Clinical trial NCT05725837: Effects of Paroxetine on Cardiovascular Function in Septic Patients
Official title: Effects of Paroxetine on Cardiovascular Function in Septic Patients: a Randomized Placebo Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Septic Shock
Sepsis
Lead sponsor: Universidade do Extremo Sul Catarinense - Unidade Academica de Ciecias da Saude
Sponsor class: OTHER
First posted: 2023-02-13
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Time to vasopressor discontinuation
timeFrame: 28 days of enrollment
Secondary outcomes:
measure: Cumulative vasopressor dose in the first 48 hours after randomization Translation results Cumulative vasopressor dose in the first 48 hours after randomization
timeFrame: 48 hours
measure: Variation in cardiovascular sequential organ failure assessment score score 24 to 120 hours after randomization
timeFrame: 120 hours
measure: Cumulative vasopressor dose for 120 hours after randomization
timeFrame: 120 hours
measure: Total sequential organ failure assessment score score variation 24 to 120 hours after randomization
timeFrame: 120 hours
measure: Length of stay in the ICU
timeFrame: 90 days
measure: Mortality during ICU stay
timeFrame: 90 daus
Other outcomes:
measure: Neutrophilic levels of total and phosphorylated GRK2
timeFrame: 120 hours
measure: Plasma levels of cytokines and chemokines
timeFrame: 120 hours
measure: Internalization of CXCR2 receptors in neutrophils
timeFrame: 120 hours
Locations:
city: Colatina
country: Brazil
facility: Hospital Maternidade São José de Colatina
state: Espirito Santo
city: Criciúma
country: Brazil
facility: Hospital São José
state: Santa Catarina
Study officials:
References: