Intensive care unit-acquired muscle atrophy and weakness in critical illness: a review of long-term recovery strategies

Titin is a giant protein that functions as a molecular spring in sarcomeres. Titin interconnects the contraction of actin-containing thin filaments and myosin-containing thick filaments. Titin breaks down to form urinary titin N-fragments, which are measurable in urine. Urinary titin N-fragment was originally reported to be a useful biomarker in the diagnosis of muscle dystrophy. Recently, the urinary titin N-fragment has been increasingly gaining attention as a novel biomarker of muscle atrophy and intensive care unit-acquired weakness in critically ill patients, in whom titin loss is a possible pathophysiology. Furthermore, several studies have reported that the urinary titin N-fragment also reflected muscle atrophy and weakness in patients with chronic illnesses. It may be used to predict the risk of post-intensive care syndrome or to monitor patients’ condition after hospital discharge for better nutritional and rehabilitation management. We provide several tips on the use of this promising biomarker in post-intensive care syndrome.

Although skeletal muscle atrophy is common in critically ill patients, biomarkers associated with muscle atrophy have not been identified reliably. Titin is a spring-like protein found in muscles and has become a measurable biomarker for muscle breakdown. We hypothesized that urinary titin is useful for monitoring muscle atrophy in critically ill patients. Therefore, we investigated urinary titin level and its association with muscle atrophy in critically ill patients. Two-center, prospective observational study. Mixed medical/surgical ICU in Japan. Nonsurgical adult patients who were expected to remain in ICU for greater than 5 days. None. Urine samples were collected on days 1, 2, 3, 5, and 7 of ICU admission. To assess muscle atrophy, rectus femoris cross-sectional area and diaphragm thickness were measured with ultrasound on days 1, 3, 5, and 7. Secondary outcomes included its relationship with ICU-acquired weakness, ICU Mobility Scale, and ICU mortality. Fifty-six patients and 232 urinary titin measurements were included. Urinary titin (normal range: 1-3 pmol/mg creatinine) was 27.9 (16.8-59.6), 47.6 (23.5-82.4), 46.6 (24.4-97.6), 38.4 (23.6-83.0), and 49.3 (27.4-92.6) pmol/mg creatinine on days 1, 2, 3, 5, and 7, respectively. Cumulative urinary titin level was significantly associated with rectus femoris muscle atrophy on days 3-7 (p ≤ 0.03), although urinary titin level was not associated with change in diaphragm thickness (p = 0.31-0.45). Furthermore, cumulative urinary titin level was associated with occurrence of ICU-acquired weakness (p = 0.01) and ICU mortality (p = 0.02) but not with ICU Mobility Scale (p = 0.18). In nonsurgical critically ill patients, urinary titin level increased 10-30 times compared with the normal level. The increased urinary titin level was associated with lower limb muscle atrophy, occurrence of ICU-acquired weakness, and ICU mortality.

Background: Post Intensive Care Syndrome (PICS) is a set of physical, cognitive, and mental health symptoms that arise following intensive care (ICU) hospitalization. Regarding physical changes, muscle weakness is highlighted, potentially leading to functional impairments during and after hospitalization. Multidisciplinary guidelines recommend early mobilization, a rehabilitation intervention, as a strategy to prevent ICU-acquired muscle weakness and reduce functionality impairments. Objective: This study aims to evaluate the effectiveness of early mobilization and positioning interventions to prevent or minimize ICU-acquired weakness in critically ill patients under invasive mechanical ventilation (IMV). Methods: A systematic review of effectiveness will be conducted following Cochrane recommendations. Searches will be made in MEDLINE (via PubMed), CINAHL, Scopus, and Web of Science. Eligible studies will include randomized controlled trials on the functional management of muscle weakness, muscle strength, and ICU-acquired muscle weakness in adults (≥18 years) who have undergone IMV. Eligible interventions (and comparators) include any manual mobilization and positioning strategy or the use of medical devices. Two reviewers will independently select studies, extract data using a piloted tool and assess bias with the RoB 2 tool. If appropriate, a meta-analysis will be conducted, pooling standardized mean differences using a random-effects model. Results: This review included primary experimental studies manipulating at least one variable, control group studies, or randomized trials comparing early intervention protocols, programs, or plans with standard care or existing approaches in the ICU. Conclusions: This review will provide meaningful comparisons of different mobilization and positioning strategies, evaluating their impact on muscle strength and functionality in critically ill patients. Systematic Review Registration: PROSPERO CRD4202348091.

