Keywords
sepsis, septic encephalopathy, critical illness neuropathy, critical illness myopathy, critical illness polyneuropathy
Injury to other organ systems may have direct or remote neurologic effects. Hepatic, cardiac, pulmonary, pancreatic, and renal dysfunction can directly impact neurologic function through a variety of mechanisms outlined elsewhere in this book. This chapter examines the immediate and long-term effects of critical illness on both the central and peripheral nervous systems (CNS and PNS).
Septic Encephalopathy
Septic encephalopathy is a nebulous term used to describe an encephalopathy encountered in critically ill patients that cannot be explained by either direct neurologic injury, indirect effects of other failing organ systems, or exogenous toxins. It is a diagnosis of exclusion. Septic encephalopathy is defined as “altered brain function due to the presence of microorganisms or toxins in the blood,” but this definition is incomplete since bacteremia is rare and exogenous substances are not mentioned. Sepsis-associated encephalopathy and sepsis-associated delirium have been proposed as more descriptive terms but are not widely used.
Epidemiology
Encephalopathy during critical illness is common. It is estimated that between 9 and 71 percent of critically ill patients become confused. The higher estimates in this range are more accurate when more sensitive tests are employed and as physicians have become more aware of the diagnosis. The presence and severity of this encephalopathy have significant impact on both immediate mortality and long-term cognitive capabilities.
Overview of the Mechanisms of Sepsis
A response to an infection is initiated when pattern-recognizing receptors on macrophages bind cellular components of microbial cell walls. Binding of these receptors initiates a signaling cascade, via the nuclear factor-κB system, to release cytosolic factors that translocate to the nucleus, activating gene transcription for a variety of proteins including pro-inflammatory cytokines (tumor necrosis factor and interleukin 1), chemokines, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and nitric oxide. These factors subsequently attract polymorphonuclear leukocytes to the site of the injury and these release local substances that account for the cutaneous changes occurring with inflammation (e.g., erythema, edema, warmth).
Inflammation is subsequently regulated through a balance between proinflammatory cytokines released by macrophages and anti-inflammatory factors released by polymorphonuclear leukocytes. This balance typically leads to local infection control. Sepsis occurs when the response to an infection generalizes beyond local boundaries to affect remote organ systems. The systemic inflammatory response syndrome (SIRS) reflects a similar process that is initiated by conditions other than acute infection. Systemic release of proinflammatory cytokines can become self-sustaining, leading to a cycle of systemic inflammation, complement activation, and stimulation of both coagulation and fibrinolytic cascades. Various single nucleotide polymorphisms increase susceptibility to sepsis on a genetic basis.
Sepsis affects organ systems primarily through its effect on the endothelium of vascular tissue. Sepsis induces both vasodilation (most likely through nitric oxide) and myocardial depression, which leads to significant hypotension. Regional circulation is altered, affecting the distribution of blood to ischemic organs. Endothelial dysfunction also leads to increased vascular permeability with subsequent tissue edema. Decreased functional capillaries at the microcirculatory level may be due to either extrinsic compression from tissue edema or intravascular coagulation. Red cell deformability is decreased in sepsis, further inhibiting oxygen delivery.
Oxygen utilization at the mitochondrial level is affected directly by proinflammatory mediators, which cause mitochondrial dysfunction through direct inhibition of respiratory chain enzymatic function. Oxidative stress–induced damage is believed to account for an increase in mitochondrial breakdown products, and cell death may be attributed to cellular inability to utilize oxygen.
Secondary cell death through apoptosis is actually decreased in sepsis. However, septic mediators and proinflammatory cytokines also delay apoptosis in macrophages and neutrophils, leading to a net effect of prolonged inflammatory physiology.
