Controls, comparator arms, and designs for critical care comparative effectiveness research: It's complicated.

BACKGROUND: Comparative effectiveness research is meant to determine which commonly employed medical interventions are most beneficial, least harmful, and/or most costly in a real-world setting. While the objectives for comparative effectiveness research are clear, the field has failed to develop either a uniform definition of comparative effectiveness research or an appropriate set of recommendations to provide standards for the design of critical care comparative effectiveness research trials, spurring controversy in recent years. The insertion of non-representative control and/or comparator arm subjects into critical care comparative effectiveness research trials can threaten trial subjects' safety. Nonetheless, the broader scientific community does not always appreciate the importance of defining and maintaining critical care practices during a trial, especially when vulnerable, critically ill populations are studied. Consequently, critical care comparative effectiveness research trials sometimes lack properly constructed control or active comparator arms altogether and/or suffer from the inclusion of "unusual critical care" that may adversely affect groups enrolled in one or more arms. This oversight has led to critical care comparative effectiveness research trial designs that impair informed consent, confound interpretation of trial results, and increase the risk of harm for trial participants. METHODS/EXAMPLES: We propose a novel approach to performing critical care comparative effectiveness research trials that mandates the documentation of critical care practices prior to trial initiation. We also classify the most common types of critical care comparative effectiveness research trials, as well as the most frequent errors in trial design. We present examples of these design flaws drawn from past and recently published trials as well as examples of trials that avoided those errors. Finally, we summarize strategies employed successfully in well-designed trials, in hopes of suggesting a comprehensive standard for the field. CONCLUSION: Flawed critical care comparative effectiveness research trial designs can lead to unsound trial conclusions, compromise informed consent, and increase risks to research subjects, undermining the major goal of comparative effectiveness research: to inform current practice. Well-constructed control and comparator arms comprise indispensable elements of critical care comparative effectiveness research trials, key to improving the trials' safety and to generating trial results likely to improve patient outcomes in clinical practice.

Comprehensive adjusted outcome data are needed to assess the impact of immune checkpoint inhibitors in cancer patients with COVID-19: Results of a systematic review and meta-analysis.

BACKGROUND: Determining how prior immune checkpoint inhibitor (ICI) therapy influences outcomes in cancer patients presenting with COVID-19 is essential for patient management but must account for confounding variables. METHODS: We performed a systematic review and meta-analysis of studies reporting adjusted effects of ICIs on survival, severe events, or hospitalisation in cancer patients with COVID-19 based on variables including age, gender, diabetes mellitus, hypertension (HTN), chronic obstructive pulmonary disease, and other comorbidities. When adjusted effects were unavailable, unadjusted data were analysed. RESULTS: Of 42 observational studies (38 retrospective), 7 reported adjusted outcomes for ICIs and 2 provided sufficient individual patient data to calculate adjusted outcomes. In eight studies, adjusted outcomes were based on ≤7 variables. Over all studies, only one included >100 ICI patients while 26 included <10. ICIs did not alter the odds ratio (95%CI) (OR) of death significantly (random effects model), across adjusted (n = 8) [1.31 (0.58-2.95) p = 0.46; I2  = 42%, p = 0.10], unadjusted (n = 30) [1.06 (0.85-1.32) p = 0.58; I2  = 0%, p = 0.76] or combined [1.09 (0.88;1.36) p = 0.41; I2  = 0%, p = 0.5)] studies. Similarly, ICIs did not alter severe events significantly across adjusted (n = 5) [1.20 (0.30-4.74) p = 0.73; I2  = 52%, p = 0.08], unadjusted (n = 19) [(1.23 (0.87-1.75) p = 0.23; I2  = 16%, p = 0.26] or combined [1.26 (0.90-1.77) p = 0.16; I2  = 25%, p = 0.14] studies. Two studies provided adjusted hospitalisation data and when combined with 13 unadjusted studies, ICIs did not alter hospitalisation significantly [1.19 (0.85-1.68) p = 029; I2  = 5%, p = 0.40]. Results of sensitivity analyses examining ICI effects based on 5 variables were inconclusive. Certainty of evidence was very low. CONCLUSIONS: Across studies with adjusted and unadjusted results, ICIs did not alter outcomes significantly. But studies with comprehensive adjusted outcome data controlling for confounding variables are necessary to determine whether ICIs impact COVID-19 outcomes in cancer patients.

