Neuromuscular complications of critical illness

Handbook of Clinical Neurology, Vol. 115 (3rd series) Peripheral Nerve Disorders G. Said and C. Krarup, Editors © 2013 Elsevier B.V. All rights reserved

Chapter 44

Neuromuscular complications of critical illness KURIEN KOSHY AND DOUGLAS W. ZOCHODNE* Department of Clinical Neurosciences and the Hotchkiss Brain Institute, University of Calgary, Alberta, Canada

INTRODUCTION Advancements in life sustaining technology have prolonged patient survival times in the intensive care setting. Concurrent neurological investigations, particularly electrophysiological approaches, have identified common, previously unrecognized complications in these patients. Critical illness, a syndrome of sepsis and multiple organ failure, is a common element. Three major neurological problems have been identified: polyneuropathy (critical illness polyneuropathy (CIP); Bolton’s neuropathy), myopathy (critical illness myopathy, CIM), and encephalopathy. Encephalopathy will not be addressed further in this chapter. Closely related are disorders of the neuromuscular junction (NMJ), often related to pharmacotherapy. There is significant overlap among all of these conditions and an individual patient may suffer from several of them. Other less well defined terms, including “acquired weakness in the ICU (ICUAW),” or neuromyopathy have been applied. Patients with CIP and CIM have significant problems in weaning from the mechanical ventilator, prolonging the time and associated morbidity of their ICU stay. Both conditions are also likely to render longterm disability. What approaches may mitigate them are uncertain at this time, beyond overall supportive therapy and withdrawal of pharmacological agents that are risk factors. Both CIP and CIM are considered in this chapter.

HISTORICAL PERSPECTIVE Osler’s observation of “rapid loss of flesh” with prolonged sepsis in 1892 may be a first description of CIP (Osler, 1892). Other examples of early, isolated cases were described following shock or cardiac arrest (Erbsloh, 1955), acute intoxication, severe metabolic crises (Mertens, 1961), burns (Henderson et al., 1971), hypotension (Rivner et al., 1983), or gentamycin administration in

a septic patient (Bischoff et al., 1977). Charles Bolton, a neurologist at the University of Western Ontario, Canada identified, initially in an abstract at the AAN, then in a follow-up paper, five critically ill patients identified between 1977 and 1981, with severe limb weakness and difficulty in weaning from the ventilator (Bolton et al., 1983, 1984). All had evidence of a severe axonal polyneuropathy, now termed critical illness polyneuropathy. Despite considerable early skepticism about the existence of CIP, Bolton and colleagues expanded their investigations. Comprehensive electrophysiological studies identified the problem as a primary distal, axonal degeneration of motor and sensory fibers. This was confirmed by detailed neuropathological evaluation of patients that succumbed to their underlying critical illness. Common features of CIP were sepsis and multiple organ failure, but no single condition, infection, or other factor could be implicated in its development (Bolton, 1996). Additional work using electrophysiological and CSF criteria distinguished CIP from Guillain–Barre´ syndrome (GBS) (Bolton et al., 1986), a distinction that addressed early critics of the validity of CIP. Bolton and colleagues demonstrated that 50–70% of septic patients with multiple organ dysfunction had evidence of CIP, and it often accompanied encephalopathy (Jackson et al., 1985; Witt et al., 1991). While initial pathological studies of muscle in CIP patients identified denervation with only rare instances of single muscle fiber necrosis, subsequent work also identified evidence of myopathy in critical illness. Direct muscle involvement ranged from severe necrosis with rhabdomyolyis, to more mild involvement with fiber atrophy and loss of myosin thick filaments (Lacomis et al., 1996). Rich and colleagues identified loss of muscle fiber membrane excitability (Rich et al., 1995, 1996). All of these features, while not prominent in Bolton’s early cohorts, indicated that a second, overlapping complication of critical illness

*Correspondence to: Dr. D.W. Zochodne, 168 Heritage Medical Research Bldg, 3330 Hospital Dr. NW, Calgary, Alberta, Canada T2N 4N1. Tel: þ1-403-220-8759, Fax: þ1-403-283-8731, E-mail: [email protected]

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termed critical illness myopathy (CIM) was an important cause of weakness and inability to wean patients from the ventilator (Bolton et al., 1984; Zochodne et al., 1987; Lacomis et al., 2000). Specific risk factors such as glucocorticoid use and paralysis with nondepolarizing muscle blocking agents (NDMBAs) have been linked to CIM. Recent consensus work has used the term ICUAW, a more general and inclusive descriptor of CIP, CIM and neuromuscular junction disorders in the ICU (Stevens et al., 2009). ICUAW presence predicts an increased ICU and hospital mortality (Sharshar et al., 2009).

CRITICAL ILLNESS, SEPSIS, MULTIPLE ORGAN FAILURE, AND SYSTEMIC INFLAMMATORY RESPONSE SYNDROME Systemic inflammatory response syndrome (SIRS) describes the human host response to an infectious or noninfectious cause of critical illness (Bolton, 1992). To standardize terminology, the Society of Critical Care Medicine and the American College of Chest Physicians convened a consensus conference in 1992 (American College of Chest Physicians, 1992). Recognizing that a severe systemic response can be evoked in the absence of infection, the panel proposed the term “systemic inflammatory response syndrome” or SIRS. Thus, bacteria, fungi or viruses, and major mechanical, thermal, or chemical trauma will induce SIRS. SIRS is associated with the release of a series of inflammatory mediators that include cytokines, chemokines, and free radicals. Their impact is widespread and may involve direct targeting of axons, muscle fibers, and microvessels. Sepsis is therefore defined as SIRS due to a presumed or known site of infection (Critchley and MacNalty, 1978). Despite advancements in medical and surgical care early death and a mortality rate of 30–50% are associated with sepsis and SIRS. The terms “severe sepsis” and “septic shock” are reserved for those patients with organ dysfunction and hypoperfusion or hypotension, despite adequate fluid replacement. The diagnosis of SIRS requires that the patient have at least two or more of the following clinical manifestations (Bone et al., 1992): ● ● ●

●

A body temperature of > 38  C or < 36  C Heart rate of > 90 beats/minute Tachypnea, as manifested by respiratory rate of > 20 breaths/minute or hyperventilation, as indicated by PaCO2 of < 4.3 kPa An alteration of the white blood cell count of > 12 000 cells/mm3, <4000 cells/mm3, or the presence of > 10% immature neutrophils (bandforms)

ACQUIRED WEAKNESS IN THE ICU Initial cohorts of patients studied by Bolton and colleagues had electrophysiological and pathological evidence of an axonal polyneuropathy. Subsequent work has identified patients with myopathy, in some instances overlapping with CIP. While some patients developed predominant myopathy associated with the prolonged use of nondepolarizing neuromuscular blocking agents (NMBAs) and corticosteroids, others developed it in the absence of exposure (Hoke et al., 1999). The development of both types of neuromuscular involvement has generated substantial debate (Wijdicks et al., 1994; Jarrett and Mogelof, 1995; Leijten et al., 1995). The electrophysiological distinction between these entities can be complex. For example, “chronic” neurogenic changes are less often encountered in acute ICU studies, although their prevalence in chronic follow-up investigations is not fully explored (Wijdicks and Fulgham, 1994). When voluntary motor unit action potentials (MUPs) can be recruited by patients, they are frequently small and polyphasic (Bolton, 1994). This feature is suggestive of a predominant myopathic cause of weakness in most patients, although early distal reinnervation is also associated with small “nascent” MUPs. Some investigators report a reduction in the amplitudes of sensory nerve action potentials (SNAPs) in CIP that improve with clinical recovery (Bolton et al., 1984, 1986; Witt et al., 1991; Rich et al., 1995). Other reports identify normal SNAPS (Wijdicks et al., 1994), especially early in the disease course. Unfortunately SNAPs may be difficult to record, or are reduced in amplitude in patients with significant lower limb edema, and their presence or absence may not always clearly distinguish CIP from CIM (Bolton et al., 1986). Direct muscle stimulation (DMS), motor unit number estimation (MUNE), and muscle punch biopsies also indicate that a significant proportion of patients with ICUAW have muscle involvement combined with neuropathy. The rapid recovery of weakness seen in some patients has prompted consideration of terminal axons and the NMJ (neuromuscular junction) as alternative sites of pathology. This hypothesis is corroborated by the presence of increased jitter, identified by single fiber EMG, albeit not to a range typically observed in myasthenia gravis. Jitter was identified in association with abnormal spontaneous activity in critical illness recorded by needle electromyography (EMG) (Schwarz et al., 1997). Overall, loss of the CMAP amplitude is the most consistent finding in patients with ICUAW whether the pathology is primarily CIP, CIM, or both, with little change in latencies and conduction velocities. The magnitude of these CMAP declines (over 50% in several motor nerve territories), can be striking, and correlates

