Update in Critical Care 2005

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Update in Critical Care 2005 Eric B. Milbrandt, Akitoshi Ishizaka, and Derek C. Angus CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Laboratory, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Medicine, Keio University, School of Medicine, Tokyo, Japan

ISSUES OF GENERAL INTEREST Randomized controlled trials (RCTs) stopped earlier than planned because of apparent benefit, such as PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) and the ARDS (Acute Respiratory Distress Syndrome) Network low tidal volume study, often generate considerable excitement and affect clinical practice. Montori and coworkers (1) systematically reviewed RCTs involving interventions stopped early for benefit, finding that such trials are becoming more common, often fail to adequately report relevant information about the stopping decision, and show implausibly large treatment effects, particularly when the number of events is small. Because the decision to stop is typically driven by highly significant p value thresholds, trials that are terminated early because of apparent benefit will frequently show large treatment effects, even when the number of events is large. In the future, journals should require adequate reporting about the stopping decision. Glance through any major medical journal and you will increasingly encounter terms from the world of molecular medicine that, unless you live in that world, are unfamiliar and sometimes meaningless. A supplement to Critical Care Medicine (2) attempts to demystify these terms with a series of short articles by international experts that use extensive illustrations and diagrams to emphasize the value of these concepts in the context of the “real world” practice of critical care medicine.

the myocardium and kidney. The authors concluded that resuscitation of neonates with pure oxygen should be reevaluated.

CARDIOVASCULAR CRITICAL CARE Nesiritide, recombinant human B-type natriuretic peptide (hBNP), is a potent vasodilator that rapidly reduces cardiac filling pressures and improves dyspnea in patients with acutely decompensated congestive heart failure. Two metaanalyses suggest that nesiritide is associated with worsening renal function (5) and increased mortality (6), prompting the manufacturer, Scios, to issue a “Dear Healthcare Provider” letter in July 2005. Importantly, nesiritide should be used only in hospitalized patients with acutely decompensated congestive heart failure who have dyspnea at rest. Ongoing trials will determine whether nesiritide improves clinically meaningful end points, such as death or rehospitalization. Atrial fibrillation and flutter are common after cardiac surgery and are associated with increased morbidity. In a metaanalysis of 10 RCTs involving 1,744 subjects, Aasbo and coworkers found that amiodarone prophylaxis reduced atrial and ventricular arrhythmias, stroke, and length of stay after cardiac surgery (7). Mitchell and coworkers (8) found similar results in 601 nonemergent cardiac surgery patients, effects that were independent of age, type of surgery, and preoperative ␤-blocker use.

MONITORING AND RESUSCITATION

INFECTIOUS DISEASE

Although knowledge of pulmonary artery catheter (PAC)– derived data has obvious appeal, concern emerged in the early 1990s that PAC use might be associated with higher mortality. The PAC-Man trial by Harvey and coworkers (3) is the largest and best-powered trial thus far in a general intensive care population and has yet again failed to demonstrate any benefit with PAC use. Given the difficulty of demonstrating clear benefit to any individual patient, clinicians must weigh carefully the perceived benefits, which may be largely intangible, against the small, but nonzero, risk of harm to the patient. Perinatal asphyxia is a leading cause of morbidity and mortality in the neonatal period. Previous studies have shown that room air resuscitation is as efficient as 100% oxygen while producing less oxidative stress in asphyxiated newborns. Vento and coworkers (4) expanded on this work by showing that room air resuscitation also diminishes ischemia–reperfusion damage to

Infection Control

(Received in original form January 5, 2006; accepted in final form January 5, 2006 ) Correspondence and requests for reprints should be addressed to Derek C. Angus, M.B., Ch.B., M.P.H., Room 604, Scaife Hall, CRISMA Laboratory, Department of Critical Care Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261. E-mail: [email protected] Am J Respir Crit Care Med Vol 173. pp 833–841, 2006 DOI: 10.1164/rccm.2601004 Internet address: www.atsjournals.org

