Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 108

Neuromuscular complications in intensive care patients ZOHAR ARGOV1* AND NICOLA LATRONICO2 Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

1 2

Department of Anesthesia Intensive Care and Postoperative Care, Division of Neuroanaesthesia and Neurocritical Care, University of Brescia, Spedali Civili, Brescia, Italy

INTRODUCTION AND DEFINITIONS Severe weakness due to polyneuropathy or myopathy was recognized as a direct complication of intensive care unit (ICU) hospitalization in the 1980s, but seemed a rare complication in critically ill patients (Bolton, 2010). Since then it has become clear that ICU-acquired weakness (ICUAW) is a common feature amongst such patients, especially when their ICU hospitalization time is long (Latronico and Bolton, 2011). The improvement in the ability to treat critically ill patients for lengthy periods in ICU and their increased survival has resulted in many patients developing severe limb and respiratory muscle weakness leading to increased risk of permanent morbidity, mortality and to prolonged and costly hospitalization. Weakness in an intensive care patient may be due to a pre-existing disorder, which was either the cause of the hospitalization or a known condition in a patient that required ICU treatment due to other medical or surgical emergencies. Such conditions will not be dealt with in this chapter, which is devoted to a newly appearing weakness while in ICU (hence the term ICUAW) (De Jonghe et al., 2002; Ali et al., 2008; Stevens et al., 2009). Such new paralysis may infrequently be due to a previously undiagnosed condition that was unmasked by the ICU conditions but usually it is the result of complications of the actual stay in the ICU. Most of the conditions lead to generalized weakness, which will be the main topic of this chapter; however, some complications result only in focal weakness. The newly acquired generalized weakness of intensive care is usually due to either a neuropathic disorder

or a myopathy, or to a combination of both, but disorders of the neuromuscular junction may also lead to a similar clinical picture. Disorders of the central nervous system, especially of the spinal cord, may also develop in the ICU patient and lead to generalized paralysis, but these rarely pose a diagnostic difficulty and will be discussed only in terms of the differential diagnosis of such severe weakness in critically ill patients. Various terms have been given to the different ICUAW conditions and we will use the terms CIP for the critical illness polyneuropathy, CIM for the critical illness myopathies and CINM for the mixed or undifferentiated neuromyopathies of intensive care patients.

INTENSIVE CARE UNIT-ACQUIRED GENERALIZED WEAKNESS Clinical presentation The typical presentation is that of severe flaccid weakness that symmetrically affects the four limbs but spares the ocular, bulbar, and usually the facial muscles (Bolton, 2005). In some patients facial weakness can be seen but ophthalmoplegia (especially ptosis) is so uncommon that it should raise a completely different list of potential diagnoses. Recently a Medical Research Council (MRC) combined muscle power score of less than 48/60 was suggested as a diagnostic criterion (De Jonghe et al., 2002). This score depends much on patient’s cooperation and may ignore the less severe forms of ICUAW, but is an independent predictor of morbidity and mortality (Ali et al., 2008). Muscle weakness is associated with marked and early atrophy, more

*Correspondence to: Zohar Argov, M.D., Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. Tel: þ972-2-677-6938, E-mail: [email protected]

1674

Z. ARGOV AND N. LATRONICO

than can be expected from the disuse atrophy of immobilization in such patients (Latronico and Bolton, 2011). Skeletal muscle weakness is frequently associated with weakness of respiratory muscles (resulting in difficulty to wean the patient from a respirator or in a need for reintubation). In many cases the condition is recognized only when a patient who was unconscious or under anesthetic or neuromuscular blocking agents regains his consciousness, the medications are stopped, but movement of the limbs is weak and respiratory effort is inefficient (Bolton et al., 1984). In fact in many instances failure to wean from a ventilator once sedation is over is the initial cause for neurologic consultation (Zochodne et al., 1987). Deep tendon reflexes are reduced or unobtainable (especially if the cause is neuropathic or the degree of weakness is severe). Sensory impairment is not as severe as the weakness and is detected only in peripheral neuropathic causes. Reduced sensation to pin prick, vibration, and temperature is usually found in the legs. It should be noted that sensory examination is at times difficult in an ICU patient with clouded sensorium. Pain and autonomic dysfunction are rare. While usually the condition appears after prolonged period in the ICU with several complications such as sepsis, systemic inflammatory response syndrome, and multiorgan failure (Latronico et al., 1996), it may be observed after relatively short ICU course and progress rapidly (Tennila et al., 2000; Khan et al., 2006; Latronico et al., 2007). The above clinical presentation is typical to most of the specific conditions to be described below.

Incidence Exact incidence of ICUAW is unknown due to wide variation in the patient population, the risk factors, the diagnostic criteria used, and the timing of evaluation (Latronico et al., 2005a; Stevens et al., 2007). The incidence varies from 25% in patients with ICUAW defined clinically by the MRC score (De Jonghe et al., 2002; Ali et al., 2008) to 33% in those who have no evidence of multiorgan failure on ICU admission (Latronico et al., 2007). It may be higher (up to 77%) with longer (>1 week) ICU stay (Coakley et al., 1998; Van den Berghe et al., 2005; Hermans et al., 2007; Nanas et al., 2008). High incidence was recorded in patients with acute respiratory distress syndrome (up to 60%) (Bercker et al., 2005; Hough et al., 2009), multiple organ failure or systemic inflammatory response syndrome (up to 80%) (Witt et al., 1991; Garnacho-Montero et al., 2001; Bednarik et al., 2003; Bednarik et al., 2005) and in almost all patients with septic shock (Tennila et al., 2000) or severe sepsis plus coma (Latronico et al., 1996).

Critical illness polyneuropathy Critical illness polyneuropathy (CIP) is an axonal sensorimotor polyneuropathy affecting the limb (usually more distally) and respiratory muscles (Zochodne et al., 1987). Limb involvement is symmetric, but is more prominent in the lower extremities. Early clinical diagnosis is difficult either because CIP is often preceded by encephalopathy (Bolton et al., 1993), usually attributed to sepsis (Pandharipande et al., 2007), or because of ongoing sedation (Latronico and Bolton, 2011). Brain imaging and cerebrospinal fluid examination are often nondiagnostic and electroencephalogram (EEG) may confirm the presence of diffuse encephalopathy. During recovery from the encephalopathy, weaning from mechanical ventilation or apparent weakness of limb movements will be the first evidence of this complication. Deep tendon reflexes are usually lost at the early stage of the disorder. If the patient is alert, distal loss to pain, temperature, and vibration is diagnostic for the neuropathic source of the problem as most other causes of ICUAW do not affect the sensory system (Latronico and Bolton, 2011).

Critical illness myopathy Critical illness myopathy (CIM) is a primary acquired myopathy in the ICU with distinctive electrophysiologic and morphologic features (Latronico and Candiani, 1998; Lacomis et al., 2000). The clinical features are usually indistinguishable from CIP apart from the lack of sensory involvement. It is reported that very few patients have ocular muscle involvement in CIM (Sitwell et al., 1991; Gorson, 2005). It was also reported to occur in pediatric patients (Kaplan et al., 1986). Evidence of a relationship between corticosteroids and CIM is conflicting. Historically, CIM was first described in asthmatic, mechanically ventilated patient treated with high-dose steroids in combination with neuromuscular blocking agents (NMBA), antibiotics, and other drugs (MacFarlane and Rosenthal, 1977). However, as in CIP, CIM evolves mainly in patients who also had severe sepsis and multiple organ failure (Latronico et al., 1996; Latronico et al., 2005a). Because the weakness becomes apparent when these medications (especially the steroids and neuromuscular blockers) are stopped, the assumption was that CIM is a drug-induced condition. However, CIM was described in patients who received only one of these agents, or had very low doses of them for short periods, and even when none was administered. Steroid administration in conjunction with intensive insulin treatment and strict blood glucose control might even exert a protective effect on muscle, possibly because its beneficial anti-inflammatory effect is not counteracted by hyperglycemia and insulin resistance

