Non-pulmonary Critical Care - part 1 docx

PREFACE Non-pulmonary Critical Care: Managing Multisystem Critical Illness Care of the critically ill patient is truly multisystem management of highly complex patients who typically have numerous acute physiological derange- ments superimposed upon underlying medical ailments. Historically, the majority of patients admitted to intensive care units (particularly medical ICUs) have respiratory failure requiring mechanical ventilation, often along with other acute and chronic pulmonary problems. Much ICU-related research and education has similarly focused on pulmonary issues such as the acute respiratory distress syndrome (ARDS), pneumonia, and mechanical ventilation. Additionally, a great majority of intensivists have received training in pulmonary and critical care medicine. Thus it is not surprising that the phrase ‘‘non- pulmonary critical care’’ has arisen to address many general critical care issues. However, this vast body of knowledge might more appropriately be considered ‘‘multisystem critical care’’ as an inclusive term that encompasses the many important organ system derange- ments that plague our ICU patients. This issue of Seminars provides scholarly and clinically relevant reviews of major non–pulmonary organ dysfunction in the ICU setting. Clearly, a comprehensive review of the numerous organ system–based medical conditions seen in our ICUs is well beyond the scope of a single issue of Seminars, more appropriately filling several thousand pages and hundreds of chapters typical of current major textbooks on critical care medicine. Nevertheless, we have iden tified a cross- section of key topics and have solicited state-of-the-art reviews by highly qualified experts. Starting at the top, so to speak, Dr. Bleck presents a discussion of neurological complications of critical illness, with particular emphasis on metabolic encephalopathies, seizures, and neuromuscular conditions. Drs. Miller and Ely share their current understanding of the rapidly evolving areas of delirium and cognitive dysfunction in the ICU. Drs. Tarditi and Hollenberg present a structured approach to the ICU patient who has cardiac arrhythmias, emphasizing the challenge s of managing tachyarrhythmias, whereas Dr. Axler discusses the evaluation and management of shock. Drs. Rinella and Sanyal provide a comprehensive review of acute hepatic failure as well as acute complications of chronic advanced 1 Division of Pulmonary and Critical Care Medicine, Virginia Com- monwealth University Health System, Richmond, Virginia. Address for correspondence and reprint requests: Curtis N. Sessler, M.D., Division of Pulmonary and Critical Care Medicine, Box 980050, Virginia Commonwealth University Health System, Richmond, VA 23298-0050. E-mail: csessler@hsc.vcu.edu. Non-pulmonary Critical Care: Managing Multisystem Critical Illness; Guest Editor, Curtis N. Sessler, M.D. Semin Respir Crit Care Med 2006;27:199–200. Copyright # 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 1 0.1055/s-2006-945524. ISSN 1069-3424. 199 liver disease. Drs. Weisbord and Palevsky examine acute renal failure, including sections on epid emiology, causes, prevention, and management. Drs. Raghavan and Marik presen t an in-depth review of adrenal insufficiency and the many issues related to hyperglycemia and glycemic control in the ICU. Drs. Mercer, Macik, and Williams expertly address hematological disorders in the ICU, with particular emphasis on thrombocytopenia and bleeding disorders. Drs. Afessa and Peters provide a practical framework for evaluating and managing the many serious infectious and non-infectious complications related to hemato- poietic stem cell transplantation. Drs. Bearman, Munro, Sessler, and Wenzel conclude with a comprehensive overview of infection control and prevention of nosoco- mial infections in the ICU, with emphasis on ventilator- associated pneumonia and catheter-related b loodstream infection. I would like to acknowledge the amazing exper- tise, attention to detail, and hard work of the authors of these articles, and convey my thanks for the steady hand of the Seminars Editor-in-Chief, Joseph P. Lynch, III, M.D., and the understanding and support of my wife and children, in creating this issue of Seminars. Curtis N. Sessler, M.D. Guest Editor 1 200 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2005 Neurological Disorders in the Intensive Care Unit Thomas P. Bleck, M.D., F.C.C.M. 1,2,3 ABSTRACT Neurological problems are