Clinical Approach to the Weak Patient in the Intensive Care Unit

Clinical Approach to the Weak Patient in the Intensive Care Unit

Upinder K Dhand MD

IntroductionUnderstanding the Causes of Weakness in ICU PatientsClinical Assessment

Limitations of Neurological Examination in the ICUClinical Setting of Motor Weakness

Neurological ExaminationCentral Nervous System LesionsSpinal Cord LesionsNeuromuscular Disorders

Laboratory EvaluationElectrophysiological Studies

Conventional Motor and Sensory Nerve ConductionNeedle EMGNeuromuscular Junction TestingRespiratory EMGSpecial Techniques

Muscle and Nerve BiopsyDisorders That Cause Neuropathic Weakness

Critical Illness PolyneuropathyGuillain-Barre SyndromeOther Acute NeuropathiesCompression NeuropathiesAcute PoliomyelitisAmyotrophic Lateral SclerosisHopkins Syndrome

Disorders That Cause Myopathic WeaknessCritical Illness MyopathyRhabdomyolysisOther Causes of Myopathy

Disorders of Neuromuscular TransmissionProlonged Neuromuscular Junction BlockadeMyasthenia GravisOther Neuromuscular Junction Disorders

Summary

Motor weakness in a patient in the intensive care unit (ICU) may be related to (1) pre-existingneuromuscular disorder that leads to ICU admission, (2) new-onset or previously undiagnosedneurological disorder, or (3) complications of non-neuromuscular critical illness. Neuromuscularsyndromes related to ICU treatment consist of critical illness polyneuropathy, critical illness my-opathy, and prolonged neuromuscular blockade, and are now recognized as a frequent cause ofnewly acquired weakness in ICU patients. Clinical features include quadriparesis, muscle wasting,and difficulty weaning from the ventilator. Evaluation of these patients is based on knowledge of

1024 RESPIRATORY CARE SEPTEMBER 2006 VOL 51 NO 9

clinical setting and predisposing factors, focused neurological examination, detailed electrophysio-logical investigation, serum creatine kinase level, other laboratory studies as needed, and histolog-ical examination of muscle biopsy. If a central nervous system (brain or spinal cord) lesion issuspected, neuroimaging studies are required. In addition to conventional nerve conduction andneedle electromyography, phrenic nerve conduction, diaphragm electromyography, blink reflex,and (recently) the technique of direct muscle stimulation have been employed. Critical illnesspolyneuropathy is an axonal motor and sensory neuropathy that often follows sepsis and multiorganfailure. Risk factors for critical illness myopathy are corticosteroids and neuromuscular blockingdrugs, acute respiratory illness, and organ transplant. Three subtypes (acute necrotizing myopathy,thick myosin filament loss myopathy, and type II fiber atrophy) are recognized. Major differentialdiagnoses of critical illness related paralysis are incidental Guillain-Barre syndrome and unmaskedmyasthenia gravis. Rarely, atypical presentation of amyotrophic lateral sclerosis, polymyositis orother myopathies, and precipitation of porphyria or rhabdomyolysis due to drugs used in the ICUhave been described. Recently a poliomyelitis-like flaccid paralysis due to West Nile virus infectionwas reported. A subgroup of patients with myasthenia gravis with muscle-specific tyrosine kinaseantibody is noted to present as respiratory crisis. Muscle biopsy in ICU paralysis syndromes maybe helpful in arriving at a specific diagnosis or to classify the type of critical illness myopathy. Nervebiopsy is only rarely indicated. Key words: critical illness polyneuropathy, critical illness myopathy,electrodiagnosis, flaccid quadriplegia, Guillain-Barre syndrome, intensive care, myasthenia gravis, neu-romuscular disorders. [Respir Care 2006;51(9):10241040. 2006 Daedalus Enterprises]

Introduction

Historically, neuromuscular disorders such as poliomy-elitis, Guillain-Barre syndrome, myasthenia gravis, andamyotrophic lateral sclerosis (ALS) have been among thecommonest causes of generalized and respiratory muscleweakness that require admission to the intensive care unit(ICU).13 Management of these patients with acute severeneuromuscular weakness in the modern ICU has led tosubstantial improvement in mortality and morbidity fromthese disorders.4 However, there has been increasing aware-ness of new onset neuromuscular weakness in patientswith non-neurological critical illness. In 1984, Bolton et al5described severe polyneuropathy in 5 patients with criticalillness, who had developed flaccid weakness of extremi-ties and could not be weaned from the ventilator as theircritical illness stabilized. They characterized it as axonalmotor and sensory neuropathy and distinguished it fromacute neuropathy of Guillain-Barre syndrome.6 About thattime, acute quadriplegic myopathy was also reported in

ICU patients, especially those with status asthmaticus whohad received neuromuscular junction blocking agents andcorticosteroids.7 Experience from various centers all overthe world in the last 2 decades has established neuromus-cular weakness as an important complication of criticalillness in the ICU.813 Three relatively distinct syndromes(critical illness polyneuropathy [CIP], critical illness my-opathy [CIM], and prolonged neuromuscular blockade)have been recognized.5,8,10,1419

Recent literature has substantially contributed to ourunderstanding of the pathophysiology and risk factors ofthese syndromes, but it has also generated controversyregarding the relative incidence, causative mechanisms,nosological description, and mode and extent of clinicalinvestigations.2024 Clinically, the difficulties stem fromthe fact that examination of ICU patients is often unreli-able, laboratory findings of the ICU-related syndromesmay overlap, and different syndromes may coexist in thesame patient.8,22,25 Despite these limitations, the aim ofclinical assessment of an ICU patient with generalizedweakness is to distinguish critical illness related compli-cations from other neurological causes, and to define thespecific nature of neuromuscular weakness due to criticalillness.

Understanding the Causes of Weaknessin ICU Patients

Causes of generalized weakness in the ICU setting maybe considered in the context of (1) pre-existing versusnew-onset weakness, and (2) localization of the disease

Upinder K Dhand MD is affiliated with the Department of Neurology,University of Missouri, Columbia, Missouri.

Upinder K Dhand MD presented a version of this paper at the 37thRESPIRATORY CARE Journal Conference, Neuromuscular Disease in Re-spiratory and Critical Care Medicine, held March 1719, 2006, in Ix-tapa, Mexico.

Correspondence: Upinder K Dhand MD, Department of Neurology, Uni-versity of Missouri, 1 Hospital Drive, M178, Columbia MO 65212. E-mail: [email protected].

CLINICAL APPROACH TO THE WEAK PATIENT IN THE INTENSIVE CARE UNIT

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process within the nervous system. Various pre-existingneurological disorders, such as Guillain-Barre syndrome,myasthenia gravis, ALS, spinal cord injury, and myopa-thies that lead to ICU admission are well known.2,2628New onset generalized extremity and/or respiratory mus-cle weakness may be further divided into previously un-diagnosed/newly acquired neurological disorders, and crit-ical illness related disorders. Some examples ofneurological disorders that may occur after admission toICU are Guillain-Barre syndrome following infective ill-ness or surgery, spinal cord infarct after aortic surgery, andmuscle weakness due to severe electrolyte disorder.

