Mechanistic insights into cell-free hemoglobin-induced injury during septic shock.

Cell-free hemoglobin (CFH) levels are elevated in septic shock and are higher in nonsurvivors. Whether CFH is only a marker of sepsis severity or is involved in pathogenesis is unknown. This study aimed to investigate whether CFH worsens sepsis-associated injuries and to determine potential mechanisms of harm. Fifty-one, 10-12 kg purpose-bred beagles were randomized to receive Staphylococcus aureus intrapulmonary challenges or saline followed by CFH infusions (oxyhemoglobin >80%) or placebo. Animals received antibiotics and intensive care support for 96 h. CFH significantly increased mean pulmonary arterial pressures and right ventricular afterload in both septic and nonseptic animals, effects that were significantly greater in nonsurvivors. These findings are consistent with CFH-associated nitric oxide (NO) scavenging and were associated with significantly depressed cardiac function, and worsened shock, lactate levels, metabolic acidosis, and multiorgan failure. In septic animals only, CFH administration significantly increased mean alveolar-arterial oxygenation gradients, also to a significantly greater degree in nonsurvivors. CFH-associated iron levels were significantly suppressed in infected animals, suggesting that bacterial iron uptake worsened pneumonia. Notably, cytokine levels were similar in survivors and nonsurvivors and were not predictive of outcome. In the absence and presence of infection, CFH infusions resulted in pulmonary hypertension, cardiogenic shock, and multiorgan failure, likely through NO scavenging. In the presence of infection alone, CFH infusions worsened oxygen exchange and lung injury, presumably by supplying iron that promoted bacterial growth. CFH elevation, a known consequence of clinical septic shock, adversely impacts sepsis outcomes through more than one mechanism, and is a biologically plausible, nonantibiotic, noncytokine target for therapeutic intervention.NEW & NOTEWORTHY Cell-free hemoglobin (CFH) elevations are a known consequence of clinical sepsis. Using a two-by-two factorial design and extensive physiological and biochemical evidence, we found a direct mechanism of injury related to nitric oxide scavenging leading to pulmonary hypertension increasing right heart afterload, depressed cardiac function, worsening circulatory failure, and death, as well as an indirect mechanism related to iron toxicity. These discoveries alter conventional thinking about septic shock pathogenesis and provide novel therapeutic approaches.

Effects-based marine ecological risk assessment at a polychlorinated biphenyl-contaminated site in Saglek, Labrador, Canada.

Although the presence and distribution of polychlorinated biphenyls (PCBs) in Arctic marine environments has been well documented, the implications for the health of biota are poorly understood. In the present study, multiple lines of evidence, including site-specific effects data, were used to assess PCB-related risks to marine biota at a contaminated military site in Saglek Bay, Labrador, Canada, from 1997 to 1999. Risks were evaluated for three components of the ecosystem: benthic invertebrates, a bottom-feeding fish (shorthorn sculpin, Myoxocephalus scorpius), and a diving seabird (black guillemot, Cepphus grylle). Average sediment PCB concentrations exceeded the Canadian interim sediment quality guideline level by 41-fold. However, sediment toxicity testing and a benthic community survey showed no evidence of adverse effects. In contrast, shorthorn sculpin and black guillemot PCB exposures (measured as sum of 55 congeners) were elevated enough to pose risks to survival or reproduction. Based on the collective evidence, the authors estimated that risks were posed by sediment PCB concentrations greater than 77 ng/g dry weight for black guillemots and 750 ng/g dry weight for shorthorn sculpins. The present study, along with two parallel studies, provided information to support the management decisions concerning potential remedial action on the contaminated sediments. This ecological risk assessment describes the steps and rationale taken to evaluate the risk posed by an area of PCB-contaminated marine sediments in an otherwise relatively pristine northern coastal environment.

Assessment of potential drug-drug interactions with a prescription claims database.

PURPOSE: The prevalence of 25 clinically important potential drug-drug interactions (DDIs) in a population represented by the drug claims database of a pharmacy benefit management company (PBM) was studied. METHODS: A retrospective cross-sectional analysis of pharmaceutical claims for almost 46 million participants in a PBM was conducted to determine the frequency of 25 DDIs previously identified as clinically important. A DDI was counted when drugs in potentially interacting combinations were dispensed within 30 days of each other during a 25-month period between April 2000 and June 2002. RESULTS: The number of DDIs ranged from 37 for pimozide and an azole antifungal to 127,684 for warfarin and a nonsteroidal antiinflammatory drug (NSAID). The highest prevalence (278.56 per 100,000 persons) and highest case-exposure rate (242.7 per 1,000 warfarin recipients) occurred with the warfarin-NSAID combination. The combination with the lowest overall prevalence (cyclosporine and a rifamycin, 0.10/100,000) differed from the combination with the lowest case-exposure rate (pimozide and an azole antifungal, 0.028 per 1,000 azole antifungal recipients). Number of cases, prevalence, and case-exposure rates for both sexes generally increased with age. An estimated 374,000 plan participants were exposed to a clinically important DDI during a 25-month period. Between 20% and 46% of prescription drug claims were reversed (canceled) for a medication with a drug interaction when a warning about the interaction was sent to the pharmacy. CONCLUSION: Analysis of prescription claims data from a major PBM found that 374,000 of 46 million plan participants had been exposed to a potential DDI of clinical importance.

Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model.

