sepsis

1. Sepsis and Septic shock
guidelines
Faisal Alsawafi

2. Sepsis
• Pathophysiology
• Definitions
• Presentation
• Management

3. Definition
Life-
threatening
organ
dysfunction
Dysregulated
host response
to infection
acute increase in SOFA score
by 2 or more

4. Sepsis: Pathophysiology
• Tissue ischemia: mismatach O2 delivery & tissue demand
• Mitochondrial dysfunction:
extraction failure/cytopathic hypoxia
• Apoptosis.
• Coagulopathy (possibly DIC)
• Loss of endothelial barrier function (glycocalyx)

8. ACCP / SCCM (1992)
SIRS. ;
Temperature, HR, RR, WBC
Sepsis. ;
Infection PLUS >= SIRS
Severe Sepsis. ;
Sepsis PLUS organ dysfunction
Septic Shock. ;
Sepsis PLUS hypotension despite
fluid resuscitation
Rangel-Frausto MS et al. The natural history of the systemic
inflammatory response syndrome (SIRS). A prospective study.
JAMA. 1995;273(2):117-23. PMID 7799491

9. ACCP / SCCM (1992)
SIRS
Sepsis
Severe Sepsis
Septic Shock

10. ACCP / SCCM (1992) SCCM/ESICM Sepsis-3 (2016)
SIRS
Sepsis Sepsis (mortality rate ≈ 10%):
• Suspected infection
• Organ dysfunction with SOFA score
increase by ≥ 2.
Could use qSOFA to screen (need 2 or more of):
 RR ≥ 22 b/m
 Altered mentation
 SBP ≤ 100 mmHg
Severe Sepsis
Septic Shock

11. ACCP / SCCM (1992) SCCM/ESICM Sepsis-3 (2016)
SIRS  Infection
Sepsis Sepsis (mortality rate ≈ 10%):
• Suspected infection
• Organ dysfunction with SOFA score
increase by ≥ 2.
Could use qSOFA to screen (need 2 or more of):
 RR ≥ 22 b/m
 Altered mentation
 SBP ≤ 100 mmHg
Severe Sepsis
Septic Shock Septic Shock (mortality rate ≈ 40%):
• Suspected infection
• Vasopressors to maintain MAP ≥ 65 mmHg
AND
• Lactate > 2 mmol/L

12. Clinical Presentation
• Infectious source
• Organ dysfunction / end-organ hypoperfusion
SOFA Score

13. Sequential Organ Failure Assessment Score
0 1 2 3 4
CNS
(Glasgow Coma Score)
15 13-14 10-12 6-9 <6
CVS (MAP or
vasopressor
requirement)
MAP ≥ 70 MAP < 70
dopamine ≤ 5
µg/kg/min or
dobutamine (any
dose)
dopamine > 5 OR
epi OR norepi ≤
0.1 µg/kg/min
dopamine > 15
µg/kg/min OR
epi or norepi >
0.1 µg/kg/min
Resp (PaO2/FiO2) ≥ 400 < 400 < 300
< 200 and
ventilated
< 100 and
ventilated
Liver (bilirubin) < 20 20-32 33-101 102-204 > 204
Renal (creatinine) < 110 110-170 171-299
300-440 or
UO <500 ml/d
> 440 or
UO < 200 ml/d
Coagulation
(platelets)
≥ 150 < 150 < 100 < 50 < 20

14. Management
• Fluids & vasoactive drugs
• Antibiotics & source control
• Additional therapies (steroids, APC)
• De-escalation

17. Landmark Trial
Rivers E et al. N Engl J Med. 2001 Nov
8;345(19):1368-77
“Rivers Protocol”

18. “Rivers Protocol”
Rivers E et al. N Engl J Med. 2001 Nov 8;345(19):1368-77
EGDT
Standard
therapy
Patients
enrolled (n)
130 133
In-hospital
Mortality (%)
30.5 46.5
P = 0.009

19. Lu Y et al.
J Intensive
Care Med.
2018 May;
33(5): 296-
309.

26. Fluids
• Crystalloid at 30ml/kg.
• Target ScvO2, CVP, MAP, and UO.
• Albumin no different than crystalloid.

27. Volume Responsiveness
• Definition
• Dynamic measures of volume responsiveness
• Echo features: LVOT VTI variation, IVC variation
• Pulse pressure or stroke volume variation
• Passive leg raise test
• Monitor response with each fluid bolus