In the largest and longest study of its kind to date, Grundmann and coworkers (9) found that as many as one in six intensive care unit (ICU)–acquired infections are explained by patientto-patient cross-transmission via health care workers. Using a spatially explicit agent-based model, Hotchkiss and coworkers (10) demonstrated that pathogen dissemination in the ICU is strongly affected by duration of caregiver pathogen carriage and per-encounter pathogen acquisition risk. Patient cohorting as well as rapid detection and isolation each diminished dissemination. These results are particularly interesting in light of the study by Cepeda and coworkers (11), which found that placing ICU patients colonized or infected with methicillin-resistant Staphylococcus aureus in single rooms or cohorting them in multibed bays had no effect on methicillin-resistant S. aureus transmission. Among the potential reasons for the finding of a lack of an effect were that nurses, but not physicians or other health care providers, were cohorted with patients, and compliance with hand hygiene was only 21% for high-risk contacts. Antibiotic rotation has been proposed as a strategy to limit antibiotic resistance. van Loon and coworkers (12) examined the effect of rotating two different antibiotic classes on gramnegative antimicrobial resistance in an eight-bed surgical ICU. The authors found that rotation stimulated development and

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spread of resistance and failed to eradicate existing resistance brought about in the previous cycle. They concluded that improving infection prevention and reducing antibiotic use are probably the only meaningful strategies to control antibiotic resistance. Bloodstream Infection

Safdar and Maki (13) found that peripherally inserted central venous catheters (PICCs), used in hospitalized (mostly ICU) patients, were associated with a rate of catheter-related bloodstream infection similar to that of conventional central venous catheters placed in the internal jugular or subclavian veins. Kim and coworkers (14) determined that risk of mortality with a health care–associated bloodstream infection was higher in those ICU patients who were less severely ill at admission, suggesting that focused interventions to prevent bloodstream infection might have greater benefit in this subgroup of patients. Hospital-acquired, Ventilator-associated, and Health Care–associated Pneumonia

A joint committee of the American Thoracic Society and the Infectious Diseases Society of America issued a new evidencebased guideline for the management of adults with hospitalacquired pneumonia (15), including ventilator-associated pneumonia (VAP). In a multicenter RCT of heated humidifiers versus heat and moisture exchanger filters, Lacherade and coworkers (16) demonstrated no difference in the incidence of VAP or endotracheal tube occlusion. They concluded that other criteria, such as cost, may justify the choice of ventilator humidification system. It is generally thought that lethal infections caused by opportunistic pathogens develop permissively by invading a host that is both physiologically stressed and immunologically compromised. For example, Tarlowe and coworkers (17) found that trauma leads to suppression of high-affinity neutrophil receptors, such as CXCR2, which may predispose these patients to the subsequent development of pneumonia. However, work by Wu and coworkers (18) suggests that some pathogens, such as Pseudomonas aeruginosa, might actively sense alterations in host immune function and respond by enhancing their virulence phenotype. In a state of the art review, Sadikot and coworkers (19) discussed pathogen–host interactions in P. aeruginosa pneumonia. Community-acquired Pneumonia

Initial antibiotic therapy in community-acquired pneumonia (CAP) is directed by evidence-based guidelines, but whether adherence to guidelines improves outcomes is unknown. Mene´ndez and coworkers (20) examined predictors of guideline adherence and outcome in 1,288 patients with CAP in 13 Spanish hospitals. The authors found that adherence depended on hospital and physician characteristics and that nonadherence was an independent risk factor for mortality. Although these findings are encouraging, there were a number of methodologic limitations in this observational study (21). Confalonieri and coworkers (22) randomized 46 patients admitted to the ICU with severe CAP to 7-d hydrocortisone infusion or placebo and found that hydrocortisone treatment was associated with reduced hospital mortality. Given the small sample size, baseline differences between groups, and low mortality rate in the treatment arm, an adequately sized multicenter RCT is needed before hydrocortisone can be recommended as routine therapy for severe CAP. Elevated proinflammatory cytokines are associated with pneumonia severity, but their role in predisposition to CAP is less clear. Interestingly, Yende and coworkers (23) found that preinfection systemic levels of tumor necrosis factor (TNF) and IL-6 were

associated with higher subsequent risk of hospitalization due to CAP for smokers and those with coexisting medical conditions. Severe Acute Respiratory Syndrome

