Septic Shock Management Guided by Ultrasound: SEPTICUS Trial

Study Overview
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Brief Summary
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This clinical study aims to compare the recent septic shock management protocol from American College of Critical Care Medicine (ACCM) to Ultrasound-guided Septic Shock Management (USSM) protocol. USSM protocol laid on Doppler ultrasonography to evaluate stroke volume, cardiac index, and systemic vascular resistance in each step of management to decide the proper fluid resuscitation and vasoactive therapy; differs from ACCM protocol which use clinical finding in its early step. ACCM protocol application elicits risk of improper therapy since clinical sign per se often could not describe the certain cardiac output. This can be prevented earlier by USSM protocol. The outcome compared of the two protocols is: mortality rate, clinical parameter, macrocirculation hemodynamic parameter, laboratory microcirculation parameter, and signs of fluid overload. The investigators hypothesized if the USSM protocol had a better outcome and less fluid overload complication.

Detailed Description
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This study is a randomized controlled trial to compare the usage of ACCM protocol and USSM protocol in fluid resuscitation for septic shock pediatric patients. The USSM protocol is the intervention, and the ACCM protocol is the control. This study implemented in septic shock pediatric patients treated in the intensive care unit. Each patient will be randomized into 2 groups, the USSM group or the ACCM group. In the initial step, all patient in each group will receive early acute/emergency therapy: oxygen support, vascular access, and fluid resuscitation. The monitoring of the patient including clinical parameters and laboratory examination for both groups, except Doppler ultrasonography that performed in each step of management of the intervention group. The monitoring is performed every 15 minutes in the first hour of resuscitation. If the patient show good response (fluid responsive shock), the monitoring stops in 1 hour. In contrast, if the patient reveal fluid refractory shock, the vasoactive agent will be administered and monitoring continues until 6 hours. All outcome parameters, except mortality rate, will be recorded at 6 hours. The mortality rates will be recorded at 72 hours and time of intensive care discharge. Sample size in this study was calculated by clinical trial formula for mortality rate with a significance level of 0.05 and study power of 0.2. From the calculation, the subject needed is 170 patients for each group (total 340 subjects). The basic characteristics of the patient will be analyzed descriptively. All parameter data will be analyzed statistically by Statistical Product and Service Solution (SPSS) 20, preceded by normality test and homogeneity test. The study analysis will be intention-to-treat. The mortality rate was analyzed by Kaplan-Meier survival analysis. Data transformation will be performed if needed in case of outlier data or out-of-range results.

Official Title
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Septic Shock Management Guided by Ultrasound: A Randomized Control Trial (SEPTICUS Trial)

Conditions
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Septic Shock

Intervention / Treatment
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* Procedure: USSM protocol
* Procedure: ACCM protocol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diagnosed as septic shock according to Pediatric Surviving Campaign (2005) Exclusion Criteria: patient with uncorrected congenital heart disease with shunting obtain fluid resuscitation before recruitment process obtain inotropic-vasoactive agent before recruitment process after undergo any heart surgery