Effects of chloroquine or hydroxychloroquine treatment on non-SARS-CoV2 viral infections: A systematic review of clinical studies.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antiviral agents for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. We performed a systematic review to examine whether prior clinical studies that compared the effects of CQ and HCQ to a control for the treatment of non-SARS-CoV2 infection supported the use of these agents in the present SARS-CoV2 outbreak. PubMed, EMBASE, Scopus and Web of Science (PROSPERO CRD42020183429) were searched from inception through 2 April 2020 without language restrictions. Of 1766 retrieved reports, 18 studies met our inclusion criteria, including 17 prospective controlled studies and one retrospective study. CQ or HCQ were compared to control for the treatment of infectious mononucleosis (EBV, n = 4), warts (human papillomavirus, n = 2), chronic HIV infection (n = 6), acute chikungunya infection (n = 1), acute dengue virus infection (n = 2), chronic HCV (n = 2), and as preventive measures for influenza infection (n = 1). Survival was not evaluated in any study. For HIV, the virus that was most investigated, while two early studies suggested HCQ reduced viral levels, four subsequent ones did not, and in two of these CQ or HCQ increased viral levels and reduced CD4 counts. Overall, three studies concluded CQ or HCQ were effective; four concluded further research was needed to assess the treatments' effectiveness; and 11 concluded that treatment was ineffective or potentially harmful. Prior controlled clinical trials with CQ and HCQ for non-SARS-CoV2 viral infections do not support these agents' use for the SARS-CoV2 outbreak.

Anti-PD-L1 Therapy Does Not Improve Survival in a Murine Model of Lethal Staphylococcus aureus Pneumonia.

BACKGROUND: Staphylococcus aureus (SA) bacterial pneumonia is a common cause of sepsis in intensive care units. Immune checkpoint inhibitors (CPIs) that target programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have been proposed for the treatment of sepsis. However, in our systematic review of sepsis preclinical models, none of the models examined CPIs in pneumonia. METHODS: Mice were inoculated intratracheally with vehicle control, low dose (LD)- or high dose (HD)-SA. Immune cell recruitment and checkpoint molecule expression were examined at 4, 24, and 48 hours after infection. Infected animals, treated with control or anti-PD-L1 antibodies, were assessed for survival, bacterial burden, lung immunophenotypes, and mediator production. RESULTS: LD-SA and HD-SA produced lethality of 15% and 70%, respectively, by 168 hours. At 24 hours, LD-infected animals exhibited increased lung monocyte PD-L1 expression (P = .0002) but lower bacterial counts (P = .0002) compared with HD animals. By 48 hours, either infection induced lung neutrophil and macrophage PD-L1 expression (P < .0001). Anti-PD-L1 treatment at the time of infection and at 24 hours following infection with low to high doses of SA reduced PD-L1 detection but did not affect survival or bacterial clearance. CONCLUSIONS: Anti-PD-L1 therapy did not alter survival in this pneumonia model. Preclinical studies of additional common pathogens and septic foci are needed.

Bacillus anthracis edema toxin inhibits hypoxic pulmonary vasoconstriction via edema factor and cAMP-mediated mechanisms in isolated perfused rat lungs.

Bacillus anthracis edema toxin (ET) inhibited lethal toxin-stimulated pulmonary artery pressure (Ppa) and increased lung cAMP levels in our previous study. We therefore examined whether ET inhibits hypoxic pulmonary vasoconstriction (HPV). Following baseline hypoxic measures in isolated perfused lungs from healthy rats, compared with diluent, ET perfusion reduced maximal Ppa increases (mean ± SE percentage of maximal Ppa increase with baseline hypoxia) during 6-min hypoxic periods (FIO2 = 0%) at 120 min (16 ± 6% vs. 51 ± 6%, P = 0.004) and 180 min (11.4% vs. 55 ± 6%, P = 0.01). Protective antigen-mAb (PA-mAb) and adefovir inhibit host cell edema factor uptake and cAMP production, respectively. In lungs perfused with ET following baseline measures, compared with placebo, PA-mAb treatment increased Ppa during hypoxia at 120 and 180 min (56 ± 6% vs. 10 ± 4% and 72 ± 12% vs. 12 ± 3%, respectively, P ≤ 0.01) as did adefovir (84 ± 10% vs. 16.8% and 123 ± 21% vs. 26 ± 11%, respectively, P ≤ 0.01). Compared with diluent, lung perfusion with ET for 180 min reduced the slope of the relationships between Ppa and increasing concentrations of endothelin-1 (ET-1) (21.12 ± 2.96 vs. 3.00 ± 0.76 × 108 cmH2O/M, P < 0.0001) and U46619, a thromboxane A2 analogue (7.15 ± 1.01 vs. 3.74 ± 0.31 × 107 cmH2O/M, P = 0.05) added to perfusate. In lungs isolated from rats after 15 h of in vivo infusions with either diluent, ET alone, or ET with PA-mAb, compared with diluent, the maximal Ppa during hypoxia and the slope of the relationship between change in Ppa and ET-1 concentration added to the perfusate were reduced in lungs from animals challenged with ET alone (P ≤ 0.004) but not with ET and PA-mAb together (P ≥ 0.73). Inhibition of HPV by ET could aggravate hypoxia during anthrax pulmonary infection.NEW & NOTEWORTHY The most important findings here are edema toxin's potent adenyl cyclase activity can interfere with hypoxic pulmonary vasoconstriction, an action that could worsen hypoxemia during invasive anthrax infection with lung involvement. These findings, coupled with other studies showing that lethal toxin can disrupt pulmonary vascular integrity, indicate that both toxins can contribute to pulmonary pathophysiology during infection. In combination, these investigations provide a further basis for the use of antitoxin therapies in patients with worsening invasive anthrax disease.

