1. Activated endothelial cells
Contemporary Challenges & Opportunities for Improving Pharmacotherapy in the Septic Patient 
Kristopher Tuttle, Matthew D. McDonald, Jisoon Chong, Carolyn Stone, Ethan J. Anderson 
 University of Iowa College of Pharmacy, Professional Discovery- Fall 2018
Background
Sepsis affects approximately 700,000 people worldwide annually and causes 210,000 deaths in the US each year. The incidence is rising by % per year since 2003, despite technological developments in intensive care units (ICUs) and advanced supportive treatment. Septic patients are generally hospitalized for extended periods and rarely ambulate before 2-3 weeks. The main organisms responsible for sepsis were G(-) in the 1970s and 1980s but are currently G(+). There is still no clear definition of sepsis due to lack of consensus. 1 
Current Standard of Care
Collect patient blood/body fluid sample for microbial identification
Initiate IV broad-spectrum antimicrobials to cover all likely pathogens
Initiate crystalloid IV fluids at 30 mL/kg within the first 3 hours
Give additional fluids as needed based on hemodynamic status of the patient
Lactate levels should be monitored as a marker for tissue hypoperfusion
Initiate norepinephrine as the first chronic vasopressor after fluid resuscitation
Continued hemodynamic monitoring
If fluids and vasopressors fail, hydrocortisone (IV) may be used (200 mg/day) 2
Pathogen
Steroids 
Sharma et al; ProCESS Trial ; Am J Respir Crit Care Med
Leaf et al; Calcitriol; Am J Crit Care Med 
Keh et al; HYPRESS Trial; JAMA
Gordon et al; VANISH Trial; JAMA 
PAMP's
Anti-TNFα
Bernard et al; Phase IIb Trial; Crit Care Med
TLR
Macrophage
Anti-IL-1
Shakoory et al; Phase III trial re-analysis; Crit Care Med 
Objectives
Gather current knowledge of the pathophysiology of multiple organ dysfunction syndrome (MODS) and failure in sepsis.
Review and critique completed clinical trials involving septic patients 
Propose future directions and opportunities for pharmacotherapies to prevent MOD and improve mortality 
TNFα
IL-1ß
IL-6
Complement pathway activation
DAMPs
Additional PMN's 
recruited
Tissue damage
CRP
Bone marrow production of PMNs
Opportunities for Improved Therapy
Clinical trials have exemplified the failures of novel drugs/targets
Novel drugs/targets are likely not the best approach to sepsis treatment
Biologics (drug type) & Inflammatory cytokines (target)
Not fully understood pathways
Standard of care remains best option for sepsis treatment, and has the most data to support it, however could use improvement
Antimicrobial drugs & Optimizing microbe identification
Fluids & Vasopressors
Introduce new clinical nomenclature to direct organ-specific or pathogen-specific therapies to decrease mortality
e.g., Renal sepsis, Pseudomonal sepsis, Hepatorenal sepsis , etc...
Hypercoagulation factors
Activated endothelial cells 
Leaky vasculature
Thrombosis
Methods
A literature search was conducted using PubMed and Google Scholar to investigate the pathophysiology of sepsis, with an emphasis on cardio-renal failure and immunological involvement. A review of randomized clinical trials (RCTs) conducted on septic patients within the last 20 years was also performed.
Anticoagulation
Annane et al; Xigris Trial (APC); Am J Respir Crit Care Med
Sharma et al; ProCESS Trial; Am J Respir Crit Care Med
Vasopressors 
Gordon et al; VANISH Trial; JAMA 
Hypoperfusion
Target organ failure
References
Riedemann, Niels C., et al. “The Enigma of Sepsis.” Journal of Clinical Investigation, vol. 112, no. 4, 2003, pp. 460–467., doi: /jci19523.
A. Rhodes et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: PMID  
Lactate Clearance 
Trzeciak et al; NO; Crit Care Med 
Hypotension