Critical illness myopathy

Author(s): Erika Moody, MD, John Harrell, MD

Originally published:11/27/2012

Last updated:08/18/2016

1. DISEASE/DISORDER:

Definition

Critical illness myopathy (CIM) refers to rapidly evolving myopathy in an intensive care unit (ICU) setting, where patients are typically exposed to high-dose steroids with or without prolonged neuromuscular blockade. This condition has been also termed acute quadriplegic myopathy, intensive care unit acquired weakness or myosin-loss myopathy.

Etiology

The etiology is not known. However, most reported cases involve the use of steroids and/or nondepolarizing neuromuscular blockade, and it is suggested that these agents result in acute loss of thick filaments (myosin) in muscle tissue, fiber atrophy and fatty degeneration of muscle fibers in the setting of critical illness. Patients with systemic inflammatory response syndrome and multiorgan dysfunction with respiratory insufficiency are prone to develop CIM.

Epidemiology including risk factors and primary prevention

The overall incidence of CIM is unknown; 30-50% of critically ill patients suffer from Critical Illness Polyneuropathy (CIP), CIM or a combination of both.1 A report suggests that at least one third of ICU patients who are treated for status asthmaticus or chronic obstructive pulmonary disease develop CIM.2 Another study shows that about 7% of patients develop CIM after liver transplant.3 Major risk factors are steroid use, neuromuscular blockade and high severity illness. Other risk factors include sepsis, multi-organ failure, prolonged immobilization, use of catecholamines, impaired glucose homeostasis and older age.  It is not known whether modifying the risk factors can prevent critical illness myopathy. In fact, some patients develop CIM in the absence of steroid use and neuromuscular blockade.

Risk Factors

There is an abundance of risk factors associated, which have all been recognized to play a role:

1) Severity of illness and prolonged ICU Length of stay
2) Sepsis, SIRS
3) Multi-organ failure
4) Female sex
5) Malnutrition, ionic abnormalities
6) Low serum albumin, parental nutrition, vasopressor catecholamine support

Patho-anatomy/physiology

The pathophysiology of CIM is complex and unclear. It is thought to involve electrical, microvascular, metabolic and bioenergenic pathophysiological mechanisms.7 One study demonstrated that impaired GLUT4 translocation to the sarcolemmal membrane is a mechanism of impaired glucose supply to muscle cells in patients with CIM. Impaired GLUT4 translocation was not eliminated despite treatment with insulin. Skeletal muscles fibers are deprived of glucose which is particularly detrimental to glycolytic metabolism dependent type 2 muscle fibers. Electrical muscle stimulation restored GLUT4 translocation to the sarcolemmal membrane and rescued fiber atrophy in patients with CIM.8

Muscle biopsies often show type 2 myofiber atrophy with or without type 1 myofiber atrophy. Scattered necrotic fibers can be seen, and there is variable degree of muscle degeneration throughout the specimen. Because of a loss of myosin, some fibers characteristically demonstrate the lack of adenosine triphosphatase staining at both higher and lower hydrogen ion concentrations. One study showed increased expression of calcium-activated protease, calpain, suggesting abnormal intracellular calcium homeostasis as an important part of pathogenesis.4 Muscle biopsies also show low glutamine levels, low protein/DNA levels and high concentrations of extracellular water, thus the body’s requirement for glutamine may not be being met and may be pathogenically linked to CIM.5,6

The role of steroids and neuromuscular blocking agents in CIM is not clear. One theory is the neuromuscular blocking agents cause denervation, which may facilitate the toxic effects of other agents, like steroids. Animal studies have demonstrated that denervation results in proliferation of steroid receptors in muscle membranes and subsequent steroid use led to muscle thick filament loss and decreased muscle excitability.5 Both experimental and electrophysiologic studies demonstrate evidence of reduced membrane excitability.

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

A typical clinical scenario would involve patients with a history of asthma or chronic obstructive pulmonary disease, who are admitted to an ICU for acute exacerbation or status asthmaticus, and are subsequently intubated using nondepolarizing neuromuscular blockade, followed by high-dose corticosteroid. The diagnosis of CIM is usually made late in the course of an ICU stay, when it is difficult to wean off mechanical ventilation.