NEUROMUSCULAR COMPLICATIONS IN INTENSIVE CARE PATIENTS (Hermans et al., 2007). In a recent series based on 208 limb and abdominal muscle biopsies taken from ICU patients, the duration of corticosteroid treatment was associated with loss of myofibrillar (mainly myosin) filaments. Taken together these results suggest that high-dose corticosteroids in critically ill patients should be used cautiously and only when strictly indicated (Derde et al., 2012). Pathologically there seem to be three types of this myopathy: thick filament (myosin) loss myopathy, necrotic, and type 2 fiber atrophy (see Pathophysiology) (Latronico and Bolton, 2011). Only the first two can be associated with a clear rise in serum creatine phosphokinase (CPK) levels; however, normal CPK levels do not exclude CIM (Stevens et al., 2009). It is not clear if these are three distinct disorders or represent histopathologic variations of a single condition. Clinically and electrophysiologically they are indistinguishable from each other (Latronico, 2003). Differential diagnosis requires muscle biopsy (see Muscle and nerve biopsy).

1675

a major risk factor since ICUAW was regarded in the past as drug-induced disorder (Op de Coul et al., 1985; Hirano et al., 1992). Later it became clear that both CIP and CIM may develop without the use of these drugs (Latronico et al., 1996; Deconinck et al., 1998; Hoke et al., 1999). Still, in patients with acute respiratory distress syndrome, treatment with steroids was the main determinant of impaired ability to exercise at 3 months after hospitalization, but no longer thereafter (Herridge et al., 2003, 2011). Immobility has been suggested as a risk factor for muscle weakness during critical illness. Repeated daily passive and early mobilization prevents muscle atrophy and improves functional independence of patients (Griffiths et al., 1995; Burtin et al., 2009; Schweickert et al., 2009). Diaphragmatic weakness and atrophy develop rapidly after initiation of mechanical ventilation, and are significantly correlated with the duration of such respiratory support (De Jonghe et al., 2002; Jaber et al., 2011).

Critical illness neuromyopathy Critical illness neuromyopathy (CINM) is a very severe form of ICUAW (Latronico et al., 1996). The patient cannot be weaned from the ventilator for a long time and limbs are severely weak or totally paralyzed. However, it is now recognized that combined CIP and CIM often occur in many ICU patients and could possibly manifest a less severe form. It is claimed that the combined form may be the commonest manifestation of neuromuscular weakness in the ICU (Latronico et al., 1996; Bednarik et al., 2003; Lefaucheur et al., 2006; Koch et al., 2011). The prognosis for recovery in these patients with the less severe form of CINM is relatively good but in general neuropathy accompanying CIM protracts ICU discharge (Koch et al., 2011).

Risk factors for critical illness polyneuropathy and myopathy Several studies have consistently identified sepsis, systemic inflammatory response syndrome, and multiple organ failure as risk factors for ICUAW (Stevens et al., 2007) but the following factors have been identified as independent risk factors in a few prospective studies (Hermans et al., 2009): severity of illness, duration of multiple organ dysfunction, duration of vasopressor and catecholamine support, duration of ICU stay, hyperglycemia, female gender, renal failure, hyperosmolality, parenteral nutrition, low serum albumin, and encephalopathy. Aminoglycoside antibiotics have been identified as risk factors in some studies, but not in others (Hermans et al., 2009). The use of neuromuscular blocking agents, especially in combination with steroids, was thought to be

Pathophysiology of critical illness polyneuropathy and myopathy Pathophysiology of CIP and CIM is still poorly understood; however, several microcirculatory, cellular and metabolic events concur to cause the axonal and muscle damage and dysfunction during critical illness (Latronico and Bolton, 2011). These events are potentially reversible (Latronico et al., 1993; Latronico, 2009; Novak et al., 2009), and common to other organ dysfunction, as CIP and CIM do not develop as isolated syndromes, but rather in association with other organ or system dysfunction and failure, such as respiratory, circulatory, renal, hepatic, coagulation, and the central nervous system. There is no direct evidence that peripheral nerve microcirculation is impaired. However, E-selectin expression is present in the vascular endothelium of both epineurial and endoneurial vessels of patients with CIP (Fenzi et al., 2003). E-selectin is not expressed in normal conditions; its activation may increase microvascular nerve permeability, facilitating the passage of neurotoxic factors into the endoneurium and formation of endoneural edema. Axonal degeneration can thus be the consequence of altered endoneurial microenvironment and impaired nerve nutrition (Bolton, 2005). In the rat, an acquired sodium channelopathy with nerve hypoexcitability or inexcitability may cause nerve dysfunction and hence muscle weakness before or possibly even in the absence of axonal degeneration (Novak et al., 2009). Critically ill patients with CIP do have nerve membrane depolarization that is related to endoneurial hyperkalemia and/or hypoxia (Z’Graggen et al., 2006).

1676

Z. ARGOV AND N. LATRONICO

In the muscle, microcirculatory alterations are prominent, particularly in patients with sepsis, in whom the density of perfused capillaries is reduced (De Backer et al., 2002, 2010). Matching of perfusion to metabolic needs is altered, and tissue perfusion and oxygenation are, therefore, compromised. Muscle ATP concentration is reduced suggesting that bioenergetic failure is an important pathophysiologic mechanism (Brealey et al., 2002). Muscle wasting in sepsis is prominent, resulting from increased calpain- and ubiquitin-proteasomemediated muscle protein degradation (Callahan and Supinski, 2009). Since many of the degraded proteins are myofibrillar, this process directly alters the muscle ability to contract (Latronico and Candiani, 1998). Thick myosin filaments are selectively lost, while Z-discs and actin filaments are relatively preserved (Helliwell et al., 1998). The selective loss of myosin causes generalized muscle weakness by reducing the number of motor proteins interacting with the thick filament. Skeletal muscle immobility causes muscle atrophy beginning within hours of bed rest or deep sedation, further enhancing muscle weakness (Kortebein et al., 2007). Acquired sodium channelopathy causing muscle electrical membrane inexcitability is a relevant event also for muscle weakness in ICU patients (Rich et al., 1998; Rich and Pinter, 2003), providing a unifying hypothesis of CIP and CIM as different manifestations of a single disorder (Khan et al., 2008).

(Wilson et al., 1974; Van Wilgenburg, 1979), and are better avoided if prolonged administration of these agents is needed, as in patients with acute respiratory distress syndrome (ARDS) (Papazian et al., 2010). In fact, evidence is now accumulating that the prognosis of ARDS is improved with early administration of neuromuscular blockers. Despite the older notion that NMBA are a major risk factor for the development of ICUAW, this improvement in ARDS prognosis has not been associated with marked increase in resulting weakness. While NMBA may still be contributing to the pathophysiology of ICUAW their early and skilled use should not be avoided.

Unmasking of myasthenia gravis Numerous drugs used in the ICU can interfere with neuromuscular junction transmission and lead to marked weakness (Argov and Mastaglia, 1979). This generalized myasthenic-like weakness involves not only the limb muscles but also the ocular and bulbar musculature. For an unclear reason acute drug induced myasthenia has a predilection for early involvement of the respiratory muscles. The clinical set up at which such NMJ blockade appears may have several circumstances: 1.

