Patho - Sepsis PDF

SEPSIS! Previously used SIRS to define her → SIRS is a systemic inflammatory response to infection or other insult (such as trauma, Originally you needed 2+ of: burn, or pancreatitis) 1. Febrile or hypothermic In this you had...

SEPSIS! Previously used SIRS to define her → SIRS is a systemic inflammatory response to infection or other insult (such as trauma, Originally you needed 2+ of: burn, or pancreatitis) 1. Febrile or hypothermic In this you had 3 stages: 2. RR > 24 1. Sepsis: SIRS with an infectious etiology) 3. HR > 90 2. Severe sepsis: sepsis but now with organ dysfunction 4. WBC → leukocytosis or leukopenia 3. Septic shock 5. Hyperglycemia BUT now we use sepsis 3 & not SIRS/severe sepsis → now known as life threatening organ dysfunction caused by a dysregulated host response to infection Still 3 stages: 1. Early stage (SIRS) a. Non-specific sxs like fever and malaise → try to recognize sepsis here but it is really hard! 2. Severe stage (Sepsis) a. Now we have hypotension and organ dysfunction 3. Septic shock a. Now we have severe hypotension (& I need pressors to maintain my BP) and multi-organ damage SO what exactly is sepsis? The body’s reaction to infection with release of a combination of pro-inflammatory and anti-inflammatory cytokines, other mediators and adaptive bioenergetic changes - The pro-inflammatory forces and cell bioenergetic changes cause a systemic illness that, if unsuccessfully treated in early stages, leads to multi-organ dysfunction/failure and can lead to shock and death - The anti-inflammatory forces can help halt the deleterious effects of inflammation: HOWEVER- these forces can lead to immunosuppression and superinfection (infection with other organisms) - Internal civil war between pro-inflammatory and anti-inflammatory mediators aided and abetted by cell adaptive responses Causes of sepsis! - Bacterial pna is the most common cause! - This is followed by UTI and intra-abdominal infections - These infx are from BOTH gram + and gram - bacteria! - Septic shock is most frequently triggered by gram-positive bacterial infections, followed by gram-negative bacteria and fungi - In the US: we like gram + - In europe: we like gram - - Fungi, viruses, and mixed organisms are less common What starts off sepsis? 10 #6 Basically the innate immune system responds to: PAMPs → pathogen-associated DAMPs → damage-associated (molecules Superantigens (recognize parts of the pathogen) derived from my own necrotic cells) ○ Bacterial proteins, usually toxins, ex: Damage can come from: that cause polyclonal T-cell ○ Gram (-) w/LPS infection activation that results in massive ○ Gram (+) w/peptidoglycan! trauma cytokine release ○ Microbial toxins chronic disease Staph aureus → toxic shock Infarct → anoxia Strep pyogenes But how? 1. PAMPs and DAMPs bind to their respective receptors (TLR, NLRs, etc) 2. Binding activates neutrophils and monocytes → create NF-κB 3. NF-κB is the transcription factor that initiates the production and secretion of inflammatory cytokines like IL-1, TNF-alpha, IL-6, IFN-gamma, and others a. These lead to direct systemic effects, vasodilation/increased permeability for overall decreased perfusion, and immunosuppression from secondary anti-inflammatory mediators 4. Certain organisms (PAMPs) can also activate complement!! a. Complement components (like C3a) can go on and further cause endothelial activation and induce proinflammatory state b. Other complement components also upregulate many diff immune cells and works as a chemoattractant for other cells 5. PAMPS can also induce factor XII for coagulation through altered endothelial function → microvascular thrombus (DIC/SIC) → tissue ischemia Concurrently → TGF-beta and leukotrienes are produced to modulate and turn down inflammation so it does not go out of control Sepsis-Induced Coagulopathy (SIC) - This is like disseminated intravascular coagulation (DIC) but induced by sepsis! 