Because most patients have multiple comorbidities, disease trajectory of CIM itself is not well understood, and the overall outcome primarily depends on the prognosis of the underlying condition. A prospective study of 100 patients who underwent orthotopic liver transplantation showed that 7 patients developed CIM; of these patients, 3 died from sepsis and multiorgan failure, and the remaining 4 patients slowly regained strength and the ability to ambulate over 1 to 3 months.2

Specific secondary or associated conditions and complications

Critical illness polyneuropathy (CIP) and prolonged neuromuscular blockade should be in the differential diagnoses when investigating for weakness developing in ICU patients. However, CIP is very difficult to distinguish from CIM, because patients may have a polyneuropathy from an underlying condition. Many experts believe that CIP is much more uncommon than CIM.4, 9 Both conditions can coexist.

Pro-inflammatory cytokines as TNF-Alpha and IL1 induce a rise in the levels of E selectin expression in endothelium of epineurial and endoneurial vessels promoting endothelial cell leukocyte activation.22

2. ESSENTIALS OF ASSESSMENT

History

Many patients with neuromuscular weakness in the ICU are identified because of difficulty weaning from mechanical ventilation.5 Therefore, because most patients are intubated, it may be difficult to obtain a thorough history. However, it is very important to understand the patient s underlying condition and the course of illness during their ICU stay to rule out other possibilities of muscle weakness. Considering that most patients are exposed to multiple drugs in the ICU, it is also crucial to review all the possible myotoxins, because some toxic myopathies can mimic CIM.

Physical examination

Patients typically develop diffuse, symmetric proximal muscle weakness, characteristically involving neck flexors and respiratory muscles. Tone is usually flaccid. There is no sensory involvement unless patients have underlying neurologic conditions that affect sensory function. Facial muscles, especially extraocular muscles, are rarely involved, and the presence of facial weakness should raise suspicion for other neurologic disorders. Deep tendon reflexes are generally normal or reduced. 10

Functional assessment

Most patients are intubated in the ICU and have an altered mental status. Functional level is largely dependent on conditions of their underlying disease(s) and cognitive status. In the early stages, self-care and bed mobility usually require maximal assistance because of proximal muscle weakness and underlying conditions. However, as patients recover from CIM, they may achieve total independence or previous functional status, although there may be residual weakness from disuse atrophy.

Laboratory studies

Creatinine kinase (CK) level may be normal or mildly elevated. Although there are some reports of high CK levels (up to 10 times higher than upper normal level) in CIM, such high levels of CK should prompt investigation for other conditions, such as rhabdomyolysis or toxic myopathies. Comprehensive laboratory evaluation is often performed to rule out other diseases and there are no validated biomarkers currently available.10 CSF is usually normal.

Electrophysiologic study is a crucial part of diagnosis, yet may be difficult to perform and interpret in the ICU setting and typically requires greater than 3 weeks of symptoms to arrive at a diagnosis.5 Sensory nerve conduction studies should be normal, unless there is a history of peripheral neuropathy or coexisting CIP. Compound muscle action potential (CMAP) amplitudes are often markedly reduced, while distal latencies and conduction velocities are normal. For an inexperienced electromyographer, reduced CMAPs with normal sensory study are often interpreted as motor neuron disease or motor neuropathy. Careful analysis of voluntary motor unit potentials will reveal a rapid or myopathic recruitment pattern, helping to rule out the possibility of motor neuron disease or motor neuropathy. Unfortunately, it is very difficult to induce volitional muscle contraction for patients who are intubated and sedated. Therefore, CIM is often diagnosed based on clinical grounds in combination with laboratory evaluation. In some occasions, a special technique called direct muscle stimulation can be used to distinguish CIM from motor neuronopathy or motor neuropathy. In this technique, a stimulating needle is directly inserted in the muscle, eliciting a CMAP in the muscle. In normal muscle, this directly stimulated CMAP (dmCMAP) should be comparable with the CMAP that is induced by motor nerve stimulation CMAP (neCMAP). However, in CIM, this dmCMAP is always smaller than the neCMAP because of reduced excitability of the muscle membrane. In CIM the neCMAP and dmCMAP amplitude ratios are >0.5 (vs. <0.5 in neuropathy). From a practical standpoint, this technique is rarely adopted, because distinguishing CIM from neuropathy will not likely change the management of patients in the ICU, and because of technical difficulties in performing this method, particularly in the ICU.11, 12, 13

Muscle biopsy can confirm muscle involvement and differentiate between the three subtypes of CIM: diffuse non-necrotizing myopathy, thick filament myopathy and acute necrotizing myopathy.6

Imaging

Careful neuraxial imaging is often necessary to rule out other possibilities of weakness, such as stroke or spinal cord infarct, especially when patients are not communicative. Magnetic resonance imaging of muscle tissue using a myositis protocol can show enhancement in short-tau inversion-recovery images when there is diffuse muscle edema. However, this finding is nonspecific and can be associated with rhabdomyolysis or inflammatory myositis. There is no specific imaging modality or finding known to be associated with CIM.