Prolonged neuromuscular junction block Prolonged neuromuscular junction (NMJ) block is defined as weakness due to persisting impairment of the synaptic transmission after treatment with neuromuscular blocking agents is terminated. Slowed elimination of competitive, nondepolarizing blockers leading to accumulation of the drugs, due to hepatic or renal pathology, is the main cause of this condition (Segredo et al., 1992). Muscle weakness commonly lasts few hours, but cases of up 42 days duration are documented (Partridge et al., 1990). Most reports that attributed weakness to prolonged neuromuscular block have not included detailed electrophysiologic studies or muscle biopsy to exclude other disorders, and serial assessment of neuromuscular transmission was not routinely performed (Gorson, 2005). Therefore, it is uncertain if prolonged (more than few hours) weakness was really caused by prolonged neuromuscular block or by a superimposed CIP or CIM. Virtually all patients recover completely and a more protracted recovery probably reflects either CIM or CIP, erroneously attributed to prolonged neuromuscular block. High-dose steroids may potentiate the effects of neuromuscular blocking agents with their potential pre- and postsynaptic effect

2.

3.

aggravation of the neuromuscular blocking agents that were administered during surgery. This usually appears as inability to wean off the respiratorassisted ventilation during surgery. This is not similar to the prolonged NMJ block of ICU and usually resolves quickly deterioration of a patient with a disease of the neuromuscular junction (myasthenia or myasthenic syndromes) treated for other conditions or for his basic disease in the ICU unmasking of a previously unknown NMJ defect by the drug. This is a very rare situation but has been described.

The ICU drugs which should be used with extra caution are listed in Table 108.1.

Rhabdomyolysis Rhabdomyolysis in the ICU is rare among the neuromuscular complications. It may occur as a complication of metabolic defect (known or unmasked) but may also be a complication of drug therapy, as in the combined use of ciclosporin and statins after heart transplantation. But special attention should be given to the unusual syndrome of pediatric rhabdomyolysis during ICU treatment for status asthmaticus (Mehta et al., 2006). This is an unusual syndrome of progressive rise of CPK values to extreme levels (>50 000 IU/L) associated at

NEUROMUSCULAR COMPLICATIONS IN INTENSIVE CARE PATIENTS Table 108.1 Drugs which can aggravate neuromuscular junction transmission in the intensive care unit patient Antibiotics Aminoglycosides, polymixin B, clindamycin Drugs with local anesthetic-like action Lidocaine, procainamide, quinidine, phenytoin Calcium channel blockers Magnesium Used for in obstetrics and tetanus treatment b-Blockers Especially propranolol Diuretics (via loss of electrolytes)

times with renal failure. There is no good description of their muscle status but the patients were probably weak with some electromyographic (EMG) evidence of myopathy. Interestingly, patients were under assisted ventilation already prior to the development of the condition which usually started after few days in the ICU and reached a maximum by the second week of hospitalization. These patients received numerous medications but it is hard to attribute the condition to one of them. This form of rhabdomyolysis occurred despite high doses of steroids, which usually reduce CPK levels in a nonspecific way. It must be differentiated from the more common form of CIM in the pediatric population, since it poses extra risk to the kidneys (Banwell et al., 2003). This is especially important as many ICU patients may have a mild to moderate rise in serum CPK during the early phase of the hospitalization (Douglass et al., 1992; De Jonghe et al., 2002), but this finding must be followed to exclude delayed or continuous rise. The borderline between rhabdomyolyis and the acute necrotizing myopathy of intensive care remains to be defined (Ramsay et al., 1993; Zochodne et al., 1994). It should also be noted that elevation of CPK levels may occur in the ICU because of other reasons such as muscle trauma (postcrush syndrome), muscle ischemia (especially in compartment syndrome), and pyomyositis. Another rare cause of marked increase in CPK with rhabdomyolysis is the propofol syndrome. Propofol is a potent hypnotic drug with rapid onset of action, short duration of effect, ability to reduce intracranial pressure and cerebral oxygen consumption, and anticonvulsant properties. As such, propofol is commonly used in the ICU as continuous intravenous infusion for patient sedation. However, high-dose propofol (5 mg/kg/hour) administered for prolonged periods (>48 hours) is associated with a rare and often fatal condition known as propofol infusion syndrome, which is characterized by metabolic acidosis, cardiac and kidney failure, rhabdomyolysis, hyperlipidemia, myoglobinuria, and fatty liver

1677

enlargement (Parke et al., 1992). Uncoupling of the mitochondrial respiratory chain and impaired utilization of fatty acids by mitochondria are key pathophysiologic events explaining this condition (Vasile et al., 2003). Overall, the occurrence of propofol infusion syndrome is low (1.1% of critically ill patients receiving it) (Roberts et al., 2009), but isolated components of the syndrome are frequently observed, particularly in patients with severe head trauma or acute inflammatory syndrome (Vasile et al., 2003). In patients with severe sepsis and multiple organ failure, propofol-related rhabdomyolysis may overlap with acute necrotizing myopathy (Latronico and Bolton, 2011). Prompt recognition of the propofol-induced syndrome is important to reduce the risk of propofol-associated mortality and morbidity, as immediate interruption of propofol administration can abort the syndrome.

Differential diagnosis of intensive care unit-acquired weakness The most important task of the neurologist called to evaluate an ICU patient with generalized weakness is to set a differential diagnosis plan so as not to miss treatable conditions, to understand better the nature of the condition and its prognosis, and to plan further patient care. The list of the main differential diagnoses of ICUAW appears in Table 108.2. First to be excluded are central nervous system disorders that may develop during the patient’s stay in the ICU. Brain pathology is usually associated with disturbed consciousness of such patients. An ICU patient may develop brainstem stroke, which manifests with respiratory failure and quadriplegia. This is more common of course in the elderly patient. Central pontine myelinolysis is a rare but well recorded complication of metabolic derangements during intensive care. Usually it is described in relation to hyponatremia but may occur in other situations and was recorded after liver transplantation without such biochemical abnormalities. In the awake patient with weakness affecting only the lower limbs one should look for spinal cord conditions; however, quadriplegia may also result from various acute myelopathies. Sensory level and marked difference between lower limb weakness and upper limb power should alert the clinician to this possibility. Compression from an ICU-acquired event (e.g., epidural abscess), inflammatory (postinfection acute transverse myelitis) and even vascular diseases (e.g., anterior spinal artery thrombosis due to coagulation disorders) should be evaluated with proper imaging and other diagnostic techniques. Metabolic impairments such as hypokalemia, hypermagnesemia, and hyophosphatemia should always be sought in the ICU weak patient with reduced reflexes

1678

Z. ARGOV AND N. LATRONICO

Table 108.2 Differential diagnosis of ICU-acquired weakness (ICUAW) Brain disorders Brainstem infarcts Brainstem encephalitis Central pontine myelinolysis Spinal cord and anterior horn disorders Anterior spinal artery infarct Acute transverse myelitis (immune-mediated) Infective myelitis (West Nile, polio, cytomegalovirus, HIV) Postinfective myelitis (zoster, West Nile) Acute spinal cord compression (epidural abscess, metastasis) Hopkins syndrome Neuropathies Critical illness polyneuropathy Guillain–Barre´ syndrome and postinfective and paraneoplastic radiculitis Toxic neuropathy Porphyria Phrenic neuropathy (idiopathic) Infective radiculitis (cytomegalovirus) Lymphomatous and carcinomatous infiltration Vasculitic neuropathy Neuromuscular junction diseases Myasthenia gravis and myasthenic syndromes Prolonged neuromuscular blockade Hypermagnesemia Myopathies Critical illness myopathy Drug-induced rhabdomyolysis Myositis and pyomyositis Toxic myopathies Metabolic myopathies, unmasked (carnitine palmityl transferase (CPT), mitochondrial) Compartment syndrome Propofol syndrome Unmasking of subclinical myopathy Cachexia and disuse General medical conditions Electrolyte disturbances (hyponateremia, hypokalemia, hypophosphatemia) Paraneoplastic disorders of peripheral and central nervous system

