Septic Shock Management Guided by Ultrasound: A Randomized Control Trial (SEPTICUS Trial)
Phase: NA
Conditions: Septic Shock
Sponsor: Saptadi Yuliarto

1 
Septic Shock Management Guided by Ultrasound: A Randomized 
Control Trial (SEPTICUS Trial) 
 
 
 
RESEARCH PROTOCOL 
 
 
 
 
dr. Saptadi Yuliarto, Sp.A(K), MKes 
 
 
 
PEDIATRIC EMERGENCY AND INTENSIVE THERAPY  
SAIFUL ANWAR GENERAL HOSPITAL, MALANG 
MEDICAL FACULTY OF BRAWIJAYA UNIVERSITY  
DECEMBER 30, 2020 

2 
SUMMARY 
Research Title 
Septic 
Shock 
Management 
Guided 
by 
Ultrasound: 
A 
Randomized Control Trial (SEPTICUS Trial) 
Research Design 
A multicentre experimental study in pediatric patients with a 
diagnosis of septic shock. 
Research Objective 
To examine the differences in fluid resuscitation outcomes for 
septic shock patients with the USSM and mACCM protocols 
• Patient mortality rate 
• Differences in clinical parameters 
• Differences in macrocirculation hemodynamic parameters 
• Differences in microcirculation laboratory parameters 
Inclusion/Exclusion Criteria 
Inclusion: Pediatric patients (1 month - 18 years old), diagnosed 
with septic shock 
Exclusion: patients with congenital heart defects, already 
receiving fluid resuscitation or inotropic-vasoactive drugs prior 
to study recruitment, patients after cardiac surgery 
Research Setting 
A multicenter study conducted in all pediatric intensive care units 
(HCU / PICU), emergency department (IGD), and pediatric 
wards in participating hospitals in Indonesia. 
Sample Size 
Calculating the minimum sample size using the clinical trial 
formula for the mortality rate, obtained a sample size of 340 
samples. 
Research Period 
The study was carried out in the period January 2021 to 
December 2022 
Data Collection Process 
Pediatric patients who met the study inclusion criteria were 
randomly divided into 2 groups, namely the intervention group 
(USSM protocol) or the control group (mACCM protocol). 
Patients who respond well to resuscitation will have their 
outcome analyzed in the first hour (15-60 minutes). Patients with 
fluid refractory shock will have their output analyzed at 6 hours. 
Evaluation of the inotropic-vasoactive administration is carried 
out every 30-60 minutes. Follow-up intervention after 6 hours 
was not part of the study, but based on the assessment of the 
DPJP. All patient outcome data will be analyzed statistically. 
 
 
 

3 
TABLE OF CONTENT 
 
Title Page 
………………………………………………………………………………………. 1 
Summary 
………………………………………………………………………………………. 2 
Table of Content 
……………………………………………………………………………… 3 
Introduction 
…………………………………………………………………………………….. 4 
     SEPTICUS Trial 
……………………………………………………………………………. 4 
     Sepsis 
………………………………………………………………………………………. 5 
Research Objective 
………………………………………………………………………….. 
6 
     Objective 
…………………………………………………………………………………… 6 
     Hypothesis 
…………………………………………………………………………………. 6 
Research Method 
…………………………………………………………………………….. 
7 
     Research Design 
…………………………………………………………………………. 
7 
     Research Time & Place 
…………………………………………………………………. 
7 
     Research Population 
…………………………………………………………………….. 
7 
     Research Approval ………………………………………………………………….......... 
7 
     Acceptance Criteria 
………………………………………………………………………. 
7 
     Sample Size Calculation 
…………………………………………………………………. 
7 
     Randomization Technique 
………………………………………………………………... 8 
     Research Variable 
………………………………………………………………………… 8 
     Operational Definition 
…………………………………………………………………….. 
9 
     Research Flow …………………………………………………………………………….. 
12 
     Processing, Analysis, and Presentation of Data 
……………………………………… 
13 
References 
…………………………………………………………………………………….. 14 
 
 

4 
INTRODUCTION 
 
SEPTICUS Trial 
 
The American College of Critical Care Medicine (ACCM) protocol for the treatment of 
septic shock has been widely used worldwide and is a guide to the 2012 Surviving Sepsis 
Campaign (SSC). Fluid resuscitation with a volume of 40-60 ml/kg in 5-10 times minutes is the 
first step in the management of septic shock.1,2 If fluid refractory shock occurs, therapy is followed 
by administration of vasoactive drugs. Furthermore, if catecholamine-resistant shock occurs 
within the 60-minute treatment, hemodynamic monitoring based on cardiac output (CO) and 
superior vena cava saturation (ScvO2) is required to guide subsequent vasoactive therapy.3,4 
neonatal intensive care unit from 97% to 9%.5–7 However, a large randomized controlled clinical 
trial had a higher mortality rate (relative risk 1.45; 95% CI, 1.13 to 1.86; P = 0.003) in these 
patients. severe infections that get fluid boluses.8 
 
Clinical signs are a basic parameter in the selection and monitoring of fluid and vasoactive 
therapy. In general, cold and warm shocks, respectively, represent hypodynamic (cardiogenic) 
and hyperdynamic (vasoplegic) mechanisms. As a consequence, the ACCM protocol 
recommends low doses of epinephrine or dopamine in cold shock and high doses of 
norepinephrine or dopamine in warm shock. However, combined monitoring with ultrasonography 
and invasive blood pressure showed that in patients with clinical symptoms of refractory shock, 
33% still had hypovolemia and 39.6% had cardiomyopathy. Likewise, some cold shock patients 
showed vasodilatory shock based on invasive blood pressure monitoring.9 These data 
demonstrate the importance of combining several hemodynamic monitoring modalities to improve 
the accuracy of the test. 
 
As the standard for monitoring cardiac output, pulmonary artery catheters show high 
validity and reliability; however, its use in the pediatric population is complicated by the difficulty 
and complication of insertion, as well as limited availability in tertiary hospitals.10 Currently, 
ultrasonography is widely used in hemodynamic monitoring of pediatric patients.11,12 
Echocardiography and ultrasound cardiac output monitor (USCOM) provide bulk information. 
heart comparable to the gold standard for pulmonary artery catheter.13,14 Ultrasound-based 
monitoring tools have the potential to be of great benefit, in terms of various examination 
parameters (cardiac output, myocardial function, structural abnormalities), as well as their non-
invasive, rapid, and practical nature. 

5 
 
Currently, data on the effectiveness of using ultrasound in pediatric septic shock patients 
are still limited. The variety of hemodynamic parameters that can be measured by 
ultrasonography should make fluid and vasoactive management more targeted and precise. This 
is expected to reduce the morbidity and mortality rates for children with septic shock. Furthermore, 
if the patient outcome is better, ultrasonography can be recommended as the standard for 
hemodynamic monitoring of septic shock. This study aimed to compare the outcome of pediatric 
septic shock patients between the ultrasound-guided septic shock management (USSM) and 
modified-ACCM-guided sepsis management (mACCM) groups. 
Sepsis 
 
Sepsis is a life-threatening organ dysfunction caused by immune dysregulation against 
infection.15 This definition has been used since 2016 in the adult population. In the pediatric 
population, they still use the 2005 criteria, namely systemic inflammatory response syndrome 
(SIRS) which is accompanied or caused by a suspect or proven infection.16 Sepsis is triggered by 
the body's immune response to pathogenic infections, which causes the release of pro-
inflammatory cytokines such as TNFα, IL-1, and IL-6. These cytokines play a role in the activation 
and proliferation of leukocytes, activation of the complement system, to increased thrombin 
production. In sepsis, the inflammatory activity has increased so that it has an effect on collateral 
damage and cell/tissue death.15,17 
 
Sepsis induces increased activation of systemic coagulation, due to increased thrombin 
production and inhibition of tissue factor. Hypercoagulability results in the formation of 
microthrombi which can progress with impaired local perfusion to tissue hypoxia. Hypoxia in the 
cardiovascular system and the activity of inflammatory mediators will lead to cardiomyopathy and 
vasodilation of arteries and veins. This results in impaired heart function and increased vascular 
permeability, resulting in systemic tissue hypoperfusion. Impaired vascular permeability also 
results in leakage of plasma fluid in the interstitial space, causing edema conditions.17,18 
  
 
 
 
 
 

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RESEARCH OBJECTIVE 
 
Objective 
The aim of this study was to compare the use of the ultrasound examination-based fluid 
resuscitation protocol (USSM) with the currently approved fluid resuscitation protocol (mACCM).  
 