In 2003, a new coronavirus (SARS-CoV) caused severe pneumonia and acute respiratory failure, or SARS. The clinical and pathological features of acute lung injury (ALI) due to SARS appear indistinguishable from those of ALI due to other causes (24). Jiang and coworkers (25) found that induction of interferoninducible protein-10 is a crucial event in the initiation of ALI and lymphocyte apoptosis in SARS. Kuba and coworkers (26) provided the first genetic proof that angiotensin-converting enzyme-2 (ACE2), a negative regulator of the renin–angiotensin system, is a crucial SARS-CoV receptor in vivo. Interestingly, ACE2 protects mice from ALI induced by acid aspiration or sepsis (27), highlighting the potential therapeutic utility of recombinant ACE2 for ALI due to viruses and other causes (28).

BIOMARKERS Investigators continue to search for biomarkers that can reliably differentiate diseases in which the clinical symptoms are ambiguous, such as determining the etiology of respiratory failure. Natriuretic peptides (NPs), such as BNP, can be used as noninvasive markers of heart failure, but their use in ICU patients is complicated by other known stimulators of their release, such as hypoxia and right ventricular strain due to lung disease itself. Jefic and coworkers (29) found that neither BNP nor N-terminal pro-BNP could differentiate between high– and low–pulmonary artery wedge pressure respiratory failure, but that levels of these markers did inversely correlate with indices of cardiac contractility. C-reactive protein is a general indicator of infection (30) and a potential indicator of VAP resolution (31). Procalcitonin seems to hold promise for identifying cases of bacterial infection, such as in VAP, in which persistently elevated levels were strong predictors of an unfavorable outcome (32). It remains to be seen whether procalcitonin should be used to guide antibiotic therapy in VAP (33). Ye and coworkers (34) found that pre–B-cell colony-enhancing factor (PBEF) has the potential to be a novel marker of acute lung injury, finding significantly increased PBEF levels in both the lungs and serum of animals and humans with ALI and a nearly eightfold higher risk of ALI when subjects had certain PBEF single-nucleotide polymorphisms. Acute renal failure (ARF) is typically diagnosed by measuring serum creatinine, which is an unreliable indicator during acute changes in kidney function. Mishra and coworkers (35) found that urine and serum levels of neutrophil gelatinaseassociated lipocalin represent sensitive, specific, and highly predictive early biomarkers for acute ischemic renal injury in children after cardiac surgery. Broader use of this marker for early recognition and treatment of ARF awaits validation in a larger population in whom additional mechanisms of renal injury might be involved.

SEPSIS AND SEPTIC SHOCK Drotrecogin Alfa (Activated)

The U.S. Food and Drug Administration approved drotrecogin alfa (activated) (DrotAA) in November 2001 for the treatment of adults with severe sepsis at high risk of death, with the added requirement that the manufacturer study the efficacy of DrotAA in adults with severe sepsis at low risk of death. In the ADDRESS (Administration of Drotrecogin Alfa [Activated] in Early Stage Severe Sepsis) study (36), subjects with severe sepsis and low risk of death (Acute Physiology and Chronic Health Evaluation [APACHE] II ⬍ 25 or single-organ failure) were randomized