and no sensory deficiency. High CPK levels will clearly point toward a myopathic condition. The most important next test in the evaluation of the weak ICU patient is the electrophysiologic evaluation, mainly the nerve stimulation studies, which not only help in determining the neuropathic basis of the patient’s weakness but may point toward possible other causes. If a patient has a neuropathy it should be determined whether it is an axonal or a demyelinating type. The latter is not typical for the ICU-acquired conditions and suggests other diagnoses. Guillain–Barre´ syndrome (GBS)

may occur after an infection that was acquired in the ICU or led to the ICU hospitalization. A well-recognized example of this situation is West Nile virus infection. West Nile fever may first lead to encephalitis and reduced consciousness but once this phase is established paralysis maybe found and several postviral GBS cases have been recently recorded after an epidemic of this viral disease (Nash et al., 2001; Jeha et al., 2003). There are some reports of surgery (Aranason and Soliven, 1993) or epidural anesthesia (Steiner et al., 1985) triggering GBS. Porphyria, with resulting GBS-like neuropathy, can also be precipitated by severe disease or medications used in the ICU. Other causes of neuropathy may be related to drug therapy although this is rare (unless chemotherapy for oncologic conditions was used). Myopathy in the ICU may be the result of toxic reactions to medication (e.g., to statin therapy with a combination of other drugs, such as ciclosporin to prevent rejection, that are also metabolized by the P450 system). Myositis may develop in an ICU patient with other autoimmune disorders (e.g., systemic lupus erythematosus). Compression muscle damage is now very rare in ICU patients due to aggressive position changes and better care of the immobilized patient. However, compartment syndrome, especially of the anterior portion of the calf, can still occur as a result of edema or compression by medical devices used to prevent venous stasis. Weakness is usually limited but the rise in CPK levels may be very high due to severe muscle necrosis. Early recognition (not trivial in the comatose patient) is of high importance to prevent permanent muscle damage. Many drugs used in the ICU have neuromuscular blocking properties, which may lead to weakness in the patient due to impaired transmission at the neuromuscular synapse (e.g., aminoglycosides, b-blockers). Such medications may show more blocking when electrolyte disturbances are present too or rarely may unmask a myasthenic condition (Argov and Mastaglia, 1979). In general, the ICU hospitalization may unmask other neuromuscular disorders such as metabolic myopathies. Fever may precipitate myoglobinuria in a patient with carnitine palmityl transferase deficiency. Any serious disease may lead to a first ever lactic acidosis crisis in a patient with mitochondrial cytopathy (especially in children, e.g., Leigh’s disease). Acute infection may lead to respiratory failure in subclinical myopathies such as acid maltase deficiency (Rosenow and Engel, 1978).

Diagnostic methods in intensive care unit-acquired weakness NERVE STIMULATION STUDIES Determining the conduction features of both motor and sensory nerves is a very important diagnostic test in

NEUROMUSCULAR COMPLICATIONS IN INTENSIVE CARE PATIENTS ICUAW. However, these studies are hard to perform in the ICU environment with electrical interference from other equipment and patients who are not easy to handle (although these tests can be done without patients’ cooperation). Simplified electrophysiologic evaluation of the peroneal nerve shows promise as a rapid, highly sensitive diagnostic test for CIP (Latronico et al., 2007). Abnormal findings in nerve stimulation studies may be an early feature in the ICU patient and may appear as early as 72 hours after the onset of the ICU hospitalization (Khan et al., 2006). Changes can even be of sudden onset within 24 hours after a normal electrophysiology evaluation (Latronico et al., 2007). Nerve conduction studies in CIP will show a reduction in amplitude of both compound muscle action potentials (CMAP) and sensory nerve action potentials with normal or only mildly reduced nerve conduction velocity (Bolton et al., 1986). CMAP duration is not significantly prolonged. Distal motor latencies are usually prolonged resulting in a general conclusion of “axonal” neuropathy. In CIM, nerve stimulation tests are also informative: there is a reduction in the amplitude of CMAPs and an increase in their duration. The prolongation of CMAP is an important diagnostic sign of CIM (Bolton, 2000; Allen et al., 2008; Goodman et al., 2009). Such a change is not observed in the axonal neuropathy of CIP but may result from other ICU related disorders leading to demyelinating neuropathies (Latronico and Bolton, 2011). The latter, however, are usually associated with marked slowing of motor conduction. Normal sensory potentials are the rule in pure CIM (Lacomis et al., 2000). Attention has been drawn to a unique feature of CIM: reduced muscle excitability on direct stimulation (Rich et al., 1996, 1997, 1998; Trojaborg et al., 2001; Lefaucheur et al., 2006). Normally the CMAP should be of the same amplitude whether the nerve or the muscle is stimulated and recording is made from the same site. If the nerve is affected then the muscle response to direct stimulation will be bigger than that evoked by nerve stimulation. In reduced muscle membrane excitability the nerve stimulation should yield a higher CMAP. It is now suggested that if the ratio of the CMAP amplitude after nerve stimulation to the muscle response upon direct stimulation is bigger than 0.5, CIM should be considered as the cause of ICUAW (Trojaborg et al., 2001). The technique used for this test requires skilled personnel. Repetitive nerve stimulation at 3 Hz (preferably at distal and proximal sites) in a search for possible decrement of CMAP amplitude is an important part of the evaluation of the severely weak ICU patient. It is especially indicated when routine conduction studies do not give a clear diagnosis of neuropathy or suspected myopathy and may be the only clue to the existence of

1679

a neuromuscular junction transmission defect. It is also of high importance when ocular or bulbar muscles are affected. In prolonged neuromuscular block, repetitive nerve stimulation demonstrates the characteristic decremental CMAP amplitude response. If, however, neuromuscular block is complete the CMAP may be absent, simulating CIP or CIM. The presence of normal sensory potentials and serial measurements is helpful in clarifying the diagnosis.

EMG Fibrillation potentials and positive sharp waves are seen in both CIP and CIM, representing either the acute denervation or the necrotizing myopthic changes. The presence of spontaneous activity in myopathy is thought to be the result of functional disconnection of the muscle fiber from its nerve end plate (Zochodne et al., 1994; Hund, 1999). Motor unit potentials are hard to quantify in the ICU because the patient’s cooperation may not be full. Thus, EMG is not helpful in distinguishing between CIM and CIP (Latronico et al., 2009). Spontaneous activity tends to disappear during recovery with an increase in motor unit amplitudes and recruitment.

MUSCLE AND NERVE BIOPSY Muscle biopsy is currently an important research tool for understanding ICUAW but its importance as a diagnostic test remains to be determined. It is now suggested that there are three types of muscle pathology associated with the CIM syndrome. However, it is not clear whether these are part of a spectrum of muscle pathology under ICU conditions or represent a different disease process (Latronico and Bolton, 2011). The first and least specific is type 2 fiber atrophy (Gutmann et al., 1996), which probably results from the disuse and undernutrition of the patient (and possibly also from an additional neuropathic component). Necrotizing myopathy, with fibers undergoing active necrosis and regeneration, is frequently demonstrated in muscle biopsies, especially in those with marked elevation of CPK levels (Ramsay et al., 1993; Zochodne et al., 1994). Inflammatory cell infiltration is uncommon (Bolton et al., 1984; Latronico et al., 1996). If present, other diagnoses should be considered. The most typical histologic finding for CIM is thick filament (myosin) loss (Sher et al., 1979; Danon and Carpenter, 1991; Helliwell et al., 1998). It is expressed in loss of central stain in ATPase stain (“doughnut appearance”) of fibers with classic loss of striated muscle structure on electron microscopy (mainly disappearance of the A band) (Hirano et al., 1992). Immunohistologic studies (Showalter and Engel, 1997; Matsumoto et al., 2000) and molecular evaluation (Larsson et al., 2000)

