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Intensive care unit-acquired weakness (ICUAW) is defined by secondary development of weakness with no other possible cause other than critical illness. It is characterized by symmetric limb and respiratory muscle weakness that spares the facial and ocular muscles.1  ICUAW is associated with difficulty weaning off the ventilator and increased long term morbidity and mortality.2,3

If the weakness is secondary to a neurogenic interference, the ICUAW can be further subclassified as critical illness polyneuropathy (CIP). Whereas, if the weakness is myogenic in origin, the ICUAW would be further subclassified as critical illness myopathy (CIM). As ICUAW can be caused by both myogenic and neurogenic damage, the term critical illness polyneuromyopathy (CIPNM) is used to capture the multifactorial pathophysiological basis of the disease.3

ICUAW has been independently associated with higher morbidity and mortality and lower physical functioning in six months after ICU discharge.4 The neuromuscular complications that result can also increase 5-year morbidity and mortality.5

A prolonged ICU stay not only leaves patients at risk for ICUAW, but also for neurocognitive decline, notably from delirium, as well as long-term neurocognitive sequelae of post-ICU care.6 Neurocognitive decline can be defined as deterioration from a previously attained level of cognitive functioning, affecting multiple domains such as executive functioning, complex attention, perceptual-motor function, language, learning/memory, and social cognition.7 Delirium is defined as an acute onset of change or fluctuations in mental status characterized by inattention, and either disorganized thinking or altered level of consciousness. Delirium is classified into hypoactive, hyperactive, or mixed. Hypoactive delirium is associated with a worse outcome as it is commonly misdiagnosed. The presence of delirium is associated with increased mortality, longer ICU stay, and cognitive impairment extending beyond the ICU stay.8 Delirium can hinder a patient’s medical treatment including physical therapy, which can extend hospitalization and further increase morbidity and mortality.  Delirium presents as fluctuations in attention and impaired cognitive function.

In 2010, the Society of Critical Care Medicine coined the term Post-Intensive Care Syndrome (PICS), which denotes the sequelae of physical, psychological and cognitive dysfunction after ICU admission.9 While the diagnostic criteria is not yet established, these sequelae have significant consequences on quality of life, autonomy and healthcare consumption.


The underlying mechanism for neuromuscular dysfunction in ICUAW includes a combination of axonal degeneration, mitochondrial damage, muscle breakdown, and sodium channel dysfunction with ensuing muscle membrane hypo-excitability.

The causes of delirium are also multifactorial including current medical conditions, past medical history and chronic diseases, premorbid cognitive function, acute pain, medications, infection, and the ICU environment itself.

Neurocognitive decline can follow delirium depending on the severity but can also occur exclusively. The cause of neurocognitive decline is not clearly delineated; however recent studies show that factors such as, but not limited to, metabolic derangements, hypoxia, glucose dysregulation, medications such as sedatives and narcotics, are associated with developing cognitive decline.10 It is important to note that all of the above factors can also increase chances of developing delirium, which itself is another critical factor of developing neurocognitive decline in ICU setting.11

Delirium not only increases length of stay in ICU, but due to nature of affecting patient’s cognitive status, it can limit patient’s participation in rehabilitation12 which would further worsen ICU acquired weakness. The hallmark presentation of ICUAW is flaccid, symmetric weakness of muscles with greater involvement of proximal muscles compared to distal muscle groups. Facial and ocular muscles are usually spared.13 Deep tendon reflexes are variably affected. Patients with ICUAW can typically respond to painful stimuli. Loss of pain, temperature, and vibration may be present in cases of CIP. Due to involvement of the phrenic nerve and muscles of respiration, failure to wean from the ventilator is often a presenting symptom.14 Contributions of small fiber neuropathy and dysautonomia have been proposed as well. Schweickert and colleagues showed that patients in an early rehabilitation program with combined PT/OT had decreased delirium, reduced length of stay in the ICU (median of 2 days less), and return to function in 59% of the intervention group compared to the control group.15 Needham and colleagues found that increased PM&R consults and dedicated therapy with a team focus on decreased sedation and early mobilization improved sedation and delirium status with improved ICU and Hospital LOS.16

