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 1.5-1.8% 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:10.1172/jci19523. A. Rhodes et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. PMID 28101605  Lactate Clearance  Trzeciak et al; NO; Crit Care Med  Hypotension