NEUROMUSCULAR COMPLICATIONS OF CRITICAL ILLNESS with clinical weakness. Some patients have complete loss of CMAPs, alternatively described as inexcitable motor nerves. Loss of CMAP amplitudes represents either loss of motor axons including distal branches, loss of muscle fibers, or muscle membrane inexcitability. In both CIP and CIM, abnormal CMAPs are accompanied by abnormal spontaneous activity in the form of fibrillation potentials and positive sharp waves noted using needle EMG. In the author’s (DZ) experience, dense abnormal spontaneous activity, as might be expected in acute denervation, is more likely in patients with predominant CIP. Prominent abnormal spontaneous activity in a primary myopathy suggests acute muscle fiber necrosis as observed in patients with rhabdomyolysis (Zochodne et al., 1994). Voluntary motor unit (MUP) evaluation is frequently limited by severe weakness or poor voluntary effort. Critically ill patients often cannot cooperate for standardized bedside motor or sensory testing. Muscle punch biopsies, less invasive than conventional biopsy (Helliwell et al., 1991; Zochodne et al., 1994), are useful in muscle assessment. They can be included in serial studies (Berek et al., 1996; Lacomis et al., 1996), but are best interpreted in conjunction with electrophysiology. An important caveat is that muscle biopsies at the site of previous needle EMG should be avoided because they may erroneously identify pathology secondary to needle trauma. Epidermal skin biopsy is an analogous technique used to evaluate neuropathies by quantitatively analyzing axons innervating the epidermis following a 3 or 5 mm punch (Lauria et al., 2005). While highly informative in other forms

Table 44.1 Summary of causes of muscle dysfunction in ICU patients

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of neuropathy, there is little published work using the technique in CIP. Some patients experience prolonged (from 6 hours to > 7 days) neuromuscular junction (NMJ) blockade specifically linked to the use of prolonged vercuronium infusions. Prolonged blockade has been associated with metabolic acidosis, elevated magnesium levels, females, renal failure, and high plasma concentrations of 3-desacetylvecuronium (Segredo et al., 1992). Like the parent agent, this metabolite of vecuronium is associated with NMJ blockade. Current forms of evaluation may not be sufficient to detect more subtle changes in neuromuscular function. For example, in several inherited disorders associated with defective channel protein gene expression, ion channels may have prolonged opening, or varying degrees of blockade associated with the use of drugs, toxins, or antibodies (Gutmann and Gutmann, 1996). In these conditions, muscle biopsy, serum creatine kinase (CK) level, and electrophysiology do not offer clues to the cause of weakness. In this context, how critical illness and its pharmacotherapy combine to generate weakness may require additional work. From a practical point of view, the most important consideration is identifying other causes of weakness in ICU patients that may superficially resemble CIM or CIP. These can include high spinal cord injury, GBS, unrecognized ALS, or pre-existing muscle dystrophy or myositis. Careful clinical, electrophysiological, and imaging analysis is essential in each patient. A brief summary of causes of muscle weakness in the ICU is given in Table 44.1.

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Critical illness polyneuropathy CIP is an acute onset motor-sensory polyneuropathy that often accompanies septic encephalopathy (Jackson et al., 1985; Young et al., 1990). It occurs in 50–70% of patients suffering from SIRS (Witt et al., 1991; Hund et al., 1997) and its prevalence is associated with the degree and extent of organ dysfunction (Leijten et al., 1995). SIRS, in turn, occurs in 20–50% of patients admitted to the ICU (Tran et al., 1990), and as a result CIP is a particularly common neuromuscular disorder. Not all patients have clinical signs of CIP and perhaps 50% may have subclinical involvement. Abnormalities that can be detected on clinical examination include flaccid weakness of the extremities, which is often severe, associated with loss of deep tendon reflexes. New loss of previously documented deep tendon reflexes is an important clue to the development of CIP. In patients originally described with CIP, cranial nerve involvement was absent (Zochodne et al., 1987). Fasciculations of the limbs, and especially tongue, are not features of CIP; if present they are important features that may help identify unrecognized ALS in ventilator-dependent patients. Sensory abnormalities in CIP can be difficult to recognize because of encephalopathy and sedative medications. An additional clinical feature that confirms the presence or absence of sensory loss is whether facial flinching can be observed after applying a painful stimulus such as deep nail bed pressure on the toes. In severe CIP, both flaccid weakness and loss of sensation may occur in combination. A painful stimulus evokes neither limb withdrawal nor facial grimacing. In isolated patients who have survived their ICU stay, neuropathic pain has emerged (Bolton et al., 1984). Electrodiagnostic studies show reduction in the amplitude or frank absence of both CMAPs and SNAPs in CIP. Needle electromyography identifies abnormal spontaneous activity (fibrillations, positive sharp waves) and loss of motor unit potentials when voluntary effort is assessed. In the acute stages of CIP, abnormal spontaneous activity may be intense, as might be expected with severe and acute denervation. Fasciculations are not recorded. Features of primary demyelination with prominent slowing of nerve conduction velocity, conduction block, dispersion, or prolonged F wave latencies are also not expected. If these are identified, GBS or rarely CIDP (chronic inflammatory demyelinating polyneuropathy) should be considered. Phrenic neuropathy is a feature of CIP and contributes to respiratory weakness and difficulty in weaning patients from mechanical ventilators (Bolton et al., 1993; Zifko et al., 1998). It is identified using phrenic nerve recordings with stimulation at the root of the neck. Differentiation of CIP from other neuropathies and causes of weakness is essential in directing

appropriate therapy. GBS, porphyria, botulism, myasthenic crises, Lambert–Eaton myasthenic syndrome, acid maltase deficiency, inflammatory myopathies, and others can be mistaken for either CIP or CIM. Pathological investigations of CIP at postmortem or using muscle biopsies may identify scattered fiber atrophy indicative of acute denervation that involves limb, trunk, and respiratory muscles. Peripheral nerves have widespread and severe axonal degeneration especially involving, but not confined to, distal nerves (Fig. 44.1).

DIAGNOSTIC CRITERIA FOR ACQUIRED WEAKNESS IN THE ICU 1. 2.

3.

4. 5.

Generalized weakness that develops after the onset of critical illness. Diffuse weakness (involving both proximal and distal muscles) that is symmetrical, flaccid, and generally spares cranial nerves. Medical Research Council (MRC) sum score < 48, or mean MRC score < 4 in all testable muscle groups noted on> two occasions separated by > 24 hours Dependence on mechanical ventilation. Causes of weakness not related to the underlying critical illness have been excluded.

The MRC sum score grades muscle strength from 0–5 with 0 representing no contraction, 1 contraction without joint movement, 2 contraction but not against gravity, 3 contraction against gravity, 4 contraction against resistance, and 5 representing normal muscle power. The score is calculated by adding values from arm abduction, forearm flexion, wrist extension, leg flexion, knee extension, and foot dorsiflexion bilaterally (normal ¼ 60) (Kleyweg et al., 1991). Minimum criteria for diagnosing ICUAW are: 1, 2, 3 or 4, 5 (Stevens et al., 2009).

DIAGNOSTIC CRITERIA FOR CRITICAL ILLNESS POLYNEUROPATHY 1. 2.

3.

4. 5.

Patient meets criteria for ICUAW. Compound muscle action potential amplitudes are decreased to < 80% of lower limit of normal in> 2 nerves. Sensory nerve action potential amplitudes are decreased to < 80% of lower limit of normal in > 2 nerves. Normal or near-normal nerve conduction velocities without conduction block. Absence of a decremental response on repetitive nerve stimulation.

(See Stevens et al., 2009.)

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OTHER ACQUIRED NEUROPATHIC CONDITIONS IN ICU PATIENTS Burn neuropathy While not routinely requiring ICU admission, patients with severe cutaneous burns are predisposed to infection, and may develop multiorgan failure with SIRS. Burn neuropathy patients present with weakness, sensory dysfunction, and hearing loss (Henderson et al., 1971). While reports are incomplete, some patients have been reported with conduction velocity slowing. In another series (Marquez et al., 1993), 19 of 800 patients admitted to a specialized burn unit were found to have neuropathy. Only one patient had an axonal polyneuropathy and most exhibited mononeuritis multiplex. Entrapment associated with scar tissue damage may contribute to multiple neuropathic deficits. In addition, direct injury to the vasa nervorum causing occlusion and ischemic damage could potentially contribute to axon damage, although this cause is speculative. In contrast, patients with generalized polyneuropathy not related to specific burn or entrapment sites may have a clinical variant of CIP.

Hopkins syndrome Hopkins syndrome is a focal amyotrophy in children that can followed asthmatic attacks (Hopkins, 1974; Liedholm et al., 1994; Sheth and Bolton, 1995). It is most often localized to cervical motor segments and develops within 2 weeks of an episode of status asthmaticus requiring glucocorticoid therapy. Hopkins syndrome is distinct from CIP and is thought to arise from localized damage to the anterior horn cells. Clinical weakness is most often restricted to one limb, even though diplegic or hemiparetic forms have also been observed. The restricted pathology is demonstrated by segmental changes of denervation by needle EMG.

