Intensive care unit acquired weakness (ICU-AW) is a spectrum of clinical conditions characterized by weakness due to variable forms of damage to muscles and the peripheral nervous system and includes critical illness polyneuropathy (CIP), critical illness myopathy (CIM) and critical illness polyneuromyopathy (CIPNM).1 CIP is a symmetrical, predominantly distal axonal polyneuropathy that mainly affects limb and respiratory muscles, and rarely the facial muscles.2-4
In some situations, CIP and CIM can coexist as CIPNM. Likewise, CIP and CIM may be hard to distinguish, but differentiation when possible is important as studies have shown that CIP is associated with significantly worse outcomes compared with CIM.5
The etiology of CIP is complex and likely multifactorial, although not fully defined amongst the adult or pediatric population. It is thought to be associated with abnormal vascular, metabolic, and electrical processes leading to ischemia, degeneration and axonal dysfunction. This is further described below in the pathophysiology section.2,6
Epidemiology including risk factors and primary prevention
CIP is rare in children, reported to affect 0.02% of pediatric intensive care unit (PICU) admissions, although this figure may be an underestimation due to underdiagnosis driven by inadequate diagnostic testing.6,7 Among critically ill pediatric patients with prolonged intensive care unit (ICU) courses, CIP is being increasingly recognized as a significant clinical problem.8
Pediatric CIP is highly associated with sepsis or systemic inflammatory response syndrome complicated with multiple organ dysfunction syndrome and invasive mechanical ventilation more than 7 days. It is also associated with hyperglycemia, renal replacement therapy, organ transplantation, toxic drug effects (corticosteroid, aminoglycosides, statins, and neuromuscular blocking agents), burns, immobility, and female sex. Risk factors that distinguish pediatric CIP patients from adults include asthma and use of extracorporeal life support.6,9,10
CIP has been shown to present with acidosis, hypocalcemia, hypoalbuminemia, hyperglycemia, decreased platelets, elevated liver enzymes and prolonged prothrombin time.6 The primary prevention of CIP consists of treating the underlying disease, sepsis, multiorgan failure and electrolyte and metabolic imbalances with aggressive control of hyperglycemia, early mobilization, nutritional supplementation, and antioxidant therapy. Intensive insulin therapy with goal glucose between 80 and 110 mg/day has been shown to reduce the incidence of CIP and/or CIM from 51 to 39% in ICU medical patients, but great care must be taken to avoid hypoglycemia.2,8
The pathophysiological changes that lead to axonal degeneration of CIP remains unclear. Pioneers in myoneuropathy proposed an interaction between microcirculatory changes, metabolic alterations, potentially reversible membrane channelopathies and a flush of pro-inflammatory cytokines. It is thought that microcirculation, commonly caused by hypovolemia, hyperglycemia or hypoalbuminemia, leads to increased vascular permeability and increased local cytokine production.2,8,11
Skin biopsies can be used to quantify intraepidermal nerve fiber density (IENFD) and corneal confocal microscopy (CCM) although neither have been shown to add clinical or prognostic value.11 Muscle biopsies may show acute denervation with atrophy of type 1 and type 2 fibers in muscles and axonal degeneration in nerves.4
Nerve conduction studies typically reveal primarily axonal degeneration with decreased compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes, normal to slightly reduced conduction velocities and normal F-wave latencies. There is no associated decrement on repetitive stimulation. Direct muscle stimulation will demonstrate reduced or absent CMAPs with stimulation of the nerve (neCMAP) as compared to stimulation of the muscle (mfCMAP). Conduction block is not typically a feature, but if present should prompt further investigation into nerve entrapment, especially in thin patients. Needle electromyography can show large, polyphasic motor unit action potentials (MUAPs) and spontaneous activity including fibrillation potentials and positive sharp waves, more marked distally but have been reported in respiratory muscles as well. This is helpful to distinguish from CIM which shows small, short-duration, polyphasic MUAPs.2
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
CIP typically appears within the first 10 days of ICU admission. It is more prevalent in those requiring mechanical ventilation and leads to difficulty weaning mechanical ventilation.11 Recovery is spontaneous but variable and can range from full recovery to persistent weakness or death. It is suggested that recovery from weakness after CIP is delayed as compared to CIM, often for several months with some with having persistent symptoms at 1 year.1