1680 Z. ARGOV AND N. LATRONICO have shown that the loss of thick filaments is due to selecmajority of patients, usually in 3–6 months (although tive myosin loss. Loss of myosin filaments can be easily CIM can also lead to incomplete recovery). In the CRIMdemonstrated by electrophoretic separation of myofibrilYNE study (Guarneri et al., 2008), patients with CIM lar proteins and measurement of myosin/actin ratio, recovered within 6 months, whereas those with CIP which is greatly reduced in this type of CIM (Stibler had a slower recovery, or did not recover at all. Mortality et al., 2003). This histologic picture is practically only may be also increased in patients with CIP (Leijten et al., recorded in CIM (although it was described in other rare 1995; Garnacho-Montero et al., 2001). conditions that are not relevant to the ICU), thus it is To date, there is no specific therapy for CIP or CIM thought to be a good marker of the disease. (Hermans et al., 2009). Nutritional, antioxidant, hormonal In CIP muscle histology will give evidence of acute therapy and immunoglobulins have all failed to show condenervation with atrophy of both type 1 and type 2 fibers. sistent benefit. Daily sessions of electrical muscle stimuDuring recovery muscle biopsy can demonstrate group lation is feasible in the ICU (Routsi et al., 2010), but its atrophy, but is rarely performed at this stage. efficacy in reducing muscle weakness still awaits convincNerve biopsy is rarely indicated in ICU patients unless ing evidence (Ali, 2010; Poulsen et al., 2011). Intensive another diagnosis is suspected for the evolving neuropinsulin therapy (IIT) titrated to maintain normal blood athy (e.g., vasculitis). It may show signs of axonal neuglucose level throughout the ICU stay has been shown ropathy if performed late in CIP (Latronico et al., 1996). in randomized controlled trials to reduce the incidence of electrophysiologically proven CIP (using denervation OTHER LABORATORY TESTS IN INTENSIVE CARE potentials as the sole diagnostic criterion) both in surgical UNIT-ACQUIRED WEAKNESS (Van den Berghe et al., 2005) and medical ICU patients (Hermans et al., 2007). The risk of CIP was almost halved Serial measurement of CPK can be of value to follow in (risk ratio 0.65; 95% confidence interval 0.55–0.77) when ICUAW. High values (>5 times the upper limit of normal blood glucose could be maintained tightly normal during range) clearly indicate a necrotic myopathy and point the ICU stay (Hermans et al., 2009). IIT also reduced the toward one of the forms of CIM or to another condition. duration of mechanical ventilation, whereas no data are Milder increases in levels are not of diagnostic value. available on the effects of IIT on limb muscle strength About 75% of asthma patients receiving assisted ventilaand function (Stevens et al., 2009). Severe hypoglycemia tion had high CK values already 4 days after the admission is a frequent complication of IIT aiming at normoglyce(Douglass et al., 1992). CPK levels may mildly increase in mia that has been associated with slightly but significantly patients on mechanical ventilation of more than a week increased mortality (Finfer et al., 2009). Thus, this treateven without ICUAW (De Jonghe et al., 2002). ment is no longer recommended (Qaseem et al., 2011). Measurements of serum electrolytes (in particular Future studies should establish the optimal blood glucose magnesium, potassium, and phosphate) is of major level to prevent or treat CIP. importance in the differential diagnosis. Prolonged immobility may exacerbate CIP or CIM. Respiratory muscle strength can be tested by measurPassive limb muscle stretching may reduce muscle atroing the maximal inspiratory and expiratory pressures phy (Griffiths et al., 1995), and active exercises with physand vital capacity. Low values are correlated with limb ical and occupational therapy may increase functional muscle weakness, and are associated with delayed extuindependence (Schweickert et al., 2009). Recent research bation, prolonged ventilation (De Jonghe et al., 2007) emphasizes the cardinal importance of early mobilization and unplanned ICU readmission (Latronico et al., 1999). in facilitating the recovery of ICU patients and reducing their weakness. The evidence for this therapeutic Outcome and prognosis approach has recently been reviewed (Lipshutz and CIP and CIM are responsible for prolonged and at times Gropper, 2013). Therefore, it seems reasonable that stratsevere disability after critical illness. There is strong eviegies to mobilize patients are implemented early on in the dence that both conditions (or a combined one) may ICU. At the least, sedation protocols that minimize doscause persistent weakness for months or even years after ages as much as possible should be considered, as they resolution of the critical illness (Leijten et al., 1995; may decrease the duration of mechanical ventilation, Zifko, 2000; Fletcher et al., 2003; Guarneri et al., impaired consciousness, delirium, and ICU and hospital 2008; Intiso et al., 2011). As a consequence, 28% of stay (Kress et al., 2000; Girard et al., 2008; Strom et al., patients with CIP, CIM, or both may not recover inde2010). A coordinated approach to daily awakening and pendent walking or persistent spontaneous ventilation spontaneous breathing trial, delirium assessment and (Latronico et al., 2005b). early exercise in critically ill, mechanically ventilated CIP is the main contributor to permanent disability, patients may reduce the burden of both delirium and while CIM is associated with complete recovery in the muscle weakness (Vasilevskis et al., 2010).

NEUROMUSCULAR COMPLICATIONS IN INTENSIVE CARE PATIENTS

INTENSIVE CARE UNIT-ACQUIRED FOCAL WEAKNESS Focal amyotrophy Polio-like disease was described in several patients recovering from West Nile virus infection. Unlike the more general GBS-like disease, this condition shows segmental, often asymmetric weakness with marked atrophy (Leis et al., 2002, 2003; Li et al., 2003). It is usually noticed when the patient is at the recovery phase from a more severe disease but can certainly be detected in the ICU if the hospitalization is prolonged. A very rarely reported condition is acute postasthmatic amyotrophic syndrome or Hopkins’ syndrome (Hopkins, 1974; Liedholm et al., 1994). It was mainly reported after a severe asthmatic bout in children, although some adults developed a similar condition. This manifests with acute flaccid monoparesis (or even paraparesis) with neurogenic EMG and muscle histology. The cause of this condition is unknown but suspected to be immunogenic based on “inflammatory” CSF and response in intravenous immunoglobulin (IVIG) treatment (Cohen et al., 1998).

Pressure palsy ICU patients may develop nerve palsy due to prolonged pressure. This could be positional or induced by a medical device. Intermittent pneumatic compression device has been associated with peroneal palsy (Lachmann et al., 1992). The typical sites for pressure palsies are the peroneal nerve around the fibular head causing foot drop; the ulnar nerve at the elbow leading to sensory impairment on the 4–5 digits and at times to small hand muscle weakness; and the peroneal nerve leading to secondary damage in anterior compartment syndrome induced in the ICU. Meticulous care in changing position should prevent many such complications.

Phrenic neuropathy This is not necessarily an ICU-related complication but may be revealed when investigating the patient with inability to wean from a respirator. Diaphragmatic paralysis can result from many different etiologies; some of them may bring the patient to the ICU (trauma, compression and surgical-related damage) and not be the result of it (Qureshi, 2009). But some of the reported causes may appear during the ICU stay (e.g., postinflammatory isolated phrenic nerve damage). It is believed that few people have idiopathic isolated diaphragmatic paresis, which goes unnoticed during regular living conditions but may be emerging in the ICU. However, there have been several reports of patients that developed this focal nerve lesion

1681

during their ICU hospitalization and it is thought to represent a localized form of ICU neuropathy. Transient phrenic nerve paralysis has been recorded in pediatric and adult patients recovering from status asthmaticus, which can be unilateral or bilateral (Rohatgi et al., 1980; Hillerdal, 1983; Santuz et al., 2004). This rare complication is often transient but will prolong the need for assisted ventilation. A method to follow the development of diaphragmatic weakness in ICU by using magnetic stimulation of the phrenic nerve in the neck has been suggested (Watson et al., 2001) but is not a common procedure.