CRITICAL ILLNESS MYOPATHY

Fig. 44.1. Histological studies of nerve and muscle taken at autopsy, from patients with CIP (critical illness polyneuropathy). (A) A semithin transverse section of a sample of peroneal nerve showing loss of myelinated axons with several profiles undergoing acute axonal degeneration (arrowhead). Regenerating clusters are also observed (arrow). (B) A teased fiber undergoing axonal degeneration (Dyck classification Type E). (C) A transverse section of an intercostal muscle, stained with hematoxylin and eosin. Note the variation in fiber size with scattered, and sometimes grouped fiber atrophy. (D) A longitudinal section from the lumbosacral plexus stained with luxol fast blue. There is severe loss of myelinated axons and two adjacent axons are undergoing acute axonal degeneration (black arrows). (Figure 44.1D reproduced with permission from Zochodne, 2005.)

CIM was identified later than CIP. Observed in somewhat different patient cohorts, it was recognized to have a wide spectrum of severity from mild myopathy with type II fiber atrophy to severe and widespread muscle necrosis. Overall it may be more common than CIP as a cause of ICUAW (Lacomis et al., 1998; Lefaucheur et al., 2006). Previous descriptors of CIM included: acute quadriplegic myopathy (Hirano et al., 1992), acute (necrotizing) myopathy of intensive care, thick filament myopathy, acute corticosteroid myopathy (although not all cases are associated with glucocorticoid use), acute hydrocortisone myopathy, acute myopathy in severe asthma, acute corticosteroid and pancuroniumassociated myopathy, floppy person syndrome, and critical care myopathy (Kaplan et al., 1986; Helliwell

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et al., 1991; Knox et al., 1991; Sitwell et al., 1991; Hirano et al., 1992; Rich et al., 1995; Lacomis et al., 1996; Lacomis et al., 1998, 1993; Lacomis et al., 2000). By definition, patients are critically ill, and weakness may occur independently of, or in association with, CIP. A combination of CIP and CIM may be more common than either condition alone (Gorson and Ropper, 1993; Wijdicks et al., 1994). What proportion of ICUAW patients have CIM is debated, but may be higher than 50%. CIM may develop in one-third of ICU patients treated for status asthmaticus (Douglass et al., 1992), and in 7% of patients after orthoptic liver transplantation (Campellone et al., 1998). It has also been identified in patients after heart transplantation (Perea et al., 2001). In a prospective study, all 22 critically ill patients showed clinical, electrophysiological, and muscle biopsy evidence of a primary myopathy (Trojaborg et al., 2001). CIM may have a better prognosis than CIP (Guarneri et al., 2008). While some clinical features, particularly flaccid weakness and prolonged ventilator dependence overlap with CIP, there are important differences. CIM may occur earlier, in close association with glucocorticoid use and infusions of nondepolarizing muscle blocking agents (NDMBAs). Consequently muscle atrophy may be less pronounced. As in CIP, limb or tongue fasciculations are not expected. CIM may be associated with intact deep tendon reflexes if not severe, although more severe instances have loss. Patients may grimace to deep nailbed (e.g., toe) stimulation but are unable to move their limbs due to weakness. Severe CIM may be associated with facial and extraocular muscle weakness and patients may be truly “locked in.” For example, ophthalmoplegia may be present (Sitwell et al., 1991). In contrast, bulbar and extraocular weakness has not been described with CIP. Superimposed NMJ blockade, a problem in patients exposed to NDMBAs, discussed below, may occur. Flaccid weakness tends to be diffuse, involving all limb muscles, neck flexors, intercostal muscles, and the diaphragm. Thus, most patients are difficult to wean from mechanical ventilation. Myalgias are not reported by patients with CIM. Electrophysiological testing identifies loss of CMAPs as in CIP, but SNAPs can be relatively preserved, a feature that may be prominent during recovery. A CMAP with broadening of the negative peak duration is an interesting finding and is described in association with CIM (Park et al., 2004). Broadened CMAPs are also noted in muscle “fatigue” during prolonged trains of supramaximal stimulation that deplete muscle bioenergetic reserves. Loss of, or low amplitude sural SNAPs, may be misinterpreted as evidence of neuropathy in patients with CIM if they are secondary to technical recording factors (see below). Needle electromyography may

identify abnormal spontaneous activity and impaired voluntary motor unit recruitment. In the author’s experience, cohorts of patients with CIM have less dense abnormal spontaneous activity with less obvious distal predominance. While subjective, the density of fibrillation potentials and positive sharp waves are indicators of the severity of muscle denervation. These potentials may be completely absent or of low grade intensity in CIM. In patients with severe necrotizing variants of CIM, however, dense abnormal spontaneous activity may instead be identified. As in inflammatory myopathies, this activity may arise because of direct muscle fiber depolarization or “functional” denervation from segmental muscle fiber necrosis that separates the endplate from the remaining myofiber. Testing muscle excitability directly is an adjunct electrophysiological approach that may help to distinguish denervation from CIM. Rich and colleagues identified failure of muscle to generate action potentials following direct stimulation of muscle using a needle electrode. In contrast, while patients with CIP or severe GBS had absent CMAPS from inexcitable motor nerves, direct stimulation of muscle was normal. Thus, in patients with absent CMAPs, direct muscle stimulation may help distinguish severe denervation from CIM (Rich et al., 1997). The approach is described in more detail below. Initial descriptions of CIM were reported in patients who received prolonged doses of glucocorticoids or NDMBAs, either as single agents or in combination (Zochodne et al., 1994; Lacomis et al., 1996; Campellone et al., 1998). However, exposure to either one or both agents is not essential for the development of CIM (Hoke et al., 1999). A spectrum of CIM likely exists. For example, patients given vecuronium have experienced very severe forms of myopathy with rhabdomyolysis, elevated CK levels, myoglobinuric renal failure, and severe muscle necrosis on histology. Others variants of CIM, particularly in association with glucocorticoids, may exhibit less severe necrosis or no necrosis but instead predominant loss of thick filament, type II atrophy and regeneration. Thick filament loss may be obscured in severe muscle fiber necrosis. Pathological changes in CIM are illustrated in Fig. 44.2.

DIAGNOSTIC CRITERIA FOR CRITICAL ILLNESS MYOPATHY Proposed major diagnostic features for critical illness myopathy by Lacomis et al. 1. 2.

SNAP amplitudes > 80% of the lower limit of normal (LLN) in two or more nerves. Needle EMG with short-duration, low amplitude MUPs with early or normal full recruitment, with or without fibrillation potentials.

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Absence of a decremental response on repetitive nerve stimulation. Muscle histopathological findings of myopathy with myosin loss.

Supportive features are: 1. 2. 3.

CMAP amplitudes < 80% LLN in two or more nerves without conduction block. Elevated serum CK levels (best assessed in the first week of illness). Demonstration of muscle inexcitability.

A definite diagnosis requires all four major features. Probable has three major features and one or more supportive features. Possible has either major features 1 and 3, or 2 and 3 with one or more supportive features. (See Lacomis et al., 2000.)

Updated Brussels roundtable diagnostic criteria for critical illness myopathy 1. 2. 3.

4.

5.

Patient meets criteria for ICUAW. Sensory nerve action potential amplitudes are > 80% of the lower limit of normal in > 2 nerves. Needle electromyogram in > 2 muscle groups demonstrates short-duration, low-amplitude motor unit potentials with early or normal full recruitment with or without fibrillation potentials. Direct muscle stimulation demonstrates reduced excitability (motor nerve/direct muscle ratio > 0.5) in > 2 muscle groups. Muscle histology consistent with myopathy.

Probable CIM: criteria 1, 2, 3 or 4; or 1 and 5 and Definite CIM: criteria 1, 2, 3 or 4, 5. (See Stevens et al., 2009.)

SPECIFIC VARIETIES OF CIM Acute disorders of the neuromuscular junction associated with nondepolarizing muscle blocking agents

Fig. 44.2. Histological studies of muscle taken from patients with CIM. (A) A hematoxylin and eosin transverse paraffin section of rectus femoris in a patient with CIM, necrotizing variant following prolonged exposure to vecuronium. Note the scattered necrotic fibers undergoing lysis and other examples of atrophic muscle fibers. (B) A transverse section of the rectus femoris muscle in a patient with a necrotizing variant of CIM. Note the widespread panfascicular necrosis with myophagocytois and a large number of small regenerating muscle fibers

Among the disorders considered under the rubric of ICUAW, disorders involving NMJ blockade are essential to recognize. Occasionally, patients may be admitted to intensive care units with previously unrecognized myasthenia gravis or Lambert–Eaton myasthenic syndrome but this is rare. While NMJ blockade secondary that contain vesicular nuclei with prominent nucleoli. (C) An electron micrograph from the rectus femoris in a patient with necrotizing CIM from an area of muscle that was not involved by necrosis. There is loss of the M line and partial loss of the H band indicating selective loss of myosin filaments. (Figures 44.2B and C reproduced with permission from Ramsay et al., 1993.)