Intensive care unit-acquired weakness (ICU-AW) is the most common complication found in the intensive care unit (ICU) patients, especially those on prolonged use of mechanical ventilation (MV). It is known to cause poor long-term outcomes, and early rehabilitation (ER) intervention has been proved to be useful in improving muscle strength, physical function, and quality of life of ICU survivors. Several obstacles, such as patients’ medical condition and limited availability of equipment or trained personnel, interfere with ER. Passive ER including functional electrical stimulation (FES) and cycling were found to be effective. The combination of FES with a cycle ergometer (FES cycling) can be implemented, but research on using this modality in the ICU is still limited. This review aimed at providing information on the use of FES cycling in ICU patients to explain its effect on physiological changes and functional abilities. The physiological effects of FES cycling are obtained through local metabolic changes in muscles due to FES and increased cardiovascular responses due to muscle contraction during cycling. Its effects on muscle strength, cross-section area, days free of MV, mobilization, cognitive ability, delirium, and quality of life were positive, and only rarely adverse events occurred during the intervention. To conclude, the use of FES cycling in the prevention and treatment of ICU-AW can be considered since this modality causes positive physiological effects and has proven safe.
 Abbreviations: EM – Early Mobilization; ER- early rehabilitation; FES - functional electrical stimulation; ICU-AW - Intensive Care Unit-Acquired Weakness; MV - mechanical ventilation; NMBA - neuromuscular blocking agents; PICS - post-intensive care syndrome; NMES - neuromuscular electrical stimulation;
 Key words: Electrical Stimulation; Intensive Care Unit; Muscle Contraction; Muscle Strength; Quality of Life
 Citation: Nazir A. The effect of a combination of functional electrical stimulation and cycle ergometer (FES-cycling) on physiological changes and functional ability in patients with ICU-acquired weakness. Anaesth. pain intensive care 2023;27(5):599−606; DOI: 10.35975/apic.v27i5.2315
 Received: July 03, 2023; Reviewed & Accepted: August 18, 2023

Prevention and Treatment of ICU-Acquired Weakness

The COVID-19 pandemic has led to an unprecedented increase in cases of acute respiratory distress syndrome (ARDS). In such cases, deep sedation using sedatives and muscle relaxants is commonly used to prevent patient self-inflicted lung injury during the early phase. However, such sedation limits the ability to perform early rehabilitation, leading to ICU-acquired muscle weakness (ICU-AW) and a worse prognosis. This study aimed to clarify the preventive effect of neuromuscular electrical stimulation (NMES) during deep sedation on ICU-AW and physical function at discharge in critically ill patients with COVID-19 with ARDS. A retrospective, single-center study was conducted on patients admitted to the ICU or advanced critical care center with severe COVID-19 with ARDS between March 1, 2020, and March 31, 2022. Patients who were managed with the Richmond Agitation-Sedation Scale between -4 and -5 for at least three days were included. Patients in the NMES group received NMES within two days of deep sedation, whereas those in the non-NMES group did not. The primary endpointwasthe incidence of ICU-AW at discharge from the ICU, and the secondary endpoints included physical activity levels, skeletal muscle mass index, time to active mobilization, and Barthel index (BI) at discharge. Statistical analyses included Pearson's chi-squared test, Fisher's exact test, and multiple logistic and linear regression analyses. Of the 129 patients, 68 (54 males and 14 females) were included after applying the exclusion criteria, with 38 in the NMES group and 30 in the non-NMES group. The incidence of ICU-AW was significantly lower in the NMES group (28.95% vs. 56.67%, p = 0.0211). NMES implementation (OR: 0.20, p = 0.03), ventilator weaning (OR: 0.10, p = 0.01), and duration of deep sedation (OR: 0.81, p < 0.01) were significant predictors of ICU-AW. Higher ICU Mobility Scale scores and shorter time to active mobilization were associated with a higher BI at discharge. Early rehabilitation using NMES during deep sedation may prevent ICU-AW in critically ill patients with COVID-19 with ARDS. NMES is associated with a reduced risk of ICU-AW and improved functional independence at discharge. This procedure can be safely performed in sedated patients and may help prevent ICU-AW, supporting early mobilization strategies in ARDS rehabilitation.

