Abdullah Chahin

Sirt1 Activation Markedly Alters Transcription Profiles and Improves Outcome in Experimental Sepsis.

ABSTRACT The sirtuin family consists of seven NAD+-dependent enzymes affecting a broad array of regulatory protein networks by primarily catalyzing the deacetylation of key lysine residues in regulatory proteins. The enzymatic activity of SIRT1 can be enhanced by small molecule activators known as SIRT1 activator compounds (STACs). We tested the therapeutic potential of the STAC SRT3025 in two preclinical models of severe infection, the murine cecal ligation and puncture (CLP) model to induce peritonitis and intratracheal installation of Streptococcus pneumoniae to induce severe bacterial pneumonia. SRT3025 provided significant survival benefits over vehicle control in both the peritonitis and pneumococcal pneumonia models when administered with appropriate antimicrobial agents. The survival benefit of SRT3025 in the CLP model was absent in SIRT1 knockout showing the SIRT1 dependency of SRT3025s effects. SRT3025 administration promoted bacterial clearance and significantly reduced inflammatory cytokines from the lungs of animals challenged with S. pneumoniae. SRT3025 treatment was also accompanied by striking changes in the transcription profiles in multiple inflammatory and metabolic pathways in liver, spleen, small bowel, and lung tissue. Remarkably, these organ-specific changes in the transcriptome analyses were similar following CLP or pneumococcal challenge despite different sets of pathogens at disparate sites of infection. Pharmacologic activation of SIRT1 modulates the innate host response and could represent a novel treatment strategy for severe infection.

CD28 Homodimer Interface Mimetic Peptide Acts as a Preventive and Therapeutic Agent in Models of Severe Bacterial Sepsis and Gram-Negative Bacterial Peritonitis

BACKGROUND Severe gram-negative bacterial infections and sepsis are major causes of morbidity and mortality. Dysregulated, excessive proinflammatory cytokine expression contributes to the pathogenesis of sepsis. A CD28 mimetic peptide (AB103; previously known as p2TA) that attenuates CD28 signaling and T-helper type 1 cytokine responses was tested for its ability to increase survival in models of polymicrobial infection and gram-negative sepsis. METHODS Mice received AB103, followed by an injection of Escherichia coli 0111:B4 lipopolysaccharide (LPS); underwent induction E. coli 018:K1 peritonitis induction, followed by treatment with AB103; or underwent cecal ligation and puncture (CLP), followed by treatment with AB103. The effects of AB103 on factors associated with and the lethality of challenge infections were analyzed. RESULTS AB103 strongly attenuated induction of tumor necrosis factor α and interleukin 6 (IL-6) by LPS in human peripheral blood mononuclear cells. Receipt of AB103 following intraperitoneal injection of LPS resulted in survival among 73% of CD1 mice (11 of 15), compared with 20% of controls (3 of 15). Suboptimal doses of antibiotic alone protected 20% of mice (1 of 5) from E. coli peritonitis, whereas 100% (15 of 15) survived when AB103 was added 4 hours following infection. Survival among mice treated with AB103 12 hours after CLP was 100% (8 of 8), compared with 17% among untreated mice (1 of 6). In addition, receipt of AB103 12 hours after CLP attenuated inflammatory cytokine responses and neutrophil influx into tissues and promoted bacterial clearance. Receipt of AB103 24 hours after CLP still protected 63% of mice (5 of 8). CONCLUSIONS Single-dose AB103 reduces mortality in experimental models of polymicrobial and gram-negative bacterial infection and sepsis, warranting further studies of this agent in clinical trials.

False alarm reduction in critical care.

High false alarm rates in the ICU decrease quality of care by slowing staff response times while increasing patient delirium through noise pollution. The 2015 PhysioNet/Computing in Cardiology Challenge provides a set of 1250 multi-parameter ICU data segments associated with critical arrhythmia alarms, and challenges the general research community to address the issue of false alarm suppression using all available signals. Each data segment was 5 minutes long (for real time analysis), ending at the time of the alarm. For retrospective analysis, we provided a further 30 seconds of data after the alarm was triggered. A total of 750 data segments were made available for training and 500 were held back for testing. Each alarm was reviewed by expert annotators, at least two of whom agreed that the alarm was either true or false. Challenge participants were invited to submit a complete, working algorithm to distinguish true from false alarms, and received a score based on their programs performance on the hidden test set. This score was based on the percentage of alarms correct, but with a penalty that weights the suppression of true alarms five times more heavily than acceptance of false alarms. We provided three example entries based on well-known, open source signal processing algorithms, to serve as a basis for comparison and as a starting point for participants to develop their own code. A total of 38 teams submitted a total of 215 entries in this years Challenge. This editorial reviews the background issues for this challenge, the design of the challenge itself, the key achievements, and the follow-up research generated as a result of the Challenge, published in the concurrent special issue of Physiological Measurement. Additionally we make some recommendations for future changes in the field of patient monitoring as a result of the Challenge.