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to aminoglycosides is listed among differential diagnoses of ICUAW, the authors have never encountered these cases. No recent well-documented reports of this theoretical linkage have been published and rare reports from several decades ago are not well documented. In contrast, patients may develop severe ICUAW secondary to NMJ blockade and the use of NDMBAs. This condition has been identified in patients who have required mechanical ventilation for several days, or possibly weeks using infusions of competitive NDMBAs to facilitate mechanical ventilation (Subramony et al., 1991). When these agents are eventually discontinued, severe flaccid limb and respiratory muscle paralysis persist despite the purported short half life of the agent. This development is largely seen with vecuronium of more than 48 hours duration (Gooch et al., 1991). One of the authors (DZ) noted that in patients with persistent vecuronium-related NMJ blockade, evidence for ongoing blockade had generally disappeared by 7 days (Zochodne et al., 1994). Despite this recovery, patients had persistent clinical weakness associated with severe necrotizing myopathy. Thus, at least two neurological problems were identified in these cases: an early, severe, NMJ disorder followed by CIM, often necrotizing, and occasionally CIP. An important early clue to concurrent unrecognized CIM during NMJ blockade in patients exposed to vecuronium was an elevated CK level confirming muscle necrosis. Rhabdomyolysis, if seen in conjunction with NMJ blockade, may be associated with myoglobinuria and secondary renal failure from muscle breakdown. NMJ blockade secondary to prolonged vecuronium infusions without added neuromuscular complications has been reported, but several cases predated the widespread recognition of CIM or CIP (Subramony et al., 1991; Kupfer et al., 1992; Segredo et al., 1992, 1990; Barohn et al., 1994). This disorder has been linked to prolonged clearance of 3-desacetylvecuronium, a metabolite of the parent drug that retains its activity in blocking NMJ transmission (Segredo et al., 1992). In renal failure, a frequent accompaniment of multiorgan failure, persistent blockade is attributed to this metabolite. Other risk factors for prolonged vecuronium paralysis are acidosis, elevated magnesium levels, and female gender. Cases of NMJ blockade secondary to pancuronium, atracurium, or other NDMBAs are reported but are less often associated with rhabdomyolysis (Rossiter et al., 1991; Barohn et al., 1994; Giostra et al., 1994; Hoey et al., 1995; Tousignant et al., 1995; Davis et al., 1998). Nonetheless, pancuronium also undergoes renal excretion, and its accumulation in renal failure may lead to prolonged paralysis (Rossiter et al., 1991). It is likely that prolonged use of high-dose NMDAs to facilitate ventilation is diminishing given the complications associated with their use. In the authors’ institution, propofol (diprivan) infusions have

been substituted for NDMBAs. Despite this change, CIM may also develop during the use of propofol (Hanson et al., 1997). This is to be distinguished from a distinct and potentially lethal complication known as propofol infusion syndrome (PRIS) associated with acidosis, cardiomyopathy, skeletal rhabdomyolysis, arrhythmias, renal failure, hepatic failure, and death (Fodale and La, 2008). Patients with generalized NMJ blockade may have severe paralysis including arreflexic flaccid limbs, bulbar paralysis, absence of respiratory effort, and ophthalmoplegia. While the “train of four” method is traditionally used to identify NMJ blockade, this simple test of muscle twitching in response to electrical stimulation may not be sensitive enough to identify blockade. In the experience of one of the authors (DZ), the “train of four” test failed to identify patients with significant NMJ blockade detected by conventional EMG equipment. Since patient cooperation was not available, repetitive stimulation studies (RNS) at 2–3 Hz and 30–50 Hz both identified a severe electrodecremental response. Baseline CMAP amplitudes were reduced, in keeping with concurrent CIM. Recovery was identified on a second test usually carried out 1 week later. Examples of tracings from repetitive nerve stimulation studies in a patient with persistent paralysis associated with a prolonged vecuronium infusion are illustrated in Fig. 44.3.

Day 3 after vecuronium discontinued

20 uV 5ms

Day 16 after vecuronium discontinued

50 uV 5 ms

Fig. 44.3. Example of tracings from serial neuromuscular transmission studies in the ulnar motor territory (2 Hz stimulation) of a patient with a prolonged neuromuscular transmission deficit following vecuronium use. Note that the CMAP (compound muscle action potential) is also reduced in amplitude in the recovery trace. The patient subsequently was noted to have evidence of CIM when the neuromuscular transmission deficit cleared. (Reproduced with permission from Zochodne and Bolton, 1996.)

NEUROMUSCULAR COMPLICATIONS OF CRITICAL ILLNESS

Thick filament myopathy Loss of thick filaments may be one of the most important pathological features identified in CIM and provides an important clue about the development of muscle dysfunction. How loss of thick (myosin) filaments, a structural alteration in the excitation–contraction apparatus of the muscle fiber, relates to loss of membrane muscle excitability in CIM is unknown. In patients with necrotizing rhabdomyolysis severe destruction of muscle fibers precluded the identification of selective myosin loss; it is uncertain if myosin loss predated necrosis. Thick filament myosin loss was first recognized in the setting of acute severe asthma and glucocorticoid use (Danon and Carpenter, 1991; Lacomis et al., 1993). Eventually this pathological finding became linked with ICUAW, noted following mechanical ventilation and prolonged administration of high-dose glucocorticoids and NDMBAs (Gooch et al., 1991; Sitwell et al., 1991; Campellone et al., 1998). Its association with glucocorticoid use in the literature may be more robust than that with NDMBAs. Many patients with CIM have had glucocorticoid exposure alone and some are exposed to neither. Thick filament myopathy presents with respiratory, limb and bulbar weakness, occasional ophthalmoparesis, and sometimes elevated CK levels (Sitwell et al., 1991). CMAPs are recordable but have declines in their amplitude. Sensory conduction studies may be normal. Repetitive nerve stimulation studies are normal whereas needle EMG identifies voluntary MUPs that are low in amplitude, short duration, and polyphasic. Electron microscopy shows loss of the thick myosin filaments (Danon and Carpenter, 1991). Finally, occasional patients may be identified outside of the ICU setting from oncology units, with a severe and profound myopathy secondary to glucocorticoids. In these patients there is no evidence of muscle fiber necrosis and biopsy may identify severe Type II fiber atrophy without thick filament loss.

Acute necrotizing myopathy with rhabdomyolysis This condition was observed in patients after discontinuation of prolonged infusions of NDMBAs who developed severe flaccid quadriplegia with bulbar and respiratory involvement including ophthalmoplegia. Initially, only sporadic reports of muscle necrosis were reported (Williams et al., 1988; Op de Coul et al., 1991; Subramony et al., 1991). Ramsay and Zochodne, however, described more severe variants of this condition with highly elevated CK levels, myoglobinuria, and acute renal failure (Ramsay et al., 1993; Zochodne et al., 1994). Recovery was prolonged, but accelerated once the CK

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level normalized. Electrophysiological studies showed low amplitude MUPs and prominent abnormal spontaneous activity with fibrillations and positive sharp waves. NMJ blockade was associated in some patients. Ramsay et al. (Ramsay et al., 1993) described five patients with acute necrotizing myopathy of intensive care, four of whom died and underwent full autopsy. Muscle showed moderate to severe panfascicular necrotizing myopathy involving both fiber types with muscle fiber vacuolation, sarcoplasmic hypereosinophilia, and invasion of myofibers by macrophages. There were areas of segmental muscle fiber necrosis and fibers with sarcoplasmic basophilia indicating regenerating fibers. Vacuoles were unstained. The patient with the longest course had smaller amounts of necrosis and focal electron-lucent expansion of the intermyofibrillar spaces, accounting for the vacuoles. Some muscle fibers that were not obscured by necrotic changes had disrupted myofilaments and streaming Z bands with disappearance of the H bands and M lines suggesting loss of myosin filaments. Mitochondria were normal and there were no primary inflammatory cell infiltrates. Muscles involved included limb muscles, diaphragm, and craniobulbar muscles.

Cachectic, catabolic, and disuse myopathy Cachectic myopathy, disuse atrophy, and catabolic myopathy are poorly defined clinical conditions cited as contributing to ICUAW (Clowes et al., 1983; Zochodne and Bolton, 1996). These disorders may exhibit muscle weakness and wasting but their exact role in contributing to ICUAW is unclear. NCS, needle EMG, and CK levels are normal. Muscle biopsy may either be normal or show nonspecific type II muscle fiber atrophy.

Pyogenic muscle infection A pyogenic muscle infection, suppurative myositis is an uncommon problem involving direct bacterial invasion of muscle and multiple abscesses. Severe muscle weakness is accompanied by pain, fever, myoglobinuria, and elevated CK levels (Armstrong, 1978; Adamski et al., 1980; Lannigan et al., 1984).

