Sepsis: An Update on Pathophysiology and Treatment Approaches

Case Studies: An Overview

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

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

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

Investigations

Laboratory:

WBC 1.0, 22% bands, Hb normal, plts normal LFTs normal, lytes, amylase normal Creat 139
Radiology:

CXR clear CT (contrast) chest & abdomen: free fluid pelvis, edematous left kidney

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

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

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

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

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

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

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 38.3C 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

Present history:

Dark urine and hasnt voided in last 8 hours Has used Ventolin inhaler 4 times in last couple of hours

Physical examination:

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

Physical examination (contd):

Positive HJ reflux Fine crackles at both lung bases, swollen ankles Right sided carotid bruit Rest unremarkable

Investigations:

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 (contd):

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

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

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

Treatment, management and rationale (contd):

D5NaCl 0.9% + KCl 40 mg/L at 80 cc/hour Not at risk for bleeding Not a candidate for rhAPC

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 doesnt count)

Case 2: COPD Jean-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)

Case 3: Pneumococcal pneumonia Bruce 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

Case 4: Post-op infection Claudio 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

Case 5: AML, febrile neutropenia Tom 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