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Neuromuscular weakness related to critical illness

Neuromuscular weakness related to critical illness
Literature review current through: Jan 2024.
This topic last updated: Jun 05, 2023.

INTRODUCTION — Neuromuscular weakness is a common occurrence in patients who are critically ill. Weakness is partly a consequence of improved survival in patients with multiorgan failure and sepsis, but may be associated with treatments administered in the intensive care unit (ICU).

Neuromuscular weakness in the ICU is most often due to critical illness myopathy (CIM), critical illness polyneuropathy (CIP), or a combination of the two. This topic will review the peripheral neuromuscular disorders of critical illness.

CLASSIFICATION AND PATHOPHYSIOLOGY — Neuromuscular weakness in the intensive care unit (ICU) is most often due to critical illness myopathy (CIM), critical illness polyneuropathy (CIP), or a combination of the two. Some authors apply the term "intensive care unit-acquired weakness" (ICUAW) for patients who have clinically detected weakness with no plausible cause other than critical illness [1].

It is likely that reduction of nerve excitability (ie, inactivation of sodium channels) and axon degeneration (the currently accepted mechanism of CIP) may represent different ends of a single pathophysiologic spectrum that varies according to the severity of the inflammatory process in CIP [2], and that muscle membrane inexcitability, myosin loss, and muscle necrosis comprise the pathophysiologic spectrum in CIM.

Critical illness myopathy — The most common form of ICU-acquired myopathy is CIM [3,4]. This disorder is also known by other names, including acute quadriplegic myopathy and thick filament myopathy.

The major histopathologic finding in CIM is relatively selective loss of myosin, which can be identified as a lack of reactivity to myosin ATPase in non-necrotic fibers (figure 1). This finding can be confirmed with immunohistochemical studies for myosin and by utilizing electron microscopy to identify loss of thick filaments. There is usually atrophy of myofibers, type 2 more than type 1. There is often evidence of myofibrillar disorganization. Some degree of necrosis may occur [5-7].

In humans, there is evidence that several processes are involved in the pathogenesis of CIM, including upregulation of calpain, an increase in muscle apoptosis, activation of the proteosome ubiquitin-degradative system, stimulation of the transforming growth factor-beta/mitogen-activated protein kinase (TGF-beta/MAPK) pathway, upregulation of serum amyloid A1 (SAA1) [8,9], and impaired muscle fiber regeneration [10].

Oxidative stress may also play a role in the development of CIM, as illustrated by the finding that sarcolemmal immunostaining of the nitric oxide synthase isoform NOS1 was reduced or absent in six patients with CIM [11]. While the significance of this finding is not clear, it is hypothesized that the loss of sarcolemmal NOS1 could lead to muscle fiber inexcitability by reducing nitric oxide release at the muscle membrane.

A steroid-denervation animal model reproduces the histopathologic and electrophysiologic findings of CIM in humans [12] and suggests that a deleterious interaction between glucocorticoids and denervation leads to a depletion of the mRNA for myosin, and to muscle atrophy [13].

Muscle sodium channel properties were also evaluated in a chronic sepsis animal model produced by needle perforation after cecal ligature [14]. Patch clamp technique revealed decreased sodium current that could lead to muscle inexcitability. However, muscle histopathology and nerve conduction studies (NCS) were not assessed in this model, so it is unknown if there was neuropathy or structural myopathy with myosin loss. Ongoing work with this model also suggests a role for defective repetitive firing in lower motor neurons due to an alteration in the normal ratio of depolarizing sodium passive inward current to opposing subthreshold potassium current [15,16].

Critical illness polyneuropathy — The second neuromuscular condition that is commonly acquired in the ICU is CIP [4,17-19]. This disorder was first recognized clinically in the late 1970s and 1980s [19,20].

CIP appears to be a common complication of severe sepsis [21-23] and is thought to represent a neurologic manifestation of the systemic inflammatory response syndrome (SIRS). There is some correlation with elevations in blood glucose and reductions in serum albumin [18]. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis" and "Pathophysiology of sepsis".)