28. Resuscitation Targets
(Restoring Perfusion)
• MAP > 65 mmHg (generic)
• Reduction in vasopressor requirements
• Urine output
• Capillary refill (normal < 3.5 sec)
• PCO2 gap: PaCO2 – PVCO2 (normal < 6 mmHg)
• Lactate clearance

29. Crystalloids

31. Crystalloids

34. Crystalloid vs Albumin
SAFE trial (n = 6997)*
• Randomized to type of resuscitation fluid: saline vs albumin 4%.
• All-cause mortality at 28 days no different between groups.
• Subgroup analysis suggested albumin may be beneficial in septic
shock patients.
ALBIOS trial (n = 1818)+
• Randomized to albumin 20% & crystalloid vs crystalloid only.
*Finfer S et al. N Engl J Med. 2004 May 27;350(22):2247-56.
+Caironi P et al. N Engl J Med. 2014 Apr 10;370(15):1412-21.

36. ALBIOS Trial
Albumin 20%
(n=910)
Crystalloid
(n=908)
P-Value
MAP in first 7 days
(mmHg)
≈87 ≈86 0.03
Median daily fluids given
in first 7 days (L)
3.74 3.8 0.1
Mortality at 28 days (%) 31.8 32 0.94
Mortality at 90 days (%) 41.1 43.6 0.29
Caironi P et al. N Engl J Med. 2014 Apr 10;370(15):1412-21.

37. Caironi P et al. N Engl J Med. 2014 Apr 10;370(15):1412-21.
ALBIOS Trial
SSC Guidelines
Suggest using albumin
(in addition to crystalloids)
in patients who require
substantial amounts of
crystalloids

38. Starch Formulations
SSC Guidelines
Do not use starch formulations
in resuscitating septic shock
patients (associated with
increased mortality and renal
failure).

39. Vasopressors
• Norepinephrine (first line), followed by vasopressin (second line). *
• Norepinephrine superior to dopamine (less arrythmias).+
• Consider inotropes if low cardiac output (e.g. dobutamine).x
*Rhodes A et al. SSC Guidelines 2016. Intensive Care Med 43:304–377
+De Backer D et al. N Engl J Med. 2010 Mar 4;362(9):779-89.
xNguyen HB et al. J Intensive Care Med. 2017 Aug;32(7):451-459.

42. Vasopressin
• SSC Recommended Dose:
up to 1.8 units/hr (0.03 units/min).*
• Addition of vasopressin (up to 1.8 u/hr) to norepi does not reduce
mortality.+
• Early use of vasopressin (up to 3.6 u/hr) instead of norepi does not
reduce renal failure free days nor mortality.X
*Rhodes A et al. SSC Guidelines 2016. Intensive Care Med 43:304–377
+Russel JA et al (VASST Study Investigators) N Engl J Med. 2008 Feb 28;358(9):877-87.
xGordon AC et al. (VANISH Study Investigators) JAMA. 2016 Aug 2;316(5):509-18.
SSC Guidelines
Suggest adding vaso to norepi
to raise MAP to target
or to reduce norepi dose

43. Vasopressin
• No effect on mortality.
• Use of vasopressin lead to
more digital ischemia but
less arrhythmias than use of
norepinephrine alone.
• Mesenteric ischemia and
acute coronary syndrome
event rates were similar
between groups.

45. Empiric Antibiotics
• Timing of administration: first hour (best right after cultures).
• Each hour of delay increases risk of death by 7.6%
(during the first 6 hours in septic shock patients). *
• Choice depends on presentation.
• Source control ideally within 6 – 12 hours.
* Kumar A et al. Crit Care Med. 2006 Jun;34(6):1589-96.

46. Clinical suspicion Choice
CAP
HAP
Aspiration
UTI
Invasive fungal infection

47. Clinical suspicion Choice
CAP 3rd gen cephalosporin + macrolide
HAP (antipseudomonal penicillin or carbapenem) ± vancomycin
Aspiration 3rd gen cephalosporin + anaerobic coverage (metronidazole or
clindamycin)
UTI 3rd gen cephalosporin or quinolone or aminoglycoside
Invasive fungal infection removal of catheter + echinocandin (e.g. caspofungin)
Risk factors for invasive fungal infection: surgery, TPN, prolonged antimicrobials,
hospitalization (esp in ICU), chemotherapy, transplant, chronic liver or renal failure,
diabetes, major abdominal surgery, vascular catheters/devices, septic shock or multisite
Candida colonization.

