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American Journal of Respiratory and Critical Care Medicine Vol 175. pp. 638-648, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200701-0123UP

Pulmonary and Critical Care Updates

Update in Critical Care 2006

Eric B. Milbrandt1, Akitoshi Ishizaka2 and Derek C. Angus1

1 The CRISMA Laboratory (Clinical Research, Investigation, and Systems Modeling of Acute Illness), Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and 2 Department of Medicine, Keio University, School of Medicine, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Derek C. Angus, M.D., M.P.H., Room 604, Scaife Hall, The CRISMA Laboratory, Critical Care Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261. E-mail: angusdc{at}upmc.edu

GENERAL INTEREST

Medical spending continues to outpace inflation. However, Cutler and coworkers demonstrated that the increase in medical spending over the last 40 years has been associated with a favorable overall cost-effectiveness ($19,900/extra yr of life) (1). Although the National Institutes of Health is sometimes criticized for funding clinical research, Johnston and coworkers estimated that clinical trials funded by the U.S. National Institute of Neurological Disorders and Stroke resulted in a net benefit to society of $15.2 billion (2). Future clinical research is threatened, however, by increasingly long and dense consent forms, in part due to the Health Insurance Portability and Accountability Act (HIPAA) privacy rule, even though Shalowitz and Wendler point out that only minimal additional text is required to satisfy HIPAA requirements (3). Unfortunately, intensive care unit (ICU) patients often fail to remember giving consent for research (4), highlighting the need for new approaches. Meanwhile, Pearson and coworkers argued that Medicare's requirement for research participation as a condition of coverage for new medical technologies is not coercive because patients are not entitled to new technologies that would not be covered in absence of the program (5).

Editorial independence came into question with the firing of John Hoey, editor-in-chief of the Canadian Medical Association Journal (6). Author- and editor-suggested reviewers did not differ in the quality of their reviews, but author-suggested reviewers tended to make more favorable recommendations for publication (7). Open review of abstracts, in which the author's identity and institutional affiliation are not concealed, may favor authors from the United States, other English-speaking countries, and prestigious academic institutions (8). Toma and coworkers found that discrepancies between the meeting abstract and subsequent full-length publication results were common (9). Abstracts of research articles are often the only part that is read, yet p values reported in abstracts are often from subgroup or secondary analyses and at times may be in error (10). Discordance between animal experiments and clinical trials is common and may be due to bias or failure of animal models to adequately mimic clinical disease (11).

Noninferiority and equivalence trials are often not adequately reported and conclusions can sometimes be misleading (12), leading the CONSORT (Consolidated Standards and Reporting Trials) group to issue an adapted CONSORT checklist for reporting these trials (13). Industry-sponsored meta-analyses (14) and cost-effectiveness analyses (15) were more likely to report favorable conclusions than those not sponsored by industry. Cardiovascular trials funded by for-profit organizations reported positive findings more commonly than those funded by not-for-profit organizations (16).

MONITORING AND RESUSCITATION

In a single-center observational study, focused assessment with sonography for trauma (FAST) was associated with altered subsequent management in nearly one of three trauma patients (17). Friese and coworkers found that older or more severely ill trauma patients had an associated survival benefit when managed with a pulmonary artery catheter (PAC) (18). In a pilot study of 28 critically injured patients, deltoid muscle tissue oxygenation measurements via an inserted probe proved useful in identifying patients who, despite appearing well resuscitated by standard measures, were at risk of developing infection and multiple organ failure (19). Changes in aortic blood flow induced by passive leg raising predicted preload responsiveness in ventilated medical ICU patients (20).

Pearse and coworkers reported that general surgery patients randomized to postoperative goal-directed therapy had fewer complications and shorter hospital stays as compared with those managed conventionally (21). In a randomized, controlled pilot study, 20% albumin administered as part of standard fluid management improved organ function in critically ill hypoalbuminemic patients (22).