Professional Issues

Because most patients cannot express themselves and may be dealing with life and death issues, it is important to identify the person who has power of attorney and closely communicate with legitimate members of family and social circles.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

Rehabilitation strategies needed to improve functional outcomes in CIM have not yet been established. There is no specific pharmacologic treatment for CIM. Early recognition of the presence of this disorder is very important in order to improve management. From a medical perspective, prevention of CIM is possible by avoiding risk factors and by aggressive medical management of critically ill patients.14 The risk of developing CIM associated with corticosteroid and neuromuscular blockade seems to increase after 24 to 48 hours of therapy, therefore prolonged neuromuscular blockade should be avoided by scheduling frequent drug holidays.5,10 Strict glycemic control with glucose levels between 80 and 110 mg/dl via insulin therapy seems to prevent CIM.23 A new therapeutic option being evaluated for prevention and treatment of CIM is early rehabilitation and mobilization of patients in the ICU. Physical interventions may be important through remediation of neuromuscular impairments during the recovery process and by reducing sequelae associated with deconditioning and immobility.

At different disease stages

Rehabilitation During the Critical Care Stay

1. Physical and Occupational Therapy15:
a. Education, positioning, respiratory techniques, therapeutic exercise, and functional mobility retraining.
b. Therapy treatment and progression based on response-dependent management, which includes physiologic status (eg, vital signs, oxygen saturation), as well as the participant’s strength, functional abilities, and self-reported fatigue. Range of motion and prevention of joint contracture is critical in restoring mobility and preventing pain.

2. Nutrition support16
3. Technology in the ICU17:

c. Neuromuscular electric stimulation.
d. Cycle ergometry.
e. Technological aids for ambulation.

• Portable ventilation.

• Portable cardiac monitor and pulse oximeter.

• Equipment to carry infusion pumps.

• Ambulation aides.

f.  Environmental controls.
g. Communication devices while intubated.

Transition to Post-ICU Care

Patients who develop CIM will often have comorbidities related to immobility and disuse in the context of a severe and potentially life-threatening underlying illness. Physiatric assessment and regular follow-up in multiple physical (i.e., weakness, range of motion, pain, fatigue, incontinence, dysphagia) and nonphysical (i.e., anxiety, depression, posttraumatic stress-related symptoms, loss of memory and attention) domains is necessary to address the patient’s needs.16

Chronic

There is an increased risk of reduced physical function and quality of life in this population. Options for management include:

  1. Continued rehabilitation in the acute care setting with physical therapy, occupational therapy, and speech and language pathology.
  2. Comprehensive integrated inpatient rehabilitation program.
  3. Subacute rehabilitation.

Coordination of care

The interdisciplinary team should include physicians, nurses, respiratory therapists, physical, occupational, and possibly speech therapists. Follow-up with a physiatrist and/or primary care provider should be arranged for functional reassessment at 2 to 3 months after the patient’s discharge from critical care.16

Patient & family education

The patient’s family and/or caregiver should also be involved in the rehabilitation goals. Some critical care units use patient diaries as a way to deliver information to the patient and their families and/or caregivers.

Emerging/unique Interventions

Several scales, including the Medical Research Council sum score, the Barthel Index, the modified Rankin Scale, and a healthy status questionnaire (Medical Outcomes Study 36-Item Short-Form Health Survey), have been used to assess patients with ICU-acquired weakness, including CIM. One study suggested that good recovery can be achieved with longstanding rehabilitation (mean, 76.2d) including 3 hours of rehabilitation and 2 hours of electric muscular stimulation daily.18

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

Traditionally, bedrest has been considered the ICU activity standard, with physical therapy postponed until after ICU discharge. Prevention appears to be the most successful treatment for CIM. Changing ICU attitudes and beliefs toward early mobilization of ICU patients is important. This involves creating a culture sensitive to patient-focused outcomes and improved interdisciplinary team work. Mobility has been shown to be facilitated by an ICU culture where activity is a key component of care.19 Range of motion is critical, and positioning and turning to prevent skin breakdown is necessary, as in any immobilized patient.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

  • Early mobilization of ICU patients.
  • Neuromuscular electric stimulation.
  • Quantitative neuromuscular ultrasound in evaluation of neuromuscular pathology early in critical illness.20
  • Use of nutritional therapies (e.g., glutamine and glutathione supplementation), and hormonal therapy may be beneficial.21

