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.

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Septic Shock
• Intervention / Treatment: Drug: Paroxetine

Detailed Description

Ethical aspects The project was approved by the Research Ethics Committee of Hospital São José, Criciúma and Hospital Maternidade São José de Colatina - ES, centers that will recruit patients (CAAE 58552222.0.0000.5062 and 57637722.6.0000.5364).

Study design and procedures Double-blind, randomized, placebo-controlled, phase two clinical trial to evaluate the response to paroxetine in patients diagnosed with septic shock. The patients included will be randomized by a random number table (created by the random number generator from graphpad.com) into three groups: placebo group, paroxetine group (40mg/day) or fluoxetine group (40mg/day). Each group will be given the respective medication or placebo for 5 days from randomization or up to 1 day after shock resolution.

Patients' medical history, including previous comorbidities, laboratory tests, demographic data, and variables related to ICU admission will be prospectively collected on a specific form directly with the patient or legal guardian, or through the patient's electronic medical record.

Plasma will be collected to evaluate the levels of chemokines and cytokines (IL-6, IL-1β, TNF-α, IL-10 and IL-8). Whole blood will be collected to evaluate the internalization of alpha-1 adrenergic receptors and CXCR2 by flow cytometry. In addition, neutrophils will be extracted from whole blood by Percoll gradient to assess levels of GRK2 and phosphorylated GRK2 by western blot. The fluoxetine group was included in the study because, despite being also a serotonin reuptake inhibitor drug like paroxetine, it has no action on GRK2. Collections will be performed on the first (before drug administration), second, third and fifth day after randomization. Around 10ml of venous blood will be collected from each patient.

Eligible patients will be invited to participate in the research, by reading and signing the Free and Informed Consent Term. If the patient is unable to make a decision, the researcher will contact the family member or legal guardian to obtain consent for the research.

Randomization

Randomization will be performed by the blind team of the participating centers, using a simple randomization table and sealed envelopes containing the patient's group.

Patients will be allocated to each of the groups in a 1:1:1 ratio. The blind research team will not be involved in the direct care of patients and will be responsible for dispensing all necessary medication.

Intervention

The intervention under study involves the drugs paroxetine and fluoxetine. Treatment will be carried out with the use of paroxetine (40 mg/day) or fluoxetine (40 mg/day) or placebo for a maximum period of 5 days or up to one day after the shock has resolved. As this is a double-blind randomized clinical trial, a third person will be responsible for randomizing and dispensing the medication. After signing the informed consent by the patient or his legal representative, the team will inform the person responsible for randomizing the subjects. The dose will consist of a capsule of paroxetine or fluoxetine or placebo (of the same shape, smell and color) that will be administered in a single daily dose orally or nasoenteral tube. The start of treatment will take place within a maximum of 24 hours after randomization.

Inclusion and exclusion criteria

Inclusion:

• 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 - TCLE before randomization.

Exclusion:

• 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 Outcome

Variation of the cardiovascular SOFA score between baseline (shortly after enrollment in the study, before administration of the investigational product) and the value 48 hours later (time at which greater effect size is expected in view of the kinetics of paroxetine on expression / GRK2 phosphorylation).

Secondary outcomes

Cumulative vasopressor dose in the first 48 hours after randomization; Variation in cardiovascular SOFA score 24 to 120 hours after randomization; Cumulative vasopressor dose for 120 hours after randomization; Total SOFA score variation 24 to 120 hours after randomization; Length of stay in the ICU; Mortality during ICU stay.

Exploratory outcomes Neutrophilic levels of total and phosphorylated GRK2 Plasma levels of cytokines and chemokines Internalization of alpha-1 adrenergic and CXCR2 receptors in neutrophils

Sample size As there are no preliminary data to estimate an effect size, initially 20 patients will be included and randomized into the 3 groups. After this inclusion period, data blinding will be broken. If there is no sign of worsening of the clinical picture (assessed as worsening of shock during treatment), the effect size will be estimated and the final sample size will be calculated to have a power of 80 and an alpha error of 0.05. Estimating an effect size of 35% on the primary outcome between the paroxetine-treated group and the placebo, the estimated final sample size is 15 patients per group (to be confirmed by the pilot study).

• Study Type: Interventional
• Enrollment (Estimated): 92
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: felipe dal-pizzol, MD; Phone Number: +55 48 991852300; Email: fdpizzol@gmail.com

Study Locations

• Brazil
  • Espirito Santo
    • Colatina, Espirito Santo, Brazil
      • Recruiting
      • Hospital Maternidade São José de Colatina
      • Contact: Rodrigo Figueiredo, MD; Phone Number: +55 279888980486
  • Santa Catarina
    • Criciúma, Santa Catarina, Brazil, 88801460
      • Recruiting
      • Hospital Sao Jose
      • Contact: Danusa Damasio, PhD; Phone Number: +5548991097906; Email: danusa.damasio@hsjose.com.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 40mg, single dose a day, by mouth or enteric tube	Drug: Paroxetine; Paroxetine, 40mg/day, once a day, for 05 consecutive days or 24 hours after shock resolution; Other Names: Fluoxetine
Experimental: Paroxetine; 40mg, single dose a day, by mouth or enteric tube	Drug: Paroxetine; Paroxetine, 40mg/day, once a day, for 05 consecutive days or 24 hours after shock resolution; Other Names: Fluoxetine

What is the study measuring?

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
Cumulative vasopressor dose for 120 hours after randomization	Dose of infused norephineprine and/or vasopressin during 120 hours after randomization	120 hours
Length of stay in the ICU	time spent in ICU	90 days
Mortality during ICU stay	Mortality in the ICU	90 daus
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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neutrophilic levels of total and phosphorylated GRK2	Expression of GRK-2 measured by western blot in isolated neutrophils	120 hours
Plasma levels of cytokines and chemokines	Plasma levels of different cytokines and chemokines measured by ELISA	120 hours
Internalization of CXCR2 receptors in neutrophils	Internalization of receptors known to be influenced by GRK-2 inhibitor by flow cytometry	120 hours

Collaborators and Investigators

• Sponsor: Universidade do Extremo Sul Catarinense - Unidade Academica de Ciecias da Saude

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2023
• Primary Completion (Estimated): December 15, 2023
• Study Completion (Estimated): February 15, 2024

Study Registration Dates

• First Submitted: February 2, 2023
• First Submitted That Met QC Criteria: February 2, 2023
• First Posted (Actual): February 13, 2023

Study Record Updates

• Last Update Posted (Actual): November 15, 2023
• Last Update Submitted That Met QC Criteria: November 10, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Sepsis; Shock, Septic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Selective Serotonin Reuptake Inhibitors; Paroxetine
• Other Study ID Numbers: Paroxetine

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No