The mechanism of axonal injury in CIP is unknown. However, speculation focuses on injury to the microcirculation of distal nerves, causing ischemia and axonal degeneration [23,24]. During the early stages of sepsis, electrical inexcitability due to sodium channel inactivation may be present in otherwise intact nerves [25]. (See 'Combined critical illness myopathy and polyneuropathy' below.)

The association of sepsis with CIP is illustrated by a prospective report that assessed electrophysiologic and clinical data from 43 patients an average of 28 days after the onset of sepsis and multiorgan failure [18]. An axonal polyneuropathy was present in 30 patients (70 percent), 15 of whom also had clinical evidence of generalized muscle dysfunction, characterized by limb muscle weakness, reduced or absent deep tendon reflexes, and/or delayed weaning from mechanical ventilation. Three severely affected patients were unable to move any of their extremities, failed to improve, and ultimately died.

Many patients with severe sepsis who develop neuromuscular weakness in the ICU have a combination of CIM and CIP. (See 'Combined critical illness myopathy and polyneuropathy' below.)

Combined critical illness myopathy and polyneuropathy — Patients with ICU-acquired weakness sometimes have a combination of both CIM and CIP [4,26,27]. This combined disorder has also been termed "critical illness polyneuromyopathy" [26].

Sepsis may be a common pathologic mechanism underlying the development of both CIM and CIP [28]. Although not established, sepsis may trigger reversible but prolonged electrical inexcitability of nerve, similar in concept to the electrical inexcitability of muscle that has been observed in patients with CIM. (See 'Electrodiagnostic testing' below.)

In a septic rat model, there were reduced mixed motor and sensory tail nerve amplitudes and reduced excitability in dorsal root sensory axons via intracellular recordings. These experiments indicated that sodium channels were inactivated [29]. The investigators interpreted these data as evidence of either a novel neuropathy in critical illness or an acquired sodium channelopathy that causes neuropathy early in the course of CIP and may be reversible without progressing to axonal degeneration. In conjunction with studies in CIM, the data further suggest that the acquired sodium channelopathy in critical illness affects different sodium channel isoforms in both nerve and muscle.

Prolonged neuromuscular junction blockade — Prolonged neuromuscular junction blockade is almost never encountered in the modern era because the use of paralytic agents has been largely replaced by the use of sedatives in the ICU. The disorder is related to prolonged use (days) of paralytic agents, often in the setting of renal or hepatic insufficiency, leading to prolonged circulation of drug metabolites [30,31]. These curare-like paralytic agents bind reversibly to acetylcholine receptors on the motor end-plates of neuromuscular junctions, thereby inhibiting neuromuscular transmission. (See "Neuromuscular blocking agents in critically ill patients: Use, agent selection, administration, and adverse effects".)

EPIDEMIOLOGY AND RISK FACTORS — Neuromuscular weakness due to critical illness myopathy (CIM) or critical illness polyneuropathy (CIP) is a common occurrence in patients who are critically ill, developing in ≥25 percent of patients who are mechanically ventilated in the intensive care unit (ICU) for at least seven days [32-35]. It may occur less frequently in children [36]. Risk factors include sepsis, multiorgan failure, and the systemic inflammatory response syndrome (SIRS). Hyperlactacidemia is also associated with the likelihood of developing "intensive care unit-acquired weakness" (ICUAW) [37].

In prospective studies, approximately one-third of patients with status asthmaticus or chronic obstructive pulmonary disease and 7 percent of those who receive a liver transplant develop CIM [33,38,39]. Patients with other critical illnesses, such as acute respiratory distress syndrome and severe coronavirus disease 2019 (COVID-19), may also be affected [40].

Earlier studies suggested that the main risk factor for CIM was the use of intravenous glucocorticoids in the ICU setting [5,38,39,41,42]. However, the glucocorticoid association is now controversial, and critically ill patients may develop CIM in the absence of exposure to intravenous glucocorticoids [43-47].

Another potential risk factor for CIM is the use of various types of paralytic agents, and a meta-analysis of ICU weakness in general suggests a modest association between neuromuscular blocking agents and neuromuscular dysfunction associated with critical illness [48].