common among critically ill patients; they often signal that other organs are failing, but are themselves important causes of morbidity and mortality. Cognitive function may suffer as a consequence of septic encephalopathy, the pathophysiology of which is poorly understood; however, the affected patients usually return to their baseline when sepsis resolves. Seizures and cerebrovascular disorders are also common in the intensive care unit. Neuromuscular complications are important causes of failure to wean from mecha nical ventilation and lead to substantial long-term morbidity. KEYWORDS: Acute quadriplegic myopathy, ARDS: acute respiratory distress syndrome, critical illness myopathy, critical illness polyneuropathy, fulminant hepatic failure, seizure, septic encephalopathy Many conditions encountered in intensive care affect the nervous system. The onset of an abrupt neurological complication is frequently obscured by the effects of the prim ary illness (e.g., metabolic encephalopathy may delay the recognition of an intracerebral hemorrhage) or its treatment (such as sedation to allow greater synchrony with a ventilator). Other neural problems, such as critical illness polyneuropathy, may develop insidiously and become apparent only as the patient improves. At times the neurological problem has been visible, but its manifestations may be inappropriately attributed to the presenting illness. 1 The intensivist should be perspicacious about changes in level of con- sciousness or movement when investigating a fall in oxygen saturation or a rising white blood cell count. 2 EPIDEMIOLOGY Isensee et al evaluated neurological problems in 100 consecutive medical intensive care unit (ICU) patients within 72 hours of admission. 3 The study included all patients in need of intensive care except those with primarily cardiac disorders. Eighteen were admitted for acute neurological disease and five others for encephalopathy caused by drug overdose. Of the remaining 67, 33% had a neurological complication of their medical conditions (11 metabolic encephalopathy, four hypoxic- ischemic enceph alopathy [HIE], and seven other neurological problems). Fifty-nine percent of the patients with neurological complications died, compared with 20% of the nonneurological patients. At the same time, we performed a 2-year prospective study of neurological complications among medical intensive care unit (MICU) patients to describe the neurological complications encountered and to identify their effects on mortality and length of stay (LOS). 4 Patients with a primarily neurological reason for admission to the MICU were excluded from analyses of mortality and LOS; more than half of this group had ischemic stroke or intracranial hemorrhage. The others Departments of 1 Neurology, 2 Neurological Surgery, 3 Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia. Address for correspondence and reprint requests: Thomas P. Bleck, M.D., University of Virginia School of Medicine, Neurology 800394, McKim Hall 2025, Charlottesville, VA 22908-0394. E-mail: tbleck@ virginia.edu. Non-pulmonary Critical Care: Managing Multisystem Critical Ill- ness; Guest Editor, Curtis N. Sessler, M.D. Semin Respir Crit Care Med 2006;27:201–209. Copyright # 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-2006-945531. ISSN 1069-3424. 201 were classified as having a complication of a critical illness if they developed a neurological problem from a medical disorder or its treatment. We collapsed the medical diagnoses into four categories: (1) sepsis, including bacteremia with shock, the sepsis syndrome, and the acute respiratory distress syndrome (ARDS); (2) acute coronary artery disease; (3) other cardiac disorders; and (4) all other patients (e.g., ventilatory failure, gastrointestinal hemorrhage, hypotension not assigned to another category). Patients with neurological complications were further divided into those with metabolic encephalopathies, seizures, cerebrovascular disorders, hypoxic-ischemic encephalopathy, or other global brain disorders. These latter categories were not mutually exclusive. Patients with clinically apparent peripheral nervous system disorders were included in the ‘‘other’’ group. We studied 1850 consecutively admitted patients; of these, 92 (4.9%) were admitted for a primary neurological reason. Of the remaining 1758 patients, 217 (12%) experienced neurological complications of their underlying medical disease (Table 1). Table 2 details the neurological complication rates