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
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rhAPC withdrawn from the market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:
- 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
- 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
- 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
- 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