NeurosurgeryREFILLNCT03810118
Fluid Challenge Infusion and Response
A study testing fluid challenge in people with Neurosurgery and Cardiovascular System, run by Humanitas Clinical and Research Center at 1 site in Italy.
Trial summary
It is unclear if the rate of administration of the fluid challenge could affect the rate of fluid responsiveness. The role of this small-dose (the so called mini-FC) has been recently tested to assess if the infusion of a small amount of fluids (100 ml in 1 minute) could predict the final effect of the residual… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Neurosurgery, Cardiovascular System, Anesthesia, General
- What is being tested?
- fluid challenge
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 49 participants
- Where
- 1 siteItaly
- Study dates
- 8 Apr 2019to 1 May 2020
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adult patients aged ≥ 18 years;
- Scheduled for elective supine neurosurgery and requiring invasive arterial monitoring;
- Glasgow coma scale 15 at recruitment
Who cannot join
- Any recurrent cardiac arrhythmias;
- Reduced left (ejection fraction <30%) or right (systolic peak velocity of tricuspid annular motion <0.17 m/s) ventricular systolic function;
- Intra-operative use of vasopressors or inotropes before FC administration or between the first and the second bolus of fluids.
- Chronic use beta-blocking agents.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Rate of Fluid Challenge Administration and Fluid Responsiveness: an Open-label, Multicentric, Randomized Clinical Trial.
It is unclear if the rate of administration of the fluid challenge could affect the rate of fluid responsiveness.
The role of this small-dose (the so called mini-FC) has been recently tested to assess if the infusion of a small amount of fluids (100 ml in 1 minute) could predict the final effect of the residual aliquot (i.e., 250 ml of FC test subdivided as follows: 100 ml in 1 minute and 150 ml in 9 minutes). Both the sudden increase in the stroke volume and the reduction of PPV and SVV after a bolus of 100 ml of crystalloids administered in 1 minute showed high sensitivity and specificity in predicting the final outcome of the FC.
Read more
The primary aim of the present study is assess whether the does the rate of infusion of fluid challenge affect fluid responsiveness in neurosurgical supine patients.
The secondary aim is to assess the reliability of the changes in SV, PPV and SVV after a mini-FC test in predicting the final fluid responsiveness.
Read the detailed description
Dedicated algorithms and protocols of anaesthetic care regarding fluid therapy are key factors to prevent perioperative hypovolaemia and/or hypervolemia, which are known to increase morbidity and length of hospital stay.
Fluid therapy is commonly used in critically ill and surgical patients to restore hemodynamics. The aim of volume expansion is to increase cardiac index and oxygen delivery and to improve tissue oxygenation. However, this occurs only in a situation of preload dependency (i.e. when the ventricle operates on the steep part of the Frank-Starling's curve). Moreover, giving fluids to a non-volume-responsive patient (preload independency) can result in detrimental pulmonary and interstitial oedema. Fluid responsiveness (i.e., increase in stroke volume, SV, after fluid challenge, FC, administration) can be detected in 35-50% of both critically ill and surgical patients. The FC consists in assessing the hemodynamic effects of giving a small amount of fluid in a short period of time. The FC allows restoring fluid depletion when indicated, while minimizing the risk of overloading, which makes it the gold standard for assessing fluid depletion in patients undergoing surgery.
Then, FC administration should be based on predictors of fluid responsiveness. Static indexes, such as the central venous pressure, do not seem appropriate, whereas dynamic indexes, such as pulse pressure variation (PPV) and stroke volume variation (SVV), reliably predict the effect of FC administration during controlled mechanical ventilation only in case of a tidal volume (VT) of at least 8 mL/kg, which unfortunately are rarely found in both critically ill and surgical patients.
To overcome this VT-related limitation of PPV and SVV, the prediction of fluid responsiveness can be also achieved by applying functional hemodynamic tests aiming at increasing venous return and enhancing right ventricle preload dependence.
