Non-pulmonary Critical Care - part 1 docx

PREFACE Non-pulmonary Critical Care: Managing Multisystem Critical Illness Care of the critically ill patient is truly multi- system 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 inten- sive care units (particularly medical ICUs) have respira- tory 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 or- gan dysfunction in the ICU setting. Clearly, a compre- hensive 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 appropri- ately 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 encepha- lopathies, seizures, and neuromuscular conditions. Drs. Miller and Ely share their current understanding of the rapidly evolving areas of delirium and cognitive dysfunc- tion 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 eval- uation 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 ad- dress 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 neuro- logical complication is frequently obscured by the effects of the prim ary illness (e.g., metabolic encephalopathy may delay the recognition of an intracerebral hemor- rhage) 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 encephal- opathy 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 neuro- logical 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 pro- spective study of neurological complications among medical intensive care unit (MICU) patients to describe the neurological complications encountered and to iden- tify their effects on mortality and length of stay (LOS). 4 Patients with a primarily neurological reason for admis- sion 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, in- cluding 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 neuro- logical complications were further divided into those with metabolic encephalopathies, seizures, cerebrovas- cular 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 in- cluded in the ‘‘other’’ group. We studied 1850 consecutively admitted patients; of these, 92 (4.9%) were admitted for a primary neuro- logical 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 cate- gory. 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 sig- nificant 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 oc- curred in 51 patients; in 27, the cause was primarily cardiac, with pulmonary disease accounting for the re- maining 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 endocar- ditis. 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 epidemio- logical 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; en- docarditis; 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 asso- ciated 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 micro- abscesses 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 identi- fied 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 inflamma- tion 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 cyto- kines 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 concen- trations 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 circula- tion; 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 dysfunc- tion 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 inflam- matory response. 33 Although cytokines have been sug- gested 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 demon- strated 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 encephalo- pathic 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 un- certain. 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 discus- sion 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 ence- phalopathy 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 pop- ulation 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 encephalop- athy 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 contrib- utes 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 con- centrations 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 recep- tor 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 con- tribute 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 com- mon in ICUs and should be actively excluded. Hypno- sedative drugs and narcotic analgesics are the most common agents in this category. Flumazenil and nalox- one 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 adminis- tered. 