The Effect of Restrictive Fluid Management on Cardiac Function and Glycocalyx Degradation

Septic Shock Clinical Trial

Official title:

The Effect of Restrictive Fluid Management on Cardiac Function and Glycocalyx Degradation, a Preplanned Substudy of the CLASSIC Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04282252
• Other study ID #: FRESH
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: February 24, 2020
• Est. completion date: April 2022

Study information

• Verified date: February 2020
• Source: Karolinska Institutet
• Contact: Maria Cronhjort, MD, PhD
• Phone: +466161000
• Email: maria.cronhjort[@]sll.se
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study aims to compare the effects of restrictive fluid management on cardiac dysfunction and vascular integrity in septic shock patients. To achieve this, patients with septic shock according to Sepsis-3 criteria admitted to several Intensive Care Units in Sweden and Denmark will be randomized to receive restrictive respectively standard fluid therapy. Blood test from these patients will be analyzed for several biomarkers of cardiac function and glycocalyx degradation. Echocardiography will also be performed to further investigate cardiac function.

Description:

This study is a substudy to the larger CLASSIC-trial that aims to investigate restrictive and standard fluid therapy in treating septic shock. Adult patients with septic shock according to the Sepsis-3 criteria who have received at least 1 L of IV fluid in the 24 hours before screening will be screened. Patients who have had septic shock for more than 12 hours at the time of screening, who have life-threatening bleeding, or acute burn injury >10% of the body surface area, who are pregnant and those in whom consent cannot be obtained will be excluded. Blood samples will be drawn at T0 (during the first hour after enrolment), T1 (the first morning after inclusion) and T2 (the second morning) and T3 (at ICU discharge (within 24 hours before discharge)). The samples will be analyzed for high-sensitivity troponin T (hsTnT), pro-BNP, proAdrenomedulin (MR-proADM), Co-Peptin (AVP), endothelin-1 (ET-1), neuregulin-1 (NRG-1), growth differentiation factor-15 (GDF-15), metalloproteinases (MMPs), hyaluronan, syndecan-1, heparan sulfate, IL-6, TNFR and Ang-2.

Systolic and diastolic function parameters for the left and right heart will be collected at study enrolment (within 24 hours from inclusion) and at 2-3 and day 7-10 or at discharge using transthoracic or transesophageal echocardiography.

Baseline clinical and demographic data will be analyzed using chi-square or Fisher's exact test for categorical data, and the Wilcoxon rank-sum test for continuous data. The baseline and first follow-up measure of the concentration of a biomarker will be modelled using a mixed effect linear model with a person specific random effect and an interaction between time of follow-up measure (interval since first measurement) and treatment group, the stratification variables for the randomization: hematological or metastatic cancer (Y/N) and trial site as fixed effects. A mixed model will be used to analyze the pattern of biomarkers over time. Differences between intervention groups will be tested by the interaction of time and group in the same mixed model analyses. Additional covariates will be added to adjust for treating center, illness severity (SMS-score), cumulative fluid balance and comorbidities.

The investigators have based sample size calculations on both primary outcomes, hsTnT and hyaluronan concentrations, and estimated predicted differences and standard deviations found in previous comparable studies. The Jakobsen-Lange will be used to adjust for two outcomes where αi for each outcome is αi=0.05/((n+1)/2) = 0,033 which is an adjustment halfway between no adjustment and full Bonferroni adjustment with n being the number of co-primary outcomes and secondary outcomes respectively. For sample size calculations a power of 80 % will be used. Using a standard deviation of 40 ng/l of hsTnT this reveals a sample size of n=120 to detect a group difference of 22 ng/l. To account for drop-out and loss-to-follow-up an extra 10% will be added, 132 patients will be included equally distributed between the two groups. Using a standard deviation of 29 ng/ml of hyaluronan concentration reveals a sample size of n=225 to detect a group difference of 11,5 ng/ml. To account for drop-out and loss-of-follow-up an extra 10% will be added, 248 patients will be included equally distributed between the two groups.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 132
• Est. completion date: April 2022
• Est. primary completion date: October 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with septic shock according to the Sepsis-3 criteria who have received at least 1 L of IV fluid in the 24 hours before screening

Exclusion Criteria:

• Patients who have had septic shock for more than 12 hours at the time of screening

• Patients who have life-threatening bleeding

• Patients with acute burn injury >10% of the body surface area

• Pregnant patients

• Patients in whom consent cannot be obtained

Related Conditions & MeSH terms

• Septic Shock
• Shock, Septic

Intervention

Drug:
• I.V. SOLUTIONS
All i.v. fluids used in an Intensive Care Unit.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Karolinska Institutet

