Critical Care Medicine

Primary Neuromuscular Disease in the ICU

Non-ICU-Acquired neuromuscular weakness

Synonym

Neuromuscular diseases in the ICU

Related Conditions

Neuromuscular respiratory failure, Guillain-Barré syndrome (GBS), myasthenia gravis (MG), amyotrophic lateral sclerosis (ALS), myopathies

1. Description of the problem

Generalized weakness and respiratory failure due to dysfunction of the peripheral nervous system or muscles. The dysfunction can either be genetic or acquired, but is not the result of critical illness or acquired in the ICU. These would include:

  1. GBS and other severe peripheral neuropathies

  2. MG and other diseases of the neuromuscular junction

  3. ALS and other motor neuron diseases

  4. Acquired and inherited myopathies

However, it should be noted that critical Illness neuromyopathy is the most common cause of new-onset weakness in the ICU.

Clinical features

Respiratory failure is the most likely reason why patients with neuromuscular diseases would require ICU management. As the spectrum of neuromuscular disease is wide, the manner and rate of respiratory decompensation is variable. Another reason why neuromuscular patients would require critical care management is autonomic dysregulation. Due to involvement of the autonomic nervous system in various diseases, especially GBS, labile blood pressure and dangerous arrhythmias may result.

Key management points

The key management points for these patients will focus on:

1. Effective ventilation

2. Airway protection

3. Autonomic instability

2. Emergency Management

A. Respiratory insufficiency and failure

The onset of respiratory failure in a patient with neuromuscular disease may be acute or subacute in many cases. Recognition of the clinical symptoms of respiratory failure prior to acute respiratory arrest is key to avoiding disaster. The presence of the following signs should prompt the institution of mechanical ventilation:

  1. Tachypnea

  2. Paradoxical diaphragmatic excursion

  3. Use of accessory respiratory muscles

In patients with severe muscle weakness, signs of impending respiratory failure may not be obvious. Weakness of the intercostal and accessory muscles such as the sternocleidomastoid and scalene muscles may blunt typical symptoms of respiratory insufficiency. Subtle indicators of respiratory failure in these patients can include:

  1. Anxiety or a sense of uneasiness

  2. Perspiration

  3. Dyspnea in the absence of tachypnea or accessory muscle use

Bedside pulmonary function tests (PFT), performed by a respiratory therapist, can be very helpful in predicting which patients will require assisted ventilation. Patients with GBS and MG should be monitored with PFTs at least once daily. Values that typically indicate the need for mechanical ventilation include:

1. Forced vital capacity <20 ml/kg

2. Negative inspiratory force <30 cmH2O

3. Negative expiratory force <40 cmH2O

Bedside clinical tests can be useful if a respiratory therapist is not available. Such bedside assessments are listed below.

1. Head flexion strength

Head flexion is a good surrogate for diaphragmatic function. A patient who is unable to lift his or her head off the bed or cannot resist mild pressure on the forehead will need to be watched closely. If the patient meets other mechanical ventilation criteria, intubation may be necessary.

2. Counting out loud

A patient who can count out loud to 30 is unlikely to have any respiratory insufficiency. Values under 10-15 typically indicate some degree of respiratory failure.

3. Palpation of accessory respiratory muscles

In cases of severe muscle weakness, palpating accessory muscles may be more helpful than visual inspection.

Intubation and tracheal tube placement

If intubation is necessary for a patient with neuromuscular respiratory failure, it is strongly advised to avoid succinylcholine. In those with muscle weakness, the administration of a depolarizing neuromuscular blocking agent may provoke fatal hyperkalemia. Rhabdomyolysis, though uncommon, is also possible in those with myopathy. In myasthenic patients, avoidance of all neuromuscular blocking agents is suggested to reduce prolonged weakness. Successful intubations can often be accomplished with sedative-hynotic agents or sedative-narcotic combinations alone.