by admission category. The mortality rate for all MICU patients was 32%, but it was 55% for the 217 patients with neurological complications, compared with 29% for those without neurological complications. Patients with neurological complications also had significantly longer MICU and hospital stays. Metabolic encephalopathy was the complication most frequently encountered, seen in 62 patients. Of these, septic encephalopathy, without evidence for significant hepatic or renal dysfunction or hypoxemia, was most common. The frequencies of different forms of metabolic encephalopathy are detailed in Table 3. Seiz- ures occurred in 61 patients, most often in patients with vascular lesions. Hypoxic-ischemic encephalopathy occurred in 51 patients; in 27, the cause was primarily cardiac, with pulmonary disease accounting for the remaining 24. Forty-eight patients suffered strokes while in the MICU. Thirty-two of these were ischemic infarcts, 14 were intracerebral hemorrhages, and two were subar- achnoid hemorrhages. Thirteen stroke patients had an identified cause other than arteriosclerosis, including underlying autoimmune diseases and bacterial endocarditis. Strok e occurred in only 1% of patients with acute myocardial infarction. This was less than the usually cited range of 1.7 to 2.4%. 5,6 SEPSIS AND SEPT IC ENCEPHALOPATHY During the past 40 years, clinical analyses and investiga- tions of cytokine mechanisms have markedly improved our understanding of the causes and pathogenesis of sepsis. 7 Although bacteremia was previously considered to be the sine qua non of systemic disease, occurring as a consequence of local infection, many patients suffer the same vasomotor disturbances and organ dysfunctions without positive blood cultures. The foregoing epidemiological data indicate that septic encephalopathy is the most frequent neurological disorder encountered in Table 1 Neurological Complications Encountered in 217 Patients at Risk with Severe Medical Illnesses in the Medical Intensive Care Unit Complication N (percent of patients with diagnosis)* Metabolic encephalopathy 62 (28.6) Seizures 61 (28.1) Hypoxic-ischemic encephalopathy 51 (23.5) Stroke 48 (22.1) Other diagnoses 50 (23.0) *A single patient could have more than one complication; therefore, the total number in this column exceeds the total number of patients. Modified from Bleck et al. 4 Table 2 Neurological Complication Rates by Primary Medical Intensive Care Unit Admission Category Percent of Patients with Complications Category Seizure Vascular HIE Metabolic Other Sepsis 11 6 10 21 11 Other medical condition 4 3 4 3 6 Coronary artery disease 1 1 1 1 1 Other cardiac condition 4 3 3 2 4 Modified from Bleck et al. 4 Table 3 Etiologies of Metabolic Encephalopathy in a Medical Intensive Care Unit Population Etiology N Sepsis 19 Hepatic 18 Renal 8 Hypertensive 7 Hyperosmolar 4 Hypoglycemic 3 Uncertain 3 Modified from Sprung et al. 12 202 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 medical intensive care; it is also one of the more poorly recognized and understood. Septic encephalopathy was described in 1827 8 but has only recently become a subject of organized neurological interest. Young and coworkers provided a thorough prospective analysis of this disorder in a large university ICU. 9 This group required fever and a positive blood culture for inclusion in their study, a very restrictive definition of sepsis, which provided a homo- geneous group for analysis. Patients were excluded for preexisting brain disease; frequent sedative or opiate administration; pulmonary, hepatic, or renal failure; endocarditis; or long bone fractures that might have pro- duced fat embolism. These workers identified 69 patients over 31 months; by clinical examination, 20 of them were not encephalopathic (NE), 17 were mildly encephalopathic (ME), and 32 were severely encephalopathic (SE). Pa- tient age, blood pressure on entry into the study, and temperature did not vary significantly among the groups. The lowest systolic and diastolic blood pressures were statistically significantly lower (but probably not biolog- ically significantly lower) in the ME and SE groups when compared with the NE group. Mortality depended on the category of encephalopathy: none of the NE patients died, whereas 35% of the ME and 53% of the SE patients died. Several laboratory values showed a linear relation- ship with the severity of encephalopathy, including white blood cell count, PaO 2 , blood urea nitrogen (BUN), creatinine, bilirubin, alkaline phosphatase, and potas- sium. The serum albumin concentration was inversely related to encephalopathy. cerebrospinal fluid (CSF) protein content was mildly elevated (60 to 85 mg/dL). Electroencephalographic abnormalities are more sensitive indicators of central nervous system (CNS) dysfunction than the clinical examination, and also a powerful pre- dictor of survival. 