Neurologic Complications in Critically III Patients

Critically ill patients are at risk for neurologic complications [1,2]. Many of these complications are part of diagnostic and therapeutic procedures; others are simply manifestations of a more fulminant disease process. Neurologic complications may put an end to the expectation of full recovery, and outcome is often poor. Neurologic complications in critically ill patients were found in 12% of 175 consecutively studied patients in a medical intensive care unit, but they are likely to be even more prevalent in trauma and transplant units. Patients in whom neurologic complications develop during critical illness have twice the length of stay and are twice as likely to die [1]. Neurologic assessment in the intensive care unit is limited because many patients are fatigued, sleep-deprived, confused, uncooperative, or heavily sedated and are often treated with neuromuscular blocking drugs. There are large gaps in our knowledge of neurologic complications in critically ill patients. Neurologic complications often revolve around three main disturbances: muscle weakness, impaired consciousness, and seizures. This review describes common clinical neurologic complications of a potentially life-threatening illness. Coma or Failure to Awaken A puzzling clinical situation is the failure of patients to awaken after the critical illness has subsided. Familiar to intensive care specialists is the patient receiving mechanical ventilation for acute respiratory failure who does not fully recover to a normal level of consciousness after withdrawal of analgesics, sedatives, and neuromuscular blocking drugs. Neurologic signs typically associated with metabolic encephalopathy, such as multifocal myoclonus, asterixis, and tremor, are absent. The differential diagnosis in these patients is shown in Table 1. Despite the use of new short-acting pharmacologic drugs, a common cause of altered consciousness in critically ill patients is related to the previous administration of sedative drugs that have accumulated over days because of diminished clearance or pharmacologic interaction. In many other patients, an anoxic-ischemic insult from brief but significant hypoxemia or hypotension may produce a diffuse encephalopathy that lingers for weeks.Table 1: Major Causes of Coma in Intensive Care UnitsIn medical intensive care units, failure to awaken often occurs in association with sepsis [3,4]. The central nervous system manifestations in sepsis have not been studied in great detail. Patients with acute confusional episodes or any other persistent cognitive abnormality have been said to have "septic encephalopathy." Whether a distinct metabolic encephalopathy of sepsis exists after exclusion of confounding factors remains unknown. In progressive multiple organ dysfunction from sepsis, severe hypoglycemia, marked hypotension necessitating increasing doses of inotropic medication, and significant hypercapnia may all contribute to impairment of consciousness. Suggested mechanisms for encephalopathy associated with sepsis are decreased cerebral blood flow with similar changes in cerebral extraction ratios, disordered amino acid transport similar to hepatic encephalopathy, microabscesses, and possibly, sustained hypotension, suggesting that septic encephalopathy may be more hypoxemic-ischemic in nature [2]. Whether cytokines, such as interleukin-1 or tumor necrosis factor, directly influence arousal remains unresolved. Other mimicking clinical conditions, such as multiple small intracranial hematomas, should be excluded and may be found as part of disseminated intravascular coagulation [5]. Outcome of patients with septic encephalopathy who remain in coma is poor [4,6]. A possibly underrecognized cause of coma after any type of critical illness is cholesterol embolization. Recent arteriographic procedures may be implicated [7,8]. In a retrospective review of pathologic material from patients who died six months after vascular catheterization, the incidence of cholesterol embolization was 25%, with embolization to the central nervous system in 5% of the patients [8]. The clinical recognition of neurologic manifestations of cholesterol embolization may be difficult, and the signs of diffuse encephalopathy, retinal hemorrhages, and transient hemiparesis are not specific. The positive predictive value of systemic manifestations, such as livedo reticularis, purple toes, renal failure, and muscle weakness, may be higher [8]. Both muscle and renal biopsy specimens may show stacked, needle-shaped crystals. It has been suggested that muscle biopsy has a high sensitivity for demonstrating cholesterol embolization [8]. By comparison, a frequent cause of coma in a surgical intensive care unit is acute renal failure producing acute uremic encephalopathy. Acute uremia occurs in approximately 20% of surgical critically ill patients; conversely, acute dialysis in the hospital is associated with perioperative acute renal failure [9,10]. Valvular heart surgery, coronary artery bypass grafting, and aortic aneurysm surgery typically are associated with postoperative acute renal failure, but the incidence is also high in liver transplantation [11,12] and in major surgical repairs complicated by sepsis or involving significant abdominal gastrointestinal exploration and repair. The development of acute uremia in surgical patients dramatically increases the risk of mortality, which approaches 100% if mechanical ventilation is necessary [10]. The most common causes of acute renal failure in surgically ill patients are renal hypoperfusion and nephrotoxic insults. Not unexpectedly, left ventricular