SEPSIS.pptx

Pathophysiology of sepsis

1. Sepsis:pathophysiology Dr. Kanika Chaudhary 1

2. 2 OVERVIEW INTRODUCTION DEFINITIONS PATHOPHYSIOLOGY ORGAN RESPONSE REFERENCES

3. INTRODUCTION Sepsis affects more than 30 million people annually worldwide, and is one of the major causes of death in critical patients worldwide. Incidence of sepsis is as high as 1–2% of all hospitalized patients. Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376. 3

4. DEFINITIONS Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.   The word sepsis is derived from the Greek word for “decomposition” or “decay,” and its first documented use was about 2700 years ago in Homer’s poems It was subsequently used in the works of Hippocrates and Galen in later centuries In the 1800s, the “Germ theory” of disease was conceived and there was some recognition that sepsis originated from harmful microorganisms. 4

5. 1914: Hugo Schottmüller wrote that “sepsis is present if a focus has developed from pathogenic bacteria, constantly or periodically, invade the blood stream in such a way that this causes subjective and objective symptoms” Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.   DEFINITIONS 5

6. In 20th century, numerous experimental and clinical trials were able to demonstrate the importance of the host immune response to the manifestations of sepsis Finally, at a SCCM-ACCP conference in 1991, Roger Bone and his colleagues laid the foundation for the first consensus definition of sepsis. Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.   DEFINITIONS 6

7. Changing Definition of Sepsis 7

8. SIRS Sepsis Severe Sepsis Criteria A clinical response arising from a nonspecific insult, including  2 of the following: Temperature  38 o C, or  36 o C HR  90 beats/min Respirations  20/min WBC count  12,000/mm 3 , or 4,000/ mm 3 , or >10% bands SIRS plus a documented infection Sepsis as a Disease Continuum Sepsis plus organ dysfunction, hypoperfusion or hypotension Septic shock Severe sepsis plus persisiting hypotension despite adequate fluid resuscitation Modifed from consensus conference definitions of SIRS, sepsis and septic shock. American College of Chest Physicians / Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Critical Care Medicine 1992; 20 864-74. 8

9. Redefining Sepsis in 2016 Changes categories to sepsis and septic shock qSOFA (Quick SOFA) as a new diagnostic screening tool, 2 of 3 indicators: Alteration in mental status Systolic blood pressure < 100 mm Hg Respirations > 22 breaths/min Septic Shock Defined: Persisting hypotension requiring vasopressors to maintain MAP ≥ 65 mm Hg Blood lactate >2 mmol /L despite adequate volume resuscitation * Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287 Terms like septicemia / severe sepsis / SIRS has been REMOVED 9

10. Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.   10

11. Evolving Definitions of Sepsis 11

12. PATHOPHYSIOLOGY Sepsis is not only a process of systemic inflammatory response or immune disorder, it rather involves changes in the function of multiple organs in the body. Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376 12

13. Loss of h omeostasis in sepsis Fibrinolysis Endothelial dysfunction Inflammation Coagulation Loss of homeostasis Proinflammatory Mediators Endothelial injury Tissue factor expression Thrombin production Increase in Coagulation and inflammation Reduction in fibrinolysis 13

14. On the cellular and molecular levels, the pathogenesis of sepsis is complex which includes Imbalance in inflammatory response Immune dysfunction Mitochondrial damage Coagulopathy Neuroendocrine immune network abnormalities Endoplasmic reticulum stress, autophagy ORGAN DYSFUNCTION Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376 14

15. PATHOGENS/COMMENSALS-express microbial-associated molecular patterns (MAMPs)/pathogen- associated molecular patterns(PAMPs) Damaged/dead cells- Damage associated molecular patterns(DAMPs) MAMPs/PAMPs/DAMPs- bind to pattern recognition receptors (PRR) on host immune cells  1 . IMBALANCE IN INFLAMMATORY RESPONSE Activation of host immune cells(macrophages, monocytes, neutrophils and natural killer cells) HOST INITIAL RESPONSE 1. Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.  2. Oxford textbook of critical care 2 nd ed 3. Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376 15

16. Activation of host immune cells(macrophages, monocytes, neutrophils and natural killer cells) 1 . IMBALANCE IN INFLAMMATORY RESPONSE IMMUNE RESPONSE TO SEPSIS exogenous factors derived from the pathogen (e.g., lipopolysaccharide (LPS )) and endogenous factors released by injured cells (e.g., high-mobility group box-1 (HMGB-1) protein) interact with various PRRs , such as Toll-like receptors (TLRs), C-type lectin receptors (CLRs), RIG-I like receptors (RLRs), and NOD(nucleotide binding oligomeric domain)-like receptors (NLRs) 1. Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.  2. Oxford textbook of critical care 2 nd ed 3. Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376 16

