Septic shock

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."

Epidemiology

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

Complications

Myocardial dysfunction

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

Treatment

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

Antibiotics

Observational studies of antibiotics.

Study	Patients	Interventions	Results
EMSHOCKNET 2011	291 ED patients • 34% bacteremia • 16% mortality	41% received antibiotics before shock	Time to appropriate antibiotics not associated with mortality
Gaieski et al 2010	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 2006	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.

Recommendations for choosing antibiotics are available.

Goal-directed resuscitation

Major trials of Goal-directed resuscitation

Trial	Patients	Interventions	Usual care	Outcomes	Results for patients		Comments
					Intervention	Control
Early Goal-Directed Therapy Collaborative Group 2001	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%
ProCESS 2014	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%
ARISE 2014	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). However, the more recent ProCESS and ARISE 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
• Less transfusions of blood.
• Use of blood lactate levels rather than central venous oxygen levels.

Protocols for the resuscitation of septic shock are:

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)" or goal of 65 mm Hg to 90 mm Hg
3. If ScvO₂ < 70% or lactate clearance < 10%

• If hematocrit is < 30%, packed red blood cells were transfused
• If hematocrit is > 30%, cardiotonic agents such as dobutamine

Vasopressors

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. Similarly, another randomized controlled trial found no difference between vasopressin and norepinephrine. Norepinephrine may be better than dopamine according to a meta-analysis.

Corticosteroids

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." 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".

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".

Randomized, controlled trials

The most recent meta-analyses of randomized controlled trials conclude benefit. 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". Adding fludrocortisone may not help according to a more recent randomized controlled trial.

Major trials of low dose corticosteroids for septic shock among patients with relative adrenal insufficiency.

Trial	Patients	Interventions	Outcomes	Results for patients with relative adrenal insufficiency		Comments
				Control	Intervention
CORTICUS 2008	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.
French study 2002	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) 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. 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.

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.

Non-randomized studies

Non-randomized studies suggest benefit from steroids.

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 If this is given, heparin should probably be continued.

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.

Transfusion

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

Polymyxin B hemoperfusion

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

Intensive insulin

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

Prognosis

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