1) Proinflammatory cytokines like TNF-alpha activates endothelial cells → stimulates coagulation pathways especially in smaller vessels a) Because these decrease production of endothelial anticoagulant factors like tissue factor pathway inhibitor (TFPI), thrombomodulin, and protein C b) Also decrease ability for fibrinolysis by increasing PAI-1 expression 2) SO we get DIC/SIC systemic activation of coagulation systems with widespread thrombosis & fibrinolysis!! a) With fibrinolysis → consumption of coagulation factors resulting in bleeding b) If I am using up all my clotting factors and platelets in my small vessels → no more coag factors to stop other bleeding so I get hemorrhaging other places 3) SO I get Thrombosis-bleeding-petechiae, purpura and organ hemorrhage ALSO playing a part in this: neutrophil extracellular traps (NETS) - Neutrophils are the 1st line of defense to come and phagocytize pathogens - BUT they also cause some organ damage :( NETS are secreted out to trap and help contain microorganisms but also believed to damage endothelial cells and stimulate coagulation through BOTH intrinsic and extrinsic coag pathways! As blood cells try to get through fibrin mesh nets → they get traumatized!! We then get to see a see a schistocyte, a torn up RBC, which tells us fibrin nets are present secondary to clots - Ultimate result is microangiopathic hemolytic anemia (basically I am anemic because the only RBCs I have that hold by Hgb are all torn) Consequences → diffuse alveolar damage → return of ARDS! With sepsis we get neutrophil and cytokine induced damage to pulmonary endothelium and epithelium See: Clinical respiratory failure → decreased PaO2/FiO2 and pulmonary infiltrates Why is this happening? Diffuse alveolar damage : direct injury to pulmonary endothelium ○ Cytokine and neutrophil-mediated endothelial and epithelial lung damage ○ Coagulation induced inflammation and neutrophil adhesion Early: Increased vascular permeability – marked pulmonary edema Intermediate: type 1 pneumocyte epithelium is lost Hyaline membranes and type two pneumocyte hyperplasia Late (if pt survives): Fibrosis Pause: what happened with COVID19? - Hypercoagulative state skewed toward thrombosis - Multiple thrombi within small pulmonary arteries - System deep venous thromboses - Pulmonary emboli - Consumption of coagulation factors, low platelet count and bleeding less frequently found than in ordinary DIC - Very high D-dimers characteristic Anyways: what about sepsis causing cardiac dysfunction/failure? Once again we see cytokine-induced damage, hypoperfusion, mitochondrial dysfunction and myocardial cell adaptation SO with all of these we may see cardiac cells shutting down to conserve energy - When we shut down cardiac cells → decreased cardiac contractility & peripheral vasodilation SO we are furthering the already present hypoperfusion and ischemia problem Worst case scenario: evidence of myocardial ischemia, necrosis and infarction similar to atherosclerotic myocardial infarction - Coagulative necrosis (ischemic) - Contraction band necrosis (pressor effect) - Reperfusion injury with oxygen free radicals - Contributes to shock - In severe sepsis, there is marked vasodilatation and decreased myocyte contraction. Hypotension and direct myocyte injury are likely involved. Nitric oxide is an antimicrobial, anti-inflammatory agent but also a potent vasodilator and, paradoxically, may have a major role in evolution of septic shock What about sepsis and the liver? The liver is super important for the conversion of lactate back to glucose (gluconeogenesis) and Acetyl-CoA for entrance into oxidative metabolism. So, if liver fails, lactic acid will accumulate Early sepsis → see hyperglycemia Late sepsis → get major liver failure → hypoglycemia Worst case scenario here: Release of hepatic enzymes from necrotic cells → elevated lactic acid dehydrogenase (LDH) - Necrosis is most marked in the region near the central vein; so-called centrilobular necrosis (Zone 3 necrosis). This releases hepatic enzymes into the blood What about sepsis and the kidney? Multi-organ failure in sepsis is likely owing to many factors including both cytokine and neutrophil-induced injury and ischemia Cell adaptive changes Mitochondrial functional changes Shunting of blood flow Can see acute tubular necrosis with coagulative necrosis of the proximal tubule of the kidney! - This comes as a result of profound hypotension! - See edema & clinical renal failure Final bit about lactic acid: - Lactic acidosis (>2mmol/L) is not specific for sepsis - Hypoxia/ hypoperfusion may not be the main cause in sepsis! - Other stuff such as medications (e.g. metformin), liver failure, severe exercise, toxins, trauma and many others) - Lactic acidosis (=>4mmol/L) is an indicator of a critically ill patient with poor prognosis but not specific for sepsis - Serial measuring of lactate and therapy directly targeting lactic acid levels is controversial and utility has been questioned SHOCK! BP refresh: - Systolic BP is determined by the pressure built up when we contract - Diastolic pressure is when relaxes BUT pressure remains up For your MAP → Systolic-diastolic and take 1/3 of that and add it back onto the diastolic = mean arterial pressure! - If this is