Sepsis

It includes new definition, pathophysiology, management of sepsis, septic shock and neutropenic sepsis and even newer evolving concepts or types of sepsis.

1. Sepsis Dr Pritish Chandra Patra Associate Professor Department of Hematology IMS and SUM Hospital, Bhubaneswar

2. Outline 2

3. Definition (Sepsis 3) Sepsis- Life-threatening organ dysfunction caused by a dysregulated host response to infection Septic shock- a subset of sepsis with circulatory, cellular and metabolic dysfunction associated with a higher risk of mortality clinically vasopressor requirement to maintain a MAP ≥ 65 mmHg serum lactate level >2mmol/L (>18mg/ dL ) no hypovolemia 40% mortality 3 Singer M etal , The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), JAMA. 2016;315(8):801-810

4. 4 History

5. The Spectrum 5 Martin GS, Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes, Expert Rev Anti Infect Ther . 2012 Jun; 10(6): 701–706 Bone RC et al, 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. Crit Care Med. 1992;20(6):864-874. Bacteremia SIRS SEPSIS Infection Parasitemia Fungemia Viremia Others Pancreatitis Burns Trauma Others SOFA score

6. Screening for sepsis: SOFA score 6 qSOFA RR ≥ 22/min SBP ≤ 100 mmHg GCS < 15 Vincent JL et al; Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med. 1996;22(7):707-710.

7. Approach to suspected sepsis 7 Singer M, The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), JAMA. 2016;315(8):801-810

8. The Burden Accounted for more than $20 billion (5.2%) of total US hospital costs in 2011 leading cause of mortality and critical illness worldwide long-term... physical psychological cognitive disabilities care and social issues 8 Singer M, The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), JAMA. 2016;315(8):801-810

9. Epidemiology of adult-population sepsis in India 9 Severe sepsis was common in Indian intensive therapy units ( ITUs) The median APACHE II score was 13 (IQR, 13 to 14) with 90.93% medical admission 16.45% of hospital admissions were due to severe sepsis 59.26% of patients with sepsis died Mortality of severe sepsis was ~ 65 % Sharmila C, et al. Indian J Crit Care Med. 2017;21(9): 573–7

10. Epidemiology: India 10 Chatterjee S etal , Epidemiology of adult-population sepsis in India: A single center 5 year experience. Indian J Crit Care Med 2017;21:573-7

11. 11 Gram Neg 73.4% Gram pos 12.6%

12. 12 Sri Ramachandra University Reasearch Institute, India T T S Paary etal , Clinical profile and outcome of patients with severe sepsis treated in an intensive care unit in India, Ceylon Medical Journal 2016; 61: 181-184 Epidemiology: India

13. 13 Epidemiology: India

14. Pathophysiology Tissue Hypo- perfusion & MODS Robbins & Cotran , Pathologic Basis of Disease , 8 th Ed 14

15. Management Goals Initial resuscitation Diagnosis & infection control Continuation of fluid and other supportive therapy to maintain organ perfusion 15

16. Initial resuscitation Medical emergency IV fluid- crystalloid- at least 30 ml/kg- 1 st 3 hrs MAP ≥ 65 mm Hg 4% albumin- if fluid requirement is more 16 Casserly B et al, Lactate measurements in sepsis-induced tissue hypoperfusion : results from the Surviving Sepsis Campaign database. Crit Care Med (2015) 43(3):567–573 ProCESS ProMISe ARISE Mar 2015 May 2014 Oct 2014 30 ml/kg 2 lit

17. Reassessment Additional fluid Dynamic measures of fluid responsiveness 17

18. Serum Lactate Tissue hypoxia Excessive β -adrenergic stimulation 18 Regardless of source- Increased lactate→ poor outcome Lactate guided Vs lactate non-guided >2 mmol /L (>18 mg/ dL ) ↓mortality Objective marker of tissue perfusion >> physical examination >> urine output

19. 19 Casserly B et al (2015) Lactate measurements in sepsis-induced tissue hypoperfusion : results from the Surviving Sepsis Campaign database. Crit Care Med 43(3):567–573

20. 20 Casserly B et al (2015) Lactate measurements in sepsis-induced tissue hypoperfusion : results from the Surviving Sepsis Campaign database. Crit Care Med 43(3):567–573

