Septic shock

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In medicine, septic shock is a form of sepsis with "associated with hypotension or hypoperfusion despite adequate fluid resuscitation. Perfusion abnormalities may include, but are not limited to lactic acidosis; oliguria; or acute alteration in mental status."[1]


Sepsis and septic shock may be the most common complications in perioperative care.[2]


Myocardial dysfunction

Transient myocardial dysfunction may occur in 59% of patients and may resolve within 12 days.[3]


Clinical practice guidelines by the Surviving Sepsis Campaign address management. The choice and timing of antibiotics may be the most important aspect of treatment.[4]


Observational studies of antibiotics.[5][6][7]
Study Patients Interventions Results
291 ED patients
• 34% bacteremia
• 16% mortality
41% received antibiotics before shock Time to appropriate antibiotics not associated with mortality
Gaieski et al[6]
261 ED patients
• 32% bacteremia
• 31% mortality
<1 hour median delay after hypotension till antibiotics Time to appropriate antibiotics associated with mortality
Kumar et al[7]
2154 ICU patients patients
• 34% bacteremia
• 56% mortality
6 hour median delay after hypotension till antibiotics Time to appropriate antibiotics associated with survival

Choosing appropriate antibiotics and starting them within an one hour is associated with better outcomes.[6]

Recommendations for choosing antibiotics are available.[8]

Goal-directed resuscitation

Major trials of Goal-directed resuscitation[9][10][11]
Trial Patients Interventions Usual care Outcomes Results for patients Comments
Intervention Control
Early Goal-Directed Therapy Collaborative Group[9]
263 patients:
• Lactate 7.3
• Blood culture positive 35%
• SBP 108 mm Hg
• 90% received antibiotics by 6 hours
Early Goal-Directed Therapy
Within 72 hrs:
• 100% central lines ScvO2
• 68% transfusion
• 37% vasopressors
• 13606 ml fluid
Usual care within 72 hrs:
• 100% central lines ScvO2
• 45% transfusion
• 51% vasopressors
• 14101 ml fluid
28-day mortality 33% 49%
1341 patients:
• Lactate 4.9
• Blood culture positive 30%
SBP 101 mm Hg
• 97% received antibiotics by 6 hours
Early Goal-Directed Therapy
Within 72 hrs:
• 93% central lines ScvO2
• 1% transfusion
• 48% vasopressors
• 7253 ml fluid
Two control groups
In no protocol group within 72 hours:
• 57% central lines
• 2% transfusion
• 43% vasopressors
• 6633 ml fluid
60-day mortality 21% 18%
1600 patients:
• Lactate 6.7
• Blood culture positive 38%
• SBP 79 mm Hg
• All received antibiotics by 2.8 hours
Early Goal-Directed Therapy
Within 72 hours:
• 90% central lines ScvO2(6 hrs)
• 14% transfusion (0-6 hrs)
• 67% vasopressors
• 6238 ml fluid
Usual care within 72 hrs:
• 62% central lines (6 hrs)
• 7% transfusion
• 58% vasopressors
• 6095 ml fluid
28-day mortality 15% 16%

Initial studies showed benefit from early goal-directed therapy (EGDT).[9] [12] However, the more recent ProCESS[10] and ARISE[11] trails have not shown benefit.

The outcomes in the control groups of of more recent trials were much more favorable than in the earlier trials. Reasons may be:

  • Less fluid replacement in spite of similar protocols
  • Quicker antibiotics
  • The use of lower tidal volumes[13]
  • Less transfusions of blood[14].
  • Use of blood lactate levels rather than central venous oxygen levels.[12]

Protocols for the resuscitation of septic shock are:[12][9]

  1. "Isotonic crystalloid was administered in boluses to achieve a central venous pressure of 8 mm Hg or higher"
  2. "Mean arterial pressure goal of 65 mm Hg or higher, if not achieved with fluid administration, was targeted by initiating and titrating vasopressors (dopamine or norepinephrine)"[12] or goal of 65 mm Hg to 90 mm Hg[9]
  3. If ScvO2 < 70% or lactate clearance < 10%


Among the choices for vasoconstrictor agents for treating septic shock, a randomized controlled trial concluded that there was no difference between the biogenic amines norepinephrine (plus dobutamine as needed for cardiac output) versus epinephrine.[15] Similarly, another randomized controlled trial found no difference between vasopressin and norepinephrine.[16] Norepinephrine may be better than dopamine according to a meta-analysis.[17]


Practice guidelines

Clinical practice guidelines by American College of Critical Care Medicine conclude "hydrocortisone should be considered in the management strategy of patients with septic shock, particularly those patients who have responded poorly to fluid resuscitation and vasopressor agents."[18] In a meta-analysis that was included with the guidelines found greater shock reversal (at day 7) with hydrocortisone and a (insignificant) trend towards benefit in mortality".[18]

