Daniel A. Sweeney

Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patients individual circumstances.These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panels recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews.

An overview of anthrax infection including the recently identified form of disease in injection drug users

PurposeBacillus anthracis infection (anthrax) can be highly lethal. Two recent outbreaks related to contaminated mail in the USA and heroin in the UK and Europe and its potential as a bioterrorist weapon have greatly increased concerns over anthrax in the developed world.MethodsThis review summarizes the microbiology, pathogenesis, diagnosis, and management of anthrax.Results and conclusionsAnthrax, a gram-positive bacterium, has typically been associated with three forms of infection: cutaneous, gastrointestinal, and inhalational. However, the anthrax outbreak among injection drug users has emphasized the importance of what is now considered a fourth disease form (i.e., injectional anthrax) that is characterized by severe soft tissue infection. While cutaneous anthrax is most common, its early stages are distinct and prompt appropriate treatment commonly produces a good outcome. However, early symptoms with the other three disease forms can be nonspecific and mistaken for less lethal conditions. As a result, patients with gastrointestinal, inhalational, or injectional anthrax may have advanced infection at presentation that can be highly lethal. Once anthrax is suspected, the diagnosis can usually be made with gram stain and culture from blood or tissue followed by confirmatory testing (e.g., PCR). While antibiotics are the mainstay of anthrax treatment, use of adjunctive therapies such as anthrax toxin antagonists are a consideration. Prompt surgical therapy appears to be important for successful management of injectional anthrax.

Palmitate incorporation into different brain regions in the awake rat

A quantitative method is presented to examine palmitate flux into a stable metabolic compartment in individual brain regions of awake rats. Following the i.v. injection of [14C]palmitate, brain radioactivity rose and then fell until, at 4 h, a stable concentration was reached that was maintained for up to 24 h. The flux of plasma palmitate into this 4 h compartment was calculated by dividing regional brain radioactivity at 4 h, as determined by quantitative autoradiography, by the integral of the plasma palmitate specific activity. Palmitate flux varied from 2.0 x 10(-5) mumol/g.s into the internal capsule to 9.3 x 10(-5) mumol/g.s into the arcuate nucleus, and generally was proportional to the regional cerebral metabolic rate for glucose, as measured with 2-deoxy-D-[1-14C]glucose. The results demonstrate that it is possible to determine unidirectional palmitate flux into a stable metabolic compartment in individual brain regions of awake rats, that flux into gray matter regions generally exceeds flux into white matter, and that palmitate flux is proportional to published values for regional brain oxidative metabolism.

Once is not enough: clinical trials in sepsis

In this issue of Intensive Care Medicine, the steering committee members of the PROWESS-Shock trial present a balanced discussion of the controversies surrounding recombinant human activated protein C (rhAPC) and the challenges intrinsic to designing an industry-sponsored trial [1]. The investigators have taken important steps to be transparent about financial conflicts of interest, to safeguard data monitoring and to ensure the validity of statistical analysis. The purpose of the upcoming PROWESS-Shock Trial is to prospectively test rhAPC in a high-risk septic population—those patients with vasopressor-dependent shock for C4 h. The need for this trial, years after the regulatory approval of rhAPC for a similar indication, is a cautionary tale that contains important lessons for health care providers who manage patients with sepsis, the pharmaceutical industry and the Food and Drug Administration (FDA). The following is an excerpt from a letter written to Dr. Jay P. Siegel, Director of the Office of Therapeutics Research and Review, FDA, on 22 October 2001 by four of the ten dissenting members of the FDA advisory panel that considered the safety and efficacy of rhAPC (Personal communication, Suffredini A for the authors, Cross AE, Munford R, Suffredini A, Warren S):

Anthrax Lethal and Edema Toxins Produce Different Patterns of Cardiovascular and Renal Dysfunction and Synergistically Decrease Survival in Canines