For example, when a FC is performed using a rapid infusion rate and a relatively "small" dose, its effect is sufficient to test whether the patient is on the ascending part of the cardiac function curve, hence showing an increase in cardiac output (CO).
The role of this small-dose (the so called mini-FC) has been recently tested to assess if the infusion of a small amount of fluids (100 ml in 1 minute) could predict the final effect of the residual aliquot (i.e., 250 ml of FC test subdivided as follows: 100 ml in 1 minute and 150 ml in 9 minutes). Both the sudden increase in the stroke volume and the reduction of PPV and SVV after a bolus of 100 ml of crystalloids administered in 1 minute showed high sensitivity and specificity in predicting the final outcome of the FC. However, the mini-FC has been tested, insofar, only in small-sized studies, needing further investigations to be confirmed.
Moreover, the response to the FC is transitory, and as such also its clinical effect. The study of Aya et al. pointed out that the effect of the FC is dissipated in about 10 minutes in both responders and non-responders and that a dose of 4 ml/kg of crystalloids is the lowest one to evocate a significant hemodynamic effect. It remains unclear, however, what the best approach to FC administration should be and, in fact, wide variability exists at this regard among studies performed both in the perioperative setting and in the intensive care unit (ICU). In fact, the rate of fluid administration is not fixed. A recent systematic review showed a significant heterogeneity. In a subgroup of 35 studies three (8.6%) reported an infusion rate of 1 ml/kg/min. In another group of 32 studies, the FC was administered in 30 minutes in 7 (21.8%) studies, in 20 minutes in 2 (6.2%) studies, in 13 minutes in 1 (3.1%) study, in 10 minutes in 15 studies (46.8%), in 5 minutes in 4 (12.5%) studies, in 3 minutes in 1 (3.1%) study, and in 2 minutes in 2 (6.2%) studies. The median (IQR) time of infusion was 10 (5-20) minutes.
After the indication of Aya et al., 4 ml/kg of crystalloids is the standard dose for the FC in our center. However, it is unclear if the rate of administration could affect the rate of fluid responsiveness. We, therefore, will perform a study to address this issue in a sample of neurosurgical patients.
The primary aim of the present study is assess whether the does the rate of infusion of fluid challenge affect fluid responsiveness in neurosurgical patients.
The secondary aim is to assess the reliability of the changes in SV, PPV and SVV after a mini-FC test in predicting the final fluid responsiveness.
- Conditions
- Neurosurgery, Cardiovascular System, Anesthesia, General
- Being tested
- fluid challenge
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
fluid challengeDiagnostic test
4 ml/kg fluid challenge infused over in either 10 or 20 minutes
| Study group | Role | What they receive |
|---|---|---|
| Treatment | Experimental | All the enrolled patients will receive the same mini-fluid challenge test of 100ml and then will complete the 4 ml/kg fluid challenge in either 10 or 20 minutes Receives: Diagnostic Test: fluid challenge |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of fluid responders
Percentage of patients showing an increase in the stroke volume above the predefined threshold of fluid responsiveness after the infusion of the fluid challenge (>10%).
Measured: 10 or 20 minutes from the start
Pharmacodynamic effect of the FC
AUC
Measured: 10 or 20 minutes from the start
Pharmacodynamic effect of the FC
dmax
Measured: 10 or 20 minutes from the start
Pharmacodynamic effect of the FC
Tmax
Measured: 10 or 20 minutes from the start
Pharmacodynamic effect of the FC
d1
Measured: 10 or 20 minutes from the start
Pharmacodynamic effect of the FC
d5
Measured: 10 or 20 minutes from the start
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jan 2019
- Study start8 Apr 2019
- Primary completion21 Feb 2020
- Study completion1 May 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for NeurosurgeryStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- A single group of patient will receive 4 ml/kg fluid challenge in either 10 or 20 minutes
- Masking
- None (open label)
- Enrolment
- 49 participants (actual)
Sponsor and investigators
- Lead sponsor
- Humanitas Clinical and Research Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Antonio Messina, Humanitas Clinical and Research Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03810118
- Sponsor's protocol ID
- REFILL
- Acronym
- REFILL
- Status last verified
- May 2020
- First submitted
- 14 Jan 2019
- Last updated
- 27 May 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Mahjoub Y, Lejeune V, Muller L, Perbet S, Zieleskiewicz L, Bart F, Veber B, Paugam-Burtz C, Jaber S, Ayham A, Zogheib E, Lasocki S, Vieillard-Baron A, Quintard H, Joannes-Boyau O, Plantefeve G, Montravers P, Duperret S, Lakhdari M, Ammenouche N, Lorne E, Slama M, Dupont H. Evaluation of pulse pressure variation validity criteria in critically ill patients: a prospective observational multicentre point-prevalence study. Br J Anaesth. 2014 Apr;112(4):681-5. doi: 10.1093/bja/aet442. Epub 2013 Dec 29.