Inhibitory Immune Checkpoint Molecule Expression in Clinical Sepsis Studies: A Systematic Review.

OBJECTIVES: Checkpoint inhibitors have been proposed for sepsis following reports of increased checkpoint molecule expression in septic patients. To determine whether clinical studies investigating checkpoint molecule expression provide strong evidence supporting trials of checkpoint inhibitors for sepsis. DATA SOURCES: PubMed, EMBASE, Scopus, Web of Science, inception through October 2019. STUDY SELECTION: Studies comparing checkpoint molecule expression in septic patients versus healthy controls or critically ill nonseptic patients or in sepsis nonsurvivors versus survivors. DATA EXTRACTION: Two investigators extracted data and evaluated study quality. DATA SYNTHESIS: Thirty-six studies were retrieved. Across 26 studies, compared with healthy controls, septic patients had significantly (p ≤ 0.05) increased CD4+ lymphocyte programmed death-1 and monocyte programmed death-ligand-1 expression in most studies. Other checkpoint molecule expressions were variable and studied less frequently. Across 11 studies, compared with critically ill nonseptic, septic patients had significantly increased checkpoint molecule expression in three or fewer studies. Septic patients had higher severity of illness scores, comorbidities, and mortality in three studies providing analysis. Across 12 studies, compared with septic survivors, nonsurvivors had significantly increased expression of any checkpoint molecule on any cell type in five or fewer studies. Of all 36 studies, none adjusted for nonseptic covariates reported to increase checkpoint molecule expression. CONCLUSIONS: Although sepsis may increase some checkpoint molecule expression compared with healthy controls, the data are limited and inconsistent. Further, data from the more informative patient comparisons are potentially confounded by severity of illness. These clinical checkpoint molecule expression studies do not yet provide a strong rationale for trials of checkpoint inhibitor therapy for sepsis.

Bacillus anthracis lethal toxin, but not edema toxin, increases pulmonary artery pressure and permeability in isolated perfused rat lungs.

Although lethal toxin (LT) and edema toxin (ET) contribute to lethality during Bacillus anthracis infection, whether they increase vascular permeability and the extravascular fluid accumulation characterizing this infection is unclear. We employed an isolated perfused Sprague-Dawley rat lung model to investigate LT and ET effects on pulmonary vascular permeability. Lungs (n ≥ 6 per experimental group) were isolated, ventilated, suspended from a force transducer, and perfused. Lung weight and pulmonary artery (Ppa) and left atrial pressures were measured over 4 h, after which pulmonary capillary filtration coefficients (Kf.c) and lung wet-to-dry weight ratios (W/D) were determined. When compared with controls, LT increased Ppa over 4 h and Kf.c and W/D at 4 h (P < 0.0001). ET decreased Ppa in a significant trend (P = 0.09) but did not significantly alter Kf.c or W/D (P ≥ 0.29). Edema toxin actually blocked LT increases in Ppa but not LT increases in Kf.c and W/D. When Ppa was maintained at control levels, LT still increased Kf.c and W/D (P ≤ 0.004). Increasing the dose of each toxin five times significantly increased and a toxin-directed monoclonal antibody decreased the effects of each toxin (P ≤ 0.05). Two rho-kinase inhibitors (GSK269962 and Y27632) decreased LT increases in Ppa (P ≤ 0.02) but actually increased Kf.c and W/D in LT and control lungs (P ≤ 0.05). A vascular endothelial growth factor receptor inhibitor (ZM323881) had no significant effect (P ≥ 0.63) with LT. Thus, LT but not ET can increase pulmonary vascular permeability independent of increased Ppa and could contribute to pulmonary fluid accumulation during anthrax infection. However, pulmonary vascular dilation with ET could disrupt protective hypoxic vasoconstriction. NEW & NOTEWORTHY The most important findings from the present study are that Bacillus anthracis lethal toxin increases pulmonary artery pressure and pulmonary permeability independently in the isolated rat lung, whereas edema toxin decreases the former and does not increase permeability. Each effect could be a basis for organ dysfunction in patients with this lethal infection. These findings further support the need for adjunctive therapies that limit the effects of both toxins during infection.