BACKGROUND High mortality in the 2001 US and recent European anthrax outbreaks suggests that better understanding of the effects of the toxins produced by this bacterium is needed to improve treatment. METHODS AND RESULTS Here, 24-h edema (ETx) and lethal (LeTx) toxin infusions were investigated for 96 hin sedated canines receiving mechanical ventilation. The initial study compared similarly lethal doses of ETx (n=8) or LeTx (n=15) alone. ETx was 24 times less lethal than LeTx, and the median time to death in nonsurvivors (n=6 and n=9, respectively) was shorter with ETx (42 vs 67 h; P=.04). Compared with controls(n=9), both toxins decreased arterial and central venous pressures and systemic vascular resistance and increased heart rate, cardiac index, blood urea nitrogen (BUN) level, creatinine (Cr) concentration, BUN:Cr ratio, and hepatic transaminase levels (P ≤ .05 for toxin effect or time interaction). However, ETx stimulated early diuresis,reduced serum sodium levels, and had more pronounced vasodilatory effects, compared with LeTx, as reflected by greater or earlier central venous pressures, systemic vascular resistance, and changes in the BUN:Cr ratio(P ≤ .01). LeTx progressively decreased the left ventricular ejection fraction (P ≤ .002). In a subsequent study, a lethal dose of LeTx with an equimolar nonlethal ETx dose (n=8) increased mortality, compared with LeTx alone (n=8; P= .05). CONCLUSION Shock with ETx or LeTx may require differing supportive therapies, whereas toxin antagonists should likely target both toxins.

Efficacy of selective mineralocorticoid and glucocorticoid agonists in canine septic shock

Objective:Corticosteroid regimens that stimulate both mineralocorticoid and glucocorticoid pathways consistently reverse vasopressor-dependent hypotension in septic shock but have variable effects on survival. The objective of this study was to determine whether exogenous mineralocorticoid and glucocorticoid treatments have distinct effects and whether the timing of administration alters their effects in septic shock. Design, Setting, Subjects, and Interventions:Desoxycorticosterone, a selective mineralocorticoid agonist; dexamethasone, a selective glucocorticoid agonist; and placebo were administered either several days before (prophylactic) or immediately after (therapeutic) infectious challenge and continued for 96 hrs in 74 canines with staphylococcal pneumonia. Measurements and Main Results:Effects of desoxycorticosterone and dexamethasone were different and opposite depending on timing of administration for survival (p = .05); fluid requirements (p = .05); central venous pressures (p ⩽ .007); indicators of hemoconcentration (i.e., sodium [p = .0004], albumin [p = .05], and platelet counts [p = .02]); interleukin-6 levels (p = .04); and cardiac dysfunction (p = .05). Prophylactic desoxycorticosterone treatment significantly improved survival, shock, and all the other outcomes stated, but therapeutic desoxycorticosterone did not. Conversely, prophylactic dexamethasone was much less effective for improving these outcomes compared with therapeutic dexamethasone with the exception of shock reversal. Prophylactic dexamethasone given before sepsis induction also significantly reduced serum aldosterone and cortisol levels and increased body temperature and lactate levels compared with therapeutic dexamethasone (p ⩽ .05), consistent with adrenal suppression. Conclusions:In septic shock, mineralocorticoids are only beneficial if given prophylactically, whereas glucocorticoids are most beneficial when given close to the onset of infection. Prophylactic mineralocorticoids should be further investigated in patients at high risk to develop sepsis, whereas glucocorticoids should only be administered therapeutically to prevent adrenal suppression and worse outcomes.

Brain palmitate incorporation in awake and anesthetized rats

Uniformly labeled [14C]palmitate was injected intravenously in awake and barbiturate-anesthetized rats, and arterial plasma radioactivity due to unesterified [14C]palmitate was determined on plasma samples removed at timed intervals up to the time of death. Overall brain radioactivity was determined by liquid scintillation spectroscopy, and regional brain radioactivity was determined by quantitative autoradiography. The transfer constant, k, for the unidirectional uptake of radiotracer palmitate into the brain at 4 h was calculated from the brain radioactivity and the integrated plasma radioactivity from injection to 4 h. The unidirectional palmitate uptake was calculated as the product of k and the plasma concentration of unesterified palmitate. Barbiturate anesthesia reduced regional palmitate transfer constants and unidirectional palmitate uptakes into different brain regions by 40-60%. Palmitate incorporation into the brains of awake rats at 4 h represents uptake into structural brain components which contain lipids. The results indicate that pentobarbital anesthesia reduces this rate of incorporation by about half.