48. Management
• Fluids & vasoactive drugs
• Antibiotics & source control
• Additional therapies (steroids, vitamin C, thiamine, APC)
• De-escalation (and de-resuscitation)

49. Crit Care Med. 2018 Jun;46(6):997-1000. The Surviving Sepsis
Campaign Bundle: 2018 Update. Levy MM et al.
SSC 2018 Update
• Sepsis is a medical
emergency.
• Hour-1 Bundle
• No hour 3 and 6
bundles.

50. Hydrocortisone
Consider hydrocortisone 200mg IV daily (50 mg IV q6hrs)
(± fludrocortisone 50 mcg per NG once daily) for 7 days.
Faster resolution of shock.*+
Reduced duration of mechanical ventilation.*
Reduced ICU & hospital length of stay.+
No increase in super-infections.*+
*Venkatesh B et al (ADRENAL Trial Investigators). N Engl J Med. 2018 Mar 1;378(9):797-808.
+Annane D et al (APROCCHSS Trial Investigators). N Engl J Med. 2018 Mar 1;378(9):809-818.

51. Hydrocortisone
However...
No (or very small) mortality benefit.+
Increased risk of neuromuscular weakness.
Increased risk of hypernatremia and hyperglycemia.
SSC Guidelines
If fluids and pressors restore
hemodynamics, don’t use.
Only use for refractory septic
shock (hydrocortisone 200
mg/d).

52. SSC Guidelines
• Early enteral nutrition (avoid TPN if possible)
• DVT prophylaxis
• Stress-ulcer prophylaxis only if at risk
• Transfusion trigger Hb < 70 gm/dL (in absence of bleeding or
myocardial ischemia)
• Treat sepsis-induced ARDS as per the standard ARDS
management strategies
• Don’t use NaHCO3 to correct acidosis if pH > 7.15

53. “The Marik Protocol”
• Hydrocortisone 50 mg IV q 6 hrs.
• Vitamin C 25 mg/kg (≈1.5 gm) IV q 6hrs
for 4 days or until ICU discharge.
• Thiamine 200 mg IV q 12 hrs
for 4 days or until ICU discharge.
Additional Therapies: Experimental
A Retrospective Before-After Study. Marik PE et al. Chest. (2017)
• 47 patients in each arm
• Propensity adjusted
odds of mortality:
0.13 (95% CI: 0.04-0.48;
P = 0.002)

54. Mortality
ICU Length of stay (days)
Vasopressor duration (hours)
VICTAS study: ongoing
Aiming for 2000 patients.
Examining combination of vitamin C,
thiamine, and steroids vs placebo.
Primary outcome: vasopressor and
ventilator free days (in first 30 d).

55. Additional Therapies: APC
• Activated Protein C….
…a thing of the past.

56. De-escalation
• De-resuscitation: reduce or stop fluids, consider diuretics.
• De-escalation of antibiotics: narrow down or stop.
Cultures negative in 50% of cases so use clinical judgement.

57. Summary
• Cornerstone of initial resuscitation is
 Rapid restoration of perfusion (fluids and pressors)
 Early antibiotics
• Glucorticoids may play a role in severe cases.
• De-escalation is usually necessary.

