Septic Shock Management Guided by Ultrasound: SEPTICUS Trial

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

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.

Study Overview

• Status: Recruiting
• Conditions: Septic Shock
• Intervention / Treatment: Procedure: USSM protocol; Procedure: ACCM protocol

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 340
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Saptadi Yuliarto, MD; Phone Number: +6281233053652; Email: saptadiy@ub.ac.id
• Study Contact Backup: Name: Nur Hidayati Azhar, MD; Phone Number: +62 822-4509-9109; Email: nur.hidayati.azhar@gmail.com

Study Locations

• Indonesia
  • Jawa Timur
    • Malang, Jawa Timur, Indonesia, 65145
      • Recruiting
      • RSUD Dr. Saiful Anwar
      • Contact: Saptadi Yuliarto, MD; Phone Number: +6281233053652; Email: saptadiy@ub.ac.id
      • Sub-Investigator: Kurniawan Taufiq Kadafi, MD
      • Sub-Investigator: Nur Hidayati Azhar, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: USSM protocol; 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; 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
Experimental: ACCM protocol; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Saptadi Yuliarto
• Investigators: Study Director: Saptadi Yuliarto, MD, University of Brawijaya

Publications and helpful links

General Publications

• Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005 Jan;6(1):2-8. doi: 10.1097/01.PCC.0000149131.72248.E6.
• Davis AL, Carcillo JA, Aneja RK, Deymann AJ, Lin JC, Nguyen TC, Okhuysen-Cawley RS, Relvas MS, Rozenfeld RA, Skippen PW, Stojadinovic BJ, Williams EA, Yeh TS, Balamuth F, Brierley J, de Caen AR, Cheifetz IM, Choong K, Conway E Jr, Cornell T, Doctor A, Dugas MA, Feldman JD, Fitzgerald JC, Flori HR, Fortenberry JD, Graciano AL, Greenwald BM, Hall MW, Han YY, Hernan LJ, Irazuzta JE, Iselin E, van der Jagt EW, Jeffries HE, Kache S, Katyal C, Kissoon N, Kon AA, Kutko MC, MacLaren G, Maul T, Mehta R, Odetola F, Parbuoni K, Paul R, Peters MJ, Ranjit S, Reuter-Rice KE, Schnitzler EJ, Scott HF, Torres A Jr, Weingarten-Arams J, Weiss SL, Zimmerman JJ, Zuckerberg AL. American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock. Crit Care Med. 2017 Jun;45(6):1061-1093. doi: 10.1097/CCM.0000000000002425. Erratum In: Crit Care Med. 2017 Sep;45(9):e993. Kissoon, Niranjan Tex [corrected to Kissoon, Niranjan]; Weingarten-Abrams, Jacki [corrected to Weingarten-Arams, Jacki].
• Weiss SL, Peters MJ, Alhazzani W, Agus MSD, Flori HR, Inwald DP, Nadel S, Schlapbach LJ, Tasker RC, Argent AC, Brierley J, Carcillo J, Carrol ED, Carroll CL, Cheifetz IM, Choong K, Cies JJ, Cruz AT, De Luca D, Deep A, Faust SN, De Oliveira CF, Hall MW, Ishimine P, Javouhey E, Joosten KFM, Joshi P, Karam O, Kneyber MCJ, Lemson J, MacLaren G, Mehta NM, Moller MH, Newth CJL, Nguyen TC, Nishisaki A, Nunnally ME, Parker MM, Paul RM, Randolph AG, Ranjit S, Romer LH, Scott HF, Tume LN, Verger JT, Williams EA, Wolf J, Wong HR, Zimmerman JJ, Kissoon N, Tissieres P. Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children. Pediatr Crit Care Med. 2020 Feb;21(2):e52-e106. doi: 10.1097/PCC.0000000000002198.
• Weiss SL, Peters MJ, Alhazzani W, Agus MSD, Flori HR, Inwald DP, Nadel S, Schlapbach LJ, Tasker RC, Argent AC, Brierley J, Carcillo J, Carrol ED, Carroll CL, Cheifetz IM, Choong K, Cies JJ, Cruz AT, De Luca D, Deep A, Faust SN, De Oliveira CF, Hall MW, Ishimine P, Javouhey E, Joosten KFM, Joshi P, Karam O, Kneyber MCJ, Lemson J, MacLaren G, Mehta NM, Moller MH, Newth CJL, Nguyen TC, Nishisaki A, Nunnally ME, Parker MM, Paul RM, Randolph AG, Ranjit S, Romer LH, Scott HF, Tume LN, Verger JT, Williams EA, Wolf J, Wong HR, Zimmerman JJ, Kissoon N, Tissieres P. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Intensive Care Med. 2020 Feb;46(Suppl 1):10-67. doi: 10.1007/s00134-019-05878-6.
• Santhanam I, Sangareddi S, Venkataraman S, Kissoon N, Thiruvengadamudayan V, Kasthuri RK. A prospective randomized controlled study of two fluid regimens in the initial management of septic shock in the emergency department. Pediatr Emerg Care. 2008 Oct;24(10):647-55. doi: 10.1097/PEC.0b013e31818844cf.
• Ranjit S, Aram G, Kissoon N, Ali MK, Natraj R, Shresti S, Jayakumar I, Gandhi D. Multimodal monitoring for hemodynamic categorization and management of pediatric septic shock: a pilot observational study*. Pediatr Crit Care Med. 2014 Jan;15(1):e17-26. doi: 10.1097/PCC.0b013e3182a5589c.
• Ceneviva G, Paschall JA, Maffei F, Carcillo JA. Hemodynamic support in fluid-refractory pediatric septic shock. Pediatrics. 1998 Aug;102(2):e19. doi: 10.1542/peds.102.2.e19.
• Horster S, Stemmler HJ, Strecker N, Brettner F, Hausmann A, Cnossen J, Parhofer KG, Nickel T, Geiger S. Cardiac Output Measurements in Septic Patients: Comparing the Accuracy of USCOM to PiCCO. Crit Care Res Pract. 2012;2012:270631. doi: 10.1155/2012/270631. Epub 2011 Nov 29.

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2021
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): June 1, 2023

Study Registration Dates

• First Submitted: December 31, 2020
• First Submitted That Met QC Criteria: January 24, 2021
• First Posted (Actual): January 28, 2021

Study Record Updates

• Last Update Posted (Actual): September 27, 2021
• Last Update Submitted That Met QC Criteria: September 20, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: septic shock; Fluid resuscitation; Fluid overload; Doppler ultrasonography; Mortality rate; Vasoactive therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock
• Other Study ID Numbers: University of Brawijaya

Drug and device information, study documents

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