Effects of Paroxetine on Cardiovascular Function in Septic Patients

Study Overview
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Brief Summary
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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.

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

Conditions
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Sepsis, Septic Shock

Intervention / Treatment
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* Drug: Paroxetine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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. The fluoxetine group was removed from the study after analysis of the first 20 patients (as foreseen in the initial protocol, after 20 patients included the blind would be broken to determine the final sample size) as it did not present an apparent benefit in the primary outcome. Considering that it had been included as a comparator for the effect of paroxetine on serotonin metabolism, and no beneficial effect from its use was anticipated, the study management committee decided to withdraw it.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>40mg, single dose a day, by mouth or enteric tube | Drug: Paroxetine<br>* Paroxetine, 40mg/day, once a day, for 05 consecutive days or 24 hours after shock resolution<br>|
| Experimental: Paroxetine<br>40mg, single dose a day, by mouth or enteric tube | Drug: Paroxetine<br>* Paroxetine, 40mg/day, once a day, for 05 consecutive days or 24 hours after shock resolution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to vasopressor discontinuation | Discontinuation of all vasopressors for at least 48 consecutive hours | 28 days of enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative vasopressor dose in the first 48 hours after randomization Translation results Cumulative vasopressor dose in the first 48 hours after randomization | Dose of infused norephineprine and/or vasopressin during the first 48 hours after randomization | 48 hours | 
| 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 | 120 hours | 
| Cumulative vasopressor dose for 120 hours after randomization | Dose of infused norephineprine and/or vasopressin during 120 hours after randomization | 120 hours | 
| Total sequential organ failure assessment score score variation 24 to 120 hours after randomization | 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 | 120 hours | 
| Length of stay in the ICU | time spent in ICU | 90 days | 
| Mortality during ICU stay | Mortality in the ICU | 90 daus |