CLINICAL APPROACH TO CRITICAL ILLNESS WEAKNESS It is critical to exclude pre-existing causes of weakness when considering a patient with ICUAW (Zochodne and Bolton, 1996; Stevens et al., 2009). A neuromuscular disorder is suspected if rising hypercarbia accompanies tachypnea during attempted weaning. Patients or relatives should be asked about a previous history of neuromuscular disease. Respiratory movements of abdomen and chest wall should be observed to assess areas of

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weakness or paradoxical movement. For example, in patients with prominent diaphragm muscle weakness, inspiration may be associated with outward movement of the chest but inward movement of the abdomen rather than normal outward movement of both. In patients with severe chest wall weakness (e.g., intercostal muscle weakness) without diaphragm weakness, inspiration is associated with outward abdominal wall movement but the chest wall itself remains immobile. Patients should be evaluated for atrophy, abnormalities of muscle tone, fasciculations, sites of potential nerve compression, and areas of skin breakdown. It may be helpful to compare the patient’s response to supraorbital forehead pressure to that of limb nailbed pressure. Patients with severe limb weakness may not withdraw their limbs to nailbed pressure, yet may grimace if sensation is intact, as seen in myopathy. A grimace in response to forehead pressure but no grimace or movement to limb nailbed pressure suggests loss of sensation from neuropathy, or a spinal cord disorder. Formal sensory testing may be unreliable but evidence of distal loss to pain, temperature, and vibration may be identified in patients who are alert and attentive (Zochodne et al., 1987; Jarrett and Mogelof, 1995; Berek et al., 1996; Zifko et al., 1998). Deep tendon reflexes are usually absent or reduced (Bolton et al., 1993; Hund et al., 1996). Depending on clinical variables, it may be necessary to perform one or more of the following assessments: ● ● ● ● ●

●

Measurements of serum CK concentration Motor and sensory nerve conduction recordings Repetitive nerve stimulation for investigation of neuromuscular transmission defect Needle electromyography of muscle Tests of the respiratory system by phrenic nerve conduction studies and needle electromyography of the diaphragm (Bolton, 1993a) Biopsy of muscle

Other forms of acute axonal motor neuropathy, including versions of GBS, may be difficult to distinguish from CIP (Bolton, 1996). GBS variants normally present with evidence of neuropathy prior to the ICU admission and demyelinating GBS can be distinguished by electrophysiological studies (Bolton et al., 1986; Bolton, 1995). Electrophysiological testing including DMS, measurements of serum CK, and muscle biopsy may be helpful in deciding the relative contributions of CIP and CIM (Sitwell et al., 1991; Bolton, 1993c; Latronico et al., 1996; Campellone et al., 1998). The presence of mononeuropathies and plexopathies in isolation or coexistent with CIP and CIM should be identified, and they occur as a result of nerve compression palsies from prolonged recumbence, direct trauma, ischemia, or hemorrhagic compression (Wilbourn et al., 1983; Lacomis

et al., 1998). It is uncertain whether SIRS and MOF render peripheral nerves more susceptible to trauma (Barohn et al., 1994). We describe diagnostic studies below. An overall approach to consultation and evaluation of patients with ICUAW is given in Fig. 44.4 and a list of differential diagnoses of weakness in the ICU is given in Table 44.2.

Electrophysiological studies A comprehensive electrophysiological evaluation includes motor and sensory nerve conduction studies in at least two territories of each of an upper and lower limb, phrenic nerve conduction studies, repetitive conduction studies, and needle EMG in upper and lower limbs. Some investigators routinely include needle EMG of the respiratory muscles (Bolton, 1993a) to establish CIP or CIM as the cause of failure to wean from the ventilator (Bolton, 1987; Lefaucheur et al., 2006). Care should be taken to check the platelet count (should be > 50 000/mL) and INR (should be < 1.5) in patients undergoing needle EMG to avoid hematomas from needle insertion. Diaphragm needle EMG should probably be avoided in patients with chronic obstructive pulmonary disease because of the risk of pneumothorax. The earliest electrophysiological sign of CIP is a reduction of the amplitude of the CMAP with relative preservation of its latency. These changes occur within 1–2 weeks of the development of SIRS and multiple organ failure (Tennila et al., 2000). Diaphragmatic CMAPs also decline in amplitude (Zifko et al., 1998). An easily identified abnormality described in CIM is prolongation of the CMAP duration, a change that may be linked with alterations in membrane excitability and muscle bioenergetic fatigue (Milner-Brown and Miller, 1986; Bolton et al., 1994; Park et al., 2004). Declines in the amplitudes of the sensory nerve action potentials (SNAPs) develop in many instances of CIP although in some series there was relative preservation of sensory conduction despite evidence of CIP and loss of motor axons (Hund et al., 1997). Sural SNAPs, for example, are recorded from behind the lateral malleolus and their amplitude directly relates to the distance between the subcutaneous trajectory of the nerve trunk, and the skin recording electrode. Normally, recordings of SNAPs using surface electrodes are carried out directly over the sural nerve trunk and local skin resistance is an important determinant of their amplitudes. In critical illness, however, lower limb edema is common and may be severe. Landmarks for recording are also obscured. Thus, low-amplitude SNAPs may be identified in the absence of sensory neuropathy. The presence of low-amplitude SNAP potentials not attributable to technical factors helps to establish a firm diagnosis of CIP and has been documented in about 71% of CIP patients (Schwarz et al.,

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Fig. 44.4. A clinical approach to consultation and evaluation of patients with ICUAW (intensive care unit acquired weakness). Only a few key aspects are outlined for simplicity. While intact sensation (if it can be judged) and reflexes are more suggestive of CIM (critical illness myopathy), they do not exclude predominant motor involvement in CIP (critical illness polyneuropathy). Intense fibrillations may occur in severe necrotizing variants of CIM. Not shown is the potential role of direct muscle stimulation in distinguishing CIM from CIP. The role for nerve and muscle biopsy is not well established although a muscle biopsy can rarely identify disorders mimicking ICUAW such as myositis.

1997; Zifko et al., 1998). Sensory conduction velocities are preserved. Fibrillation potentials and positive sharp waves are also observed somewhat later, often 3 weeks into the illness. They are recorded in the distal limb, proximal limb, intercostal, diaphragmatic, and rarely facial muscles (despite the absence of clinical facial weakness) (Hund et al., 1996). Voluntary motor unit potentials (MUPs) may be difficult to recruit because of concurrent encephalopathy or sedation. MUPs may be normal, of low amplitude, polyphasic, or reduced in number. “Nascent” MUPs are small polyphasic potentials that appear during early reinnervation; they may resemble abnormal “myopathic” units from primary muscle damage (Zochodne et al., 1987). Stimulation single-fiber EMG (SFEMG) studies may indicate dysfunction of terminal motor axons (Schwarz et al., 1997), a feature of partial denervation and reinnervation. These smaller changes are to be distinguished from those of a NMJ disorder, described above (Zifko et al., 1998). In contrast, repetitive nerve stimulation studies may confirm a NMJ disorder in patients who have received NMBAs. As with other acute neuropathies, electrophysiological findings depend on the stage of the disorder and the time the examination is carried out. Serial studies may help ascertain the evolution of the condition and the relative contributions of CIP and

CIM. A summary of electrophysiological abnormalities encountered in ICUAW is given in Table 44.3.

Measurement of muscle fiber excitability by direct muscle stimulation This technique, first applied in the ICU by Rich and coworkers (Rich et al., 1997), is an evaluation of muscle fiber excitability by direct stimulation and recording from muscle. This direct muscle stimulation (DMS) recording is compared with CMAPs evoked from nerve stimulation using conventional techniques (motor nerve stimulation, MNS). Patients with CIM have a decrease in the DMS potential that parallels loss of the CMAP. Subsequently, an index of muscle fiber excitability was described, calculated as the ratio of CMAP amplitude (MNS) to that evoked by DMS. Weakness from neuropathy had a ratio of < 0.5 whereas in myopathy the ratio was > 0.5. The ratio is most often applied to studies carried out in the tibialis anterior, biceps brachii, abductor pollicis brevis, and vastus lateralis muscles (Rich et al., 1997; Bird and Rich, 2002). DMS can therefore be a helpful supplement in distinguishing CIP from CIM (Rich et al., 1997). It may be particularly useful in patients with “inexcitable motor nerves” when MNS CMAPs are

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Table 44.2 Differential diagnosis of weakness in the ICU Clinical findings

Causes other than CIP, CIM

Flaccid quadriparesis with intact bulbar function  bladder dysfunction Flaccid quadriparesis with or without bulbar involvement

High cervical myelopathy Low brainstem lesion

Flaccid quadriparesis with respiratory involvement  cardiac rhythm disturbances Flaccid quadriparesis with absent vertical eye movements Respiratory dysfunction with facial and bulbar weakness

Quadriparesis with facial and bulbar involvement  upper motor neuron (UMN) signs and respiratory dysfunction

Guillain–Barre´ syndrome Acute porphyria Inflammatory myopathy Acid maltase deficiency Motor neuron disease Heavy metal poisoning Central pontine myelinolysis Pontine infarction or hemorrhage or other lesions Periodic paralyses Severe hypokalemia

Central pontine myelinolysis Pontine infarction or hemorrhage or other lesions Neuromuscular junction transmission disorders (myasthenia gravis, Lambert–Eaton myasthenic syndrome, other) Motor neuron disease Motor neuron disease

completely absent but a DMS response is recorded, indicating severe axon damage but preserved muscle fiber excitability. In a series of 30 consecutive patients with ICUAW, evidence for neuropathy was found in 57% and for myopathy in 83% using a DMS alogorithm as a criterion (Lefaucheur et al., 2006).