The potential contributions of lethal and edema toxins to the pathogenesis of anthrax associated shock.

Outbreaks of Bacillus anthracis in the US and Europe over the past 10 years have emphasized the health threat this lethal bacteria poses even for developed parts of the world. In contrast to cutaneous anthrax, inhalational disease in the US during the 2001 outbreaks and the newly identified injectional drug use form of disease in the UK and Germany have been associated with relatively high mortality rates. One notable aspect of these cases has been the difficulty in supporting patients once shock has developed. Anthrax bacilli produce several different components which likely contribute to this shock. Growing evidence indicates that both major anthrax toxins may produce substantial cardiovascular dysfunction. Lethal toxin (LT) can alter peripheral vascular function; it also has direct myocardial depressant effects. Edema toxin (ET) may have even more pronounced peripheral vascular effects than LT, including the ability to interfere with the actions of conventional vasopressors. Additionally, ET also appears capable of interfering with renal sodium and water retention. Importantly, the two toxins exert their actions via quite different mechanisms and therefore have the potential to worsen shock and outcome in an additive fashion. Finally, both toxins have the ability to inhibit host defense and microbial clearance, possibly contributing to the very high bacterial loads noted in patients dying with anthrax. This last point is clinically relevant since emerging data has begun to implicate other bacterial components such as anthrax cell wall in the shock and organ injury observed with infection. Taken together, accumulating evidence regarding the potential contribution of LT and ET to anthrax-associated shock supports efforts to develop adjunctive therapies that target both toxins in patients with progressive shock.

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.

Angeli's salt counteracts the vasoactive effects of elevated plasma hemoglobin.

Plasma hemoglobin (Hb) released during intravascular hemolysis has been associated with numerous deleterious effects that may stem from increased nitric oxide (NO) scavenging, but has also been associated with reactive oxygen species generation and platelet activation. Therapies that convert plasma oxyHb to metHb, or metHb to iron-nitrosyl Hb, could be beneficial because these species do not scavenge NO. In this study, we investigated the effects of Angelis salt (AS; sodium α-oxyhyponitrite, Na2N2O3), a nitroxyl (HNO) and nitrite (NO2(-)) donor, on plasma Hb oxidation and formation of iron-nitrosyl Hb from metHb and on the vasoactivity of plasma Hb. We hypothesized that AS could ameliorate hemolysis-associated pathology via its preferential reactivity with plasma Hb, as opposed to red-cell-encapsulated Hb, and through its intrinsic vasodilatory activity. To test this hypothesis, we infused (n=3 per group) (1) cell-free Hb and AS, (2) cell-free Hb+0.9% NaCl, (3) AS+3% albumin, and (4) 3% albumin+0.9% NaCl (colloid controls for Hb and AS, respectively) in a canine model. Co-infusion of AS and cell-free Hb led to preferential conversion of plasma Hb to metHb, but the extent of conversion was lower than anticipated based on the in vivo concentration of AS relative to plasma Hb. This lower metHb yield was probably due to reactions of nitroxyl-derived AS with plasma components such as thiol-containing compounds. From a physiological and therapeutic standpoint, the infusion of Hb alone led to significant increases in mean arterial pressure (p=0.03) and systemic vascular resistance index (p=0.01) compared to controls. Infusion of AS alone led to significant decreases in these parameters and co-infusion of AS along with Hb had an additive effect in reversing the effects of Hb alone on the systemic circulation. Interestingly, in the pulmonary system, the decrease in pressure when AS was added to Hb was significantly less than would have been expected compared to the effects of Hb and AS alone, suggesting that inactivation of scavenging with AS reduced the direct vasodilatory effects of AS on the vasculature. We also found that AS reduced platelet activation when administered to whole blood in vitro. These data suggest that AS-like compounds could serve as therapeutic agents to counteract the negative vasoconstrictive consequences of hemolysis that occur in hemolytic anemias, transfusion of stored blood, and other diseases. Increases in metHb in the red blood cell, the potential of AS for neurotoxicity, and hypotension would need to be carefully monitored in a clinical trial.