Needle damage ICU patients are usually given intavenous (IV) medications but in some instances the intramuscular (IM) route is sought. Very rarely this can lead to mechanical damage to a peripheral nerve close to the injection site, usually the sciatic nerve during IM injection in the gluteal area (Small, 2004). The damage to the nerve can result from several mechanisms: direct physical injury to the nerve with a section of fibers, compression by the injected volume of the drug, and toxic effect of the injected substance. Microsurgery in the pediatric group was suggested (Senes et al., 2009), but no controlled studies are available to assess this approach. Venipuncture is also not fully safe and there are series reports of nerve damage in the proximity of this procedure (Berry and Wallis, 1977; Horowitz, 1994; Sander et al., 1998). Arterial puncture in the elbow region or the wrist can also result in nerve lesion (Watson, 1995).

SUMMARY ICUAW can be caused by many disorders of various etiologies. The more frequent disorders, CIP, CIM, or the combined condition, are of major importance to the modern management of ICU patients and pose a challenge to all physicians and researchers dealing with these conditions as they have a major impact on the course, survival, and sequelae of ICU stay. While some pathophysiologic mechanisms have already been elucidated, the full understanding of the spectrum of causes of generalized ICU-associated weakness remains to be identified. Controlled therapeutic interventional studies are highly required to prevent or rehabilitate ICUAW.

REFERENCES Ali NA (2010). Have we found the prevention for intensive care unit-acquired paresis? Crit Care 14: 160. Ali NA, O’Brien JM Jr, Hoffmann SP et al. (2008). Acquired weakness handgrip strength and mortality in critically ill patients. Am J Respir Crit Care Med 178: 261–268. Allen DC, Arunachalam R, Mills KR (2008). Critical illness myopathy: further evidence from muscle-fiber excitability

1682

Z. ARGOV AND N. LATRONICO

studies of an acquired channelopathy. Muscle Nerve 37: 14–22. Aranason BGW, Soliven B (1993). Acute inflammatory demyelinating polyneuropathy. In: PJ Dyck, PK Thomas, JW Griffin, PA Low, JF Podulso (Eds.), Peripheral Neuropathy. WB Saunders, Philadelphia, pp. 1437–1497. Argov Z, Mastaglia FL (1979). Drug therapy: disorders of neuromuscular transmission caused by drugs. N Engl J Med 301: 409–413. Banwell BL, Mildner RJ, Hassall AC et al. (2003). Muscle weakness in critically ill children. Neurology 61: 1779–1782. Bednarik J, Lukas Z, Vondracek P (2003). Critical illness polyneuromyopathy: the electrophysiological components of a complex entity. Intensive Care Med 29: 1505–1514. Bednarik J, Vondracek P, Dusek L et al. (2005). Risk factors for critical illness polyneuromyopathy. J Neurol 252: 343–351. Bercker S, Weber-Carstens S, Deja M et al. (2005). Critical illness polyneuropathy and myopathy in patients with acute respiratory distress syndrome. Crit Care Med 33: 711–715. Berry PR, Wallis WE (1977). Venepuncture nerve injuries. Lancet 1: 1236–1237. Bolton CF (2000). Evidence of neuromuscular dysfunction in the early stages of the systemic inflammatory response syndrome. Intensive Care Med 26: 1179–1180. Bolton CF (2005). Neuromuscular manifestations of critical illness. Muscle Nerve 32: 140–163. Bolton CF (2010). The discovery of critical illness polyneuropathy: a memoir. Can J Neurol Sci 37: 431–438. Bolton CF, Gilbert JJ, Hahn AF et al. (1984). Polyneuropathy in critically ill patients. J Neurol Neurosurg Psychiatry 47: 1223–1231. Bolton CF, Laverty DA, Brown JD et al. (1986). Critically ill polyneuropathy: electrophysiological studies and differentiation from Guillain–Barre´ syndrome. J Neurol Neurosurg Psychiatry 49: 563–573. Bolton CF, Young GB, Zochodne DW (1993). The neurological complications of sepsis. Ann Neurol 33: 94–100. Brealey D, Brand M, Hargreaves I et al. (2002). Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360: 219–223. Burtin C, Clerckx B, Robbeets C et al. (2009). Early exercise in critically ill patients enhances short-term functional recovery. Crit Care Med 37: 2499–2505. Callahan LA, Supinski GS (2009). Sepsis-induced myopathy. Crit Care Med 37: S354–S367. Coakley JH, Nagendran K, Yarwood GD et al. (1998). Patterns of neurophysiological abnormality in prolonged critical illness. Intensive Care Med 24: 801–807. Cohen HA, Ashkenasi A, Ring H et al. (1998). Poliomyelitislike syndrome following asthmatic attack (Hopkins’ syndrome) – recovery associated with IV gamma globulin treatment. Infection 26: 247–249. Danon MJ, Carpenter S (1991). Myopathy with thick filament (myosin) loss following prolonged paralysis with vecuronium during steroid treatment. Muscle Nerve 14: 1131–1139.

De Backer D, Creteur J, Preiser JC et al. (2002). Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 166: 98–104. De Backer D, Ospina-Tascon G, Salgado D et al. (2010). Monitoring the microcirculation in the critically ill patient: current methods and future approaches. Intensive Care Med 36: 1813–1825. De Jonghe B, Sharshar T, Lefaucheur JPA et al. (2002). Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA 288: 2859–2867. De Jonghe B, Bastuji-Garin S, Durand MC et al. (2007). Respiratory weakness is associated with limb weakness and delayed weaning in critical illness. Crit Care Med 35: 2007–2015. Deconinck N, Van Parijs V, Beckers-Bleukx G et al. (1998). Critical illness myopathy unrelated to corticosteroids or neuromuscular blocking agents. Neuromuscul Disord 8: 186–192. Derde S, Hermans G, Derese I et al. (2012). Muscle atrophy and preferential loss of myosin in prolonged critically ill patients. Crit Care Med 40: 79–89. Douglass JA, Tuxen DV, Horne M et al. (1992). Myopathy in severe asthma. Am Rev Respir Dis 146: 517–519. Fenzi F, Latronico N, Refatti N et al. (2003). Enhanced expression of E-selectin on the vascular endothelium of peripheral nerve in critically ill patients with neuromuscular disorders. Acta Neuropathol (Berl) 106: 75–82. Finfer S, Chittock DR, Su SY et al. (2009). Intensive versus conventional glucose control in critically ill patients. N Engl J Med 360: 1283–1297. Fletcher SN, Kennedy DD, Ghosh IR et al. (2003). Persistent neuromuscular and neurophysiologic abnormalities in long-term survivors of prolonged critical illness. Crit Care Med 31: 1012–1016. Garnacho-Montero J, Madrazo-Osuna J, Garcia-Garmendia JL et al. (2001). Critical illness polyneuropathy: risk factors and clinical consequences. A cohort study in septic patients. Intensive Care Med 27: 1288–1296. Girard TD, Kress JP, Fuchs BD et al. (2008). Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 371: 126–134. Goodman BP, Harper CM, Boon AJ (2009). Prolonged compound muscle action potential duration in critical illness myopathy. Muscle Nerve 40: 1040–1042. Gorson KC (2005). Approach to neuromuscular disorders in the intensive care unit. Neurocrit Care 3: 195–212. Griffiths RD, Palmer TE, Helliwell T et al. (1995). Effect of passive stretching on the wasting of muscle in the critically ill. Nutrition 11: 428–432. Guarneri B, Bertolini G, Latronico N (2008). Long-term outcome in patients with critical illness myopathy or neuropathy: the Italian multicentre CRIMYNE study. J Neurol Neurosurg Psychiatry 79: 838–841. Gutmann L, Blumenthal D, Gutmann L et al. (1996). Acute type II myofiber atrophy in critical illness. Neurology 46: 819–821.