The novel immunotherapeutic oligodeoxynucleotide IMT504 protects neutropenic animals from fatal Pseudomonas aeruginosa bacteremia and sepsis

ABSTRACT IMT504 is a novel immunomodulatory oligonucleotide that has shown immunotherapeutic properties in early preclinical and clinical studies. IMT504 was tested in a neutropenic rat model of Pseudomonas aeruginosa bacteremia and sepsis. This animal system recapitulates many of the pathological processes found in neutropenic patients with Gram-negative, bacterial infections. The research was conducted in the setting of an academic research laboratory. The test subjects were Sprague-Dawley rats. Animals were rendered neutropenic by administration of cyclophosphamide, colonized with P. aeruginosa by oral feeding, and then randomized to receive IMT504 over a range of doses and treatment regimens representing early and late therapeutic interventions. IMT504 immunotherapy conferred a significant survival advantage over the 12-day study period compared with the results seen with placebo-treated animals when the therapy was administered at the onset of neutropenia and even in the absence of antibiotics and after the onset of fever and systemic infection. Notably, even late salvage IMT504 monotherapy was highly effective (13/14 surviving rats with IMT504 therapy versus 2/14 controls, P = <0.001). Moreover, late salvage IMT504 monotherapy was as effective as antibiotic therapy (13/14 surviving rats versus 21/21 rats, P = 0.88). In addition, no antagonism or loss of therapeutic efficacy was noted with combination therapy of IMT504 plus antibiotics. IMT504 immunotherapy provides a remarkable survival advantage in bacteremia and sepsis in neutropenic animals and deserves further study as a new treatment option in patients with, or at risk for, severe Gram-negative bacterial infections and sepsis.

Severe Pneumonia Caused by Legionella pneumophila: Differential Diagnosis and Therapeutic Considerations

Severe legionella pneumonia poses a diagnostic challenge and requires early intervention. Legionnaires disease can have several presenting signs, symptoms, and laboratory abnormalities that suggest that Legionella pneumophila is the pathogen, but none of these are sufficient to distinguish L pneumophila pneumonia from other respiratory pathogens. L pneumophila is primarily an intracellular pathogen and needs treatment with antibiotics that efficiently enter the intracellular space.

Management of Atrial Fibrillation with Rapid Ventricular Response in the Intensive Care Unit: A Secondary Analysis of Electronic Health Record Data.

Purpose: Atrial fibrillation with rapid ventricular response (RVR) is common during critical illness. In this study, we explore the comparative effectiveness of three commonly used drugs (metoprolol, diltiazem, and amiodarone) in the management of atrial fibrillation with RVR in the intensive care unit (ICU). Methods: Data pertaining to the first ICU admission were extracted from the Medical Information Mart for Intensive Care III database. Patients who received one of the above pharmacologic agents while their heart rate was > 110 bpm and had atrial fibrillation documented in the clinical chart were included. Propensity score weighting using a generalized boosted model was used to compare medication failure rates (second agent prior to termination of RVR). Secondary outcomes included time to control, control within 4 h, and mortality. Results: One thousand six hundred forty-six patients were included: 736 received metoprolol, 292 received diltiazem, and 618 received amiodarone. Compared with those who received metoprolol, failure rates were higher amongst those who received amiodarone (OR 1.39, 95% CI 1.03–1.87, P = 0.03) and there was a trend towards increased failure rates in patients who received diltiazem (OR 1.35, CI 0.89–2.07, P = 0.16). Amongst patients who received a single agent, patients who received diltiazem were less likely to be controlled at 4-h than those who received metoprolol (OR 0.64, CI 0.43–097, P = 0.03). Initial agent was not associated with in-hospital mortality. Conclusions: In this study, metoprolol was the most commonly used agent for atrial fibrillation with RVR. Metoprolol had a lower failure rate than amiodarone and was superior to diltiazem in achieving rate control at 4 h.

AB103, a CD28 antagonist peptide: a new therapeutic agent in a model of severe sepsis

AB103 is a novel CD28 antagonist peptide currently in clinical development that modulates CD28 signaling in T cells, without affecting the normal humoral immune response. In experimental models of Gram-positive, Gram-negative and polymicrobial sepsis, AB103 demonstrated significant activity, increasing overall survival.

Risk factors for prolonged H1N1 influenza among hospitalized patients

In our study, 50% of 42 hospitalized patients with 2009 H1N1 pandemic influenza experienced symptoms longer than 1 week. Older age and delay in oseltamivir initiation were associated with prolonged illness. Patients with pneumonia and fever ≥7 days were more likely to have polymerase chain reaction-positive nasopharyngeal swabs beyond 1 week.

One-year mortality after recovery from critical illness: A retrospective cohort study

Rationale Factors associated with one-year mortality after recovery from critical illness are not well understood. Clinicians generally lack information regarding post-hospital discharge outcomes of patients from the intensive care unit, which may be important when counseling patients and families. Objective We sought to determine which factors among patients who survived for at least 30 days post-ICU admission are associated with one-year mortality. Methods Single-center, longitudinal retrospective cohort study of all ICU patients admitted to a tertiary-care academic medical center from 2001–2012 who survived ≥30 days from ICU admission. Cox’s proportional hazards model was used to identify the variables that are associated with one-year mortality. The primary outcome was one-year mortality. Results 32,420 patients met the inclusion criteria and were included in the study. Among patients who survived to ≥30 days, 28,583 (88.2%) survived for greater than one year, whereas 3,837 (11.8%) did not. Variables associated with decreased one-year survival include: increased age, malignancy, number of hospital admissions within the prior year, duration of mechanical ventilation and vasoactive agent use, sepsis, history of congestive heart failure, end-stage renal disease, cirrhosis, chronic obstructive pulmonary disease, and the need for renal replacement therapy. Numerous effect modifications between these factors were found. Conclusion Among survivors of critical illness, a significant number survive less than one year. More research is needed to help clinicians accurately identify those patients who, despite surviving their acute illness, are likely to suffer one-year mortality, and thereby to improve the quality of the decisions and care that impact this outcome.

Risk factors for death in chronic critical illness

As early recognition, resuscitation and technological advancement in the treatment of critically ill patients have improved, efforts to understand patient outcomes after an acute period of illness are being undertaken. While it has been noted that one-year mortality among survivors of critical illness is extremely high, awareness is increasing regarding patients who, despite survival, remain “chronically critically ill”. This is important considering that patients who have short-term survival after ICU discharge have poor quality of life leading to death.