In addition, certain disorders may be unmasked (eg, my-asthenia gravis) or precipitated (eg, rhabdomyolysis) by in-fection or medications used in the ICU.2830 Finally, patientswith rapidly progressive weakness and respiratory compro-mise(Guillain-Barre syndrome,acute transversemyelitis)mayget admitted to ICU before there is enough time to establishthe diagnosis, or patients with unusual presentation of isolat-ed/predominant respiratory muscle weakness (ALS, myotonicmuscular dystrophy) may remain unrecognized for a consid-erable time after admission to the ICU.2628

However, neuromuscular disorders as a consequence ofcritical illness are now recognized as the most important causeof newly acquired weakness in the ICU. Occurrence of CIP,CIM, or a combination of the two is reported in 3050% of

patients with critical illness. A study of 92 patients with neu-romuscular weakness in an ICU reported CIM in 42%, CIP in12%, demyelinating neuropathy in 13%, motor neuron dis-ease in 7%, neuromuscular junction disorders in 3%, andother neuropathies in 13% of those patients.31

Another approach, which is very relevant to clinicalassessment, is to classify the causes of weakness in an ICUpatient according to central (intracranial) nervous system,spinal cord, and peripheral (neuromuscular) lesions. Neu-romuscular disorders are, in turn, best understood as af-fecting different parts of the motor unit. By definition, themotor unit consists of the anterior horn cell body, its axon,terminal nerve endings, and the number of muscle fibersthat it innervates.32 It is helpful to divide neuromusculardisorders based on involvement of components of the mo-tor unit: the anterior horn cell, peripheral nerve, neuro-muscular junction, and muscle. Table 1 summarizes thepre-existing and new onset causes of weakness in relationto site of involvement. The neuromuscular complicationsof critical illness, as noted, also affect all the componentsof the motor unit.

Clinical Assessment

Onset of weakness in ICU patients may not be appre-ciated in the presence of severe underlying systemic ill-

Table 1. Classification of Neurological Causes of Motor Weakness in Intensive Care Unit Patients

Localization Pre-existing Previously Undiagnosed/New-Onset Critical Illness Related

Spinal cord Trauma Acute ischemia Not describedInfarction Epidural abscessTransverse myelitis Acute transverse myelitis

Anterior horn cell Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis Hopkins syndromePoliomyelitis (West Nile virus) (predominant diaphragm weakness)

West Nile virus poliomyelitis

Peripheral nerve Guillain-Barre syndrome Incidential Guillain-Barre syndrome Critical illness polyneuropathyChronic inflammatory demyelinating

polyneuropathyPorphyria, vasculitis, toxic, compressive

Neuromuscular junction Myasthenia gravis Unmasked myasthenia gravis Prolonged neuromuscular blockadeLambert-Eaton syndrome Atypical myasthenia gravis (predominantBotulism respiratory weakness, muscle-specific

tyrosine kinase antibody)Toxic

Muscle Muscular dystrophy Rhabdomyolysis Critical illness myopathyPolymyositis Toxic myopathiesPeriodic paralysis PolymyositisMetabolic/congenital Myotonic dystrophyMitochondrial Adult-onset acid maltase deficiency

PyomyositisHypokalemicHypophosphatemic



ness, sedation, and encephalopathy. It is often brought toattention because of flaccidity and wasting of extremitiesor difficulty in weaning the patient from mechanical ven-tilation. Evaluation of such a patient requires a systematicapproach and consideration of special aspects of the ICUenvironment.

Limitations of Neurological Examination in the ICU

It is often difficult to elicit patients cooperation be-cause of inability to communicate, poor attention, seda-tion, and fatigability. Muscle strength testing may be in-adequate and sensory examination not reliable. Acute motordeficits due to central nervous system (upper motor neu-ron) injury may cause hypotonia and hyporeflexia similarto lower motor-neuron lesions, and clinical differentiationbetween central and peripheral causes becomes difficult.33Also, neuromuscular and central nervous system (CNS)involvement may be coincidental. Knowledge of clinicalbackground or setting in which the weakness evolves is animportant guide to differential diagnosis

Clinical Setting of Motor Weakness

Preceding or underlying illness and its treatment in theICU may have bearing on the nature of motor weakness.CIP often follows sepsis, systemic inflammatory responsesyndrome, and multiorgan failure,5,9,34 whereas CIM oftenoccurs in the setting of treatment with intravenous corti-costeroids and nondepolarizing neuromuscular blockingagents.7,16,35,36 Patients with asthma, pneumonia, organtransplant, and renal failure seem to be predisposed todevelopment of CIM.36,37 Guillain-Barre syndrome mayfollow an antecedent infective illness, surgery, or traumafor which the patient may have been initially admitted tothe ICU.3 Neuromuscular blocking agents and aminogly-cosides may unmask latent myasthenia gravis. Similarly,drugs, infection, or trauma may precipitate rhabdomyoly-sis.30,38 The list of medications received by the patient inthe ICU should always be checked (Table 2).

Neurological Examination

Central Nervous System Lesions

It is useful to proceed systematically to exclude CNS(intracranial) causes of weakness. These may coexist withneuromuscular disorders or be solely responsible for neu-rological impairment. Three major features point towardCNS involvement: asymmetric neurologic signs (right orleft cerebral hemisphere), altered mental status (encepha-lopathy), and cranial nerve palsies (brain stem). Appropri-ate imaging (computed tomography, magnetic resonanceimaging) and electroencephalogram usually provide the

diagnosis. Important CNS processes to be considered forgeneralized weakness are brain stem infarct, hemorrhage,or central pontine myelinolysis, which may result inlocked-in syndrome. Various neuromuscular disorderswith generalized extremity, bulbar, and ocular involve-ment (eg, Guillain-Barre syndrome, myasthenia gravis, andbotulism) can also mimic locked-in syndrome, and shouldbe considered in the differential diagnosis if neuroimagingstudies are negative. Rarely, patients with fulminant Guil-lain-Barre syndrome have had complete motor and sen-sory paralysis and absent brain stem reflexes, giving theappearance of brain death. In such patients with suspectedbrain death, when no cause of brain stem syndrome wasdetected, further investigation showed normal electroen-cephalogram, presence of visual evoked potentials, or pre-served oculocardiac response, which refuted the diagnosisof brain death.39,40 CSF and electromyography studies ledto diagnosis of Guillain-Barre syndrome, and some of thesepatients were successfully treated.

Spinal Cord Lesions

History of trauma in a patient with quadriplegia or para-plegia strongly favors traumatic spinal cord injury. How-ever, many spinal cord lesions, such as acute transversemyelitis, epidural abscess, and spinal cord infarct, maypresent as pre-existing or new onset causes of generalizedweakness in ICU patients. In the presence of flaccid weak-ness due to spinal shock, upper versus lower motor neuronparalysis cannot be distinguished. Presence of sensory level

Table 2 Drugs Associated With Neuromuscular Weakness in theIntensive Care Unit

Peripheral NerveCancer chemotherpyAmiodaroneMetronidazole

Neuromuscular JunctionNondepolarizing neuromuscular blocking agents

(vecuronium, pancuronium)Aminoglycosides, clindamycin, polymyxin-BBeta blockersCalcium-channel blockersProcainamidePhenytoin, fosphenytoinHypermagnesemia

MuscleCorticosteroidsColchicineAmiodaroneProcainamidePenicillamineCholesterol-lowering drugsZidovudine



on trunk, Babinski sign, flexor spasms, loss of anal reflex,loss of sphincter control, and arms weaker than legs aresome useful signs of spinal cord involvement.33,38 Anysuspicion of a spinal cord lesion should lead to radiologicinvestigation. Magnetic resonance imaging of the spine isthe most useful procedure.

