Electric Muscle Stimulation for Weaning from Mechanical Ventilation in Elder Patients with Severe Sepsis and Acute Respiratory Failure A Pilot Study ilable at ScienceDirect International Journal of Ge[.]
International Journal of Gerontology xxx (2017) Contents lists available at ScienceDirect International Journal of Gerontology journal homepage: www.ijge-online.com Original Article Electric Muscle Stimulation for Weaning from Mechanical Ventilation in Elder Patients with Severe Sepsis and Acute Respiratory Failure e A Pilot Study* Sheng-Yeh Shen 1, Chao-Hsien Lee 2, Rong-Luh Lin 1, Kuang-Hua Cheng 1, * Division of Chest Medicine, Departments of Internal Medicine, Mackay Memorial Hospital, Critical Medicine Department, Mackay Memorial Hospital, Taipei, National Taiwan University College of Medicine, Graduate Institute of Clinical Medicine, Taiwan a r t i c l e i n f o s u m m a r y Article history: Received 13 January 2017 Accepted 13 January 2017 Available online xxx Background: Patients with severe sepsis and acute respiratory failure often developed muscle weakness because of their critical illness and immobility We hypothesized electric muscle stimulation (EMS) may prevent the weakness and shorten the duration of mechanical ventilation (MV) Methods: Elderly patients with severe sepsis and acute respiratory failure were enrolled and randomized to EMS or control group on the third day of MV The EMS was applied to both quadriceps 32 minutes in weekdays with minimal voltage to induce visible muscle contraction (device: HELEX 573®, programmed strength aggravating mode) Control group had passive exercise of extremities Duration of MV support was compared Results: 545 patients were screened and 25 patients were randomized in 2:1 ratio (18 patients into EMS and into control group) 64% of the acute respiratory failures resulted from pneumonia Both group had similar demographic data and median age of all participants was 78 years-old (interquartile range 72 e82) The mean duration of ventilator dependence was days (IQR 6e15) in control group and 6.5 days (IQR 5e10) in EMS group (P ¼ 0.85) Conclusion: EMS did not help critical-ill septic elderly to reduce the duration of mechanical ventilation in our pilot study Further larger study is warranted with adequate study power and identical weaning strategy to test the EMS benefits Copyright © 2017, Taiwan Society of Geriatric Emergency & Critical Care Medicine Published by Elsevier Taiwan LLC This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/) Keywords: mechanical ventilation, electric muscle stimulation, sepsis, weaning Introduction Critical-ill patients may have muscle wasting and general weakness when they are bed-bound in intensive care unit (ICU) with acute severe disease The intensive care unit acquired weakness (ICUAW) typically affects proximal limb muscles symmetrically and respiratory muscles The main risk factors for ICUAW include * Disclosure of conflicts of interest: I certify that all my affiliations with or financial involvement in, within the past years and foreseeable future, any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript are completely disclosed (e.g., employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, royalties) * Correspondence to: Dr Kuang-Hua Cheng, Critical Medicine Department, Mackay Memorial Hospital No 92, Sec 2, Zhongshan N Rd., Taipei City 10449, Taiwan E-mail address: jeff01@mmh.org.tw (K.-H Cheng) high severity of illness upon admission, sepsis, multiple organ failure, prolonged immobilization, and hyperglycemia, and also older patients have a higher risk1 After described in early 1980, critical illness polyneuropathy and myopathy (CIPM) are increasingly recognized as one of important causes in ICUAW2 The muscle weakness was reported in 32e100% of critically ill adult patients ventilated for longer than days3 and 69% in critical primary neurological diseases4 Administration of glucocorticoids and nondepolarizing muscle relaxants, sepsis and multi-organ failure per se as well as elevated levels of blood glucose and muscular immobilization are the risk factors of CIPM5 Diaphragm was affected in CIPM and weaning from mechanical ventilation could be delayed4,6 In management of CIPM and ICUAW, no specific pharmacotherapy was validated Infection control and early mobilization are the cornerstone of the management The earlier the physical rehabilitation started, the better improvement was observed in body functions7,8 However, active rehabilitation is not always http://dx.doi.org/10.1016/j.ijge.2017.01.001 1873-9598/Copyright © 2017, Taiwan Society of Geriatric Emergency & Critical Care Medicine Published by Elsevier Taiwan LLC This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Please cite this article in press as: Shen S-Y, et al., Electric Muscle Stimulation for Weaning from Mechanical Ventilation in Elder Patients with Severe Sepsis and Acute Respiratory Failure e A Pilot Study, International Journal of Gerontology (2017), http://dx.doi.org/10.1016/ j.ijge.2017.01.001 S.