10 Evoked potential studies suggest that brain dysfunction is even more prevalent in sepsis, being abnormal in 84%. 11 A Veterans Administration (VA) cooperative sepsis study also showed that ‘‘alterations in mental status are common in septic patients, and are associated with significantly higher mortality.’’ 12 Eidelman and colleagues studied 50 patients with severe sepsis and showed that encephalopathy was associated with bacteremia and hepatic dysfunction. 13 The severity of encephalopathy correlated with mortality. PATHOLOGY AND PATHOPHYSIOLOGY The pathological basis of septic encephalopathy remains obscure. Jackson et al autopsied 12 patients dying after severe, prolonged sepsis. 14 They found cerebral microabscesses in eight patients and proliferation of astrocytes and microglia in three others; these findin gs suggested metastatic infection. Three of these patients also had central pontine myelinolysis, and three had ischemic strokes. The remaining patient demonstrated only pur- puric lesions. Eight of the patients had electroencepha- lograms (EEGs), three of which showed multifocal epileptiform activity. Pendlebury and associates identified 35 patients with multiple CNS microabscesses among 2107 consecu tive autopsies. 15 All these patients had chronic, usually immunocompromising, diseases, and were frequently septic before death. The most common organisms implicated were Staphylococcus aureus and Candida albicans. In contrast, we did not find microabscesses in four patients autopsied of our 14 fatal septic encephalopathy cases; this may represent sampling error or other differen ces in the populations studied. 4 The pathophysiology of septic encephalopathy is of great interest. The systemic mediators of inflammation are capable of damaging the blood–brain barrier. 16 Such disruption has been documented in an animal model early in sepsis. 17 The behavioral effects of cytokines vary with the neuroanatomical structures affected but include thermogenic behaviors in the hypothala- mus 18 and somnolence in the locus caeruleus. 19 Inter- ferons also alter individual cortical and hippocampal neuronal functions, suggesting a myriad of effects on memory and emotion. 20 Brain catecholamine concentrations are decreased in experimental sepsis. 21 Sepsis leads to the release of S-100B, a protein predominantly expressed in CNS glial cells, into the systemic circulation; this leakage was not affected by steroids in a human trial. 22 Increased serum concentrations of S-100B are usually viewed as evidence of cellular damage, which may not be reparable. Cerebral blood flow (CBF) and cerebral oxygen extraction decrease in septic encephalopathy, 23 along with the development of cerebral edema and disruption of the blood–brain barrier. 24 Preliminary human studies suggest that these problems occur in several gray matter structures of the brain. 25,26 Failure of cerebrovascular autoregulation is likely to compound these disorders, 27 producing cerebral ischemia. Both cerebral edema and blood–brain barrier disruption appear to correlate with damage to astrocytic foot-processes. 28,29 Aquaporin-4 expression increases in septic encephalopathy, but the cellular events that trigger this change in sepsis require further research. 30 The cause of the changes in CBF and oxygen extraction are less well understood. Focal elevations in intracellular free calcium may cause neuronal dysfunction and also contribute to apoptotic 31 or necrotic cell loss. 32 Activation of adenosine A 1 receptors may be important in the development of a local CNS inflammatory response. 33 Although cytokines have been suggested as mediators, a study of the effects of tumor necrosis factor was unable to confirm its role in this regard. 34 However, a decline in CSF ascorbic acid concentration may reflect difficulty in safely handling the oxygen-derived free radicals potentially resulting from both cytokine and nitric oxide excess. 35 These NEUROLOGICAL DISORDERS I N THE I CU/BLECK 203 radicals may interfere with the mitochon drial electron transport chain, leading to cellular energy deprivation. 