1-year follow-up after discharge from hospital. The total in-hospital and re-hospitalization costs in the intervention group will be also analyzed and compared to control group to assess the cost-effectiveness of the rehabilitation program.To our knowledge, this study is the first randomized controlled trial examining the efficacy and safety of a multi-component PT program in critically ill sepsis patients on ventilator. Given that rehabilitation is not a routine therapy across most ICUs in China, If this PT program is found to be of mortality benefit, it will provide an alternative non-pharmaceutical approach to deal with these lethal ICU-related complications and reduce the subsequent death. It will also provide useful information for clinical decision and local medical policies making, as well as identifying sepsis patient population who might best benefit from early rehabilitation program.

Official Title
-----------------
Southern Medical University Clinical Research Project Initiative：Efficacy and Safety of a Multicomponent Physical Therapy Program in Mechanically Ventilated Patient With Sepsis

Conditions
-----------------
Sepsis

Intervention / Treatment
-----------------
* Other: Early multicomponent physical therapy program


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosed with sepsis in accordance with the Sepsis-3 Criteria. 16 ≤ age ≤ 75 years. Mechanically ventilated for less than 72 hours at recruitment and expected to continue for at least 3 days. Ability to obtain informed consent from patient or proxy. Exclusion Criteria: acute central nervous system disease (e.g. severe cerebral injury, acute cerebral hemorrhage, brain infarction). active neuromuscular diseases that limiting patient to physical training (e.g. amyotrophic lateral sclerosis, multiple sclerosis, myasthenia gravis, polymyositis, muscular dystrophy). severe thoracic or abdominal trauma. acute myocardial infarction, severe arrhythmia, acute heart failure, hemo-dynamic instability or shock. drug abuse, alcohol addiction, opiates or other drug dependence and psychiatric disorder history. known pregnancy. malignant tumor, cachexia, end stage of chronic illness. contraindications to rehabilitation therapy. inability to obtain an informed consent from patient or a proxy. any other factors such as fractures or limb malformation, that would prevent response to physical exercise or cause injury to the patient.