Pathogenesis of the Encephalopathy
The endothelial and microvascular effects of sepsis affect all organs. The subsequent hypoxia from pulmonary failure, uremia from renal failure, and alterations in amino acid metabolism from hepatic failure may contribute to the encephalopathy commonly encountered in septic patients. However, an encephalopathy may also develop early in the course of sepsis or SIRS that precedes the development of secondary organ failure. Although the exact mechanism of this neurologic dysfunction is unknown, it is generally believed that septic mediators, primarily the proinflammatory cytokines and complement factors, gain access to the brain neuropil, leading to functional disruption of neurologic transmission and eventual cell damage and death.
How these factors gain access to the brain has been an area of considerable study. Animal models have supported a direct toxic effect of some mediators on the integrity of the blood–brain barrier. Neonatal kittens exposed to E. coli lipopolysaccharide develop diffuse cerebral white matter disruption with noted extravasation of Evans blue dye throughout the brain. Similarly, horseradish peroxidase is transported into the septic rat neuropil in a retrograde fashion, disrupting the blood–brain barrier. Lipopolysaccharide exposures have been linked to direct transport of cytokines across the blood–brain barrier in mice. Inflammatory mediators in the cerebrospinal fluid (CSF) may also gain access to the brain through the circumventricular organs located around the midline ventricular system.
Blood–brain barrier disruption may not be necessary for leukocyte-induced inflammatory mediators to gain access to the brain. Tissue necrosis factor and interferon-γ directly increase the permeability of cerebral endothelial cells through increased pinocytosis without immediate disruption of the blood–brain barrier’s intercellular tight junctions. Radiolabeled amino acids and albumin have been detected in the brains of septic rats. The CSF profile in septic patients is generally acellular, but protein concentration may be increased.
Once inflammatory mediators have gained access to the brain parenchyma, the effects are similar to those seen in other organs. Localized cerebral edema can occur due to endothelial damage.
Cerebral blood flow and metabolism are depressed in septic patients and cerebral autoregulation is disturbed. The resulting cerebral hypoperfusion may contribute to encephalopathy. These vascular changes may result from direct neural involvement of inflammatory mediators. Astrocytes contain receptors for these inflammatory mediators and damage to their end foot processes has been demonstrated in animal models of sepsis, leading to poor blood flow coupling. Decreased cerebral blood flow during sepsis may also be the direct result of mitochondrial dysfunction or a response to decreased cerebral metabolism. Direct mitochondrial dysfunction from endotoxemia is probably mediated through nitric oxide.
Cerebral ischemia is present in many cases of sepsis. Dead neurons have been identified in septic pigs with maintained cerebral perfusion, and microvascular lesions are commonly found in humans at pathology and on neuroimaging. Neuronal apoptosis in the setting of ischemia is presumably due to mitochondrial dysfunction. Postmortem studies have shown inducible nitric oxide synthase leading to apoptosis in the hippocampus.
The parasympathetic nervous system may in part mediate the inflammatory response as increased vagal tone appears to decrease inflammation and improve mortality in animal models of sepsis.
Presentation and Evaluation
The encephalopathy associated with sepsis and SIRS may present acutely or subtly with a slow progression. Disorientation, impaired cognition, and inattentiveness can progress to agitation, delirium, stupor, and coma. The pupils are typically small and minimally reactive. Brainstem reflexes are generally maintained until late in the course. Focal signs are rare but may occur.
The diagnosis remains one of exclusion. The patient should be evaluated for meningitis and encephalitis of infectious and autoimmune or paraneoplastic origin. Similarly, encephalopathies secondary to failure of other organ systems (e.g., hepatic, renal, pulmonary, and pancreatic) should be considered and treated. Clearance and metabolism of sedative medications commonly employed to treat critically ill patients may be delayed in multiorgan failure, complicating evaluation. Direct cerebral hypoperfusion from cardiac failure may also contribute to encephalopathy.