Morphological studies of nerve and muscle (nerve/muscle biopsy) Analysis of nerve morphology at autopsy in patients who have had CIP-related ICUAW has shown fiber loss and primary axonal degeneration, often extensive, with distal nerve segments particularly involved. Axonal degeneration has been diffuse with both motor and sensory fiber damage (Bolton et al., 1984; Zochodne et al., 1987). While detailed postmortem investigations are

largely confined to one of the original reports on this condition, clear axonal degeneration was also identified in proximal nerves segments such as the lumbosacral plexus. Not all reports addressing CIM or CIP have used high-quality histological preparations such as semithin and thin sections and teased fiber preparations. For example, one report that failed to identify intramuscular targeting of axons, likely a case of CIM, relied on paraffin material, an inadequate approach toward highquality interpretation (Sander et al., 2002). Segmental or paranodal demyelination are not features of CIP. Teased fiber specimens as graded in Dyck’s classification had 4.5% to 94.4% type E fibers (axonal degeneration). Central chromatolysis of anterior horn cells and moderate loss of dorsal root ganglion cells that confirm peripheral axonal degeneration are also documented. There is no reported evidence of inflammation in the peripheral nervous system in CIP. Muscle specimens show evidence of denervation with scattered fiber atrophy, and in chronic instances grouped fiber atrophy. Single fiber necrosis may be a feature of acute denervation or CIM. Changes of denervation have been observed in a variety of proximal, distal, trunk, and respiratory muscles (Zochodne et al., 1987). Primary axonal degeneration of intercostal muscles, phrenic nerves, and denervation atrophy of respiratory muscles have accompanied respiratory insufficiency. In other series, features of a primary myopathy do not accompany neurogenic atrophy (Zochodne et al., 1987; Hund et al., 1996). For example, in some autopsy studies (Lycklama et al., 1987) relatively normal nerve histology has been reported. Wokke et al. described normal intramuscular nerves with nodal, preterminal, and ultraterminal sprouting in two patients with critical illness and weakness who had been exposed to vecuronium bromide (Wokke et al., 1988). We have encountered a very severe case of CIP with very prominent intramuscular nerve axonal degeneration without primary muscle disease (Jarvis, George and Zochodne, unpublished data). Op de Coul and colleagues (Op de Coul et al., 1991) describe patients who have primary abnormalities of muscle but also neurogenic features including fiber type grouping and loss of myelinated axons in the sural nerve. Early pathological reports of CIM included a description of “myosin lysis” in a patient exposed to glucocorticoids (Sher et al., 1979). Op de Coul (Op de Coul et al., 1991) described increased internal nuclei, basophilic fibers with vacuoles filled with glycogen, fiber necrosis, atrophy, hypertrophy, and “myophagy” with increased connective tissue and intermysial cellular proliferation. Coakley et al. (Coakley et al., 1993) described neurogenic or diffuse atrophy in 22 muscle biopsy samples of ICUAW patients with scattered necrotic fibers in two patients and “degenerative”

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Table 44.3 Summary of electrophysiological changes in critical illness Predominant subtype of ICUAW

Nerve conduction studies

CIP

Reduced CMAPs Reduced SNAPs Reduced phrenic CMAPs

CIM

Reduced CMAPs Normal SNAPs Reduced phrenic CMAPs

NMJ blockade

Reduced CMAPs Normal SNAPs Reduced phrenic CMAPs

Electromyography Active denervation if > 3weeks MUP–normal or low amplitude, polyphasic MUP–low amplitude polyphasic with some showing prolonged duration Normal

changes that included three with abnormal mitochondrial architecture or distribution. Definitive descriptions of pathology in CIM followed those of CIP by a few years (Danon and Carpenter, 1991; Sitwell et al., 1991). Danon and Carpenter (Danon and Carpenter, 1991) described detailed muscle pathology in a 20-year-old female hospitalized with status asthmaticus treated with high-dose glucorticoids and vecuronium who developed a flaccid quadriplegia and high CK levels. Muscle fibers had profound atrophy with rare necrosis, targetoid changes, prominent atrophy and angulation of type II fibers, excessive accumulation of fat droplets, normal intramuscular nerve bundles, and loss of the normal A band in most muscle fibers. Mitochondrial profiles were abnormal. Some fibers had empty central spaces with loss of all contractile elements. EM showed extensive loss of myosin thick filaments with relative preservation of thin filaments and Z discs. Mitochondria were abnormal in size, shape, and distribution. Central areas of muscle fibers were sometimes filled with glycogen particles. Overall the authors commented that these histological changes were unusual and atypical for most other known muscle disorders. Muscle biopsies in CIM were also reported by Showalter and Engel (Showalter and Engel, 1997), who described the detailed histological changes in five patients of whom three received a glucocorticoid, two received brief infusions with vecuronium or pancuronium, and two who did not have significant exposure to either an NDMBA or a glucocorticoid. There was atrophy of only type II fibers most often, some atrophy in

Direct muscle stimulation

Repetitive nerve stimulation

MNS CMAP/DMS CMAP < 0.5

May or may not show decremental response

MNS CMAP/DMS CMAP > 0.5

May or may not show decremental response

MNS CMAP/DMS CMAP > 0.5

Shows decremental response on RNS

type I fibers (less often reported), or atrophy in fibers of all histochemical types. There was variation in myofiber size and focal loss of ATPase reactivity and of myosin. In particular, myosin loss occurred in both fiber types and in both atrophic and nonatrophic fibers. Atrophic fibers also had increased immunoreactivity for calpain and desmin. Necrosis and vacuolar changes were less commonly seen. Electron microscopy in a number of studies has confirmed selective loss of thick (myosin) filaments (Ramsay et al., 1993; Lacomis et al., 1996). Widespread necrosis in acute necrotizing myopathy (Ramsay et al., 1993) or milder necrosis in acute rhabdomyolysis have also been reported in critically ill patients. Identification of the specific CIM subtypes as detailed above may aid in prognostication. Rarely, muscle biopsies in critical care patients may be helpful in excluding unrecognized pre-existing disorders such as muscular dystrophies, acid maltase deficiency, sarcoid myopathy, or myositis.

RISK FACTORS FOR DEVELOPING ACQUIRED WEAKNESS IN THE ICU Independent risk factor assessment studies show strong links between sepsis (Hund et al., 1997), multiple organ failure syndrome, and development of neuromuscular dysfunction in the critical illness setting (Zochodne et al., 1987). The severity of these disorders impacts on the duration of ICU stay (Garnacho-Montero et al., 2005). Hyperglycemia and low serum albumin are other factors that have a correlation with impaired peripheral nerve function during sepsis. Medications

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may contribute toward axonal damage or NMJ deficits (Sokoll and Gergis, 1981; Op de Coul et al., 1985). Metronidazole, for example, is neurotoxic. Indirect indices of sepsis such as the APACHE (acute physiology and chronic health evaluation) and MODS (multiorgan dysfunction syndrome) scores (Barie et al., 1996), along with hyperglycemia, duration of MODS, and central neurological failure are all associated with the risk of ICUAW development. Hypophosphatemia may also contribute to ICUAW (Gravelyn et al., 1988), noted in patients receiving antacids, intravenous dextrose, having diabetic ketoacidosis (Fisher et al., 1983), withdrawing from alcohol (Betro and Pain, 1972), or having a respiratory illness (Juan and Elrazak, 1979). Isolated reports link ICUAW to female gender, the use of midazolam or furosemide, and mode of nutrition as risk factors but these have not been corroborated in larger studies. CIM develops in a substantial proportion of ICU patients treated for status asthmaticus (Kupfer et al., 1992), in 7% of patients after liver transplantation (Campellone et al., 1998), and in an undetermined percentage of adults and children with other critical illnesses. Major risk factors for development of this condition are prolonged administration of intravenous glucocorticoids, NDMBAs, and other NMJ blocking agents (Wokke et al., 1988; Subramony et al., 1991; Ramsay et al., 1993; Zochodne et al., 1994). Not all risk factors have been identified within individual patients. A prospective study assessing CIM in severe asthmatic patients requiring mechanical ventilation showed that weakness was proportional to the total dose of vecuronium (Kupfer et al., 1992). Multiorgan failure and sepsis have traditionally been thought to predispose to CIP (Gurtubay et al., 1998; Gutmann and Gutmann, 1999; Tennila et al., 2000), whereas organ transplantation, pneumonia, severe asthma, renal failure, glucocorticoids, and NDMBAs are associated with CIM (Ramsay et al., 1993; Giostra et al., 1994; Zochodne et al., 1994; Tousignant et al., 1995).