Epidemiology including risk factors and primary prevention

ICUAW is common. The reported incidence ranges from 26-65% for patients intubated for a duration of 5-7 days, and up to 67% of patients with prolonged periods of intubation (>10 days).4 Observational and randomized controlled trials have identified a wide range of non-modifiable and modifiable risk factors associated with the risk of developing weakness in the ICU. Non-modifiable risk factors include older age, female sex, premorbid obesity, multiorgan failure, prolonged mechanical ventilation, higher injury severity score and sepsis. Modifiable risk factors include prolonged immobilization, hyperglycemia, use of parenteral nutrition, and several medications including β-agonists, corticosteroids, vancomycin, aminoglycosides.1 Targeting these risk factors by avoiding hyperglycemia and use of parenteral nutrition, minimizing sedation, and implementing early mobilization and neuromuscular electrical stimulation can be used to prevent development of ICUAW.

Up to 80% of adult ICU patients on mechanical ventilation develop delirium. 30-80% of ICU survivors demonstrate long-term cognitive impairment. Premorbid cognitive impairment (ie. dementia), psychiatric history, substance use history especially alcoholism, increased severity of illness, untreated pain, use of physical restraints and sensory deficits are risk factors to develop delirium.8


The pathophysiology of ICUAW is not clearly described and is thought to be multifactorial in origin. Studies using animal models as well as human muscle and nerve biopsies have added insight into possible physiological alterations that may contribute to loss of muscle and subsequent function. Muscle atrophy has been associated with increased activity of Ubiquitin Proteasome Systems (UPS). In mice models and human biopsies, activity of E3 Ub-protein ligases, such as MAFbx or MuRF, were upregulated, causing increased  ubiquitination of target proteins for degradation.17

Dysregulated autophagy and mitochondrial dysfunction was also noted in limb biopsies of ICU patients.17 Balanced autophagy is required for proper skeletal muscle turnover; however critically ill patients have been noted to have insufficiently activated autophagy, contributing to mitochondrial damage. Mitochondrial damage is primarily caused by inflammation, hyperglycemia and free radicals.1 Decreased mitochondrial enzyme activity as well as reduced mitochondrial density have been reported in muscle biopsies in critically ill patients, which suggest energy demands are not being met; this further contributes to the formation of free radicals, which will subsequently lead to further damage of organelles.1,17

Vasodilation, leukocyte extravasation, cytokine production, ensuing edema, may affect oxygen delivery and cause compression of neighboring muscles and nerves.  Possible channelopathy as a mechanism of injury has been proposed based on animal studies.4 Dysfunction of sodium channels lead to hypo-excitability of muscle membranes and nerves, contributing to weakness.13,14

Delirium and cognitive impairment represent dysfunctions of the brain arising from a complex interplay of risk factors including the underlying disease, age, polypharmacy, pain, duration of intubation, environmental stimulation, and sleep deprivation. The pathophysiology of delirium and neurocognitive decline after ICU admission is not well known.8Potential factors that have been suggested include functional anatomic deficits, neurotransmitter dysfunction, impaired cerebral oxidative metabolism and disruption of the blood brain barrier secondary to inflammation and cytokine dysfunction.18

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Patients with persistent and a higher severity of ICUAW have an increased risk of death within one year.13 Some studies suggest that CIM may recover faster than CIP.19 Survivors do make substantial functional gains with most recovering within weeks to months, reaching a stable state approximately one year later. While chronic fatigue and weakness are common complaints, 77% of survivors can return to work within five years. 

Elderly patients who experience delirium however have higher hospital and overall mortality at one year as well as admission to long-term care.20 In addition the duration of delirium is an independent predictor of 3-month and 12-month cognitive decline.21

Those that develop PICS demonstrate modest improvement at 6 and 12 months after ICU discharge but many patients develop prolonged disability impacting work, quality of life, and higher mortality rates.22

Specific secondary or associated conditions and complications

It is suggested that 3 to 11% of strength is lost for each day a patient spends in bed in an ICU setting. Days of bed rest are independent predictors for decreased overall function.23 The complications of prolonged immobility are myriad, and beyond the scope of this discussion. Nevertheless, it would be remiss to neglect the cardiopulmonary effects, risk of venous thromboembolism, pressure sores, contractures, osteoporosis, and fluid and electrolyte imbalances which can occur.

While evidence to support rehabilitation in the ICU is compelling, there is a significant gap in this established knowledge and real-world clinical practice. The mechanism of ICUAW is still unclear, and no specific drug or effective treatment is currently available. Instead, the focus has been on interventions that can improve prognosis. The implementation of an effective rehabilitation program in the ICU setting appears to be best accomplished through an interdisciplinary team approach and using a structured approach to quality improvement.

