Dichotomy in duration and severity of acute inflammatory responses in humans arising from differentially expressed proresolution pathways.

Lipoxins (Lxs) and aspirin-triggered epi-Lxs (15-epi-LxA(4)) act through the ALX/FPRL1 receptor to block leukocyte trafficking, dampen cytokine/chemokine synthesis, and enhance phagocytic clearance of apoptotic leukocytes-key requisites for inflammatory resolution. Although studies using primarily inbred rodents have highlighted resolution as an active event, little is known about the role resolution pathways play in controlling the duration/profile of inflammatory responses in humans. To examine this, we found two types of responders to cantharidin-induced skin blisters in male healthy volunteers: those with immediate leukocyte accumulation and cytokine/chemokine synthesis followed by early resolution and a second group whose inflammation increased gradually over time followed by delayed resolution. In early resolvers, blister 15-epi-LxA(4) and leukocyte ALX were low, but increased as inflammation abated. In contrast, in delayed resolvers, 15-epi-LxA(4) and ALX were high early in the response but waned as inflammation progressed. Elevating 15-epi-LxA(4) in early resolvers using aspirin increased blister leukocyte ALX but reduced cytokines/chemokines as well as polymorphonuclear leukocyte and macrophage numbers. These findings show that two phenotypes exist in humans with respect to inflammation severity/longevity controlled by proresolution mediators, namely 15-epi-LxA(4). These data have implications for understanding the etiology of chronic inflammation and future directions in antiinflammatory therapy.

Targeted temperature management in critical care: a report and recommendations from five professional societies.

OBJECTIVE: Representatives of five international critical care societies convened topic specialists and a nonexpert jury to review, assess, and report on studies of targeted temperature management and to provide clinical recommendations. DATA SOURCES: Questions were allocated to experts who reviewed their areas, made formal presentations, and responded to questions. Jurors also performed independent searches. Sources used for consensus derived exclusively from peer-reviewed reports of human and animal studies. STUDY SELECTION: Question-specific studies were selected from literature searches; jurors independently determined the relevance of each study included in the synthesis. CONCLUSIONS AND RECOMMENDATIONS: 1) The jury opines that the term "targeted temperature management" replace "therapeutic hypothermia." 2) The jury opines that descriptors (e.g., "mild") be replaced with explicit targeted temperature management profiles. 3) The jury opines that each report of a targeted temperature management trial enumerate the physiologic effects anticipated by the investigators and actually observed and/or measured in subjects in each arm of the trial as a strategy for increasing knowledge of the dose/duration/response characteristics of temperature management. This enumeration should be kept separate from the body of the report, be organized by body systems, and be made without assertions about the impact of any specific effect on the clinical outcome. 4) The jury STRONGLY RECOMMENDS targeted temperature management to a target of 32°C-34°C as the preferred treatment (vs. unstructured temperature management) of out-of-hospital adult cardiac arrest victims with a first registered electrocardiography rhythm of ventricular fibrillation or pulseless ventricular tachycardia and still unconscious after restoration of spontaneous circulation (strong recommendation, moderate quality of evidence). 5) The jury WEAKLY RECOMMENDS the use of targeted temperature management to 33°C-35.5°C (vs. less structured management) in the treatment of term newborns who sustained asphyxia and exhibit acidosis and/or encephalopathy (weak recommendation, moderate quality of evidence).

The impact of enhanced cleaning within the intensive care unit on contamination of the near-patient environment with hospital pathogens: a randomized crossover study in critical care units in two hospitals.