dysfunction, diabetes, and use of nephrotoxic antibiotics are major risk factors in patients with preexisting renal dysfunction. Coma from uremic encephalopathy usually develops gradually from drowsiness, asterixis, and myoclonus to an unresponsive state with virtually no motor response to pain. Frontal release signs may be seen, such as marked snout response or brief jerks of retroflexion of the neck after glabellar tapping and grasp reflexes. Typically, the cranial nerves remain intact, as in many metabolic encephalopathies. Uremic encephalopathy usually is the clear overriding cause of coma when blood urea nitrogen and creatinine have doubled in value, but hypoxemia from significant acute respiratory distress syndrome or increased bilirubin from liver failure may contribute. The effect of dialysis is critical in prognostication. Failure to awaken may indicate that hypoxemic, anoxic, or hypotensive events have occurred. The clinical signs of uremic encephalopathy may completely resolve after dialysis, but in many patients in the surgical intensive care unit, a baseline drowsiness persists after dialysis. After dialysis, a dysequilibrium syndrome may occur, but it is rare. The typical presentation includes combative behavior, severe throbbing headache when lying flat, and myoclonic jerks and cramps. The circumstances almost always include rapid dialysis, extreme baseline predialysis blood urea nitrogen, and first dialysis. More dramatic presentations may include cortical blindness and coma preceded by seizures. Computed tomography scanning may demonstrate significant swelling. Many patients die hours after onset [13,14]. In surgical intensive care units, failure to awaken can be associated with ischemic strokes in multiple arterial territories. This devastating complication frequently occurs after major cardiovascular repairs [15]. Patients in coma from ischemic strokes immediately after surgery often have had a significant perioperative event. Typically, the level of consciousness fails to improve after washout of high doses of narcotic analgesics and anesthetics. In these patients, a brief but significant hypotensive episode may have been noted during surgery, but the anatomical territories of ischemic stroke, often multiple, in these patients do not fit a typical watershed territory Figure 1. Other established sources of postoperative ischemic stroke are retained left ventricular thrombus, severe atherosclerosis of the ascending aorta with marked circumferential involvement of most of this segment and protruding atheroma [16], and postoperative atrial fibrillation [17].Figure 1: Computed tomography scan in a patient with multiple strokes after coronary artery bypass grafting. Note hypodensities in both anterior and middle cerebral artery territories.In many patients, microemboli may cause prolonged neuropsychologic abnormalities. Intellectual deterioration may vary greatly and become evident after the patients return home [18]. With extensive neuropsychologic testing, there may be a prevalence of 30%, which is much higher than that in ischemic strokes in large cerebrovascular territories. In fact, magnetic resonance imaging scans did not find any detectable change after coronary artery bypass grafts [19]. Resuscitation for cardiac or respiratory arrest during any type of critical illness may result in postanoxic-ischemic encephalopathy [20]. Comatose patients after cardiac resuscitation may show clinical signs portending a dismal outlook. Coma alone has no predictive value in the first three days [20]. Certainly, if fixed pupils and myoclonus status epilepticus (brief, persistent, and generalized jerks in limbs and face) are associated with a sustained upward gaze, the probability of a persistent vegetative state and death is high in comatose survivors after cardiac arrest [21,22]. In 40% of comatose patients with myoclonus status epilepticus, computed tomographic scan abnormalities of multiple cerebral infarcts or cerebral edema are demonstrated. It is highly probable that status myoclonus is an agonal phenomenon and should be considered a clinical marker for devastating damage to the brain. Patients in coma after cardiac or respiratory resuscitation can be further investigated by somatosensory evoked potentials. The absence of a bilateral cortical somatosensory response (N20 and P27) with a preserved cervical somatosensory response strongly predicts a vegetative state [23]. Further management decisions should be influenced by these findings. Another population of critically ill patients with a propensity for central nervous system involvement are those who have undergone transplantation, notably liver and heart recipients. After liver transplantation, prompt awakening often signifies adequate graft function. When perioperative sedation has been excluded, failure of patients to awaken after liver transplantation may have several causes. Patients with fulminant hepatic failure are prone to the development of increased intracranial pressure from brain edema [24] and during the anhepatic phase may even have a brief surge in intracranial pressure. In an extremely unfortunate situation, brain death is diagnosed postoperatively [24]. Typically, recovery from cerebral edema takes days before level of consciousness improves. In approximately 10% of patients after liver transplantation, neurotoxicity to cyclosporine develops as early as three days after intravenous administration [25,26]. An acute confusional state with paranoid behavior, tremors, and speech abnormalities may be seen. Some patients become mute, but coma with abnormal motor responses is rare, occurring only if cyclosporine neurotoxicity is