NEUROMUSCULAR COMPLICATIONS IN INTENSIVE CARE PATIENTS Helliwell TR, Wilkinson A, Griffiths RD et al. (1998). Muscle fibre atrophy in critically ill patients is associated with the loss of myosin filaments and the presence of lysosomal enzymes and ubiquitin. Neuropathol Appl Neurobiol 24: 507–517. Hermans G, Wilmer A, Meersseman W et al. (2007). Impact of intensive insulin therapy on neuromuscular complications and ventilator dependency in the medical intensive care unit. Am J Respir Crit Care Med 175: 480–489. Hermans G, De Jonghe B, Bruyninckx F et al. (2009). Interventions for preventing critical illness polyneuropathy and critical illness myopathy. Cochrane Database Syst Rev CD006832. Herridge MS, Cheung AM, Tansey CM et al. (2003). One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 348: 683–693. Herridge MS, Tansey CM, Matte A et al. (2011). Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 364: 1293–1304. Hillerdal G (1983). Idiopathic diaphragmatic paralysis and asthma bronchiale. Respiration 44: 234–236. Hirano M, Ott BR, Raps EC et al. (1992). Acute quadriplegic myopathy: a complication of treatment with steroids nondepolarizing blocking agents or both. Neurology 42: 2082–2087. Hoke A, Rewcastle NB, Zochodne DW (1999). Acute quadriplegic myopathy unrelated to steroids or paralyzing agents: quantitative EMG studies. Can J Neurol Sci 26: 325–329. Hopkins IJ (1974). A new syndrome: poliomyelitis-like illness associated with acute asthma in childhood. Aust Paediatr J 10: 273–276. Horowitz SH (1994). Peripheral nerve injury and causalgia secondary to routine venipuncture. Neurology 44: 962–964. Hough CL, Steinberg KP, Taylor Thompson B et al. (2009). Intensive care unit-acquired neuromyopathy and corticosteroids in survivors of persistent ARDS. Intensive Care Med 35: 63–68. Hund E (1999). Myopathy in critically ill patients. Crit Care Med 27: 2544–2547. Intiso D, Amoruso L, Zarrelli M et al. (2011). Long-term functional outcome and health status of patients with critical illness polyneuromyopathy. Acta Neurol Scand 123: 211–219. Jaber S, Petrof BJ, Jung B et al. (2011). Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans. Am J Respir Crit Care Med 183: 364–371. Jeha LE, Sila CA, Lederman RJ et al. (2003). West Nile virus infection: a new acute paralytic illness. Neurology 61: 55–59. Kaplan PW, Rocha W, Sanders DB et al. (1986). Acute steroidinduced tetraplegia following status asthmaticus. Pediatrics 78: 121–123. Khan J, Harrison TB, Rich MM et al. (2006). Early development of critical illness myopathy and neuropathy in patients with severe sepsis. Neurology 67: 1421–1425. Khan J, Harrison TB, Rich MM (2008). Mechanisms of neuromuscular dysfunction in critical illness. Crit Care Clin 24: 165–177.

1683

Koch S, Spuler S, Deja M et al. (2011). Critical illness myopathy is frequent: accompanying neuropathy protracts ICU discharge. J Neurol Neurosurg Psychiatry 82: 287–293. Kortebein P, Ferrando A, Lombeida J et al. (2007). Effect of 10 days of bed rest on skeletal muscle in healthy older adults. JAMA 297: 1772–1774. Kress JP, Pohlman AS, O’Connor MF et al. (2000). Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 342: 1471–1477. Lachmann EA, Rook JL, Tunkel R et al. (1992). Complications associated with intermittent pneumatic compression. Arch Phys Med Rehabil 73: 482–485. Lacomis D, Zochodne DW, Bird SJ (2000). Critical illness myopathy. Muscle Nerve 23: 1785–1788. Larsson L, Li X, Edstrom L et al. (2000). Acute quadriplegia and loss of muscle myosin in patients treated with nondepolarizing neuromuscular blocking agents and corticosteroids: mechanisms at the cellular and molecular levels. Crit Care Med 28: 34–45. Latronico N (2003). Neuromuscular alterations in the critically ill patient: critical illness myopathy critical illness neuropathy or both? Intensive Care Med 29: 1411–1413. Latronico N (2009). Axonal inexcitability and axonal degeneration: two sides of the same coin. J Clin Invest 119: Eletter. http://wwwjciorg/eletters/view/36570. Latronico N, Bolton CF (2011). Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis in the critically ill patient. Lancet Neurol 10: 931–941. Latronico N, Candiani A (1998). Muscular wasting as a consequence of sepsis. In: A Gullo (Ed.), Anaesthesia Pain Intensive Care and Emergency Medicine APICE. 13th edn. Springer-Verlag, Milan, pp. 517–522. Latronico N, Fenzi F, Boniotti C et al. (1993). Acute reversible paralysis in critically ill patients. Acta Anaesthesiol Ital 44: 157–171. Latronico N, Fenzi F, Recupero D et al. (1996). Critical illness myopathy and neuropathy. Lancet 347: 1579–1582. Latronico N, Guarneri B, Alongi S et al. (1999). Acute neuromuscular respiratory failure after ICU discharge. Report of five patients. Intensive Care Med 25: 1302–1306. Latronico N, Peli E, Botteri M (2005a). Critical illness myopathy and neuropathy. Curr Opin Crit Care 11: 126–132. Latronico N, Shehu I, Seghelini E (2005b). Neuromuscular sequelae of critical illness. Curr Opin Crit Care 11: 381–390. Latronico N, Bertolini G, Guarneri B et al. (2007). Simplified electrophysiological evaluation of peripheral nerves in critically ill patients: the Italian multi-centre CRIMYNE study. Crit Care 11: R11. Latronico N, Shehu I, Guarneri B (2009). Use of electrophysiologic testing. Crit Care Med 37: S316–S320. Lefaucheur JP, Nordine T, Rodriguez P et al. (2006). Origin of ICU acquired paresis determined by direct muscle stimulation. J Neurol Neurosurg Psychiatry 77: 500–506. Leijten FS, Harinck-De Weerd JE, Poortvliet DC et al. (1995). The role of polyneuropathy in motor convalescence after prolonged mechanical ventilation. JAMA 274: 1221–1225.

1684

Z. ARGOV AND N. LATRONICO

Leis AA, Stokic DS, Polk JL et al. (2002). A poliomyelitis-like syndrome from West Nile virus infection. N Engl J Med 347: 1279–1280. Leis AA, Fratkin J, Stokic DS et al. (2003). West Nile poliomyelitis. Lancet Infect Dis 3: 9–10. Li J, Loeb JA, Shy MES et al. (2003). Asymmetric flaccid paralysis: a neuromuscular presentation of West Nile virus infection. Ann Neurol 53: 703–710. Liedholm LJ, Eeg-Olofsson O, Ekenberg BE et al. (1994). Acute postasthmatic amyotrophy (Hopkins’ syndrome). Muscle Nerve 17: 769–772. Lipshutz AK, Gropper MA (2013). Acquired neuromuscular weakness and early mobilization in the intensive care unit. Anesthesiology 118: 202–215. Macfarlane IA, Rosenthal FD (1977). Severe myopathy after status asthmaticus. Lancet 310: 615. Matsumoto N, Nakamura T, Yasui Y et al. (2000). Analysis of muscle proteins in acute quadriplegic myopathy. Muscle Nerve 23: 1270–1276. Mehta R, Fisher LE Jr, Segeleon JE et al. (2006). Acute rhabdomyolysis complicating status asthmaticus in children: case series and review. Pediatr Emerg Care 22: 587–591. Nanas S, Kritikos K, Angelopoulos ES et al. (2008). Predisposing factors for critical illness polyneuromyopathy in a multidisciplinary intensive care unit. Acta Neurol Scand 118: 175–181. Nash D, Mostashari F, Fine A et al. (2001). The outbreak of West Nile virus infection in the New York City area in 1999. N Engl J Med 344: 1807–1814. Novak KR, Nardelli P, Cope TC et al. (2009). Inactivation of sodium channels underlies reversible neuropathy during critical illness in rats. J Clin Invest 119: 1150–1158. Op De Coul AA, Lambregts PC, Koeman J et al. (1985). Neuromuscular complications in patients given Pavulon (pancuronium bromide) during artificial ventilation. Clin Neurol Neurosurg 87: 17–22. Pandharipande P, Cotton BA, Shintani A et al. (2007). Motoric subtypes of delirium in mechanically ventilated surgical and trauma intensive care unit patients. Intensive Care Med 33: 1726–1731. Papazian L, Forel JM, Gacouin A et al. (2010). Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 363: 1107–1116. Parke TJ, Stevens JE, Rice AS et al. (1992). Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports. BMJ 305: 613–616. Partridge BL, Abrams JH, Bazemore C et al. (1990). Prolonged neuromuscular blockade after long-term infusion of vecuronium bromide in the intensive care unit. Crit Care Med 18: 1177–1179. Poulsen JB, Moller K, Jensen CV et al. (2011). Effect of transcutaneous electrical muscle stimulation on muscle volume in patients with septic shock. Crit Care Med 39: 456–461. Qaseem A, Humphrey LL, Chou R et al. (2011). Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med 154: 260–267.

