Electric muscle stimulation for weaning from mechanical ventilation in elder patients with severe sepsis and acute respiratory failure a pilot study

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[.]

Original Article

Electric Muscle Stimulation for Weaning from Mechanical Ventilation

Sheng-Yeh Shen1, Chao-Hsien Lee2, Rong-Luh Lin1, Kuang-Hua Cheng1,3*

1 Division of Chest Medicine, Departments of Internal Medicine, Mackay Memorial Hospital, 2 Critical Medicine Department, Mackay Memorial Hospital,

Taipei, 3 National Taiwan University College of Medicine, Graduate Institute of Clinical Medicine, Taiwan

a r t i c l e i n f o

Article history:

Received 13 January 2017

Accepted 13 January 2017

Available online xxx

Keywords:

mechanical ventilation,

electric muscle stimulation,

sepsis,

weaning

s u m m a r y 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 7 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 6 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/)

1 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

weak-ness (ICUAW) typically affects proximal limb muscles symmetrically

and respiratory muscles The main risk factors for ICUAW include

high severity of illness upon admission, sepsis, multiple organ fail-ure, 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 3 days3 and 69% in critical primary neurological diseases4 Administration of glucocorticoids and non-depolarizing muscle relaxants, sepsis and multi-organ failure per

se as well as elevated levels of blood glucose and muscular immo-bilization 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 pharmaco-therapy 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

* Disclosure of conflicts of interest: I certify that all my affiliations with or

financial involvement in, within the past 5 years and foreseeable future, any

or-ganization 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

testi-mony, 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).

Contents lists available atScienceDirect

International Journal of Gerontology

jo u rn a l h o m e p a g e :w w w i j g e - o n l i n e c o m

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/ ).

eligible for ICU patients because of the stupor consciousness,

sedation or restraint in ICU Electric muscle stimulation (EMS)

in-duces 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 signi

fi-cantly improved peripheral muscles strength in bed-bound

pa-tients with mechanical ventilation for chronic obstructive

pulmonary disease9 For septic patients requiring mechanical

ventilation and having 1 or more organ failure other than

respira-tory 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

dura-tion of mechanical ventiladura-tion (MV) in critically septic patients

2 Materials and methods

2.1 Study design

The study was a prospective randomized control study

approved by institutional Review Board in Mackay Memorial

hos-pital (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

Suc-cessful weaning was defined as spontaneous breath without

inspiratory pressure support more than 6 hours The second

out-comes 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

patient-ephysician ratio 8:1 The weaning strategy was driven by the

crit-ical care physicians

2.2 Participants

Adult patients (20e90 years-old) admitted with mechanical

ventilator were daily screened and recorded as eligible If they

ful-filled criteria of sepsis according to definition of 1992 American

College of Chest Physicians and the Society of Critical Care

Medi-cine15 The randomization was performed when the eligible

pa-tients required mechanical ventilation longer than 72 hours

(defined as need of inspiratory mechanical support in ventilator

setting) They were randomly assigned to electric muscle stimula-tion (Intervenstimula-tion 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:

1 Skin defect or infection around the thighs

2 Acute myocardial infarction within one week

3 Life-threatening cardiac arrhythmia

4 Pregnancy

5 Dying patient with life expectance shorter than one month

6 Severe encephalopathy with coma and no spontaneous breath drive

7 Uncontrolled seizure

8 Patient is fully awake and has adequate muscle power to cooperate active limb exercise

9 Air-born contagious diseases eg Tuberculosis and Influenza virus infection

10 Moderate to severe adult respiratory distress syndrome with requirement of neuromuscular blocker

11 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, 5 days per week (Monday to Friday) EMS was conducted with a com-mercial 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 3 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)

3 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 pa-tients (52.84%) could be weaned from bi-level ventilator support, 17

patients (3.12%) expired, 84 patients (15.41%) refused the study and

131 patients (24.04%) met the exclusion criteria Theflowchart of

screening and exclusion were listed inFig 1 Eventually, 25 patients

underwent randomization and 17 patients were assigned to EMS

group and 8 patients were allocated to control group The baseline

demographic data of the participants were comparable and were

shown inTable 1 The median age of all participants was 78

years-old (IQR 72e82) The sources of infection in 16 (64%) participants

were pulmonary infections; 4 (16%) were urinary tract infections; 3

(12%) were blood stream infections and 2 (8%) were

intra-abdominal 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 2 patients (11.1%)

died and 4 patients (22.2%) refused further muscle stimulation

Among the dropped-out group, only 1 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 6 (IQR 6e15) days in control group and 6.5(IQR 5e10) days in EMS group (P¼ 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 P¼ 0.82)

4 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 1 Results of screening, exclusion and randomization ECMO: Extracorporeal Membrane Oxygenation.