Adequate cardiopulmonary resuscitation (CPR) is difficult to perform for an extended period and a number of CPR devices, such as the load-distributing band, are in various stages of testing. Two studies, one observational (23) and one cluster-randomized (24), compared load-distributing-band CPR with manual CPR after out-of-hospital cardiac arrest. The former found benefit, whereas the latter was halted early for futility and possible harm. Details of device use, differences in patient populations, and the adequacy of manual CPR may explain the disparate findings (25).

Cardiocerebral resuscitation, which seeks to minimize interruptions of chest compressions, was associated with improved survival and neurologic outcome of adult patients with witnessed out-of-hospital cardiac arrest and an initially shockable rhythm (26). Aminophylline failed to increase the rate of return of spontaneous circulation after out-of-hospital bradysystolic cardiac arrest (27). The use of a clinical prediction rule may help clinicians decide whether to terminate resuscitative efforts in patients having an out-of-hospital cardiac arrest (28). A large segment of the population desires the presence of significant others during CPR (29).

CARDIOVASCULAR CRITICAL CARE

Recent observational studies suggest that aprotinin, an antifibrinolytic agent used in cardiac surgery patients to mitigate bleeding, is associated with serious cardiovascular, renal, and cerebrovascular adverse events (30, 31). Off-pump surgery resulted in better clinical outcomes and shorter hospital stays for patients undergoing multivessel coronary artery bypass as compared with conventional surgery using cardiopulmonary bypass (32). In a small single-center study, Birks and coworkers found that sustained reversal of severe heart failure could be achieved in selected patients with a left ventricular assist device and a specific pharmacologic regimen (33). Although pacemaker reliability has improved over time, implantable cardioverter-defibrillator (ICD) malfunction appears to be increasing (34, 35). ICD replacement in response to advisories and recalls is associated with a substantial rate of complications (36), hindering decision making for patients with older devices.

INFECTIOUS DISEASE

Infection Control
Methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly prevalent in the community. MRSA was the most common identifiable cause of skin and soft-tissue infections among patients presenting to emergency departments in 11 U.S. cities (37). A strategy linking rapid MRSA screening to preemptive isolation and cohorting substantially reduced MRSA cross-infections in the medical, but not the surgical, ICU (38). Admission to an ICU room previously occupied by a patient with MRSA or vancomycin-resistant enterococci (VRE) significantly increased the odds of MRSA and VRE acquisition, although this route was a minor contributor to overall transmission (39). All tested hospital computer keyboards had growth of two or more microorganisms, but could be decontaminated with a variety of disinfectants without causing cosmetic or functional problems (40). An evidence-based intervention resulted in a large and sustained reduction in rates of catheter-related bloodstream infection (41).

Community-acquired Pneumonia
Rates of antibiotic-resistant invasive pneumococcal infections decreased in young children and older persons after introduction of the pneumococcal conjugate vaccine (42). In an observational study of patients with community-acquired pneumonia (CAP) requiring 24 hours or more of endotracheal intubation, compliance with Infectious Diseases Society of America antibiotic guidelines was associated with a 3-day reduction in duration of mechanical ventilation (43). After finding that many Medicare patients diagnosed with pneumonia present in an atypical manner, Metersky and coworkers suggest that a 100% performance target for initial delivery of antibiotics within 4 hours may lead to inappropriate antibiotic use (44). However, this study did not use biomarkers, such as procalcitonin, which was shown in a single-center trial to reduce antibiotic use in patients hospitalized with CAP (45). A simple score using clinical data available at the time of emergency department presentation identified patients at risk of evolving to severe CAP (46). Yoshida and coworkers found that cytoskeletal rearrangements may result in neutrophil sequestration within the lungs during pneumonia (47).