Regarding whether the use of steroids should be confined to patients with relative adrenal insufficiency, the guidelines state "ACTH stimulation test should not be used to identify those patients with septic shock or ARDS who should receive GC".[18]

Randomized, controlled trials

The most recent meta-analyses of randomized controlled trials conclude benefit.[19][18] In a meta-analysis that was included with the American College of Critical Care Medicine guidelines found greater shock reversal (at day 7) with hydrocortisone and a (insignificant) trend towards benefit in mortality".[18] Adding fludrocortisone may not help according to a more recent randomized controlled trial.[20]

Major trials of low dose corticosteroids for septic shock among patients with relative adrenal insufficiency.[21][22]
Trial Patients Interventions Outcomes Results for patients with
relative adrenal insufficiency
Control Intervention
499 patients
• Onset of shock ≤ 72 hours
• Adrenal insufficiency: 47%
• SAPS II score: 50
• Intratracheal intubation: 100%
• Arterial lactate: 4.0
200 mg/day of hydrocortisone for 7 days 28-day mortality 36% 39% In a post hoc analysis, the sickest patients ("systolic blood pressure persisting at less than 90 mm Hg within 30 hours") had better outcomes when given corticosteroids.[21]
French study[22]
300 patients
• Onset of shock ≤ 3 hours
• Adrenal insufficiency: 76%
• SAPS II score: 59
• Intratracheal intubation: 88%
• Arterial lactate: 4.5
200 mg/day of hydrocortisone for 7 days
50 microgram/day fludrocortisone
28-day mortality 63% 53%

Although the largest and most recent randomized controlled trial (CORTICUS[21]) was negative, its patients were less sick (as evidenced by less stringent inclusion criteria and less mortality in the control group) and mineralcorticoids were not given as a co-treatment as compared to the French trial be Annane[22]. In a post hoc analysis of the CORTICUS study, the sickest patients ("systolic blood pressure persisting at less than 90 mm Hg within 30 hours") had better outcomes when given corticosteroids.[21]

The lack of mineralocorticoid in the new study may not be important. In the new trial, the total hydrocortisone per day in the new trial is 200 mg. This equates to 200/250 or 0.8 mg (800 microgram) fludrocortisone (see relative potency table for corticosteroids). The French study by Annane used 50 microgram daily of fludrocortisone.[22]

Non-randomized studies

Non-randomized studies suggest benefit from steroids.[23][24]

Activated protein C

Recombinant human activated protein C, also called drotrecogin alpha, has been shown in a randomized controlled trial to be associated with reduced mortality (number needed to treat (NNT) of 16) in patients with multi-organ failure[25] If this is given, heparin should probably be continued.[26]

Tissue factor pathway inhibitor

Recombinant human tissue factor (thromboplastin) pathway inhibitor, also called tifacogin, was found not to be effective in a randomized controlled trial.[27]


Similar outcomes occur if the threshhold for erythrocyte transfusion is 7 or 9 g per deciliter.[14]

Polymyxin B hemoperfusion

Hemoperfusion through a polymyxin B column, intended to reduce circulating endotoxin,[28] may be beneficial according to a systematic review of randomized controlled trials.[29]

Intensive insulin

Intensive insulin for a target serum glucose of 80 and 110 mg/dL does not help.[20]


The mortality from severe sepsis and septic shock has dropped by almost half since the initial study of goal-directed therapy.[30]