Purpose: Treatment in intensive care units (ICUs) often results in swallowing dysfunction. Recent longitudinal studies have described the recovery of critically ill people, but we are not aware of studies of the recovery of swallowing function in patients with ICU-acquired muscle weakness. This paper aims to describe the time course of regaining water swallowing function in patients with ICU-acquired weakness in the post-acute phase and to describe the risks of regaining water swallowing function and the risk factors involved.Methods: This cohort study included patients with ICU-acquired muscle weakness in our post-acute department, who were unable to swallow. We monitored the process of regaining water swallowing function using the 3-ounce water swallowing test.Results: We included 108 patients with ICU-acquired muscle weakness. Water swallowing function was regained after a median of 12 days (interquartile range =17) from inclusion in the study and after a median of 59 days (interquartile range= 36) from the onset of the primary illness. Our multivariate Cox Proportional Hazard model yielded two main risk factors for regaining water swallowing function: the number of medical tubes such as catheters at admission to the post-acute department (adjusted hazard ratio [HR] = 1.282; 95% confidence interval [CI]: 1.099–1.495) and the time until weaning from the respirator in days (adjusted HR =1.02 per day; 95%CI: 0.998 to 1.008).Conclusion: We describe a time course for regaining water swallowing function based on daily tests in the post-acute phase of critically ill patients. Risk factors associated with regaining water swallowing function in rehabilitation are the number of medical tubes and the duration of weaning from the respirator.Implications for rehabilitationLittle guidance is available for the management of swallowing dysfunction in the rehabilitation of critically ill patients with intensive-care-units acquired muscle weakness.There is a time dependent pattern of recovery from swallowing dysfunction with daily water swallowing tests in the post-acute phase of critically ill patients.Daily water swallowing tests can be used to test swallowing dysfunction in the post-acute phase of critically ill patientsThe amount of medical tubes and the duration of weaning from respirator are associated risk factors for recovery of swallowing dysfunction.

BackgroundCritical illness survivors frequently suffer from long-term impairments, often described as post-intensive care syndrome (PICS). PICS encompasses physical, cognitive, and mental impairments. Additionally, the term intensive care unit (ICU)-acquired weakness (ICUAW) was coined for muscle weakness after critical illness. Research on the progression and outcome of individuals affected by PICS and ICUAW is scant. Thus we aimed to assess the health status and its progression during neurorehabilitation in critically ill patients using comprehensive outcome measures, describe the prevalence of PICS, and evaluate factors associated with rehabilitation outcomes.MethodsPatients with mixed reasons for critical illness who received ≥ 5 days of mechanical ventilation on the ICU and who were admitted to neurorehabilitation, were eligible to be included in this prospective cohort study. A number of outcomes (patient-reported, clinician-reported, and performance) were assessed after discharge from the ICU (V1) and shortly before discharge from inpatient neurorehabilitation (V2). The prevalence of PICS, defined as having at least one impairment in any PICS dimension), was calculated at V1 and V2. Multiple logistic regressions were conducted to identify factors associated with rehabilitation outcome (poor outcome = modified Rankin Scale > 2) and ICUAW at V2 (MRC sum score < 48).ResultsIn total, 250 critical illness survivors (62 ± 14 years, 34% female, median stay on ICU 55 days, median inpatient rehabilitation 65 days) were included. 11 participants (4.4%) died before V2. All outcomes improved significantly during rehabilitation except sensory impairment and pain. PICS was present in 96% at V1 and in 85% at V2, whereby mainly the physical domain (V1: 87%, V2: 66%; ICUAW with MRC sum score < 48) and the cognitive domain (V1:65%, V2:55%; Montreal Cognitive Assessment < 26) were affected. Mental impairment was lower (V1:48%, V2:29%; Hospital Anxiety and Depression Scale > 7), but still affected a considerable number of participants. Accordingly, health-related quality of life was rather low at discharge (0.64 ± 0.28, index value of EQ-5D-5L). MRC sum score at V1, duration of mechanical ventilation, and female gender were significantly associated with a poor rehabilitation outcome. Grip strength in % of reference at V1, age, female gender, and comorbidities were significantly associated with persistent ICUAW at discharge.ConclusionsDespite significant improvements during rehabilitation, survivors after critical illness experience a substantial burden of PICS and ICUAW at discharge from rehabilitation care. Survivors of critical illness require long-term follow-up, supportive structures, and tailored long-term multi-disciplinary therapies even after intensive rehabilitation.Trial registration: German Clinical Trials Register, DRKS00021753. Registered 03 September, 2020. https://drks.de/search/en/trial/DRKS00021753.

