The coagulopathy of acute sepsis Simmons, Jeff; Pittet, Jean-Francois
Current opinion in anaesthesiology,
04/2015, Volume:
28, Issue:
2
Journal Article
Open access
Sepsis, defined by the presence of infection and host inflammation, is a lethal clinical syndrome with an increasing mortality rate worldwide. In severe disease, the coagulation system becomes ...diffusely activated, with consumption of multiple clotting factors resulting in disseminated intravascular coagulation (DIC). When present, DIC portends a higher mortality rate. Understanding the mechanisms that tie inflammation and diffuse thrombosis will allow therapeutic interventions to be developed. The coagulopathy of acute sepsis is a dynamic process that is time and disease burden specific. Whole-blood testing of coagulation may provide more clinically useful information than the classical tests. Natural anticoagulants that regulate thrombosis are downregulated in sepsis. Patients may benefit from the modulation of the coagulation system when systemic inflammation and hypercoagulopathy exist. Proper timing of anticoagulant therapy may ultimately lead to decreased incidence of multisystem organ dysfunction.
The pathogenesis of coagulopathy in sepsis is driven by an upregulation of procoagulant mechanisms and simultaneous downregulation of natural anticoagulants. Inflammation caused by the invading organism is a natural host defense that cannot be eliminated during treatment. Successful strategies to prevent multisystem organ dysfunction center on stratifying patients at high risk for DIC and restoring the balance of inflammation and coagulation.
The prevention of DIC in septic patients is a key therapeutic target in preventing death from multisystem organ failure. Stratifying patients for therapy using thromboelastometry, specific markers for DIC, and composite scoring systems is an area of growing research.
Physiological hemostasis is a balance between pro- and anticoagulant pathways, and in sepsis, this equilibrium is disturbed, resulting in systemic thrombin generation, impaired anticoagulant ...activity, and suppression of fibrinolysis, a condition termed sepsis-induced coagulopathy (SIC). SIC is a common complication, being present in 24% of patients with sepsis and 66% of patients with septic shock, and is often associated with poor clinical outcomes and high mortality. 1 , 2 Recent preclinical and clinical studies have generated new insights into the molecular pathogenesis of SIC. In this article, we analyze the complex pathophysiology of SIC with a focus on the role of procoagulant innate immune signaling in hemostatic activation--tissue factor production, thrombin generation, endotheliopathy, and impaired antithrombotic functions. We also review clinical presentations of SIC, the diagnostic scoring system and laboratory tests, the current standard of care, and clinical trials evaluating the efficacies of anticoagulant therapies.
Catecholamines, including β‐adrenergic and dopaminergic neurotransmitters, have an essential role in regulating the “fight or flight” reflex and also affects immune cell proinflammatory action. ...However, little is known about whether catecholamines prevent dysfunction of metabolic pathways associated with inflammatory organ injury, including development of acute lung injury (ALI). We hypothesize that selected catecholamines may reduce metabolic alterations in LPS‐stimulated macrophages and in the lungs of mice subjected to endotoxin‐induced ALI, a situation characterized by diminished activity of AMP‐activated protein kinase (AMPK). We found that activation of the dopamine 1 receptor (D1R) with fenoldopam, but not stimulation of adrenergic receptors with norepinephrine, resulted in a robust activation of AMPK in peritoneal macrophages, human monocytes, or alveolar epithelial cells (AECs). Such AMPK activation was mediated by a phospholipase C (PLC)–dependent mechanism. Unlike norepinephrine, D1R activation also prevented Thr172–AMPK dephosphorylation and kinase inactivation in LPS‐treated macrophages. Furthermore, we show that a culture of AECs with either fenoldopam or the AMPK activator metformin effectively diminished IL‐1β–induced release of adverse paracrine signaling, which promotes the macrophage proinflammatory response. In vivo, fenoldopam reduced the severity of LPS‐induced ALI, including development of pulmonary edema, lung permeability, and production of inflammatory cytokines TNF‐α, MIP‐2, or KC and HMGB1. Fenoldopam also prevented AMPK dephosphorylation in the lungs of LPS‐treated mice and prevented loss of mitochondrial complexes NDUFB8 (complex I) and ATP synthase (complex V). Collectively, these results suggest that dopamine is coupled to AMPK activation, which provides a substantial anti‐inflammatory and bioenergetic advantage and reduces the severity of endotoxin‐induced ALI.