not recognized. Magnetic resonance imaging changes in the white matter have been reported with severe manifestations of cyclosporine toxicity [25]. Seizures may occur in the first postoperative days, and, if nonconvulsive status epilepticus follows, it may be a potential cause of failure to awaken. This phenomenon can be recognized in many patients by waxing and waning alertness, stereotypical behavior, and occasional twitching in the face and limbs. Central pontine myelinolysis is a less common cause for failure to awaken in recipients of liver transplants, but it may be underreported [27]. In our series of patients undergoing liver transplantation, we found an incidence of 1% and all presented with stupor. Rapid shifts in plasma osmolality and plasma sodium have been implicated [28,29], but the relationship was not evident in our survey of patients with central pontine myelinolysis [30]. Central pontine myelinolysis can be confirmed by magnetic resonance imaging, which shows a typical bat- or trident-shaped abnormality on axial T2-weighted images. (The trident shape is explained by relative preservation of the corticospinal tracts Figure 2.) Central pontine myelinolysis, although dramatic in its clinical and neuroimaging presentation, has a reasonable potential for recovery [31,32].Figure 2: Axial T2-weighted magnetic resonance image of the pons showing typical trident-shaped high-intensity signal after liver transplantation.Intracranial hematomas are uncommon (less than 1%) but have been found more often in patients with associated thrombocytopenia, bacteremia, or fungemia [33]. In some patients, a mycotic aneurysm can be implicated. Generally, infectious causes of coma after liver transplantation are uncommon. Patients with a transplanted heart generally do well in the perioperative phase. Neurotoxicity from immunosuppression (cyclosporine, OKT3) is uncommon in the intensive care unit [34-36]. Possible reasons are meticulous monitoring of OKT3 dosage by determination of the degree of decrease in CD3 cells in OKT3 and use of cyclosporine at a later stage rather than induction therapy in many immunosuppressive protocols. Patients with cardiac transplants, however, are at particular risk for ischemic stroke [36]. A history of stroke and preoperative carotid stenosis of more than 50% significantly increase the risk of ischemic stroke. After heart or heart-lung transplantation, however, ischemic stroke is most frequently associated with retained thrombi within the graft anastomosis. In summary, multiple causes of coma can be considered in critically ill patients. The setting (medical or surgical intensive care unit) may be important in the differential diagnosis. Unexplained coma should be evaluated by cerebrospinal fluid examination and repeat computed tomography scanning, but the decision to perform additional diagnostic tests in patients who are critically ill and become comatose depends on the underlying condition. In many patients, the cause of coma is obvious after careful review of the medical record. Particular attention should be paid to acute changes in laboratory values (e.g., major shifts in plasma sodium or osmolality), hypoxemic periods or cardiac arrhythmias documented during recent invasive procedures, and any recent change in medication or dosage. Computed tomography scanning should be repeated when initial findings are normal and the neurologic examination is not localizing. Cerebral infarcts may become more evident two to three days after sudden neurologic deterioration. The major causes of coma in medical and surgical intensive care units are summarized in Table 1. Generalized Muscle Weakness Fatigue can be expected in critically ill patients after they have survived their illness. An underlying neurologic abnormality should be considered when the patient is mobilized in a chair but appears considerably weak, when the patient cannot support weight, or when weaning failure cannot be readily explained by previous lung disease or new lung injury. At least three major categories have been recognized: axonal polyneuropathy (critical illness polyneuropathy), typically associated with sepsis; acute steroid myopathy, potentially associated with use of neuromuscular junction blockers; and an as yet undefined prolonged muscle weakness after neuromuscular junction blockers, which may represent a toxic myopathy. (The results of electromyographic and nerve conduction studies are often normal.) The definition of all these syndromes continues to be confusing. Many other possibilities should be considered, and in some patients a previously undiagnosed neurologic disorder may have been present that with respiratory The differential to be considered in patients in medical and surgical intensive care units are in Table 2: Causes of Generalized studies of causes of weakness in the intensive care unit are is most a cause of generalized weakness in the intensive care unit illness The prevalence in intensive care units is not but it may occur in of all patients with sepsis and in 50% of patients in the unit more than two of critical illness is often in association with associated with this type of polyneuropathy include stay in the intensive care unit, and The clinical of critical illness polyneuropathy are normal cranial nerve although may be weakness is usually severe and more in the is muscle may be is usually diminished in a The disorder in a stereotypical in the and of the limbs is by weaning and later recovery of the of the limbs. Outcome is generally if the patient the critical illness expected with axonal three to months is for A recent found a severe in 20% of survivors with polyneuropathy