Sepsis, Septic Shock
Conditions
Keywords
septic shock, norepinephrine, sepsis, hypotension
Brief summary
The goal of this clinical trial is to determine whether early initiation of norepinephrine with rapid dose adjustment improves clinical outcomes in adult patients with septic shock. The study aims to evaluate the effect of early norepinephrine administration on mortality, hemodynamic stabilization, and resuscitation efficiency in adults aged 18 years and older diagnosed with septic shock. The main questions it aims to answer are: * Does early norepinephrine administration with rapid dose titration reduce 28-day mortality compared with standard treatment? * Does early norepinephrine administration with rapid dose tiration lead to faster shock control and reduced fluid requirements without increasing treatment-related adverse events? Researchers will compare early norepinephrine administration with rapid dose adjustment to placebo with standard sequential resuscitation and rescue norepinephrine as needed to see if early vasopressor initiation improves survival, shock resolution, and safety outcomes. Participants will: * Receive either norepinephrine or placebo infusion initiated within one hour of septic shock diagnosis, with dose adjustment every 15 minutes according to a standardized protocol * Undergo close hemodynamic and safety monitoring, including frequent vital sign assessment and limb perfusion evaluation * Receive standard sepsis care, including fluid resuscitation, antibiotics, and organ support as clinically indicated * Be followed for clinical outcomes and adverse events for up to 28 days after enrollment
Interventions
DRUGEarly norepinephrine administration and rapid dose adjustment
Norepinephrine 4 mg in 250 mL D5W, initiated at 0.05 mcg/kg/min. Titrate by 0.025 mcg/kg/min every 15 minutes if MAP \<65 mmHg, up to 0.15 mcg/kg/min maximum. Rescue norepinephrine available if needed (separate line). Limb ischemia monitoring every 15 minutes. Duration: 24 hours.
DRUGControl
Placebo (D5W 250 mL) with an identical dosing schedule. Rescue norepinephrine available via a separate line. Same monitoring protocols.
Sponsors
Siriraj Hospital
Maharaj Nakorn Si Thammarat
Kalasin Hospital
Khon Kaen Hospital
Udon Thani Regional Hospital
Hat Yai Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years * Sepsis: SOFA ≥2 with suspected infection * Mean arterial pressure \<65 mmHg * Diagnosed within 3 hours
Exclusion criteria
* Do-not-resuscitate orders * Pregnancy * Severe concurrent conditions (acute stroke, acute coronary syndrome, acute pulmonary edema, status asthmaticus, active gastrointestinal bleeding, status epilepticus, severe burn, severe trauma, and fatal drug overdose, End-stage malignancy * Peripheral arterial disease * Prior norepinephrine administration * Recurrent shock in the same patient
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 28-day survival | From enrollment to 28 days after enrollment | Survival at 28-day after enrollment. Telephone follow-up for patients who are discharged before 28 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with shock control achieved | From enrollment to 6 hours after enrollment | Shock control defined as mean arterial pressure greater than 65 mmHg combined with urine output greater than 0.5 milliliters per kilogram per hour OR lactate clearance greater than 10 percent within 6 hours |
| Duration of intensive care unit stay | From enrollment to hospital discharge or 90 days (whichever comes first) | Days of intensive care unit stay |
| Duration of hospital stay | From enrollment to hospital discharge or 90 days (whichever comes first) | Days of hospital stay |
| Duration of mechanical ventilation | From enrollment to hospital discharge or 90 days (whichever comes first) | Days on mechanical ventilation, including endotracheal tube and tracheostomy |
| Duration of renal replacement therapy | From enrollment to hospital discharge or 90 days (whichever comes first) | Days requiring renal replacement therapy, including continuous renal replacement therapy, intermittent hemodialysis, and peritoneal dialysis, that is newly initiated during this admission. Maintaining chronic hemodialysis is excluded. |
| Duration of vasopressor therapy | From enrollment to hospital discharge or 90 days (whichever comes first) | Days requiring vasopressor therapy |
| Time to Achievement of Early Goal-Directed Therapy Targets | From study drug initiation until achievement of all EGDT targets or up to 6 hours | Time in hours to achieve ALL EGDT targets: MAP ≥65 mmHg, urine output ≥0.5 mL/kg/hr, lactate clearance ≥10%, and ScvO₂ ≥70% (when measured) |
| Cumulative Fluid Volume Administered | Multiple assessments at: - Before randomization (baseline) - 1 hour after study drug initiation - 6 hours after study drug initiation - 24 hours (Day 1) 48 hours (Day 2) 72 hours (Day 3) after study drug initiation | Total volume in milliliters of intravenous crystalloid and colloid fluids administered during first 24 hours and first 72 hours Time Frame: At 1 hour, 6 hours, 24 hours (Day 1), 48 hours (Day 2), and 72 hours (Day 3) after treatment initiation |
| Incidence of Pulmonary Edema | From diagnosis until hospital discharge 90 days or death | New-onset cardiogenic pulmonary edema or non-cardiogenic pulmonary edema |
| Treatment-Related Adverse Events Including Cardiac Arrhythmias | From study drug initiation until hospital discharge or death, assessed 90 days | Composite outcome including new-onset arrhythmias (AF, AFL, SVT, VT, VF, AV block, bradycardia), limb/mesenteric ischemia, skin necrosis, and severe hypertension |
Countries
Thailand
Contacts
CONTACTTitaporn Nasaarn, Medical Doctor
CONTACTChairat Permpikul, Professor
PRINCIPAL_INVESTIGATORChairat Permpikul, Professor
Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University
Outcome results
None listed