Serum levels of neuron specific enolase and S-100B are markers of neuronal and astrocytic damage; both have been shown to increase with septic encephalopathy and correlate with a worse outcome, but typically are not useful in clinical practice. The electroencephalogram (EEG) may be normal but becomes slower with increasing encephalopathy, progressing from theta to delta activity and finally to a burst-suppression pattern ( Fig. 56-1 ). Mortality correlates with worsening EEG findings. Nonconvulsive status epilepticus is probably under-recognized; continuous EEG monitoring may be helpful in its detection. Magnetic resonance imaging (MRI) is most sensitive to the changes that can occur during sepsis. Microhemorrhages and small ischemic lesions are detected in approximately 10 percent of patients, white matter changes are common, and cortical atrophy may occur in severe cases. The utility of somatosensory evoked potentials, functional MRI, and positron emission tomography (PET) requires more study.
Pathologically, small ischemic lesions are found in most autopsy samples. Additional findings include microhemorrhages in approximately 25 percent, microthrombi in 9 percent, white matter damage in 9 percent, and microabscesses in less than 5 percent.
Management and Future Studies
Unfortunately, there are no specific treatments for the encephalopathy associated with sepsis and SIRS. Early recognition and treatment of the underlying illness is the most effective therapy.
The multitude of inflammatory mediators that are believed to be involved in the development of the encephalopathy make specific targets for treatment difficult to ascertain. Inhibitors of nitric oxide synthase have been disappointing in animal studies, but inhibitors of glutamate, antioxidants, and complement factors have shown some promise.
Neuromuscular Conditions in Critically Ill Patients
Critically ill patients may have neuromuscular signs due to many possible etiologies that affect the CNS as well as the PNS ( Table 56-1 ). Lesion localization is particularly challenging to the clinician faced with multiple confounding factors in the setting of critical illness, including the frequent inability to obtain a history from patients, given mental status changes and physical impediments (e.g., endotracheal and orogastric tubes). In the modern intensive care unit (ICU), the multiplicity of invasive lines, tubings, electrodes and wiring for monitoring equipment, limb splints, restraints, occlusive dressings, and bandages all represent formidable physical obstructions to the clinical examination. Neuromuscular diagnoses are often delayed in critically ill patients due to the severity of underlying illness. Many primary critical care conditions will present with respiratory dysfunction and motor impairment that can be difficult to separate from primary neurologic conditions.
| Encephalopathy | Neuromuscular Transmission Defects |
| Septic | Neuromuscular blocking agents |
| Anoxic-ischemic | Aminoglycoside toxicity |
| Other | Myasthenia gravis |
| Myelopathy | Lambert–Eaton myasthenic syndrome |
| Anoxic-ischemic | Hypocalcemia |
| Traumatic | Hypomagnesemia |
| Other | Organophosphate poisoning |
| Neuropathy | Wound botulism |
| Critical illness polyneuropathy | Tick-bite paralysis |
| Thiamine deficiency | Myopathy |
| Vitamin E deficiency | Critical illness (myosin-deficient) myopathy |
| Nonspecific nutritional deficiency | Cachexia |
| Pyridoxine abuse | Acute rhabdomyolysis |
| Hypophosphatemia | Acute necrotizing myopathy of intensive care |
| Aminoglycoside toxicity | Electrolyte disturbances: potassium, phosphate, calcium, magnesium |
| Penicillin toxicity | Corticosteroid myopathy |
| Guillain–Barré syndrome | Muscular dystrophy |
| Motor neuron disease | Polymyositis |
| Porphyria | Acid maltase deficiency |
| Carcinomatous polyneuropathy | |
| Compression neuropathy | |
| Diphtheria |
Electrodiagnostic testing is an important part of the routine evaluation of critically ill patients with unexplained neuromuscular deficits. These investigations, however, are also significantly hampered by ICU conditions including electric interference, cool and edematous limbs, restricted access to sites of stimulation and recording due to physical barriers, and limited patient cooperation.