36 Magnesium administration may be able to attenuate some of these problems, 37 although this remains to be demonstrated in humans. Abnormal systemic metabolism in sepsis may also contribute to CNS dysfunction. Mizock et al demonstrated altered phenylalanine metabolism (elevated blood and CSF levels, and elevated phenylalanine metabolites) in 11 patients with septic encephalopathy; in contrast, patients with hepatic encephalopathy had elevated CSF concentrations of many other aromatic amino acids. 38 Sprung and coworkers found elevated serum levels of phenylalanine, ammonia, and tryptophan in encephalopathic patients compared with infected patients with normal sensoria, along with lower concentrations of isoleucine. 39 Other studies have confirmed this, and find it linked to concentrations of calcitonin precursors and interleukin-6. 40 The significance of these correlative studies for the pathogenesis of encephalopathy is uncertain. Several authors have tried to implicate abnormal hepatic and muscular metabolism of aromatic amino acids in both hepatic and sep tic encephalopathies, but this hypothesis has been challenged (see further discussion in the next section). Antibiotic treatment of septic patients may actually enha nce these problems. 41 Septic patients are prey to a wide variety of other metabolic disorders and intoxications that cause encephalopathy apart from the direct effects of sepsis on the brain and on cerebral blood flow. 42 Nonconvulsive status epilepticus is an underrecognized problem in the population at risk. 43 There is neither a diagnostic test to discriminate sepsis from other causes of encephalopathy nor a specific treatment for the CNS disturbance. From a clinical standpoint, the diagnosis of septic encephalopathy remains one of exclusion. 44 Hepatic Failure and the Central Nervous System The current debate over the pathogenesis of hepatic encephalopathy is of great importance to clinical neuro- scientists. In fulminant hepatic failure (FHF), increased intracranial pressure (ICP) has become a major cause of death in patients awaiting transplantatio n. 45 Patients whose ICP has been elevated may survive a transplant but be left with CNS deficits. 46 The mechanism of the cer ebral edema that devel- ops in FHF appears to be related to mitochondrial dysfunction 47 ; it requires aggressive treatment. 48 Ste- roids are not effective, but mannitol has been useful. 49 As in many other causes of brain edema, abnormal function of matrix metalloproteinases probably contributes to the problem. 50 As with most other causes of brain edema, aquaporin-4 expression is involved; it may be possible to decrease this by the administration of calci- neurin antagonists. 51 Hyperventilation had previously been thought to increase mortality, but a controlled trial demonstrated its utility. 52 High-dose barbiturates may be used if mannitol and hyperventilation fail to control ICP. 53 The effect of posture is unpredictable, 54 and computed tomographic (CT) scanning is debated as an indicator of the severity of intracranial hypertension. 55,56 Attempts to lower ICP by reducing extracellular volume through hemofiltration have not been effective. 57 Dialysis against albumin may hold more promise. 58 There is no current substitute for invasive ICP monitoring in patients with FHF who are in grade 3 (stuporous) or grade 4 (comatose). The need for monitoring extend s through the liver transplant operation into at least the first postoperative day. 59 Recombinant factor VII administration immediately before ICP monitor placement appears to reduce the risk of intracerebral hemor rhage. 60 Patients with FHF may also have elevated levels of apparently endogenou s 1,4-benzodiazepines,(3) which may explain stupor or coma in patients who do not have ICP elevations. An interaction between gamma-amino butyric acid (GABA) and elevated concentrations of ammonia may be important in both FHF and more chronic forms of hepatic encephalopath y. 61 More recent work has concentrated on the putative role of neurosteroid agonists of the benzodiazepine receptor 62 because researchers have been unable to identify a compound that structurally resembles the pharmaceut- ical benzodiazepine nucleus. Chronic hepatic encephalopathy does not appear to cause ICP elevation unless intracranial bleeding supervenes. As in FHF, endogenous benzodiazepine- like compounds (GABA A agonists) likely play a major role,(4) and the use of GABA antagonists is being actively investigated but has not yet become standard practice. About 70% of chronic hepatic encephalopathy patients awaken rapidly when given flumazenil (for the duration of the drug’s effect). 