Ages Eligible for Study
-----------------
Minimum Age: 16 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: prospective, multicenter, assessor-blinded, randomized controlled trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: intervention group<br>Early multicomponent physical therapy program plus sepsis standard therapy | Other: Early multicomponent physical therapy program<br>* Positioning (upright bed standing; turning, moving on bed). Peripheral muscle strength training (active or passive full range of motion, lower extremities ergometer cycling). Respiratory muscle training (supine abdominal breathing training). Neuromuscular electrical stimulation (NMES) on target muscles (bilateral bicipital muscles, quadriceps femoris muscles and rectus femoris). Gut rehabilitation (midfrequency NMES; abdominal manual or vibration massage).<br>|
| No Intervention: control group<br>Sepsis standard therapy, including early initiation of intravenous antibiotics, infection source debriding, appropriate fluid therapy, minimum sedation, protocolized weaning procedure, blood glucose control and early enteral feeding, etc. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ICU 28-day mortality | Sepsis or non-sepsis related death, undetermined cause of death. | Through 28-day study period in the ICU. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of ICU-required weakness | Using the Medical Research Council (MRC) Score for Muscle Strength to test 12 muscle groups in upper extremities (wrist flexion, elbow flexion, shoulder abduction) and lower extremities (dorsiflexion, knee extension, hip flexion). The MRC sum score ranges from 0 (complete paralysis) to 60 (full strength) as determined by manual muscle testing (MMT), which grades muscle strength from 0 (paralysis) to 5 (normal muscle strength) in each muscle group tested. Patient with a MRC sum score of < 48 or a mean MRC score of < 4 per muscle group will be considered to have ICUAW. If measurement is impossible at recruitment, patient will be deemed as without ICUAW by a Barthel Index score > 60, which ranges from 0 (complete dependence) to 100 (complete independence), collected from a proxy reflecting baseline independent functional status 2 weeks prior to critical illness. | Assessed on the day of recruitment, repeated on the days of first try to wean from ventilator, ICU discharge and hospital discharge, with an average of 1 month. | 
| Incidence of delirium | Acute cerebral dysfunction with altered mental status, inattention, and either disordered thinking or an altered level of consciousness as determined by the Confusion Assessment Method for the ICU (CAM-ICU). If assessment is impossible at recruitment, patient will be considered without delirium by absence of a history of insanity collected from a proxy reflecting baseline mental status 2 weeks prior to critical illness. | Assessed on the day of recruitment, repeated on the days of first try to wean from ventilator, ICU discharge and hospital discharge, with an average of 1 month. | 
| Incidence of diaphragmatic dysfunction | Maximum negative inspiratory pressure (PImax) less than - 80 cm H2O is usually considered to have clinically important inspiratory muscle weakness. Measurements will be performed by using inspiratory hold key on ventilator (intubated patient) or a one-way exhalation valve placed on the opening of mouth (extubated patient). Patient will be instructed to perform maximal inspiratory efforts for 20 seconds against occluded airway at functional residual lung volume (FRC), and change in pressure be recorded by an external data acquisition system (Powerlab/16sp ML795, Australia ADInstruments) through a physiological pressure sensor (MLT 844, Australia ADInstruments) connected to the opening of endotracheal tube or the valve. The signal sampling frequency will be set at 100 Hz and low-pass filtering frequency at 20 Hz. The signal collected will be digitalized and analyzed in a manner of time-domain, and the PImax be recorded after 3 repetitions. | Assessed on the day of first try to wean from ventilator, repeated on the days of ICU discharge and hospital discharge, with an average of 1 month. | 
| Incidence of acute gastrointestinal injury | Malfunctioning of the GI tract in critically ill patients due to their acute illness, distinguished and graded by severity of GI symptoms (e.g., feeding intolerance, vomiting, diarrhoea, paralysis, high gastric residual volumes (HGRVs). Acute gastrointestinal injury (AGI) grade I: increased risk to develop GI dysfunction or failure; AGI grade II: GI dysfunction (interventions required); AGI grade III: GI failure (GI function cannot be restored with interventions); AGI grade IV: dramatically manifesting GI failure. | Assessed on the day of recruitment, repeated on the days of first try to wean from ventilator, ICU discharge and hospital discharge, with an average of 1 month. | 
| Ventilator dependence | Referred to one of the following categories: difficult weaning: fail initial weaning and require up to 3 spontaneous breath test (SBT) or ≤7 days to achieve success; delayed weaning: fail at least 3 weaning attempts or require > 7 days to weaning after the first SBT; prolonged mechanical ventilation (PMV): requiring ventilator support for more than 21 days. | Number of days required to weaning after the first try, number of days on ventilator, assessed within an average of 3 weeks. | 
| Adverse events | Unexpected physiologic response or patient complaints to physical exercise, e.g., more than 20% variability in rest heart rate; 110 mmHg < mean arterial pressure < 60 mmHg; decremental pulse oximetry < 90%; severe dyspnea as determined by the Modified Borg Dyspnea Scale > 4 (ranged from 0-10, indicative of dyspnea degree from just noticeable to maximum); patient-ventilator asynchrony; altered mentation; catheters or tubes displacement; documented organ damage; accidental death. | Through physical therapy periods, an average of 1 month. | 
| Length of stay | Number of days spent in the ICU or hospital. | From admission to ICU discharge and hospital discharge, estimated between 4 to 6 weeks. | 
| Independent functional status | Referred to ability to perform 10 activities of daily living (ADL's), including eating, transfer from bed to chair, dressing, toileting, bathing, grooming, walking, stair climbing, maintaining continence. Independent functional status is determined by a Barthel Index Score > 60, which ranged from 0 (complete dependence) to 100 (complete independence). | The 3rd, 6th and 12th months of 1-year follow up after hospital discharge. | 
| Health-related quality of life (HRQOL) | Evaluated by using the mandarin version Short-Form-36 Questionnaire translated by the Zhejiang University, China., consisting of eight domains (e.g., physical function (PF), role limitations due to physical problems (RP), body pain (BP), general health (GH), vitality (VT), social function (SF), role limitations due to emotional problems (RE), mental health (MH). The combined score for each domain is obtained by summing score of each item contained in the domain and directly converted into a 0-100 score scale using the Likert method of summated ratings. A score scale of zero is equivalent to maximum disability and 100 equals to the best possible health state. | The 3rd, 6th and 12th months of 1-year follow up after hospital discharge. | 
| One-year mortality | All-cause death during 1-year follow-up after hospital discharge. | One year. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
sepsis, critical illness, intensive care unit, mechanical ventilation, rehabilitation, mortality, physical function, health-related quality of life