Critical illness polyneuropathy and myopathy are important conditions, but in diagnosing them, the clinician should be diligent in excluding the other disorders listed in Table 56-2 . Electrodiagnostic studies are ordered to support a clinical diagnosis such as Guillain–Barré syndrome and myasthenia gravis. The more extensive use of electrodiagnostic testing has allowed for the diagnosis of relatively uncommon neuromuscular conditions including Lambert–Eaton myasthenic syndrome and primary motor neuron disease, which may also be “unmasked” by intercurrent critical illness.
| Condition | Incidence | Clinical Features | Electrophysiologic Findings | Serum Creatine Kinase Level | Muscle Biopsy | Prognosis |
|---|---|---|---|---|---|---|
| Polyneuropathy | ||||||
| Critical illness polyneuropathy | Common | Flaccid limbs and respiratory weakness | Axonal degeneration of motor and sensory fibers | Nearly normal | Denervation atrophy | Variable |
| Neuromuscular Transmission Defect | ||||||
| Transient neuromuscular blockade | Common with neuromuscular blocking agents | Flaccid limbs and respiratory weakness | Abnormal repetitive nerve stimulation studies | Normal | Normal | Good |
| Critical Illness Myopathy | ||||||
| Thick-filament myosin loss | Common with steroids, neuromuscular blocking agents, and sepsis | Flaccid limbs and respiratory weakness | Abnormal spontaneous activity | Mildly elevated | Loss of thick (myosin) filaments | Good |
| Rhabdomyolysis | Rare | Flaccid limbs and myoglobinuria | Near normal | Markedly elevated (myoglobinuria) | Normal or mild necrosis | Good |
| Necrotizing myopathy of intensive care | Rare | Flaccid weakness and myoglobinuria | Severe myopathy | Markedly elevated (myoglobinuria) | Marked necrosis | Poor |
| Disuse (cachectic) myopathy | Common? | Muscle wasting | Normal | Normal | Normal or type II fiber atrophy | Good |
| Combined polyneuropathy and myopathy | Common | Flaccid limbs and respiratory weakness | Indicate combined polyneuropathy and myopathy | Variable | Denervation atrophy and myopathy | Variable |
Muscle biopsies are increasingly employed in critically ill patients with clinical suspicion of myopathy and the need to distinguish between inflammatory (e.g., dermatomyositis, polymyositis) and noninflammatory (e.g., corticosteroid- or statin-related) etiologies.
Disorders of Nerve
Critical Illness Polyneuropathy
Critical illness polyneuropathy (CIP) was first diagnosed in the 1980s. It may affect one-half to three-quarters of ICU patients, and may cause both limb and respiratory muscle weakness. The major risk factors for critical illness polyneuropathy include SIRS, sepsis, multiorgan failure, and hyperglycemia. Definite associations with drug treatments like corticosteroids remain controversial.
Failure to wean from mechanical ventilation is a common presenting feature and may be the only sign of the condition. This cause of failure to wean is important to differentiate from other etiologies in the ICU including encephalopathy-related central drive failure, phrenic nerve trauma, neuromuscular junction dysfunction, and myopathies. Decreased maximal inspiratory and expiratory pressures and vital capacities correlate with limb muscle weakness and are associated with delayed extubation, prolonged ventilation, and unplanned readmission to the ICU.
The facial muscles are typically spared in critical illness polyneuropathy. This feature allows for the recognition of a fairly specific pattern of preserved facial grimacing with flaccid or absent limb movements in response to deep nail-bed pressure. Typically, there is loss of previously preserved muscle stretch reflexes. If the patient is cooperative, muscle strength can be tested using the Medical Research Council (MRC) scale or handgrip dynamometry. An “MRC sum score” of less than 48 establishes ICU-acquired paresis and is associated with protracted mechanical ventilation, prolonged length of stay in the ICU, increased mortality, and reduced quality of life in survivors. Although predominantly a motor problem, loss of pain, temperature, proprioception, and vibration sensation may be noted occasionally. In some circumstances weakness may be generalized rather than length-dependent. Although most patients improve, the degree of residual disability after discharge from the acute care setting is variable and depends heavily upon the electrodiagnostic findings.