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 dur- ing the course of ICU treatment. One of our poorly nourished patients developed Wernicke’s encephalop- athy from the dextrose administered as the vehicle for a lidocaine infusion to treat ventricular arrhythmias after an acute myocardial infarction. The clinician must al- ways 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 generaliza- tion), 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 epi- lepticus and were treated with pentobarbital coma. Three patients were admitted to the MICU for refrac- tory 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 secon- dary generalization was usually noted and adequately described. This was a useful guide to management because patients with partial seizures generally experi- enced 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, phe- nytoin 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 treat- ment of choice for refractory status epilepticus in ICU patients. We have adopted the use of high-dose mid- azolam in this circumstance. 71 This method appears to be more rapidly effective and to have substantially fewer and less severe adverse effects than pentobarbital, thio- pental, 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 patholog- ical 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 im- paired 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 chil- dren 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 fur- ther investigation is clearly needed. Critical illness myo- pathy 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 weak- ness 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 fre- quently 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 neuromus- cular 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 diag- nostic study, and muscle biopsy is only rarely required. 95 Again, no specific treatment is available, but the con- dition will resolve; whether it will resolve faster if systemic steroids are reduced or discontinued is uncer- tain. 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 pa- tients requiring mechanical ventilation for more than 48 hours to determine the reasons for their ventilatory problems. 95 Neurological problems, primarily encepha- lopathies, 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 im- proved 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 prob- lems. Only seven of these 13 patients had critical illness polyneuropathy; other neuropathic conditions and un- suspected motor neuron disease were also uncovered. Most intensivists will also be familiar with the less common acute myopathies which may complicate crit- ical illnesses, especially in patients who have received neuromuscular junction blockade. 99 REFERENCES 1. Bleck TP. Why isn’t this patient awake? J Intensive Care Med 1993;8:155–156 2. Wijdicks EF. Neurologic complications in critically ill patients. Anesth Analg 1996;83:411–419 3. Isensee LM, Weiner LJ, Hart RG. Neurologic disorders in a medical intensive care unit: a prospective survey. J Crit Care 1989;4:208–210 4. Bleck TP, Smith MC, Pierre-Louis SJ, Jares JJ, Murray J, Hansen CA. Neurologic complications of critical medical illnesses. Crit Care Med 1993;21:98–103 5. Komrad MS, Coffey CE, Coffey KS, McKinnis R, Massey EW, Califf RM. Myocardial infarction and stroke. Neurology 1984;34:1403–1409 6. Thompson PL, Robinson JS. Stroke after acute myocardial infarction: relation to infarct size. BMJ 1978;2:457–459 7. Nathan BR, Bleck TP. Central nervous system complications of critical medical illness. In: Miller DH, Raps EC, eds. Critical Care Neurology. Boston: Butterworth-Heineman; 1999:331–340 8. Bright R. Reports of Medical Cases Selected with a View of Illustrating the Symptoms and Cure of Diseases, with a Reference to Morbid Anatomy. London: Longman, Rees, Orme, Brown and Green; 1827 9. Young GB, Bolton CF, Austin TW, Archibald YM, Gonder J, Wells GA. The encephalopathy associated with septic illness. Clin Invest Med 1990;13:297–304 10. Young GB, Bolton CF, Archibald YM, Austin TW, Wells GA. The electroencephalogram in sepsis-associated ence- phalopathy. J Clin Neurophysiol 1992;9:145–152 11. Zauner C, Gendo A, Kramer L, et al. Impaired subcortical and cortical sensory evoked potential pathways in septic patients. Crit Care Med 2002;30:1136–1139 12. Sprung CL, Peduzzi PN, Shatney CH, et al. Impact of encephalopathy on mortality in the sepsis syndrome. The Veterans Administration Systemic Sepsis Cooperative Study Group. Crit Care Med 1990;18:801–806 13. Eidelman LA, Putterman D, Putterman C, Sprung CL. The spectrum of septic encephalopathy: definitions, etiologies, and mortalities. JAMA 1996;275:470–473 14. Jackson AC, Gilbert JJ, Young GB, Bolton CF. The encephalopathy of sepsis. Can J Neurol Sci 1985;12:303–307 15. Pendlebury WW, Perl DP, Munoz DG. Multiple micro- abscesses in the central nervous system: a clinicopathologic study. J Neuropathol Exp Neurol 