Hypothesis 
Fluid resuscitation using the USSM protocol provides a better outcome than mACCM via 
the following parameters: 
 
Lower mortality rate 
 
Better 1st and 6th-hour clinical parameters 
 
Better 1st and 6th-hour macrocirculation hemodynamic parameters 
 
Better 1st and 6th-hour microcirculation laboratory parameters 
 
The incidence of fluid overload is less 
 
 
 
 
 
 
 
 
 
 
 
 
 

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RESEARCH METHODS 
 
Research design  
This research was conducted in a multicentre with a Non-blinded experimental design, 
Randomized Controlled Trial (RCT).  
Research Place and Time 
The research was conducted in the High Care Unit (HCU) room, the Pediatric Intensive 
Care Unit (PICU), the Emergency Room (IGD), or the pediatric ward of the Hospital. Held in 
January 2021 - December 2022  
Research Population  
The study population was pediatric patients with septic shock who were admitted to the 
intensive care room, emergency room, or pediatric ward. 
Research Approval 
This research was conducted after obtaining approval by the Committee for Research 
Ethics at Saiful Anwar General Hospital, Faculty of Medicine, Brawijaya University, Malang. 
Acceptance Criteria 
 
Inclusion criteria: 
a. Children diagnosed clinically and supported as septic shock 
b. Between 1 month old (corrected gestational age> 37 weeks) to 18 years 
 
Exclusion Criteria: 
a. Patients with uncorrected shunt congenital heart disease 
b. Patients who had already received fluid resuscitation prior to recruitment 
c. Patients who had received vasoactive-inotropes prior to recruitment 
d. Postoperative cardiac patients who find it difficult to distinguish between postoperative 
cardiogenic shock and septic shock  
Sample Size Calculation  
The sample size calculation used in this study uses the clinical trial formula for mortality 
rate: 

8 
 
 
 
 
 
N =  sampel size 
α = significance level with 0,05, thus zα = 1,96 
β = power of study with 0,2, thus zβ = 0,842 
M = Median time survival (time when 50% of subjects survive) 
 
M intervention = 72 hours 
 
M control = 48 hours 
Λ = insidence rate  
T = monitoring time = 72 hours 
 
So from this calculation, the sample size (n) is 170 samples per group. The total sample 
size is 340 samples 
Randomization technique 
 
Simple randomization was used to group the samples into treatment groups with 
randomization tables through a computer program. Each sample gets a serial number according 
to the order in which the patient was entered into the study sample. 
Research variable 
 
Independent Variable 
The independent variables in this study are: 
1. USSM Protocol 
2. mACCM protocol 
 
Dependent variable 
The variables bound in this study are: 
1. Mortality: amount and time 

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2. Clinical parameters 
3. Macrocirculation hemodynamic parameters 
4. Fluid overload parameter 
5. Microcirculation laboratory parameters 
 
Basic Characteristics Variable 
1. Age 
2. Gender 
3. Predicted mortality rate (PIM-2 score) 
4. Organ dysfunction score (PELOD-2 score) 
5. Diagnosis 
6. Blood culture results 
7. Volume of fluid resuscitation 
8. Vasoactive-inotropic score 
9. Duration of PICU care 
Operational Definition 
a. Sepsis: A sign of systemic inflammatory response syndrome (SIRS) that is accompanied or 
caused by a suspect or proven infection. The criteria for SIRS and infection were referred to the 
International pediatric sepsis consensus conference. 
b. Septic Shock: Sepsis and cardiovascular organ dysfunction are characterized by: (i) drop in 
blood pressure (hypotension) <P5 for age or systolic <2SD below normal for age; (ii) requires 
vasoactive drugs to maintain blood pressure within normal ranges (dopamine> 5 µg / kg / min or 
dobutamine, epinephrine or norepinephrine); (iii) satisfies two of: unexplained metabolic acidosis 
(base deficit> 5 mEq / L; increase in arterial lactate> 2 times the normal value; oligouria: urine 
production <0.5 mL / kg / hr; increased capillary refill time (CRT) )> 5 seconds; core temperature 
difference >3ºC. 
c. USSM protocol (Ultrasound-guided septic shock management): An ultrasound cardiac output 
monitor (USCOM) guided shock management protocol. Algorithms are listed in the research flow 
section. 