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

  • Strategies to develop the most effective way of identifying patients at risk of critical illness-associated physical morbidity, psychologic morbidity, and cognitive dysfunction.
  • Comparative studies evaluating the resources needed to safely mobilize and exercise an ICU patient.
  • Studies to elucidate the mechanisms by which immobility and other aspects of critical illness lead to neuromuscular dysfunction and injury.
  • Randomized controlled trials evaluating early rehabilitation strategies and optimal timing during critical illness6
  • Possible preventative effects of electrical muscle stimulation6

REFERENCES

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  2. Campellone JV, Lacomis D, Kramer DJ, Van Cott AC, Giuliani MJ. Acute myopathy after liver transplantation. Neurology. 1998;50:46-53.
  3. Douglass JA, Tuxen DV, Horne M, et al. Myopathy in severe asthma. Am Rev Respir Dis. 1992;146:517-519.
  4. Showalter CJ, Engel AG. Acute quadriplegic myopathy: analysis of myosin isoforms and evidence for calpain-mediated proteolysis. Muscle Nerve. 1997;20:316-322.
  5. Osias J and Manno E. Neuromuscular complications of critical illness. Crit Care Clin. 2014;30:785-794.
  6. Hermans G, De Jonghe B, Buryninckx F, Van den Berghe G. Interventions for preventing critical illness polyneuropathy and critical illness myopathy. Cochrane Database of Systemic Reviews. 2014;1:1-24.
  7. Mehrholz J, Pohl M, Kugler J, Burridge J, Mückel S, Elsner B. Physical rehabilitation for critical illness myopathy and neuropathy. Cochrane Database of Systemic Reviews. 2015;3:1-23.
  8. Weber-Carstens S, Schneider J, Wollersheim T, Assmann A, Bierbrauer J, Marg A, Al Hasani H, Chadt A, Wenzel K, Koch S, Fielitz J, Kleber C, Faust K, Mai K, Spies CD, Luft FC, Boschmann M, Spranger J, Spuler S. Critical illness myopathy and GLUT4. Am J Respir Crit Care Med. 2013;187(4)387-396.
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  12. Lefaucheur JP, Nordine T, Rodriguez P, Brochard L. Origin of ICU acquired paresis determined by direct muscle stimulation. J Neurol Neurosurg Psychiatry. 2006;77:500-506.
  13. Marrero HG and Stålberg EV. Optimizing testing methods and collection of reference data for differentiating critical illness polyneuropathy from critical illness myopathies. Muscle Nerve. 2016;53:555-563.
  14. Bird SJ. Diagnosis and management of critical illness polyneuropathy and critical illness myopathy. Curr Treat Options Neurol. 2007;9:85-92.
  15. Nordon-Craft A, Schenkman M, Ridgeway K, Benson A, Moss M. Physical therapy management and patient outcomes following ICU-acquired weakness: a case series. J Neurol Phys Ther. 2011;35:133-140.
  16. National Institute for Health and Clinical Excellence. Rehabilitation after critical illness. March 2009. Available at: http://www.nice.org.uk/CG83. Accessed October 16, 2012.
  17. Needham DM, Truong AD, Fan E. Technology to enhance physical rehabilitation of critically ill patients. Crit Care Med. 2009;37(10 Suppl):S436-441.
  18. Intiso D, Amoruso L, Zarrelli M, et al. Long-term functional outcome and health status of patients with critical illness polyneuromyopathy. Acta Neurol Scand. 2011;123:211-219.
  19. Bailey PP, Miller RR 3rd, Clemmer TP. Culture of early mobility in mechanically ventilated patients. Crit Care Med. 2009;37(10 Suppl):S429-435.
  20. Bunnell A, Ney J, Gellhorn A, Hough CL. Quantitative neuromuscular ultrasound in intensive-care acquired weakness: a systematic review. Muscle Nerve. 2015; 52:701-708.
  21. Burnham EL, Moss M, Ziegler TR. Myopathies in critical illness: characterization and nutritional aspects. J Nutr. 2005;135:1818S-1823S.
  22. Latronico NN. Critical illness and neuropathy. Current Opinion in Critical Care. 2005;11(2):126-132.
  23. Hermans G, De Jonghe B, Bruyninck F, Van den Berghe G. Clinical review: critical illness polyneuropathy and myopathy. Crit Care. 2008;12:238-246.

Original Version of the Topic:

Erik Hoyer, MD, MA. Critical Illness Myopathy. Publication Date: 2012/11/27.

Author Disclosure

Erika Moody, MD
Nothing to Disclose

John Harrell, MD
Nothing to Disclose

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