Intensive care unit-acquired weakness is a frequent complication that affects the prognosis of critical illness during hospital stay and after hospital discharge. To determine if a multicomponent protocol of early active mobility involving adequate pain control, non-sedation, non-pharmacologic delirium prevention, cognitive stimulation, and family support, reduces intensive care unit-acquired weakness at the moment of discharge. We carried out a non-randomized clinical trial in two mixed intensive care units in a high-complexity hospital, including patients over 14 years old with invasive mechanical ventilation for more than 48 hours. We compared the intervention –the multicomponent protocol– during intensive care hospitalization versus the standard care. We analyzed 82 patients in the intervention group and 106 in the control group. Muscle weakness acquired in the intensive care unit at the moment of discharge was less frequent in the intervention group (41.3% versus 78.9%, p<0.00001). The mobility score at intensive unit care discharge was better in the intervention group (median = 3.5 versus 2, p < 0.0138). There were no statistically significant differences in the invasive mechanical ventilation-free days at day 28 (18 versus 15 days, p<0.49), and neither in the mortality (18.2 versus 27.3%, p<0.167). A multi-component protocol of early active mobility significantly reduces intensive care unit-acquired muscle weakness at the moment of discharge.

Background: Post-intensive care syndrome (PICS) encompasses cognitive, psychiatric, and physical impairments that may persist following ICU and hospital discharge. Despite its clinical importance, PICS has been insufficiently studied in the context of cardiovascular disease. This study aimed to evaluate the extent of ICU-acquired weakness (ICU-AW), a physical manifestation of PICS, in patients with type B acute aortic dissection (AAD). Methods: We retrospectively analyzed 95 patients admitted with type B AAD who received conservative treatment in the ICU. Computed tomography (CT) was performed at admission, approximately one week later, and one month after symptom onset. The cross-sectional area of the psoas muscle at the mid-level of the third lumbar vertebra (L3) was manually measured at each time point. Muscle mass loss was calculated, and nutritional status was assessed using the Geriatric Nutritional Risk Index (GNRI). ICU-AW was defined as a ≥15% reduction in psoas muscle area at one month compared to baseline. Extensive patent false lumen was defined as dissection extending below the diaphragm. Acute kidney injury (AKI) was defined as a ≥0.3 mg/dL or ≥1.5-fold increase in serum creatinine during hospitalization. Results: The average psoas muscle area decreased from 12.5 cm 2 at admission to 11.3 cm 2 at one month, representing a mean reduction of 9.6% (p &lt; 0.01). ICU-AW was identified in 14 patients (14.7%). The incidence of extensive patent false lumen was significantly higher in the ICU-AW group compared to the non-ICU-AW group (71.4% vs. 38.3%, p = 0.02). AKI was more frequently observed in the ICU-AW group (71.4% vs. 42.0%, p = 0.04). Furthermore, a decline in GNRI between ICU discharge and hospital discharge was more common in the ICU-AW group (78.6% vs. 35.8%, p &lt; 0.01). (see table 1) Conclusions: Patients with type B acute aortic dissection often develop ICU-acquired muscle weakness, which persists beyond the acute phase. ICU-AW was significantly associated with greater disease severity, nutritional decline, and renal dysfunction, highlighting the need for comprehensive monitoring and rehabilitation strategies in this population.