Antibiotic- and Fluid-Focused Bundles Potentially Improve Sepsis Management, but High-Quality Evidence Is Lacking for the Specificity Required in the Centers for Medicare and Medicaid Service's Sepsis Bundle (SEP-1).

OBJECTIVE: To address three controversial components in the Centers for Medicare and Medicaid Service's sepsis bundle for performance measure (SEP-1): antibiotics within 3 hours, a 30 mL/kg fluid infusion for all hypotensive patients, and repeat lactate measurements within 6 hours if initially elevated. We hypothesized that antibiotic- and fluid-focused bundles like SEP-1 would probably show benefit, but evidence supporting specific antibiotic timing, fluid dosing, or serial lactate requirements would not be concordant. Therefore, we performed a meta-analysis of studies of sepsis bundles like SEP-1. DATA SOURCES: PubMed, Embase, ClinicalTrials.gov through March 15, 2018. STUDY SELECTION: Studies comparing survival in septic adults receiving versus not receiving antibiotic- and fluid-focused bundles. DATA EXTRACTION: Two investigators (D.J.P., P.Q.E.). DATA SYNTHESIS: Seventeen observational studies (11,303 controls and 4,977 bundle subjects) met inclusion criteria. Bundles were associated with increased odds ratios of survival (odds ratio [95% CI]) in 15 studies with substantial heterogeneity (I = 61%; p < 0.01). Survival benefits were consistent in the five largest (1,697-12,486 patients per study) (1.20 [1.11-1.30]; I = 0%) and six medium-sized studies (167-1,029) (2.03 [1.52-2.71]; I = 8%) but not the six smallest (64-137) (1.25 [0.42-3.66]; I = 57%). Bundles were associated with similarly increased survival benefits whether requiring antibiotics within 1 hour (n = 7 studies) versus 3 hours (n = 8) versus no specified time (n = 2); or 30 mL/kg fluid (n = 7) versus another volume (≥ 2 L, n = 1; ≥ 20 mL/kg, n = 2; 1.5-2 L or 500 mL, n = 1 each; none specified, n = 4) (p = 0.19 for each comparison). In the only study employing serial lactate measurements, survival was not increased versus others. No study had a low risk of bias or assessed potential adverse bundle effects. CONCLUSIONS: Available studies support the notion that antibiotic- and fluid-focused sepsis bundles like SEP-1 improve survival but do not demonstrate the superiority of any specific antibiotic time or fluid volume or of serial lactate measurements. Until strong reproducible evidence demonstrates the safety and benefit of any fixed requirement for these interventions, the present findings support the revision of SEP-1 to allow flexibility in treatment according to physician judgment.

Evidence Underpinning the Centers for Medicare & Medicaid Services' Severe Sepsis and Septic Shock Management Bundle (SEP-1): A Systematic Review.