Neuromuscular Disorders

The main clinical features of neuromuscular diseasesare weakness and wasting of extremities, hypotonia, andhyporeflexia/areflexia, with or without respiratory and/orcranial musculature involvement. It is customary to local-ize neuromuscular disorders to different parts of the motorunit (ie, anterior horn cell, peripheral nerve, neuromuscu-lar junction, or skeletal muscle). Diseases of the anteriorhorn cell, neuromuscular junction, and muscle producepure motor syndromes, whereas most peripheral nerve dis-orders have sensory and motor findings. Clinical distinc-tion among these categories may be obscured in the ICUsetting because of difficulty in eliciting signs, overlappingfeatures, and simultaneous occurrence of more than onesyndrome.23,33,41,42

Some helpful clinical signs are asymmetric weaknessand fasciculations (ALS, viral poliomyelitis); paresthesia,sensory deficits, and distal symmetric weakness (periph-eral neuropathy); cranial nerve palsies and dysautonomia(Guillain-Barre syndrome); and combination of ptosis andweakness of eye closure (myasthenia gravis, prolongedneuromuscular junction blockade).28,35,38 Further investi-gation with biochemical studies, nerve conduction and nee-dle electromyography (EMG), and muscle biopsy are oftennecessary to arrive at a definitive diagnosis.

Laboratory Evaluation

Serum creatine kinase is elevated in primary muscledisease. The highest levels ( 10,000 international units)are seen with acute necrotizing myopathy, acute polymy-ositis, and rhabdomyolysis.43 In CIM, creatine kinase maybe 10100-fold higher than normal, peak early in illness(around 34 days), and tend to normalize beyond 10days.28,44 Of note, creatine kinase may be elevated follow-ing trauma to muscle or after needle EMG examination.The investigations are tailored to the clinical differentialdiagnosis; for example, serum electrolytes for hypocalce-mia, hypophosphatemia, and hypermagnesemia; immuno-logical studies for vasculitides; and human immunodefi-ciency virus antibody testing and cerebrospinal fluid (CSF)examination for Guillain-Barre syndrome.

Electrophysiological Studies

Ever since the initial description of CIP, standard EMGand nerve conduction techniques have been employed

widely to identify and classify neuromuscular disorders inthe ICU setting.5,9,1922,26,34,41,45 Some studies specificallyanalyzed the data on ICU patients referred for electrophys-iological investigations, whereas others prospectively eval-uated the pattern of electrophysiological abnormality.12,31Experience in the last 2 decades has established the role ofEMG and nerve conduction study (1) to confirm the pres-ence of neuromuscular disorder, (2) to distinguish betweenprimary muscle, nerve, and neuromuscular junction in-volvement, thus narrowing the differential diagnosis, and(3) at times, to arrive at a specific diagnosis for the givenclinical picture. At the same time, methodological diffi-culties in the ICU, complexity of interpretation of find-ings, and patient discomfort pose considerable challeng-es.2,8,10,16,2123,42,46 The technical aspects and basis ofinterpretation of conventional nerve conduction and nee-dle EMG, and other special techniques relevant to the ICUsetting, are discussed.

Conventional Motor and Sensory Nerve Conduction

These techniques are standard, reproducible, and widelyused. Percutaneous stimulation and surface recording elec-trodes are employed.47,48 Motor response is elicited bysupramaximal electrical stimulation of an extremity nerve,with recording from an appropriate distal muscle inner-vated by that nerve (Fig. 1). The compound muscle actionpotential (CMAP) is the summated response of all stimu-lated muscle fibers within that muscle. Stimulation at 2

Fig. 1. Motor-nerve-conduction study. The median nerve is stim-ulated at the wrist, elbow, and axilla, and the recording is madefrom the thenar muscle. The compound muscle-action potentialshows longer latency with increasing distance along the nerve.The motor-nerve conduction velocity is calculated by dividing thedistance between 2 stimulation points by the difference in latency.The amplitude of the compound muscle-action potential is mea-sured from baseline to negative peak. (From Reference 47, withpermission.)



points along the nerve is required to calculate motor nerveconduction velocity in that segment. Distal motor latencyalone cannot be used to calculate motor conduction veloc-ity, because it incorporates the delay at the neuromuscular

junction. Sensory or mixed nerve action potential is ob-tained by supramaximal stimulation of a sensory or mixednerve, with recording electrodes placed along the samenerve, usually 814 cm distal or proximal to the stimulat-ing electrode. The distal motor and sensory latencies, mo-tor and sensory conduction velocity, amplitude (onset tonegative peak) of CMAP and nerve action potential, andwaveforms of these potentials are noted.4749 Abnormalityof motor and sensory nerve conduction strongly favors aneuropathic process. In axonal neuropathy, CMAP andnerve action potential amplitude is reduced (correspondingto loss of axons), with normal conduction velocity in sur-viving axons.2,26,33,48 Demyelinating neuropathy is charac-terized by marked slowing of conduction and/or presenceof conduction block indicated by 50% reduced CMAPamplitude on proximal stimulation of a motor nerve, com-pared to that on distal stimulation (Fig. 2).26,33,46,48,50

F Wave. Supramaximal stimulation of a motor nerve (eg,median or ulnar nerve at wrist, or peroneal or tibial nerve atankle) produces an orthodromic volley of impulse distally tothe muscle, as well as an antidromic volley that travels prox-imally along motor axons to the anterior horn cells. A pro-portion of the anterior horn cells then fire back, and theimpulse travels down again to the muscle and is recorded asa late motor response, which is termed an F wave (Fig. 3).This represents conduction along the length of the motornerve, including the proximal segment.51 In generalized neu-ropathy, marked slowing or absence of the F wave with rel-atively normal CMAP is compatible with demyelination.52,53The F wave may be absent or lack persistence if CMAP ismarkedly reduced due to other causes (eg, motor neuron dis-ease, axonal neuropathy, or advanced myopathy). The F waveis also inhibited in acute CNS lesions, as well as in sedated orunconscious patients.54

Fig. 2. Patterns of motor nerve conduction abnormality. A: Normalconduction velocity andcompoundmuscle actionpotential (CMAP)amplitude. B: Normal conduction velocity with reduced CMAP am-plitude, which suggests axonal neuropathy or axonal loss. C:Mark-edly slow conduction with normal CMAP amplitude, consistentwith demyelinating neuropathy. D: Slow conduction with reducedamplitude and temporal dispersion of CMAP on proximal stimu-lation, which signifies conduction block and focal demyelination.DL distal latency. CV conduction velocity. (FromReference 46,with permission.)

Fig. 3. Recording the F wave in the median nerve, on stimulationat the wrist. The direct motor response (compound muscle actionpotential or M wave) and late (F wave) responses are shown.