Associated and perhaps triggering factors may include a higher illness severity index, hyperglycemia, and hyperthyroidism [33,49]. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)

The CRIMYNE study of 92 patients who had normal nerve conductions at 24 hours after ICU admission showed that serial electrodiagnostic studies were helpful in predicting development of CIM and/or CIP [50]. A reduction of >25 percent in the peroneal motor amplitude (compound muscle action potential) was the most useful measure, with the best combination of sensitivity and specificity (100 and 67 percent, respectively). In some patients, the transition to CIM/CIP was abrupt (ie, within 24 hours). In others, it occurred over days. In this study, CIM and/or CIP were associated with multiorgan failure but not with a SIRS, sepsis, drugs, or nutrition. The simplified electrophysiologic test used in this study was not able to distinguish CIM from CIP, and the investigators suggested performing a complete electrodiagnostic evaluation for patients with a >25 percent reduction from baseline in the peroneal compound muscle action potential on two consecutive days. The utility of this peroneal nerve test was validated in other prospective CIM/CIP studies with a sensitivity of 94 to 100 percent and a specificity of 85 to 91 percent [51,52].

CLINICAL MANIFESTATIONS — Common features of critical illness myopathy (CIM) and critical illness polyneuropathy (CIP) include symmetric, flaccid limb weakness and ventilatory muscle weakness. Extraocular muscles are relatively spared, and facial muscles are usually but not always spared. Tendon reflexes are often reduced, especially with CIP.

CIM often begins within several days of intensive care unit (ICU) admission. The time of onset of the myopathy may not be known in patients who are comatose or encephalopathic.

The most common presenting features of CIM are [5,24,33,42-44,53-55]:

Flaccid quadriparesis that may affect proximal more than distal muscles

Failure to wean from mechanical ventilation

Facial muscle weakness is also relatively common, but extraocular muscle weakness rarely occurs.

In the ICU setting, it is often difficult to assess sensation due to the presence of encephalopathy and diminished consciousness. For patients with CIM, sensation should be normal if it can be tested reliably. Patients should at least grimace to pain stimuli even when they are encephalopathic. Deep tendon reflexes may be normal or attenuated.

CIP usually occurs in patients who are in the ICU for one or especially two weeks or more. The clinical features can overlap with those of CIM. In many cases, patients with CIP require prolonged weaning from mechanical ventilation [22,56].

Affected patients manifest a sensorimotor polyneuropathy characterized clinically by [57]:

Limb muscle weakness and atrophy

Reduced or absent deep tendon reflexes

Loss of peripheral sensation to light touch and pinprick

Relative preservation of cranial nerve function

While patients with CIP may exhibit distal sensory loss, this finding can only be assessed if a reliable sensory examination is possible in an awake, alert, and cooperative patient. However, encephalopathy is a frequent accompaniment of critical illness, and often precludes a detailed sensory examination.

Combined CIM/CIP has clinical features that overlap the individual but closely corresponding features of CIM and CIP, with symmetric weakness of all four limbs, typically affecting proximal more than distal muscles; reduced or absent deep tendon reflexes; and peripheral sensory loss (in patients where a reliable sensory examination is possible).

EVALUATION AND DIAGNOSIS — The diagnosis of neuromuscular weakness related to critical illness is suspected in patients who develop flaccid muscle weakness and ventilatory failure after the onset of critical illness. In the appropriate setting, the diagnosis is confirmed when other, unrelated causes of weakness are excluded or deemed unlikely (algorithm 1 and table 1). However, it is often difficult to distinguish critical illness myopathy (CIM) (table 2) from critical illness polyneuropathy (CIP) (table 3) on the basis of clinical features and neurologic examination findings alone.