Consideration should also be given to fiberoptic endotracheal tube placement if the intubation is not emergent. Fiberoptic intubation can be successfully performed with significantly lower doses of sedatives, thus decreasing the risk of hypotension and prolonged weakness.

Institution of mechanical ventilation - invasive versus non-invasive

For neuromuscular patients with respiratory insufficiency, the method of mechanical ventilation chosen depends upon the expected duration of therapy and the presence of bulbar weakness.

It is generally recommended that those with GBS receive endotracheal intubation due to the protracted course of the disease. The duration of the disease is typically at least 2-4 weeks in those with respiratory failure.

For patients with MG and other diseases where mechanical ventilation is expected to be of short duration, non-invasive ventilation such as BiPAP can be used intermittently for diaphragmatic rest. Myasthenic crises can improve quickly with prompt treatment in many cases. BiPAP can also be used for patients with ALS if they do not have significant bulbar weakness. However, tracheostomy may be chosen by the patient due to the progressive nature of disease.

In patients with minimal respiratory insufficiency but significant bulbar weakness, worsening dysphonia or an inability to clear secretions is an indication that airway protection is necessary. Delaying endotracheal intubation in these patients may result in acute respiratory failure from mucous plugging or upper airway obstruction.

B. Autonomic dysregulation

Autonomic failure is a common feature of severe GBS. Severe bradycardia, alternating tachy-brady arrhythmias, and labile blood pressure are common features of autonomic dysregulation. Medical intervention and, in severe cases, pacing and defibrillation are necessary. It is noteworthy that the development of autonomic dysfunction frequently parallels the severity of motor weakness.

Due to labile blood pressure and heart rate in these patients, short-acting agents or titratable infusions are preferred for treatment. Many patients are often unusually sensitive to cardioactive medications as well. Therefore, small doses should be administered initially.

1. Hypertension

  A. Labetalol 5-10 mg IV Q1hr

  B. Hydralazine 10 mg IV Q30minutes

  C. Nicardipine infusion

  D. Clevidipine infusion

2. Tachycardia

  A. Metoprolol 2.5-5 mg IV Q6hr

  B. Esmolol infusion

  C. Diltiazem 5 mg IV or infusion

3. Severe Bradycardia

  A. Atropine 100-1000 mcg IV as needed

  B. Glycopyrrolate 0.1-0.2 mg IV as needed

3. Diagnosis

Establishing the diagnosis

Many patients who present to the ICU with neuromuscular disease and respiratory failure will have an established diagnosis. In those who do not, the mnemonic "MUSCLES" can be helpful. However, a neurology consult is necessary in many circumstances.

M - Medications - Numerous medications can cause weakness or unmask subclinical neuromuscular disease. These medicines include:

1. Corticosteroids

2. Neuromuscular blockers

3. Zidovudine

4. Amiodarone

Certain types of medicines are known to acutely exacerbate weakness in patients with MG. The most common offending agents include:

1. Aminoglycosides

2. Fluoroquinolones

3. Calcium channel blockers

4. Beta-blockers

5. Corticosteroids

6. Phenytoin

U - Undiagnosed conditions

Patients with undiagnosed neuromuscular conditions can either present or develop weakness in the ICU as a result of infection, certain medications, or progression of the disease.

From a recent study, the most common conditions to be newly diagnosed in the ICU include:

1. GBS

2. MG

3. ALS

4. Myopathies, including poly- and dermatomyositis

S - Spinal Cord Disease

Differentiating upper from lower motor neuron causes of weakness is important in the initial evaluation of new weakness. Injuries to the spinal cord including trauma, ischemia, infection, and inflammation can produce limb and axial muscle weakness.

C - Critical Illness Neuromyopathy

ICU-acquired neuromuscular disease is commonly encountered in the ICU and should always be on the differential diagnosis for those with new-onset weakness.

