Sepsis

1. Sepsis

2. Sepsis

3. Epidemiology

4. Epidemiology

5. The # of hospitalizations for sepsis is greater than those for acute myocardial infarction. • Sepsis is responsible for more deaths than the combined # of deaths annually in the U.S. from AIDS, prostate and breast cancer. • Severe sepsis is the most expensive condition treated in U.S. hospitals. Increasing Incidence

6. Epidemiology

7. Mortality

8. Animal models consistently demonstrate male sex as a risk factor for adverse outcomes in infection. Clinical data conflicts This may be due to gender differences in care, database sources, study design or comorbidities. Mortality: Is Female Sex Protective?

9. Risk Factors

10. Burn incidence > in Male sex associated w/ sepsis post-trauma Burns & Trauma Preexisting Diabetes Approx. 20% of sepsis patients have DM Tight glycemic control risk of post-op infection Poorer glycemic control observed in Risk of severe sepsis 15x greater in patients with hematological malignancy observed Cancer Incidence of hematological cancers > in > 65 yrs. of age is independent risk factor + predictor of mortality Age • Surgical site infections post- • abdominal surgery > • cardiac surgery > Surgical sepsis accounts for approx. 30% of sepsis cases Surgery Gendered-based treatment disparities? Conflicting clinical data Sex & Gender Risk Factors

11. Respiratory infections + Gram positive infections higher in Higher incidence of sepsis with respiratory infections, particularly pneumonia Infection > Proportion of glucocorticoid users are Immunosuppression Predictor of early mortality Chronic Kidney Disease  Risk of infection due to chronic inflammatory + immunodeficient state Higher prevalence in Acute/chronic alcohol exposures suppress immune function,  risk of bacterial translocation in gut Alcohol > rates of alcohol related hospitalizations 30% to 50% of cirrhoticspresent with bacterial infections on admission Cirrhosis Higher prevalence in Risk Factors

12. Genetics

13. Microbiology

14. Sepsis may occur from any type of bacterial, viral or fungal infections. • Bacterial infections are the most common source of sepsis.2 • Gram-positive superseded Gram-negative infections in the 1980s as leading cause of sepsis in the U.S.3 • Clinical data reflects significantly lower rates of Gram-positive bacteremia's in females1,4,5 but higher rates of E. coli bacteremia.6 Pathobiology

15. Source of Infection

16. Anatomy & Pathology

17. Pathophysiology

18. PAMPs DAMPS HSPs Fibrinogen Hyaluronan Biglycan DNA RNA IL-1a, IL-33 MRP8/14 PRRs LPS LTA Lipopeptide Peptidoglycan Flagella DNA RNA • Impaired immune functioning • Impaired phagocytosis • Expansion of Tregs and myeloid suppressor cells Septic Response Complement activation Cytokines (IL-1, IL-2, IL-6, IL-8, IL-15, TNF-α), prostaglandin, leukotriene, oxidative species, kinins, histamine, etc. • Inhibition of proinflammatory gene transcription • Anti-inflammatory cytokines • Soluble cytokine receptors • Neg. regulators of TLR signaling • Nitric oxdide Coagulation activation Cell injury/death Neuroendocrine regulation Immune Response Proinflammatory response  inflammation, tissue damage Immune suppression  Susceptibility to secondary infection

19. Sex Hormones

20. The human immune system is sexually dimorphic. Male and female sex steroids demonstrate significant immune-modulating properties in humoral and cell-mediate responses. Sex Differences in Immunity

21. Both immunosuppressive & immunostimulating depending on dose & condition • Immune effect + cytoprotection  improved cell mediated disease / worsened antibody mediated disease Estrogens • Anti-inflammatory Progestogens • Beneficial to autoimmunity • Generally Immunosuppressive Androgens • Beneficial to autoimmunity Sex Hormones

22. Sex Steroids & Immunity Effects of Estrogen Effects of Testosterone Effects of Progesterone

23. High levels of estrogen  increase anti-inflammatory effect Low levels of estrogen  increase proinflammatory effect • Increases the activity of humoral immune response1 • Enhances NK cell cytotoxicity, stimulates synthesis of proinflammatory cytokines IL-1, IL-6 and TNFɑ • Modulates all subsets of T Cells that include CD4+2 • Alters macrophage function via regulation of chemotaxis, phagocytic activity and induction of iNOS and NO2 • Plays a role in the activity of Treg cells which are critical in the down regulation of immune responses • Estrogen treatment dose-dependentlyreverses cytotoxic effects of TNFɑ in T Cells3 Estrogens & Immunity

24. Testosterone • 5α-dihydrotestosteroenegativelyinfluences cell-mediated and humoral immunity.1 • Androgens inhibit B and T cell maturation2 • Testosterone increases IL-10 production • Testosterone suppresses pro-inflammatory cytokine1-3 • Decreases auto-antibody production4 • IncreasesTreg levels4 Androgens in Immunity

