Decatecholaminisation of Septic Shock With Dexmedetomidine and In-hospital Mortality

Study Overview
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Brief Summary
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The study aims to determine whether the infusion of DEX in septic shock can reduce in-hospital mortality, norepinephrine infusion, need and duration for mechanical ventilation, and acute kidney injury without significant adverse events.

Detailed Description
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During septic shock, acute stress response includes neural and humoral autonomic flaring, which tend to be beneficial in the short term. Once shock occurs, it is a failure of the compensation trial. In addition, chronic autonomic stimulation risks myocardial injury, immunosuppression, insulin resistance, and thrombo-embolic tendency. The investigators hypothesized that dacatecholaminisation with dexmedetomidine - as calibrated by heart rate control - would reduce the in-hospital mortality in septic shock, whether the patient is mechanically ventilated or not. The study aims to determine whether the infusion of DEX in septic shock can reduce in-hospital mortality, norepinephrine infusion, need and duration for mechanical ventilation, and acute kidney injury without significant adverse events.

Official Title
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Decatecholaminisation With Dexmedetomidine for Reduction of Mortality in Septic Shock: A Randomized Clinical Trial

Conditions
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Septic Shock, Sepsis

Intervention / Treatment
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* Drug: Dexmedetomidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (≥ 18 years) patients of either sex who develop septic shock with heart rate (HR) > 90 beats per minute (bpm). We choose the definition of septic shock as the start of norepinephrine (NE) infusion to maintain the mean arterial blood pressure (MAP) of ≥ 65 mmHg in a case of sepsis (≥ 2 SIRS criteria plus suspicion or confirmation of infection). Exclusion Criteria: Patient refusal or inability to obtain consent Failure of hemodynamic stabilization or hemoglobin < 7 gm/dl at time of inclusion Severe cardiac dysfunction (Ejection Fraction (EF) < 30%) History of heart block or patient on pacemaker Chronic liver Disease (Child-Pugh classification C) Severe valvular heart disease Pregnancy

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: An open label randomized controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexmedetomidine<br>Patients will receive dexmedetomidine infusion according to the protocol plus the usual care. We will evaluate patients for inclusion in the study after 6 hours on NE infusion, given stabilization of the MAP > 65 mmHg. In the DEX group, we will commence DEX infusion at the rate of 0.2 mcg.kg-1.h-1 without a loading dose, then titrate DEX infusion to maintain the HR from 60 to 90 bpm. Titration of the DEX infusion rate will not be more than 0.1 mcg.kg-1.h-1 every 30 minutes at any time. The maximum DEX infusion rate will be 0.7 mcg.kg-1.h-1. We aim to continue DEX infusion for 48 hours. After 48 hours of DEX infusion, we will taper the DEX infusion over one hour. According to our protocol, DEX infusion would trigger either STOP events or hemodynamic assessment events: | Drug: Dexmedetomidine<br>* A highly-selective alpha-2 agonist with sedative, analgesic, and sympatholytic effects.<br>* Other names: Precedex, Dexdor, Dexdomitor, Sileo;|
| No Intervention: Usual care without dexmedetomidine infusion<br>The patients in this group will receive the usual care. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In-hospital mortality | The investigators will review the patient status on discharge from the hospital, alive or dead | Through study completion, an average of 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Norepinephrine equivalent dose (NED) | reported as the average of the serial measurements; the NED of epinephrine will be estimated as 1:1 ratio, reported as mcg/kg/min (Shruti Goradia et al, 2021) | over the first 3 days after enrolment or death, which comes first | 
| Need for epinephrine infusion | Categorical variable (as yes/no outcome) | over the first 3 days after enrolment or death, which comes first | 
| Heart rate (HR) beat per minute | reported as the average of the serial measurements | over the first 3 days after enrolment or death, which comes first | 
| Mean arterial blood pressure (MAP) mmHg | reported as the average of the serial measurements | over the first 3 days after enrolment or death, which comes first | 
| Initiation of invasive mechanical ventilation (IMV) in non-ventilated patients | Categorical variable (as yes/no outcome) | Through study completion, an average of 3 months | 
| Early acute kidney injury | Categorical variable (as yes/no outcome) - as defined by Khwaja, A., 2012. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clinical Practice, 120(4), pp.c179-c184. | 48 hours after ICU admission in previously normal kidney function | 
| Late acute kidney injury | Categorical variable (as yes/no outcome) - as defined by the Khwaja, A., 2012. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clinical Practice, 120(4), pp.c179-c184. | 7 days after ICU admission in previously normal kidney function | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dexmedetomidine, randomized controlled trial