17. 1 . IMBALANCE IN INFLAMMATORY RESPONSE exogenous factor: (LPS ) and endogenous factor: HMGB-1 protein interact with various PRRs , such as (TLRs), (CLRs), (RLRs), and (NLRs) Activation of intracellular signal transduction pathways Transcription and release of proinflammatory cytokines such as interleukin (IL)-1 , IL-6 , tumor necrosis factor-alpha (TNF-alpha), interferon (IFN) regulatory factor 7 (IRF7) and adaptor protein 1 (AP-1) 1. Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.  2. Oxford textbook of critical care 2 nd ed 3. Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376 17

18. Proinflammatory cytokines causes Activation and proliferation of leukocytes Activation of the complement system Upregulation of endothelial adhesion molecules and chemokine expression Tissue factor production Induction of hepatic acute phase reactants 1 . IMBALANCE IN INFLAMMATORY RESPONSE 1. Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.  2. Oxford textbook of critical care 2 nd ed 3. Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376 18

19. 1 . IMBALANCE IN INFLAMMATORY RESPONSE SEVERAL HOURS AFTER EXPOSURE TO INFECTIOUS STIMULI Apoptotic host cells (macrophages, dendritic cells, and natural killer cells) trigger the release of  HMGB1 HMGB1 binds to bacterial endotoxin(LPS) Bacterial endotoxin is transported to the cytoplasm through receptor for advanced glycation end- products  (RAGE) receptors expressed on vascular endothelial cells and macrophages 1. Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.  2. Oxford textbook of critical care 2 nd ed 3. Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376 19

20. 1 . IMBALANCE IN INFLAMMATORY RESPONSE Bacterial endotoxin causes cysteinase caspase-11-mediated cell death ( pyroptosis ) Shock, multiple organ failure, and death 1. Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.  2. Oxford textbook of critical care 2 nd ed 3. Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376 20

21. 2. IMMUNE DYSFUNCTION The initial proinflammatory state of sepsis is often superseded by a prolonged state of immunosuppression. Decrease in the number of T cells (helper and cytotoxic) as a result of apoptosis and a decreased response to inflammatory cytokines Global depletion of CD4+ and CD8+ T cells, mostly in the lymphoid organs such as the spleen Decreased production of cytokines such as IL-6 and TNF in response to endotoxin A low lymphocyte count early in sepsis (day 4 of diagnosis) is predictive of both 28-day and 1-year mortality and early lymphopenia serve as a biomarker for immunosuppression in sepsis Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.   21

22. 3. MITOCHONDRIAL DAMAGE Sepsis Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376 Decreased oxygen supply, incomplete oxidative reaction, hypoxia and damaged antioxidant machinery Host immune cells exposed to DAMPs or PAMPs Activate the leukocytes Release inflammatory cytokines 22

23. 3. MITOCHONDRIAL DAMAGE Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376 Cytokines Increases inducible nitric oxide synthase ( iNOS ) activity Overproduction of reactive nitrogen species (RNS) and NO NO bind to ROS peroxides to form RNS Irreversible inhibition of electron transfer chain (ETC) activity 23

24. 3. MITOCHONDRIAL DAMAGE Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376 Irreversible inhibition of electron transfer chain (ETC) activity Additional ROS production Mitochondrial damage, mitochondrial matrix swells and mitochondrial membrane ruptures INIATIATION OF APOPTOSIS 24

25. 4. COAGULOPATHY SEPSIS Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.   Endothelial dysfunction due to complement activation ENDOTHELIOPATHY Release of tissue factor 25

26. 4. COAGULOPATHY Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.   Release of tissue factor Activation of the coagulation cascade Production of thrombin, activation of platelets, and formation of platelet–fibrin clots Microthrombi formation Tissue hypoxia and organ dysfunction 26

27. 4. COAGULOPATHY Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.   SEPSIS Decreased plasma levels of protein C, downregulation of thrombomodulin, and low levels of protein S Unregulated propagation of the coagulation cascade 27

28. 4. COAGULOPATHY Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.   SEPSIS Increase in TNF α and IL-1 β levels, increase in plasminogen activator inhibitor type 1 (PAI-1) Diminished fibrinolysis and fibrin removal Microvascular thrombosis 28

29. 5. NEUROENDOCRINE–IMMUNE NETWORK ABNORMALITIES The central nervous system responds to sepsis through three main mechanisms: (1) the autonomic nervous system, in which primary afferent nerves ( vagus and trigeminal nerves) and sensory nerves are associated with PAMPs and lead to inflammatory cytokine activation (2) circulatory inflammatory mediators, via the choroid plexus and the ventricle organs connected to the central nervous system (3) by means of activation of endothelial cells through the blood–brain barrier, causing the release inflammatory mediators (NOS metabolites) Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376 29

30. 6. ENDOPLASMIC RETICULUM STRESS The endoplasmic reticulum (ER) is an intracellular organelle that is involved in protein translocation, folding, posttranslational modification and further transport to the Golgi apparatus The unfolded or misfolded proteins are accumulated in the ER during sepsis, altering its homeostasis, and leading to oxidative stress and severe calcium disorders that result in ER stress Under ER stress, unfolded protein response sensors switch their signals to stimulate the cell death Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376 30