63,64 These patients have numerous other m etabolic abnormalities that may contribute to their encephalopathy, including abnormalities in the Krebs cycle 65 and of methionine metabolism. 66 OTHER CAUSES OF ENCEPHALOPATHY IN THE INTENSIVE CARE UNIT SETTING Renal and hypoxic encephalopathies are quite common in the ICU environment. Details of their diagnosis and management are beyond the scope of this article, and have been reviewed. 67 Iatrogenic causes of encephalopathy are also common in ICUs and should be actively excluded. Hypno- sedative drugs and narcotic analgesics are the most common agents in this category. Flumazenil and naloxone will reverse these drug-induced encephalopathies. The need to reverse the effects of these drugs in an individual ICU patient should be carefully assessed 204 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 because the emergence of agitation or severe pain may be detrimental to the patient. If these drugs are used to determine whether encephalopathy is due to medica- tions, doses much smaller than those to treat respiratory depression shou ld be used initially. Flumazenil (0.1 to 0.2 mg intravenously over 15 seconds), may be given every 60 seconds to a maximum of 1.0 mg. The risk of seizures is always present when this drug is administered. 68 Naloxone, 0.04 to 0.08 mg intravenously, may be given every 60 seconds to a total dose of 0.8 mg. Barbiturates are not antagonized by available agents. It should be apparent from the preceding section on hepatic encephalopathy that a response to flumazenil is not specific for a benzodiazepine overdose. Other encephalopathic conditions may arise during the course of ICU treatment. One of our poorly nourished patients developed Wernicke’s encephalopathy from the dextrose administered as the vehicle for a lidocaine infusion to treat ventricular arrhythmias after an acute myocardial infarction. The clinician must always be aware that admission to the ICU does not prevent the development of intercurrent illnesses. Seizures in the Intensive Care Unit In our epidemiological study, 34 patients had simple partial seizures (with or without secondary generalization), and six had complex partial seizures (with or without secondary generalization). 4 Twenty patients had seizures that appeared to be generalized at onset, and six patients developed status epilepticus in the MICU; all required at least two agents to terminate their status (usually a benzodiazepine and phenytoin). Two of these patients developed refractory status epilepticus and were treated with pentobarbital coma. Three patients were admitted to the MICU for refractory hypotension after receiving phenytoin infusions at rates between 25 and 50 mg/min. The blood pressures of these patients did not improve with fluid resus citation alone; all required dopamine infusions for several hours to maintain blood pressure and systemic perfusion. In contrast to our experience in other hospitalized patients, the focal onset of partial seizures with secondary generalization was usually noted and adequately described. This was a useful guide to management because patients with partial seizures generally experienced seizure recurrence and thus probably benefited from anticonvulsant treatment. 69 The diagnosis and management of seizures should be pursued differently in ICU patients than in other patients. We had hoped to develop rules to predict which patients having seizures in the ICU might be evaluated without imaging procedures, but were unable to do so because most patients had vascular or infectious causes for their seizures. All patients experiencing a single seizure in the ICU were treated with some form of anticonvulsant therapy; this was often justified by the argument that their underlying medical condition might be adversely affected by subsequent seizures. We believe that this constitutes excessively aggressive management and that it postpones an appropriate search for etiology. For example, all three patients with recurrent seizure s caused by nonketotic hyperglycemia were treated with at least two anticonvulsants; these drugs are known to be ineffective in this condition. 