This article has been corrected. To see what has changed, please read the Letter to the Editor and the authors' response. The original version (PDF) is appended to this article as a Supplement. Background: The Severe Sepsis and Septic Shock Early Management Bundle (SEP-1), the sepsis performance measure introduced in 2015 by the Centers for Medicare & Medicaid Services (CMS), requires the reporting of up to 5 hemodynamic interventions, as many as 141 tasks, and 3 hours to document for a single patient. Purpose: To evaluate whether moderate- or high-level evidence shows that use of the 2015 SEP-1 or its hemodynamic interventions improves survival in adults with sepsis. Data Sources: PubMed, Embase, Scopus, Web of Science, and ClinicalTrials.gov from inception to 28 November 2017 with no language restrictions. Study Selection: Randomized and observational studies of death among adults with sepsis who received versus those who did not receive either the entire SEP-1 bundle or 1 or more SEP-1 hemodynamic interventions, including serial lactate measurements; a fluid infusion of 30 mL/kg of body weight; and assessment of volume status and tissue perfusion with a focused examination, bedside cardiovascular ultrasonography, or fluid responsiveness testing. Data Extraction: Two investigators independently extracted study data and assessed each study's risk of bias; 4 authors rated level of evidence by consensus using CMS criteria published in 2013. High- or moderate-level evidence required studies to have no confounders and low risk of bias. Data Synthesis: Of 56 563 references, 20 studies (18 reports) met inclusion criteria. One single-center observational study reported lower in-hospital mortality after implementation of the SEP-1 bundle. Sixteen studies (2 randomized and 14 observational) reported increased survival with serial lactate measurements or 30-mL/kg fluid infusions. None of the 17 studies were free of confounders or at low risk of bias. In 3 randomized trials, fluid responsiveness testing did not alter survival. Limitations: Few trials, poor-quality and confounded studies, and no studies (with survival outcomes) of the focused examination or bedside cardiovascular ultrasonography. Use of the 2015 version of SEP-1 and 2013 version of CMS evidence criteria, both of which were updated in 2017. Conclusion: No high- or moderate-level evidence shows that SEP-1 or its hemodynamic interventions improve survival in adults with sepsis. Primary Funding Source: National Institutes of Health. (PROSPERO: CRD42016052716).

Bacillus anthracis Edema Toxin Increases Fractional Free Water and Sodium Reabsorption in an Isolated Perfused Rat Kidney Model.

Bacillus anthracis edema toxin (ET) consists of protective antigen (PA), necessary for host cell toxin uptake, and edema factor (EF), the toxic moiety which increases host cell cyclic AMP (cAMP). Since vasopressin stimulates renal water and sodium reabsorption via increased tubular cell cAMP levels, we hypothesized the ET would also do so. To test this hypothesis, we employed an isolated perfused rat kidney model. Kidneys were isolated and perfused with modified Krebs-Henseleit buffer. Perfusate and urine samples were obtained at baseline and every 10 min over 150 min following the addition of challenges with or without treatments to the perfusate. In kidneys perfused under constant flow or constant pressure, compared to PA challenge (n = 14 or 15 kidneys, respectively), ET (13 or 15 kidneys, respectively) progressively increased urine cAMP levels, water and sodium reabsorption, and urine osmolality and decreased urine output (P ≤ 0.04, except for sodium reabsorption under constant pressure [P = 0.17]). In ET-challenged kidneys, compared to placebo treatment, adefovir, an EF inhibitor, decreased urine cAMP levels, water and sodium reabsorption, and urine osmolality and increased urine output, while raxibacumab, a PA-directed monoclonal antibody (MAb), decreased urine cAMP levels, free water reabsorption, and urine osmolality and increased urine output (P ≤ 0.03 except for urine output with raxibacumab [P = 0.17]). Upon immunohistochemistry, aquaporin 2 was concentrated along the apical membrane of tubular cells with ET but not PA, and urine aquaporin 2 levels were higher with ET (5.52 ± 1.06 ng/ml versus 1.51 ± 0.44 ng/ml [means ± standard errors of the means {SEM}; P = 0.0001). Edema toxin has renal effects that could contribute to extravascular fluid collection characterizing anthrax infection clinically.

Analysis of Anthrax Immune Globulin Intravenous with Antimicrobial Treatment in Injection Drug Users, Scotland, 2009-2010.

We studied anthrax immune globulin intravenous (AIG-IV) use from a 2009-2010 outbreak of Bacillus anthracis soft tissue infection in injection drug users in Scotland, UK, and we compared findings from 15 AIG-IV recipients with findings from 28 nonrecipients. Death rates did not differ significantly between recipients and nonrecipients (33% vs. 21%). However, whereas only 8 (27%) of 30 patients at low risk for death (admission sequential organ failure assessment score of 0-5) received AIG-IV, 7 (54%) of the 13 patients at high risk for death (sequential organ failure assessment score of 6-11) received treatment. AIG-IV recipients had surgery more often and, among survivors, had longer hospital stays than did nonrecipients. AIG-IV recipients were sicker than nonrecipients. This difference and the small number of higher risk patients confound assessment of AIG-IV effectiveness in this outbreak.

Shock and lethality with anthrax edema toxin in rats are associated with reduced arterial responsiveness to phenylephrine and are reversed with adefovir.