Lack of mobilization and prolonged stay in the intensive care unit (ICU) are major factors resulting in the development of ICU-acquired muscle weakness (ICUAW). ICUAW is a type of skeletal muscle dysfunction and a common complication of patients after cardiac surgery, and may be a risk factor for prolonged duration of mechanical ventilation, associated with a higher risk of readmission and higher mortality. Early mobilization in the ICU after cardiac surgery has been found to be low with a significant trend to increase over ICU stay and is also associated with a reduced duration of mechanical ventilation and ICU length of stay. Neuromuscular electrical stimulation (NMES) is an alternative modality of exercise in patients with muscle weakness. A major advantage of NMES is that it can be applied even in sedated patients in the ICU, a fact that might enhance early mobilization in these patients. To evaluate safety, feasibility and effectiveness of NMES on functional capacity and muscle strength in patients before and after cardiac surgery. We performed a search on Pubmed, Physiotherapy Evidence Database (PEDro), Embase and CINAHL databases, selecting papers published between December 2012 and April 2023 and identified published randomized controlled trials (RCTs) that included implementation of NMES in patients before after cardiac surgery. RCTs were assessed for methodological rigor and risk of bias via the PEDro. The primary outcomes were safety and functional capacity and the secondary outcomes were muscle strength and function. Ten studies were included in our systematic review, resulting in 703 participants. Almost half of them performed NMES and the other half were included in the control group, treated with usual care. Nine studies investigated patients after cardiac surgery and 1 study before cardiac surgery. Functional capacity was assessed in 8 studies via 6MWT or other indices, and improved only in 1 study before and in 1 after cardiac surgery. Nine studies explored the effects of NMES on muscle strength and function and, most of them, found increase of muscle strength and improvement in muscle function after NMES. NMES was safe in all studies without any significant complication. NMES is safe, feasible and has beneficial effects on muscle strength and function in patients after cardiac surgery, but has no significant effect on functional capacity.

Survivors of intensive care unit (ICU) are increasingly numerous because of better hospital care. However, several consequences of an ICU stay, known as post-intensive care syndrome, worsen long-term prognoses. A predominant feature in survivors is reduced muscle strength, mass, and physical function. This leads to lower exercise capacity, long-lasting physical disability, higher mortality risk, and subsequent health costs. While ICU-acquired muscle weakness has been extensively studied these past decades, underlying mechanisms of post-ICU muscle weakness remain poorly understood, and there is still no evidence-based treatment for improving long-term physical outcomes. One hypothesis, among others, could be that the pathophysiology is dynamic over time, differing between the acute ICU and post-ICU recovery periods. This narrative review aims to address the clinical, physiological and biological determinants of persistent muscle dysfunction in ICU survivors, with particular attention to the molecular, cellular and systemic mechanisms involved. Specifically, pre-ICU health factors such as obesity and sarcopenia, ICU-related complications and treatments, and post-ICU management all influence recovery. Dysfunctions in the neuroendocrine, vascular, neurological, and muscle systems contribute as physiological determinants of the muscle weakness. Complex and multifaceted biological mechanisms drive the post-ICU muscle dysfunction with mitochondrial and autophagy dysfunction, epigenetic modifications, cellular senescence, muscle inflammation with altered cell–cell communication, including dysfunction of immune cells, stem cell exhaustion and extracellular matrix remodelling. The review also sheds light on new and innovative therapeutic approaches and discusses future research directions. Emphasis is placed on the potential for multi-approach treatments that integrate nutritional, physical, and biological interventions. Addressing these aspects in a holistic and dynamic manner, from ICU to post-ICU phases, may provide avenues for mitigating the long-term burden of muscle weakness and physical disability in ICU survivors.