21. 21 Am J Respir Crit Care Med Vol 182. pp 752–761, 2010

22. 22

23. Blood cultures Microbiologic cultures (including blood)- before starting antimicrobial therapy shouldn’t delay starting of antimicrobials 23 Kaasch AJ et al, Differential time to positivity is not predictive for central line related Staph. aureus blood stream infection in routine clinical care. J Infect (2014), 68(1):58–61 Cultures can become sterile shortly after Abx initiation CVAD for >48hrs- site of infection not proven- paired samples for c/s 2 sets of blood cultures aerobic anaerobic

24. Antimicrobials Start ≤ 1 hr Each hour delay- measurable increase in mortality Choice of Abx - Anatomic site Prevalent organisms Local resistance patterns- if any Age and co-morbidities Empiric therapy- Broad Spectrum Adequate doses Adjusted for organ impairment Daily assessment- de-escalation Empirical antifungal 24 Kumar A,et al , Crit Care Med, 2006, 34(6):1589–1596 Ferrer R,et al, Crit Care Med, 2014, 42(8):1749–1755

25. Hour-1 bundle-of-care elements: Surviving Sepsis Campaign a Remeasure lactate if initial lactate is elevated (>2 mmol/L) Minasyan S. J Trauma Resusc Emerg Med. 2019;27:19. 25

26. Hour-1 bundle-of-care elements: Surviving Sepsis Campaign 26

27. Code Sepsis Protocol ICU, intensive care unit, SBP, systolic blood pressure. 1. Whitfield PL, et al. Am J Emerg Med. 2020 May;38(5):879-882. 27

28. Initiation of Code sepsis and its benefits ICU, intensive care unit; PSA, Perfect score attainment; SBP, systolic blood pressure. 1. Boter NR, et al. Med Clin (Barc). 2019;152(7):255–260. 2. CHA 2019, Available at: https://cha.com/wp-content/uploads/2019/04/6.10-Screening-and-Code-Sepsis-Best-Practices.pdf . Accessed on: 05 JUN 2020. 3. García-López L, et al. Med Intensiva . 2017;41:12---20. 4. Whitfield PL, et al. Am J Emerg Med. 2020 May;38(5):879-882. 5. Kim HI, et al. Tuberc Respir Dis (Seoul). 2019 Jan;82(1):6-14. 28

29. Implementation of an adult code sepsis protocol and its impact: A retrospective cohort study Whitfield PL, et al. Am J Emerg Med. 2020 May;38(5):879-882.

30. Implementation of an adult code sepsis protocol and its impact: A comparative observational study Population: Patients admitted to the ICU with severe sepsis or septic shock. A total of 92 patients with severe sepsis or septic shock were enrolled (42 in the POST-SC group and 50 in the PRE-SC group) Post-SC, post implementation of sepsis protocol; Pre-SC, pre implementation of sepsis protocol. García-López L, et al. 2016. Med Intensiva. 2017;41(1):12---20. 30 P < 0.05 indicate significant difference The implementation of a Sepsis Code Protocol a significant reduction in mortality In addition, it will also: improve antibiotic use with a significant increase in gradual therapeutic reduction a lower use of restricted use antibiotics a tendency towards a shorter ICU stay

31. Initial empirical antibiotics Carbapenem Extended spectrum penicillin/ β - lactamase inhibitors comb. Third/fourth generation cephalosporins Risk factors MDR - (Pseudomonas, Acinetobacter ) supplemental gram - ve MRSA Vancomycin Teicoplanin Atypical Macrolide Fluoroquinolone Antimicrobials 31 β - lactam + aminoglycoside / fluoroquinolone Carbapenem + aminoglycoside Cefepime + aminoglycoside Micek ST,et al, Empiric combination antibiotic therapy is associated with improved outcome in gram-negative sepsis: a retrospective analysis. Antimicrob Agents Chemother (Bethesda). 2010; 54(5):1742–1748

32. Use of teicoplanin in sepsis Schaison G, et al. J Chemother. 2000;12(Sup5):26 – 33. 32

33. Dosing strategies Full, high end loading dose Rapid achievement of therapeutic drug level Increased volume of distribution Peak plasma concentration Comparable efficacy + less renal toxicity Fluoroquinolones Aminoglycosides Loading dose Low volume of distribution Teicoplanin Colistin Extended infusion β- lactams more effective than intermittent rapid infusion Initial doses- bolus/rapid infusion Further doses- extended infusion of drug over several hours 33

34. When to modify?

35. De-escalation longer courses- slow clinical response undrainable foci of infection bacteremia with S. Aureus Immunocompromised (neutropenia) shorter courses- rapid clinical resolution following effective source control 35 Daily assessment for de-escalation of antimicrobial therapy Andrew Rhodes et al, Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med (2017) 43:304–377