Needle EMG

Needle EMG is performed with a monopolar or a con-centric bipolar needle electrode, in judiciously selectedmuscles, based on clinical and nerve conduction find-ings.46,55 The standard procedure involves 3 steps (Fig. 4):

1. Spontaneous and insertion activity. Needle electrodeinsertion into a normal muscle at rest elicits a brief burst ofinsertion activity but no spontaneous activity other thanend-plate noise or spikes if the needle is close to the motorend-plate region. Presence of fibrillation potentials andpositive sharp waves indicates denervation or muscle ne-crosis separating the muscle fibers from their end-platezone. Fasciculation potentials are seen in anterior horn cellor peripheral nerve disease. Certain abnormalities (eg, myo-tonic discharges) may provide specific diagnosis.55

2. Steady mild voluntary contraction. With slight volun-tary activation of the muscle, low threshold, semi-rhythmi-cally firing motor unit potentials (MUPs) are recorded. Theduration, amplitude, and number of phases of the MUPs areassessed. In neuropathic lesions with axonal loss, reinnerva-tion of denervated muscle fibers through collateral sproutingof surviving axons results in large polyphasic MUPs. On theother hand, myopathic processes are associated with a re-duced number of functional muscle fibers within each motorunit, and therefore MUPs are of small duration and low am-plitude.32,5557 Myopathic MUPs also show marked polypha-sia due to decreased synchronization of muscle fiber actionpotentials within the motor unit.

3. Increasing/maximum voluntary contraction. Increas-ing the force of voluntary contraction increases the firing

rate of initial MUPs and produces systematic recruitmentof additional MUPs.58 Normally, a large number of over-lapping MUPs are recorded at maximum effort, which

Fig. 4. Needle electromyography (EMG). There are 3 steps to the procedure, and these waveforms show typical EMG patterns. Theneurogenic pattern shows the presence of spontaneous activity, large polyphasic motor-unit potentials (MUPs), and a reduced interferencepattern. The myopathic pattern shows variable spontaneous activity, small polyphasic MUPs, and a low-amplitude, full interference pattern.SA spontaneous activity. Recr recruitment. IP interference pattern.

Fig. 5. Repetitive nerve stimulation at a low stimulation rate (2 Hz)in a patient with prolonged neuromuscular junction blockade.A: Decrement response that suggests neuromuscular transmis-sion defect. B: Normal repetitive nerve stimulation response onrecovery. (From Reference 26, with permission.)



creates what is called an interference pattern. Loss of func-tional motor units with axonal injury or conduction blockproduces an incomplete or reduced recruitment/interfer-ence pattern. Myopathic diseases have the normal com-plement of motor units but reduced numbers of functionalmuscle fibers, which causes a normal interference patternwith reduced amplitude. Recruitment of a large number ofMUPs with weak voluntary force (early recruitment) ischaracteristic of a myopathic pattern.46,55

Neuromuscular Junction Testing

Repetitive Nerve Stimulation. With an electrode setupsimilar to that used for motor nerve conduction, a train of10 supramaximal stimuli at 23 Hz is applied. A 10%decrement of CMAP amplitude from first to fourth re-sponse is considered significant and indicates compromiseof neuromuscular transmission (eg, in myasthenia gravisand neuromuscular junction blockade) (Fig. 5).26,46,59 Pre-synaptic neuromuscular junction disorders (eg, Lambert-Eaton syndrome and botulism) have low baseline CMAPamplitude. An increment response of 100% can be elic-ited following a 10-second exercise of muscle being testedor with fast (2050 Hz) repetitive stimulation (Fig. 6).60

Single-Fiber EMG. The basis of single-fiber EMG is torecord a pair of muscle fiber action potentials belonging tothe same motor unit. Variability in the interspike interval(termed jitter) and absence (blocking) of second poten-tial is observed (Fig. 7). Prolonged jitter and/or blockingcharacterizes neuromuscular junction dysfunction.61,62 Sin-gle-fiber EMG is more sensitive than repetitive nerve stim-ulation; however, it is technically demanding and requires

special expertise. The procedure can be modified to stim-ulated single-fiber EMG for patients unable to performvoluntary contraction.63

Train-of-4 Stimulation. Train-of-4 stimulation is a sim-ple bedside procedure, physiologically similar to repetitivenerve stimulation, and is used to monitor nondepolarizingneuromuscular blockade. Typically, the ulnar nerve is stim-ulated at the wrist (4 impulses at 2 Hz). The patientsthumb is gently supported in abducted position, and ad-duction twitch, due to contraction of the adductor pollicismuscle, can be felt.64 Normally, all 4 responses are elicitedand the nondepolarizing neuromuscular blockade dose istitrated to produce 1 or 2 twitches. Absence of twitchesindicates complete blockade (nondepolarizing neuromus-cular blockade overdose).65 However, whether train-of-4monitoring has a definitive role in improving recoverytime from neuromuscular blockade is controversial.66

Respiratory EMG

Phrenic Nerve Conduction. The phrenic nerve conduc-tion study is particularly relevant in patients with sus-pected respiratory muscle weakness and those who have

Fig. 6. Repetitive nerve stimulation in a patient with Lambert-Eatonsyndrome. A: Decrement response on low (2-Hz) rate of stimula-tion. B: Increment response on 50 Hz stimulation.

Fig. 7. Single-fiber electromyography and recording of jitter be-tween 2 muscle fiber action potentials of the same motor unit.A: Normal. B: Increased jitter. C: Increased jitter with blocking.Recordings B and C are from a patient with myasthenia gravis.(From Reference 61, with permission.)



difficulty weaning from the ventilator. Percutaneous stim-ulation of the phrenic nerves is performed bilaterally in thesupraclavicular fossa, unless precluded by a central line onone or the other side of the neck (Fig. 8). DiaphragmCMAP is recorded with surface disk electrodes placed16 cm apart, at the xiphoid process and the costal mar-gin.67,68 Latency to onset and amplitude of CMAP arenoted. Reduced diaphragm CMAP amplitude with nearnormal phrenic motor latency has been observed inCIP.2,68,69 Demyelinating neuropathies (eg, Guillain-Barresyndrome) show markedly prolonged latency and/or re-duced amplitude and temporal dispersion of CMAP.70,71 Aunilateral abnormality often suggests a traumatic or post-operative lesion of the phrenic nerve.71,72

Needle EMG of the Diaphragm. The needle electrodeis inserted through any intercostal space, just above thecostal margin, between the anterior axillary and medialclavicular lines. Diaphragm activity is identified in theform of bursts of MUPs during inspiration. Spontaneousactivity can be assessed during quiet intervals between thebursts.68 To evaluate EMG activity of voluntary respi-ration, intermittent mandatory ventilation is temporarilydiscontinued under close supervision. Spinal cord (C3-C5) lesions, phrenic nerve injury, and CIP are associatedwith findings of active denervation.68,69,73 Severe chronicobstructive pulmonary disease, ileus, and bleeding diathe-sis are contraindications for needle EMG of the diaphragm.

Special Techniques

Blink Reflex. Blink reflex may be considered the electri-cal correlate of the corneal reflex, with the ipsilateral trigem-inal nerve as the afferent limb and the bilateral facial nerve asthe efferent limb of the reflex arc. Blink reflex has been usedin evaluation of peripheral and central lesions of those nerves.

