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Investigational and Ineffective Therapies for Sepsis

Other Therapies being Investigated:

  • Inhibition of innate immunity
  • Intravenous immune globulin
  • Cytokine and endotoxin inactivation or removal
  • Interferon gamma
  • Granulocyte-macrophage colony stimulating factor
  • Stem cell therapy
  • Hemofiltration
  • Antcoagulants
  • Naloxone
  • Pentoxifylline
  • Statins
  • Beta-Blockade

Hydrocortisone, Vitamin C, and Thiamine

PROWESS-SHOCK Trial

Study Design: Multicenter, double blind, parallel design, randomized, placebo-controlled trial

  • N=1,664 patients with sepsis
  • DrotAA (n=842)
  • Placebo (n=822)
  • Setting: 208 sites in multiple continents
  • Enrollment: 2008-2010
  • Analysis: Intention-to-treat
  • Follow-up: 90 days

Results: Among patients with septic shock, activated protein C provides no mortality benefit at 28 or 90 days

Recombinant Human Activated

Protein C - rhAPC

(Xigiris or drotrecogin alpha)

Retrospective study- synergistically reverses the pathophysiologic changes of sepsis

Patients with a primary admitting diagnosis of severe sepsis or septic shock and a PCT level > 2 ng/mL were treated with:

  • IV vitamin C (1.5 g every 6 h for 4 days or until ICU discharge)
  • Hydrocortisone (50 mg every 6 h for 7 days or until ICU discharge followed by a taper over 3 days)
  • IV thiamine (200 mg every 12 h for 4 days or until ICU discharge)

Results:

  • Vitamin C regimen associated with reduced in-hospital morality, more rapid weaning from vasopressors, and prevention of organ dysfunction

rhAPC withdrawn from the market

While encouraging, methodological flaws with this study - randomized control trials needed before vitamin C protocols can be used routinely

  • Promotes fibrinolysis and inhibits thrombosis
  • Hypothesized it would benefit septic patients by modulating procoagulant response believed to contribute to multisystem organ dysfunction
  • Initial PROWESS trial - improved 28 day mortality
  • Conflicting data from subsequent trials lead to PROWESS-SHOCK trial

Defining Sepsis

Anesthetic Management Considerations

According to the updated Sepsis-3 definition, sepsis should be defined as:

“Life-threatening organ dysfunction caused by a dysregulated host response to infection.”

  • Source control procedures may be required
  • Volume resuscitation should be attempted prior to induction
  • Majority of anesthetics are cardiac depressants and inhibit compensatory hemodynamic responses
  • Further reduction in preload and afterload
  • Etomidate should be avoided - despite its minimal cardiovascular effects- due to adrenal suppression
  • Associated with increased mortality
  • Inhalational anesthetic requirements are lessened by severe sepsis

Defining Septic Shock:

“A subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to substantially increase mortality.”

Clinically Identified as:

  • Vasopressor required to maintain MAP >65
  • Serum lactate >2mmol/L in absence of hypovolemia

Medications in the Treatment of Sepsis

Hannah Zimmerman, RNAI

Advanced Pharmacology DNAP 723

Surviving Sepsis Campaign Recommendations

Other Surviving Sepsis Recommendations:

Blood Products

Mechanical Ventilation

  • For Sepsis-induced ARDS:
  • Higher PEEP
  • Prone positioning if PaO2/FIO2 <150
  • Recommend against use of beta-2 agonists in sepsis-induced ARDs without bronchospasm
  • Lower tidal volumes

Objectives:

  • RBC transfusion for hemoglobin<7
  • Earlier for MI, severe hypoxemia, or acute hemorrhage
  • Recommend against use of:
  • Erythropoietin for anemia associated with sepsis
  • FFP for clotting abnormalities in the absence of bleeding or planned invasive procedures
  • Platelets recommended for:
  • <10,000 in absence of bleeding
  • <20,000 if significant risk of bleeding
  • Higher counts >50,000 advised for active bleeding, surgery, or invasive procedures

Antibiotics

Glucose Control

Vasoactive Medications

  • Insulin dosing recommended when 2 consecutive blood glucose levels >180
  • Target blood glucose <180
  • Monitoring Q1-2 hours until glucose values are stable, then every 4 hours
  • Arterial blood use for POC testing recommended > capillary blood if arterial catheter in place

  • Overview of updated definition of sepsis and septic shock
  • Overview of medication management recommended by Surviving Sepsis Campaign guidelines
  • Anesthetic considerations

Corticosteroids

  • Obtain cultures prior to initiation of antibiotics
  • Initiation within 1 hour of recognition of sepsis or septic shock
  • Empiric broad-spectrum therapy initially
  • Combination therapy - using 2 antibiotics of different antimicrobrial classes recommended for septic shock
  • Narrowed once pathogen and sensitivities determined.
  • MAP of 65mmHg recommended
  • Arterial catheter recommended for all patients requiring vasopressors
  • Recommended against use of corticosteroids if IV fluid and vasopressors are successful in restoring hemodynamics
  • If hemodynamic stability not achievable:
  • 200mg/day IV hydrocortisone recommended
  • Norepinephrine first vasopressor of choice
  • Vasopressin - added to raise MAP to goal OR to decrease amount of norepi
  • Dopamine recommended for: patients with low risk of tachyarrhythmias and absolute or relative bradycardia
  • Dobutamine recommended in patients with persistent hypoperfusion despite adequate fluid loading and use of vasopressor agents

Fluid Resuscitation

Respiratory rate >22

Glasgow Coma Scale <15

SBP of 100 or less

Initial Resusitation:

30mg/kg of crystalloid within first 3 hours

Recommended to use LACTATE to help guide resuscitation

Goal is to normalize lactate

  • Crystalloids are fluid of choice for initial resuscitation
  • Addition of albumin suggested when substantial amounts of crystalloids are required

Additional fluids should be based off frequent reassessment of hemodynamic status

  • Heart Rate
  • Blood Pressure
  • Arterial oxygen saturation
  • Respiratory rate
  • Temperature
  • Urine output

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