-Y Shen et al eligible for ICU patients because of the stupor consciousness, sedation or restraint in ICU Electric muscle stimulation (EMS) induces muscle contraction without patient's cooperation and was proposed as an adjunctive rehabilitation modality In 2003, Zanotti et al reported EMS in addition to active limb mobilization significantly improved peripheral muscles strength in bed-bound patients with mechanical ventilation for chronic obstructive pulmonary disease9 For septic patients requiring mechanical ventilation and having or more organ failure other than respiratory dysfunction enrolled in the intensive care unit, Rodriguez et al reported EMS was associated with an increase in strength of the stimulated muscle10 Further research showed early EMS applied to legs in critically ill patients with an Acute Physiology and Chronic Health Evaluation (APACHE) score 13 prevented the development of CIPM and also resulted in shorter duration of weaning11 Two system-review also reported EMS was an effective means of improving muscle weakness in adults with progressive diseases such as COPD, chronic heart and critical illness12,13 Previous EMS studies did not focus in acute respiratory failure following severe sepsis However, the most acute respiratory failure acquiring mechanical ventilation in my constitution resulted from elderly patients with severe sepsis and multiple comorbidities Mean age of the ICU patients were increasing globally, and severe sepsis and septic shock remain leading cause of respiratory failure in the elderly Age itself may not predict mortality14, and adequate therapy should be given to the elderly Therefore, we conducted the pilot study to investigate the feasibility and effect of early EMS in the elderly with sepsis and acute respiratory failure Optimal setting of EMS (muscle site, daily duration, electric voltage and frequency) was not clearly defined so far, and we also want to evaluate the effect of a programed electric stimulation device (HELEX 573®) applied in weekdays The aim of our study was to assess the effect of EMS on muscle power preservation and duration of mechanical ventilation (MV) in critically septic patients Materials and methods 2.1 Study design The study was a prospective randomized control study approved by institutional Review Board in Mackay Memorial hospital (13MMHIS060) in June, 2013 (ClinicalTrials.gov ID: NCT01895647A) Informed consent was explained and obtained from all of the participants' surrogates before the enrollment The primary end-point was duration of mechanical ventilation Successful weaning was defined as spontaneous breath without inspiratory pressure support more than hours The second outcomes were mortality after randomization and hand grip strength measured by digital handgrip dynamometer every three day after randomization Mackay Memorial Hospital is a teaching hospital in Taipei, and the adult medical ICU had 28 beds The ICU had patientenurse ratio 2:1, patienterespiratory therapist ration 10:1, and patientephysician ratio 8:1 The weaning strategy was driven by the critical care physicians 2.2 Participants Adult patients (20e90 years-old) admitted with mechanical ventilator were daily screened and recorded as eligible If they fulfilled criteria of sepsis according to definition of 1992 American College of Chest Physicians and the Society of Critical Care Medicine15 The randomization was performed when the eligible patients required mechanical ventilation longer than 72 hours (defined as need of inspiratory mechanical support in ventilator setting) They were randomly assigned to electric muscle stimulation (Intervention group, arm biceps or thigh quadriceps) or passive arm biceps or thigh quadriceps limb mobilization (Control group) in 1:1:1 ratio The exclusion criteria were following: 10 11 Skin defect or infection around the