Sepsis and Shock PDF

Systemic inflammatory response syndrome (SIRS) Sepsis Septic shock 1. A cytokine civil war is being waged in the body between pro- and anti-inflammatory forces a) However, both have beneficial and harmful effects! 2. Consensus conference...

Systemic inflammatory response syndrome (SIRS) Sepsis Septic shock 1. A cytokine civil war is being waged in the body between pro- and anti-inflammatory forces a) However, both have beneficial and harmful effects! 2. Consensus conference civil war over definitions and language and treatment protocols is being waged as well 10/2/2024 Vicki J. Schnadig, M.D. ([email protected]) 1 Professor Emerita, UTMB Department of Pathology  Aphorisms for 21st Century 1. “Half of what you’ll learn in medical school will be shown to be either dead wrong or out of date within five years of your graduation; the trouble is that nobody can tell you which half—so the most important thing to learn is how to learn on your own.” David Sackett 2  Aphorisms for 21st Century 2. “Without clinical expertise, practice risks becoming tyrannised by evidence,....”Evidence- based medicine is not ”cookbook medicine”. Because it requires a bottom up approach that integrates the best external evidence with individual clinical expertise and patients' choice...” * *Sackett DL et al. Evidence-based medicine: what it is and what it isn’t. BMJ 1996;312:71-72 Underlying is mine. Note: D. Sackett is considered the father of EBM. 3  Aphorisms for 21st Century 3. “.. in the complex condition of sepsis nothing will ever replace the well trained, experienced, thinking physician who takes all of the available information at the bedside and then makes a decision.” László et al. Sepsis: from pathophysiology to individualized patient care. J Immunol Res 2015; 2015;2015:510436. doi: 10.1155/2015/510436. Epub 2015 Jul 15. Review 4  Aphorisms for 21st Century 4. “For adults with suspected sepsis or septic shock but unconfirmed infections we recommend continuously re-evaluating and searching for alternative diagnoses..” Best Practice Statement “no [gold standard] test to diagnose sepsis” in the setting of organ dysfunction. Need to have differential. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 5 https://doi.org/10.1007/s00134-021-06506-y  SIRS and Sepsis Definitions 1. SIRS (1991): Systemic inflammatory response to infection or other insult (such as trauma, burn, or pancreatitis) 1. Sepsis=SIRS with an infectious etiology 2. Severe sepsis - sepsis with organ dysfunction 3. Septic shock- sepsis induced hypotension despite fluids 2. Sepsis 3 ( Terms SIRS and severe sepsis are no longer used): Life threatening organ dysfunction caused by a dysregulated host response to infection. Note: Use of term sepsis indicates infectious or probable infectious etiology! 6  SIRS and Sepsis Definitions 2. Sepsis 3* ( Terms SIRS and severe sepsis are no longer used): Sepsis-Life threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock-A subset of sepsis cases in which underlying circulatory and cellular/metabolic abnormalities are profound enough substantially increase mortality risk. Need to elevate mean arterial pressure (MAP) to ≥ 65 mmgHg and lactate >2 mmol/L after adequate fluid resuscitation. Singer M et al. The third international consensus definitions for sepsis and septic shock. JAMA 2016;315:801-10 doi:10.1001/jama.2016.0287 7  What is Sepsis? Simplified explanation:* a) The body reacts to infection with release of a combination of pro-inflammatory and anti- inflammatory cytokines, other mediators and adaptive bioenergetic changes. b) 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 unauthorized edition ** Severe trauma and non- 8 infectious organ injury can cause the same reaction.  