Laboratory findings may be consistent with SIRS, sepsis, and multiorgan failure. Lumbar puncture is not usually required but will typically show a normal CSF protein concentration without albuminocytologic dissociation such as occurs in Guillain–Barré syndrome.
The pattern of electrodiagnostic abnormalities seen in critical illness polyneuropathy is consistent with a length-dependent, sensorimotor, axonal polyneuropathy. The initial changes are marked by a reduction in the amplitude of sensory nerve and compound muscle action potentials, predominantly in the lower extremities. In keeping with an axonal neuropathy, distal latencies and conduction velocities are typically normal or minimally abnormal ( Fig. 56-2 ). Additionally, some have argued that for a diagnosis of “definite” critical illness polyneuropathy, repetitive nerve stimulation testing should be performed to demonstrate the absence of a decremental response as occurs in myasthenia gravis. Technical difficulties including edema and other cutaneous factors (which increase impedance and produce spuriously low recordings) are often encountered in critical care patients and should raise concern when interpreting the electrophysiologic findings.
There is some evidence that compound muscle action potential duration may be slightly prolonged, a change typically seen in critical illness myopathy due to muscle fiber membrane dysfunction. This finding may implicate a subtle component of overlapping pathophysiologies.
It may not be possible to elicit motor unit potentials when consciousness is depressed as voluntary activation of muscles is required. If present, they can be normal or mildly myopathic. It typically takes 2 to 3 weeks after the initial nerve injury for the emergence of abnormal spontaneous activity including positive sharp waves and fibrillation potentials, by which time further reduction of the sensory nerve and compound muscle action potentials may have occurred due to ongoing axon loss. Even in severe cases, axonal changes predominate without evidence of a concomitant demyelinating process. As recovery occurs, spontaneous activity tends to subside and, by about 2 months, motor unit potentials are longer and larger than normal, and many are polyphasic.
It has been suggested that patients at risk of critical illness polyneuropathy should be monitored in the ICU with serial fibular (peroneal) motor nerve conduction studies to identify the process early in its course.
The specific clinical and electrodiagnostic features of CIP usually obviate the need for tissue diagnosis. However, distal-predominant motor and sensory nerve fiber degeneration has been demonstrated on nerve and muscle biopsies as well as on autopsy findings in patients with critical illness polyneuropathy ( Figs. 56-3 and 56-4 ). Histopathologic examination reveals acute denervation atrophy of muscle (both type I and type II fibers) with scattered, angulated fibers ( Fig. 56-5 ). As the process advances, some degree of reinnervation occurs, as evidenced by fiber-type grouping; group atrophy has also been described. Inflammation in either nerve or muscle is conspicuously absent. The CNS is generally devoid of changes except for chromatolysis of the anterior horn cells secondary to distal motor axonal injury. Intercostal and phrenic nerves undergo a similar process of motor axon loss, resulting in denervation atrophy of respiratory muscles, explaining the associated respiratory compromise.
A component of potentially reversible functional disruption precedes structural degeneration of nerves in critical illness polyneuropathy. Such a phenomenon is mirrored simultaneously in multiple failing organs and is likely a result of shared microcirculatory, cellular, and metabolic pathophysiologic mechanisms. The basis of this reversible peripheral nerve dysfunction may lie in abnormal nerve excitability due to an induced channelopathy. The evidence points to a shift in the voltage dependence of sodium channel fast inactivation towards a more negative potential so that affected peripheral nerves tend to remain in the depolarized state.
This early functional disruption may be the basis for electrophysiologic changes in peripheral nerves and muscles that are rapid in onset (often within hours) and may be reversible, corresponding to the rapid onset of clinical deficits. These patients generally have a better prognosis than those already developing axonal degeneration.