ICU-AW overall is associated with longer requirement of mechanical ventilation, longer hospitalization, increased mortality, decreased independence and increased cost.11 Approximately 70% of people with ICUAW are able to achieve a good recovery defined by a Medical Research Council (MRC) grade of 4/5 in all muscles.1
Specific secondary or associated conditions and complications
Prolonged immobility from profound weakness is also associated with compression neuropathies, muscle atrophy and joint contractures. It is then important to identify the presence of ICU-AW, including CIP, in comatose patients to prevent overly pessimistic prognostication resulting in inappropriate withdrawal of care. PICU admissions are associated with functional and cognitive impairments that may influence normal development, school performance and social interactions. Additional factors that may contribute to these sequelae in combination with ICU-AW are PICU complications from procedures and continued underlying illness.12
In patients with COVID-19 as compared to other patients with ICU-AW, there is a predominance of CIN as opposed to CIM in the non-COVID groups according to multiple emerging studies.12,14 In one study, there is a male predominance as compared to female predominance in non-COVID ICU-AW, though further research is required to fully characterize these patterns.13 Presentation and neurophysiologic parameters remain the same. This may be associated with the prolonged mechanical ventilation and use of neuromuscular blocking agents in COVID-19 patients. Nonetheless, CIN should remain in the differential diagnosis of ICU admitted COVID-19 patients with weakness as there are important implications on prognosis.13,14
Essentials of Assessment
A thorough functional history including premorbid functioning in addition to current functioning, taking into consideration the effect of sedative medication and respiratory deficits, can be useful in differentiating between CIM, CIP, and CIPNM. Special consideration should be given when critically ill children are not making proper progress in their recovery, placing them at increased risk for developing CIP.15
CIP typically involves symmetric, flaccid limb weakness with sparing of facial and ocular muscles. Muscle stretch reflexes are decreased or absent. Pain, temperature, vibration, or proprioception may also be absent or reduced. The diaphragm is commonly involved, which has important consequences for ventilator weaning and overall respiratory health.2
It may be difficult to assess a child’s functional abilities if they have profound weakness, difficulty understanding the commands given during testing, or low premorbid functional skills. Manual muscle testing (MMT) can be done with children 4 years of age and older; for younger children, observation and evaluation of movement are effective.16 It is important to note that MMT was designed to quantify muscle strength and not function.1 According to a recent study, a simplified CIP criteria including strength testing with Medical Research Council (MRC) sum score <48 (on testing of six bilateral muscle groups including shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension, ankle dorsiflexion) and tibial motor and sural sensory nerves amplitudes <80% of the lower limit of normal and was most predictive of clinical outcomes. Implementing these simplified criteria may allow early identification of CIP in the ICU, enabling prompt intervention for patients with an unfavorable prognosis.17
Serum creatine kinase is usually normal in CIP unless severe muscle necrosis is present. Elevation in plasma neurofilament, a biomarker of axonal injury, may be seen. Muscle biopsy is well known to distinguish between CIP and CIM; however, it is invasive and increases the risk of bleeding of ICU patients. (18) In emerging studies of COVID-19 patients who later developed CIP, many had significantly higher GFAp and IL-6 in the early phase of ICU care, suggesting potential for predictive biomarkers of CIP.14,19
Supplemental assessment tools
Electrodiagnostic testing, including nerve conduction studies and needle electromyography is the most helpful in definitive diagnosis, distinguishing CIP from CIM and other neuromuscular dysfunction as detailed above in the “Pathoanatomy/physiology” section. While EMG is the best way to diagnose CIP, the ICU environment introduces technical challenges including electrical interference, hypothermia, peripheral edema, or limited patient involvement.6 Neuroimaging may be obtained in comatose patients to rule out abnormality within the neuroaxis. A standardized ultrasound algorithm, consisting of measurement and scoring of 12 nerve cross-sectional areas on a patient, can serve as a fast bedside test for the presence of neuropathy in ICU-AW. Nerve ultrasonography reliably detects neuropathy in ICU-AW, although cannot differentiate between sensory neuropathy and CIP.20