1989;48:290–300 16. Quagliarello VJ, Wispelwey B, Long WJ Jr, Scheld WM. Recombinant human interleukin-1 induces meningitis and blood-brain barrier injury in the rat: characterization and comparison with tumor necrosis factor. J Clin Invest 1991;87: 1360–1366 17. du Moulin GC, Paterson D, Hedley-Whyte J, Broitman SA. E. Coli peritonitis and bacteremia cause increased blood–brain barrier permeability. Brain Res 1985;340:261–268 18. Dinarello CA, Cannon JG, Wolff SM. New concepts on the pathogenesis of fever. Rev Infect Dis 1988;10:168–189 19. De Sarro GB, Masuda Y, Ascioti C, Audino MG, Nistico G. Behavioural and ECoG spectrum changes induced by intra- cerebral infusion of interferons and interleukin 2 in rats are antagonized by naloxone. Neuropharmacology 1990;29:167– 179 20. Reyes-Vazquez C, Prieto-Gomez B, Georgiades JA, Dafny N. Alpha and gamma interferons’ effects on cortical and hippocampal neurons: microiontophoretic application and single cell recording. Int J Neurosci 1984;25:113–121 21. Kadoi Y, Saito S, Kunimoto F, Imai T, Fujita T. Impairment of the brain beta-adrenergic system during experimental endotoxemia. J Surg Res 1996;61:496–502 22. Mussack T, Briegel J, Schelling G, Biberthaler P, Jochum M. Effect of stress doses of hydrocortisone on S-100B vs. interleukin-8 and polymorphonuclear elastase levels in human septic shock. Clin Chem Lab Med 2005;43:259–268 23. Maekawa T, Fujii Y, Sadamitsu D, et al. Cerebral circulation and metabolism in patients with septic encephalopathy. Am J Emerg Med 1991;9:139–143 24. Papadopoulos MC, Davies DC, Moss RF, Tighe D, Bennett ED. Pathophysiology of septic encephalopathy: a review. Crit Care Med 2000;28:3019–3024 25. Finelli PF, Uphoff DF. Magnetic resonance imaging abnormalities with septic encephalopathy. J Neurol Neurosurg Psychiatry 2004;75:1189–1191 26. Sharshar T, Annane D, de la Grandmaison GL, Brouland JP, Hopkinson NS, Francoise G. The neuropathology of septic shock. Brain Pathol 2004;14:21–33 27. Terborg C, Schummer W, Albrecht M, Reinhart K, Weiller C, Rother J. Dysfunction of vasomotor reactivity in severe sepsis and septic shock. Intensive Care Med 2001;27:1231– 1234 28. Papadopoulos MC, Lamb FJ, Moss RF, Davies DC, Tighe D, Bennett ED. Faecal peritonitis causes oedema and neuronal injury in pig cerebral cortex. Clin Sci (Lond) 1999; 96:461–466 29. Ari I, Kafa IM, Kurt MA. Perimicrovascular edema in the frontal cortex in a rat model of intraperitoneal sepsis. Exp Neurol 2006;198:242–249 30. Davies DC. Blood–brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 2002;200:639–646 31. Semmler A, Okulla T, Sastre M, Dumitrescu-Ozimek L, Heneka MT. Systemic inflammation induces apoptosis with variable vulnerability of different brain regions. J Chem Neuroanat 2005;30:144–157 32. Zhan RZ, Fujiwara N, Shimoji K. Regionally different elevation of intracellular free calcium in hippocampus of septic rat brain. Shock 1996;6:293–297 33. Weeks SG, Silva C, Auer RN, Doig CJ, Gill MJ, Power C. Encephalopathy with staphylococcal endocarditis: multiple neuropathological findings. Can J Neurol Sci 2001;28:260–264 34. Moller K, Strauss GI, Qvist J, et al. Cerebral blood flow and oxidative metabolism during human endotoxemia. J Cereb Blood Flow Metab 2002;22:1262–1270 35. Voigt K, Kontush A, Stuerenburg HJ, Muench-Harrach D, Hansen HC, Kunze K. Decreased plasma and cerebrospinal NEUROLOGICAL DISORDERS IN THE ICU/BLECK 207 fluid ascorbate levels in patients with septic encephalopathy. Free Radic Res 2002;36:735–739 36. Barichello T, Fortunato JJ, Vitali AM, et al. Oxidative variables in the rat brain after sepsis induced by cecal ligation and perforation. Crit Care Med 2006;34:886–889 37. Esen F, Erdem T, Aktan D, et al. Effect of magnesium sulfate administration on blood–brain barrier in a rat model of intraperitoneal sepsis: a randomized controlled experimental study. Crit Care 2005;9:R18–R23 38. Mizock BA, Sabelli HC, Dubin A, Javaid JI, Poulos A, Rackow EC. Septic encephalopathy: evidence for altered phenylalanine metabolism and comparison with hepatic encephalopathy. Arch Intern Med 1990;150:449–449 39. Sprung CL, Cerra FB, Freund HR, et al. Amino acid alterations and encephalopathy in the sepsis syndrome. Crit Care Med 1991;19:753–757 40. Basler T, Meier-Hellmann A, Bredle D, Reinhart K. Amino acid imbalance early in septic encephalopathy. Intensive Care Med 2002;28:293–298 41. Eggers V, Fugener K, Hein OV, et al. Antibiotic-mediated release of tumour necrosis factor alpha and norharman in patients with hospital-acquired pneumonia and septic ence- phalopathy. Intensive Care Med 2004;30:1544–1551 