70 When ICU patients do require treatment, phenytoin remains a reasonable first choice. However, a second agent, usually phenobarbital, was required in most patients. Lorazepam was useful for the suppression of breakthrough seizures, but the use of this drug was often continued without adequate attention to optimal use of phenytoin or phenobarbital. Pentobarbital coma is often considered the treatment of choice for refractory status epilepticus in ICU patients. We have adopted the use of high-dose midazolam in this circumstance. 71 This method appears to be more rapidly effective and to have substantially fewer and less severe adverse effects than pentobarbital, thiopental, or propofol. 72 NEUROMUSCULAR COMPLICATIONS OF SEPSIS Although recognized by earlier authors such as Osler, the modern era of interest in this problem began with the independent reports of three group s reported by Rivner et al (four patients), 73 Bolton et al (17 patients), 74 and Roelofs (four patients). 75 Bolton’s group followed their initial description with a series of papers that character- ized the clinical, 76 electrophysiological, 77 and pathological aspects of critical illness polyneuropathy. 78 Although many other groups have made significant contributions to this area (e.g., Op de Coul et al), 75 the work of Bolton and his colleagues is in great measure responsible for the recognition of this problem among intensivists. More recent work continues to show a high incidence of this condition. 79 These neuromuscular complications are presently categorized anatomically. Critical illness polyneuropathy is an axonal disorder affecting both sensory and motor nerves. 78 Electrophysiologic al evidence of this condition, as already noted, is present in 70% of septic patients, but the percentage with weakness sufficient to impede ventilator weaning or ambulation is less. The phrenic nerves are typically the most severely involved. Neuro- muscular junction (NMJ) dysfunction in the setting of critical illness is typicall y a consequence of a prolonged effect of NMJ blocking agents, usually because of impaired clearance. 80 Myopathy in critically ill patients is most commonly seen in those who have received NMJ blocking agents and corticosteroids in the treatment of severe asthma. 81 Although this has been reported most NEUROLOGICAL DISORDERS I N THE I CU/BLECK 205 commonly after vecuronium use, it also occurs after NMJ blocking agents that do not depend on renal or hepatic excretion (e.g., atracurium). 82 Myopathy may also occur in the setting of some viral infections, such as influenza. A syndrome of disseminated pyogenic myopathy has also been described, 83 presumably as a consequence of bac- teremic seeding of muscles. Critical illness polyneuropathy has also been noted after organ transplantation without sepsis. 84 Although most of the patients reported to have critical illness polyneuropathy have been adults, this condition has been recognized with increasing frequency in children as well. 85 In contrast to the body of experimental work on septic encephalopathy, very little is understood about the pathogenesis of the neuromuscular complications of sepsis. 86 Hyperglycemia correlates with the development of critical illness polyneuropathy, but these may be independent markers of disease severity. However, the dramatic reduction in critical illness polyneuropathy with intensive control of blood glucose in both medical 87 and surgical 88 ICU patients points to an important role of hyperglycemia in the genesis of this condition, as well as in many other neurological problems seen in critical care units. 89 The neuronal microenvironment is similar to that of the extracellular space of the brain; the same alterations that produce septic encephalopathy may be responsible for critical illness polyneuropathy, but further investigation is clearly needed. Critical illness myopathy may result from the functional denervation induced by NMJ blockade; it does not appear to be simply a severe form of steroid myopathy. Diagnosis, Differential Diagnosis, and Prognosis Recognition of a neuromuscular complication of sepsis generally occurs as the patient begins to recover from the critical illness that first required ventilatory support. Critical illness polyneuropathy is usually suspected when the patient’s pulmonary mechanics (e.g., static compliance) and gas exchange suggest that weaning should be possible, but the patient is too weak to tolerate it. 90 There is commonly some evidence of distal weakness on examination. Tendon reflexes are often absent or diminished, but critical illness polyneuropa thy may be present without alteration in reflexes. 