Apart from systemic and microcirculatory factors that promote peripheral nerve ischemia, there is evidence for mitochondrial dysfunction with reduced ATP biosynthesis and energy generation (cytopathic hypoxia). Metabolic disruptions include an increase in the production of cytokines, nitric oxide, and stress hormones that can lead to hyperglycemia from increased insulin resistance. Decreased metabolic demands reduce hormonal stimulation, which, in conjunction with direct mitochondrial inhibition from nitrogen and oxygen reactive species, leads to mitochondrial ATP generation failure. Impairment in axonal transport systems due to energy failure may be responsible for the distal-predominant pattern of nerve fiber involvement.
In patients with critical illness polyneuropathy, the vascular endothelium of epineurial and endoneurial vessels has increased expression of E-selectin, a marker of endothelial cell activation. As a consequence, activated leukocytes within the endoneurial space produce local cytokines that increase microvascular permeability. The subsequent endoneurial edema compromises the blood–nerve barrier. Such deleterious fluid dynamics are enhanced by hyperglycemia and hypoalbuminemia. The peripheral axon which is exposed to this process is then further susceptible to circulating toxins in the setting of sepsis.
Recommendations for patient management include the prevention and aggressive treatment of sepsis and related multiple organ failure. Although malnutrition is not clearly implicated in the pathogenesis of critical illness polyneuropathy, benefits are likely when nutritional status is optimized by the timely use of total parenteral or enteral nutrition. Early intervention with rehabilitative exercises should be encouraged.
There is no evidence to support the use of intravenous immunoglobulin or other agents (e.g., antioxidants, hormones) thought to abort the septic cascade. Insulin therapy to maintain euglycemia reduces the incidence of critical illness polyneuropathy and the duration of mechanical ventilation in critically ill patients. Studies have demonstrated a 20 to 44 percent reduction in the incidence of neuromuscular dysfunction in patients receiving intensive treatment for hyperglycemia. However, intensive insulin therapy to maintain strict blood glucose control also increases mortality in adult ICU patients so the optimum glycemic target remains unclear for these patients.
The underlying systemic condition is responsible for a mortality rate of up to 50 percent in patients with critical illness polyneuropathy. A study of long-term outcomes demonstrated that 21 percent of patients with critical illness polyneuropathy still had severe residual disability 1 year after the acute illness.
Motor Neuropathy and Neuromuscular Blocking Agents
Competitive (nondepolarizing) neuromuscular blocking agents including pancuronium and vecuronium have been associated with electrophysiologic evidence of long-term neuromuscular junction dysfunction and polyneuropathy. These agents traditionally have been used for muscular relaxation during mechanical ventilation. Discontinuation after prolonged use is associated with difficulty in weaning the patient from the ventilator, often accompanied by limb weakness.
Under these circumstances, injury appears to occur at multiple sites. A myopathic component is suggested by a mild-to-moderate elevation in serum creatine kinase level. Postsynaptic deficits in transmission at the neuromuscular junction can be demonstrated by low-frequency repetitive nerve stimulation. Motor-predominant axon-loss changes are detected on nerve conduction studies and supported by needle electromyography.
It is unclear whether denervation occurs as a primary or secondary process. In some circumstances there may be no actual axonal disruption. Electrodiagnostic findings may thus be the result of profound and prolonged neuromuscular junction blockade producing a “functional denervation” in affected muscles that may manifest varying degrees of denervation atrophy and muscle necrosis.
Zifko and colleagues suggested a major role for sepsis in the pathogenesis of this condition and that, if various systemic complications can be treated successfully, spontaneous improvement and rapid recovery may ensue. It is generally recommended that the dose and duration of neuromuscular blocking agents be judiciously minimized as a reasonable preventive measure.
Fortunately, the routine use of pancuronium and vecuronium for ventilated, critically ill patients has become less common. When neuromuscular blockade is required, the use of alternative nondepolarizing agents is recommended; data suggest that cisatracurium besylate improves survival and decreases mechanical ventilation time in patients with acute respiratory distress syndrome with fewer apparent deleterious effects on muscle function.
