Effects of Paroxetine on Cardiovascular Function in Septic Patients

Effects of Paroxetine on Cardiovascular Function in Septic Patients: a Randomized Placebo Controlled Trial

It is known that septic shock is characterized by arterial hypotension, decreased peripheral vascular resistance and hyporeactivity to vasoconstrictor agents, with NO being an important mediator of this organ dysfunction. Data in the literature have shown that hyporeactivity to catecholamines is associated with a decrease in the density of α and ß receptors in the aorta and heart, respectively, as well as an increase in GRK2 levels and that NO contributes to the increase of this kinase in sepsis . Based on this, it is hypothesized that cardiac dysfunction and decreased peripheral vascular resistance observed in sepsis may result from an increase in GRK2 activity and/or expression and its inhibition may be a relevant therapeutic target in septic shock patients. Based on this line, a measurable clinical benefit of paroxetine through the regulation of GRK2 expression in patients with septic shock is postulated.

After 20 patients randomized the advisory board will unblind subjects to determine if the fluoxetine arm should be continued. Since it is not expected to have any beneficial effect of this treatment (it is only a comparative control to the effect of paroxetine on serotonin metabolism). Based on the decision of the committee the study could exclude the serotonin arm and the definitive sample size is going to be calculated.

Fluoxetine, as paroxetine, has activity upon serotonin uptake, but not on GRK-2 40mg, single dose a day, by mouth or enteric tube

Cumulative vasopressor dose in the first 48 hours after randomization Translation results Cumulative vasopressor dose in the first 48 hours after randomization

Variation in cardiovascular sequential organ failure assessment score score 24 to 120 hours after randomization

Variation of the cardiovascular sequential organ failure assessment score score between baseline daily until 120 hours later. Cardiovascular sequential organ failure assessment score varies between 0 and +4 points, higher scores meaning worse cardiovascular dysfunction

Variation of the total sequential organ failure assessment score score between baseline daily until 120 hours later. Total sequential organ failure assessment score varies between 0 and +24 points, higher scores meaning worse organ dysfunction

Inclusion Criteria: Patient over 18 years of age; Patient diagnosed with septic shock for less than 48 hours and using a minimum dose of noradrenaline (0.01 mcg/kg/min); Patients and/or legal guardians who consented to participate in the study through the free and informed consent term before randomization. Exclusion Criteria: Pregnant women; Patients with inability to use the gastrointestinal tract; Patients with known intolerance to paroxetine and/or fluoxetine; Patients on concomitant use of medications that may potentiate the occurrence of serotonin syndrome (tramadol, citalopram, escitalopram, sertraline, desvenlafaxine, venlafaxine, duloxetine, sibutramine, bupropion, amitriptyline, nortriptyline, lithium); Patients in end-of-life care or with an expected survival of less than 24 hours at the time of eligibility