L - Loss of muscle mass

The loss of muscle mass itself can result in weakness. Conditions that can result in muscle loss include:

1. Rhabdomyolysis

2. Inherited and acquired myopathies

3. Cachectic myopathy

E - Electrolytes

A severe depletion or excess of various electrolytes can result in diffuse muscle weakness.

1. Potassium

Severe hypokalemia as a result of inadequate intake, renal and gastrointestinal losses, and alkalosis can result in muscular weakness. Hypokalemia, in rare circumstances, can also be the result of inherited conditions such as hypokalemic periodic paralysis.

Hyperkalemia as a result of renal disease, overdose, and acidosis can result in severe muscle weakness.

2. Magnesium

Hypermagnesemia is typically iatrogenic from overdose of magnesium salts, especially in patients with predisposing conditions like renal disease.

Hypomagnesemia occurs with malnutrition and administration of medicines including loop diuretics and antibiotics.

3. Sodium

Hypo- and hypernatremia can both cause muscle weakness when the imbalance is severe. Disorders of sodium are common in the ICU and occur in many disease states.

4. Phosphorus

Hypophosphatemia, classically as a result of malnutrition, is a well-known cause of muscle weakness. Vigilance for hypophosphatemia is essential for any intubated patient.

S - Systemic conditions

Many systemic conditions feature muscle weakness as a part of their symptomatology. Notable conditions include HIV, acute intermittent porphyria, and toxin exposure. Various toxins and heavy metals cause weakness, including organophosphates and arsenic.

Diagnostic algorithm for neuromuscular weakness in the ICU

This algorithm is an adaptation of that proposed by Maramattom and Widjicks in Reference 1.

Step 1. Rule out toxic, metabolic, and infectious causes of weakness.

a. Suggested laboratory studies to obtain include serum electrolytes, liver function tests, complete blood count, and cultures, if sepsis is suspected.

Step 2. Consider brain and spine imaging.

a. CT or MRI of the brain is suggested if central nervous system dysfunction cannot be ruled out clinically.

1. A central cause of weakness should be suspected in any patient with encephalopathy, hyperreflexia, increased tone, or a positive Babinski sign.

b. Imaging of the spinal cord may be indicated if the patient has significant back pain, motor or sensory loss at a spinal level, or bowel or bladder incontinence. This is necessary to rule out spinal cord infarction, epidural abscess, or hematoma.

Step 3. Obtain EMG/NCS.

a. EMG/NCS testing is performed to assess the function of the peripheral nervous system, including the muscles. Multiple disease patterns can be determined from performing these tests. The disease pattern found will determine the next step in testing.

Step 4. Proceed with further testing, if indicated.

a. If a disease of the nerve or muscle is found, biopsy is often required to make a precise diagnosis. If a disorder of the neuromuscular junction or anterior horn cell is suspected, further neurophysiologic, imaging, and serologic testing is required.

EMG/NCS patterns of disease

1. Neuropathic

  a. Neuropathic disease can be either axonal (critical illness neuropathy and toxic neuropathy) or demyelinating (GBS).

  b. Neuropathic disease may require a nerve or nerve and muscle biopsy if other testing is unclear.

2. Myopathic

  a. Myopathies are diagnosed with an abnormal EMG in the setting of normal nerve conduction studies.

  b. The identity of the myopathy usually requires a muscle biopsy and specific serum laboratory testing in conjunction with characteristic historical findings.

3. Myoneuropathic

  a. The most common form of weakness in the ICU, critical illness neuromyopathy, often has mixed features on EMG/NCS.

   b. Mixed neuromyopathic patterns require biopsy of both the nerve and muscle to make the appropriate diagnosis.

4. Anterior horn cell disorder

   a. Further tests for these disorders are dictated by the clinical presentation of the patient. For example, if ALS is suspected, brain or spine imaging and genetic testing may be helpful if EMG/NCS diagnositc criteria have been met.

   b. Weakness in the setting of a meningoencephalitis may suggest West Nile encephalitis. This can be confirmed with serologic testing.