Previous analysis showed that selective inhibitors of five different host inflammatory mediators administered for sepsis, although beneficial with severe sepsis and high-control mortality rates, were ineffective or harmful with less severe sepsis. We hypothesized that severity of sepsis would also influence inhibition of superoxide anion, another inflammatory mediator. To test this, 6-h infusions of M40401, a selective SOD mimetic, or placebo were given to antibiotic-treated rats (n=547) starting 3 h after challenge with differing doses of intravenous Escherichia coli designed to produce low- or high-control mortality rates. There was a positive and significant (P=0.0008) relationship between the efficacy of M40401 on survival rate and control mortality rates. M40401 increased or decreased the log (odds ratio of survival) (means +/- SE), dependent on whether control mortality rates were greater or less than the median (66%) (+0.19 +/- 0.12 vs. -0.25 +/- 0.10, P=0.01). In a subset of animals examined (n=152) at 9 h after E. coli challenge, M40401 increased (mean effect +/- SE compared with control) mean arterial blood pressure (8 +/- 5 mmHg) and decreased platelets (-37 +/- 22 cells x 10(3)/ml) with high-control mortality rates but had opposing effects on each parameter (-3 +/- 3 mmHg and 28 +/- 19 cells x 10(3)/ml, respectively) with low rates (P < or = 0.05 for the differing effects of M40401 on each parameter with high- vs. low-control mortality rates). A metaregression analysis of published preclinical sepsis studies testing SOD preparations and SOD mimetics showed that most (16 of 18) had control mortality rates >66%. However, across experiments from published studies, these agents were less beneficial as control mortality rate decreased (P=0.03) in a relationship not altered (P=not significant) by other variables associated with septic challenge or regimen of treatment and which was similar, compared with experiments with M40401 (P=not significant). Thus, in these preclinical sepsis models, possibly related to divergent effects on vascular function, inhibition of superoxide anion improved survival with more severe sepsis and high-control mortality rates but was less effective or harmful with less severe sepsis. Extrapolated clinically, inhibition of superoxide anion may be most efficacious in septic patients with severe sepsis and a high risk of death.

Prevalence of the use of central venous access devices within and outside of the intensive care unit: results of a survey among hospitals in the prevention epicenter program of the Centers for Disease Control and Prevention.

OBJECTIVE: To determine the prevalence of central venous catheter (CVC) use among patients both within and outside the ICU setting. DESIGN: A 1-day prevalence survey of CVC use among adult inpatients at six medical centers participating in the Prevention Epicenter Program of the CDC. Using a standardized form, observers at each Epicenter performed a hospital-wide survey, collecting data on CVC use. SETTING: Inpatient wards and ICUs of six large urban teaching hospitals. RESULTS: At the six medical centers, 2,459 patients were surveyed; 29% had CVCs. Among the hospitals, from 43% to 80% (mean, 59.3%) of ICU patients and from 7% to 39% (mean, 23.7%) of non-ICU patients had CVCs. Despite the lower rate of CVC use on non-ICU wards, the actual number of CVCs outside the ICUs exceeded that of the ICUs. Most catheters were inserted in the subclavian (55%) or jugular (22%) site, with femoral (6%) and peripheral (15%) sites less commonly used. The jugular (33.0% vs 16.6%; P < .001) and femoral (13.8% vs 2.7%; P < .001) sites were more frequently used in ICU patients, whereas peripherally inserted (19.9% vs 5.9%; P < .001) and subclavian (60.7% vs 47.3%; P < .001) catheters were more commonly used in non-ICU patients. CONCLUSIONS: Current surveillance and infection control efforts to reduce morbidity and mortality associated with bloodstream infections concentrate on the high-risk ICU patients with CVCs. Our survey demonstrated that two-thirds of identified CVCs were not in ICU patients and suggests that more efforts should be directed to patients with CVCs who are outside the ICU.

Preventing central venous catheter-associated primary bloodstream infections: characteristics of practices among hospitals participating in the Evaluation of Processes and Indicators in Infection Control (EPIC) study.

OBJECTIVES: To describe the conceptual framework and methodology of the Evaluation of Processes and Indicators in Infection Control (EPIC) study and present results of CVC insertion characteristics and organizational practices for preventing BSIs. The goal of the EPIC study was to evaluate relationships among processes of care, organizational characteristics, and the outcome of BSI. DESIGN: This was a multicenter prospective observational study of variation in hospital practices related to preventing CVC-associated BSIs. Process of care information (eg, barrier use during insertions and experience of the inserting practitioner) was collected for a random sample of approximately 5 CVC insertions per month per hospital during November 1998 to December 1999. Organization demographic and practice information (eg, surveillance activities and staff and ICU nurse staffing levels) was also collected. SETTING: Medical, surgical, or medical-surgical ICUs from 55 hospitals (41 U.S. and 14 international sites). PARTICIPANTS: Process information was obtained for 3,320 CVC insertions with an average of 58.2 (+/- 16.1) insertions per hospital. Fifty-four hospitals provided policy and practice information. RESULTS: Staff spent an average of 13 hours per week in study ICU surveillance. Most patients received nontunneled, multiple lumen CVCs, of which fewer than 25% were coated with antimicrobial material. Regarding barriers, most clinicians wore masks (81.5%) and gowns (76.8%); 58.1% used large drapes. Few hospitals (18.1%) used an intravenous team to manage ICU CVCs. CONCLUSIONS: Substantial variation exists in CVC insertion practice and BSI prevention activities. Understanding which practices have the greatest impact on BSI rates can help hospitals better target improvement interventions.