10 
d. MACCM protocol (modified American College of Critical Care Medicine): A shock management 
protocol based on ACCM guidelines that is based on clinical assessment only, with modifications 
in the form of: (1) fluid bolus duration extended to 15-20 minutes, (2) no 60th minute evaluation. 
use advanced hemodynamic monitoring tools.1 Algorithms are listed in the subsection of the 
research flow. 
e. Fluid resuscitation: Administration of crystalloid fluids (Ringer Lactate / Ringer Acetate) in the 
amount of 20 ml / kg per bolus within 15-20 minutes.10 Technique of fluid administration using a 
pressure bag or Push-Pull technique (PPT) 
f. Vasoactive drugs: drugs for shock therapy; consists of groups: 
1. Inotropes: dopamine 5-10 mcg / kg / minute, dobutamine 5-20 mcg / kg / minute, 
epinephrine 0.05-0.3 mcg / kg / minute, or milrinone 0.25-0.75 mcg / kg / minute 
2. Vasodilators: milrinone 0.25-0.75 mcg / kg / min or sodium nitroprusside 0.5-4 mcg / kg / 
min 
3. Vasopressors: norepinephrine 0.05-2 mcg / kg / minute, vasopressin 0.3-4 mU / kg / 
minute, epinephrine 0.3-1 mcg / kg / minute, or dopamine 10-20 mcg / kg / minute 
g. Mortality: subject mortality measured at 2-time points, ie 72 hours and time of discharge from 
intensive care. What is measured is the number and time of death in the two periods of time. The 
time of death is expressed in minutes from recruitment. 
h. Clinical parameters: clinical signs consisting of: 
1. Heart rate: the number of heartbeats per minute, seen from a vital sign monitor. Expressed 
in beats per minute. 
2. Capillary refill time (CRT): capillary filling time, checked on the sternum or glabella. 
Expressed in seconds. 
3. Peripheral pulse strength: radial or brachial pulse strength compared to the central (carotid 
or femoral) pulse. Weak category, when the peripheral pulse is weaker than the central 
pulse or both are equally weak. Strong category when the peripheral pulse is as strong as 
the central pulse.  
i. Cold shock: shock phenotype characterized by cold extremity temperature, CRT> 2 seconds, 
mottled skin, weak peripheral pulse strength, or narrowed pulse pressure 
j. Warm shock: a shock phenotype characterized by warm extremity temperature, CRT <2 
seconds, bounding pulse, or dilated pulse pressure.  

11 
k. Fluid overload parameter: 
1. Pulmonary Edema: accumulation of fluid in the alveolar or interstitial spaces indicated by 
rhonchi sounds or increased LUS. 
2. Lung Ultrasound Score (LUS): measurement of pulmonary parenchyma aeration using 
ultrasound on 12 scan areas (6 areas per 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: 
 
0 = no (or very few) B-lines 
 
1 = B-lines look many but separate (separated B-lines) 
 
2 = many B-lines and converge (coalescent B-lines) 
 
3 = lung consolidation 
3. Liver Span: the width of the liver or the length between the upper and lower borders of the 
liver. Determined by light percussion of the abdomen in the right midclavicular line at the 
level of the umbilicus towards the cranial direction (starting from the tympanic region to 
the lower border of the liver) and light percussion of the chest wall in the right midclavicular 
line from cranial to caudal (starting from the sonor area to the Dim, Expressed in 
centimeters (cm). 
4. ∆ Liver Span: difference in value between liver span before and after fluid resuscitation. 
Expressed in centimeters (cm). 
l. Macrocirculation hemodynamic parameters: 
1. Systolic blood pressure (TDS): systolic blood pressure that is measured non-invasively or 
invasively. Expressed numerically in mmHg and categorically (hypotensive if TDS <P5 
appropriate for age and normotension if TDS ≥ P5). P5 according to age is determined by 
the provisions or formula: 2.26 • 1 month - 1 year: 70 mmHg • 1 year - 10 years: (70 + 2n) 
mmHg, n = years • 10 - 18 years: 90 mmHg 
2. Mean blood pressure or mean arterial pressure (MAP): mean blood pressure as measured 
non-invasively or invasively. Expressed numerically in mmHg and categorically 
(hypotensive if MAP <P5 appropriate for age and normotensive if MAP ≥ P5). P5 according 
to age is determined by the formula: 1.5 n + 40 mmHg. 