Electrical stimulation of the supraorbital nerve elicits a direct(R1) ipsilateral response and a delayed (R2) bilateral simul-taneous response from the orbicularis oculi muscles.74 Ap-plication of the blink reflex in ICU patients with neuromus-cular disorders is based on the experience that blink reflex isabnormal in acquired demyelinating neuropathies (eg, Guil-lain-Barre syndrome and chronic inflammatory demyelinat-ing polyneuropathy) and is unaffected in axonal neuropa-thies, and thus may help distinguish between Guillain-Barresyndrome and CIP.75

Direct Muscle Stimulation. Rich et al20 initially appliedthe technique of direct muscle stimulation in ICU patients,and they found inexcitability of muscle in patients withacute quadriplegic myopathy. Direct muscle stimulation isperformed by placing both stimulating and recording nee-dle electrodes in the muscle distal to the end-plate zone(Fig. 9). A direct muscle-stimulated CMAP is recorded,and then the motor nerve of the muscle is stimulated toobtain a nerve stimulated CMAP with the same recordingelectrode. In neuropathic lesions (eg, CIP), nerve stimu-lated CMAP may be reduced or absent, but direct muscle-stimulated CMAP is normal. In contrast, CIM is associ-ated with reduced or absent CMAP on nerve stimulation,as well as on direct muscle stimulation. This observationformed the basis for investigating direct muscle stimula-tion to distinguish between CIP and CIM. Later studiesused the ratio of the nerve-stimulated CMAP to the directmuscle-stimulated CMAP, or the absolute amplitude of thedirect muscle-stimulated CMAP, to determine musclemembrane excitability.21,22,76 Rich and Pinter77 also stud-ied an experimental model of acute quadriplegic myopathyand found that inexcitability of muscle membrane wasrelated to inactivation of sarcolemma Na channels. Thetechnique has provided a diagnostic method and helped to

Fig. 8. Phrenic nerve conduction. A: Electrode placement for stimulation (S), ground (Gr), and recording (G1 and G2). B: Normal diaphragmcompound muscle action potential (CMAP) (top trace) and reduced amplitude of diaphragm CMAP (bottom trace). C: Needle electromyo-graphy (EMG) recording from the diaphragm, which shows normal EMG bursts during inspiration.



understand the pathophysiology of CIM. The procedure,however, is technically demanding and has been used onlyin a few centers so far.

Muscle and Nerve Biopsy

Nerve and muscle histological studies have substantiallycontributed to our understanding of the wide clinicopath-ological spectrum of new onset weakness in critically illpatients.10,16,18,34,35,78 Various studies on nerve histology(autopsy or surgical pathology) in patients with CIP haveconfirmed axonal degeneration of motor and sensory nervefibers without inflammation.10,34 Through muscle biopsystudies it became obvious that CIM, as an isolated syn-drome or in combination with CIP, may be more commonthan the neuropathic syndrome. Experience with musclebiopsy has led to definition of various histological sub-types (eg, acute necrotizing myopathy, thick myosin fila-ment loss myopathy [Fig. 10], and type II fiber atro-phy).10,16,7880 Many patients have various combinationsof these changes. Generally, the role of muscle biopsy ina weak ICU patient is 2-fold: (1) to distinguish a neuro-pathic from a myogenic process, and (2) to determine thespecific etiology, based on morphologic characteristics (eg,polymyositis/dermatomyositis, mitochondrial myopathy,or CIM). Percutaneous punch muscle biopsy or open mus-cle biopsy can be performed, and the interpretation shouldbe done by experienced individuals. Therefore, the proce-dure is often carried out for research purposes or when an

underlying neuromuscular disorder is suspected becauseof an absence of risk factors for CIM or lack of improve-ment in 34 weeks. Nerve biopsy is not indicated in clin-ical investigations of these patients, unless a specific dis-order, such as vasculitic neuropathy, is suspected.

Disorders That Cause Neuropathic Weakness

Critical Illness Polyneuropathy

CIP has a rather stereotypical evolution in the ICU.Initial critical illness (eg, sepsis, burn, trauma) is followedby multiorgan failure, septic encephalopathy, difficultyweaning from the ventilator in the absence of cardiopul-monary compromise, and generalized muscle weakness.5Electrophysiological and pathological studies confirm thepresence of axonal motor and sensory polyneuropathy inthese patients.34 CIP is now recognized as an importantand serious complication of sepsis and critical ill-ness.6,810,13,19,25 Weakness is indicated by the patientsinability to move extremities in response to pain, whilestrong facial grimacing shows wakeful status. The degreeof weakness ranges from moderate paresis with hypore-flexia to severe areflexic quadriplegia. The weakness ispredominant distally and in the lower extremities. Thecranial nerves are spared, although facial weakness is oc-casionally reported. Sensory impairment occurs in only50% of patients, and this may reflect difficulty in perform-ing sensory examination in the ICU. Hyporeflexia/areflexiais common, although muscle stretch reflexes may be nor-mal in about one third of the patients, and at times may beexaggerated if there is concomitant CNS involvement.81

Fig. 9. Direct muscle stimulation. Both the stimulating and recordingelectrodes are placed in the muscle. A: Potentials on direct muscleand nerve stimulation are obtained. B: Direct muscle potential is nor-mal in nerve lesions. C: Direct muscle potential is absent or reducedin myopathy. (From Reference 25, with permission.)

Fig. 10. Electron micrograph from a biceps muscle of an intensive-care patient with quadriplegia, showing thick myosin filament loss.(From Reference 80, with permission.)



EMG and nerve-conduction studies show low amplitudeof CMAP and nerve action potential, with near normalconduction velocity and the presence of fibrillation andpositive sharp wave potentials consistent with axonopa-thy.2,6,12,19,34,42,69 Abnormal phrenic nerve conduction (bi-lateral reduced or absent diaphragm CMAP) is reported inabout 5080% of patients.19,82 Clinical CIP may occur in3050% of ICU patients, but prospective electrophysio-logical studies describe an incidence of 7080%.24,69,82The occurrence of CIP correlates with duration of ICUstay and severity of sepsis. High mortality (60%) in pa-tients with CIP probably relates to underlying critical ill-ness, but some investigators think that mortality is higherin patients with CIP than in those with comparable AcutePhysiology and Chronic Health Evaluation (APACHE III)

score without CIP.83 Follow-up studies showed severe pa-ralysis in 4 of 15 survivors, and impaired quality of life in11 of 13 survivors. Long-term outcome with moderate-to-severe deficits is variably reported in 3080% of cases andappears to be much less favorable than Guillain-Barre syn-drome or CIM.13,84 Clinical and laboratory features that dis-tinguish among these syndromes are outlined in Table 3.