Pathophysiology

GBS or acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is an autoimmune neuropathy affecting peripheral and radicular (spinal) nerves that occurs after an antecedent respiratory or gastrointestinal infection. In most cases, a virus or bacteria is responsible for triggering the immune system to generate antibodies against peripheral myelin through molecular mimicry.

Campylobacter jejuni, Epstein-Barr virus, and Streptococcus are among the many microbes that have been implicated in causing GBS. The most common presentation begins with distal paresthesias followed by ascending weakness starting in the legs. These symptoms occur several days to weeks after an infection. In most cases, GBS progresses over 1 to 2 weeks and reaches a nadir 4 weeks after the first symptoms appear.

MG is an autoimmune disorder where antibodies are targeted against post-synaptic acetylcholine receptors. The spectrum of clinical disease in MG can vary, but fatigable weakness of the extraocular muscles and proximal musculature is found in most cases. Approximately 15-30% of patients with MG experience a crisis at some point during their life.

Often triggered by an infection, medication or other stressor, weakness becomes severe and frequently involves respiratory and bulbar muscles. Mechanical ventilation is frequently required for patients with myasthenic crisis. While in the ICU, care must be taken to avoid the use of certain medications, including many antibiotics, calcium channel blockers, and magnesium. Overzealous use of cholinesterase inhibitors and corticosteroids may also worsen the patient’s weakness

Other neuromuscular conditions

Other, less frequent causes of neuromuscular junction disease in the ICU include botulism and Lambert-Eaton myasthenic syndrome (LEMS). LEMS is similar to MG but affects presynaptic calcium channels. It is an uncommon disease that may spare respiratory musculature but has prominent autonomic dysregulation as part of its clinical spectrum.

ALS is a disorder of the corticospinal tracts and anterior horn cells. ALS rarely manifests with neuromuscular respiratory failure as the presenting symptom of the disease. Most patients are admitted after the development of primary respiratory failure or infection. As with many neurologic conditions, transient worsening of symptoms may be induced by physiological stressors. Many of these patients will require mechanical ventilation, if not tracheostomy and gastrostomy tube.

Other motor neuron diseases

Although ALS is the most common motor neuron disease requiring ICU admission,other motor neuron diseases such as West Nile encephalomyelitis, polio, and certain paraneoplastic disorders may require ICU admission for respiratory support. Where West Nile infection remains prevalent, patients can develop acute flaccid paralysis similar to GBS.

Diseases of the muscle such as inflammatory and inherited myopathies require admission to the ICU in some cases. One recent study found myopathy to be the cause of ICU admission in 14% of the cases in the series. The most common adult myopathy, myotonic dystrophy, is an inherited disease of ion channels that presents with a constellation of findings, including distal motor weakness, cataracts, facial dysmorphism (“hatchet face”), and frontal balding.

Cardiac conduction defects requiring pacemaker implantation are a common occurrence. Late in the disease course, respiratory muscle weakness and restrictive lung disease can result in recurrent pneumonia and pulmonary sepsis.

Inflammatory myopathies, including polymyositis and dermatomyositis, may be seen in the ICU due to respiratory failure. These diseases occur with a similar frequency to GBS but less often require critical care.

Other myopathies

Other rare causes of muscle disease include toxic or metabolic myopathies and florid rhabdomyolysis.

Epidemiology

Neuromuscular diseases are commonly seen in the hospital, typically on a neurology services. The precise prevalence of these diseases in the ICU are unknown. However, the most common diseases to require critical care are GBS, MG, ALS, and various myopathies.

GBS occurs in approximately 1-2 per 100,000 and is now the most common cause of acute flaccid paralysis in the United States. Since the advent of mechanical ventilation, the mortality of the disease has decreased significantly and is approximately 2-3% in US hospitals. Pulmonary complications are among the most common to occur in the disease, with 9-10% requiring intubation. Increasing age, systemic infection, and cardiopulmonary complications are independent predictors of prolonged disability and mortality.