Pulmonary and Critical Care Updates

to DrotAA infusion versus placebo. The study was stopped early after 2,640 subjects were enrolled, when it became clear that there was no mortality benefit, yet more frequent serious bleeding, with DrotAA use. ENHANCE (Extended Evaluation of Recombinant Human Activated Protein C) (37) was an open label, single-arm trial of DrotAA in 2,378 subjects with severe sepsis and one or more sepsis-induced organ dysfunctions. The authors found similar 28-d mortality, yet higher serious bleeding rates, compared with PROWESS. Early DrotAA initiation (less than 24 h after first sepsis-induced organ dysfunction) was associated with lower mortality (22.9 vs. 27.4%, p ⫽ 0.01). Taken together, these results confirm that DrotAA should be used only in subjects at high risk of death with low likelihood of bleeding and suggest that early treatment may be important. DrotAA is thought to improve outcomes in severe sepsis through alterations in coagulation, inflammatory cytokine production, and leukocyte–endothelial interactions. van der Poll and coworkers (38) added to the growing body of evidence in this area by showing that DrotAA inhibits local coagulation after intrapulmonary delivery of endotoxin in humans. Steroids and Adrenal Insufficiency

Oppert and coworkers (39) found that low-dose hydrocortisone infusion (about 300 mg/d) improves shock reversal and reduces IL-6 levels, with the hemodynamic effects, but not the immune effects, being more pronounced in nonresponders to the 250-␮g short adrenocorticotropic hormone stimulation test. Siraux and coworkers showed that the low-dose (1 ␮g) adrenocorticotropic hormone stimulation test could identify a subgroup of septic shock patients with inadequate adrenal reserve who had worse outcome and would have been missed by the high-dose (250-␮g) test (40). Importantly, the current evidence showing improved mortality with steroid use is in nonresponders to the high-dose test. It remains to be seen whether the subgroup identified by the low-dose test will also see improved mortality with steroids.

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understanding. Wesselkamper and coworkers (47) investigated the role of transforming growth factor-␤ in acute lung injury after nickel exposure and showed that transforming growth factor-␤ acts as a central mediator of ALI through alteration of several molecular pathways. Vada´sz and coworkers (48) revealed that oleic acid may promote alveolar edema formation and contribute to the development of ARDS by impairing the two essential transepithelial active sodium transport mechanisms. Hypocapnea also appears to promote alveolar edema formation through one of these mechanisms (49). O’Dea and coworkers (50) showed that in the setting of early endotoxemia, lungmarginated monocytes exert local, cell-associated TNF signaling within the pulmonary microcirculation that may play a significant role in the subsequent evolution of pulmonary vascular injury. Severgnini and coworkers (51) reported that Jak and Src kinases participate in LPS-induced ALI and that selective tyrosine kinase inhibitors could potentially serve as novel therapeutic agents. Arndt and coworkers (52) demonstrated that systemic inhibition of c-Jun N-terminal kinase attenuated LPS-induced pulmonary neutrophil influx, perhaps through inhibition of neutrophil actin cytoskeleton assembly. He and coworkers (53) revealed that IL-11 and vascular endothelial growth factor exert protective effects in hyperoxia-induced ALI by increasing the expression of Bcl-2–related protein A1, which prevents mitochondrial disruption and cell death. Jiang and coworkers (54) reported that hyaluronan, an extracellular matrix glycosaminoglycan produced after tissue injury, interacts with Toll-like receptor (TLR)4 and TLR2 to initiate inflammatory responses, maintain epithelial cell integrity, and promote recovery from ALI. Casey and coworkers (55) observed that alveolar surfactant protein D may play an antiinflammatory role in the lung response to noninfectious, subacute lung injury via modulation of oxidative–nitrative stress. Mochizuki and coworkers (56) indicated that 15-deoxy-⌬12,14prostaglandin J2 plays a protective role against ALI by exploiting the Nrf2-mediated transcriptional pathway.