OBJECTIVES: To determine the effect of enhanced cleaning of the near-patient environment on the isolation of hospital pathogens from the bed area and staff hands. DESIGN: Prospective randomized crossover study over the course of 1 yr. SETTING: Intensive care units at two teaching hospitals. PATIENTS: There were 1252 patients staying during enhanced cleaning and 1331 staying during standard cleaning. INTERVENTIONS: In each of six 2-month periods, one unit was randomly selected for additional twice-daily enhanced cleaning of hand contact surfaces. MEASUREMENTS AND MAIN RESULTS: Agar contact samples were taken at five sites around randomly selected bed areas, from staff hands, and from communal sites three times daily for 12 bed days per week. Patients admitted in the year commencing April 2007 were analyzed for hospital-acquired colonization and infection. Over the course of 1152 bed days, 20,736 samples were collected. Detection of environmental methicillin-resistant Staphylococcus aureus per bed-area day was reduced during enhanced cleaning phases from 82 of 561 (14.6%) to 51 of 559 (9.1%) (adjusted odds ratio, 0.59; 95% confidence interval, 0.40-0.86; p = .006). Other targeted pathogens (Acinetobacter baumannii, extended-spectrum ß-lactamase-producing Gram-negative bacteria, vancomycin-resistant enterococci, and Clostridium difficile) were rarely detected. Subgroup analyses showed reduced methicillin-resistant Staphylococcus aureus contamination on doctors' hands during enhanced cleaning (3 of 425; 0.7% vs. 11 of 423; 2.6%; adjusted odds ratio, 0.26; 95% confidence interval, 0.07-0.95; p = .025) and a trend to reduction on nurses' hands (16 of 1647; 1.0% vs. 28 of 1694; 1.7%; adjusted odds ratio 0.56; 95% confidence interval, 0.29-1.08; p = .077). All 1252 critical care patients staying during enhanced and 1,331 during standard cleaning were included, but no significant effect on patient methicillin-resistant Staphylococcus aureus acquisition was observed (adjusted odds ratio, 0.98; 95% confidence interval, 0.58-1.65; p = .93). CONCLUSIONS: Enhanced cleaning reduced environmental contamination and hand carriage, but no significant effect was observed on patient acquisition of methicillin-resistant Staphylococcus aureus. TRIAL REGISTRY: ISRCTN. Identifier: 06298448. http://www.controlled-trials.com/isrctn/.

Effects of low-dose aspirin on acute inflammatory responses in humans.

Aspirin is a unique nonsteroidal anti-inflammatory drug; at high doses (aspirin(high), 1g), it is anti-inflammatory stemming from the inhibition of cyclooxygenase and proinflammatory signaling pathways including NF-kappaB, but is cardioprotective at lower doses (aspirin(low), 75 mg). The latter arises from the inhibition of thromboxane (Tx) B(2), a prothrombotic eicosanoid also implicated in polymorphonuclear leukocyte trafficking. As a result, aspirin(low) is widely used as a primary and secondary preventative against vascular disease. Despite this and its ability to synthesize proresolution 15-epi-lipoxin A(4) it is not known whether aspirin(low) is anti-inflammatory in humans. To address this, we generated skin blisters by topically applying cantharidin on the forearm of healthy male volunteers, causing an acute inflammatory response including dermal edema formation and leukocyte trafficking. Although not affecting blister fluid volume, aspirin(low) (75 mg, oral, once daily/10 days) reduced polymorphonuclear leukocyte and macrophage accumulation independent of NF-kappaB-regulated gene expression and inhibition of conventional prostanoids. However, aspirin(low) triggered 15-epi-lipoxin A(4) synthesis and up-regulated its receptor (FPRL1, ALX). From complimentary in vitro experiments, we propose that 15-epi-lipoxin A(4) exerts its protective effects by triggering antiadhesive NO, thereby dampening leukocyte/endothelial cell interaction and subsequent extravascular leukocyte migration. Since similar findings were obtained from murine zymosan-induced peritonitis, we suggest that aspirin(low) possesses the ability to inhibit mammalian innate immune-mediated responses. This highlights 15-epi-lipoxin A(4) as a novel anti-inflammatory working through a defined receptor and suggests that mimicking its mode of action represents a new approach to treating inflammation-driven diseases.

Adhesion molecule-dependent mechanisms regulate the rate of macrophage clearance during the resolution of peritoneal inflammation.

Macrophage clearance is essential for the resolution of inflammation. Much is known about how monocytes enter the inflammatory site but little is known about how resultant macro-phages are cleared. We have previously demonstrated that macrophage clearance from resolving peritonitis occurs by emigration into draining lymphatics rather than local apoptosis. We now examine mechanisms for this process, in particular by evaluating the hypothesis that modulation of adhesion interactions between macrophages and cells lining the lymphatics regulates the rate of macrophage clearance. We demonstrate in vivo that macrophages adhere specifically to mesothelium overlying draining lymphatics and that their emigration rate is regulated by the state of macrophage activation. We observed that macrophage-mesothelial adhesion is Arg-Gly-Asp (RGD) sensitive and partially mediated by very late antigen (VLA)-4 and VLA-5 but not alpha(v) or beta(2) integrins. Moreover, macrophage clearance into lymphatics can be blocked in vivo by RGD peptides and VLA-4 and VLA-5 but not beta(2) blocking antibodies. This is the first evidence that macrophage emigration from the inflamed site is controlled and demonstrates that this is exerted through specific adhesion molecule regulation of macrophage-mesothelial interactions. It highlights the importance of adhesion molecules governing entry of cells into the lymphatic circulation, thus opening a new avenue for manipulating the resolution of inflammation.

Isolation of patients in single rooms or cohorts to reduce spread of MRSA in intensive-care units: prospective two-centre study.