PATHOPHYSIOLOGY OF CRITICAL ILLNESS POLYNEUROPATHY AND CRITICAL ILLNESS MYOPATHY Many factors have been thought responsible for the pathogenesis of CIP: the type of primary illness or injury, immune mediators, GBS, malnutrition, antibiotics, neuromuscular blocking agents, nerve vulnerability due to premorbid conditions, hypoxia (Giostra et al., 1994), hypotension, hyperpyrexia, iatrogenic mechanisms, endotoxin, tumor necrosis factor, hyperosmolality, and hyperglycemia (Rivner et al., 1983; Op de Coul et al., 1985; Bolton et al., 1986; Waldhausen et al., 1989; Wilmshurst et al., 1995; Van Den Berghe et al., 2001; De et al., 2009). While initially suspected to arise

as an end-organ complication of sepsis (Zochodne et al., 1987; Witt et al., 1991), subsequent studies have confirmed this idea and clearly linked CIP to sepsis, multiple organ failure, and SIRS (Wijdicks et al., 1994; Berek et al., 1996, 1998; Schwarz et al., 1997; Tennila et al., 2000). No specific pathogen or nutritional abnormality has been linked despite speculation on the cause (Jeejeebhoy et al., 1977; Holman et al., 1982; Zochodne et al., 1987). The severity of CIP is an important determinant of ICU length of stay (Maher et al., 1995; Hund et al., 1997; Gurtubay et al., 1998; Zifko et al., 1998). Diffuse tissue hypoxia and defects in the oxygen transport chain (mitochondrial function) resulting from impaired microcirculation and tissue perfusion are described in septic patients (Fry, 1988). Hyperglycemia may exacerbate these abnormalities, although its role in altering nerve microcirculation may be overstated (Zochodne, 2002). Control of hyperglycemia may be of benefit in critical illness and CIP but this may be due to the direct neurotrophic properties of insulin rather than its impact on glucose levels. For example, the incidence of CIP/CIM, as well as in-hospital mortality, are reduced by intensive insulin therapy (IIT) aimed at maintaining blood glucose levels between 80 and 110 mg/dL (Van Den Berghe et al., 2009). In this cohort of 1548 patients requiring ventilation in an intensive care unit, the incidence of CIP was reduced by 44% (from 52% to 29%). CIP risk directly correlated with mean glucose level. Trials of insulin therapy in other patient groups, however, have not identified this benefit (Elke et al., 2008). Other theoretical changes to the nerve microcirculation have an uncertain role in CIP since severe selective nerve ischemia, not routinely encountered in ICU patients, is generally required to alter axonal function and induce axonal degeneration (Schmelzer et al., 1989). The parenchymal oxygen debt from hypoxia during critical illness may not be restored by mechanical ventilation (Glauser et al., 1991; Landry and Oliver, 2001). The role of cellular level histotoxic hypoxia is suggested by studies of muscle biopsies in critically ill septic patients, which identify mitochondrial dysfunction (Brealey et al., 2002). 31P-NMR spectroscopic studies of human muscle in patients with critical illness weakness have also shown bioenergetic failure (Bolton et al., 1994). Levels of muscle phosphocreatine were depleted in patients with critical illness and rose with recovery, paralleling changes observed in rat models (Jacobs et al., 1988b; Bolton et al., 1994). It is uncertain whether similar mitochondrial dysfunction in peripheral axons might induce CIP axonal degeneration. Muscle fiber energy failure associated with low amplitude and prolonged CMAPs may be observed in healthy persons with muscle fatigue, resembling the changes described in CIM (Milner-Brown and Miller, 1986; Miller et al., 1987). Immunohistochemical

NEUROMUSCULAR COMPLICATIONS OF CRITICAL ILLNESS studies have shown enhanced expression of E-selectin adhesion molecules in the vascular endothelium of the peripheral nerve and similar studies of muscle biopsies have identified activated leukocytes generating proand anti-inflammatory cytokines. Examples of specific molecules linked to sepsis include: interleukins 1, 2, 4, 6 and 8, tumor necrosis factor alpha (TNF-a), platelet activating factor, leukotrienes, thromboxane A2, prostagladins E2 and I2, interferon-g, granulocyte–macrophage colony-stimulating factor, endothelin-1, nitric oxide, complement fragments C3a and C5a, adhesion molecules, vascular endothelial growth factors, bradykinin, thrombin, fibrin, plasminogen activator inhibitors, endorphins, heat shock proteins, transforming factors-b1, and chemokines (Fink, 2001). Newer molecules linked to SIRS include HMGB1, ICCAM1, VCAM1, and Toll-like receptors (TLRs) (Tsukamoto et al., 2010). Proinflammatory molecules are also accompanied by concurrent release of anti-inflammatory cytokines and other species. Finally, a low-molecular-weight toxin identified in the serum of CIP patients may also contribute to axon damage (Druschky et al., 2001). How all of these specific molecules generate neuropathy or myopathy is uncertain. For example, there may not be a clear correlation between ICUAW and levels of TNF-a or interleukin-6 (Verheul et al., 1994). The correlation between sepsis and circulating levels of TNF-a is not robust and TNF-a inhibitors were not effective in the treatment of sepsis. Part of the difficulty in linking sepsis, multiple organ failure, and its complications, such as ICUAW, may be that TNF-a rises only transiently, setting in motion a series of downstream effectors (Tsukamoto et al., 2010). Levels of NO rise with sepsis (Landry and Oliver, 2001), after axotomy in sensory neurons (Verge et al., 1992) and may contribute to axonal degeneration. The isoform of nitric oxide synthase (NOS) that is most relevant to sepsis is the inflammatory/inducible (iNOS) generated by macrophages, Schwann cells, and smooth muscle cells (Parratt, 1998). Interleukin-1 that is elaborated during muscle proteolysis (Clowes et al., 1983; Baracos et al., 1983; Goldberg et al., 1984; Fink, 2001) in sepsis also induces iNOS: NO combines with superoxide anion to form peroxynitrite (ONOO-). Peroxynitrite is a potent oxidizing agent that is toxic to thiol-containing proteins, DNA, and the contractile apparatus of muscle fibers (Supinski et al., 1999). A direct action of NO in causing axonal degeneration has been identified experimentally (Smith et al., 2001). Sepsis has direct impacts on impairing muscle fiber mitochondrial function and contractility (Callahan et al., 2001a, b; Callahan and Supinski, 2005; see review by Griffiths and Hall, 2010). Overall, the direct impact of SIRS on muscle has implicated a number of important and interrelated mechanisms: direct loss of muscle contractility and its force generation,

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abnormalities of oxidative phosphorylation, alterations of specific mitochondrial proteins, mitochondrial bioenergetics and function, defects in sarcolemmal integrity, actions of proinflammatory cytokines in muscle, rises in free radical species including nitric oxide, increases in muscle proteolysis, decreases in muscle protein synthesis, and upregulated caspase and calpain activity (see review by Callahan and Supinski, 2009.) It has been postulated that NMJ blocking agents cause functional denervation through prolonged blockade (Wernig et al., 1980). Karpati and coworkers (Massa et al., 1992) and Rouleau et al. proposed that denervated muscle develops a myosin-deficient myopathy when exposed to glucocorticoids (Rouleau et al., 1987). Similarly, denervated muscle fibers exposed to glucocorticoids develop inexcitability associated with muscle membrane depolarization and a hyperpolarizing shift in the voltage dependence of fast inactivation of sodium channels (Rich et al., 1998; Rich and Pinter, 2003). Myosin filament destruction and acute necrosis may represent downstream consequences of these changes (Danon and Carpenter, 1991; Rich et al., 1998; Gutmann and Gutmann, 1999). While this mechanism of myosin loss has merit, it is not a particularly satisfying explanation in a number of patients. For example, patients may have never had pre-existing CIP severe enough to cause pre-exisiting paralysis and others may have never been exposed to NDMBAs. Dysfunction or inactivation of voltage-gated sodium channels may also contribute to reduced muscle excitability (Rich and Pinter, 2001). Abnormalities of gene transcription may be critical in decreasing myosin mRNA and protein levels leading to myosin depletion (Larsson et al., 2000; Bird and Rich, 2002). Showalter and Engel (Showalter and Engel, 1997) found evidence of enhanced expression of calpain, a calcium-activated protease, in atrophic myofibers. Such findings suggest that altered cellular calcium homeostasis may also play a role in the loss of myosin, and perhaps other key muscle proteins. A further impact may occur through the cytokine TNF-b, which decreases the resting transmembrane potential of skeletal muscle fibers and other tissues including the brain and peripheral nerve. Di Giovanni et al. (Di Giovanni et al., 2004) utilizing a genomewide microarray analysis of human skeletal muscle in CIM showed that neurogenic atrophy and myogenic atrophy shared the same ubiquitin proteosome pathway, but only acute quadriplegic myopathy activated the TGFb/MAPK pathway (transforming growth factorb/ mitogen-associated protein kinase). Both CIM and neurogenic atrophy also showed upregulation of the muscle-specific ubiquitin ligase atrogin-1. In CIM alone, there was colocalization of TGF-b receptor II, ASK1, p38 MAPK, c-myc, and c-jun in apoptotic atrophic myofibers.