Risk Prediction

In a 28-ICU study involving 1,531 patients, Alberti and coworkers (41) found that one in four patients presenting with infection or sepsis progressed to severe sepsis or shock and that a score could quantify this risk. Leclerc and coworkers (42) found that septic states were common and occurred early in the ICU course of critically ill children and that sepsis and organ dysfunction were synergistic in worsening mortality. Although most genetic risk prediction studies have focused on the immune system, recovery after sepsis may also be dependent on mitochondrial function, which is compromised by the illness itself (43). Baudouin and coworkers (44) found that mitochondrial DNA haplogroup H, which is associated with enhanced respiratory chain activity, conferred a 2.1-fold increase in 6-mo survival after severe sepsis compared with individuals without haplogroup H, potentially suggesting a means of risk stratification or new avenues for therapeutic intervention.

ALI AND ARDS Bernard (45) provided an excellent historical perspective of ARDS. Zhou and coworkers (46) reported that an oleic acid– mouse model of ALI showed both the structural and functional characteristics of ALI, with endotoxin providing potent synergistic effects. Cellular and Molecular Mechanisms

The cascade of cellular and molecular pathways mediating ALI and its repair is complex and incompletely defined, although a number of interesting studies are beginning to expand our

Treatment

Calfactant, a natural lung surfactant containing high levels of surfactant-specific protein B, significantly reduced hospital mortality (19.5 vs. 36.0%, p ⫽ 0.03) in children and adolescents with ALI (57). Differences in the predominant mechanism of lung injury may explain the positive results of this study compared with adult studies, although differences in the surfactant-specific protein B content of surfactant preparations may have also been a factor. Kallet and coworkers (58) showed that implementation of the ARDS Network low tidal volume ventilation protocol was feasible in a real-world setting and was associated with lower mortality compared with historical controls. In reviewing available human and animal data, Hager and coworkers (59) were unable to identify a safe upper limit for plateau pressures in patients with ALI/ARDS. Grasso and coworkers (60) found that the ARDS Network Assessment of Low tidal Volume and elevated End-expiratory volume to Obviate Lung Injury (ALVEOLI) study’s higher positive end-expiratory pressure (range, 14 to 24 cm H2O)/lower FiO2 strategy frequently failed to induce alveolar recruitment and may have increased the risk of alveolar overinflation as compared with the lower positive end-expiratory pressure strategy. In hypoproteinemic patients with ALI/ARDS, Martin and coworkers (61) demonstrated that the addition of albumin to furosemide therapy improved oxygenation and achieved greater net negative fluid balance while maintaining hemodynamic stability. Additional study is needed to determine whether such an approach improves clinical outcomes.

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Hypercapnia, a frequent result of low tidal volume ventilation strategies, is thought to have beneficial effects. In an animal model of sepsis, however, Lang and coworkers (62) found that hypercapnia, via reduced rate and tidal volume, amplified LPSinduced lung injury. It is not clear whether hypercapnia itself or the means of achieving hypercapnia was responsible for their findings (63). The aspiration of gastric acid is an increasingly important cause of ALI. Safdar and coworkers (64) showed that intravascular infusion of hyperosmolar sucrose, either before or shortly after acid instillation, protects against acid-induced ALI in rats, an effect that may be due to strengthening of vascular barriers. Outcome Prediction

Outcome prediction in ALI/ARDS remains challenging. In pediatric ALI/ARDS, Flori and coworkers (65) found that, in contrast to adults, initial severity of arterial hypoxemia correlates well with mortality. A significant fraction of pediatric patients with ALI/ARDS could be identified before intubation was required, providing a valuable group for testing new therapies. In adults with ALI, an increased number of circulating endothelial progenitor cells was associated with improved survival (66), possibly because of the ability of endothelial progenitor cells to differentiate into mature endothelium and to assist in repairing damaged vasculature.