On the basis of strong research evidence, Duchenne muscular dystrophy (DMD), the most common severe childhood form of muscular dystrophy, is an X-linked recessive disorder caused by out-of-frame mutations of the dystrophin gene. Thus, it is classified asa dystrophinopathy. The disease onset is before age 5 years. Patients with DMD present with progressive symmetrical limb-girdle muscle weakness and become wheelchair dependent after age 12 years. (2)(3). On the basis of some research evidence,cardiomyopathy and congestive heart failure are usually seen in the late teens in patients with DMD. Progressive scoliosis and respiratory in sufficiency often develop once wheelchair dependency occurs. Respiratory failure and cardiomyopathy are common causes of death, and few survive beyond the third decade of life. (2)(3)(4)(5)(6)(7). On the basis of some research evidence, prednisone at 0.75 mg/kg daily (maximum dose, 40 mg/d) or deflazacort at 0.9 mg/kg daily (maximum dose, 39 mg/d), a derivative of prednisolone (not available in the United States), as a single morning dose is recommended for DMD patients older than 5 years, which may prolong independent walking from a few months to 2 years. (2)(3)(16)(17). Based on some research evidence, treatment with angiotensin-converting enzyme inhibitors, b-blockers, and diuretics has been reported to be beneficial in DMD patients with cardiac abnormalities. (2)(3)(5)(18). Based on expert opinion, children with muscle weakness and increased serum creatine kinase levels may be associated with either genetic or acquired muscle disorders (Tables 1 and 3). (14)(15)

Post-intensive care syndrome (PICS) is a triad of physical, cognitive, and mental impairments that occur during or following the intensive care unit (ICU) stay, affecting the long-term prognosis of the patient and also the mental health of the patient’s family. While the severity and duration of the systemic inflammation are associated with the occurrence of ICU-acquired weakness (ICU-AW), malnutrition and immobility during the treatment can exacerbate the symptoms. The goal of nutrition therapy in critically ill patients is to provide an adequate amount of energy and protein while addressing specific nutrient deficiencies to survive the inflammatory response and promote recovery from organ dysfunctions. Feeding strategy to prevent ICU-AW and PICS as nutrition therapy involves administering sufficient amounts of amino acids or proteins later in the acute phase after the hyperacute phase has passed, with specific attention to avoid energy overfeeding. Physiotherapy can also help mitigate muscle loss and subsequent physical impairment. However, many questions remain to be answered regarding the potential role and methods of nutrition therapy in association with ICU-AW and PICS, and further research is warranted.

To evaluate the efficacy of acupuncture combined with rehabilitation training in patients with intensive care unit (ICU)-acquired muscle weakness (ICUAW), a single-blinded, randomized, sham-controlled clinical trial is designed for execution. In total, 56 participants with ICUAW will be randomly assigned to the treatment and control groups with 28 participants in each group. The participants will be treated with acupunctures or sham procedures at LI15, LI11, ST36, GB34, and ST31, 5 times per week for a total of 20 sessions in 4 weeks while they will receive rehabilitation training. Patients will be followed up every month for 3 months after treatment. The primary outcomes include changes in quadriceps femoris muscle area, thickness, vastus intermediate muscle thickness, subcutaneous tissue thickness, and ultrasonic intensities of the rectus femoris. The secondary outcomes consist of the modified Barthel index score and the Medical Research Council total score. Participants' mechanical ventilation, the rate of detachment at the second week, the 28-day survival rate, and the occurrence of adverse reactions will be measured, and any side effects will be reported and recorded. Patient outcomes between the treatment and control groups will be compared and statistically tested. We anticipate that the therapeutic regimen of acupuncture combined with rehabilitation training would be more effective than the rehabilitation training alone for the treatment of the ICUAW. The findings of this study could help develop a better strategy for the treatment of the ICUAW disease and explore a clinical application of an acupuncture technique. Trial registration: Chinese Clinical Trial Register ChiCTR2000038779. Registered 30 September, 2020, https://www.chictr.org.cn/showproj.aspx?proj=62284.