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32. 32 ORGAN RESPONSE CELLULAR RESPONSE:- Inadequate tissue perfusion Reduced amount of both oxygen and substrate Shift from aerobic to anerobic metabolism Lactic acid accumulation , fall in pH  metabolic acidosis Cell membrane dysfunction and associated increase in intracellular sodium and water

33. 33 Swelling of mitochondria and other intracellular organelles including lysosomes If this process continues cell membranes break down and enzymes are released, causing destruction of the cell and local tissue damage Proteolytic enzymes released from damaged cells initiate formation of plasma kinins , activation of intravascular coagulation and activation of complement Kinins increase capillary permeability, dilate small blood vessels and depress myocardial function

34. 34 2. MICROCIRCULATION:- Impairment of the microcirculation  derangement of cellular metabolism  organ failure Failure of the integrity of the endothelium of the microcirculation  capillary leak  intracellular swelling  the development of an extracellular fluid deficit  decreased capillary hydrostatic pressure  loss of extracellular fluid volume

35. 35 Capillary dysfunction also occurs secondary to activation of endothelial cells by circulating inflammatory mediators generated in sepsis  exacerbates endothelial cell swelling and capillary leak, as well as increases leukocyte adherence  capillary occlusion 2. MICROCIRCULATION:-

36. 36 3. NEUROENDOCRINE RESPONSE:- Hypotension  disinhibits the vasomotor center  increased adrenergic output and reduced vagal activity. Release of norepinephrine  peripheral and splanchnic vasoconstriction R educed vagal activity  increases the heart rate and cardiac output Loss of vagal activity  upregulate the innate immune inflammatory response E pinephrine  increased glycogenolysis and gluconeogenesis and reduced insulin release

37. 37 4. CARDIOVASCULAR RESPONSE Hypovolemia Decreased ventricular preload  decreased stroke volume Increased catecholamine release from adrenal medulla Increased heart rate and contractility

38. 38 5. PULMONARY RESPONSE:- S timulation of pulmonary J receptors and carotid body chemoreceptors, hypo-perfusion of the medullary respiratory center  increased minute volume (tachypnea, hyperpnea ), hypocapnia and primary respiratory alkalosis. I ncreased minute volume and decreased cardiac output  increased V/Q ratio

39. 39 6. RENAL RESPONSE:- Hypoperfusion Decreased renal blood flow, particularly blood flow to cortex Activation of RAAS Aldosterone release by adrenal cortex and vasopressin by posterior pituitary Reduced GFR +increased aldosterone and vasopressin= OLIGURIA

40. 40 The net effect is a decreased glomerular filtration rate. The three pathologic changes seen are (a) Tubular necrosis (b) Tubular obstruction by casts or debris and (c) Tubular epithelial damage 6. RENAL RESPONSE:-

41. 41 7. GASTROINTESTINAL:- Ileus, erosive gastritis,pancreatitis , acalculous cholecystitis and colonic submucosal hemorrhage Enteric bacteria and antigens translocate from the gut lumen into the systemic circulation during gut ischemia causing irreversible shock 8. LIVER:- Centrilobular injury with mild increases of transaminases and lactate dehydrogenases usually peaks in 1-3 days of ischemic insult and resolves over 3-10 days Shock liver associated with massive ischemic necrosis and a major elevation of transaminases is atypical in the absence of extensive hepatocellular disease

42. 42 9. HEMATOLOGICAL DISTURBANCES:- Trigger Coagulation activation Intravascular coagulation Consumption of clotting factors & platelets Fibrin deposition Fibrinolysis Fibrin degradation products HAEMORRHAGE Microvascular thrombosis ORGAN DYSFUNCTION

43. 43 10. METABOLIC DISTURBANCES:- D isruption of the normal cycles of carbohydrate, lipid, and protein metabolism Anaerobic metabolism  lactate Increased hepatic gluconeogenesis Hepatic lipogenesis Increased Triglycerides Protein catabolism Muscle wasting

44. 44 TAKE HOME MESSAGE New definition of sepsis and septic shock. Terms like septicemia / severe sepsis / SIRS has been REMOVED Sepsis is an overactivation of immune response Homeostasis is not maintained Three main processes involved in the septic response: Inflammatory process Coagulation Fibrinolysis

45. 45 1.Robbin’s Basic pathology, 9 th ed 2.Harrison’s principle of internal medicine, 19 th ed 3. Oxford textbook of critical care 2 nd ed 4.Wylie and Churchill-Davidson's A Practice of Anesthesia , 5 th ed 5. Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. International journal of molecular sciences. 2019 Jan;20(21):5376. 6. Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management.  SAGE Open Medicine . January 2019.  7. Modifed from consensus conference definitions of SIRS, sepsis and septic shock. American College of Chest Physicians / Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Critical Care Medicine 1992; 20 864-74 8. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287 9. Chang JC. Sepsis and septic shock: endothelial molecular pathogenesis associated with vascular microthrombotic disease. Thromb J. 2019 May 30;17:10. doi : 10.1186/s12959-019-0198-4. PMID: 31160889; PMCID: PMC6542012. REFERENCES

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