MECHANICAL VENTILATION Invasive Ventilation

Using diaphragm electrical activity as an index of respiratory drive, Spahija and coworkers (67) demonstrated that target drive ventilation could automatically adjust pressure-support ventilation to compensate for changes in respiratory demand. Tassaux and coworkers (68) showed that setting the expiratory trigger at a higher percentage of peak inspiratory flow in patients with obstructive lung disease improved patient–ventilator synchrony during pressure support ventilation and reduced inspiratory muscle effort. In a surfactant-deficient model of ALI, Richter and coworkers (69) found that the prone position improved gas exchange by restoring aeration and decreasing shunt, preserving perfusion in dorsal lung regions, and making the distribution of ventilation more uniform. Noninvasive Ventilation

Squadrone and coworkers (70) randomized 209 patients who developed severe hypoxemia after major elective abdominal surgery to continuous positive airway pressure (CPAP) or oxygen therapy alone and found that CPAP decreased the incidence of intubation, pneumonia, and sepsis while reducing ICU length of stay. L’Her and coworkers (71) examined the physiologic effects of noninvasive ventilation during ALI and found that pressure-support ventilation combined with positive endexpiratory pressure was required to reduce work of breathing and that CPAP alone improved oxygenation but failed to unload respiratory muscles. Ventilator-induced Lung Injury and Diaphragm Injury

Vlahakis and Hubmayr (72) provided a state of the art review of cellular stress failure in ventilator-induced lung injury (VILI). Kornecki and coworkers (73) found that adult rats were more susceptible to VILI than were infant rats, probably reflecting differences in intrinsic susceptibility or inflation pattern. Hypercapnic acidosis appears to impair plasma membrane wound resealing in VILI, but also minimizes the adverse effects of high-volume ventilation on vascular barrier function (74). Leukotrienes (75), inducible nitric oxide synthase (76), and low molecular weight

hyaluronan (77) were each shown to play important roles in VILI. DeRuisseau and coworkers (78) found that diaphragm unloading via controlled mechanical ventilation results in rapid changes in diaphragmatic gene expression, which may contribute to the atrophy and contractile dysfunction seen with prolonged mechanical ventilation. Weaning

Although a large number of physiologic variables have been proposed to determine readiness for weaning, there is little agreement as to what physiologic variables should be monitored during weaning, such as during a spontaneous breathing trial. Jubran and coworkers (79) found that monitoring esophageal pressure swings during a spontaneous breathing trial provided additional guidance over tests used to determine readiness, such as the frequency-to-tidal volume ratio.

INSULIN AND TIGHT GLUCOSE CONTROL Tight blood sugar control (maintaining blood sugar between 80 and 110 mg/dl) with intensive insulin therapy may reduce ICU mortality. Angus and Abraham (80) provided a thoughtful review of current and emerging evidence and ongoing trials in this area. In subsets of subjects from their original study, the Van den Berghe group reported evidence of endothelial protection (81) and reduced hepatocyte mitochondrial damage (82) with intensive insulin therapy, potentially explaining why tighter glucose control would be beneficial. Kanji and coworkers (83) compared the accuracy and clinical impact of three common methods of bedside glucose measurement with central laboratory measurements in ICU patients, many of whom were either vasopressor dependent or had significant peripheral edema. They found that differences were common and led to frequent disagreements regarding insulin dose titration.

NEUROLOGIC CRITICAL CARE The CRASH (Corticosteroid Randomisation after Significant Head Injury) trial randomized 10,008 adults with traumatic head injury to a 48-h infusion of corticosteroids or placebo (84). Corticosteroids increased both short- and long-term mortality and should not be used routinely in the treatment of acute traumatic head injury. In a two-center observational study, Cremer and coworkers (85) found that monitoring and targeted management of intracranial pressure and cerebral perfusion pressure in patients with severe head injury were associated with prolonged mechanical ventilation and increased levels of therapy intensity, without evidence of improved outcomes, as compared with supportive intensive care. This is inconsistent with other recent, albeit less methodologically sound, studies in this area and an RCT seems warranted. Mayer and coworkers (86) reported that treatment with recombinant activated factor VII within 4 h of primary intracerebral hemorrhage limited hematoma growth, reduced mortality, and improved 90-d functional outcomes. Baseline differences between groups and a nonsignificant trend toward increased thrombotic events in the recombinant activated factor VII group have tempered enthusiasm. A phase III trial is currently underway (87). Mounting evidence suggests that mild to moderate hypothermia can mitigate neurologic injury. Shankaran and coworkers (86) found that whole-body hypothermia (33.5⬚C for 72 h) reduced the risk of death or disability in infants with moderate or severe hypoxic–ischemic encephalopathy. Reaching target