Early predictions of outcomes
In general, ICU-AW is associated with prolonged ICU and hospital stay, prolonged duration of ventilator support, increased ICU and hospital morbidity and mortality, increased healthcare related hospitalization costs, decreased likelihood of being discharged directly to home, reduced functional outcomes and lower quality of life post discharge.6,10,16 Amongst those with ICU-AW, absence or 25% reduction in CMAP and SNAP amplitudes from baseline is considered a predictor of long-term dysfunction. Presence of CIP also tends to have poorer prognosis compared to CIM alone.16
Identifying the anticipated home setting at discharge is necessary to determine services and equipment needs. Similarly, appropriate provisions for school attendance may be required, including those related to the school architecture, such as wheelchair ramps and accessible bathroom, and school services such as provision of an aide or scribe and extra time for assignments, available.
Social role and social support system
Critical illness has a reaching effect on the entire family unit. Up to one-third of parents go on to develop acute stress disorder, 84% with post-traumatic stress symptoms, up to 50% with anxiety and 30% with depression. Siblings are similarly impacted. Families should be educated on the various necessary adjustments anticipated to care for a child after CIP which may include constant care and physical assistance, use of durable medical equipment and the associated financial burden. This should be taken into consideration throughout the course of hospitalization ensure all members of the family get the support they need and can best equip themselves to support the child.12
Although children with CIP can initially present with severe weakness and inability to communicate, it is important to address rehabilitation management and strategies to prevent the complications of immobility. With proper attention to these issues, many patients with CIP will have the potential for significant recovery and a good quality of life.1,12
Rehabilitation Management and Treatments
At different disease stages
CIP is best addressed with a multimodal approach with emphasis on swift control of the underlying injury, early discontinuation of mechanical ventilation and early mobility.11 Various interventions and medications have been utilized to treat CIP, but a standardized treatment has not been established.21
Acute setting: Utilizing early mobilization as early as within the first three days of PICU admission can help mitigate physical impairments as demonstrated by the PICU UP! initiative.22 The PICU UP! initiative incorporated daily planning of mobilization goals by the multidisciplinary team for each patient, involving range-of-motion exercises, sitting, transfer to a chair, orthostasis, ambulation and play. In patients undergoing invasive mechanical ventilation, only range-of-motion exercises were considered.23 The most commonly reported barriers to early mobilization after PICU Up! Initiative implementation was availability of appropriate equipment (primarily age-appropriate seating devices and positioning materials).24
Subacute setting: Once weaned off ventilator support, revaluation to determine the appropriate level of ongoing rehabilitation is warranted. This may include ongoing acute therapies within acute hospitalization, admission to an inpatient rehabilitation program for a more intensive therapies, or discharge home with an outpatient therapy program.
Chronic/stable: Majority of pediatric patients with ICU-AW can continue with persistent upper and lower extremity weakness months to years after discharge.6 In order to achieve optimal results, physical medicine and rehabilitation (PM&R) physicians should be involved throughout the recovery phase. A PM&R physician’s role includes determining whether further therapy and appropriate rehabilitation equipment are needed, as well as addressing the long-term effects of diminished mobility. It is imperative to include longitudinal assessments during and after a PICU stay, especially for children at a higher risk of poor functional outcome.25
Coordination of care
Early mobilization of children with ICU-AW requires a team approach to be successful. This team should consist of critical care medicine, consultant medical services, PM&R, respiratory therapy, physical therapy, occupational therapy, nursing, social worker, care management, and the patient’s family.