Health Care–associated Pneumonia
In a multicenter study of 740 patients with suspected ventilator-associated pneumonia (VAP), there were no differences in clinical outcomes or antibiotic use between those randomized to a diagnostic strategy of bronchoalveolar lavage (BAL) with quantitative culture or endotracheal aspiration with nonquantitative culture (48). The calibrated loop technique for quantitative culture of BAL fluid in suspected VAP appears as reliable as the serial dilution technique, yet less labor intensive (49). Oral decontamination with chlorhexidine reduced the incidence of VAP in patients mechanically ventilated for 48 hours or more (50) and prevented nosocomial infection after cardiac surgery (51). Routine 5-year use of selective digestive decontamination was not associated with increased antimicrobial resistance in a surgical ICU (52). Prophylatic oral iseganan, an antimicrobial peptide, failed to prevent VAP in a randomized multicenter study of 709 mechanically ventilated patients (53). Medicosurgical ICU patients mechanically ventilated for more than 5 days had a lower incidence of VAP when randomized to a heated humidifier as opposed to a heat and moisture exchanger (54). In long-term alcoholics, perioperative intervention with low-dose ethanol, morphine, or ketoconazole altered the immune response to surgical stress, reduced postoperative pneumonia rates, and shortened ICU stay (55). Schussler and coworkers reported that postoperative pneumonia is a frequent complication after major lung resection (56). Knapp and coworkers demonstrated that CD14 and Toll-like receptor 4 (TLR4) enhanced, whereas TLR2 delayed, lung clearance of Acinetobacter baumannii, an increasing cause of nocosomial pneumonia (57).

Other Infections
In a systematic review of influenza antivirals, Jefferson and coworkers noted that evidence does not support the use of amantadine and rimantadine and that neuraminidase inhibitors should only be used in serious epidemic or pandemic outbreaks alongside other public health measures (58). Klebsiella oxytoca is a cause of antibiotic-associated hemorrhagic colitis that should be considered in symptomatic patients who test negative for Clostridium difficile (59). Maskell and coworkers reported that pleural infection differs bacteriologically from pneumonia and requires different treatment (60). Segal and coworkers reviewed the current approaches to diagnosis and treatment of invasive aspergillosis (61).

ACUTE LUNG INJURY AND ACUTE RESPIRATORY DISTRESS SYNDROME

Clinical Trials and Observational Studies
In the multicenter Fluid and Catheter Treatment Trial (FACTT) involving 1,000 patients with established acute lung injury (ALI), PAC-guided therapy did not improve survival or organ function but was associated with more complications than central venous catheter–guided therapy (62). In this same trial, a conservative fluid management strategy improved lung function and shortened duration of mechanical ventilation and intensive care without increasing nonpulmonary organ failures (63). Elsewhere, methylprednisolone improved cardiopulmonary physiology but did not reduce mortality in 180 patients with persistent acute respiratory distress syndrome (ARDS) (64). In 136 patients with severe ARDS, prone ventilation was feasible and safe, with a nonsignificant mortality reduction (43 vs. 58%, p = 0.12) compared with supine ventilation, when initiated early and for most of the day (65). Partial liquid ventilation did not improve outcomes in adult patients with ARDS compared with conventional mechanical ventilation (66). A 7-day course of intravenous salbutamol reduced extravascular lung water in patients with ALI/ARDS (67). In a secondary analysis of the ARDS Network ALI tidal volume trial, hypercapnic acidosis was associated with reduced 28-day mortality in the high tidal volume, but not low tidal volume, group (68).

Several authors used computed tomography (CT) scanning to determine the effect of respiratory maneuvers. Galiatsou and coworkers demonstrated that prone position augments recruitment and prevents overinflation in ALI (69). Gattinoni and co- workers showed that the percentage of potentially recruitable lung is extremely variable in ARDS and strongly associated with the response to positive end-expiratory pressure (70). Borges and coworkers found that a bedside recruitment strategy reversed hypoxemia and fully recruited the lung in early ARDS, although at the expense of transient hemodynamic and hypercapnic side effects (71).

ARDS, even in previously healthy adults, is not only followed by poor survival, quality of life, and function but is also followed by high costs of care and postdischarge resource utilization (72). Even 2 years after ICU discharge, survivors of ARDS have functional impairment and compromised health-related quality of life, with postdischarge health care use and costs that are driven by readmissions and rehabilitation (73). A telephone-administered test battery was feasible and valid for assessing cognitive function in ARDS survivors and may be a useful research tool when in-person interviews are not possible (74). Much like caregivers of patients with Alzheimer's, informal caregivers of ARDS survivors experience negative health outcomes that persist almost 2 years after ARDS resolution (75).