thighs Acute myocardial infarction within one week Life-threatening cardiac arrhythmia Pregnancy Dying patient with life expectance shorter than one month Severe encephalopathy with coma and no spontaneous breath drive Uncontrolled seizure Patient is fully awake and has adequate muscle power to cooperate active limb exercise Air-born contagious diseases eg Tuberculosis and Influenza virus infection Moderate to severe adult respiratory distress syndrome with requirement of neuromuscular blocker Patients with Extracorporeal Membrane Oxygenation 2.3 Intervention protocol The patients in the intervention group received EMS on both quadriceps (vastus medialis) and biceps, 32 minutes per day, days per week (Monday to Friday) EMS was conducted with a commercial stimulator (HELEX 573®, EverProsperous company, Taiwan) with adhesive electrode (4.7 cm 4.7 cm) The stimulator output current was 0e75 mA in biphasic waves with carrier frequency of 1500 Hz We used its strength aggravation mode which protocol consisted with warm-up, exercise and cool-down The lowest stimulation current was given to induce visible muscle contraction Bilateral hands grip strengths were measured and recorded by digital hand dynamometer (CAMRY, model: EH101, China, (range 0e90 Kg)) before EMS and every days The test was performed with the arm at right angles and the elbow by the side of the body Three trials were allowed for each hand alternatively, with a pause of 60 seconds between each test The control group had active or passive exercise of extremities the extent of exercise was decided and performed by the physical rehabilitation therapist after the consultation The actual exercise was individualized clinically 2.4 Statistical analyses All continuous variables were presented by median (25e75% quartile range) Categorical data were presented in exact ratio The differences between groups were evaluated by nonparametric test (Two-sample Wilcoxon rank-sum (ManneWhitney) test) for continuous variable and Fisher's exact test for categorical variables The statistical significance of P value was set at 0.05 The KaplaneMeier method was used to compare the duration of ventilator support between patients assigned to the EMS and control groups All analyses were done with small STATA 12.1 (StataCorp, Texas USA) Result From 1st Aug, 2013 to 30 Sept 2015, 545 patients were screened as eligible at their ICU admission The major cause of their sepsis and acute respiratory failure resulted from pneumonia and urinary tract infection After three days of mechanical ventilation, 288 patients (52.84%) could be weaned from bi-level ventilator support, 17 Please cite this article in press as: Shen S-Y, et al., Electric Muscle Stimulation for Weaning from Mechanical Ventilation in Elder Patients with Severe Sepsis and Acute Respiratory Failure e A Pilot Study, International Journal of Gerontology (2017), http://dx.doi.org/10.1016/ j.ijge.2017.01.001 Electric Muscle Stimulation for Weaning patients (3.12%) expired, 84 patients (15.41%) refused the study and 131 patients (24.04%) met the exclusion criteria The flowchart of screening and exclusion were listed in Fig Eventually, 25 patients underwent randomization and 17 patients were assigned to EMS group and patients were allocated to control group The baseline demographic data of the participants were comparable and were shown in Table The median age of all participants was 78 yearsold (IQR 72e82) The sources of infection in 16 (64%) participants were pulmonary infections; (16%) were urinary tract infections; (12%) were blood stream infections and (8%) were intraabdominal infections We used handgrip dynamometer to assess the change of muscle power during the study But 17/25 (68%) of participants were too weak, stupor or reluctant to cooperate the handgrip strength test Eight participants could perform the test, and 2e5 kg hand strength were measured The handgrip result was much lower than normal reference (20e33 Kg for population older than 70 years-old)16 Six patients dropped out in the EMS group because patients (11.1%) died and patients (22.2%) refused further muscle stimulation Among the dropped-out group, only patient survived at his discharge One patient (14.29%) expired in the control group before the ventilator weaning Adverse effects of EMS were closely monitored during the muscle stimulation sessions, and neither skin damage nor arrhythmia was observed The mean duration of ventilator