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum 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: Each eligible patient will be randomized into 2 groups of treatment, the USSM protocol or the ACCM protocol. All of subjects in each group will receive emergency management: oxygen support, vascular access, and fluid resuscitation. In intervention group, each step of fluid and vasoactive management will be guided by clinical sign and Doppler ultrasonography, whereas in control group only guided by the clinical sign.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: USSM protocol<br>patient in the intervention group receive fluid resuscitation and inotropic-vasoactive agent, if needed, in accordance to USSM protocol of fluid resuscitation. | Procedure: USSM protocol<br>* In the initial step, all subjects will receive emergency management: oxygen support, vascular access, and fluid therapy. Doppler ultrasonography by Ultrasound Cardiac Output Monitoring (USCOM) is also performed to record initial stroke volume (SV), cardiac index (CI), and systemic vascular resistance (SVR). The initial fluid resuscitation is 20 mL/kg body weight, then the response measured by clinical and USCOM examination. If any improvement of clinical sign and normal SVI, CI, SVR, intervention will be stopped. In contrary, if shock persist, subsequent fluid resuscitation and/or vasoactive therapy will be administered, guided by USCOM. The therapeutic goal of USCOM: SVI 30-60 mL/m2, CI 3.3-6.0 L/minute/m2, and SVRI 800-1600 d.s/cm5/m2<br>|
| Experimental: ACCM protocol<br>patient in the control group receive fluid resuscitation and inotropic-vasoactive agent, if needed, in accordance to ACCM protocol of fluid resuscitation. | Procedure: ACCM protocol<br>* In the initial step, all subjects will receive emergency management: oxygen support, vascular access, and fluid therapy. Doppler ultrasonography by Ultrasound Cardiac Output Monitoring (USCOM) is also performed to record initial stroke volume (SV), cardiac index (CI), and systemic vascular resistance (SVR). The initial fluid resuscitation is 20 mL/kg body weight, then the response measured by clinical. If any improvement of clinical sign, intervention will be stopped. In contrary, if shock persist, subsequent fluid resuscitation and/or vasoactive therapy will be administered, guided by clinical parameter.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality rate | Time of mortality occurrence since randomization, comparing intervention and control group. | 72 hours of the initial fluid resuscitation | 
| Number of mortality | Amount of non-survivor subject, comparing intervention and control group. | 72 hours of the initial fluid resuscitation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart rate | Heart rate is measured by vital sign monitor device, reported in beat/minute, and classified into bradycardia (below normal rate according to age of PALS criteria), normal, and tachycardia (above normal rate according to age of PALS criteria). | 1 hour in fluid-responsive subject or 6 hour in fluid-refractory subject after fluid resuscitation initiated | 
| Capillary refill time | Capillary refill time is measured by pressing forehead and sternal skin; time needed for the pink color to return will be measured and reported in second, then classified based on WHO criteria, into prolonged (above 3 seconds) or normal (below or equal than 3 seconds). | 1 hour in fluid-responsive subject or 6 hour in fluid-refractory subject after fluid resuscitation initiated | 
| Peripheral pulse strength | Peripheral pulse strength is measured by comparing peripheral radial pulse and central (carotid or femoral) pulse, reported qualitatively as weak or normal/strong | 1 hour in fluid-responsive subject or 6 hour in fluid-refractory subject after fluid resuscitation initiated | 
| Systolic blood pressure | Systolic blood pressure is measured by vital sign monitor device and reported in mmHg, and classified into hypotension (below 5th percentiles according to age of PALS criteria), normal (above or equal than 5th percentiles according to age of PALS criteria), and high (above 95th percentiles according to age of PALS criteria). | 1 hour in fluid-responsive subject or 6 hour in fluid-refractory subject after fluid resuscitation initiated | 
| Mean arterial pressure | Mean arterial pressure (MAP) is measured by vital sign monitor device and reported in mmHg, and classified into hypotension (below 5th percentiles according to age of PALS criteria), normal (above or equal than 5th percentiles according to age of PALS criteria), and high (above 95th percentiles according to age of PALS criteria). | 1 hour in fluid-responsive subject or 6 hour in fluid-refractory subject after fluid resuscitation initiated | 
| Systemic vascular resistance index | Systemic vascular resistance index (SVRI) is measured by USCOM, reported in d.s/cm5/m2, and classified into low (below 800), normal (800 to 1600), and high (above 1600) | 1 hour in fluid-responsive subject or 6 hour in fluid-refractory subject after fluid resuscitation initiated | 
| Stroke volume index | Stroke volume index (SVI) is measured by USCOM, reported in mL/m2, and classified into low (below 30), normal (30 to 60), and high (above 60). | 1 hour in fluid-responsive subject or 6 hour in fluid-refractory subject after fluid resuscitation initiated | 
| Cardiac index | Cardiac index (CI) is measured by USCOM, reported in L/minute/m2, and classified into low (below 3.3), normal (3.3 to 6.0), and high (above 6.0). | 1 hour in fluid-responsive subject or 6 hour in fluid-refractory subject after fluid resuscitation initiated | 
| Base deficit | Base deficit is measured by blood gas analysis examination, reported in mmol/L, and classified into low (below -3), normal (-3 to 3), and high (above 3). | 1 hour in fluid-responsive subject or 6 hour in fluid-refractory subject after fluid resuscitation initiated | 
| Blood lactate level | Blood lactate level is measured from arterial blood, reported in mmol/L, and classified into normal (below or equal to 2.0) or high (above 2.0). | 1 hour in fluid-responsive subject or 6 hour in fluid-refractory subject after fluid resuscitation initiated | 
| Liver span increase | The increase of liver span is clinically measured from mid-costal right arch to the edge of liver, and reported in centimeters. | 1 hour in fluid-responsive subject or 6 hour in fluid-refractory subject after fluid resuscitation initiated | 
| Lung ultrasound score | Lung Ultrasound Score is examined with ultrasound using linear transducer (7.5 to 11 Mhz) to measure pulmonary parenchyma aeration on 12 scan areas (6 areas in each hemithorax), by a doctor who is ultrasound-certified lung. Each hemithorax is divided by 3 vertical lines (parasternal, anterior axillary, and posterior axillary) so that it becomes 3 areas (anterior, lateral, and posterior); and 1 horizontal line dividing the hemithorax into 2 equal parts. In each area a score is recorded. The final result is a total score of 12 areas. The scores are stated as follows: i. 0 = no (or very few) B-lines ii. 1 = B-lines look many but separate (separated B-lines) iii. 2 = many B-lines and converge (coalescent B-lines) iv. 3 = lung consolidation | 1 hour in fluid-responsive subject or 6 hour in fluid-refractory subject after fluid resuscitation initiated | 
| Vasoactive-inotropic score (VIS) | The Vasoactive-Inotropic Score (VIS), quantifies the amount of cardiovascular support required by subjects and includes dopamine, dobutamine, epinephrine, milrinone, vasopressin, and norepinephrine. | 1 hour in fluid-responsive subject or 6 hour in fluid-refractory subject after fluid resuscitation initiated | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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septic shock, Doppler ultrasonography, Fluid resuscitation, Vasoactive therapy, Mortality rate, Fluid overload