Although edema toxin (ETx) and lethal toxin (LTx) contribute to Bacillus anthracis shock and lethality, the mechanisms underlying their cardiovascular effects are unclear. We have previously shown that ETx but not LTx inhibited phenylephrine-stimulated contraction of aortic rings prepared from healthy rats and that adefovir, a selective inhibitor of ETx cAMP production, blocked this effect. Here, we examined arterial function in rats that received 24-h ETx or LTx infusions. Compared with control rats, ETx reduced mean arterial pressure (MAP) and survival over 48 h (P ≤ 0.0003) and increased plasma cAMP at 4, 24, and 48 h (P < 0.0001) and nitric oxide (NO) at 24 and 48 h (P ≤ 0.01). Compared with control animals, at 24- and 48-h phenylephrine stimulation of aortic rings from ETx animals produced decreased maximal contractile force (MCF; P = 0.05 and 0.006) and in vivo phenylephrine infusion in ETx animals produced decreased proportional increases in MAP (P < 0.0001 and P = 0.05). In ETx-treated animals, compared with placebo-treated animals, adefovir treatment prevented all lethality (P = 0.01), increased MAP (P ≤ 0.0001), decreased plasma and aortic tissue cAMP at 24 and 48 h, respectively (P ≤ 0.03), and plasma NO at both times (P ≤ 0.004), and increased phenylephrine-stimulated increases in MCF in aortic rings and MAP in vivo at 48 h (P = 0.02). LTx decreased MAP and survival also, but it did not alter the response to phenylephrine of MCF in aortic rings prepared from LTx animals or of MAP in vivo. In conclusion, in rats, hypotension and lethality are associated with reduced arterial contractile function with ETx but not LTx and adefovir improves ETx-induced hypotension and lethality.NEW & NOTEWORTHY The most important aspects of the present study are the findings that 1) in vivo challenge with anthrax edema but not lethal toxin depresses arterial contractile function measured both ex vivo and in vivo and 2) adefovir inhibits the effects of edema toxin on arterial hypotension and improves survival with lethal dose of edema toxin challenge.

Nitric oxide production contributes to Bacillus anthracis edema toxin-associated arterial hypotension and lethality: ex vivo and in vivo studies in the rat.

We showed previously that Bacillus anthracis edema toxin (ET), comprised of protective antigen (PA) and edema factor (EF), inhibits phenylephrine (PE)-induced contraction in rat aortic rings and these effects are diminished in endothelial-denuded rings. Therefore, employing rat aortic ring and in vivo models, we tested the hypothesis that nitric oxide (NO) contributes to ET's arterial effects. Compared with rings challenged with PA alone, ET (PA + EF) reduced PE-stimulated maximal contractile force (MCF) and increased the PE concentration producing 50% MCF (EC50) (P < 0.0001). Compared with placebo, l-nitro-arginine methyl-ester (l-NAME), an NO synthase (NOS) inhibitor, reduced ET's effects on MCF and EC50 in patterns that approached or were significant (P = 0.06 and 0.03, respectively). In animals challenged with 24-h ET infusions, l-NAME (0.5 or 1.0 mg·kg(-1)·h(-1)) coadministration increased survival to 17 of 28 animals (60.7%) compared with 4 of 27 (14.8%) given placebo (P = 0.01). Animals receiving l-NAME but no ET all survived. Compared with PBS challenge, ET increased NO levels at 24 h and l-NAME decreased these increases (P < 0.0001). ET infusion decreased mean arterial blood pressure (MAP) in placebo and l-NAME-treated animals (P < 0.0001) but l-NAME reduced decreases in MAP with ET from 9 to 24 h (P = 0.03 for the time interaction). S-methyl-l-thiocitrulline, a selective neuronal NOS inhibitor, had effects in rings and, at a high dose in vivo models, comparable to l-NAME, whereas N'-[3-(aminomethyl)benzyl]-acetimidamide, a selective inducible NOS inhibitor, did not. NO production contributes to ET's arterial relaxant, hypotensive, and lethal effects in the rat.

Increased body mass index and adjusted mortality in ICU patients with sepsis or septic shock: a systematic review and meta-analysis.