Effective early mobilization requires individual patient assessment and goal setting, using a collaborative interdisciplinary, patient- and family-centered approach, to ensure mobility goals and physical activities are appropriate for the patient’s age, condition, premorbid function, strength, endurance and developmental level.26 Communication among team members to coordinate therapy in the complex setting of the ICU is imperative to ensure the success of early mobilization efforts. Interprofessional collaboration from dedication healthcare professions are required to overcome the obstacles necessary to establish a successful program in the ICU setting.27
Patient & family education
In the ICU early stages, families and medical staff are understandably focused on the medical care and the potential for life-threatening complications. Family members should be educated about early mobilization and the concept of a rehabilitation team at the time of the patient’s medical stabilization, or earlier if the care team considers it appropriate. The PICU Up! Initiative has been well received by hospital staff, increasing role satisfaction and PICU team dynamics. Patients and family members appear enthusiastic about mobility efforts, leading to an increase in staff support.28
Previous outcome measures in critical care have focused on length of stay, mortality, respiratory status, and ability to return to premorbid activities. More recently, there has been an effort to explore more functional outcome measures, such as pediatric overall performance category, pediatric cerebral performance category, and Functional Status Scale.29 For patients requiring more long-term therapy intervention, functional outcome measures typically used in the pediatric rehabilitation setting can be used to document functional changes over time (WeeFIM, Pediatric Evaluation of Disability Inventory, Gross Motor Function Measure).
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
- Consider the presence of ICU-AW in patients with risk factors as delineated above. A high index of suspicion is needed, as early diagnosis may be difficult, especially when the patient is still receiving sedation and/or paralytic drugs.
- When ICU-AW is suspected, assess muscle strength, if possible. MRC < 48 suggests the presence of ICU-AW. If physical examination is unreliable, obtain an electrodiagnostic study. Changes can be seen within 24 to 48 hours after onset of this condition and can precede clinic findings.11
- Although muscle biopsy may be helpful in determining the degree of CIM versus CIP, there is not a consensus on routinely obtaining biopsies in children.
- Early mobility is a consistent recommendation in the literature for patients with ICU-AW.
- In children admitted to the ICU with COVID-19, CIP and associated prolonged recovery is more common than CIM and complete recovery.
Cutting Edge/ Emerging and Unique Concepts and Practice
Direct muscle stimulation can help differentiate the degree of CIP from CIM. This technique is minimally invasive and can be done in children.2
Early mobilization while the patient is still on ventilator support is possible with coordination of team members to reduce sedation and monitor respiratory status for adjustments to the ventilator.22-24
Serial electrodiagnostic evaluation of the common peroneal nerve for reduction in CMAP may be helpful in the early diagnosis of ICU-AW in select populations.16
The development of a standardized practice algorithm may promote early detection and treatment of patients with CIP. This will hopefully result in reductions in previously discussed complications.
Gaps in the Evidence-Based Knowledge
Pediatric ICU patients may have higher rates of CIP than studies indicate. A high index of suspicion is needed, as early diagnosis may be difficult, especially when the patient is still receiving sedation or paralytic drugs. This is especially true for patients who are making progress since this diagnosis is less likely to be entertained under such circumstances.
In the pediatric population, there are no interventions specific to CIP with measures of long-term outcomes leading to emphasis on prevention and prophylaxis measures. Most of the studies to date have been conducted at only one center with a small number of participants making generalizations difficult.2 COVID-19 related CIP is recognized though incompletely understood with more studies needed to describe clinical and neurophysiological findings in COVID patients.13,30
- Intiso D, Centra AM, Bartolo M, Gatta MT, Gravina M, Di Rienzo F. Recovery and long term functional outcome in people with critical illness polyneuropathy and myopathy: a scoping review. BMC Neurol. 2022;22(1):50.