Cellular and Molecular Mechanisms
Gharib and coworkers integrated expression profiling with gene ontology and promoter analysis to investigate the synergistic effects of mechanical ventilation and lipopolysaccharide (LPS) in promoting ALI (76). Xu and coworkers established a mouse model of avian influenza A virus–induced ARDS in mice (77). Reutershan and coworkers revealed a previously unrecognized role of endothelial and epithelial CXC chemokine receptor 2 in LPS-mediated neutrophil recruitment and lung injury (78). Bhandari and coworkers discovered that angiogenic growth factor angiopoietin 2 (Ang2) is a mediator of epithelial necrosis in hyperoxic ALI (79). Ang2 also appears to be an autocrine regulator of endothelial inflammatory responses (80).

Jenkins and coworkers showed that protease-activated receptor 1–mediated enhancement of integrin-dependent transforming growth factor-beta activation could be a mechanism by which coagulation cascade activation contributes to the development of ALI (81). Parthasarathi and coworkers reported a novel role of connexin 43–mediated gap junctions as conduits for spread of proinflammatory signals in the lung capillary bed (82). Zarbock and coworkers completely reversed acid- and sepsis-induced ALI in mice by blocking platelet–neutrophil aggregation (83). Looney and coworkers found that neutrophils and their Fc{gamma} receptors are essential in a mouse model of transfusion-related ALI (84). Nonas and coworkers demonstrated that oxidized phospholipids reduce vascular leak and inflammation in a rat model of ALI (85). Uchida and coworkers established that the receptor for advanced glycation end products is a marker of type I alveolar epithelial cell injury in rats and patients with ALI (86).

MECHANICAL VENTILATION

Weaning and Tracheostomy
In a multicenter randomized trial, computer-driven protocolized weaning reduced mechanical ventilation duration and ICU length of stay as compared with a physician-controlled weaning process (87). In a single-center study of 93 medical ICU patients, early identification of adrenal insufficiency and appropriate supplementation with stress dose hydrocortisone increased the success of ventilator weaning and shortened the weaning period (88). In 200 mechanically ventilated medicosurgical ICU patients, percutaneous and surgical tracheostomies were equally safe when performed at the bedside by experienced practitioners (89).

Nonconventional Approaches to Ventilation
In 162 high-risk patients, early use of noninvasive ventilation (NIV) after extubation averted respiratory failure and decreased ICU mortality as compared with conventional management (90). Before intubation of hypoxemic patients, preoxygenation using NIV reduced arterial desaturation better than bag-valve mask ventilation (91). In 39 patients with exacerbation of chronic obstructive pulmonary disease who initially failed NIV, ventilation via an uncuffed small-bore minitracheostomy tube reduced duration of mechanical ventilation and ICU length of stay as compared with conventional invasive ventilation (92). Using oxygenation to guide recruitment in open lung, high-frequency ventilation was feasible and safe in preterm infants and enabled reductions in the fraction of inspired oxygen (93). In infants receiving high-frequency ventilation, it was possible to delineate the deflation limb using a quasi-static lung volume optimization maneuver; in doing so, greater lung volume and oxygenation could be achieved, often at lower airway pressures (94). In preterm infants with respiratory failure, inhaled nitric oxide improved pulmonary outcome in one study (95), whereas in another study, it only did so in those infants weighing at least 1,000 g (96). Reassuringly, there was no increase in risk of brain injury in either study. In piglets with saline lavage–induced ALI, a recruitment maneuver performed after surfactant administration modified the spatial distribution of ventilation (97).

Ventilator-induced Lung Injury
Ventilation of rabbits with large tidal volumes induced expression of the proinflammatory mediator HMGB1 (high mobility group box protein 1) in lung macrophages and neutrophils (98). Blocking HMGB1 limited the subsequent development of ventilator-induced lung injury. In rats subjected to injurious ventilation, atelectasis caused alveolar injury in nonatelectatic lung regions (99). In rats, hemorrhagic shock followed by resuscitation rendered the lung and kidney more susceptible to mechanical ventilation–induced organ injury (100).