BACKGROUND: At least 25 % of adults admitted to intensive care units (ICU) in the United States have an overweight, obese or morbidly obese body mass index (BMI). The effect of BMI on adjusted mortality in adults requiring ICU treatment for sepsis is unclear. We performed a systematic review of adjusted all-cause mortality for underweight, overweight, obese and morbidly obese BMIs relative to normal BMI for adults admitted to the ICU with sepsis, severe sepsis, and septic shock. METHOD: PubMed, the Cochrane Library, and EMBASE electronic databases were searched through November 18, 2015, without language restrictions. We included studies that reported multivariate regression analyses for all-cause mortality using standard BMI categories for adults admitted to the ICU for sepsis, severe sepsis, and septic shock. Articles were selected by consensus among multiple reviewers. Electronic database searches yielded 10,312 articles, of which six were eligible. Data were extracted by one reviewer and then reviewed by three independent reviewers. For the meta-analyses performed, the adjusted odds ratios (aOR) of mortality were combined using a random-effects model. Risk of bias was assessed using the Newcastle-Ottawa quality assessment scale for cohort studies. RESULTS: Four retrospective (n = 6609 patients) and two prospective (n = 556) studies met inclusion criteria. Compared to normal BMI, across five studies each, overweight or obese BMIs reduced the adjusted odds ratio (95 % CI) of mortality [aOR] [0.83 (0.75, 0.91) p < 0.001 and 0.82 (0.67, 0.99) p = 0.04, respectively] with low or moderate heterogeneity (I(2) = 15.7 %, p = 0.31 and I(2) = 53.0 %, p = 0.07, respectively). Across three studies each, morbidly obese BMI and underweight BMI did not alter aOR [0.90 (0.59, 1.39), p = 0.64; I(2) = 43.3 %, p = 0.17; and 1.24 (0.79, 1.95), p = 0.35; I(2) = 15.6 %, p = 0.31 respectively]. Only one study clearly defined how and when height and weight measurements were calculated. Site of underlying infection and illness severity may have favored overweight and obese BMIs. CONCLUSIONS: This is the first meta-analysis to show that overweight or obese BMIs reduce adjusted mortality in adults admitted to the ICU with sepsis, severe sepsis, or septic shock. More rigorous studies that address these limitations are needed to clarify the impact of BMI on sepsis ICU outcomes. TRIAL REGISTRATION: PROSPERO International prospective register of systematic reviews 10.15124/ CRD42014010556 . Registered on July 11, 2014.

Bacillus anthracis edema but not lethal toxin challenge in rats is associated with depressed myocardial function in hearts isolated and tested in a Langendorff system.

Although direct myocardial depression has been implicated in the lethal effects of Bacillus anthracis lethal toxin (LT), in hearts isolated from healthy rats and perfused under constant pressure, neither LT or edema toxin (ET) in typically lethal concentrations depressed myocardial function. In the present study, we challenged rats with LT and ET and performed in vivo and ex vivo heart measures. Sprague-Dawley rats infused over 24 h with LT (n = 94), ET (n = 99), or diluent (controls; n = 50) were studied at 8, 24, or 48 h. Compared with control rats (all survived), survival rates with LT (56.1%) and ET (37.3%) were reduced (P < 0.0001) similarly (P = 0.66 for LT vs. ET). LT decreased mean arterial blood pressure from 12 to 20 h (P ≤ 0.05), whereas ET decreased it progressively throughout (P < 0.05). On echocardiography, LT decreased left ventricular (LV) ejection fraction at 8 and 48 h but increased it at 24 h and decreased cardiac output (P ≤ 0.05 for the time interaction or averaged over time). ET decreased systolic and diastolic volumes and increased LV ejection fraction at 24 h (P ≤ 0.05). In isolated hearts perfused for 120 min under constant pressure, LT did not significantly alter LV systolic or developed pressures at any time point, whereas ET decreased both of these at 24 h (P < 0.0001 initially). ET but not LT progressively increased plasma creatine phosphokinase and cardiac troponin levels (P < 0.05). In conclusion, despite echocardiographic changes, in vivo lethal LT challenge did not produce evidence of myocardial depression in isolated rat hearts. While lethal ET challenge did depress isolated heart function, this may have resulted from prior hypotension and ischemia.

Hypothalamic-pituitary-adrenal axis in lethal canine Staphylococcus aureus pneumonia.

The clinical significance and even existence of critical illness-related corticosteroid insufficiency is controversial. Here, hypothalamic-pituitary-adrenal (HPA) function was characterized in severe canine Staphylococcus aureus pneumonia. Animals received antibiotics and titrated life-supportive measures. Treatment with dexamethasone, a glucocorticoid, but not desoxycorticosterone, a mineralocorticoid, improves outcome in this model. Total and free cortisol, adrenocorticotropic hormone (ACTH). and aldosterone levels, as well as responses to exogenous ACTH were measured serially. At 10 h after the onset of infection, the acute HPA axis stress response, as measured by cortisol levels, exceeded that seen with high-dose ACTH stimulation but was not predictive of outcome. In contrast to cortisol, aldosterone was largely autonomous from HPA axis control, elevated longer, and more closely associated with survival in early septic shock. Importantly, dexamethasone suppressed cortisol and ACTH levels and restored ACTH responsiveness in survivors. Differing strikingly, nonsurvivors, sepsis-induced hypercortisolemia, and high ACTH levels as well as ACTH hyporesponsiveness were not influenced by dexamethasone. During septic shock, only serial measurements and provocative testing over a well-defined timeline were able to demonstrate a strong relationship between HPA axis function and prognosis. HPA axis unresponsiveness and high aldosterone levels identify a septic shock subpopulation with poor outcomes that may have the greatest potential to benefit from new therapies.