The gold standard for the diagnosis of ICUAW remains

electro-myography (EMG), but it seldom was used in screening The clinical

guideline suggested manual muscle strength to identify the

dis-tribution and degree of muscle weakness17 The handgrip

dyna-mometry 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

break-down23 Mechanical ventilation 18 to 69 hours would result in

diaphragmatic inactivity and marked atrophy of human diaphragm

myofibers because of increased diaphragmatic proteolysis24 But

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 atrophy26and CIPM in critical ill patients10e12,18 Many studies reported EMS help muscle strength12 and may have sys-temic effect in the strength of muscles not stimulated18,27 The systemic effect of EMS could be partially explained by peripheral cytokine change (Increased 6 and reduced interleukin-1/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 didfinal analysis including participant died after randomization to compare mor-tality, 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, cardio-vascular, respiratory and, hemodynamic interaction was not observed in previous29and 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 func-tion and CIPM recovery30 Muscle strength is important, but effective and timely antimicrobial treatment, adequate infection source control, baseline cardiopulmonary function, and the wean-ing 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 ventila-tion 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 38.3C 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-ac-quired infection may happen and had negative impact on EMS ef-fect 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 war-ranted 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

Table 1

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 78 (73e83) 77.5 (72e81) 0.69

Gender, male/female 2/5 12/6 0.18

Coma scale 8 (6e10) 9 (7e10) 0.78

APACHE II on admission 25 (21e27) 23.5 (19e28) 0.86

Charson score on admission 3 (2e4) 3 (2e3) 0.71

Blood glucose (mg/dL) 161 (112e210) 157 (129e222) 0.93

Creatinine (mg/dL) 2.2 (1.3e2.8) 1.35 (0.9e1.8) 0.13

Bilirubin (T) (mg/dL) 1.1 (0.8e1.6) 0.8 (0.6e1.2) 0.15

Albumin (g/dL) 2.7 (2.5e3.5) 2.65 (2.3e2.9) 0.32

Septic shock 4/7 11/18 1.0

Fever days 3 (1e7) 4 (2e10) 0.52

Steroid days 0 (0e5) 0 (0e2) 0.73

Outcome measurement

Hospital mortality 2/7 (28.57%) 5/18 (27.78%) 1.0

MV days 6 (6e15) 6.5 (5e10) 0.85

Successful spontaneous breath 6/7 14/18 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.

Fig 2 KaplaneMeier curve comparing probability of ventilator-dependent days in

patient with or without EMS (Log-rank test: P ¼ 0.82).

5 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 further study design

Reference

1 Hermans G, Van den Berghe G Clinical review: intensive care unit acquired

weakness Crit Care 2015;19:274

2 Latronico N, Bolton CF Critical illness polyneuropathy and myopathy: a major

cause of muscle weakness and paralysis Lancet Neurol 2011;10:931e941

3 Bercker S, Weber-Carstens S, Deja M, et al Critical illness polyneuropathy and

myopathy in patients with acute respiratory distress syndrome Crit Care Med.

2005;33:711e715

4 Schorl M, Valerius-Kukula SJ, Kemmer TP Critical-illness-polyneuropathy as

sequelae of severe neurological illness: incidence and impact on ventilator

therapy and rehabilitation NeuroRehabilitation 2013;32:149e156

5 Judemann K, Lunz D, Zausig YA, et al [Intensive care unit-acquired weakness in

the critically ill: critical illness polyneuropathy and critical illness myopathy].

Anaesthesist 2011;60:887e901

6 Santos PD, Teixeira C, Savi A, et al The critical illness polyneuropathy in septic

patients with prolonged weaning from mechanical ventilation: is the

dia-phragm also affected? A pilot study Respir Care 2012;57:1594e1601

7 Novak P, Vidmar G, Kuret Z, et al Rehabilitation of critical illness

poly-neuropathy and myopathy patients: an observational study Int J Rehabil Res.