Guillain-Barre Syndrome

Guillain-Barre syndrome is the most common neuro-muscular disorder that requires admission to the ICU, aswell as the most important differential diagnosis for CIP.Antecedent illness, rapid ascending flaccid paralysis, and

Table 3. Clinical Features and Laboratory Findings of Critical-Illness Polyneuropathy, Guillain-Barre Syndrome, and Critical Illness Myopathy

Findings

Critical Illness Polyneuropathy Guillain-Barre Syndrome Critical Illness Myopathy

Clinical setting Sepsis Antecedent viral Neuromuscular blocking drugsMultiorgan failure Surgery CorticosteroidsSeptic encephalopathy Campylobacter jejuni Asthma

HIV Organ transplant

Motor weakness Generalized or distal predominant Generalized, ascending, areflexia Generalized or proximalpredominant

Cranial nerve palsy Rare Common OccasionalUnilateral/bilateral facial Ophthalmoparesis, bilateral facialBulbar

Dysautonomia No Yes No

Sensory deficit Distal Mild, distal No

Creatine kinase Normal Normal Elevated

Nerve conduction Reduced CMAP and SNAP amplitude Marked slowing, conduction block Reduced CMAP amplitudeNormal SNAP amplitude

Needle EMG Abnormal spontaneous activity Abnormal spontaneous activity may Mild or no abnormal spontaneouscommon be seen activity (pronounced in

Reduced recruitment Reduced recruitment necrotizing)Large, polyphasic MUPs Normal MUPs initially; may be

large, polyphasic MUPs laterSmall polyphasic MUPs; early

recruitment

Direct muscle stimulation Normal Normal Absent or reduced

Muscle biopsy Neuropathic changes Neuropathic changes MyopathicThick myosin filament lossWidespread muscle-fiber necrosis

in acute necrotizing

HIV human immunodeficiency virusCMAP compound muscle action potentialSNAP sensory nerve action potentialEMG electromyographyMUP motor unit potential



cranial nerve involvement are characteristic features. Ele-vated CSF protein and electrodiagnostic findings of mark-edly slow nerve conduction, prolonged or absent F waves,and conduction block (which suggest demyelinating neu-ropathy) clearly distinguish it from CIP.6,33,50 The pres-ence of dysautonomia, abnormal blink reflex, and pro-longed phrenic nerve latency are also helpful.50,71,75 Theaxonal variant of Guillain-Barre syndrome (about 5% ofcases) may be difficult electrophysiologically to differen-tiate from CIP. This variant is reported most often in as-sociation with Campylobacter jejuni infection and GM1ganglioside antibody.25 In general, testing for gangliosideantibody levels is not indicated. It is important to distin-guish incidental Guillain-Barre syndrome in the ICU (whichmay follow a medical illness or surgery) from CIP, be-cause specific treatment with intravenous immunoglobulinor plasmapheresis is indicated for Guillain-Barre syndrome.

Other Acute Neuropathies

Occasionally, acute neuropathies due to uncommoncauses have been encountered in the ICU setting. Humanimmunodeficiency virus infection is associated with vari-ous clinical forms of peripheral neuropathy and may alsopresent with acute polyneuropathy similar to Guillain-Barresyndrome.38 In the presence of risk factors, human immu-nodeficiency virus antibody testing is relevant.

Rarely, neuropathy of acute intermittent porphyria maydevelop in the ICU, because acute attack can be precipi-tated by medications or infection. It is an acute axonalneuropathy, CSF protein is not elevated, and features suchas seizures, arrhythmia, abdominal pain, and psychiatricsymptoms may be associated.28,38 Toxic neuropathies areunlikely to be encountered in the ICU. Some possibilitiesare prior cancer chemotherapy (platinum, taxanes, vincaalkaloids, suramin), amiodarone, and metronidazole.38

Peripheral nerve involvement in vasculitis usually pre-sents as subacute onset of mononeuritis multiplex. Wide-spread involvement may mimic symmetric or asymmetricpolyneuropathy.85 Involvement of other organs and find-ings of multifocal axonal neuropathy on EMG are sugges-tive of the diagnosis. Suspicion of vasculitic neuropathy isan important indication for nerve biopsy.

Compression Neuropathies

ICU patients may be prone to development of focalneuropathies at compression sites (eg, ulnar nerve at el-bow, peroneal nerve at fibular head, and radial nerve inspiral groove), due to positioning, weight loss, et cetera.Multiple bilateral focal compressive syndromes may mimicdistal polyneuropathy. On electrophysiologic testing, focalslowing of nerve conduction and/or conduction block atcommon sites of compression, and neurogenic EMG pat-

tern in corresponding muscles, are diagnostic.45,47 Com-pression neuropathies superimposed on CIP have been re-ported to contribute to long-term deficits.86

Acute Poliomyelitis

Poliomyelitis due to poliovirus is no longer prevalent;however, similar acute paralysis may occur due to non-poliovirus infection. Acute, flaccid, and often asymmetricparalysis due to West Nile virus is being increasingly rec-ognized.87 Bulbar and respiratory muscles may also beinvolved. Patients may be admitted to the ICU for alteredmental status due to West Nile virus encephalitis or men-ingitis and later develop flaccid paralysis. Predominantlyproximal, asymmetric weakness, preserved reflexes, andnormal sensation distinguish West Nile virus paralysis fromGuillain-Barre syndrome and CIP. CSF shows increasedprotein level and lymphocytic pleocytosis, and immuno-globin M antibody to West Nile virus is detected in serumor CSF. Electrodiagnostic studies show reduced CMAPwith normal motor nerve conduction velocity, normal sen-sory responses, and neurogenic EMG in segmental pattern.Rarely, West Nile virus has been associated with demy-elinating neuropathy similar to Guillain-Barre syndrome.88

Amyotrophic Lateral Sclerosis

Previously undiagnosed patients with ALS may presentwith acute ventilatory failure due to isolated or predomi-nant respiratory muscle weakness.31,89 They fail to weanfrom the ventilator and show signs of limb wasting, gen-eralized fasciculations, and brisk reflexes. Diagnosis isconfirmed by electrodiagnostic studies, which reveal wide-spread active denervation, chronic reinnervation, and fas-ciculation potentials. Lacomis et al recognized 5 patientswith ALS among 92 ICU patients referred for electrophys-iological study.31

Hopkins Syndrome

In 1974, Hopkins90 reported a polio-like syndrome inchildren following acute asthma. About 30 patients havebeen reported since then.91 There is acute flaccid mono-paresis or, at times, paraparesis. Marked atrophy and per-sistent deficits are noted on follow-up. EMG is consistentwith motor neuron involvement, and muscle biopsy showsgrouped atrophy. Recently, the disorder was reported inadults as well. The etiology is not known; however, in-creased CSF protein and lymphocytic pleocytosis, and oc-casional improvement after intravenous immunoglobulintherapy, may point to an immune or inflammatory pro-cess.92



Disorders That Cause Myopathic Weakness

Critical Illness Myopathy

A syndrome of acute myopathy in a patient with asthmawho received neuromuscular blocking agents and cortico-steroids was documented in the 1970s.7 Primary muscleinvolvement in ICU patients initially remained under-rec-ognized, but there has been increasing interest in and multi-modal investigations of ICU paralysis syndromes, whichhave indicated that CIM may be the commonest newlyacquired neuromuscular disorder in the ICU.8,16,21,22,31,35Predisposing factors are acute asthma, exacerbation ofchronic obstructive pulmonary disease, organ transplant,acute respiratory distress syndrome, sepsis, and use of highdoses of corticosteroids and neuromuscular-blockingagents. Patients develop symmetric diffuse weakness of allextremities, muscle wasting, hyporeflexia, and failure towean from the ventilator. The major differential diagnosisis from CIP and, rarely, other acute myopathies (rhabdo-myolysis, acute polymyositis, electrolyte disorders). Theclinical setting, preserved reflexes, normal sensory exam-ination, ophthalmoparesis, and facial weakness may favorthe possibility of CIM; however, there are no definitiveclinical findings to distinguish CIM from CIP, and theexamination in the ICU may be unreliable.18,33,78