Pulmonary and Critical Care Updates

temperature takes at least 2 h, using the fastest currently available cooling techniques. Polderman and coworkers (89) demonstrated that induction of hypothermia by means of ice-cold intravenous fluid combined with ice water–cooling blankets was safe, efficacious, and quick (about 60 min).

SEDATION AND ANALGESIA In a secondary analysis of 61 patients with ALI enrolled in the ARDS Network tidal volume trial, Kahn and coworkers (90) found that, contrary to popular belief, low tidal volume ventilation does not increase sedation use. Controversy regarding the use of etomidate for endotracheal intubation continues to brew (91–97), with some calling for complete abandonment of the drug because it may be an important cause of adrenal insufficiency in critically ill patients.

ACUTE RENAL FAILURE Uchino and coworkers (98) prospectively evaluated nearly 30,000 patients at 54 centers in 23 countries and found a period prevalence of ARF in the ICU of approximately 6%, with close to two-thirds of such patients receiving renal replacement therapy. Sepsis was the dominant cause of ARF, hospital mortality was 60%, and most survivors were dialysis independent at hospital discharge. Chertow and coworkers (99) examined the marginal effects of changes in serum creatinine in 9,210 patients admitted to an urban academic medical center and found that relatively small changes in serum creatinine were significantly associated with mortality, length of stay, and costs.

CLINICAL RISK PREDICTION Trachsel and coworkers (100) found that the oxygenation index ([mean airway pressure ⫻ FiO2 ⫻ 100]/PaO2 ) predicts outcome in children with acute hypoxemic respiratory failure. McAlister and coworkers (101) demonstrated that several perioperative factors, including age, positive cough test, nasogastric tube, and duration of anesthesia, predicted increased risk for pulmonary complications after elective nonthoracic surgery. In a systematic review, Quiroz and coworkers (102) reported that the clinical validity of a computed tomography scan to rule out pulmonary embolism was similar to that reported for conventional pulmonary angiography.

QUALITY OF LIFE AND LONG-TERM OUTCOMES As greater numbers of patients survive intensive care it is becoming increasingly evident that quality of life after critical illness is not always optimal. Hopkins and coworkers (103) found that nearly half of patients who survive ARDS manifest neurocognitive sequelae 2 yr after their illness. Anxiety and depression were also common and quality of life was poor. Critical illness not only affects patients, but family members as well. Azoulay and coworkers found that 90 d after an ICU stay, as many as one-third of family members reported symptoms consistent with a moderate to major risk of post-traumatic stress disorder (104). Those who believed information was incomplete or who shared in end-of-life decisions had even greater risk.

END-OF-LIFE CARE Curtis and coworkers (105) found that in nearly one-third of conferences with families about end-of-life care in the ICU, physicians had missed opportunities to provide support or information; the most common were missed opportunities to listen and respond to family members. Mularski and coworkers (106) found that family members rated the quality of dying highest

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when the patient’s end-of-life care included not only managing pain, but also supporting dignity, respect, and peace, while maximizing patient control.