INSULIN AND TIGHT GLUCOSE CONTROL

In the subgroup of patients with a medical ICU stay of 3 or more days, intensive insulin therapy (IIT) reduced hospital mortality (101). Yet, mortality was greater with IIT in patients with shorter ICU stays. IIT requires frequent glucose measurements, which, in the future, may be facilitated by subcutaneous monitoring systems (102, 103). In a decision analysis of IIT in postoperative ICU patients, the number needed to treat to prevent ICU death and to cause hypoglycemia varied markedly according to patient characteristics (104). In a post hoc cost analysis of the original surgical ICU IIT trial, IIT was associated with substantial cost savings compared with conventional insulin therapy (105), results that were confirmed in a before-and-after study of medicosurgical ICU patients (106).

SEVERE SEPSIS AND SEPTIC SHOCK

Clinical Observations
Vincent and Abraham provided a review of the last 100 years of sepsis (107). The Sepsis Occurrence in Acutely Ill Patients (SOAP) study provided a clear view of the incidence and characteristics of sepsis in 3,147 adult patients admitted to European ICUs (108). The systemic inflammatory response syndrome (SIRS) proved to be quite common in this patient population and predicted infections, severity of disease, organ failure, and outcome (109). In the subset of SOAP patients with shock, dopamine administration was associated with increased mortality as compared with other vasopressor agents (110). In another sepsis cohort, elevated serum S-100beta, a marker of brain injury, was associated with the development of septic encephalopathy, suggesting that brain injury occurs in sepsis (111).

Cellular and Molecular Mechanisms
The cytokine storm seen in a phase 1 trial of an anti-CD28 monoclonal antibody offered insight into the SIRS syndrome in absence of contaminating pathogens, endotoxin, or underlying disease (112). In mice, severe bacteremia resulted in loss of hepatic bacterial clearance, which may be an important determinant of outcome in sepsis (113). A receptor antagonist of gastrin-releasing peptide, which is released by postganglionic fibers of the vagus nerve, attenuated proinflammatory cytokine release and improved survival in established rodent sepsis (114). The epithelium of gastrointestinal tract, instead of activated macrophages, may be the major source of HMGB1 release in sepsis and other inflammatory conditions (115). Apoptotic cells promote HMGB1 release by macrophages, which may explain why antiapoptotic treatments or genetic manipulations can improve survival in rodent sepsis models (116). Caspase-1 is important in the host response to sepsis, at least in part via its regulation of sepsis-induced splenic cell apoptosis (117).

Impairment of forkhead box M1 activation impairs endothelial repair after LPS-induced vascular injury (118). In animal and human models of sepsis, vascular endothelial growth factor appears to be an important determinant of morbidity and mortality (119). Calcineurin, a protein phosphatase that activates IL-2 transcription, regulates myocardial function during acute endotoxemia (120). Superoxide-derived free radicals play a critical role in the development of sepsis-induced cardiac dysfunction, suggesting that free radical scavengers may be beneficial in sepsis (121). The diaphragm, as compared with limb muscles, may be relatively predisposed to LPS-induced proinflammatory responses (122).

In patients with sepsis, the IL-1 receptor–associated kinase (IRAK-1) variant haplotype is associated with increased nuclear translocation of nuclear factor-{kappa}B, more severe organ dysfunction, and higher mortality (123). IL-1 receptor–associated kinase-M mediates sepsis-induced suppression of innate lung immunity, resulting in an immunocompromised state during sepsis (124). Nuclear factor-erythroid 2–related factor 2 is a critical regulator of innate immunity and survival during experimental sepsis (125). Mitogen-activated protein kinase phosphatase 1 controls innate immune reponses and suppresses endotoxic shock (126). Systemic activation of dendritic cells by TLR ligands impairs cross-presentation, helping to explain the immunosuppressive effects of systemic infection (127).