What is SIRS or Sepsis? Simplified explanation:* c) The anti-inflammatory forces aim to help halt the deleterious effects of inflammation: HOWEVER- these forces can lead to immunosuppression and superinfection (infection with other organisms) Internal civil war or a power struggle between pro-inflammatory and anti-inflammatory mediators aided and abetted by cell adaptive responses * The unauthorized edition 9  The Sepsis/SIRS spectrum 1. Early stage: Recognition crucial for successful treatment but symptoms and signs are non-specific (SIRS) 2. Severe stage: Hypotension and organ dysfunction- Sepsis 3. Shock: Severe hypotension (requiring pressors) and multi-organ failure-Septic shock 10  History Time The Conception, Birth and Childhood of Sepsis 11  Sepsis I (Sepsis Syndrome)* Sepsis syndrome idea conceived in 1980 in a hotel room in Las Vegas* Chicago 1991consensus criteria for sepsis syndrome– birth of SIRS – SIRS/Sepsis- early stage – Severe Sepsis-hypotension and organ dysfunction – Septic Shock-Severe hypotension needing therapy to maintain blood pressure – End game-irreversible multi-organ failure *Laszlo I et. al. Sepsis from pathophysiology to individualized patient care. J Immunol Res. 2015;2015:510436. doi: 10.1155/2015/510436. Epub 2015 12 Jul 15. Review Systemic inflammatory response syndrome (SIRS): Originally defined as patient with at least 2 of the following : 1. Oral temperature > 38°C or 12,000/μL or 10% immature WBC-leukocytosis or leukopenia or left shift 5. Hyperglycemia in the absence of known diabetes 13  Systemic Inflammatory Response Syndrome (SIRS) SIRS criteria somewhat sensitive but not specific 1. Advantages: 1. Can allow for initiation of therapy at an early stage that should improve outcome 2. Does not exclude non-infectious problems such as pancreatitis or trauma that can have similar signs 2. Disadvantages: 1. Non-specific and aggressive sepsis treatment can be harmful for non-septic patients. 2. Not always sensitive, especially in some groups 14  Common Sense and Clinical Judgment Needed Not sepsis: Rapid breathing and tachycardia after running to catch a bus Not Sepsis: Elevated white blood cell count in patient with chronic leukemia Not Sepsis: Uncomplicated influenza with fever, myalgia and mild leukopenia Concept borrowed from Dellinger et al. To Sirs with love. Crit Care Med 1998;26:178-179 15  Common Sense and Clinical Judgment Needed Sepsis: Patient with influenza who is lying in bed with fever, tachypnea, tachycardia and somnolence and who looks really really sick is very probably septic. Concept borrowed from Dellinger et al. To Sirs with love. Crit Care Med 1998;26:178-179 16  Some reasons that sepsis is such a $%%# problem Best chance for good outcome is early recognition Owing to heterogeneous presentations, early accurate recognition of sepsis is very difficult! On the other hand, aggressive treatment of non-septic can be harmful. “as the physicians say of hectic fever, that in the beginning of the malady, it is difficult to detect but easy to treat, but in the course of time having neither detected nor treated in the beginning, it becomes easy to detect but difficult to treat.” Machiavelli, The Prince 1532. Quoted in Simpson SQ. SIRS in 17 the time of sepsis-3. Chest 2018;153:34-37 “The truth is rarely pure and never simple” Oscar Wilde The Third International Consensus Definitions for Sepsis and Septic Shock. JAMA 2016;315:810-810 AKA Sepsis-3 Sepsis: Life-threatening organ dysfunction caused by a dysregulated host response to infection Septic Shock: Treatment required to maintain systolic blood pressure and deal with lactic acidosis (we will discuss lactic acid measurement controversy later) Note: SIRS and Severe Sepsis deleted from Sepsis 3 lexicon 18 FIGURE 2. Sepsis can affect functioning of multiple organs within the body to varying degrees. (Figure created with BioRender.com). From: Arina P, Singer M. Pathophysiology of Sepsis. Curr Opin Anesthesiol 19 2021, 34:77–84 DOI:10.1097/ACO.000000000000 “The truth is rarely pure and never simple” Oscar Wilde The Third International Consensus Definitions for Sepsis and Septic Shock. JAMA 2016;315:810-810 AKA Sepsis-3 Criteria for sepsis: Sequential organ failure assessment (AKA SOFA) Used to predict risk of mortality In ICU: Multiple tests to determine organ dysfunction/failure Outside ICU: So-called quick SOFA (AKA qSOFA) just measures respiratory rate, mental status and blood pressure* * Recently not recommended for screening by new Surviving 20 Sepsis owing to poorer sensitivity How to Predict Probability that Patient will become Septic in the Clinic or Outside the Hospital??????? Big difficult question - views differ SIRS/qSOFA/NEWS* Common sense answer: Get a thorough history- physical as needed-use your best clinical judgement guided by one of the above and Learn and be guided by your teachers *National Early Warning Score 21  “The truth is rarely pure and never simple” Oscar Wilde Some reasons that sepsis is such a $%%# Sepsis involves a combination of both pro- inflammatory immune system activation and immunosuppression and cell adaptive responses Immunosuppressive therapy such as glucocorticoids and therapy specifically targeting coagulation or organ dysfunction-associated proteins or cytokines have not proven consistently beneficial Different patient populations, different bugs and 22 different virulence of bugs  “The truth is rarely pure and never simple” Oscar Wilde Obfuscating Data Mortality statistics vary with different countries and populations (mortality 20-50%) – Over classification of sepsis owing to varied use of coding, MEWS* and fear of missing cases likely has led to false estimates of reduced mortality.** – In countries where access to adequate healthcare facilities and documentation is limited, deaths from sepsis are likely higher than acknowledged *Modified early warning score **Rhee CJ , Klompas M. Sepsis trends: increasing incidence and decreasing mortality, or changing denominator? Thorac Dis 2020;12(Suppl 1):S89-S100 23 | http://dx.doi.org/10.21037/jtd.2019.12.51 Potential Harms of Rush to Diagnose Sepsis “Lacto-biotic Reflex” 1 1. Overuse of antibiotics leading to increased emergence of drug-resistant microorganisms1 2. Failure to think of other diagnoses leading not just to overuse of sepsis protocol but to delay in making correct diagnosis1,2 3. Overestimates of sepsis incidence and underestimates of true sepsis mortality rate 1. Weinberger J, et al. What is the utility of measuring lactate levels in patients with sepsis and septic shock? Semin Respir Crit Care Med. 2021;42:650- 661 DOI https://doi.org/ 10.1055/s-0041-1733915 2. Rhee C et al. Infectious disease society position paper: recommended revisions to the national SEP-1 sepsis quality measure. Clinc Infect Dis. 2021:72:541-552 DOI: 10.1093/cid/ciaa059 24  Sepsis and the “Lacto-bolo Reflex” 1 “ The lacto-bolo reflex ,a well-known pathological reflex observed in the majority of house staff and a large portion of attending physicians.”1 1. Many or most lactate elevations in sepsis are not related to tissue hypoperfusion 2. ?? Is lactate level guided aggressive fluid actually more likely to be harmful or unhelpful? 1. Spiegel et al. The origins of the lacto-bolo reflex: the mythology of lactate in sepsis. J Thorac Dis. 25 2020;12:S48-53. doi: 10.21037/jtd.2019.11.48.  Suggestions from some clinicians in the trenches 1. Immediate antibiotics (after cultures) for very sick patients with suspected or possible bacterial infection and shock or very high lactic acid levels. 2. Continue to monitor, stop or de-escalate antibiotics as indicated clinically 3. Uncertain of diagnosis and not too sick yet. Consider alternative dx, evaluate for other diagnoses and continue to monitor Revisions to the national SEP-1 sepsis quality measure. Clin Infect Dis. 2021:72:541-552 DOI: 10.1093/cid/ciaa0 2. Prescott HC et al. Improving sepsis treatment by embracing diagnostic 26 uncertainty. Ann Am Thorac Soc 2019;16:426–429, No gold standard for sepsis diagnosis! Many non-infectious conditions can mimic sepsis; some can significantly elevate serum lactic acid! Acute pancreatitis Burns and inhalation injury Acute trauma Myocardial infarction Heat stroke Medications Diabetic ketoacidosis 27  Causes of Sepsis Bacterial pneumonia most common cause – Followed by intra-abdominal and urinary tract infections Both Gram positive and Gram negative bacteria are common causes of sepsis – USA: 1979-2000 Gram positives predominated – Europe: Recently Gram negatives predominated Fungi, viruses, mixed organisms less common Angus DC, van der Poll, Severe sepsis and septic shock. New Engl J Med. 2013;369:840-9. 