12 
3. Inotropy: The power of the heart pump which on the USCOM examination is represented 
by the SMII (Smith-Madigan Inotropy Index) measurement and is expressed in Watts per 
meter squared (W / m²). Normal values range from 1.2-2.2 W / m². 
4. Systemic Vascular Resistance Index (SVRI): Systemic vascular resistance is the burden 
facing the heart. Measured by USCOM and expressed in units d.s / cm5 / m². Normal 
value 800-1600. Classification: low SVRI <800, high CI> 1600. 
5. Stroke volume index (SVI): ventricular ejection volume per beat divided by body surface 
area expressed in units of milliliters per meter squared (mL / m²). Normal value 30-60, 
Classification: low SVI <30, high SVI> 60. 
6. Cardiac Index (CI): ventricular ejection volume in one minute divided by the body surface 
area expressed in units of liters per minute per meter squared (L / min / m²). Normal value 
3,3-6,0. Classification: low CI <3.0, high CI> 6,0. 
m. Microcirculation laboratory parameters: 
1. Base deficit: base deficit value from blood gas analysis. 
2. Blood lactate: lactate levels from arterial blood. Expressed in mmol / L. 
n. Fluid refractory shock: persistent shock after fluid resuscitation, which is accompanied by: 
1. Increased SVI or CI <10% post fluid bolus (in the USSM group), or 
2. Addition of liver span or appearance of crackles/rales (in the mACCM group) 
Research Flow 
 
All patients who met the inclusion criteria were randomized and divided into intervention 
(USSM) or control (ACCM) groups. The research subjects will undergo 1 or 2 stages of research: 
(1) subjects who have achieved the target of therapy in stage 1 (fluid resuscitation), will stop their 
intervention and have all their outcomes analyzed in the first hour (15-60 minutes); (2) subjects 
with fluid refractory shock entered the second phase of the study (vasoactive-inotropic therapy), 
their intervention was discontinued and the outcome was analyzed at 6 hours. Evaluation of 
vasoactive-inotropic administration is carried out every 30-60 minutes. All interventions after the 
6th hour were not part of the study but were based on the assessment and advice of the doctor 
in charge of services (DPJP). Advanced hemodynamic monitoring tools, measurement 
modalities, or management outside the study protocol can be used after 6 hours; or in the duration 
of the study period if the DPJP deems it necessary for patient safety. Observation of mortality was 
continued until the 72nd hour and on discharge of intensive care. All matters that deviate from the 

13 
protocol are recorded in the data collection sheet; the subjects will still be analyzed according to 
the randomization group. 
Processing, Analysis, and Presentation of Data 
This study uses an intention to treat analysis. All loss of follow up cases will still be 
analyzed as dead subjects. All cases with protocol violence or treatment outside the protocol were 
still analyzed in the same group, according to randomization results. An interim analysis will be 
performed after 30 and 70 percent of the subjects have achieved. If the mortality outcome was 
clinically and statistically significant, the study would be terminated. All basic characteristics were 
analyzed descriptively, presented in the form of mean ± SD or median ± IQR (interquartile range) 
in the frequency table. For all dependent variables, a Normality test was performed using the 
Shapiro-Wilk and a variant test (to determine whether the data variance was the same or not) 
using Levene's test. Independent T-test was used for comparison of numerical data with normal 
distribution. If the distribution of data is not normal and the variance of the data is not the same, 
the Mann Whitney test is used. Chi-Square and Fisher's Exact tests were used to determine 
differences in categorical variables between the two groups. The difference in mortality rates was 
tested using the Kaplan-Meier survival analysis. This research is significant if the p-value <0.05. 
All data processing techniques are performed using the 20 PS (SPSS 20PS) statistical product 
and service solution software. 
 
 
 
 
 
 
 
 
 
 
 
 

14 
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