BACKGROUND: Hospital-acquired infection due to meticillin-resistant Staphylococcus aureus (MRSA) is common within intensive-care units. Single room or cohort isolation of infected or colonised patients is used to reduce spread, but its benefit over and above other contact precautions is not known. We aimed to assess the effectiveness of moving versus not moving infected or colonised patients in intensive-care units to prevent transmission of MRSA. METHODS: We undertook a prospective 1-year study in the intensive-care units of two teaching hospitals. Admission and weekly screens were used to ascertain the incidence of MRSA colonisation. In the middle 6 months, MRSA-positive patients were not moved to a single room or cohort nursed unless they were carrying other multiresistant or notifiable pathogens. Standard precautions were practised throughout. Hand hygiene was encouraged and compliance audited. FINDINGS: Patients' characteristics and MRSA acquisition rates were similar in the periods when patients were moved and not moved. The crude (unadjusted) Cox proportional-hazards model showed no evidence of increased transmission during the non-move phase (0.73 [95% CI 0.49-1.10], p=0.94 one-sided). There were no changes in transmission of any particular strain of MRSA nor in handwashing frequency between management phases. INTERPRETATION: Moving MRSA-positive patients into single rooms or cohorted bays does not reduce crossinfection. Because transfer and isolation of critically ill patients in single rooms carries potential risks, our findings suggest that re-evaluation of isolation policies is required in intensive-care units where MRSA is endemic, and that more effective means of preventing spread of MRSA in such settings need to be found.

Pro/con clinical debate: isolation precautions for all intensive care unit patients with methicillin-resistant Staphylococcus aureus colonization are essential.

Antibiotic-resistant bacteria are an increasingly common problem in intensive care units (ICUs), and they are capable of impacting on patient outcome, the ICU's budget and bed availability. This issue, coupled with recent outbreaks of illnesses that pose a direct risk to ICU staff (such as SARS [severe acute respiratory syndrome]), has led to renewed emphasis on infection control measures and practitioners in the ICU. Infection control measures frequently cause clinicians to practice in a more time consuming way. As a result it is not surprising that ensuring compliance with these measures is not always easy, particularly when their benefit is not immediately obvious. In this issue of Critical Care, two experts face off over the need to isolate patients infected with methicillin-resistant Staphylococcus aureus.

Audit of audit: review of a clinical audit programme in a teaching hospital intensive care unit.

OBJECTIVE: A comprehensive review of the clinical audit programme in a teaching hospital intensive care unit. DESIGN: A retrospective analysis of the clinical audit projects undertaken within the intensive care unit over the preceding 2 years and compared with published national guidelines for clinical audit. SETTING: A 27-bedded teaching hospital intensive care unit in the UK. MEASUREMENTS: Each audit project was reviewed independently by two assessors. The following questions were assessed. 1. Were the projects true audits? 2. Were they prospective of retrospective? 3. Did the projects have input from appropriate members of the multidisciplinary team. 4. How many of the audit projects were re-audits? 5. Of the re-audits how many showed evidence of service improvement? each audit project was also scored against the Audit Project Assessment Tool produced by the UK Clinical Governance Support Team. RESULTS: Of the twenty five audit projects reviewed twenty two were considered to be true audits. All of the projects used only retrospective data. Audit projects were contributed from all sections of the multidisciplinary critical care team but there were few truly multidisciplinary projects. Four of the audit projects were re-audits, of these three showed service improvement and one showed deterioration. Of the twenty two true audit projects reviewed, eleven were classified as good quality projects using the Audit Project Assessment Tool. CONCLUSIONS: Despite the clinical audit programme being active and well supported, objective evidence of clinical governance benefit was lacking. The overall clinical audit programme has been revitalised by a series of improvements since undertaking this review and this approach is recommended to other organizations who are interested in improving their clinical audit performance.

Importance of the environment for patient acquisition of methicillin-resistant Staphylococcus aureus in the intensive care unit: a baseline study.

OBJECTIVE: To assess the degree of environmental contamination with methicillin-resistant Staphylococcus aureus (MRSA) in critical care and the likelihood of subsequent new patient acquisition if carriers were or were not moved to single rooms. DESIGN: Randomized sequential sampling of bed areas. SETTING: Intensive care units of two teaching hospitals. PATIENTS: Medical and surgical patients requiring critical care. INTERVENTIONS: Six environmental sites around randomly selected patients plus two communal sites were sampled using contact plates during periods when patients with MRSA were physically isolated or not. Admission, weekly, and discharge screening patient swabs were taken to identify patients admitted with, or newly acquiring, MRSA. MEASUREMENTS AND MAIN RESULTS: A total of 2,436 samples were taken from environments around 114 patients, plus a further 349 samples from doctors' hands and telephones. Of the 47 bed areas where MRSA strains were identified that were not found initially on patients, only one patient subsequently acquired the same strain. Five other patients became colonized with new MRSA strains, but these were not found in their environment beforehand. Of 52 patients colonized with MRSA, 34 had a similar strain found subsequently in their environment. CONCLUSIONS: Whereas the MRSA-colonized patient frequently contaminates his or her local environment, transmission of MRSA from the environment to the patient was not commonly identified. Studies elucidating possible routes of MRSA transmission are urgently needed to inform infection control policies.