ORGANIZATION, STAFFING, AND SAFETY In the most comprehensive examination to date of errors and adverse events in the ICU, Rothschild and coworkers (107) found that adverse events and serious errors were common and often potentially life-threatening. Their findings translate into a daily rate of 0.8 adverse events and 1.5 serious errors for a 10bed ICU. Using data from Cleveland Health Quality Choice, Durairaj and coworkers (108) found a significant relationship between ICU volume and risk-adjusted mortality for patients with gastrointestinal diagnoses and for sicker patients with respiratory diagnoses, yet not for those with neurologic diagnoses. The relatively small number of hospitals (n ⫽ 29) and unmeasured patient and hospital characteristics may have led to their failure to find a consistent association. In observational studies, medical emergency team (MET) systems are associated with reductions in unplanned ICU admissions, cardiac arrests, and deaths. The MERIT (Medical Early Response Intervention and Therapy) study (109) randomized 23 hospitals in Australia to continue functioning as usual or to introduce an MET system. Although this was the most rigorous study of MET to date, the study was underpowered to show a difference in their composite outcome of cardiac arrest, unexpected death, or unplanned ICU admission because event rates were significantly lower than anticipated. Jones and coworkers (110) reported that introduction of an MET system into a teaching hospital was not only effective, but sustainable over a 4-yr period. Peak levels of MET service activation followed a circadian pattern, with most occurring around the time of routine observations and nursing handover (111).

COMPLEX SYSTEMS MODELING Complex systems, like the human body in critical illness, display nonlinear behavior that appears chaotic at times. Understanding this behavior requires us to move beyond the traditional reductionist approach. Calvano and coworkers (112) used a structured network–based approach to analyze changes in human blood leukocyte gene expression patterns after intravenous administration of bacterial endotoxin. They found that endotoxin challenge resulted in transient dysregulation of leukocyte bioenergetics and modulation of translational machinery. Janes and coworkers (113) developed a systems-based model of intracellular signaling events associated with apoptosis. Their model revealed previously unsuspected molecular mechanisms connecting signaling to apoptosis. Covert and coworkers (114) used computational modeling coordinated with molecular and biochemical techniques to understand the dynamics of nuclear factor (NF)-␬B activation via LPS binding to TLR4. They found that one of the two TLR4-dependent signaling pathways required a time delay, during which TNF-␣ was synthesized.

NOVEL THERAPEUTICS Each year there are a number of articles about novel therapeutics, most of which are not ready for clinical use, yet quite fascinating for their insights into mechanisms associated with critical illness. Hydrogen sulfide, a reversible inhibitor of the electron transport chain, induced a suspended animation-like state in mice, lowering metabolic demand in a way that could potentially be used to reduce physiologic damage resulting from trauma or other severe insults (115). Inhaled low-dose carbon monoxide did not influence the systemic cytokine response to intravenous

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LPS in humans (116), but did protect rodents and swine from postoperative ileus (117). In mice, statins attenuated LPSinduced pulmonary inflammation (118) and improved survival when given after the onset of sepsis (119). Haloperidol use was associated with lower hospital mortality in mechanically ventilated patients (120). Salmeterol exerted antiinflammatory effects in the pulmonary compartment of humans exposed to LPS (121). The use of inhaled nitric oxide in premature infants with severe respiratory failure did not decrease rates of death or bronchopulmonary dysplasia (122). Thrombomodulin was shown to bind high-mobility group-B1, thereby preventing its interaction with RAGE (receptor for advanced glycation end-products) and suppressing induction of proinflammatory events via a mechanism that was distinct from the anticoagulant activity of thrombomodulin (123). At least some of the beneficial antiinflammatory effects of ethyl pyruvate may be due to modification of Rel protein p65, thereby inhibiting signaling via the NF-␬B pathway (124). High-fat enteral nutrition stimulated cholecystokinin receptors, attenuating the inflammatory response to hemorrhagic shock by way of the efferent vagus nerve and nicotinic receptors (125). Heme oxygenase-1 activity resulted in cytoprotection against oxidative injury and cellular stresses (126).

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18. Conflict of Interest Statement : E.B.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.I. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.C.A. has received consulting fees from Chiron, GlaxoSmithKline, Eli Lilly, ICOS, INO Therapeutics, Takeda, and ZD Associates and received lecture fees from Eli Lilly. He has received grant funding from Amgen, GlaxoSmithKline, ICOS, INO Therapeutics, OrthoBiotech, NIGMS, NHLBI, AHRQ, and the Robert Wood Johnson Foundation.

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