58. References
• Chest. 1992 Jun;101(6):1644-55. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American
College of Chest Physicians/Society of Critical Care Medicine. Bone RC1, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ.
• JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Singer M1, Deutschman CS2, Seymour CW3,
Shankar-Hari M4, Annane D5, Bauer M6, Bellomo R7, Bernard GR8, Chiche JD9, Coopersmith CM10, Hotchkiss RS11, Levy MM12, Marshall JC13, Martin GS14, Opal SM12, Rubenfeld GD15, van der
Poll T16, Vincent JL17, Angus DC18.
• N Engl J Med. 2001 Nov 8;345(19):1368-77. Early goal-directed therapy in the treatment of severe sepsis and septic shock. Rivers E1, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson
E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group.
• J Intensive Care Med. 2018 May;33(5):296-309. doi: 10.1177/0885066616671710. Epub 2016 Oct 22. Early Goal-Directed Therapy in Severe Sepsis and Septic Shock: A Meta-Analysis and Trial
Sequential Analysis of Randomized Controlled Trials. Lu Y1, Zhang H1, Teng F1, Xia WJ1, Sun GX1, Wen AQ1.
• N Engl J Med. 2014 Apr 10;370(15):1412-21. doi: 10.1056/NEJMoa1305727. Epub 2014 Mar 18. Albumin replacement in patients with severe sepsis or septic shock. Caironi P1, Tognoni G, Masson
S, Fumagalli R, Pesenti A, Romero M, Fanizza C, Caspani L, Faenza S, Grasselli G, Iapichino G, Antonelli M, Parrini V, Fiore G, Latini R, Gattinoni L; ALBIOS Study Investigators.
• N Engl J Med. 2012 Jul 12;367(2):124-34. doi: 10.1056/NEJMoa1204242. Epub 2012 Jun 27. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. Perner A1, Haase N, Guttormsen
AB, Tenhunen J, Klemenzson G, Åneman A, Madsen KR, Møller MH, Elkjær JM, Poulsen LM, Bendtsen A, Winding R, Steensen M, Berezowicz P, Søe-Jensen P, Bestle M, Strand K, Wiis J, White JO,
Thornberg KJ, Quist L, Nielsen J, Andersen LH, Holst LB, Thormar K, Kjældgaard AL, Fabritius ML, Mondrup F, Pott FC, Møller TP, Winkel P, Wetterslev J; 6S Trial Group; Scandinavian Critical Care
Trials Group.
• Crit Care Med. 2006 Jun;34(6):1589-96. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Kumar A1, Roberts
D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M.
• N Engl J Med. 2010 Mar 4;362(9):779-89. doi: 10.1056/NEJMoa0907118. Comparison of dopamine and norepinephrine in the treatment of shock. De Backer D1, Biston P, Devriendt J, Madl C,
Chochrad D, Aldecoa C, Brasseur A, Defrance P, Gottignies P, Vincent JL; SOAP II Investigators.
• N Engl J Med. 2008 Feb 28;358(9):877-87. doi: 10.1056/NEJMoa067373. Vasopressin versus norepinephrine infusion in patients with septic shock. Russell JA1, Walley KR, Singer J, Gordon AC,
Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D; VASST Investigators.
• J Intensive Care Med. 2017 Aug;32(7):451-459. doi: 10.1177/0885066616647941. Epub 2016 May 6. Comparative Effectiveness of Second Vasoactive Agents in Septic Shock Refractory to
Norepinephrine. Nguyen HB1,2,3, Lu S4, Possagnoli I2, Stokes P4.

59. References
• N Engl J Med. 2018 Mar 1;378(9):809-818. doi: 10.1056/NEJMoa1705716. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. Annane D1, Renault A1, Brun-Buisson C1, Megarbane
B1, Quenot JP1, Siami S1, Cariou A1, Forceville X1, Schwebel C1, Martin C1, Timsit JF1, Misset B1, Ali Benali M1, Colin G1, Souweine B1, Asehnoune K1, Mercier E1, Chimot L1, Charpentier C1,
François B1, Boulain T1, Petitpas F1, Constantin JM1, Dhonneur G1, Baudin F1, Combes A1, Bohé J1, Loriferne JF1, Amathieu R1, Cook F1, Slama M1, Leroy O1, Capellier G1, Dargent A1, Hissem T1,
Maxime V1, Bellissant E1; CRICS-TRIGGERSEP Network.
• N Engl J Med. 2018 Mar 1;378(9):797-808. doi: 10.1056/NEJMoa1705835. Epub 2018 Jan 19. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. Venkatesh B, Finfer S, Cohen J,
Rajbhandari D, Arabi Y, Bellomo R, Billot L, Correa M, Glass P, Harward M, Joyce C, Li Q, McArthur C, Perner A, Rhodes A, Thompson K, Webb S, Myburgh J; ADRENAL Trial Investigators and the
Australian–New Zealand Intensive Care Society Clinical Trials Group.
• N Engl J Med. 2004 May 27;350(22):2247-56. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. Finfer S1, Bellomo R, Boyce N, French J, Myburgh J, Norton R;
SAFE Study Investigators.
• Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R et al (2017) Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care
Med 43:304–377
• Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ et al (2008) Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 358:877–887
• N Engl J Med. 2008 Feb 28;358(9):877-87. doi: 10.1056/NEJMoa067373. Vasopressin versus norepinephrine infusion in patients with septic shock. Russell JA1, Walley KR, Singer J, Gordon AC,
Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D; VASST Investigators.
• JAMA. 2016 Aug 2;316(5):509-18. doi: 10.1001/jama.2016.10485. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical
Trial. Gordon AC1, Mason AJ2, Thirunavukkarasu N3, Perkins GD4, Cecconi M5, Cepkova M6, Pogson DG7, Aya HD5, Anjum A3, Frazier GJ3, Santhakumaran S3, Ashby D3, Brett SJ8; VANISH
Investigators.
• Crit Care Med. 2018 Jun;46(6):997-1000. doi: 10.1097/CCM.0000000000003119. The Surviving Sepsis Campaign Bundle: 2018 Update. Levy MM1, Evans LE2, Rhodes A3.