ABSTRACT
OBJECTIVES: To compare the attributes and clinical outcomes of patients with cardiac arrest in the setting of drug overdose (OD) to patients with cardiac arrest from non-drug related etiologies. METHODS: We utilized a US inpatient cardiac arrest registry used to study targeted temperature management (TTM) to identify patients with cardiac arrest in the setting of drug overdose between 2005 and 2013. Data regarding the cardiac arrest, resuscitation interventions, use of post-arrest TTM, urine drug screen, survival, and neurologic outcome were examined. These results were compared to patients suffering cardiac arrest from other causes during the same time period using Wilcoxon rank-sum tests for continuous variables and chi-square tests on categorical variables. RESULTS: Approximately 2.5% (64/2584) of cardiac arrests occurred in the setting of drug overdose. Patients in the OD cohort were younger, more likely to be male, and more likely to have an out-of-hospital cardiac arrest that was unwitnessed with no bystander CPR and from a non-shockable rhythm. However, the patients in the OD cohort had similar rates of survival and good neurologic outcomes (Cerebral Performance Category 1-2) compared to non-OD patients. A fraction of initially resuscitated patients in each group (8% in OD cohort vs. 15% in non-OD cohort, p=ns) did not receive post-arrest TTM due to prompt awakening following resuscitation. CONCLUSIONS: Patients resuscitated from cardiac arrest in the setting of drug OD have neurologic and survival outcomes comparable to non-OD patients despite lower rates of bystander CPR, shockable rhythms, and witnessed arrest.
Subject(s)
Cardiopulmonary Resuscitation/methods , Drug Overdose/complications , Emergency Medical Services , Heart Arrest/therapy , Hypothermia, Induced/methods , Registries , Adult , Aged , Female , Follow-Up Studies , Heart Arrest/etiology , Humans , Male , Middle Aged , Retrospective Studies , Treatment OutcomeABSTRACT
The control of innate immune responses through activation of the nuclear transcription factor NF-kappaB is essential for the elimination of invading microbial pathogens. We showed that the bacterial N-(3-oxo-dodecanoyl) homoserine lactone (C12) selectively impairs the regulation of NF-kappaB functions in activated mammalian cells. The consequence is specific repression of stimulus-mediated induction of NF-kappaB-responsive genes encoding inflammatory cytokines and other immune regulators. These findings uncover a strategy by which C12-producing opportunistic pathogens, such as Pseudomonas aeruginosa, attenuate the innate immune system to establish and maintain local persistent infection in humans, for example, in cystic fibrosis patients.
Subject(s)
4-Butyrolactone/analogs & derivatives , Gene Expression Regulation , Homoserine/analogs & derivatives , Macrophages/immunology , Macrophages/metabolism , NF-kappa B/metabolism , Pseudomonas aeruginosa/pathogenicity , Signal Transduction , 4-Butyrolactone/physiology , Adult , Animals , Cyclic AMP Response Element-Binding Protein/metabolism , Cystic Fibrosis/microbiology , Female , Homoserine/physiology , Humans , I-kappa B Kinase/metabolism , I-kappa B Proteins/metabolism , Immunity, Innate , Interferon-gamma/immunology , Lipopolysaccharides/immunology , Macrophage Activation , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Middle Aged , NF-KappaB Inhibitor alpha , Phosphorylation , Pseudomonas Infections/immunology , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/immunology , Pseudomonas aeruginosa/physiology , Toll-Like Receptors/metabolism , Transcription Factor RelA/metabolismABSTRACT
Innate immune system receptors function as sensors of infection and trigger the immune responses through ligand-specific signaling pathways. These ligands are pathogen-associated products, such as components of bacterial walls and viral nuclear acids. A common response to such ligands is the activation of mitogen-activated protein kinase p38, whereas double-stranded viral RNA additionally induces the phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha). Here we have shown that p38 and eIF2alpha phosphorylation represent two biochemical markers of the effects induced by N-(3-oxo-acyl)homoserine lactones, the secreted products of a number of Gram-negative bacteria, including the human opportunistic pathogen Pseudomonas aeruginosa. Furthermore, N-(3-oxo-dodecanoyl)homoserine lactone induced distension of mitochondria and the endoplasmic reticulum as well as c-jun gene transcription. These effects occurred in a wide variety of cell types including alveolar macrophages and bronchial epithelial cells, requiring the structural integrity of the lactone ring motif and its natural stereochemistry. These findings suggest that N-(3-oxo-acyl)homoserine lactones might be recognized by receptors of the innate immune system. However, we provide evidence that N-(3-oxo-dodecanoyl)homoserine lactone-mediated signaling does not require the presence of the canonical innate immune system receptors, Toll-like receptors, or two members of the NLR/Nod/Caterpillar family, Nod1 and Nod2. These data offer a new understanding of the effects of N-(3-oxo-dodecanoyl)homoserine lactone on host cells and its role in persistent airway infections caused by P. aeruginosa.