Qureshi A (2009). Diaphragm paralysis. Semin Respir Crit Care Med 30: 315–320. Ramsay DA, Zochodne DW, Robertson DM et al. (1993). A syndrome of acute severe muscle necrosis in intensive care unit patients. J Neuropathol Exp Neurol 52: 387–398. Rich MM, Pinter MJ (2003). Crucial role of sodium channel fast inactivation in muscle fibre inexcitability in a rat model of critical illness myopathy. J Physiol 547: 555–566. Rich MM, Teener JW, Raps EC et al. (1996). Muscle is electrically inexcitable in acute quadriplegic myopathy. Neurology 46: 731–736. Rich MM, Bird SJ, Raps EC et al. (1997). Direct muscle stimulation in acute quadriplegic myopathy. Muscle Nerve 20: 665–673. Rich MM, Pinter MJ, Kraner SD et al. (1998). Loss of electrical excitability in an animal model of acute quadriplegic myopathy. Ann Neurol 43: 171–179. Roberts RJ, Barletta JF, Fong JJS et al. (2009). Incidence of propofol-related infusion syndrome in critically ill adults: a prospective multicenter study. Crit Care 13: R169. Rohatgi N, Fields A, Sly RM (1980). Status asthmaticus complicated by transient phrenic nerve paralysis. Ann Allergy 45: 177–179. Rosenow EC 3rd, Engel AG (1978). Acid maltase deficiency in adults presenting as respiratory failure. Am J Med 64: 485–491. Routsi C, Gerovasili V, Vasileiadis I et al. (2010). Electrical muscle stimulation prevents critical illness polyneuromyopathy: a randomized parallel intervention trial. Crit Care 14: R74. Sander HW, Conigliari MF, Masdeu JC (1998). Antecubital phlebotomy complicated by lateral antebrachial cutaneous neuropathy. N Engl J Med 339: 2024. Santuz P, Piccoli A, Zaglia F et al. (2004). Transient phrenic nerve paralysis associated with status asthmaticus. Pediatr Pulmonol 38: 269–271. Schweickert WD, Pohlman MC, Pohlman AS et al. (2009). Early physical and occupational therapy in mechanically ventilated critically ill patients: a randomised controlled trial. Lancet 373: 1874–1882. Segredo V, Caldwell JE, Matthay MA et al. (1992). Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med 327: 524–528. Senes FM, Campus R, Becchetti F et al. (2009). Upper limb nerve injuries in developmental age. Microsurgery 29: 529–535. Sher JH, Shafiq SA, Schutta HS (1979). Acute myopathy with selective lysis of myosin filaments. Neurology 29: 100–106. Showalter CJ, Engel AG (1997). Acute quadriplegic myopathy: analysis of myosin isoforms and evidence for calpain-mediated proteolysis. Muscle Nerve 20: 316–322. Sitwell LD, Weinshenker BG, Monpetit V et al. (1991). Complete ophthalmoplegia as a complication of acute corticosteroid- and pancuronium-associated myopathy. Neurology 41: 921–922. Small SP (2004). Preventing sciatic nerve injury from intramuscular injections: literature review. J Adv Nurs 47: 287–296.

NEUROMUSCULAR COMPLICATIONS IN INTENSIVE CARE PATIENTS Steiner I, Argov Z, Cahan C et al. (1985). Guillain-Barre´ syndrome after epidural anesthesia: direct nerve root damage may trigger disease. Neurology 35: 1473–1475. Stevens RD, Dowdy DW, Michaels RK et al. (2007). Neuromuscular dysfunction acquired in critical illness: a systematic review. Intensive Care Med 33: 1876–1891. Stevens RD, Marshall SA, Cornblath DR et al. (2009). A framework for diagnosing and classifying intensive care unitacquired weakness. Crit Care Med 37 (Suppl): 299–308. Stibler H, Edstrom L, Ahlbeck K et al. (2003). Electrophoretic determination of the myosin/actin ratio in the diagnosis of critical illness myopathy. Intensive Care Med 29: 1515–1527. Strom T, Martinussen T, Toft P (2010). A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial. Lancet 375: 475–480. Tennila A, Salmi T, Pettila V et al. (2000). Early signs of critical illness polyneuropathy in ICU patients with systemic inflammatory response syndrome or sepsis. Intensive Care Med 26: 1360–1363. Trojaborg W, Weimer LH, Hays AP (2001). Electrophysiologic studies in critical illness associated weakness: myopathy or neuropathy – a reappraisal. Clin Neurophysiol 112: 1586–1593. Van Den Berghe G, Schoonheydt K, Becx P et al. (2005). Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 64: 1348–1353. Van Wilgenburg H (1979). The effect of prednisolone on neuromuscular transmission in the rat diaphragm. Eur J Pharmacol 55: 355–361.

1685

Vasile B, Rasulo F, Candiani A et al. (2003). The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med 29: 1417–1425. Vasilevskis EE, Ely EW, Speroff T et al. (2010). Reducing iatrogenic risks: ICU-acquired delirium and weakness – crossing the quality chasm. Chest 138: 1224–1233. Watson ME (1995). Median nerve damage from brachial artery puncture: a case report. Respir Care 40: 1141–1143. Watson AC, Hughes PD, Louise Harris M et al. (2001). Measurement of twitch transdiaphragmatic esophageal and endotracheal tube pressure with bilateral anterolateral magnetic phrenic nerve stimulation in patients in the intensive care unit. Crit Care Med 29: 1325–1331. Wilson RW, Ward MD, Johns TR (1974). Corticosteroids: a direct effect at the neuromuscular junction. Neurology 24: 1091–1095. Witt NJ, Zochodne DW, Bolton CF et al. (1991). Peripheral nerve function in sepsis and multiple organ failure. Chest 99: 176–184. Z’Graggen WJ, Lin CS, Howard RS et al. (2006). Nerve excitability changes in critical illness polyneuropathy. Brain 129: 2461–2470. Zifko UA (2000). Long-term outcome of critical illness polyneuropathy. Muscle Nerve Suppl 9: S49–S52. Zochodne DW, Bolton CF, Wells GA et al. (1987). Critical illness polyneuropathy. A complication of sepsis and multiple organ failure. Brain 110: 819–841. Zochodne DW, Ramsay DA, Saly V et al. (1994). Acute necrotizing myopathy of intensive care: electrophysiological studies. Muscle Nerve 17: 285–292.