Initial evaluation — The basic steps in the initial evaluation include [1]:

Identifying generalized weakness and assessing muscle strength

Reviewing prehospital functional status and patient and family history of conditions that might be causing or contributing to weakness

Analyzing the time course of neurologic symptoms

Searching for factors associated with neuromuscular weakness related to critical illness, including:

Sepsis

Multiorgan failure

Mechanical ventilation

Hyperglycemia

Exposure to glucocorticoids and/or neuromuscular blocking agents

Exposure to intravenous glucocorticoids may suggest the diagnosis of CIM, but the association is inconsistent. (See 'Epidemiology and risk factors' above.)

Examination — In an awake and cooperative patient with unfettered ability to voluntarily move the limbs, muscle strength can be tested manually in each limb and graded on the Medical Research Council (MRC) scale (table 4), which ranges from 0 (no contraction) to 5 (normal power). Some investigators use the MRC sum score, which involves testing the strength of three movements from each arm (shoulder abduction, elbow flexion, wrist extension) and each leg (hip flexion, knee extension, and ankle dorsiflexion), yielding a maximum combined score of 60; a combined score of <48 is considered diagnostic of intensive care unit (ICU)-acquired weakness [32]. Similarly, a mean MRC score of <4 per muscle group is consistent with ICU-acquired weakness [1,58]. However, manual muscle testing may not be practical in the ICU if encephalopathy and pain limit voluntary muscle contraction [59]. This limitation may also make it difficult or impossible to reliably exclude a central nervous system (CNS) problem as the cause of generalized weakness. It may be helpful to temporarily interrupt sedatives and analgesics, if doing so does not compromise patient safety, to facilitate the neurologic evaluation.

CIM can be distinguished from CIP if preservation of sensory function (indicative of the former) can be demonstrated. However, like strength testing, sensory evaluation can be difficult in critically ill patients, particularly when obtunded, comatose, or intubated, and it may be difficult to distinguish CIM from CIP on the basis of clinical features and neurologic examination findings alone. Furthermore, some patients have features of combined CIM and CIP. (See 'Combined critical illness myopathy and polyneuropathy' above.)

Neuroimaging — Neuroimaging is indicated if the neurologic assessment of weakness is unreliable, or if the evaluation reveals evidence that raises suspicion for a CNS lesion. Magnetic resonance imaging (MRI) is preferred to computed tomography (CT), particularly if there is concern for a brainstem lesion, and MRI is required if there is concern for a spinal cord lesion.

Laboratory studies — It is reasonable to obtain a serum creatine kinase (CK) level in all patients who have critical illness associated with weakness. An elevation in serum CK is usually present with CIM and supports the diagnosis but can occur in the absence of CIM among patients treated with intravenous glucocorticoids [39].

In a prospective study of 25 patients with status asthmaticus who were treated with intravenous glucocorticoids, 9 patients had clinically detectable myopathy, while 19 had an elevated serum CK, with a median value of 1575 international units/L (range 66 to 7430 international units/L) [39]. The increase in serum CK peaked around four days after initial treatment with glucocorticoids, and lasted for as long as 16 days.

Other laboratory studies and investigations may be helpful for select patients with critical illness and weakness.

Lumbar puncture and cerebrospinal fluid analysis are appropriate if an infectious or inflammatory cause of acute generalized weakness is a consideration in the differential diagnosis. Examples include infectious or immune-mediated encephalitides, myelopathies, and the acute motor axonal neuropathy form of Guillain-Barré syndrome (GBS). In the last case, a normal cerebrospinal fluid protein level would be supportive of CIP rather than GBS.

Electroencephalography (EEG) is appropriate in patients with altered consciousness to evaluate for seizures (particularly nonconvulsive or subclinical seizures) and certain metabolic encephalopathies (eg, hepatic) or infectious encephalitides (eg, viral) that have characteristic EEG patterns.

Muscle biopsy is rarely performed unless another treatable condition, such as an inflammatory myopathy, is in the differential diagnosis. For patients with CIM or combined CIM and CIP, muscle biopsy and histopathology can confirm the presence of myopathy. In CIP, muscle biopsy findings are those of neurogenic atrophy.