Essentials of Assessment


Weakness and delirium increase with severity of illness, and the presence of delirium is associated with increased length of stay. Delirium is independently associated with poorer outcomes in ICU patients including increased mortality, functional loss, neuro-cognitive impairments, and long-term care placement. A physiatric history includes severity of illness and ongoing evidence of delirium, identification of potential delirium promoting medications, including opiates and benzodiazepines, as well as assessment of pain. In addition, physiatrists can contribute to effective post-acute care planning and coordination. Information on the patient’s previous living situation, cognition, functional independence, social support, and availability of family and caregivers are important variables when developing post-acute care plans.

Physical examination

The physical examination should begin with assessment of mental status which includes the ability to follow directions, orientation, attention, language, memory, executive function, praxis, and visuospatial ability. Assessments of muscle strength, tone, coordination, balance, range of motion, reflexes, skin, and sensation should then be performed. Standardized bedside exams such as the CAM-ICU can be utilized to assist in diagnosis of delirium.

Functional assessment

Care must be taken with regards to patient safety and the presence of tubes, lines, and drains in the functional assessment of ICU patients. Collaborative efforts involving ICU personnel (e.g., medical intensivist, respiratory therapists, nurses) and rehabilitation professionals (physicians, physical therapists, and occupation therapists) have proven helpful in comprehensive functional assessment and interventions in the ICU setting.

The MRC (Medical Research Council) sum score is a validated screening tool that is used in the intensive care setting to diagnose ICUAW, indicated by a score less than 48.13 Wrist extension, elbow flexion, shoulder abduction, dorsiflexion, knee extension, and hip flexion are graded on a scale of 0-5 strength bilaterally for a maximum score of 60.  This method requires patient alertness and cooperation. It also has use as an independent predictor of prolonged need for ventilation, prolonged ICU and hospital stay, as well as one-year mortality.14 A limitation of the test is the inability to identify causes of weakness, or to distinguish between CIP or CIM. The ordinal scale in which the MRC sum score employs also limits its sensitivity to detect more subtle changes in muscle function. Less commonly used assessments include the “Scored Physical Function in Intensive Care Test”, “Functional Status Score for the ICU”, and the “Chelsea Critical Care Assessment Tool”.1

Hand grip strength measured by dynamometer has been shown to be an alternative to the MRC sum score, especially in patients with significant weakness who are unable to activate the proximal muscle groups required for the MRC sum score.13,14 However, it is unclear whether hand grip strength is an appropriate substitute for global muscle strength.

Laboratory studies

There are no specific laboratory studies to diagnose ICUAW. Systemic causes of weakness and neurocognitive deficits must be actively pursued including but not limited to infectious causes and metabolic derangements. Serum creatine kinase can be elevated in cases of muscle fiber loss but is a nonspecific finding. GDF-15 is a biomarker, which is thought to play a role in causing muscle atrophy seen in ICUAW. A recent study demonstrated that levels in blood plasma increased over a 7-day period correlating with declines in muscle strength during an ICU stay. Elevated levels may also be indicative of a poor prognosis.24

Electrodiagnostic studies can be used to help diagnose ICUAW. Both CIP and CIM will usually show reduced CMAP amplitudes; however, CIM will most likely have increased CMAP duration unlike CIP which will have normal CMAP duration.1 SNAP amplitude may be decreased in CIP, but will be normal in CIM. Nerve conduction velocities may be normal to near normal in both CIP and CIM.13 EMG at rest may show increased fibrillation potentials and positive sharp waves in both CIP and. On EMG, CIP may show polyphasic motor unit potentials (MUP) of longer duration, high amplitude to indicate signs of reinnervation in denervated muscle fibers; CIM may show polyphasic MUPs that are small and shorter in duration with low amplitudes, suggesting reduced functional muscle fibers. CIPNM may present with mixed findings on electrodiagnostic studies but will most likely show reduced CMAP with variable SNAP amplitudes; EMG at rest will show increased fibrillation potentials and positive sharp waves.1,25

Electrodiagnosis can be limited by poor volitional strength.14 For diagnosis of CIP and CIM, particularly in uncooperative patients, the addition of direct muscle stimulation may be helpful, as CIM shows reduced muscle excitability, while CIP muscle excitability is normal.1 Overall, CIP would show evidence of an axonal sensorimotor polyneuropathy while CIM would show evidence of motor unit recruitment dysfunction,  impaired excitability with muscle stimulation with preserved sensory function.25 There is some literature on muscle or nerve biopsies.23 However, such tests are invasive and are not practical for routine clinical use.


