Clinical trial NCT03020407
Conditions: Septic Shock
Keywords: Septic Shock Inferior vene cava diameter Resuscitation Mortality
Sponsor: Chulalongkorn University
Start date: 2017-01-18; Completion date: 2020-07-31
Enrollment: 211 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary aim of this study is to evaluate the 30-day mortality outcome of the septic shock patients who are treated with ultrasound-assisted fluid management using change of the inferior vene cava (IVC) diameter during respiratory phases in the first 6 hours compared with those treated with "usual-care" strategy.

Detailed description:
Septic shock (SS) is globally prevalent in with high mortality rate.The current focuses on initial treatment of this condition emphasize on the early recognition, prompt administration of antibiotic, and restoration of hemodynamic with aggressive fluid resuscitation and vasopressor. Regarding the initial fluid therapy, administration of empirical crystalloid at the dose of 30 ml/kg is recommended in the guideline. The ultrasound-assisted management of shock patients has been introduced in the past decade and now is widely used. By using the measurement of inferior vena cava (IVC) diameter change during respiratory phases, physicians can predict the fluid responsiveness in the shock patients and tailor the fluid therapy during the resuscitation.Unfortunately, clinical outcome related to the use of this concept in SS resuscitation has not been well studied. Inadequate resuscitation with fluid therapy is related with higher mortality; however, fluid bolus or positive fluid balance that may result from "too aggressive" fluid administration is also associated with increased mortality in SS patients. The primary aim of this study was to evaluate the 30-day mortality outcome of the SS patients who were treated with ultrasound-assisted fluid management using change of the IVC during respiratory phases in the first 6 hours compared with those who were treated with "usual-care" strategy. The secondary outcomes were to compare the rate of the need for mechanical ventilation (MV) and renal replacement therapy (RRT) as well as the 6-hours lactate clearance and the change in Sequential Organ Failure (SOFA) score in 72 hours.

Arms: arm 1: The treating physician will promptly assess the IVC diameter to obtain the collapsibility index (IVCCI) (or distensibility index, IVCDI) of an eligible patient. A previous study showed that IVCCI \> 40% were strongly associated with fluid responsiveness. Accordingly, the patient will be given 10 ml/kg of bolus of 0.9% normal saline solution (NSS) each time when the IVCCI \> 40% is discovered and serial measurements will be done after each intravenous bolus is achieved until the IVCCI \< 40 % during our protocol. Prompt empirical antibiotics will be given to the patients within one hour before the treatment allocation. arm 2: Patients will be promptly and empirically treated by 30 ml/kg loading of NSS in this treatment arm. After the NSS bolus, treatment with either the additional intravenous fluid or a vasopressor is given depended on physicians' discretion during the 6-hour study period. Prompt empirical antibiotics will be given to the patients within one hour before the treatment allocation.
Interventions: intervention 1: IVC Ultrasound-guided intervention 2: Antibiotics intervention 3: Vasopressor
Intervention descriptions: intervention 1: IVC is identified in longitudinal section in the subcostal area of a patient using the curvilinear probe of standard ultrasound. The selected area of IVC diameter measurement is set at 2 centimeters distal to the confluence of hepatic vein by M-mode coupled by two-dimensional mode on frozen screen images using the Sonosite® X-porte. intervention 2: Prompt empirical antibiotics will be given to the patients within one hour before the treatment allocation. intervention 3: The threshold to the need of a vasopressor is set at mean arterial pressure below 65 mmHg if a patient's condition does not response to the fluid therapy.

Protocol documents:
Prot_SAP_000.pdf: 
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Randomized Controlled Trial of Ultrasound-guided Fluid 
Resuscitation of Sepsis-Induced Hypoperfusion and Septic Shock  
NCT identifier 03020407 
Updated 1 October 2020 
Study Protocol 
In our protocol we prepared the preplanned, permuted block-of-four randomization list that 
was blinded to the investigators before patient allocation. Randomization was set at a 1:1 ratio of 
the ultrasound-guided and usual-care arms. When an eligible patient was identified and informed 
consent was obtained, demographic data, preexisting condition, bloodwork, diagnostic 
investigations, microbiologic workups, and blood lactate were collected at ED arrival (hour 0). 
Prompt empirical antibiotics were given to every patient within one hour after ED arrival. Then, 
the patient was rapidly assigned in accordance with the randomization and treated with one of 
the two treatment strategies as follows: 
 
Ultrasound-guided fluid management (UGFM) strategy  
In this treatment arm, the treating emer gency physician promptly assessed the IVC diameter 
to obtain the IVC collapsibility index (IVCCI) (or distensibility index, IVCDI; see below for the 
description, formulation and measurement method) of each patient while venous access was 
performed and initial laboratory specimens were collected. A previous study showed that IVCCI 
> 40% was strongly associated with fluid responsiveness. 24 Accordingly, the patient was given 
a 10 milliliters (mL)/ kg bolus of 0.9% normal saline solution (NSS) without delay if an IVCCI > 
40% was discovered, and serial measurements were immediately performed after each IV bolus 
was achieved an IVCCI < 40% during our protocol. Then, the rate of IV fluid administration was 
maintained based on the individual’s condition. If the patients in this arm subsequently required 
endotracheal intubation and MV with sedation within six hours after initiation of therapy , the 
IVCDI was measured as a replacement for IVCCI. The same amount of NSS was given when 
IVCDI > 18% 17 until IVCDI < 18% was achieved. The IVC evaluation was serially performed 
and recorded every two hours until six hours after ED presentation. The same treatment protocol 
was repeated when the threshold of IVCCI (or IVCDI) percentage for potential fluid 
responsiveness was identified.  
 