Confirmed Bacillus anthracis infection among persons who inject drugs, Scotland, 2009-2010.

In Scotland, the 2009 outbreak of Bacillus anthracis infection among persons who inject drugs resulted in a 28% death rate. To compare nonsurvivors and survivors, we obtained data on 11 nonsurvivors and 16 survivors. Time from B. anthracis exposure to symptoms or hospitalization and skin and limb findings at presentation did not differ between nonsurvivors and survivors. Proportionately more nonsurvivors had histories of excessive alcohol use (p = 0.05) and required vasopressors and/or mechanical ventilation (p≤0.01 for each individually). Nonsurvivors also had higher sequential organ failure assessment scores (mean ± SEM) (7.3 ± 0.9 vs. 1.2 ± 0.4, p<0.0001). Antibacterial drug administration, surgery, and anthrax polyclonal immune globulin treatments did not differ between nonsurvivors and survivors. Of the 14 patients who required vasopressors during hospitalization, 11 died. Sequential organ failure assessment score or vasopressor requirement during hospitalization might identify patients with injectional anthrax for whom limited adjunctive therapies might be beneficial.

Tidal volume and plateau pressure use for acute lung injury from 2000 to present: a systematic literature review.

OBJECTIVE: Since publication of the Respiratory Management of Acute Lung Injury and Acute Respiratory Distress Syndrome (ARMA) trial in 2000, use of tidal volume (VT) less than or equal to 6 mL/kg predicted body weight with corresponding plateau airway pressures (PPlat) less than or equal to 30 cm H2O has been advocated for acute lung injury. However, compliance with these recommendations is unknown. We therefore investigated VT (mL/kg predicted body weight) and PPlat (cm H2O) practices reported in studies of acute lung injury since ARMA using a systematic literature review (i.e., not a meta-analysis). DATA SOURCES: PubMed, Scopus, and EMBASE. STUDY SELECTION: Randomized controlled trials and nonrandomized studies enrolling patients with acute lung injury from May 2000 to June 2013 and reporting VT. DATA EXTRACTION: Whether the study was a randomized controlled trial or a nonrandomized study and performed or not at an Acute Respiratory Distress Syndrome Network center; in randomized controlled trials, the pre- and postrandomization VT (mL/kg predicted body weight) and PPlat (cm H2O) and whether a VT protocol was used postrandomization; in nonrandomized studies, baseline VT and PPlat. DATA SYNTHESIS: Twenty-two randomized controlled trials and 71 nonrandomized studies were included. Since 2000 at acute respiratory distress syndrome Network centers, routine VT was similar comparing randomized controlled trials and nonrandomized studies (p = 0.25) and unchanged over time (p = 0.75) with a mean value of 6.81 (95% CI, 6.45, 7.18). At non-acute respiratory distress syndrome Network centers, routine VT was also similar when comparing randomized controlled trials and nonrandomized studies (p = 0.71), but decreased (p = 0.001); the most recent estimate for it was 6.77 (6.22, 7.32). All VT estimates were significantly greater than 6 (p ≤ 0.02). In randomized controlled trials employing VT protocols, routine VT was reduced in both acute respiratory distress syndrome Network (n = 4) and non-acute respiratory distress syndrome Network (n = 11) trials (p ≤ 0.01 for both), but even postrandomization was greater than 6 (6.47 [6.29, 6.65] and 6.80 [6.42, 7.17], respectively; p ≤ 0.0001 for both). In 59 studies providing data, routine PPlat, averaged across acute respiratory distress syndrome Network or non-acute respiratory distress syndrome Network centers, was significantly less than 30 (p ≤ 0.02). CONCLUSIONS: For clinicians treating acute lung injury since 2000, achieving VT less than or equal to 6 mL/kg predicted body weight may not have been as attainable or important as PPlat less than or equal to 30 cm H2O. If so, there may be equipoise to test if VT less than or equal to 6 mL/kg predicted body weight are necessary to improve acute lung injury outcome.