Electrodiagnostic testing — We suggest electrodiagnostic testing with nerve conduction studies (NCS), electromyography (EMG), and repetitive nerve stimulation for all critically ill patients who have unexplained severe weakness, do not improve over one to two weeks, or cannot be reliably assessed by clinical examination [1]. Electrodiagnostic testing with NCS and EMG can help to confirm the diagnosis of CIM, CIP, or combined CIM/CIP. Additionally, electrodiagnostic studies can help to identify other causes of weakness in the differential diagnosis; examples include GBS, motor neuron disease, and myasthenia gravis.

However, electrodiagnostic studies have important limitations including lack of universal ICU availability, particularly outside of tertiary centers, and reduced utility in patients who lack the ability to voluntarily contract muscles, are encephalopathic, or have severe weakness or peripheral edema. Differentiating CIM from CIP may not change management, but may impact prognosis. The presence of neuropathy with or without myopathy portends a worse prognosis than myopathy in most studies. (See 'Prognosis' below.)

In the author's clinical experience, a normal NCS study by day 7 or so would rule out CIM and CIP.

In CIM, abnormalities on NCS and EMG are seen within a few days following onset of weakness. The major nerve conduction findings (table 2) are normal to low motor amplitudes with frequent broadening (prolonged duration) of the compound muscle action potential [54,60-64]; these findings are essentially diagnostic of CIM. Phrenic motor amplitudes may also be low. Sensory responses are normal or only mildly reduced, unless there is a coexisting polyneuropathy. Rarely, neuromuscular junction blockade occurs and can be identified transiently via low rates of repetitive stimulation that reveal a decremental response [65].

Needle examination often (in >70 percent) but not uniformly reveals fibrillation potential activity [61]. Depending upon the degree of weakness, observation of the recruitment of motor unit potentials (MUPs) may be difficult. When it is possible to evaluate, recruitment tends to be early. MUPs are short in duration, low in amplitude, and sometimes polyphasic [66].

Some muscles exhibit electrical inexcitability to direct muscle stimulation [67,68]. This inexcitability is due to a defect in muscle membrane depolarization, which may be related to increased inactivation of sodium channels at the resting potential. Direct muscle stimulation is especially useful in differentiating CIM from motor axonopathy (table 2) [55,61,62]. However, some patients also have a coexisting peripheral neuropathy.

Direct muscle stimulation can be performed using a stimulating monopolar needle electrode placed just proximal to the tendon insertion. The tibialis anterior muscle is commonly tested. After obtaining a muscle twitch, a recording needle electrode is placed in the center of the muscle proximal to the site of stimulation, and the maximal muscle-stimulated compound muscle action potential (mCMAP) is recorded. The recording electrode is kept in place and the appropriate nerve undergoes surface stimulation, recording a nerve-evoked compound muscle action potential (nCMAP). The nCMAP-to-mCMAP ratio is calculated; a value >0.5 suggests impaired muscle membrane excitability [67,69,70]. However, it should be noted that direct muscle stimulation is not usually performed in routine clinical practice.

Electrodiagnostic studies in patients with CIP typically reveal findings consistent with a generalized axonal sensorimotor polyneuropathy with low motor and sensory amplitudes on NCS (table 3) [61,71]. Over two to three weeks, fibrillation potentials will be evident on EMG needle examination. Phrenic motor amplitudes are commonly reduced. Some patients appear to have predominant motor involvement, but myopathy should be excluded in such patients. Demyelination is not seen in CIP and would be an exclusion to the diagnosis.

In patients with CIP, direct muscle stimulation using a needle electrode elicits a relatively higher-amplitude response compared with the response recorded from muscle after nerve stimulation. By contrast, in CIM, there are proportionally low direct muscle- and nerve-evoked responses.

The development of CIM and CIP was illustrated by a prospective longitudinal cohort study of 48 patients who had baseline neurologic examinations and NCS within 72 hours of developing severe sepsis [28]. EMG was performed for patients who developed clinical weakness or had a ≥30 percent reduction in nerve conduction response amplitudes. Clinical and electrophysiologic examinations were repeated weekly for the duration of the ICU stay. Abnormal NCS were present at baseline in 63 percent of patients, and an abnormality on baseline NCS was significantly associated with hospital mortality compared with a normal baseline NCS (55 versus 0 percent, respectively). In 20 patients who remained in the ICU long enough to have serial NCS, neuromuscular dysfunction developed in 10 patients (50 percent). Electrophysiologic evidence of both CIM and CIP was present in 8 of 10 patients with neuromuscular dysfunction.