Chronic Polyneuropathies
On occasion, the neuropathy found in critically ill patients represents an exacerbation or worsening of a long-standing chronic polyneuropathy. This neurologic decompensation may manifest as sensorimotor deficits in the limbs as well as respiratory muscle weakness. Patients who may be affected in this manner include those with chronic inflammatory demyelinating polyneuropathy (CIDP) or diabetic polyneuropathy.
These cases are best confirmed with electrodiagnostic studies including phrenic nerve conduction studies and diaphragmatic needle electrode examination (optimally, in conjunction with neuromuscular ultrasound).
Neuromuscular Transmission Disorders and Myopathies
Features of preexisting neuromuscular junction disorders and myopathies are difficult to differentiate from the myriad of possible causes of muscle weakness in the critical care setting. A fatigable pattern of weakness with prominent oculobulbar findings should raise suspicion of a neuromuscular junction disorder. These disorders as well as myopathies may transiently worsen with intercurrent illness. In patients with central core disease, malignant hyperthermia is a significant risk (see Chapter 55 ) . Succinylcholine and volatile anaesthetics should be strictly avoided in these patients. Electrodiagnostic studies with repetitive nerve stimulation and (rarely) muscle biopsy may be employed to establish a specific diagnosis.
Transient Neuromuscular Junction Blockade
In cases where neuromuscular junction blocking agents are used for muscle relaxation in mechanically ventilated patients, normal liver and kidney function facilitates rapid metabolism and clearance of the drug. However, in critical illness, renal and hepatic function may be compromised, and neuromuscular junction blocking agents may remain active long after discontinuation due to the protracted half-life in these patients. This prolonged blockade may augment some of the injuries to the peripheral nervous system attributed to sepsis itself, and convalescence may require weeks to months. Electrodiagnostic evaluation with repetitive nerve stimulation may help in the confirmation and quantification of this deficit.
Critical Illness Myopathy
While critical illness polyneuropathy was being characterized in the 1980s, clinicians were also appreciating an acute myopathy in severely ill patients treated for conditions such as status asthmaticus and organ transplantation. Various terms have marked the condition’s etymologic evolution including acute quadriplegic myopathy, critical care myopathy, acute necrotizing myopathy of intensive care, thick filament myopathy, and pancuronium-associated myopathy. Eventually, the term “critical illness myopathy” was accepted for standard reference to this disorder.
Although critical illness myopathy may occur independently of critical illness polyneuropathy, these conditions most often coexist. Difficulty with differentiation has led to the nonspecific but frequent reference to “polyneuromyopathy” in the literature. There is a strong correlation between the severity of critical illness and sepsis and the early onset and severity of critical illness polyneuropathy and myopathy. Patients at particular risk of critical illness myopathy specifically include those with status asthmaticus, among whom up to one-third may be affected. It may also be seen in up to 7 percent of patients after orthotopic liver or heart transplantation. A predisposition for myopathy in transplant populations with coexisting renal failure has also been demonstrated. Other risk factors include exposure to corticosteroids and neuromuscular junction blockers, especially when pathologic examination shows myosin loss.
The exact time course is often difficult to determine in the context of septic encephalopathy and administration of sedating medications and neuromuscular blocking agents. The most prominent clinical feature is generalized flaccid weakness affecting the appendicular, truncal, and cranial musculature. There is usually no myalgia or muscle tenderness. An important manifestation is neck flexor weakness, which correlates well with diaphragmatic weakness and difficulty in weaning from mechanical ventilation. Although a pupil-sparing ophthalmoparesis may be present, ocular muscle involvement should prompt exclusion of a neuromuscular junction transmission disorder. The loss of muscle stretch reflexes is a variable finding, although in most cases they are depressed.
In the laboratory evaluation, serum creatine kinase levels are usually mildly increased in at least 50 percent of patients. This is in contrast to patients with critical illness polyneuropathy, who typically have normal serum creatine kinase levels. More marked elevation should raise suspicion of other myopathies listed in Table 56-2 . The highest serum creatine kinase levels are seen with necrotizing myopathies and rhabdomyolysis, in which there is often concomitant myoglobinuria. Patients receiving corticosteroids may have at least a 10-day delay in serum creatine kinase elevation related to critical illness myopathy.