Steroids and Adrenal Insufficiency
Using the overnight metyrapone stimulation test as a gold standard, adrenal insufficiency was likely in patients with severe sepsis with baseline cortisol levels of less than 10 µg/dl or delta cortisol levels of less than 9 µg/dl, and unlikely with cosyntropin-stimulated cortisol levels of 44 µg/dl or greater or delta cortisol levels of 16.8 µg/dl or greater (128). Variability of cortisol assays can confound the diagnosis of adrenal insufficiency in septic patients (129). The incidence of relative adrenal insufficiency in patients with septic shock was increased when the cosyntropin test was performed after the administration of etomidate (130). In post hoc analysis of Annane and colleagues' low-dose steroids for septic shock trial, the benefit of steroids appeared confined to the subgroup with early ARDS who were cosyntropin nonresponders (131).

Early Goal-directed Therapy
Early goal-directed therapy (EGDT) endpoints were reliably achieved in real-world clinical practice with an apparent decrease in ICU PAC utilization (132). In a before-and-after study, implementation of an EGDT-based standard order set was associated with improvements in care processes and lower 28-day mortality (133). Paired central venous and mixed venous oxygen saturations (ScvO2 and SvO2) differed significantly, suggesting that ScvO2 should not be used as a surrogate of SvO2 after the initial EGDT resuscitation period (134).

Drotrecogin Alfa (activated)
Drotrecogin alfa activated (DAA) rapidly improved sepsis-induced microvascular alterations in adults; cessation of the drug was associated with transient deterioration in microvascular perfusion (135). The Researching Severe Sepsis and Organ Dysfunction in Children: A Global Perspective (RESOLVE) trial, a randomized study of DAA in children with severe sepsis, was stopped early for futility. DAA failed to reduce mortality but increased the incidence of central nervous system bleeding (136). DAA labeling now states that the drug is contraindicated for pediatric use.

Other Therapeutic Agents
In a single-center study of 103 mechanically ventilated patients with severe sepsis and who tolerated enteral nutrition, a diet enriched with omega-3 and omega-6 essential fatty acids and antioxidants reduced 28-day mortality (137). Molgramostim (granulocyte-macrophage colony–stimulating factor) reduced infectious complications, length of hospitalization, and cost in 58 patients with nontraumatic abdominal sepsis (138). Intratracheal recombinant surfactant protein D prevented endotoxin shock in newborn preterm lambs (139).

NEUROLOGIC CRITICAL CARE

In rodents, activated protein C blocked tissue plasminogen activator (tPA)-mediated brain hemorrhage after transient brain ischemia and embolic stroke (140). In 37 patients with ischemic stroke, treatment with desmoteplase 3 to 9 hours after onset was safe; at higher doses, it also appeared to improve outcome (141). Multivariable risk–benefit profiling identified a subset of patients with ischemic stroke who could benefit from thrombolysis in the 3- to 6-hour window (142). Oddo and coworkers demonstrated that the benefit of hypothermia for coma after out-of-hospital cardiac arrest can be safely achieved outside the setting of randomized trials (143). A single transcutaneous Doppler measurement was inferior to xenon-CT for detecting vasospasm in patients with subarachnoid hemorrhage (144). Changes in transcutaneous Doppler velocities over time may still yield useful information. In 2,602 patients presenting to the emergency department with mild head injury, immediate CT-guided management led to similar clinical outcomes and lower costs as compared with hospital admission for observation (145, 146). Preliminary data from a randomized pilot study suggest that long-term oral administration of creatine may improve clinical outcomes in children with traumatic brain injury (147). In a retrospective study of unconscious trauma patients, helical CT appeared to reliably clear the cervical spine, obviating the need for dynamic screening (148).

SEDATION AND ANALGESIA

In a meta-analysis of clinical studies, Ranji and coworkers reported that, although opiate administration may alter physical examination findings, these changes did not result in significant management errors (149). For medical patients requiring more than 48 hours of mechanical ventilation, sedation with propofol resulted in fewer ventilator days compared with intermittent lorazepam when sedatives were interrupted daily (150).