Muscle ultrasound — Muscle ultrasound is being used to evaluate muscle thickness and echogenicity in neuromuscular conditions, and it may be useful in screening patients for CIM/CIP. In a prospective study of 95 patients with critical illness, probable CIM/CIP was diagnosed in 17 (18 percent) by electrodiagnostic criteria [52]. Among 67 patients in whom ultrasound of the biceps brachii, forearm, or mid-thigh muscles was also performed, increased echogenicity in any muscle was found to be 82 percent sensitive and 57 percent specific for CIM/CIP. An abnormal ultrasound was associated with a lower chance of discharge to home, suggesting that ultrasound may also have prognostic potential. (See "Diagnostic ultrasound in neuromuscular disease".)

DIFFERENTIAL DIAGNOSIS — The broad differential diagnosis of acute generalized weakness in a critically ill patient includes bilateral or paramedian brain or brainstem lesions, disorders of the spinal cord, peripheral nerve lesions, neuromuscular junction disorders, and muscle disorders (table 1).

However, in a critically ill patient who develops flaccid generalized weakness, the major considerations in the differential diagnosis are critical illness myopathy (CIM), critical illness polyneuropathy (CIP), or a combination of the two. Prolonged neuromuscular junction blockade is rare. Each of these disorders is discussed in detail above. (See 'Classification and pathophysiology' above and 'Clinical manifestations' above.)

Other acute and subacute myopathies can occur in critically ill patients, including rhabdomyolysis and cachectic myopathy. In addition, rare acute neuropathies such as Guillain-Barré syndrome (GBS) can also develop in the intensive care unit (ICU), and subclinical myasthenia gravis may become symptomatic during critical illness or treatment with intravenous magnesium and some antibiotics.

Central causes — Central nervous system (CNS) disorders involving the brain, brainstem, or spinal cord may cause acute generalized weakness in critically ill patients (table 1). Differentiating whether weakness is due to central or peripheral nervous system lesions is often challenging in the setting of the ICU; voluntary movement and the ability to cooperate with the examination may be limited in critically ill patients due to sedation, encephalopathy, pain, tissue injury, peripheral edema, and/or medical device and line placement [59]. Furthermore, an acute CNS disorder can initially present with transiently decreased tone and reflexes, thereby mimicking a peripheral nervous system disorder [72].

In cases where neurologic examination cannot reliably exclude a central cause of generalized weakness, neuroimaging of the brain and/or spinal cord should be obtained. Magnetic resonance imaging (MRI) is preferred to computed tomography (CT), particularly if there is concern for a brainstem lesion, and MRI is required if there is concern for a spinal cord lesion.

Rhabdomyolysis — Some critically ill patients develop rhabdomyolysis due to their illness or medications [73]. (See "Rhabdomyolysis: Clinical manifestations and diagnosis".)

Potential causes include:

Viral, bacterial, and fungal infections

Neuroleptic malignant syndrome or serotonin syndrome (see "Neuroleptic malignant syndrome" and "Serotonin syndrome (serotonin toxicity)")

Medications such as neuroleptics, anticholinergics, amphotericin, vecuronium, and others

In patients with rhabdomyolysis, serum creatine kinase (CK) levels are usually at least five times the upper limit of normal, but range from approximately 1500 to over 100,000 international units/L. There may be mild to moderate weakness with muscle swelling and myalgias, but there is usually only a mild degree of muscle necrosis histologically, and the electromyography (EMG) abnormalities can be minimal with only mild fibrillation potential activity [74]. (See "Rhabdomyolysis: Clinical manifestations and diagnosis".)