dependence was (IQR 6e15) days in control group and 6.5(IQR 5e10) days in EMS group (P ¼ 0.85) The hospital mortality was also similar in both groups Due to the censored data, The KaplaneMeier surviving method was used to compare the time-to-weaning probability (Fig 2), and the probability of ventilator dependence was not significantly different in the two groups (Log rank P ¼ 0.82) Discussion Our pilot study revealed EMS were feasible and safe in elderly ventilated patients, but the duration of mechanical ventilation was not significantly shorten compared to passive limb rehabilitation Drowsiness and muscle weakness were common in elder patients with severe sepsis and acute respiratory failure, and handgrip dynamometer measurement was often impracticable For the elderly patient could cooperate the handgrip test, the results were much lower than predicted and ICUAW should be considered Fig Results of screening, exclusion and randomization ECMO: Extracorporeal Membrane Oxygenation Please cite this article in press as: Shen S-Y, et al., Electric Muscle Stimulation for Weaning from Mechanical Ventilation in Elder Patients with Severe Sepsis and Acute Respiratory Failure e A Pilot Study, International Journal of Gerontology (2017), http://dx.doi.org/10.1016/ j.ijge.2017.01.001 S.-Y Shen et al Table The demographic characteristic and clinical outcomes of patients in EMS and control groups (median (25the75th percentiles)) Parameter Control group (N ¼ 7) EMS group (n ¼ 18) P value Age Gender, male/female Coma scale APACHE II on admission Charson score on admission Blood glucose (mg/dL) Creatinine (mg/dL) Bilirubin (T) (mg/dL) Albumin (g/dL) Septic shock Fever days COPD CHF Malignancy Steroid use Steroid days Outcome measurement Hospital mortality MV days Successful spontaneous breath 78 (73e83) 2/5 (6e10) 25 (21e27) (2e4) 161 (112e210) 2.2 (1.3e2.8) 1.1 (0.8e1.6) 2.7 (2.5e3.5) 4/7 (1e7) 2/7 5/7 2/7 3/7 (0e5) 77.5 (72e81) 12/6 (7e10) 23.5 (19e28) (2e3) 157 (129e222) 1.35 (0.9e1.8) 0.8 (0.6e1.2) 2.65 (2.3e2.9) 11/18 (2e10) 4/18 10/18 6/18 7/18 (0e2) 0.69 0.18 0.78 0.86 0.71 0.93 0.13 0.15 0.32 1.0 0.52 1.0 0.66 1.0 1.0 0.73 2/7 (28.57%) (6e15) 6/7 5/18 (27.78%) 6.5 (5e10) 14/18 1.0 0.85 1.0 Coma scale: Glasgow coma scale, only including eye (1e4) and motor response (1e6) APACHEII ¼ Acute Physiology and Chronic Health Evaluation II COPD: chronic obstructive pulmonary disease CHF: congestive heart failure MV: mechanical ventilation The gold standard for the diagnosis of ICUAW remains electromyography (EMG), but it seldom was used in screening The clinical guideline suggested manual muscle strength to identify the distribution and degree of muscle weakness17 The handgrip dynamometry performance correlated well with the Medical Research Council (MRC) score for clinical assessment of muscle strength18 However, only approximately to 25 to 29 percent of patients are adequately awake to assess muscle strength19 The finding was consistent with our study Early rehabilitation/mobilization in the ICU has been shown to prevent and treat ICUAW1,7,8 Exercise with muscle contraction was believed to have beneficial effect on anti-inflammatory cytokines20e22, glucose metabolism and diminish protein breakdown23 Mechanical ventilation 18 to 69 hours would result in diaphragmatic inactivity and marked atrophy of human diaphragm myofibers because of increased diaphragmatic proteolysis24 But Fig KaplaneMeier curve comparing probability of ventilator-dependent days in patient with or without EMS (Log-rank test: P ¼ 0.82) barrier to adequate exercise in ICU included sedation, restrain, endotracheal tube, femoral catheters and delirium EMS may generate visible muscle contraction in such condition and increase microcirculation, oxygen consumption25, prevent the inactivity diaphragm atrophy26 and CIPM in critical ill patients10e12,18 Many studies reported EMS help muscle strength12 and may have systemic effect in the strength of muscles not stimulated18,27 The systemic effect of EMS could be partially explained by peripheral cytokine change (Increased interleukin-6 and reduced interleukin1/tumor necrosis factor alpha20,28) Compared to the single study reported positive effect of EMS on MV weaning by Routsi et al11, our participants were older with higher APACHE II score (Age 77 ± 46.7 vs 61 ± 19; APACHE II 24.67 ± 6.19 vs 18 ± 4) Our participants were limited to severe sepsis with acute respiratory failure in contrast to