36. De-escalation 36 Andrew Rhodes et al, Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med (2017) 43:304–377

37. Procalcitonin Differentiating infectious and non-infectious Duration shortening of antibiotics Discontinuation of empiric antibiotics (≤0.05ng/ml: Normal) 37 Andrew Rhodes et al, Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med (2017) 43:304–377

38. Vasopressors 38

39. Dopamine- alternative to norepinephrine only in highly selected patients (patients with low risk of tachyarrhythmias and absolute or relative bradycardia ) Low-dose dopamine- renal protection to be avoided 39 Vasopressors Norepinephrine Dopamine Increases MAP Increases MAP More potent Less potent Vaso -constrictive ↑ CO x HR x SV ↑HR ↑SV Less arrythmogenic More arrythmogenic Lower mortality

40. Inotropes Dobutamine in persistent hypoperfusion - despite IVF and vasopressor agents myocardial dysfunction (↑cardiac filling pressures and ↓CO) Trial of dobutamine infusion up to 20 μ g/kg/min be administered or added to vasopressor 40

41. 41

42. Steroids If fluid resuscitation and vasopressor- failed IV hydrocortisone @ 200 mg per day Tapered when vasopressors are no longer required ? fixed duration ? tapering ? abrupt cessation Shouldn’t be used to prevent septic shock 42 Andrew Rhodes et al, Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med (2017) 43:304–377

43. Blood products RBC transfusion- if Hb <7.0 g/ dL Prophylactic platelet transfusion If <10,000/mm 3 - in the absence of bleeding If <20,000/mm 3 - if significant risk of bleeding ≥50,000/mm 3 - if active bleeding, surgery or invasive procedures FFP to correct clotting abnormalities in the absence of bleeding or planned invasive procedures- avoided EPO- not recommended 43 Andrew Rhodes et al, Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med (2017) 43:304–377

44. Insulin- 2 consecutive blood glucose levels >180 mg/ dL target an upper blood glucose ≤180 mg/ dL Blood glucose monitored every 1–2 hrs until glucose values and insulin infusion rates are stable and then every 4 hr thereafter Glucose levels of capillary blood may not accurately estimate plasma glucose values 44 Blood glucose control

45. Sedation (continuous or intermittent) minimized in sepsis patient on MV Renal Replacement Therapy CRRT facilitates management of fluid balance in hemodynamically unstable septic patients Bicarbonate therapy Not recommended Venous thromboembolism prophylaxis LMWH > UFH- in the absence of contraindications Stress ulcer prophylaxis PPIs or H2RAs 45 Other supportive therapy

46. higher PEEP prone > supine position- sepsis induced ARDS No NIV conservative fluid strategy β 2 agonists- avoid in sepsis-induced ARDS without bronchospasm 46 Mechanical ventilation: ARDS

47. Neutropenic Sepsis 47

48. Limitations Both qSOFA & SOFA score cannot be used without restrictions in neutropenic patients: Mental status may change independently from the onset of sepsis and assessment is therefore sometimes limited. Tumor-associated symptoms or complications can lead to neurological deficits. Platelet count cannot be used due to chemotherapy-associated or tumor-related thrombocytopenia, and Chemotherapy-induced elevation of bilirubin and creatinine may influence the sofa score calculation. Negative qSOFA score (< 2) should not cause any delays in starting treatment for sepsis if there is clinical suspicion in high-risk population Ann Intern Med 168:266–211 Crit Care Lond Engl 22:28.

49. Prevalence Proportion of sepsis or septic shock in patients with neutropenia ranges from 7% to 45%

50. Diagnosis Management of sepsis in neutropenic cancer patients: 2018 guidelines from the Infectious Diseases Working Party (AGIHO) and Intensive Care Working Party ( iCHOP ) of the German Society of Hematology and Medical Oncology (DGHO)

51. What’s new? 51

52. Decreasing harmful capillary leak and edema formation by protecting or restoring endothelial cell function Selepressin INF-β Thrombomodulin Reversing sepsis-induced immunosuppression by immunostimulation GM-CSF INF- γ Anti PD-1 Ab Removal of harmful mediators from the blood using extracorporeal techniques Hemofiteration-cytosorb /polymyxin B 52 Crit Care Clin (2017)

53. Types of sepsis by machine learning 53 Seymour CW et al. Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis. JAMA. 2019 May 28;321(20):2003-2017.

54. 54

55. Types of sepsis by machine learning Seymour CW et al. Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis. JAMA. 2019 May 28;321(20):2003-2017. 55