25. Prolactin has proinflammatory properties1 Enhances proliferation of lymphocytes and macrophages1,2,6 • Early observational and animal studies show that prolactin may have a role in acute stress hormonal response2,3 in the early-onset inflammatory processand in autoimmunedisease1 • Prolactin’s role in the immune response to infection or sepsis may be dose-dependent.4,5 Prolactin

26. Circulating levels of estrogen changes throughout the female lifespan with notable effects on female immune system. • Menopause  lower levels of estrogen stimulates proinflammatory pathways (TNFɑ, IL1-ß), and reduced total lymphocytes, and reduced CD4+/CD8++ ratios are observed post-menopause Possible loss of protective effects of estrogen6 • Premenopausalstatus has been found to be associated with survival advantage in several large ICU studies.2,3 • Further studies have observed that postmenopausalwomen no longer see survival advantage. 3-5 Menopause

27. Diagnosis

28. SEPSIS SEVERE SEPSIS SEPTIC SHOCK Sepsis-3 New Guidelines

29. Sequential [Sepsis-related] Organ Failure Assessment (SOFA) A mortality prediction score based on degree of dysfunction in 6 organ systems. • Calculated on admission and q 24hrs • ∆ in SOFA scores useful in monitoring organ dysfunction • Does not considerpatientsex SOFA Score *With Respiratory Support **Administered for at least 1 hr (g/kg/min)

30. Sepsis-3 Quick SOFA (qSOFA) Modification of SOFA scoring for more rapid evaluation of patients for possible sepsis. If patient has 2 or more qSOFA criteria  recommend closer evaluation and possible referral to critical care. • A Swedish cohort study found SOFA score on admission to be a stronger risk factor for hospital mortality for women. • Mainly related to coagulation and renal sub-scores Screening

31. Clinical Manifestations

32. Sepsis is dynamic and clinical manifestations may change through the course of the phenomena. • INFECTION • Suspected infection,incision, trauma, • T >38ºC or < 36ºC • Elevated WBC, bands • Tachycardia • NEW ORGAN DYSFUNCTION • qSOFA2 • Tachypnea • Encephalopathy, ∆ LOC • Hypotension MAP <65 mm Hg • Coagulation dysfunction • Decreased urine output/acute increase in creatinine • Acidosis Clinical Manifestations

33. Cardiovascular Hypotension due to vasodilation, Reduced contractility • Pulmonary • PaO2/FiO2 • Diffuse alveolar damage, ARDS Renal AKI,  Creatinine, Urine output, edema Elevated transaminases, bilirubin, hypoglycemia,  coagulation factors , jaundice Hepatic Encephalopathy,  Glasgow Coma Scale score, temperature instability CNS New Organ Dysfunction

34. Widespread intravascular coagulation with potential for thrombosis and hemorrhage • Spectrum of organ dysfunction, from mild dysfunction to irreversible organ failure • Circulatory and cellular/metabolic abnormalities profoundly increase mortality • Life-threatening organ dysfunction caused by dysregulated host response to infection Complications

35. Cardiovascular dysfunction in sepsis is an important component of multiorgan failure. • contractility and impaired myocardial compliance, left ventricular dysfunction • CO, CI and EF • Increased cardiac troponin levels2 • Increased circulating inflammatory cytokines (IL-1, IL-8 & TNFα associated w/altered production of NO) • Disturbed oxygen utilization • Metabolic alterations in septic myocardium • Increased lactate extraction, glucose uptake Cardiovascular Effects

36. Estrogen •  increases nitric oxide (NO) production • NO reduces neutrophil accumulation, is a vasodilator and is beneficial at low levels. Sepsis leads to expression of iNOS which significantly increases NO causing myocardial dysfunction • Animal studies show female mice have reduced expression of iNOS compared to males •  Estradiol inhibits TNF-ɑ and IL-6 production in mice •  Estradiol activates cardiac Aktreduction in cardiac dysfunction •  Animal studies demonstrate 15ß estradiol and prolactin levels are associated with improved myocardial contractility following hemorrhage or trauma. (Legato p295). Estrogen, Cardiovascular Effects & Sepsis

37. Cardiovascular: Sex Differences Figure 1. Schematic illustration of the effect of gender on cardiovascular performance and cellular immunity following trauma and severe blood loss.

38. In a prospective study, a serum level of estradiol > 40 pg/mL and APACHE II score ≥ 25 were found to be independent predictors of day 28 mortality and concomitant AKI1 • Serum estradiol and progesterone levels significantly increased in non-survivors of pneumonia-related septic shock patients and may be a novelmarkertopredictnewAKI in septic shock patients. • While estrogen generally provides immuno-protection, super-physiologic levels of estrogen and progesterone may negatively influence outcome, possibly due to increase NO production 60–70% of patients who develop septic shock also develop acute kidney injury (AKI). Women with sepsis are less likely to receive hemodialysis2 Renal

39. Estradiol and New Onset AKI

40. Sepsis • Diagnosis & Treatment • EEG • Manage underlying cause • Manage seizures (rare) and coma Cytokines  BBB alterations  Humoral pathway Neural pathway Microglial activation Metabolic disturbances -glucose dysregulation -electrolyte imbalance -fever -hypoxia  Circulatory Failure -hypotension -CBF disturbance Acute brain dysfunction Environment, medications Encephalopathy  Long-term neurological sequelae BBB, Blood-brain Barrier CBF, cerebral blood flow