In critical illness myopathy, typical findings on nerve conduction studies are low-amplitude compound muscle action potentials, which are often increased in duration to more than twice normal, most pronounced in the lower limbs. Slowing of muscle fiber conduction has been a proposed explanation for this finding. Sensory nerve action potentials are expected to be normal but may be technically difficult to obtain due to skin conditions and tissue edema; this difficulty may be minimized by the use of near-nerve recordings.
The needle electrode examination often shows evidence of abnormal spontaneous activity including fibrillation potentials and positive sharp waves. Activation typically reveals short-duration, low-amplitude motor unit potentials, an increased number of polyphasic potentials, and normal or early recruitment. In unresponsive patients, some authors have suggested recording from the tibialis anterior, employing reflexive activation after plantar stimulation. Alternatively, direct muscle stimulation may be used and, although technically challenging, can demonstrate reduced muscle membrane excitability. This occurs when the compound muscle action potential amplitude after direct muscle stimulation is less than 3 mV and the ratio of the amplitude after nerve stimulation to that after direct muscle stimulation is more than 0.5. Since a response to direct muscle stimulation but not nerve stimulation is seen in critical illness polyneuropathy, this test may be helpful in differentiating between these two related conditions, although it is less helpful when both disorders coexist. Repetitive nerve stimulation testing should be performed to demonstrate the absence of a decremental response as occurs with defects of neuromuscular transmission. In patients with critical illness myopathy and respiratory impairment, the findings on phrenic nerve conduction studies and needle electrode examination of the diaphragm may be similar to those in critical illness polyneuropathy. Motor unit potentials occurring during attempted inspiration or sniffing usually have a myopathic appearance regardless of the underlying diagnosis.
Typical muscle biopsy findings include type II–predominant fiber atrophy with myofibrillar disorganization. There may be variable degrees of both necrosis and myofiber regeneration. Thick-filament myosin loss is the most characteristic feature and may be related to a decreased transcription rate or loss of myosin messenger RNA.
The underlying pathophysiology of critical illness myopathy includes muscle inexcitability due to a shift in the voltage dependence of sodium channel fast inactivation similar to that seen in critical illness polyneuropathy. This process seems to be augmented by sepsis. Evidence also supports muscle perfusion deficits at the capillary level. Muscle wasting is primarily due to degradation of myofibrillar proteins, which comprise 60 to 70 percent of total muscle protein; as a consequence, there is prominent loss of myosin filaments with sarcomeric disorganization. Similar to critical illness polyneuropathy and other organ failure during sepsis, there is muscle fiber bioenergetic failure due to mitochondrial dysfunction. Toxicity appears to be mediated by ATP depletion, intracellular antioxidant diminution, and nitric oxide production.
Thick-Filament Myosin Loss
This feature of critical illness myopathy has been specifically associated with the term “acute quadriplegic myopathy” and is also referred to as “myosin-deficient” myopathy (see Chapter 55 ). Classically, cases occur in severe asthmatic and post-transplant patients who are mechanically ventilated after receiving high-dose corticosteroids and neuromuscular blocking agents. There may be a slight elevation in serum creatine kinase levels, and muscle biopsy shows selective loss of thick (myosin) filaments. Although these changes can be appreciated on light microscopy, they are better seen on electron microscopy along with varying degrees of muscle necrosis ( Fig. 56-6 ).
Related posts:
Neurologic Complications of Cardiac Surgery
Neurologic Manifestations of Nutritional Disorders
Neurologic Complications of Chemotherapy and Radiation Therapy
Abnormalities of Thermal Regulation and the Nervous System
Neurologic Complications of Organ Transplantation and Immunosuppressive Agents
Neuromuscular Complications of General Medical Disorders
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