ACUTE RENAL FAILURE

In a multicenter study of 360 ICU patients requiring renal replacement therapy, there was no difference in 60-day survival between those randomized to intermittent hemodialysis versus continuous venovenous hemofiltration (151). In 354 patients with acute myocardial infarction undergoing primary angioplasty, N-acetylcysteine prevented contrast-induced nephropathy and improved hospital outcome in a dose-dependent fashion (152). The RIFLE criteria (risk, injury, failure, loss, end-stage), which classify acute renal injury into three groups (risk, injury, and failure), were useful in predicting hospital mortality for both ward (153) and ICU patients (154).

RISK PREDICTION

The Acute Physiology and Chronic Health Evaluation (APACHE) IV score predicts hospital mortality for ICU patients with good discrimination and calibration (155), but was less accurate for predicting ICU length of stay (156), especially at extremes of length of stay and risk of death. In trauma patients, reduced heart rate variability is an independent predictor of death that appears to increase in response to inflammation, infection, and multiple organ failure (157). Low levels of temperature curve complexity predict poor prognosis in patients with multiple organ failure equally as good as the Sequential Organ Failure Assessment score (158). Diabetes mellitus, not obesity alone, predicts mortality after acute organ failure (159). A decision algorithm can reliably assist in predicting poor outcome in comatose patients after cardiopulmonary resuscitation for cardiac arrest (160).

ORGANIZATION, STAFFING, AND PATIENT SAFETY

In the United States, intensive care is heterogeneously provided, with many patients being managed in ICUs with little access to intensivists (161). Meeting the Leapfrog initiative will likely require widespread reorganization of ICU services. In an ICU with 24-hour onsite intensivist staffing, outcomes for weekend and weeknight admissions were the same as those of weekday admissions (162). Uninsured Americans use ICU services less often than those with insurance and experience worse outcomes when admitted to the ICU, possibly because they are sicker when seeking care (163). There are large differences among intensivists in the amount of resources they use to manage critically ill patients (164). Higher resource use was not associated with improved outcomes. Differential use of hospitals with greater rates of terminal ICU use explains the majority of higher end-of-life ICU service use among blacks and Hispanics (165). Of registered ICU nurses who responded to a survey, 17% indicated intending to leave their position in the coming year, with the majority identifying working conditions as the reason (166). Risk of death was significantly lower for trauma patients cared for in regional trauma centers, especially for patients with more severe injuries (167).

Medicare hospital performance measures for acute myocardial infarction, heart failure, and pneumonia predicted only small differences in mortality (168). Yet, every 10% increase in adherence with American College of Cardiology/American Heart Association acute coronary syndrome guidelines was associated with a 10% decrease in likelihood of hospital mortality (169). Ongoing monitoring of pay-for-performance incentive programs will be critical to determine their effectiveness and possible unintended consequences (170).

Care in high-volume ICUs (171) and hospitals with high mechanical-ventilation case volume (172) was associated with reduced mortality, although some of this benefit may be limited to high-risk patients (171). Another study found no benefit of hospital volume for mechanically ventilated surgical patients and possible harm for medical patients cared for in low-volume hospitals that do not routinely transfer patients (173).

Extended-duration work shifts were associated with increased risk of medical errors, adverse events, and attention failures (174). Residents working extended shifts were at increased risk of percutaneous injuries (175) and showed evidence of vascular inflammation and dysfunction (176). Repeated episodes of sleep loss could contribute to increased long-term cardiovascular risk. Cognitive performance immediately on waking, such as after being awakened by a page, was worse than performance during subsequent sleep deprivation (177). Coverage to allow a nap during an extended shift can increase sleep and decrease fatigue for residents (178). Drinking coffee or napping at night reduced driving impairment without altering subsequent sleep (179).