Cachectic myopathy — Patients with critical illness can develop a subacute myopathy due to protein catabolism and disuse, a disorder that has been termed "cachectic myopathy."

In cachectic myopathy, there is proximal-predominant weakness with muscle wasting, a normal serum CK level, laboratory evidence of malnutrition, normal or mildly "myopathic" motor unit potential (MUP) changes on EMG without fibrillation potentials, and type 2 muscle fiber atrophy histologically. Cachectic myopathy is a diagnosis of exclusion [71].

In a prospective study of 63 patients with critical illness who were followed for the first 10 days of ICU admission, serial ultrasound examination of the rectus femoris muscle revealed early reductions of cross-sectional area that were statistically significant at days 7 and 10 [75]. In a subset of patients who had serial muscle biopsy, there were decreases in the muscle fiber cross-sectional area and the ratio of protein to DNA, consistent with loss of muscle mass, while studies of protein metabolism and signaling suggested decreased muscle synthesis and increased muscle breakdown. The muscle loss was greater in those with multiorgan failure and occurred despite enteral nutrition. Biopsy specimens showed muscle necrosis in approximately 50 percent of patients, suggesting they might be categorized as having CIM (see 'Critical illness myopathy' above) rather than cachectic myopathy.

Guillain-Barré syndrome — Acute inflammatory demyelinating polyneuropathy (GBS) is an uncommon occurrence in critically ill patients. Patients with GBS typically have features of a demyelinating polyneuropathy on nerve conduction studies (NCS) and a high cerebrospinal fluid protein concentration. Other features may overlap with CIP. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)

MANAGEMENT — Treatment of both critical illness myopathy (CIM) and critical illness polyneuropathy (CIP) is directed toward aggressive management of medical conditions, avoidance of additional complications such as venous thrombosis, and rehabilitation [76,77]. Minimizing sedation, limiting or avoiding use of neuromuscular blockers, and early mobilization of critically ill patients may help to prevent or mitigate neuromuscular weakness [78], although supporting data are limited. Despite controversy regarding causality, it still seems reasonable to discontinue or reduce glucocorticoids as soon as possible.

Although not established, two studies have reported that intensive insulin therapy (target blood glucose 80 to 110 mg/dL [4.4 to 6.1 mmol/L]) may lower the incidence of CIM and CIP among critically ill patients who remain in the intensive care unit (ICU) for seven or more days [79-81]. These studies are limited by methodologic issues; both were subgroup analyses, and the diagnosis of CIP/CIM was made based upon electromyography (EMG) criteria only. In addition, tight control of hyperglycemia in the ICU is controversial because of concern that it may result in increased mortality. (See "Glycemic control in critically ill adult and pediatric patients".)

Another potential but unestablished therapy is neuromuscular electrical stimulation (NMES). A 2020 meta-analysis found that NMES may play a role in preventing or reducing acquired weakness in the ICU, but there is no evidence that NMES improves the functional status of ICU patients [82]. Higher-quality studies on patients with CIM and CIP are desirable.

PROGNOSIS — Many patients who survive critical illness experience prolonged impairment in cognition, mental health, and physical function, known as post-intensive care syndrome (PICS). Neuromuscular weakness related to critical illness is often a significant aspect of this syndrome, with sequelae that may include persistent generalized weakness, joint contractures, poor mobility, falls, and disabilities in activities of daily living. The presence of intensive care unit (ICU)-acquired neuromuscular weakness at discharge may also negatively impact five-year morbidity and mortality [83]. (See "Post-intensive care syndrome (PICS) in adults: Clinical features and diagnostic evaluation".)

Critical illness myopathy (CIM) is usually reversible over weeks to months [57,70] but leads to prolonged ICU stays and increased length of hospital stay overall.

Patients with CIM tend to have better outcomes than those with critical illness polyneuropathy (CIP). In survivors of CIP with mild or moderate nerve injury, recovery of muscle strength generally occurs over weeks to months. However, electrodiagnostic testing may demonstrate residual nerve dysfunction several years after initial presentation, and a small outcomes study found that 4 of 11 patients still required assistance in their daily routine at 12 months after discharge from the ICU [84,85]. Patients with severe CIP may remain quadriplegic.

