Pilot Study of Bevacizumab (Avastin) in Patients With Septic Shock

Sepsis is responsible for significant morbidity, mortality, and costs to patients in our healthcare system. The hospital case mortality rate for severe sepsis (sepsis with acute organ system dysfunction) is between 30-50%,7-12 with an incidence of approximately 751,000 cases and 215,000 deaths nationally per year. The overall cost of care is estimated at $16.7 billion annually in the US.Despite significant advances in medical science, the overall mortality rate for severe sepsis has not improved substantially over time.

VEGF signaling and sepsis. VEGF contributes to inflammation and coagulation - the key elements in sepsis pathophysiology. For example, under in vitro conditions, VEGF induces the expression of cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1) in endothelial cells and promotes adhesion of leukocytes. Moreover, VEGF signaling upregulates tissue factor mRNA, protein and procoagulant activity. Several studies have shown increased circulating levels of VEGF in patients with sepsis. In one study, maximum VEGF levels were increased in survivors versus non-survivors in sepsis. In another study of patients with meningococcal meningitis, elevated VEGF levels were associated with shock and upregulation of IL-1beta, IL-10, IL-12, complement activation and increased permeability.We have additional human data on 83 patients demonstrating an association of VEGF with SOFA score, IL-1, and IL-6. Consistent with its critical role in inflammation, VEGF inhibition using a VEGF trap resulted in attenuation of plasma interleukin IL-6 and IL-10 levels in a mouse cecal ligation puncture (CLP) model.

VEGF signaling is an important determinant of sepsis morbidity and mortality in animal models. We have recently shown that sepsis is associated with a time-dependent increase in circulating levels of VEGF in animal and human models of sepsis.2 The overexpression of sFlt-1 as well as the addition of exogenous sFLT-1 (each binds and neutralizes VEGF) in mice attenuated lipopolysaccharide- and CLP-mediated mediated morbidity (cardiac dysfunction, vascular permeability and endothelial activation) and mortality in sepsis. Importantly, these findings have been reproduced and extended by others.6 The striking and reproducible reduction in morbidity and mortality make a compelling case for further exploration in human sepsis.

A role for Bevacizumab in treating patients with severe sepsis. There are several advantages in employing Bevacizumab as a lead agent for inhibiting VEGF signaling in patients with severe sepsis. First, as a humanized monoclonal antibody, it has a sufficiently long half-life that it may be given as a single injection in this patient population. Second, it is already FDA approved for use in patients with certain types of cancer. Thus, there is extensive knowledge of its pharmacokinetics and pharmacodynamics (at least in the latter population). Moreover, it should not be difficult to obtain permission for use in septic patients. Third, its chief side effect, namely hypertension, will not be a major concern in sepsis, since this condition is associated with hypotension.