Some patients have persistent weakness of the from of the nerve of the nerve may occur when limbs are can this studies in critical illness polyneuropathy may show typical of axonal with of muscle and nerve fibrillation and positive but nerve conduction are nerve conduction is often or nerve biopsy specimens show severe axonal of in the Another important cause of generalized muscle weakness is the use of neuromuscular blocking drugs, and patients recover within days after administration is but some remain for The of weakness is unresolved. repeated studies of the neuromuscular junction have not been and findings may be normal marked A recent found that of may in patients with renal failure, metabolic and for these patients with prolonged weakness were not recovery can be expected The prevalence of prolonged weakness is a recent noted the in only of studied patients. It is monitoring with a nerve can this complication A but uncommon complication of neuromuscular blocking drugs is acute myopathy, possibly when the is in with large doses of to The typical patient in whom the complication occurs has status of has been reported The outcome appears to be but are a was in lung transplant patients. Muscle biopsy of patients large doses of but no neuromuscular blocking and sepsis did not virtually excluded as a The underlying cause of this of is is it clear this a new syndrome or a of acute steroid found that severe was more common than polyneuropathy in liver transplant patients but were to further the abnormality may be a of weakness in critically ill patients. The most common causes are of large muscle from arterial and can be found when is Many patients have weakness and pain. and are on and may Figure of muscle from to weakness by may that the circumstances critical illness patients considerably more to but generalized are uncommon in the intensive care jerks may be more common because of their association with many of the drugs, such as and in the medical intensive care Acute metabolic and and multiple are studies in the intensive care unit have been In a of neurologic complications in patients, had had and had that were generalized at epilepticus in six patients [1]. of these patients had a stroke or an infectious disease at the of In a recent from the of patients to intensive care units had at least episode of generalized during their stay in a unit the patients, had a history of had or drugs, were from organ transplantation, and had surgical trauma or injury. In the patients, were new in in the intensive care unit are often the result of toxicity [2]. Some antibiotics the for but renal failure or a recent sudden increase in dosage is a more common event. but increased of rather than the is a cause of seizures. associated with in intensive care units are summarized in Table with Seizures in the Intensive Care associated with withdrawal may occur in of the patients. In a recent that of patients had associated with withdrawal narcotic toxicity was in patients documented toxicity in and from drugs in In many were for and in all patients, doses were repeated for at least Seizures two to days after sudden withdrawal of In patients who have most of which occur in those with a history of diagnosis is a almost always develops in these patients, but may An underlying to be excluded by cranial computed tomographic scan are frequently to sedation in patients. status epilepticus may occur after of administration of increase the risk of but risk is related to the of the The risk of to abnormalities is in the intensive care unit occur in patients with postoperative and the cause is often patients with severe have an impaired level of consciousness, which is by generalized seizures. A syndrome associated with postoperative in has been and others are for their of severe in after surgery, but this complication was not found in a recent survey at the Many of these had administration of in sodium of less than most likely associated with or postoperative syndrome of may also have patients had within by respiratory Many in a vegetative and several patients brain More hospital are necessary to the prevalence of this severe occurs in undergoing of the but the outcome is In this of patients, is high from of which is frequently as an Rapid of by the plasma This result that the changes in are much more important than a change in plasma sodium and that should not be to may cause but in of the series of patients with hypoglycemia, many were to have or were may occur and do not a preexisting Seizures are more prevalent in critically ill patients with or may result in status epilepticus, usually with poor may occur when the is less than in a critically ill patient is usually associated with neck surgery but may also result from by sepsis, or changes in more patients have muscle and which should not be as seizures. Seizures in patients with transplanted often indicate that the immunosuppressive has toxic In patients with transplanted the incidence of is increased by or toxicity Figure ischemic encephalopathy, or left Magnetic resonance imaging findings in a patient with and Note marked signal in the on typically in patients with liver signal in white matter and in appears on T2-weighted in a patient with and an impaired level of consciousness. There was of both abnormalities in The management is often when additional neurologic develops in patients in intensive care units. In some patients with a severe underlying an acute neurologic is a in it is a The outcome from neurologic complications can be but signs of poor should be early and when management decisions are The clinical of the neurologic of critical illness is to and become