critical-illness with or without ventilator The two studies both have low rate of enrollment Routsi et al excluded patients died after randomization and the APACHE II score became significantly incomparable and higher in the control group On the contrary, we did final analysis including participant died after randomization to compare mortality, and the APACHE II score kept similar in the two groups EMS intervention was 55 minutes daily in Routsi study, and 32 minutes/ weekdays in our protocol This may be another explanation of the different outcome Potential hazard of electric stimulation, e.g skin burn, cardiovascular, respiratory and, hemodynamic interaction was not observed in previous29 and our study We believe EMS may be safe and effective exercise in ICU But only Routsi et al had reported EMS shorten duration of mechanical ventilation No study demonstrated EMS effect on mortality so far Weaning from ventilator for a patient t with severe sepsis is a complex process involving sepsis control, cardiopulmonary function and CIPM recovery30 Muscle strength is important, but effective and timely antimicrobial treatment, adequate infection source control, baseline cardiopulmonary function, and the weaning strategy may influence the duration of mechanical ventilation Thus one limitation of our study was lacking records of baseline heart and lung function such as ventricular ejection fraction and forced expiratory volume in one second Another weakness of our trial was the weaning strategy dependent on the ICU physicians Some physicians in our hospital used “intermittent T-piece” method when the patients are weak, and the mechanical ventilation was resumed at night After gradually prolonging T-piece trial were gradually prolonged and the extubation was subsequently performed several days later Thus we arbitrarily decided the six hours for criterial of successful spontaneous breath trial Poor control of sepsis hindered weaning Thus initial duration of fever more than 38.3 C was recorded to stand for the infection control, and the fever duration were comparable in our two groups Nevertheless, heterogeneous source and severity of infection may still affect the comparison of ventilation weaning And ICU-acquired infection may happen and had negative impact on EMS effect and mortality The major limitation is the small sample size after high rate of exclusion/dropout We had to pool arm biceps and thigh quadriceps stimulation group into EMS arm According to Routsi trial, we want to enroll 60 patients initially Based on our available result, if we want to confirm one-day difference in the two groups (standard deviation 5e6; type I error rate 0.05; power 0.8), the estimated sample size is 393e566 in each group Thus further recruitment was stopped because of slow recruitment Further study is warranted to confirm EMS effect with larger sample size, multi-center enrollment, antibiotic guideline-adherence, heart/lung function recording, stratified sepsis source/severity and standardized weaning protocol Please cite this article in press as: Shen S-Y, et al., Electric Muscle Stimulation for Weaning from Mechanical Ventilation in Elder Patients with Severe Sepsis and Acute Respiratory Failure e A Pilot Study, International Journal of Gerontology (2017), http://dx.doi.org/10.1016/ j.ijge.2017.01.001 Electric Muscle Stimulation for Weaning Conclusion EMS could be the only way to induce active muscle contraction and prevent the inactivity muscle weakness in uncooperative or sedated ICU patients For the patients with severe sepsis and acute respiratory failure, our study demonstrated general weakness was frequent complication EMS was feasible but did not shorten the duration of ventilation support Nevertheless, further larger study with adequate power is warranted to examine the impact of EMS in bedridden ICU patients who are mechanically ventilated The cardiopulmonary function, weaning protocol, infection severity and guideline-adherence should be clearly elucidated in 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Please cite this article in press as: Shen S-Y, et al., Electric Muscle Stimulation for Weaning from Mechanical Ventilation in Elder Patients with Severe Sepsis and Acute Respiratory Failure e A. .. Drowsiness and muscle weakness were common in elder patients with severe sepsis and acute respiratory failure, and handgrip dynamometer measurement was often impracticable For the elderly patient