In vitro susceptibility of Gram-positive pathogens to linezolid and teicoplanin and effect on outcome in critically ill patients.

OBJECTIVES: To determine the prevalence of teicoplanin and linezolid resistance amongst Gram-positive pathogens isolated in the intensive care unit (ICU) and the impact of any resistance on clinical outcome. METHODS: Gram-positive isolates were collected from two critical care units over 1 year. All patients were screened weekly for methicillin-resistant Staphylococcus aureus (MRSA). Susceptibility to teicoplanin and linezolid was tested by Etest. The length of hospital and critical care unit stay and the use of antibiotics in each patient were recorded. RESULTS: Reduced susceptibility to teicoplanin (MIC>or=16 mg/L) was found in 21 [3.3% (95% CI 2.0-5.0%) 6 patients] of 643 strains of MRSA versus none of 374 methicillin-susceptible S. aureus (MSSA) [<0.3% (95% CI 0-0.9%)]. Of 49 enterococci 3 were teicoplanin-resistant. All Gram-positive isolates were susceptible to linezolid. The length of treatment with teicoplanin and outcome of patients infected with these strains were similar to that of susceptible strains. MRSA was a more common cause of infection than MSSA but a less frequent colonizer. CONCLUSIONS: Resistance to teicoplanin remains at a comparatively low level and there was no clear relationship between susceptibility and outcome in this critically ill population. There was no resistance in Gram-positives to linezolid but this should be kept as a reserve antibiotic to maintain its activity.

Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is an often fatal condition for which a genetic predisposition is postulated, although no specific genes have been identified to date. Angiotensin converting enzyme (ACE) has a potential role in the pathogenesis of ARDS via effects on pulmonary vascular tone/permeability, epithelial cell survival, and fibroblast activation. Forty-seven percent of the variance in plasma ACE activity is accounted for by the ACE insertion/deletion (I/D) polymorphism, the D allele being associated with higher activity. We therefore hypothesized that the presence of the D allele would be associated with the development of ARDS. Ninety-six white patients fulfilling American/European Consensus Committee criteria for ARDS were genotyped for the ACE polymorphism together with individuals from three comparison groups: 88 white patients with non-ARDS respiratory failure ventilated in the intensive care unit (ICU), 174 ICU patients undergoing coronary artery bypass grafting, and 1,906 individuals from a general population group. DD genotype frequency was increased in the patients with ARDS compared with the ICU (p = 0.00008), coronary artery bypass grafting (p = 0.0009), and general population group (p = 0.00004) control groups and was significantly associated with mortality in the ARDS group (p < 0.02). These data suggest a potential role for renin-angiotensin systems in the pathogenesis of ARDS and for the first time implicate genetic factors in the development and progression of this syndrome.

Severity of lung injury in cyclooxygenase-2-deficient mice is dependent on reduced prostaglandin E(2) production.

Levels of prostaglandin E(2) (PGE(2)), a potent inhibitor of fibroblast function, are decreased in the lungs of patients with pulmonary fibrosis, which has been shown to be because of limited expression of cyclooxygenase-2 (COX-2). To further investigate the relative importance of COX-2 and PGE(2) in the development of fibrosis we have used a selective COX-2 inhibitor and COX-2-deficient ((-/-) and (+/-)) mice in studies of bleomycin-induced lung fibrosis. We demonstrate in wild-type mice that bleomycin-induced lung PGE(2) production is predominantly COX-2 mediated. Furthermore, COX-2(+/-) mice show limited induction of PGE(2) and an enhanced fibrotic response with increased lung collagen content compared with wild-type mice after bleomycin injury (P < 0.001). In contrast, COX-2(-/-) mice show increased levels of lung PGE(2), compared with wild-type mice after injury (P < 0.05), because of compensatory up-regulation of COX-1, which appears to be associated with macrophage/monocytes but not fibroblasts derived from these mice. COX-2(-/-) mice show an enhanced and persistent inflammatory response to bleomycin, however the fibrotic response to injury was unaltered compared with wild-type animals. These data provide further direct evidence for the importance of up-regulating COX-2 and PGE(2) expression in protecting against the development of fibrosis after lung injury.