MG occurs in about 20 patients per 100,000 in the US. It is most common in women under the age of 40 and men between the ages of 50 to 70. Muscle weakness in myasthenia gravis is variable: some patients have only ocular involvement while others have diffuse, severe symptoms. Approximately 15-30% of patients with MG will experience respiratory difficulty and may require assisted ventilation. LEMS is much less common than MG and is most often seen as a paraneoplastic syndrome accompanying lung malignancies. Some estimate that it occurs in 1-3% of those suffering from small cell lung cancer.

Disorders of the anterior horn cell are less common than GBS and MG when presenting to the ICU but may represent up to 10% of admissions for neuromuscular weakness. The prevalence of ALS is approximately 1 in 100,000 in the US, with a variable number of patients requiring critical care. Due to the progressive, fatal nature of the disease, many patients will be in hospice before respiratory symptoms occur.

The prevalence of West Nile encephalitis is shifting throughout the US. When it was introduced to the US, many cases were present on the East Coast. However, in the past decade more cases are being recognized in the western US. However, cases are still reported each year in the mid-Atlantic and Southeastern US. It is likely that many cases of West Nile encephalitis will require critical care during the course of the illness. However, such rates are unknown at this time.

Other neuromuscular conditions in the ICU are less frequent. The prevalence of inflammatory myopathies such as poly- and dermatomyositis is 1-2 per 100,000, with a subset of those patients requiring critical care management. Conditions such as rhabdomyolysis, which may contribute to weakness, are more frequently encountered but usually in the setting of trauma, compression injury, or toxin exposure. Likewise, infectious causes (tick bite paralysis), metabolic (porphyria and mitochondrial myopathy), or inflammatory conditions (vasculitic neuropathy) are infrequent causes of neuromuscular respiratory failure in the ICU.

Special considerations for nursing and allied health professionals.

NA

What's the evidence?

Maramattom, B, Widjicks, E. "Acute neuromuscular weakness in the ICU". Critical Care Medicine. vol. 34. 2006. pp. 2835-41.

(This is an excellent review of the causes, work-up, and treatment of neuromuscular diseases in the ICU.)

Lacomis, D, Petrella, JT, Giuliani, M. "Causes of neuromuscular weakness in the ICU: a study of 92 Patients". Muscle and Nerve. vol. 21. 1998. pp. 610-7.

(A prospective study of the causes of neuromuscular weakness in the ICU.)

Serrano, MC, Rabinstein, AA. "Causes and outcomes of acute neuromuscular respiratory failure". Archives of Neurology. vol. 67. 2010. pp. 1089-94.

(One of the few articles documenting non-ICU-acquired neuromuscular weakness in the ICU.)

Wijdicks, EFM, Borel, CO. "Respiratory management in neurologic illness". Neurology. vol. 50. 1998. pp. 11-20.

(Excellent article describing the respiratory and ventilator management of patients with neurologic disease.)

Thomas, CE. "Myasthenic crisis: clinical features, mortality, complications, and risk factors for prolonged intubation". Neurology. vol. 48. 1997. pp. 1253-60.

(Study examining the precipitants, risk factors for prolonged mechanical ventilation, and complications of myasthenic crisis.)

Alshekhlee, A. "Guillain-Barré syndrome: Incidence and mortality rates in US hospitals". Neurology. vol. 70. 2008. pp. 1608-13.

(An article reviewing the current incidence, complications, and morbidity and mortality rates for GBS in the United States.)

Siddharth, M. "Cardiovascular complications of the Guillain-Barré Syndrome". Am J Cardiol. vol. 104. 2009. pp. 1452-5.

(A great review of the frequent cardiac complications of GBS.)

Seneviratne, J. "Noninvasive ventilation in myasthenic crisis". Arch Neurol. vol. 65. 2008. pp. 54-8.

(An interesting prospective, non-randomized trial of non-invasive mechanical ventilation in patients with myasthenic crisis.)
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