- Tankisi H, de Carvalho M, Z’Graggen WJ. Critical Illness Neuropathy. J Clin Neurophysiol. 2020;37(3):205-7.
- Bolton CF, Gilbert JJ, Hahn AF, Sibbald WJ. Polyneuropathy in critically ill patients. J Neurol Neurosurg Psychiatry. 1984;47(11):1223-31.
- Latronico N, Candiani A. Predominant involvement of motor fibres in patients with critical illness polyneuropathy. Br J Anaesth. 1997;79(4):547-8.
- Cheung K, Rathbone A, Melanson M, Trier J, Ritsma BR, Allen MD. Pathophysiology and management of critical illness polyneuropathy and myopathy. J Appl Physiol (1985). 2021;130(5):1479-89.
- Plaut T, Weiss L. Electrodiagnostic Evaluation Of Critical Illness Neuropathy. StatPearls. Treasure Island (FL)2022.
- Wilmshurst JM, Ouvrier RA, Ryan MM. Peripheral nerve disease secondary to systemic conditions in children. Ther Adv Neurol Disord. 2019;12:1756286419866367.
- Thabet Mahmoud A, Tawfik MAM, Abd El Naby SA, Abo El Fotoh WMM, Saleh NY, Abd El Hady NMS. Neurophysiological study of critical illness polyneuropathy and myopathy in mechanically ventilated children; additional aspects in paediatric critical illness comorbidities. Eur J Neurol. 2018;25(7):991-e76.
- Sunnetci Silistre E, Erbas O. The Ameliorative Effects of Ascorbic Acid on Critical Illness Polyneuropathy in Rodent Sepsis Model. J Pediatr Intensive Care. 2020;9(4):265-70.
- Harnisch LO, Riech S, Mueller M, Gramueller V, Quintel M, Moerer O. Longtime Neurologic Outcome of Extracorporeal Membrane Oxygenation and Non Extracorporeal Membrane Oxygenation Acute Respiratory Distress Syndrome Survivors. J Clin Med. 2019;8(7).
- Garcia-Martinez MA, Montejo Gonzalez JC, Garcia-de-Lorenzo YMA, Teijeira S. Muscle weakness: Understanding the principles of myopathy and neuropathy in the critically ill patient and the management options. Clin Nutr. 2020;39(5):1331-44.
- Watson RS, Choong K, Colville G, Crow S, Dervan LA, Hopkins RO, et al. Life after Critical Illness in Children-Toward an Understanding of Pediatric Post-intensive Care Syndrome. J Pediatr. 2018;198:16-24.
- Bocci T, Campiglio L, Zardoni M, Botta S, Coppola S, Groppo E, et al. Critical illness neuropathy in severe COVID-19: a case series. Neurol Sci. 2021;42(12):4893-8.
- Frithiof R, Rostami E, Kumlien E, Virhammar J, Fallmar D, Hultstrom M, et al. Critical illness polyneuropathy, myopathy and neuronal biomarkers in COVID-19 patients: A prospective study. Clin Neurophysiol. 2021;132(7):1733-40.
- Shepherd S, Batra A, Lerner DP. Review of Critical Illness Myopathy and Neuropathy. Neurohospitalist. 2017;7(1):41-8.
- Kasinathan A, Sharawat IK, Singhi P, Jayashree M, Sahu JK, Sankhyan N. Intensive Care Unit-Acquired Weakness in Children: A Prospective Observational Study Using Simplified Serial Electrophysiological Testing (PEDCIMP Study). Neurocrit Care. 2021;34(3):927-34.
- Jung C, Choi NJ, Kim WJ, Chun YM, Lee HJ, Kim TH, et al. Simplified Diagnosis of Critical Illness Polyneuropathy in Patients with Prolonged Mechanical Ventilation: A Prospective Observational Cohort Study. J Clin Med. 2020;9(12).