Inferior vena cava diameter measurement and indicators of fluid responsiveness  
In our protocol, IVC was identified in longitudinal section in the subcostal area using the 
curvilinear or phased array transducers (cardiac) of a standard ultrasound machine. The selected 
area of IVC diameter measurement was set at 2 centimeters distal to the confluence of the 
hepatic vein by M-mode coupled with two-dimensional mode on frozen screen images using the 
Sonosite X-porte (Fujifilm Sonosite, Inc., Bothell, WA). All treating physicians including 
attending staff and residents regularly participated in hands-on training twice a year (as usual 
basis) by a qualified international instructor in critical care ultrasonography (the third author). 
The residents who were allowed to perform the study protocol required at least six months 


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exposure in real clinical experience and had passed formal performance evaluation on 
ultrasonographic IVC measurement. If the patient was breathing spontaneously, the IVCCI, 
which reflects the decrease in IVC diameter on spontaneous inspiration, was used. IVCCI is 
calculated as follows:  
[(IVC diametermax - IVC diametermin)/ IVC diametermax]×100%.  
If the patient required MV for respiratory support, the IVCDI, which reflects the increase in IVC 
diameter on mechanical inspiration, was used. IVCDI is calculated as follows:  
[(IVC diametermax - IVC diametermin)/ IVC diametermin]×100%.  
Sample images of ultrasonographic landmark and respirophasic diameter changes of an IVC 
during volume expansion are shown in Figures S1A and S1B in the Supplemental material.  
 
Usual-care strategy  
Patients were promptly treated with 30 mL/kg loading of NSS in this treatment arm. After the  
NSS bolus, treatment with either the additional IV fluid or a vasopressor was given at the 
physicians’ discretion during the six-hour study period. The threshold for the need of a 
vasopressor was set at mean arterial pressure below 65 mm Hg if a patient did not respond to 
fluid therapy during each treatment protocol, and the time of vasopressor administration was 
noted. However, ancillary fluid administration was allowed at treating physicians’ judgment in 
both treatment arms. Other adjunctive therapies, such as colloid administration, central venous 
catheterization, or surgical removal of the infectious source, were not prohibited in our protocol 
and were used at the discretion of the treating physicians. The study patients were closely 
monitored while we recorded their clinical parameters every two hours for study purposes. Our 
resuscitative study protocol stopped at six hours after initiation of the treatment. After this 
period, patients were treated according to the physicians’ judgment.  
 
Outcome Measurements  
At six hours after treatment, the cumulative fluid volume was recorded, and blood lactate was 
obtained for lactate clearance calculation. At 72 hours after ED presentation, the cumulative fluid 
volume from the initial presentation was again recorded, and the patients were followed for 
clinical condition evaluation and blood chemistry tests to calculate the SOFA score and assess its 
change from the hour-zero baseline. The in-hospital requirement and time to start renal 
replacement therapy or MV were followed and recorded by searching the electronic data 
summary of a patient. The indication to initiate these life-saving procedures was at the discretion 
of the treating physicians. To identify the deceased patients for mortality analysis, we retrieved 
the electronic database of in- and outpatient clinical records or made a telephone call to the 
patients or their personal contact in every case at 30 days after the day of hospital presentation. 
The clinical data retrieval was performed and recorded by the trained non-investigators.  
Data Analysis  
Sample-size determination  
According to the results of large trials of septic shock treatment, the 90-day mortality was 
30% in the usual-care group.9-11 Based on this information, we calculated that a sample of 254 
patients would have a power of 80% to detect a relative reduction of 50% in risk (15 percentage 
points of absolute risk reduction) in the UGFM group, allowing for a loss to follow-up or 
withdrawal of 5%. The target number for primary outcome analysis would be 121 patients per 


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group. One interim analysis was performed after the enrollment of 50% of the patients, with the 
use of a two-sided symmetric O’Brien–Fleming (or alpha spending method) design. 
Statistical analysis  
We used Stata version 14.0 (StataCorp LLC, College Station, TX) for all statistical tests and 
production of graphics. The normally and non-normally distributed data were analyzed using the 
two independent-samples t test and Mann-Whitney U test, respectively. A χ2 test with odds ratio 
(OR) was performed to compare the proportions between the groups. No data were imputed for 
any missing information. We used the Kaplan-Meier curve and the log-rank test to compare the 
30-day mortality between the treatment arms. All tests were two-sided for superiority testing and 
considered statistically significant at a p < 0.05.