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Left ventricular systolic function, global longitudinal strain	To investigate if conservative fluid management improves left ventricular strain measured in per cent using echocardiography.	Compare result within 24 hours of enrolment with day 2-3 and day 7-10 or at discharge
Other	Effect of a conservative fluid management strategy on C-terminal pro-endothelin-1 (CT-proET-1) concentrations.	To investigate the effect of a conservative fluid management strategy on C-terminal pro-endothelin-1 (CT-proET-1) concentrations in pmol/L.	Compare result within 24 hours of enrolment with day 2-3 and day 7-10 or at discharge
Other	Effect of a conservative fluid management strategy on neuregulin-1 (NRG-1) concentrations.	To investigate the effect of a conservative fluid management on neuregulin-1 (NRG-1) concentrations in ng/ml.	Compare result within 24 hours of enrolment with day 2-3 and day 7-10 or at discharge
Other	Effect of a conservative fluid management strategy on mid-regional pro-adrenomedullin (MR-proADM) concentrations.	To investigate the effect of a conservative fluid management strategy mid-regional pro-adrenomedullin (MR-proADM) in nmol/l.	Compare result within 24 hours of enrolment with day 2-3 and day 7-10 or at discharge
Other	Effect of a conservative fluid management strategy on Growth differentiation factor-15 (GDF-15) concentrations.	To investigate the effect of a conservative fluid management strategy on concentrations of Growth differentiation factor-15 (GDF-15) in pg/ml.	Compare result within 24 hours of enrolment with day 2-3 and day 7-10 or at discharge
Other	Association between glycocalyx hyaluronan concentrations and cumulative fluid balance day three/patient weight, separately in each randomization group	To analyze the association between hyaluronan concentrations (ng/ml) at inclusion with cumulative fluid balance day 3/patient weight (ml/kg), corrected for fluid volumes given before randomization, separately in each randomization group.	Day 3 after randomization
Other	Association between heparan sulfate concentrations and cumulative fluid balance day three/patient weight, separately in each randomization group	To analyze the association between heparan sulfate concentrations (ng/ml) at inclusion with cumulative fluid balance day 3/patient weight (ml/kg), corrected for fluid volumes given before randomization, separately in each randomization group.	Day 3 after randomization
Other	Association between syndecan-1 concentrations and cumulative fluid balance day three/patient weight, separately in each randomization group	To analyze the association between syndecan-1 concentrations (pg/ml) at inclusion with cumulative fluid balance day 3/patient weight (ml/kg), corrected for fluid volumes given before randomization, separately in each randomization group.	Day 3 after randomization
Other	Association between Tumor Necrosis Factor Receptor concentrations and cumulative fluid balance day three/patient weight, separately in each randomization group	To analyze the association between Tumor Necrosis Factor Receptor concentrations (ng/ml) at inclusion with cumulative fluid balance day 3/patient weight (ml/kg), corrected for fluid volumes given before randomization, separately in each randomization group.	Day 3 after randomization
Other	Association between IL-6 concentrations and cumulative fluid balance day three/patient weight, separately in each randomization group	To analyze the association between IL-6 concentrations (pg/ml) at inclusion with cumulative fluid balance day 3/patient weight (ml/kg), corrected for fluid volumes given before randomization, separately in each randomization group.	Day 3 after randomization
Other	Association between Angiopoetin-2 concentrations and cumulative fluid balance day three/patient weight, separately in each randomization group	To analyze the association between Angiopoetin-2 concentrations (ng/ml) at inclusion with cumulative fluid balance day 3/patient weight (ml/kg), corrected for fluid volumes given before randomization, separately in each randomization group.	Day 3 after randomization
Other	Glycocalyx integrity defined by levels of heparan sulfate.	To compare the difference in concentration of heparan sulfate at the first morning after enrolment(T1) in the restrictive group compared with the control group, adjusted for the T0 values.	First morning after enrollment (within 24 hours from enrollment)
Other	Glycocalyx integrity defined by levels of IL-6.	To compare the difference in concentration of IL-6 at the first morning after enrolment(T1) in the restrictive group compared with the control group, adjusted for the T0 values.	First morning after enrollment (within 24 hours from enrollment)
Other	Glycocalyx integrity defined by levels of TNFR.	To compare the difference in concentration of TNFR at the first morning after enrolment(T1) in the restrictive group compared with the control group, adjusted for the T0 values.	First morning after enrollment (within 24 hours from enrollment)
Other	Glycocalyx integrity defined by levels of Ang-2.	To compare the difference in concentration of Ang-2. at the first morning after enrolment(T1) in the restrictive group compared with the control group, adjusted for the T0 values.	First morning after enrollment (within 24 hours from enrollment)
Other	Left ventricular systolic function, LVEF	To investigate if conservative fluid management improves left ventricular ejection fraction measured in per cent using echocardiography.	Compare result within 24 hours of enrollment with day 2-3 and day 7-10 or at discharge
Other	Left ventricular systolic function, TDI	To investigate if conservative fluid management improves left ventricular tissue doppler index measured in cm/s using echocardiography.	Compare result within 24 hours of enrollment with day 2-3 and day 7-10 or at discharge
Other	Right ventricular systolic function, TDI	To investigate if conservative fluid management improves right ventricular tissue doppler index measured in cm/s using echocardiography.	Compare result within 24 hours of enrollment with day 2-3 and day 7-10 or at discharge
Other	Right ventricular systolic function, TAPSE	To investigate if conservative fluid management improves right annular plane systolic excursion measured in mm using echocardiography.	Compare result within 24 hours of enrollment with day 2-3 and day 7-10 or at discharge
Primary	Myocardial injury	To investigate if IV fluid restriction decreases myocardial injury measured as plasma highly sensitive Troponin T (hsTnT) concentrations.	Compare result within 24 hours of enrolment with day 2-3 and day 7-10 or at discharge
Primary	Hyaluronan levels	To study the effect of conservative fluid management versus standard care on the glycocalyx by measuring the levels of hyaluronan.	First morning after enrolment (within 24 hours from enrollment)
Secondary	Left ventricular systolic function, MAPSE	To assess the effect of IV conservative fluid management on left ventricular systolic function measured as difference in mitral annular plane systolic excursion measured in millimeters using echocardiography.	Compare result within 24 hours of enrolment with day 2-3 and day 7-10 or at discharge
Secondary	Difference in Syndecan-1 levels	To compare the difference in concentration of syndecan-1 at the first morning after enrolment (T1) in the conservative fluid management group versus standard care group, adjusted for the T0 values.	First morning after enrolment (within 24 hours from enrollment)