Elevated serum creatine kinase in acute weakness is animportant diagnostic feature, especially in the early part ofthe illness. Typical EMG features include low amplitude,short duration and polyphasic MUPs, with good recruit-ment pattern despite pronounced weakness. CMAP ampli-tude is reduced and sensory potentials are normal. Fibril-lation and positive sharp wave potentials, which are usuallyindicative of axonal injury, also occur in necrotizing my-opathies. There are many caveats to interpreting electro-physiological studies in the ICU. Assessment of voluntaryEMG may be difficult when the patient cannot activatemotor units due to severe weakness, sensory potentialsmay be technically difficult to elicit, and reduced CMAPwith normal motor nerve conduction is seen in CIP as wellas CIM. It is therefore not surprising that many investiga-tors have pointed out the difficulties in distinguishing be-tween the 2 neuromuscular syndromes.10,21,22,25,42 Thenewer technique of direct muscle stimulation demonstratesmuscle membrane inexcitability in CIM.20 The ratio ofnerve-stimulated CMAP to direct muscle-stimulatedCMAP is reduced in neuropathic lesions and is closer to1.0 in CIM.21 Recent studies show that combining directmuscle stimulation with routine studies is useful in properclassification of neuromuscular weakness in the ICU; how-ever, the technique is not routinely applicable as yet.22,76

Muscle biopsy shows varying severity of myopathicchanges, in contrast to grouped atrophy in neuropathy, but,being an invasive procedure, it is not routinely employed

for clinical diagnosis. Histopathological studies show vary-ing degrees of muscle fiber necrosis, most prominently inacute necrotizing myopathy, without inflammatory cells.Thick myosin filament loss is a distinctive abnormality inCIM (see Fig. 10). Predominant type II muscle fiber atro-phy has been termed cachectic myopathy.78 Stibler et al93noted decreased myosin/actin ratio in percutaneously ob-tained muscle biopsies of CIM patients, and suggested thatit may be useful for rapid diagnosis. For clinical purposes,the combination of predisposing events, clinical findings,and electrophysiological investigation allows a reasonablediagnosis of CIP or CIM (see Table 3). Muscle biopsy isconsidered if other causes of myopathy (eg, polymyositis)are suspected. Most of the advanced techniques are rele-vant for research purposes.

Rhabdomyolysis

Trauma, sepsis, and various medications (see Table 2)can precipitate acute rhabdomyolysis in ICU patients. Mus-cle pain, swelling, predominant proximal or generalizedweakness, and markedly raised serum creatine kinase arenoted. Myoglobinuria, acute renal failure, and other sys-temic complications are present.28,43

Other Causes of Myopathy

Several primary muscle diseases may present with ini-tial manifestations of respiratory compromise (eg, poly-myositis, mitochondrial myopathy, and acid maltase defi-ciency). Patients with myotonic muscular dystrophy orcongenital myopathies may decompensate after generalanesthesia. Such patients are emergently admitted to ICU,and the underlying muscle disease may be suspected andevaluated only later during the ICU stay.38,94 Muscle bi-opsy is diagnostic and needs to be considered if a patientin whom CIM is suspected does not show improvementover a few weeks.

Disorders of Neuromuscular Transmission

Prolonged Neuromuscular Junction Blockade

Patients treated with high doses of nondepolarizing neu-romuscular blocking agents such as vecuronium and pan-curonium may have persistent weakness and fail weaningfrom the ventilator, even after the blocking drugs havebeen discontinued.14,15 This prolonged blockade may lastfrom several hours to weeks. Patients with renal failure,hepatic dysfunction, acidosis, or hypermagnesemia aremore prone to this complication. Examination shows gen-eralized weakness, normal or reduced reflexes, and normalsensation. Bilateral ptosis, and facial and jaw muscle weak-ness may be present.26,33 Electrophysiologic features are



reduced CMAP amplitude and decrementing response on23 Hz repetitive nerve stimulation. The physiologic ab-normality reverses on clinical recovery.26,38 Patients withuncomplicated prolonged neuromuscular blockade recovercompletely, usually in 12 weeks. The condition may co-exist with CIP or CIM and has been reported to progressto CIM on sequential studies. Recognition of prolongedneuromuscular blockade has led to more judicious use ofneuromuscular blocking drugs in the ICU.65

Myasthenia Gravis

Patients with myasthenia gravis typically require admis-sion to the ICU for myasthenic crisis or cholinergic crisis.Several factors, such as infection, electrolyte disorder anddrugs used in the ICU (see Table 2), may unmask latentmyasthenia gravis. Rarely, respiratory failure may be thepresenting feature in myasthenia gravis. Clinically, ptosis,ophthalmoparesis, and facial and bulbar weakness are com-mon, in addition to generalized weakness. Diagnosis isbased on positive edrophonium test, decrementing responseon repetitive nerve stimulation, and presence of serumacetylcholine receptor antibody. Abnormal jitter on single-fiber EMG is a very sensitive diagnostic test, but is notroutinely employed. Between 85% and 90% of patientswith generalized myasthenia gravis are seropositive foracetylcholine receptor antibody. Among the seronegativepatients, a subgroup with antibody to muscle-specific ty-rosine kinase has been identified.95 These patients withmyasthenia gravis have certain atypical features, includingprominent neck extensor, facial and respiratory muscleweakness, and poor response to acetylcholine-esterase in-hibitors. Respiratory crisis may be a presenting feature, soin a patient with suspected generalized myasthenia graviswho is seronegative for acetylcholine receptor antibody,serum assay for muscle-specific tyrosine kinase antibodyshould be considered.

Other Neuromuscular Junction Disorders

Lambert-Eaton Syndrome. This is a presynaptic neu-romuscular transmission disorder due to calcium channelantibodies, which impair acetylcholine release from thenerve terminal. It is usually associated with small-cell lungcancer but may also occur as an idiopathic autoimmunedisorder. Reduced CMAP on nerve conduction and incre-menting response on high frequency repetitive nerve stim-ulation are characteristic. Similar to myasthenia gravis,patients with Lambert-Eaton syndrome may also presentwith previously unrecognized or unmasked weakness inthe ICU.28,29

Botulism. Generalized weakness and cranial nerve in-volvement in botulism may resemble Guillain-Barre syn-

drome, but paralysis is often described as descending, anddeep tendon reflexes may be preserved.38 Blurred visionand dilated pupils due to paralysis of accommodation arenoted. This is also a presynaptic disorder, and electro-physiologic findings of reduced CMAP and increment ontetanic stimulation are observed.

Summary

Complications of critical illness, including CIP, CIM,and prolonged neuromuscular blockade, are now regardedas the major cause of new onset weakness in the ICUsetting. These need to be distinguished from other neuro-logical disorders that may begin after admission to theICU, or when a diagnosis has not been established prior toan emergency admission. The first step in clinical exam-ination is to distinguish CNS lesions, especially brain stemand spinal cord lesions, and to obtain magnetic resonanceimaging or computed tomography of the brain or spine, ifindicated. Special attention should be paid to patients withlocked-in syndrome, since this may result from struc-tural brain stem lesions or neuromuscular disorders. Neu-rological examination in the ICU can be challenging; how-ever, combined clinical and electrophysiologicalassessment helps delineate anterior horn cell, nerve, mus-cle, and neuromuscular junction disorders. The nature ofthe underlying illness and the drugs received in the ICUshould be noted. Some of the neurological causes to beconsidered are new onset Guillain-Barre syndrome, latentmyasthenia gravis, predominant respiratory involvementin ALS, rhabdomyolysis, flaccid paralysis associated withWest Nile virus, and muscle-specific tyrosine kinase an-tibody myasthenia gravis presenting with respiratory cri-sis.