Electrodiagnostic studies with direct muscle stimulation show that patients with both CIM and CIP usually develop CIM first [3]. Patients with CIM and CIP remain hospitalized longer than those with CIM alone. Of those who are discharged to rehabilitation units, most improve over 6 to 12 months, and those with persistent disabilities are more likely to have had CIP with or without CIM [86]. A one-year follow-up of 13 survivors from the CRIMYNE study showed a mixture of tetraplegia, partial recovery, and full recovery in patients with combined CIM/CIP in contrast to complete recovery in three to six months for CIM alone [87]. A minority of patients with CIP had persistent weakness.

SUMMARY AND RECOMMENDATIONS

Neuromuscular weakness often develops in patients who are critically ill. The most common causes are critical illness myopathy (CIM), critical illness polyneuropathy (CIP), or a combination of the two. Risk factors include sepsis, multiorgan failure, and the systemic inflammatory response syndrome (SIRS). The use of intravenous glucocorticoids is another possible risk factor for CIM. (See 'Classification and pathophysiology' above.)

Typical features of CIM and CIP include symmetric, flaccid limb weakness, which is usually worse in proximal compared with distal muscles. Extraocular muscles are relatively spared, and facial muscles are usually but not always spared. (See 'Clinical manifestations' above.)

The diagnosis of neuromuscular weakness related to critical illness is suspected in patients who develop flaccid muscle weakness and ventilatory failure after the onset of critical illness. In the appropriate setting, the diagnosis is confirmed when other, unrelated causes of weakness are excluded or deemed unlikely (table 1). However, it is often difficult to distinguish CIM (table 2) from CIP (table 3) on the basis of clinical features and neurologic examination findings alone. Neuroimaging is indicated if the neurologic assessment of weakness is unreliable, or if the evaluation reveals evidence that raises suspicion for a central nervous system (CNS) lesion. We suggest electrodiagnostic testing with nerve conduction studies (NCS), electromyography (EMG), and repetitive nerve stimulation for all patients who have unexplained severe weakness, do not improve over one to two weeks, or cannot be reliably assessed by clinical examination. Differentiating CIM from CIP may not change management, but may impact prognosis. (See 'Evaluation and diagnosis' above and 'Management' above and 'Prognosis' above.)

The broad differential diagnosis of acute generalized weakness in a critically ill patient includes bilateral or paramedian brain or brainstem lesions, disorders of the spinal cord, peripheral nerve lesions, neuromuscular junction disorders, and muscle disorders (table 1). However, in a critically ill patient who develops flaccid generalized weakness, the major considerations in the differential diagnosis are CIM, CIP, or a combination of the two. Other acute and subacute myopathies can occur in critically ill patients, including rhabdomyolysis and cachectic myopathy. In addition, rare acute neuropathies such as Guillain-Barré syndrome (GBS) can also develop in the intensive care unit (ICU), and subclinical myasthenia gravis may become symptomatic during critical illness or treatment with intravenous magnesium and some antibiotics. (See 'Differential diagnosis' above.)

Treatment of both CIM and CIP is directed toward aggressive management of medical conditions, avoidance of additional complications such as venous thrombosis, and rehabilitation. Minimizing sedation and early mobilization of critically ill patients may help to prevent or mitigate neuromuscular weakness. (See 'Management' above.)

Many patients who survive critical illness experience prolonged impairment in cognition, mental health, and physical function, known as post-intensive care syndrome (PICS). Neuromuscular weakness related to critical illness is often a significant aspect of this syndrome, with sequelae that may include persistent generalized weakness, joint contractures, poor mobility, falls, disabilities in activities of daily living, and a higher than expected five-year mortality. In survivors of CIP with mild or moderate nerve injury, recovery of muscle strength generally occurs over weeks to months. Patients with severe CIP may remain quadriplegic. Patients with CIM tend to have better outcomes than those with CIP. (See 'Prognosis' above.)

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Topic 5144 Version 21.0

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