ABSTRACT
Patients who recover from pneumonia subsequently have elevated rates of death after hospital discharge as a result of secondary organ damage, the causes of which are unknown. We used the ...bacterium Pseudomonas aeruginosa, a common cause of hospital‐acquired pneumonia, as a model for investigating this phenomenon. We show that infection of pulmonary endothelial cells by P. aeruginosa induces production and release of a cytotoxic amyloid molecule with prion characteristics, including resistance to various nucleases and proteases. This cytotoxin was self‐propagating, was neutralized by anti‐amyloid Abs, and induced death of endothelial cells and neurons. Moreover, the cytotoxin induced edema in isolated lungs. Endothelial cells and isolated lungs were protected from cytotoxin‐induced death by stimulation of signal transduction pathways that are linked to prion protein. Analysis of bronchoalveolar lavage fluid collected from human patients with P. aeruginosa pneumonia demonstrated cytotoxic activity, and lavage fluid contained amyloid molecules, including oligomeric t and Ab. Demonstration of long‐lived cytotoxic agents after Pseudomonas infection may establish a molecular link to the high rates of death as a result of end‐organ damage in the months after recovery from pneumonia, and modulation of signal transduction pathways that have been linked to prion protein may provide a mechanism for intervention.—Balczon, R., Morrow, K. A., Zhou, C., Edmonds, B., Alexeyev, M., Pittet, J.‐F., Wagener, B. M., Moser, S. A., Leavesley, S., Zha, X., Frank, D. W., Stevens, T. Pseudomonas aeruginosa infection liberates transmissible, cytotoxic prion amyloids. FASEB J. 31, 2785–2796 (2017). www.fasebj.org
Recent studies have identified an acute traumatic coagulopathy that is present on admission to the hospital and is independent of iatrogenic causes. We have previously reported that this coagulopathy ...is due to the association of severe injury and shock and is characterized by a decrease in plasma protein C (PC) levels. Whether this early coagulopathy and later propensity to infection, multiple organ failure and mortality are associated with the activation of PC pathway has not been demonstrated and constitutes the aim of this study.
This was a prospective cohort study of 203 major trauma patients. Serial blood samples were drawn on arrival in the emergency department, and at 6, 12, and 24 hours after admission to the hospital. PT, PTT, Va, VIIIa, PC aPC t-PA, and D-dimer levels were assayed. Comprehensive injury, resuscitation, and outcome data were prospectively collected. A total of 203 patients were enrolled. Patients with tissue hypoperfusion and severe traumatic injury showed a strong activation of the PC which was associated with a coagulopathy characterized by inactivation of the coagulation factors V and VIII and a derepression of the fibrinolysis with high plasma levels of plasminogen activator and high D-dimers. Elevated plasma levels of activated PC were significantly associated with increased mortality, organ injury, increased blood transfusion requirements, and reduced ICU ventilator-free days. Finally early depletion of PC after trauma is associated with a propensity to posttraumatic ventilator-associated pneumonia.
Acute traumatic coagulopathy occurs in the presence of tissue hypoperfusion and severe traumatic injury and is mediated by activation of the PC pathway. Higher plasma levels of aPC upon admission are predictive of poor clinical outcomes after major trauma. After activation, patients who fail to recover physiologic plasma values of PC have an increased propensity to later nosocomial lung infection.