2011;34:336e342

8 Morris PE, Goad A, Thompson C, et al Early intensive care unit mobility therapy

in the treatment of acute respiratory failure Crit Care Med 2008;36:

2238e2243

9 Zanotti E, Felicetti G, Maini M, et al Peripheral muscle strength training in

bed-bound patients with copd receiving mechanical ventilation: effect of electrical

stimulation Chest 2003;124:292e296

10 Rodriguez PO, Setten M, Maskin LP, et al Muscle weakness in septic patients

requiring mechanical ventilation: protective effect of transcutaneous

neuro-muscular electrical stimulation J Crit Care 2012;27:319.e1e319.e8

11 Routsi C, Gerovasili V, Vasileiadis I, et al Electrical muscle stimulation prevents

critical illness polyneuromyopathy: a randomized parallel intervention trial.

Crit Care 2010;14:R74

12 Maffiuletti NA, Roig M, Karatzanos E, et al Neuromuscular electrical stimula-tion for preventing skeletal-muscle weakness and wasting in critically ill pa-tients: a systematic review BMC Med 2013;11:137

13 Maddocks M, Gao W, Higginson IJ, et al Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease Cochrane Database Syst Rev 2013;1:CD009419

14 Chen C-M, Cheng K-C, Chan K-S, et al Age may not influence the outcome of patients with severe sepsis in intensive care units Int J Gerontol 2014;8:22e26

15 American college of chest physicians/society of critical care medicine consensus conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis Crit Care Med 1992;20:864e874

16 Massy-Westropp NM, Gill TK, Taylor AW, et al Hand grip strength: age and gender stratified normative data in a population-based study BMC Res Notes 2011;4:127

17 Fan E, Cheek F, Chlan L, et al An official american thoracic society clinical practice guideline: the diagnosis of intensive care unit-acquired weakness in adults Am J Respir Crit Care Med 2014;190:1437e1446

18 Karatzanos E, Gerovasili V, Zervakis D, et al Electrical muscle stimulation: an effective form of exercise and early mobilization to preserve muscle strength in critically ill patients Crit Care Res Pract 2012;2012, 432752

19 Hough CL, Lieu BK, Caldwell ES Manual muscle strength testing of critically ill patients: feasibility and interobserver agreement Crit Care 2011;15:R43

20 Pedersen BK Muscles and their myokines J Exp Biol 2011;214:337e346

21 Argiles JM, Lopez-Soriano FJ, Busquets S Therapeutic potential of interleukin-15: a myokine involved in muscle wasting and adiposity Drug Discov Today 2009;14:208e213

22 Pedersen BK, Fischer CP Beneficial health effects of exerciseethe role of il-6 as

a myokine Trends Pharmacol Sci 2007;28:152e156

23 Weber-Carstens S, Schneider J, Wollersheim T, et al Critical illness myopathy and glut4: significance of insulin and muscle contraction Am J Respir Crit Care Med 2013;187:387e396

24 Levine S, Nguyen T, Taylor N, et al Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans N Engl J Med 2008;358:1327e1335

25 Gerovasili V, Tripodaki E, Karatzanos E, et al Short-term systemic effect of electrical muscle stimulation in critically ill patients Chest 2009;136: 1249e1256

26 Ayas NT, McCool FD, Gore R, et al Prevention of human diaphragm atrophy with short periods of electrical stimulation Am J Respir Crit Care Med 1999;159:2018e2020

27 Hirose T, Shiozaki T, Shimizu K, et al The effect of electrical muscle stimulation

on the prevention of disuse muscle atrophy in patients with consciousness disturbance in the intensive care unit J Crit Care 2013;28(4):536.e1e536.e7

28 Truong AD, Kho ME, Brower RG, et al Effects of neuromuscular electrical stim-ulation on cytokines in peripheral blood for healthy participants: a prospective, single-blinded study Clin Physiol Funct Imaging 2015 http://dx.doi.org/10.1111/ cpf.12290

29 Meesen RL, Dendale P, Cuypers K, et al Neuromuscular electrical stimulation as

a possible means to prevent muscle tissue wasting in artificially ventilated and sedated patients in the intensive care unit: a pilot study Neuromodulation 2010;13:315e320 discussion 21

30 Sellares J, Ferrer M, Cano E, et al Predictors of prolonged weaning and survival during ventilator weaning in a respiratory icu Intensive Care Med 2011;37: 775e784