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In 80% of critically ill patients with septic shock, there is a significant decrease in QRS amplitude on the electrocardiogram suggesting dysfunction of cardiac muscle. The changes are reversible following recovery from sepsis. In critically ill patients concentrations of reduced glutathione, as well as total glutathione, are diminished in skeletal muscle (Berard et al., 2000). Moreover, ICU patients have a low ratio of reduced and total glutathione concentrations, indicating that the muscle tissue is in a more oxidized state (Hammarqvist et al., 1997), possibly due to increased oxidative stress. This further impairs the function of mitochondrial enzymes, leading to a diminished capacity to neutralize reactive free radicals (Corbucci et al., 1985). In experimental work, depletion of body pools of glutathione alter the hepatocellular energy status and leads to hepatocyte injury. The reutilization of oxidized glutathione is also impaired during critical illness because of a low availability of nicotinamide adenine dinucleotide phosphate (NADPH) that is required for conversion of oxidized glutathione to its reduced form in the presence of the enzyme glutathione reductase. The availability of NADPH is interrelated with the pentose phosphate pathway, which in turn decreases when glycolysis is impaired. When oxidized glutathione is not reutilized by reduction, it either undergoes local degradation or transport out of the cell (Hong et al., 1992). Consequently, an increased exposure to oxidative stress increases the susceptibility of the tissue to oxidative damage and may contribute to severe muscle protein catabolism in critically ill patients. Glucocorticoids have been shown to induce myopathy through at least three separate mechanisms (Murray et al., 2006). They alter the electrical excitability of muscle fibers by inactivation of sodium channels, induce loss of thick (myosin) filaments decreasing the ability of the muscle fibers to contract, and inhibit protein synthesis leading to an increase in muscle catabolism. Glucocorticoids also act at the presynaptic and postsynaptic junctions, decreasing the mini-end plate potentials that are elicited by tonic release of acetylcholine into the synapse. Glucocorticoid receptors are upregulated in denervated muscle (DuBois and Almon, 1981). NDMBA metabolites are likely responsible for the persistent weakness seen in as many as 70% of patients after prolonged administration of an NDMBA (Meyer et al., 1994). Given the high concentration of cholesterol in the phospholipid membrane immediately surrounding the neuromuscular junction, aminosteroidal NDMBAs have high permeability (Murray et al., 2006). Hypothalamic–anterior pituitary function is altered and a resulting neuroendocrine “dysfunction” may contribute to several metabolic problems present during critical illness (Landry and Oliver, 2001). When critical illness is prolonged with the patient requiring ongoing

intensive medical care, reduced (hypothalamic) stimulation and decreased pulsatile secretion of anterior pituitary hormones impairs anabolism.

RESPIRATORY DYSFUNCTION IN ACQUIRED WEAKNESS IN THE ICU The contribution of ICUAW to prolonged mechanical ventilation has been studied in many cohorts of ICU patients (Bolton, 1993b; Wijdicks et al., 1994; Gurtubay et al., 1998). Measurements of inspiratory muscle strength are of value in the prediction of weaning; however, such measurements are difficult to obtain reliably in intubated patients. Measurement of maximum inspiratory pressure and vital capacity, dependent on patient comprehension and cooperation, are often hindered. Their accuracy in confirming respiratory neuromuscular dysfunction is questionable (Multz et al., 1990; Conti et al., 2004). In contrast, electrophysiological abnormalities of the diaphragm help to identify CIP as a cause of both weaning failure and limb weakness (Maher et al., 1995). Phrenic nerve stimulation may help in monitoring inspiratory muscle contractility (Watson et al., 2001). There is an association between ICUAW and an increased duration of weaning or failure to wean (Coronel et al., 1990; De et al., 2004; GarnachoMontero et al., 2005). In two analyses, ICUAW was an independent risk factor for predicting the duration of mechanical ventilation and weaning failure, including the need for tracheostomy. Ventilator-induced diaphragm dysfunction and critical illness oxidative stress, causing loss of the diaphragm’s force-generating capacity, may be additional issues. The preferred mode of mechanical ventilation for patients with neuromuscular diseases is controversial. However, assist-control (AMV) and intermittent mechanical (mandatory) ventilation (IMV) are limited to patients capable of generating substantial respiratory efforts. Consequently, most patients with severe weakness or paralysis are ventilated, at least initially, in the controlled mode (CMV).

PERSISTENT WEAKNESS AND LONGTERM OUTCOME OF ICUAW Severe weakness and abnormal clinical neurological findings requiring prolonged rehabilitation are common sequelae in survivors of protracted critical illness. Neurophysiological evidence of chronic partial denervation of muscle can be found up to 5 years following intensive care unit discharge in > 90% of long-stay ICU patients. There are few systematic studies of the long-term neurological impact of CIP or CIM. Most published reports have involved only relatively small numbers of patients followed up for relatively short periods of time (Zochodne et al., 1987). Patients did experience

NEUROMUSCULAR COMPLICATIONS OF CRITICAL ILLNESS neuromuscular improvement in some follow-up studies, whereas others with progressive or static disease were less likely to survive (Bolton et al., 1986; Coronel et al., 1990). Berek et al. (Berek et al., 1996) prospectively identified, in 15 patients followed with CIP, persistent mild to moderate weakness in six, wasting in five, sensory loss in nine, and reduced or absent reflexes in seven at 2–3 months after their original diagnosis. All were able to walk again and electrophysiology identified persistent signs of CIP in 11 patients. The presence and severity of ICUAW, defined as weakness on a summed score of muscle strength using the MRC grading scale, were both associated with increased ICU and hospital mortality (Sharshar et al., 2009). The longer-term prognosis for CIP survivors ranges from complete recovery over a period of several months with resolution of neurophysiological signs to persisting weakness with evidence of denervation up to 3–4 years after ICU discharge. Jacobs et al. (Jacobs et al., 1988a) found that 38% of patients retained major functional impairment after critical illness with a 58% survival at 1 year. Premorbid status was the best predictor of subsequent outcome. Zifko (Zifko, 2000) showed that 11 of 13 patients with CIP in his study had clinical manifestations 13–24 months after diagnosis. Lacomis et al. (Lacomis et al., 1998) observed a functional recovery to ambulation in CIP and CIM patients within 4 months (48% CIM and 44% with axonal neuropathies). Many patients are able to provide a clear history of a prolonged recovery period after hospital discharge, associated with significant muscle wasting, weakness, fatigue, and difficulty with mobilization. Signs of weakness and denervation are more frequent in the distal muscles of the lower limbs. The sensory findings prove to be more variable in long-term survivors. Prolonged symptoms can include reduced endurance, poor physical stress tolerance, and easy fatigability, all of which are associated with significant functional disability. Other factors that contribute toward an ongoing poor quality of life include problems from other organ dysfunction, contractures, mononeuropathies, pain, and depression. Angel et al. (Angel et al., 2007) followed 16 survivors of acute respiratory distress syndrome (ARDS) from 6 to 24 months after their ICU discharge. At these time intervals, patients had persistent sensory complaints and findings (nine with abnormal sensory testing), focal or diffuse weakness (nine patients), largely normal electrophysiological studies (two with “myopathic changes”), and nonspecific abnormalities that included fiber atrophy on muscle biopsy. Seven patients among the group had entrapment mononeuropathies. CIP rather than CIM was a major determinant of prolonged motor convalescence (Guarneri et al., 2008). Fletcher et al. (Fletcher et al., 2003) carried out long term followup (12–57 months) on 22 patients. Sensory deficits were noted in

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27%, motor weakness in 18%, and both in 14%. Two patients studied 24 and 42 months after ICU discharge had prominent persistent signs, symptoms, and electrophysiological abnormalities (fibrillations) of CIP. Overall, as more patients survive prolonged critical illness due to rapid advances in life-sustaining medical care, it is important that hospital clinicians, general practitioners, and those involved in rehabilitation, including nurses and physiotherapists, are aware of the frequency and severity of residual neuromuscular weakness, and understand its causes, clinical manifestations, and neurophysiological features.

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