Ultrasound is considered the most promising imaging modality for assessing muscle weakness. It can be used to identify changes in muscle architecture and indirectly detect muscle atrophy by using muscle size as a surrogate measure.26,27 However, the evidence supporting its use is lacking. CT scan is another option, which can detect fatty infiltration of muscle, but is expensive and exposes patients to high levels of radiation.1

Imaging is not used to diagnose delirium but may be useful to rule out differential diagnoses.

Supplemental assessment tools

The Confusion Assessment Method for the ICU (CAM-ICU) is a widely used delirium assessment tool in ICU research and practice.28 It has been shown to have a high sensitivity and specificity for detecting delirium by non-psychiatric trained providers.

Early predictions of outcomes

Limb and respiratory muscle weakness are predictors of prolonged mechanical ventilation and failed extubation rates. Patients with an MRC sum score of less than 48 had a higher one year mortality as well as worse five year survival. Evaluation of patients one year after ICU discharge show that CIM had a better prognosis than neurogenic forms of ICUAW.1 Failure of extubation can be more severe in neurogenic ICUAW due to involvement of the phrenic nerve and subsequent diaphragmatic dysfunction.25

Delirium, prolonged bed rest, poor sleep hygiene, prolonged mechanical ventilation and increased use of sedative and pain medications are potentially modifiable predictors of poor outcomes. Early mobilization in ICU patients improves function at hospital discharge.29


Increased numbers of rehabilitation therapists and reduction in the use of sedative and pain medications are associated with improved functional outcomes in the ICU. Environmental modifications to reduce noise, promote sleep and increase exposure to natural sunlight result in improvements in orientation and the ability to participate in rehabilitation.16,30

Social role and social support system

Assessments of social, financial, and caregiver resources are pivotal to effective planning following the ICU stay and acute hospitalization. In addition, early caregiver education and involvement promotes engagement with discharge planning and should facilitate optimal long-term functional outcomes.

Professional issues

In coordination with ICU staff, rehabilitation professionals, due to their expertise in functional prognosis may have the opportunity to participate in end-of-life discussions. With our focus on long-term functional outcomes, we have the responsibility to advocate for safe post-acute care plans. While community discharge with family is generally preferred, the physiatrist has a responsibility to communicate to staff and family if a particular home discharge is deemed unsafe.

Rehabilitation Management and Treatments

Available or current treatment guidelines

While no definitive treatment exists for ICUAW, preventative measures have been explored to reduce morbidity. The safety and efficacy of early mobility and exercise of ICU patients has been well established.31 With proper training and an interdisciplinary approach, rehabilitation professionals can safely mobilize, exercise, and ambulate medically complex, debilitated patients including those on mechanical ventilation. Reducing sedative and pain medication as well as implementing sleep hygiene are important foci of treating both ICUAW and delirium. Treatment of delirium is focused on identifying and reversing the underlying cause. When delirium results in dangerous behavior that puts the patient or others at risk, pharmacologic intervention is warranted. Typical antipsychotics such as haloperidol and atypical antipsychotics such as quetiapine or olanzapine have been utilized to target psychotic symptoms i.e., perceptual disturbances, paranoid/persecutory delusions. Other medications such as valproic acid have been utilized in patients with impulsive behaviors and co-morbid cognitive impairment and/or traumatic brain injuries. Alpha-2 agonists medications such as dexmedetomidine and clonidine have been utilized in symptomatic management of delirium.32

At different disease stages

Consultants recommending an appropriate rehabilitation level of care for post discharge from a prolonged ICU stay are often faced with difficult decisions. Patients may not have the endurance to tolerate the three hours of daily therapy required in a comprehensive integrated inpatient rehabilitation program. There is some flexibility in the Medicare guidelines, governing Inpatient Rehabilitation Facilities permitting 15 hours spread over seven rather than five days. Patients often are too medically complex to be safely sent to a subacute rehabilitation facility. Transitional care units in hospitals or long-term acute care hospital units offer other potential dispositions.