Typical features of CIP include evidence of systemicinflammatory response syndrome and multiorgan dysfunc-tion, followed by generalized or distal weakness, distalsensory deficits, spared cranial nerves, and findings ofaxonopathy on EMG. CIM often follows use of high dosesof neuromuscular blocking drugs and corticosteroids. Gen-eralized or proximal weakness, elevated creatine kinase,and myopathic pattern on EMG are noted. Severe areflexicquadriplegia, markedly elevated creatine kinase, myoglo-binuria, and muscle fiber necrosis on muscle biopsy arecharacteristic of acute necrotizing myopathy. Thick myo-sin filament loss is another distinct pathological feature ofCIM. The technique of direct muscle stimulation has de-fined inexcitability of muscle membrane as a mechanismof weakness in CIM and has been used by some investi-gators to distinguish CIM from neuropathic lesions. Mus-cle biopsy may be used to distinguish between neuropathicversus myopathic lesions, to define type of CIM, and toestablish a specific diagnosis when an underlying muscledisease is suspected.



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Discussion

Deem: Which patients should re-ceive muscle biopsy? How do you de-termine when to do a muscle biopsy?

Upinder Dhand: The main reasonfor muscle biopsy is to diagnose pre-viously unsuspected underlying mus-cle disease or to distinguish betweenICU-related syndromes. The lattermay become more relevant from a re-search point of viewthat is, under-standing the relationship of variousICU factors to different neuromuscu-lar syndromes. Most of the time, mus-cle biopsy is clinically indicated onlyin selected cases in whom an addi-tional or previously undiagnosed pri-mary muscle disease is suspected.

Deem: Do you use direct musclestimulation in your hospital?

Upinder Dhand: No, Im not usingthat technique. I am aware of only 2groups doing it: Richs, at Universityof Pennsylvania,1 and Trojaborgs, atColumbia University.2

REFERENCES

1. Bird SJ, Rich MM. Critical illness myop-athy and polyneuropathy. Curr Neurol Neu-rosci Rep 2002;2(6):527533

2. Trojaborg W, Weimer LH, Hays AP. Elec-trophysiologic studies in critical illness as-sociated weakness: myopathy or neuropa-thy: a reappraisal. Clin Neurophysiol 2001;112(9):15861593.

Jubran: In what clinical settings doyou use needle electrodes to obtaindiaphragm EMG? Do you use ultra-sound to help guide the measurements?How well do patients tolerate the pro-cedure?

Upinder Dhand: When Im doingan EMG study in the ICU, and thequestion is about difficulty in wean-ing, I test the phrenic nerve conduc-tion and the diaphragm with needleEMG, except when there is an obvi-ous contraindication. For example, ina patient with severe COPD, the lungmay be at a much lower level and theprocedure could be risky. Or in a pa-tient who has had laparotomy and ac-cessing the diaphragm may be diffi-cult. But usually its not difficult.

When you put the needle through theintercostal space, you first run into theintercostal muscles, and, incidentally,you can look for denervation in the in-tercostal muscle itself, and then go on tothe diaphragm. The last portion of thediaphragm is actually directly by the tho-racic cage, and the pleura is already re-flected about an inch or so higher. I thinkICU patients probably tolerate the pro-cedure better than other patients, but Ido it in my routine laboratory also, inpatients with breathing difficulty andneuromuscularweakness. It is fairlywelltolerated.

Mehta: We have a really difficulttime getting EMGs. It can take months.

So mainly it comes down to suspicionof critical illness polyneuropathy ormyopathy. And weve concluded thatit really doesnt matter which one itis, because clinically you deal withthem in the same way. What do youthink?

Upinder Dhand: I think we all areprobably learning from experience. AsSteve Deem was also saying, thesemay be considered as one entity. Nowyou may just call it a neuromuscularsyndrome in the ICU setting, and someauthors have used the term critical-illness neuromyopathy. But there isconfusion for several reasons. One isthat clinical examination and investi-gations may not clearly distinguish be-tween critical illness neuropathy andmyopathy, or the 2 syndromes maycoexist. Maybe there is a whole spec-trum with neuropathy at one end, my-opathy at the other, and overlap in be-tween. The reason I want todifferentiate between the two is be-cause of the outcome. The long-termcare may be different.

I think critical illness neuropathyprobably has more residual deficits andgreater chance of mortality, whereasin critical illness myopathy the out-come is probably much betterotherthan patients who have fulminant, ne-crotizing myopathy. Moreover, inves-tigations may help identify a differentneurological cause. And, finally, Ithink it is particularly important for



people who are interested in this sub-ject to distinguish between the two,because we are still in the process ofunderstanding these disorders. So I stillprefer to investigate.

With regard to getting the EMGs inthe ICU, we have a policy that if weget a call for an in-patient EMG, it isdone within 24 hours. I dont come atnight, but it is within 24 hours.

Mehta: We cant get EEGs within24 hours!

Hill: You cited a mortality rate of60% for critical illness polyneuropathy,but I see it as a manifestation of multi-ple organ system failure, in associationwith the sepsis syndrome, as in ARDS[acute respiratory distress syndrome], inwhich mortality is 40% to 50%. Butpeople generally dont die of respira-tory failure. Is that thecase with criticalillness polyneuropathy? Are people dy-ing of multiple organ system failurerather than the neuropathy, per se?

Upinder Dhand: Yes. Various au-thors have mentioned that the mortal-

ity is related to the severe underlyingillness, so it is not directly the resultof critical illness polyneuropathy.

Deem: Ill address that question inmy upcoming talk. I have a questionabout train-of-4 monitoring and neu-romuscular blockade in the ICU. Atour institution we dont use prolongedneuromuscular blockade nearly asmuch as we used to, and I dont thinkwe see prolonged neuromuscularblockade as a cause of weakness muchany more. Im interested to know whatother people report in that regard. Per-sonally, I dont think train-of-4 mon-itoring is very useful, because its tech-nically difficult, like EMG. Theresedema, and the nurses arent very fa-miliar with the technique. I saw aninstance where they were having prob-lems and we discovered that the nervestimulators battery was dead. I thinkthe best way to prevent prolonged neu-romuscular blockade is to not use thedrugs, or to use them for short periodsof time, and to stop them every dayand reassess the patient.

Mehta: I have one more commentrelated to Herridges outcomes studywith 100 ARDS patients.1 The most in-teresting finding was that these patientsare not limited by pulmonary functionat all. Their pulmonary function within3, 6, and 12 months was essentially nor-mal. But theyre limited by peripheralmuscle weakness. And the next phaseof Herridges research program is goingto focus on preventive measures for thatweakness. A major contributor may beneuromuscular blockers. We use neuro-muscular blockers much less frequentlythan we used to. We dont usually usedaily interruption of the blockers, butthats a really good strategy. Were verystrict about using train-of-4 monitoring,even when using short-acting agentssuch as cisatracurium.

REFERENCE

1. Herridge MS, Cheung AM, Tansey CM,Matte-Martyn A, Diaz-Granados N, Al-Saidi F, et al; Canadian Critical Care TrialsGroup. One-year outcomes in survivors ofthe acute respiratory distress syndrome.N Engl J Med 2003;348(8):683693.



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Clinical Approach to the Weak Patient in the Intensive Care Unit

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