42. Kunze K. Metabolic encephalopathies. J Neurol 2002;249: 1150–1159 43. Towne AR, Waterhouse EJ, Boggs JG, et al. Prevalence of nonconvulsive status epilepticus in comatose patients. Neu- rology 2000;54:340–345 44. Bleck TP. Sepsis on the brain. Crit Care Med 2002;30:1176– 1177 45. Nora PM, Bleck TP. Increased intracranial pressure compli- cating acute hepatic failure. J Crit Illn 1989;4:87–96 46. O’Brien CJ, Wise RJ, O’Grady JG, Williams R. Neurological sequelae in patients recovered from fulminant hepatic failure. Gut 1987;28:93–95 47. Norenberg MD, Rao KV, Jayakumar AR. Mechanisms of ammonia-induced astrocyte swelling. Metab Brain Dis 2005; 20:303–318 48. Bleck TP. Neurologic consequences of fulminant hepatic failure. Mayo Clin Proc 1995;70:195–196 49. Canalese J, Gimson AE, Davis C, Mellon PJ, Davis M, Williams R. Controlled trial of dexamethasone and mannitol for the cerebral oedema of fulminant hepatic failure. Gut 1982;23:625–629 50. Nguyen JH, Yamamoto S, Steers J, et al. Matrix metal- loproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice. J Hepatol 2005 Nov 7; [Epub ahead of print] 51. Rama Rao KV, Chen M, Simard JM, Norenberg MD. Suppression of ammonia-induced astrocyte swelling by cyclosporin A. J Neurosci Res 2003;74:891–897 52. Ede RJ, Gimson AE, Bihari D, Williams R. Controlled hyperventilation in the prevention of cerebral oedema in fulminant hepatic failure. J Hepatol 1986;2:43–51 53. Forbes A, Alexander GJ, O’Grady JG, et al. Thiopental infusion in the treatment of intracranial hypertension complicating fulminant hepatic failure. Hepatology 1989; 10:306–310 54. Davenport A, Will EJ, Davison AM. Effect of posture on intracranial pressure and cerebral perfusion pressure in patients with fulminant hepatic and renal failure after acetaminophen self-poisoning. Crit Care Med 1990;18:286– 289 55. Munoz SJ, Robinson M, Northrup B, et al. Elevated intracranial pressure and computed tomography of the brain in fulminant hepatocellular failure. Hepatology 1991;13:209– 212 56. Wijdicks EF, Plevak DJ, Rakela J, Wiesner RH. Clinical and radiologic features of cerebral edema in fulminant hepatic failure. Mayo Clin Proc 1995;70:119–124 57. Davenport A, Will EJ, Losowsky MS. Rebound surges of intracranial pressure as a consequence of forced ultrafiltration used to control intracranial pressure in patients with severe hepatorenal failure. Am J Kidney Dis 1989;14:516–519 58. Sen S, Rose C, Ytrebo LM, et al. Effect of albumin dialysis on intracranial pressure increase in pigs with acute liver failure: a randomized study. Crit Care Med 2006;34:158–164 59. Keays R, Potter D, O’Grady J, Peachey T, Alexander G, Williams R. Intracranial and cerebral perfusion pressure changes before, during and immediately after orthotopic liver transplantation for fulminant hepatic failure. Q J Med 1991;79:425–433 60. Shami VM, Caldwell SH, Hespenheide EE, et al. Recombi- nant activated factor VII for coagulopathy in fulminant hepatic failure compared with conventional therapy. Liver Transpl 2003;9:138–143 61. Jones EA, Basile AS. Does ammonia contribute to increased GABA-ergic neurotransmission in liver failure? Metab Brain Dis 1998;13:351–360 62. Ahboucha S, Butterworth RF. Role of endogenous benzo- diazepine ligands and their GABA-A–associated receptors in hepatic encephalopathy. Metab Brain Dis 2005;20:425–437 63. Bansky G, Meier PJ, Rieder E, et al. Effects of the benzodiazepine receptor antagonist flumazenil in hepatic encephalopathy in humans. Gastroenterology 1989;97:744– 750 64. Grimm G, Ferenci P, Katzenschlager R, et al. Improvement of hepatic encephalopathy treated with flumazenil. Lancet 1988;2:1392–1394 65. Bessman SP, Wang W, Mohan C. Ammonia inhibits insulin stimulation of the Krebs cycle: further insights into the mechanism of hepatic coma. Neurochem Res 1991;16:805– 811 66. Blom HJ, Ferenci P, Grimm G, et al. The role of methanethiol in the pathogenesis of hepatic coma. Hepatol- ogy 1991;13:445–454 67. Bleck TP. Metabolic encephalopathy. In: Weiner WJ, Shulman LM, eds. Emergent and Urgent Neurology. 2nd ed. Philadelphia: Lippincott; 1999:223–253 68. Seger DL. Flumazenil–treatment or toxin. J Toxicol Clin Toxicol 2004;42:209–216 69. Frucht MM, Bleck TP. Seizures in the intensive care unit patient. In: Delanty M, ed. Seizures: Medical Causes and Management. Totowa: Humana Press; 2002:309–318 70. Singh BM, Strobos RJ. Epilepsia partialis continua associated with nonketotic hyperglycemia: clinical and biochemical profile of 21 patients. Ann Neurol 1980;8:155–160 71. Kumar A, Bleck TP. Intravenous midazolam for the treat- ment of refractory status epilepticus. Crit Care Med 1992;20: 483–488 72. Prasad A, Worrall BB, Bertram EH, Bleck TP. Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 2001;42:380–386 73. Rivner MH, Kim S, Greenberg M, Swift TR. Reversible generalized paresis following hypotension: a new neurologic entity. Neurology 1983;33(Suppl 2):164 208 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 [...]... Health Services Research, 6th Fl Medical Center East 610 0, Vanderbilt University Medical Center, Nashville, TN 3723 2-8 300 E-mail: russell.miller@vanderbilt.edu Semin Respir 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 DELIRIUM AND COGNITIVE DYSFUNCTIONIN THEICU/MILLER,... neurologic complications in critically ill patients ACP J Club 2006 ;14 4:20 90 Bleck TP The expanding spectrum of critical illness polyneuropathy Crit Care Med 19 96;24 :12 82 12 83 91 Hund EF, Fogel W, Krieger D, DeGeorgia M, Hacke W Critical illness polyneuropathy: clinical findings and outcomes of a frequent cause of neuromuscular weaning failure Crit Care Med 19 96;24 :13 28 13 33 92 Gorson KC Approach to... disorders in the intensive care unit Neurocritical Care 2005;3 :19 5– 212 93 Bolton CF AAEM minimonograph 340: clinical neurophysiology of the respiratory system Muscle Nerve 19 93 ;16 : 809– 818 94 Griffin JW, Li CY, Ho TW, et al Pathology of the motor´ sensory axonal Guillain-Barre syndrome Ann Neurol 19 96; 39 :17 –28 95 Kelly BJ, Matthay MA Prevalence and severity of neurologic dysfunction in critically ill patients:... Neurol 19 95 ;10 :346–352 86 Bolton CF Sepsis and the systemic inflammatory response syndrome: neuromuscular manifestations Crit Care Med 19 96;24 :14 08 14 16 87 Van den Berghe G, Wilmer A, Hermans G, et al Intensive insulin therapy in the medical ICU N Engl J Med 2006;354:449–4 61 88 van den Berghe G, Wouters P, Weekers F, et al Intensive insulin therapy in critically ill patients N Engl J Med 20 01; 345 :13 59 13 67... respiratory paralysis in critically ill patients Neurology 19 83;33(Suppl 2) :18 6 75 Roelofs RJ, Cerra F, Bielka N, Rosenberg L, Delaney J Prolonged respiratory insufficiency due to acute motor neuropathy: a new syndrome? Neurology 19 83;33(Suppl 2):240 76 Bolton CF, Gilbert JJ, Hahn AF, Sibbald WJ Polyneuropathy in critically ill patients J Neurol Neurosurg Psychiatry 19 84;47 :12 23 12 31 77 Bolton CF, Laverty... multiorgan failure Intensive Care Med 2006;32:2 51 259 80 Segredo V, Caldwell JE, Matthay MA, et al Persistent paralysis in critically ill patients after long-term administration of vecuronium N Engl J Med 19 92;327:524–528 81 Zochodne DW, Ramsay DA, Saly V, Shelley S, Moffatt S Acute necrotizing myopathy of intensive care: electrophysiological studies Muscle Nerve 19 94 ;17 :285–292 82 Davis NA, Rodgers... Laverty DA, Brown JD, Witt NJ, Hahn AF, Sibbald WJ Critically ill polyneuropathy: electrophysiologic ´ studies and differentiation from the Guillain-Barre syndrome J Neurol Neurosurg Psychiatry 19 86;49:563–573 78 Zochodne DW, Bolton CF, Wells GA, et al Critical illness polyneuropathy: a complication of sepsis and multiple organ failure Brain 19 87 ;11 0: 819 –842 79 Eikermann M, Koch G, Gerwig M, et al Muscle... of prolonged ventilator dependency Muscle Nerve 19 92 ;15 :682–686 99 Zochodne DW, Ramsay DA, Saly V, Shelley S, Moffatt S Acute necrotizing myopathy of intensive care: electrophysiological studies Muscle Nerve 19 94 ;17 :285–292 209 Delirium and Cognitive Dysfunction in the Intensive Care Unit Russell R Miller III, M.D., M.P.H .1 and E Wesley Ely, M.D., M.P.H .1, 2,3 ABSTRACT Delirium remains an underrecognized,... analgesics, critical care I n 2002, the Society of Critical Care Medicine suggested that all critically ill patients should be monitored both for level of sedation and for delirium .1 With the advent of diagnostic tools to assess for sedation and delirium since the last version of this topic in Seminars in 20 01, 2 the Society’s guidelines have become possible No longer should delirium be a ‘ part of the... 19 94 ;17 :285–292 82 Davis NA, Rodgers JE, Gonzalez ER, Fowler AA III Prolonged weakness after cisatracurium infusion: a case report Crit Care Med 19 98;26 :12 90 12 92 83 Young GB Neurologic complications of systemic critical illness Neurol Clin 19 95 ;13 :645–658 84 Rezaiguia-Delclaux S, Lefaucheur JP, Zakkouri M, Duvoux C, Duvaldestin P, Stephan F Severe acute polyneuropathy complicating orthotopic liver allograft . 333 Seventh Avenue, New York, NY 10 0 01, USA. Tel: +1( 212 ) 58 4-4 662. DOI 10 .10 55/s-200 6-9 455 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