Sentinel events related to medication, indwelling lines, airway, and equipment failure in ICUs occur with considerable frequency (180). Findings of the First Consensus Conference on Medical Emergency Teams provide a road map for improving patient safety through rapid response systems (181). Four benchmark institutions have demonstrated that health information technologies improve quality and efficiency. Whether and how other institutions can achieve similar benefits, and at what costs, are unclear (182). Computerization can create safety hazards, as evidenced by a bar-coding near miss (183). Few internal medicine residency programs have comprehensive transfer-of-care systems and most do not provide formal training in sign-out skills (184). A targeted intervention, including a focused transfer call, charted care summary, and discharge checkup, reduced the increased rate of surgical ICU readmissions seen after residents were reallocated to address duty-hour restrictions (185). Simulation-based learning was superior to problem-based learning for the acquisition of critical assessment and management skills (186). For internal jugular vein catheterization, real-time ultrasound guidance increased success rates while reducing access times and complication rates (187). A handheld device detected retained surgical sponges using radiofrequency identification technology (188).

END-OF-LIFE

Patient-designated and next-of-kin surrogates incorrectly predicted patients' end-of-life treatment preferences in one-third of cases (189). Implementation of new guidelines was associated with an increase in the number of resuscitations withheld by emergency medical services personnel, primarily due to honoring verbal requests (190). A large percentage of internists would be unwilling to adhere to some patient wishes to withhold or withdraw life-sustaining treatment (191). ICU clinicians may improve experiences of patients' families by providing explicit support for end-of-life decisions and assuring families continuity of high-quality care and patient comfort (192).

ANEMIA AND BLOOD TRANSFUSION

Early-onset anemia in patients with septic shock was associated with defective erythropoiesis related to excess apoptosis that could be counterbalanced in vitro by recombinant human erythropoietin (rHuEPO) (193). Small reductions in phlebotomy volume were associated with significantly reduced transfusion requirements in patients with prolonged ICU length of stay (194). In patients admitted to a long-term acute care facility, weekly rHuEPO administration resulted in a significant reduction in red blood cell transfusions (195).

NOVEL THERAPEUTICS

Each year, there are a number of manuscripts about novel therapeutics, most of which are not ready for widespread clinical use, yet quite fascinating. Statins continue to generate great interest as agents to improve outcome in patients with infection. Recent observational studies associate statins with reduced long-term mortality after bacteremia (196) and lower risk of subsequent sepsis after hospitalization for vascular disease (197). Simvastatin suppresses endotoxin-induced up-regulation of TLR4 and TLR2 in healthy volunteers, revealing a potential mechanism for the apparent beneficial effects of statins in sepsis (198). However, one study has suggested that the protective effect seen in observational studies may be the result of confounding due to healthy user effects (199), as was the case for hormone replacement in women.

Aneja and Fink provided a review of promising therapeutic agents for sepsis (200). A selective estrogen receptor-beta agonist protected against death in experimental septic shock (201). A cyanobacterial LPS antagonist prevented endotoxin shock and blocked the sustained TLR4 stimulation required for cytokine expression in human dendritic cells (202). Cortistatin, a neuropeptide related to somatostatin, reduced inflammation and protected against mortality in mouse sepsis models (203). A novel cyclohexene derivative, TAK-242, selectively blocks TLR4-dependent cytokine production and is in phase II trials for sepsis (204). In hemorrhage shock, pretreatment with dobutamine improved liver function through induction of heme oxygenase-1, suggesting potential utility for major liver surgery or transplant (205).

Pyrimidine synthesis or release pathways may provide novel therapeutic targets to counter the pathophysiologic sequelae of impaired alveolar fluid clearance in respiratory syncytial virus disease (206). Antioxidant treatment ameliorates respiratory syncytial virus–induced disease and lung inflammation in mice (207). Leptin, an adipocyte-derived hormone, corrects host defense defects after acute starvation in murine pneumococcal pneumonia (208). Mast cells protect mice from mycoplasma pneumonia (209).

FOOTNOTES

Conflict of Interest Statement: E.B.M. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.I. has no 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, and OrthoBiotech.

Received in original form January 22, 2007; accepted in final form January 22, 2007

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