Sepsis: An Update on Pathophysiology and Treatment Approaches

1. Sepsis: An Update on Pathophysiology and Treatment Approaches Case Studies: An Overview

2. Learning objectives • Review real cases to understand when to use activated Protein C • Note important differences between cases that influence decision to use or not use aPC • Discuss “red flags” for particular patients that could make you nervous about using aPC

3. Starting from common ground… • Appropriate supportive care • ABCs • Fluids • Vasopressors/inotropes • Organ support (ventilation, dialysis, etc.) • Appropriate empiric and adjusted antibiotics • Source control • Avoiding delays in diagnosing severe sepsis/septic shock, providing supportive care

4. Case #1 • 26 year old female • Past history of seizure disorder, on phenytoin • Presents with 12 hour history of fever/chills/rigors, lower abdominal pain, no dysuria, no cough • 39.4 degrees C • HR 125, BP 75/40 --> 90/50 after 2L NS • No CV angle tenderness • No other obvious source • Urinalysis • 5-20 WBC/hpf • Bacteria seen

5. Investigations • Laboratory: • WBC 1.0, 22% bands, Hb normal, plts normal • LFT’s normal, lytes, amylase normal • Creat 139 • Radiology: • CXR clear • CT (contrast) chest & abdomen: free fluid pelvis, edematous left kidney

6. Case: Deterioration • Started on empiric antibiotics following cultures • (Cefotaxime, Cipro, Ampicillin, Flagyl) • 12hrs later: • HR to 180, BP 65/P despite ++ fluids • Shortness of breath, RR 40+ • Hypoxemia, bilateral pulmonary infiltrates • 7.23/PCO2 33/pO2 100/bic 14 on 80% O2 • Metabolic acidosis, lactate 2.6 • Increased transaminases, decreased urine output • Increased INR to 2.4

7. Case • Intubated, mechanical ventilation, central venous catheter, arterial catheter, vasopressor • Blood cultures: Gram negative bacillus 2/2 bottles • PA catheter • Cardiac index 2.5L/min/m2 • PCWP 17 • Expected mortality now >40% • Septic Shock, ARDS

8. Source Control in Sepsis • Localize and treat site of infection • Undrained pockets are lethal • Reviewed details of anticonvulsant therapy • Agent known to contribute to renal stones! • Repeat CT -> non-contrasted: left ureteric stone • To OR for basket extraction • Not possible -> stent placed

9. Questions about the case… • Appropriate supportive care (including antibiotics)? • Timely source control? • Candidate for activated Protein C?

10. Case: Activated Protein C • Infusion of activated Protein C started 24 hours after admission to ICU • INR 2.4 -> 2.0 prior to aPC, 1.3 on infusion • Infusion x 96 hours total • 12 hour window for OR (stent placed) • Stabilized clinically, inotropes weaned • Extubated day 7 • Discharged for urologic followup

11. Lessons from Case 1 • Case history • 26-year-old female presents to ER • Diagnosed with severe Gram-negative sepsis with multisystem failure, septic shock, and ARDS • Undergoes surgery to remove kidney stone • Drotrecogin alfa (activated) infusion • Significance of case • Condition initially unrecognized, resolved with treatment for underlying condition

12. Case #2 • 73-year-old male, retired • Heavy smoker of 2 packs/day until five years ago • Presented with increased shortness of breath, yellowish sputum production over the last week and slight fever at 38.3°C two days prior to admission • Chronic bronchitis on Ventolin®, Atrovent® • Last FEV1 in 1999 was 0.8 L/min • Pneumococcal pneumonia with severe sepsis, ICU admission and mechanical ventilation in 1996 — yearly vaccinations since

13. Present history: • Dark urine and hasn’t voided in last 8 hours • Has used Ventolin® inhaler 4 times in last couple of hours

14. Physical examination: • 23:00 • On admission, 80 kg • Laboured breathing at 35/min, prolonged expiratory time, accessory muscle use • Temperature 38.2°C • Distended internal jugulars, tachycardia at 110/min NSR, BP 90/50

15. Physical examination (cont’d): • Positive HJ reflux • Fine crackles at both lung bases, swollen ankles • Right sided carotid bruit • Rest unremarkable

16. Outstanding lab results: Na+ = 148 K+ = 3.2 BUN Urea = 15 PO2 = 130 Hg = 156 Hct = .47 Plat = 175 000 WBC = 12 500 no bands ABG = 7.27/56/26/55 room air Investigations:

17. Investigations (cont’d): • CXR: hyperfiltration, suspect bronchiectasis both lung bases and doubtful left LL infiltrate • aPTT = 35/INR 1.3 • Lactates normal • ECG right axis deviation, negative T waves V1-V4 anterior leads

18. Treatment, management and rationale: • 23:40 • BiPAP started in ER 12/5, 40% PIO2 • Solumedrol 40 mg IV q 6 hours, cefuroxime 1 gm IV q 8 hours and ICU consult • 500 mL Pentaspan given over 1 hour after bladder catheter revealed 20 cc of dark yellow urine with absence of blood on strip reagent

19. Is this SIRS, sepsis, severe sepsis, or septic shock? • Is this patient a candidate for aPC?

20. Treatment, management and rationale (cont’d): • D5NaCl 0.9% + KCl 40 mg/L at 80 cc/hour • Not at risk for bleeding • Not a candidate for rhAPC

21. Lessons from Case 2 • Recognize non-specific nature of SIRS criteria • Alternative causes for hypotension, oliguria • Need for appropriate search for presumed or proven infection (COPD exacerbation doesn’t count)

22. Case 2: COPDJean-Gilles Guimond, MD • Case history • 73-year-old male presents to ER with COPD/acute tracheobronchitis, ?pneumonia • Case highlights • Patient not a candidate for drotrecogin alfa (activated) therapy because suffering from COPD exacerbation not sepsis • Significance of case • Patient follows SIRS criteria but does not have sepsis • Patient recovers; not treated with drotrecogin alfa (activated)

23. Case 3: Pneumococcal pneumoniaBruce Light, MD • Case history • 26-year-old woman, alcoholic, drug user • Taken to emergency by friends; in confused state, bad cough with yellow, bloody sputum, febrile • Obvious right lower lobe pneumonia on chest x-ray • Case highlights • Diagnosis: acute pneumococcal pneumonia with hypoxemic respiratory failure, septic shock requiring vasopressor infusion, acute renal insufficiency, and mild coagulopathy • Treated with drotrecogin alfa (activated) • Patient transferred to rehabilitation ward after 4 weeks • Significance of case • “Typical” scenario

24. Case 4: Post-op infectionClaudio Martin, MD • Case history • 67-year-old male undergoes coronary artery bypass surgery 3 weeks prior to presentation • Re-admitted 3-weeks post-surgery for management of sternal dehiscence associated with infection • Develops respiratory distress; requires intubation and admitted to ICU • Started on drotrecogin alfa (activated) • Requires chest tube for large pleural effusion (?infected) • Drops Hb by 30 in 12 hours • Recovers • Significance of case • When to discontinue treatment transiently vs permanently

25. Case 5: AML, febrile neutropeniaTom Stewart, MD • Case history • Patient with AML, pancytopenic with severe neutropenia and suspected lung infection • Case highlights • Patient excluded from PROWESS study due to low platelet count (15 000/mm3). Family approach physician about possible treatment with drotrecogin alfa (activated) • Case taken to clinical management team. Objections from oncologist (effect on leukemia and risk of bleeding) and pharmacist (cost and concern about use outside of guidelines) • Drotrecogin alfa (activated) not given; patient dies • Significance of case • Example of scenario where drotrecogin alfa not used