91 Gorson provides an excellent framework for the evaluation of patients with these problems. 92 The diagnosis depends on electrophysiological studies, which demonstrate an axonal disorder. Electro- myographic studies of the diaphragm confirm the pres- ence of denervation. 93 The differential diagnosis is usually limited to consideration of the axonal form of the Guillain-Barre ´ syndrome; this condition usually causes much more severe generalized weakness than critical illness polyneuropathy, and typically causes an increased cerebrospinal fluid protein concentration. An- tecedent infection with Campylobacter jejeuni is frequently in patients with the axonal form of Guillain- Barre ´ . 94 Other differential diagnostic concerns are bot- ulism, which impairs presynaptic acetylcholine release, and myasthenia gravis, in which the motor end plate is damaged. These conditions have characteristic nerve conduction and electromyographic characteristics. No specific treatment for critical illness polyneuropathy is available. Anecdotal evidence does not favor the use of plasma exchange or intravenous immunoglobulin, but there have been no definitive trials. Almost all patients recover eventually, but this may require 6 months or more of ventilatory support. The prolonged effect of NMJ blocking agents can be suspected by lack of tendon reflexes and inability to produce muscle contraction with a bedside neuromuscular stimulator. If the diagnosis is in question, it can be confirmed by formal nerve conduction studies and elec- tromyography. There is no specific treatment, but the condition will resolve when the agent in question has cleared. Critical illness myopathy is often accompanied by substantial elevation of the serum creatine kinase (CK) concentration, which serves to distinguish this condition from steroid myopathy, in which the CK is usually normal. Electromyo graphy is usually an adequate diagnostic study, and muscle biopsy is only rarely required. 95 Again, no specific treatment is available, but the condition will resolve; whether it will resolve faster if systemic steroids are reduced or discontinued is uncertain. A more recently described syndrome of acute quadriplegic myopathy is also probably associated with steroids; in this condition, muscle is electrically inexcit- able even with direct stimulation. 96 Nerves are histolog- ically normal, but muscles show thick filament loss. 97 Although no treatment is known, the prognosis for this condition is for more rapid recovery than that for critical illness polyneuropathy. There are many other neurological problems that may arise during the course of an ICU stay which may impede weaning from mechanical ventilation. Kelly and Matthay prospectively studied 66 consecutive adult patients requiring mechanical ventilation for more than 48 hours to determine the reasons for their ventilatory problems. 95 Neurological problems, primarily encephalopathies, were held responsible for the continuing need for ventilatory support in 32% of the patients, and contributed to this problem in another 41%. Although this study was not directed at patients who failed to wean after resolution of their presenting disease, it does high- light the role of neurological problems early in critical illness. Spitzer and colleagues studied 21 patients who failed to wean after their presenting disease had improved to the point that their intensivists believed that mechanical ventilation should no longer have been 206 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 necessary. 98 Thirteen (62%) of these patients had a neuromuscular disorder that was either the major cause of or contributed substantially to their ventilatory problems. Only seven of these 13 patients had critical illness polyneuropathy; other neuropathic conditions and un- suspected motor neuron disease were also uncovered. 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Tel: +1( 212 ) 58 4-4 662. DOI 10 .10 55/s-200 6-9 455 31. ISSN 10 6 9-3 424. 2 01 were classified as having a complication of a critical illness if they developed. Crit Care Med 2006;27 :19 9–200. Copyright # 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10 0 01, USA. Tel: +1( 212 ) 58 4-4 662. DOI 1 0 .10 55/s-200 6-9 45524. ISSN 10 6 9-3 424. 19 9 liver. Crit Care Med 2006;27: 210 –220. Copyright # 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10 0 01, USA. Tel: +1( 212 ) 58 4-4 662. DOI 10 .10 55/s-200 6-9 45532. ISSN 10 6 9-3 424. 210 WHAT

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