Patient & family education

The recent Pain, Agitation, and Delirium (PAD) guidelines recommended by the Society of Critical Care Medicine emphasize the critical importance of family education and empowerment to improve ICU outcomes.8 Patient and family education should include functional prognosis, education about delirium and weakness, appropriate infectious isolation precautions, and bed positioning, as well as, potentially, bedside range of motion.

Emerging/unique interventions

Impairment-based measure:

The 6-minute walk test for endurance assesses aerobic capacity and endurance. Survivors of critical illness often experience clinically significant deficits up to 20-30 meters compared to a healthy population.33 The Timed Up and Go (TUG)/Get Up and Go (GUG) test can be used to determine functional ability and detect balance impairments.34 Cognitive impairment is important to detect as it predicts worse rehabilitative outcomes. The two most used assessment tools are the Montreal Cognitive Assessment Mini-Mental Status Examination (MMSE).35

Measurement of Patient Outcomes:

Rehabilitation and environmental interventions in the ICU setting are associated with positive outcomes in cognition, physical functioning, and discharge destination. It has not been shown to consistently have an effect on mortality.36–38

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Despite the established benefit of rehabilitation and environmental changes in the ICU to reduce delirium and promote function, there remains a disconnect between research and practice in many ICUs. A Quality Improvement (QI) approach is useful in the implementation of rehabilitation in an ICU. Management of delirium is part of the Pain, Agitation, and Delirium (PAD) guidelines recommended by the Society of Critical Care Medicine. Regular assessment for the development of delirium using the Confusion Assessment Method for the ICU (ICU-CAM), or The Intensive Care Delirium Screening Checklist (ICDSC) is supported. There is no validated assessment tool to assess for cognitive decline after ICU discharge which warrants its development.

One highly successful QI project with mechanically ventilated patients in the ICU used the 4 E’s approach: Engage, Educate, Execute, and Evaluate.39 The initial Engagement portion highlighted interactive learning. All stakeholders (leaders, supervisors, frontline clinical staff) learned the benefits of the new initiative and the value of an interdisciplinary approach. Staff were encouraged to exchange patient anecdotes; patients returned to the ICU to share their stories; and guest lectures reviewed the current knowledge. The Education portion highlighted specific skill acquisition such as physical therapists learning basics of ventilators and respiratory therapists demonstrating safe patient transfer techniques. The Execution of the project homed in on interventions and strategies to identify barriers. The Evaluation of the project occurred though multidisciplinary meetings structured around specified outcomes.

Cutting Edge/ Emerging and Unique Concepts and Practice

New approaches to diagnosing ICUAW are emerging. Ultrasound imaging combined with serum markers such as syndecan-1 and procalcitonin have correlated well with the development of ICUAW in a small retrospective study.40 Some programs are now using neuromuscular electrical stimulation to facilitate muscle movement in patients who are too sedated or delirious to participate in an active exercise program. However, the current evidence for this therapy is inconclusive.

Nocturnal administration of dexmedetomidine, a sympatholytic drug, was recently shown to be effective in decreasing incidence of PICS and psychological impairment in patients after cardiac surgery.41

Gaps in the Evidence-Based Knowledge

  • Diagnosis and quantification of ICUAW (immobility and weakness associated with neuromuscular dysfunction).
  • Clinical research on reducing delirium and Post-intensive Care Syndrome
  • Post- ICU Functional Outcomes (cognitive and physical).
  • Effect of physical therapy or alternative treatment on functional outcomes that are meaningful to patients compared to typical ICU management.
  • Association of premorbid disability to development of ICUAW and overall prognosis.
  • Strategies and equipment to mobilize patients including electrical neurostimulation, exercise equipment in bed (e.g., cycle ergometry for UE or LE), and tilt bed for bed bound patients.
  • Use of neurostimulants and their potential efficacy in the setting of ICUAW.
  • Outcomes Research and Rehab QI in the ICU – including team functioning and patient participation.


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Original Version of the Topic

Dale Strasser, MD. ICU Acquired Weakness and Neurocognitive Decline. 12/27/2012.

Previous Revision(s) of the Topic

Reina Nakamura, MD, Peter P Yonclas, MD. ICU Acquired Weakness and Neurocognitive Decline. 4/3/2017.

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Charnette Lercara, MD
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Jayne Ha, DO
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Elver Ho
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