28  PAMPs and DAMPs What gets sepsis/SIRS started? Innate immune system responds to either – Pathogen-associated molecular patterns (PAMPS) Molecules derived from microbes or microbial toxins that elicit an innate immune response – Damage-associated molecular patterns (DAMPS) Danger signal molecules derived from necrotic cells that elicit a response similar to PAMPS 29  Superantigens What gets sepsis/SIRS started? Bacterial proteins, usually toxins, that can cause polyclonal T-cell activation that results in massive cytokine release. – Staphylococcus aureus – Toxic shock syndrome – Streptococcus pyogenes (group A strep) – Streptococcal toxic shock 30  PAMPs and DAMPs What gets sepsis/SIRS started? PAMPS /DAMPS bind with TLRs or other receptors Intranuclear translocation of nuclear factor kappa B (NF-kB) resulting in release of multiple cytokines, complement activation and cell proliferation stimulation. Cell and organ function alterations that can lead to multiorgan dysfunction and shock Concomitant or subsequent activation of immune suppressive systems Review of PAMPS and DAMPS can be found in Robbins or more detail in Abbas, Basic Immunology. Also see Figure 4.21 in Robbins, Chapter4, page 136 31  Some Examples Gram negative bacteria: Lipopolysaccharide LPS binds to macrophage CD14 and Toll-like receptors TLR4) with release of transcription proteins and pro-inflammatory cytokines Gram positive bacteria: Peptidoglycans and lipoteichoic acid: Bind Toll- like receptors (TLR2) and also generate pro-inflammatory cytokines 32  Necrosis also activates immune system via DAMPS Damage – associated molecular patterns (danger molecules) also recognized by toll-like receptors May explain why SIRS and Septic-shock-like conditions may occur with trauma or other causes of tissue necrosis such as pancreatitis DAMPS can also be produced by sepsis-associated cell necrosis 33 Let’s look at some theories about mechanism of organ dysfunction/failure Neutrophils Called in as first line of defense to phagocytize and kill but also cause organ damage Neutrophil extra-cellular traps - help contain microorganisms but also believed to damage endothelial cells and stimulate coagulation and intravascular thrombosis 34  Sepsis-Induced Coagulopathy (SIC) SIC is sepsis (inflammation) induced activation of coagulation that may progress to disseminated intravascular coagulation (DIC) DIC/SIC systemic activation of coagulation system with widespread thrombosis, fibrinolysis, consumption of coagulation factors resulting in bleeding. Complex process but damage to endothelium and production of pro-coagulation factors and probably NETS important. Thrombosis-bleeding-petechiae, purpura and organ hemorrhage 35 Fibrin thrombi within glomerular capillaries. In image on right, fibrin stains red. In DIC, there are intravascular thrombi (where coagulation should not occur). These can sometimes be seen at autopsy as fibrin thrombi within capillary blood vessels and contribute to tissue ischemia and necrosis and multiorgan failure! 36 Fibrin microvascular thrombi traumatize erythrocytes as they pass through the small blood vessels. Result is microangiopathic hemolytic anemia. The above cell (arrow) is called a schistocyte an is a torn up erythrocyte traumatized by 37 passage through fibrin net. Petechia and purpura in kidney and ureter Massive adrenal hemorrhage Classic Waterhouse-Friderichsen Syndrome Consumption of clotting factors and platelets Bleeding caused by decreased platelets and other 38 coagulation factors and increased vascular permeability  Diffuse Alveolar Damage- Acute Respiratory Distress Syndrome Neutrophil and cytokine induced damage to pulmonary endothelium and epithelium