- Marrero H, Stalberg EV, Cooray G, Corpeno Kalamgi R, Hedstrom Y, Bellander BM, et al. Neurogenic vs. Myogenic Origin of Acquired Muscle Paralysis in Intensive Care Unit (ICU) Patients: Evaluation of Different Diagnostic Methods. Diagnostics (Basel). 2020;10(11).
- Bax F, Lettieri C, Marini A, Pellitteri G, Surcinelli A, Valente M, et al. Clinical and neurophysiological characterization of muscular weakness in severe COVID-19. Neurol Sci. 2021;42(6):2173-8.
- Gruber L, Loizides A, Gruber H, Skalla E, Haushammer S, Horlings C, et al. Differentiation of Critical Illness Myopathy and Critical Illness Neuropathy Using Nerve Ultrasonography. J Clin Neurophysiol. 2022.
- Stoian A, Bajko Z, Maier S, Cioflinc RA, Grigorescu BL, Motataianu A, et al. High-dose intravenous immunoglobulins as a therapeutic option in critical illness polyneuropathy accompanying SARS-CoV-2 infection: A case-based review of the literature (Review). Exp Ther Med. 2021;22(4):1182.
- Ames SG, Alessi LJ, Chrisman M, Stanger M, Corboy D, Sinha A, et al. Development and Implementation of Pediatric ICU-based Mobility Guidelines: A Quality Improvement Initiative. Pediatr Qual Saf. 2021;6(3):e414.
- Piva TC, Ferrari RS, Schaan CW. Early mobilization protocols for critically ill pediatric patients: systematic review. Rev Bras Ter Intensiva. 2019;31(2):248-57.
- Wieczorek B, Ascenzi J, Kim Y, Lenker H, Potter C, Shata NJ, et al. PICU Up!: Impact of a Quality Improvement Intervention to Promote Early Mobilization in Critically Ill Children. Pediatr Crit Care Med. 2016;17(12):e559-e66.
- Bossen D, de Boer RM, Knoester H, Maaskant JM, van der Schaaf M, Alsem MW, et al. Physical Functioning After Admission to the PICU: A Scoping Review. Crit Care Explor. 2021;3(6):e0462.
- Morrow BM. Building a culture of early mobilization in the pediatric intensive care unit-a nuts and bolts approach. Transl Pediatr. 2021;10(10):2845-57.
- Ghafoor S, Fan K, Williams S, Brown A, Bowman S, Pettit KL, et al. Beginning Restorative Activities Very Early: Implementation of an Early Mobility Initiative in a Pediatric Onco-Critical Care Unit. Front Oncol. 2021;11:645716.
- Patel RV, Redivo J, Nelliot A, Eakin MN, Wieczorek B, Quinn J, et al. Early Mobilization in a PICU: A Qualitative Sustainability Analysis of PICU Up! Pediatr Crit Care Med. 2021;22(4):e233-e42.
- Pollack MM, Holubkov R, Funai T, Clark A, Moler F, Shanley T, et al. Relationship between the functional status scale and the pediatric overall performance category and pediatric cerebral performance category scales. JAMA Pediatr. 2014;168(7):671-6.
- Cabanes-Martinez L, Villadoniga M, Gonzalez-Rodriguez L, Araque L, Diaz-Cid A, Ruz-Caracuel I, et al. Neuromuscular involvement in COVID-19 critically ill patients. Clin Neurophysiol. 2020;131(12):2809-16.
Original Version of the Topic
Douglas G. Kinnett, MD. Pediatric Critical Illness Neuropathy. 9/20/2014.
Previous Revision(s) of the Topic
Marina Ma, MD, Douglas G. Kinnett, MD. Pediatric Critical Illness Neuropathy. 5/29/2018.
Robert Rinaldi, MD
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Kayla Williams, MD
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