ABSTRACTPatients with nosocomial pneumonia exhibit elevated levels of neurotoxic amyloid and tau proteins in the cerebrospinal fluid (CSF). In vitro studies indicate that pulmonary endothelium ...infected with clinical isolates of either Pseudomonas aeruginosa, Klebsiella pneumoniae, or Staphylococcus aureus produces and releases cytotoxic amyloid and tau proteins. However, the effects of the pulmonary endothelium‐derived amyloid and tau proteins on brain function have not been elucidated. Here, we show that P. aeruginosa infection elicits accumulation of detergent insoluble tau protein in the mouse brain and inhibits synaptic plasticity. Mice receiving endothelium‐derived amyloid and tau proteins via intracerebroventricular injection exhibit a learning and memory deficit in object recognition, fear conditioning, and Morris water maze studies. We compared endothelial supernatants obtained after the endothelia were infected with P. aeruginosa possessing an intact P. aeruginosa isolated from patient 103 (PA103) supernatant or defective mutant strain of P. aeruginosa lacking a functional type 3 secretion system needle tip complex (ΔPcrV) supernatant type 3 secretion system. Whereas the PA103 supernatant impaired working memory, the ΔPcrV supernatant had no effect. Immunodepleting amyloid or tau proteins from the PA103 supernatant with the A11 or T22 antibodies, respectively, overtly rescued working memory. Recordings from hippocampal slices treated with endothelial supernatants or CSF from patients with or without nosocomial pneumonia indicated that endothelium‐derived neurotoxins disrupted the postsynaptic synaptic response. Taken together, these results establish a plausible mechanism for the neurologic sequelae consequent to nosocomial bacterial pneumonia.—Balczon, R., Pittet, J.‐F., Wagener, B. M., Moser, S. A., Voth, S., Vorhees, C. V., Williams, M. T., Bridges, J. P., Alvarez, D. F., Koloteva, A., Xu, Y., Zha, X.‐M., Audia, J. P., Stevens, T., Lin, M. T. Infection‐induced endothelial amyloids impair memory. FASEB J. 33, 10300–10314 (2019). www.fasebj.org
Management of the Traumatized Airway Jain, Uday; McCunn, Maureen; Smith, Charles E ...
Anesthesiology (Philadelphia),
2016-January, Volume:
124, Issue:
1
Journal Article
Peer reviewed
There is a lack of evidence-based approach regarding the best practice for airway management in patients with a traumatized airway. General recommendations for the management of the traumatized ...airway are summarized in table 5. Airway trauma may not be readily apparent, and its evaluation requires a high level of suspicion for airway disruption and compression. For patients with facial trauma, control of the airway may be significantly impacted by edema, bleeding, inability to clear secretions, loss of bony support, and difficulty with face mask ventilation. With the airway compression from neck swelling or hematoma, intubation attempts can further compromise the airway due to expanding hematoma. For patients with airway disruption, the goal is to pass the tube across the injured area without disrupting it or to insert the airway distal to the injury using a surgical approach. If airway injury is extensive, a surgical airway distal to the site of injury may be the best initial approach. Alternatively, if orotracheal intubation is chosen, spontaneous ventilation may be maintained or RSI may be performed. RSI is a common approach. Thus, some of the patients intubated may subsequently require tracheostomy. A stable patient with limited injuries may not require intubation but should be watched carefully for at least several hours. Because of a paucity of evidence-based data, the choice between these approaches and the techniques utilized is a clinical decision depending on the patient's condition, clinical setting, injuries to airway and other organs, and available personnel, expertise, and equipment. Inability to obtain a definitive airway is always an absolute indication for an emergency cricothyroidotomy or surgical tracheostomy.
Coagulopathy following major trauma is conventionally attributed to activation and consumption of coagulation factors. Recent studies have identified an acute coagulopathy present on admission that ...is independent of injury severity. We hypothesized that early coagulopathy is due to tissue hypoperfusion, and investigated derangements in coagulation associated with this.
This was a prospective cohort study of major trauma patients admitted to a single trauma center. Blood was drawn within 10 minutes of arrival for analysis of partial thromboplastin and prothrombin times, prothrombin fragments 1+2, fibrinogen, thrombomodulin, protein C, plasminogen activator inhibitor-1, and D-dimers. Base deficit (BD) was used as a measure of tissue hypoperfusion.
A total of 208 patients were enrolled. Patients without tissue hypoperfusion were not coagulopathic, irrespective of the amount of thrombin generated. Prolongation of the partial thromboplastin and prothrombin times was only observed with an increased BD. An increasing BD was associated with high soluble thrombomodulin and low protein C levels. Low protein C levels were associated with prolongation of the partial thromboplastin and prothrombin times and hyperfibrinolysis with low levels of plasminogen activator inhibitor-1 and high D-dimer levels. High thrombomodulin and low protein C levels were significantly associated with increased mortality, blood transfusion requirements, acute renal injury, and reduced ventilator-free days.
Early traumatic coagulopathy occurs only in the presence of tissue hypoperfusion and appears to occur without significant consumption of coagulation factors. Alterations in the thrombomodulin-protein C pathway are consistent with activated protein C activation and systemic anticoagulation. Admission plasma thrombomodulin and protein C levels are predictive of clinical outcomes following major trauma.
PDF