Clinical respiratory failure - decreased PaO2/FiO2 and pulmonary infiltrates Pathology: Diffuse alveolar damage Early: Increased vascular permeability – marked pulmonary edema Intermediate: Hyaline membranes and type two pneumocyte hyperplasia Late (if pt survives): Fibrosis 39 Diffuse Alveolar Damage: Direct injury to pulmonary endothelium and later to type I pneumocyte epithelium Neutrophils, Cytokines, Ischemia 1. Cytokine and neutrophil- mediated endothelial and epithelial lung damage 2. Coagulation induced inflammation and neutrophil adhesion 40 Diffuse Alveolar Damage: This is what the pathologist sees at autopsy. Wt 325 gm Wt 900 gm 41 Normal Lung Early stage of Diffuse alveolar damage  Intra-alveolar edema Hyaline membrane Diffuse alveolar damage leads to failure to oxygenate blood and 42 widespread tissue hypoxia Covid 19: Lung at autopsy. This finding is uncommon in bacterial and other types of viral sepsis. 43  Covid 19- original version Sepsis with a Difference 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 44  Sepsis and Cardiac Dysfunction/Failure Again, it’s complicated Combination of cytokine-induced damage, hypoperfusion, mitochondrial dysfunction and myocardial cell adaption – Cells may shut down some operations and proliferation in order to conserve energy similar to cell hibernation Decreased cardiac contractility and peripheral vasodilation contribute to systemic organ hypoperfusion and ischemia 45  Impaired Myocardial Function Impaired myocardial contractility 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 Contributes to shock 46 The left shows coagulative necrosis and hemorrhage typical of ischemic necrosis with reperfusion. The right is contraction band necrosis as is seen in reperfusion free radical injury. In severe sepsis, there is marked vasodilatation and decreased myocyte contraction. Hypotension and direct myocyte injury are likely involved. Nitric oxide is an anti-microbial, anti-inflammatory agent but also a potent vasodilator and, paradoxically, may 47 have  Hepatic Changes in Sepsis Functional: Liver important in conversion of lactate back to glucose (gluconeogenesis) and Acetyl-CoA for entrance into oxidative metabolism. So, if liver fails, lactic acid will accumulate. Early in sepsis, may have hyperglycemia Late, with liver failure, hypoglycemia 48  Massive hepatic necrosis Worse case scenario Normal Release of hepatic enzymes from necrotic cells Elevated lactic acid dehydrogenase (LDH) Patient liver enzyme elevations: Aspartate aminotransferase (AST) 800 IU/L (normal 10-40), alanine aminotransaminase ALT–936 IU/L (normal 7- 56) 49 Necrosis most marked in the region near the central vein; so- called centrilobular necrosis (Zone 3 necrosis). This releases50 New Ideas About Acute Renal Injury in Sepsis 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 Pathologist may see acute tubular necrosis but often no pathologic changes at autopsy of patients with clinical renal failure There likely is more going on at the subcellular and chemical level 51  Pathology of classic acute tubular necrosis Coagulative necrosis of proximal tubules Effect of profound hypotension on kidneys: Acute tubular injury ❑ Edema ❑ Clinical renal failure 52  Lactic Acid Measurement Obsession and Controversy1 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 1.Weinberger J et al. What is the utility of measuring lactate levels in patients with sepsis and septic shock? Semin Respir Crit Care Med. 2021;42:650-661 53 DOI https://doi.org/ 10.1055/s-0041-1733915.  Sepsis Conundrum Defining sepsis, recognizing it early enough for a good outcome and treating it is really tough! Aggressively treating non-septic patients with sepsis protocols may be harmful! “.. in the complex condition of sepsis nothing will ever replace the well trained, experienced, thinking physician who takes all of the available information at the bedside and then makes a decision.” László et al, cited previously 54 Questions???? 55 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