41. Treatment

42. There is currently no FDA approved pharmacological therapeutic intervention directed against a specific mediator of sepsis. • Recommended guidelines exist for early goal-directed medical care to improve resuscitation • Surviving Sepsis Campaign - joint collaboration of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine • Potential novel treatments: • Estrogen therapy1 - early animal studies are promising2,3 • Cytokine therapy4 • Vitamin C Treatment

43. TO BE COMPLETED WITHIN 3 HRS OF TIME OF PRESENTATION*: 1. Measure lactate level 2. Obtain blood cultures prior to administration of antibiotics 3. Administer broad spectrum antibiotics 4. Administer 30ml/kg crystalloid for hypotension or lactate ≥4mmol/L TO BE COMPLETED WITHIN 6 HOURS: 5. Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain MAP ≥65 mm Hg 6. Persistent hypotension after initial fluid resuscitation or initial lactate ≥4mmol/L ►reassess volume status + tissue perfusion, document per Table 1 7. Re-measure lactate if initial lactate elevated TABLE 1 Document reassessment of volume status + tissue perfusion with EITHER: • Repeat focused exam (after initial fluid resuscitation) including vital signs, cardiopulmonary, capillary refill, pulse, and skin findings. OR TWO OF THE FOLLOWING: • Measure CVP or • Measure ScvO2 SSC Bundles

44. Administration of initial empiric intravenous antimicrobials is recommended within the first hour of recognition of septic shock, however…. ….empiric combination therapy is not recommended for > 3–5 days  de-escalateto the most appropriate single as soon as the susceptibility profile is known. - Procalcitonin (PCT) levels can be used to guide antimicrobial therapy If source control in septic patient is required, intervention associated with the least physiologic insult should be used first (e.g., percutaneous vs. surgical drainage of an abscess) Antimicrobial Therapy

45. Surviving Sepsis Campaign Guidelines • Norepinephrine - first choice vasopressor • Epinephrine - added to and potentially substituted for norepinephrine if needed • Vasopressin - not recommended as the single initial vasopressor for treatment of sepsis-induced hypotension • Dopamine – an alternative vasopressor agent to norepinephrine only patients with low risk of tachyarrhythmias and absolute or relative bradycardia • Dobutamine – Use is indicated with myocardial dysfunction and persistent hypotension Vasopressors Goal = MAP ≥ 65 mm Hg

46. Sepsis is both a complication and most common cause of acuterespiratory distress syndrome (ARDS). Patients with sepsis-induced ARDS have a higher fatality rates.10,12 • Lung protective ventilation (LPV) strategy is widely advocated11 • Target tidal volume 6mL/kg predicted body wt. • Use of positive end-expiratory pressure (PEEP) • Ventilator-associated pneumonia prevention bundle • Conservative fluid strategy if no evidence of tissue hypo-perfusion • Prone position for pts. with PaO2/FiO2 ratio  100 mm Hg • Weaning protocol with spontaneous breathing trials to consider extubation • Recommendations against routine use of beta 2-agonists and pulmonary arterial catheters • Sex Differences •  Alveolar fluid clearance in females • Shorter height in females may influence calculated tidal volumes  Females likely to receive excessive tidal volumes • Possible sex-specific genetic susceptibility to ARDS • Gender Disparity • Women less likely than men to receive mechanical ventilation in ICU setting3 Mechanical Ventilation & ARDS

47. Coagulopathy is a frequent complication of sepsis.1 Sexual Dimorphism in Coagulability • Estrogen/progestin  promotes coagulability • Plasminogen activator inhibitor type 1 (PAI-1),a strong procoagulant, associated with poor outcome and increases severity of DIC4 • Estrogen decreasesPAI-1 levels5,6 • Testosterone decreases PAI-1 in a dose dependent manner7 Further studies on sex differences in sepsis-induced DIC are needed. Disseminated Intravascular Coagulation (DIC)

48. Early Goal Directed Therapy (EGDT)significantly reduces in-hospital and 29-day mortality rates for septic patients.9 • The Surviving Sepsis Campaign designed the 3 and 6-hour resuscitation bundle to reduce sepsis-mortality via EGDT • The DISPARITY study found that women are less likely to have EDGT initiated.7 • Other studies have observed that women with sepsis or severe sepsis experience longer delays in initial antibiotictreatment than men6-8 • Possible gender-related disparities in treatment Gender Differences

49. Pregnancy

50. Sepsis is one of the four main causes of pregnancy-related mortality worldwide.1 • Sepsis definitions are based on non-pregnant individuals and septic obstetric patients’ presentation may differ from the overall population. Physiological differences in pregnancy may mask the early signs of sepsis. • Emergency Cesarean delivery, postpartum hemorrhage and preterm delivery associated with severe sepsis2 Sepsis & Pregnancy