  1. Anonymous (2021), Septic shock (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. Moore, Laura J.; Frederick A. Moore, S. Rob Todd, Stephen L. Jones, Krista L. Turner, Barbara L. Bass (2010-07-01). "Sepsis in General Surgery: The 2005-2007 National Surgical Quality Improvement Program Perspective". Arch Surg 145 (7): 695-700. DOI:10.1001/archsurg.2010.107. Retrieved on 2010-07-20. Research Blogging.
  3. Post F, Weilemann LS, Messow CM, Sinning C, Münzel T (November 2008). "B-type natriuretic peptide as a marker for sepsis-induced myocardial depression in intensive care patients". Crit. Care Med. 36 (11): 3030–7. DOI:10.1097/CCM.0b013e31818b9153. PMID 18824903. Research Blogging.
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  6. 6.0 6.1 6.2 Gaieski DF, Mikkelsen ME, Band RA, Pines JM, Massone R, Furia FF et al. (2010). "Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department.". Crit Care Med 38 (4): 1045-53. DOI:10.1097/CCM.0b013e3181cc4824. PMID 20048677. Research Blogging.
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  9. 9.0 9.1 9.2 9.3 9.4 Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B et al. (2001). "Early goal-directed therapy in the treatment of severe sepsis and septic shock.". N Engl J Med 345 (19): 1368-77. DOI:10.1056/NEJMoa010307. PMID 11794169. Research Blogging. Review in: ACP J Club. 2002 May-Jun;136(3):90
  10. 10.0 10.1 10.2 ProCESS Investigators. Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA et al. (2014). "A randomized trial of protocol-based care for early septic shock.". N Engl J Med 370 (18): 1683-93. DOI:10.1056/NEJMoa1401602. PMID 24635773. PMC PMC4101700. Research Blogging. Review in: Ann Intern Med. 2014 Jun 17;160(12):JC9
  11. 11.0 11.1 11.2 ARISE Investigators. ANZICS Clinical Trials Group. Peake SL, Delaney A, Bailey M, Bellomo R et al. (2014). "Goal-directed resuscitation for patients with early septic shock.". N Engl J Med 371 (16): 1496-506. DOI:10.1056/NEJMoa1404380. PMID 25272316. Research Blogging.
  12. 12.0 12.1 12.2 12.3 Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA et al. (2010). "Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial.". JAMA 303 (8): 739-46. DOI:10.1001/jama.2010.158. PMID 20179283. Research Blogging.
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  14. 14.0 14.1 Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S et al. (2014). "Lower versus higher hemoglobin threshold for transfusion in septic shock.". N Engl J Med 371 (15): 1381-91. DOI:10.1056/NEJMoa1406617. PMID 25270275. Research Blogging.
  15. Annane D, Vignon P, Renault A, et al (2007). "Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial". Lancet 370 (9588): 676-84. DOI:10.1016/S0140-6736(07)61344-0. PMID 17720019. Research Blogging.
  16. Russell, J. A., Walley, K. R., Singer, J., Gordon, A. C., Hebert, P. C., Cooper, D. J., et al. (2008). Vasopressin versus norepinephrine infusion in patients with septic shock, N Engl J Med, 358(9), 877-887. DOI:10.1056/NEJMoa067373.
  17. De Backer D, Aldecoa C, Njimi H, Vincent JL (2012). "Dopamine versus norepinephrine in the treatment of septic shock: A meta-analysis*.". Crit Care Med 40 (3): 725-30. DOI:10.1097/CCM.0b013e31823778ee. PMID 22036860. Research Blogging.
  18. 18.0 18.1 18.2 18.3 18.4 Marik PE, Pastores SM, Annane D, et al (June 2008). "Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine". Crit. Care Med. 36 (6): 1937–49. DOI:10.1097/CCM.0b013e31817603ba. PMID 18496365. Research Blogging.
  19. Annane D, Bellissant E, Bollaert PE, et al. (June 2009). "Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review". JAMA 301 (22): 2362–75. DOI:10.1001/jama.2009.815. PMID 19509383. Research Blogging.
  20. 20.0 20.1 COIITSS Study Investigators. Annane D, Cariou A, Maxime V, Azoulay E, D'honneur G et al. (2010). "Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial.". JAMA 303 (4): 341-8. DOI:10.1001/jama.2010.2. PMID 20103758. Research Blogging.
  21. 21.0 21.1 21.2 21.3 21.4 Sprung CL, Annane D, Keh D, et al (2008). "Hydrocortisone therapy for patients with septic shock". N. Engl. J. Med. 358 (2): 111–24. DOI:10.1056/NEJMoa071366. PMID 18184957. Research Blogging.
  22. 22.0 22.1 22.2 22.3 Annane D, Sébille V, Charpentier C, et al (August 2002). "Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock". JAMA 288 (7): 862–71. PMID 12186604[e]
  23. Miller RR, Dong L, Nelson NC, Brown SM, Kuttler KG, Probst DR et al. (2013). "Multicenter implementation of a severe sepsis and septic shock treatment bundle.". Am J Respir Crit Care Med 188 (1): 77-82. DOI:10.1164/rccm.201212-2199OC. PMID 23631750. PMC PMC3735248. Research Blogging.
  24. Funk D, Doucette S, Pisipati A, Dodek P, Marshall JC, Kumar A et al. (2014). "Low-dose corticosteroid treatment in septic shock: a propensity-matching study.". Crit Care Med 42 (11): 2333-41. DOI:10.1097/CCM.0000000000000518. PMID 25072758. Research Blogging.
  25. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 Mar 8;344(10):699-709. PMID 11236773
  26. Levi M, Levy M, Williams MD, et al (2007). "Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated)". Am. J. Respir. Crit. Care Med. 176 (5): 483–90. DOI:10.1164/rccm.200612-1803OC. PMID 17556722. Research Blogging.
  27. Abraham E, Reinhart K, Opal S, et al (July 2003). "Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial". JAMA 290 (2): 238–47. DOI:10.1001/jama.290.2.238. PMID 12851279. Research Blogging.
  28. Cruz DN et al. (2009 Jun 17), "Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial.", JAMA 301 (23): 2445-52
  29. Cruz DN, Perazella MA, Bellomo R, et al. (2007). "Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review". Crit Care 11 (2): R47. DOI:10.1186/cc5780. PMID 17448226. PMC 2206475. Research Blogging.
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