PubMed 24374504Biais M, de Courson H, Lanchon R, Pereira B, Bardonneau G, Griton M, Sesay M, Nouette-Gaulain K. Mini-fluid Challenge of 100 ml of Crystalloid Predicts Fluid Responsiveness in the Operating Room. Anesthesiology. 2017 Sep;127(3):450-456. doi: 10.1097/ALN.0000000000001753.
PubMed 28640019Muller L, Toumi M, Bousquet PJ, Riu-Poulenc B, Louart G, Candela D, Zoric L, Suehs C, de La Coussaye JE, Molinari N, Lefrant JY; AzuRea Group. An increase in aortic blood flow after an infusion of 100 ml colloid over 1 minute can predict fluid responsiveness: the mini-fluid challenge study. Anesthesiology. 2011 Sep;115(3):541-7. doi: 10.1097/ALN.0b013e318229a500.
PubMed 21792056Aya HD, Ster IC, Fletcher N, Grounds RM, Rhodes A, Cecconi M. Pharmacodynamic Analysis of a Fluid Challenge. Crit Care Med. 2016 May;44(5):880-91. doi: 10.1097/CCM.0000000000001517.
PubMed 26683506
Study at a glance
From the registry record, last updated by the sponsor on 27 May 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Rate of Fluid Challenge Administration and Fluid Responsiveness: an Open-label, Multicentric, Randomized Clinical Trial.
- ClinicalTrials.gov ID
- NCT03810118
- Acronym / sponsor ID
- REFILL / REFILL
- Conditions
- Neurosurgery, Cardiovascular System, Anesthesia, General
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 49 participants (actual)
- Lead sponsor
- Humanitas Clinical and Research CenterUniversity, hospital or other
- Study start
- 8 Apr 2019 (actual)
- Primary completion
- 21 Feb 2020 (actual)
- Study completion
- 1 May 2020 (actual)
- First posted
- 18 Jan 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
It is unclear if the rate of administration of the fluid challenge could affect the rate of fluid responsiveness.
The role of this small-dose (the so called mini-FC) has been recently tested to assess if the infusion of a small amount of fluids (100 ml in 1 minute) could predict the final effect of the residual aliquot (i.e., 250 ml of FC test subdivided as follows: 100 ml in 1 minute and 150 ml in 9 minutes). Both the sudden increase in the stroke volume and the reduction of PPV and SVV after a bolus of 100 ml of crystalloids administered in 1 minute showed high sensitivity and specificity in predicting the final outcome of the FC.
The primary aim of the present study is assess whether the does the rate of infusion of fluid challenge affect fluid responsiveness in neurosurgical supine patients.
The secondary aim is to assess the reliability of the changes in SV, PPV and SVV after a mini-FC test in predicting the final fluid responsiveness.
Detailed description
Dedicated algorithms and protocols of anaesthetic care regarding fluid therapy are key factors to prevent perioperative hypovolaemia and/or hypervolemia, which are known to increase morbidity and length of hospital stay.
Fluid therapy is commonly used in critically ill and surgical patients to restore hemodynamics. The aim of volume expansion is to increase cardiac index and oxygen delivery and to improve tissue oxygenation. However, this occurs only in a situation of preload dependency (i.e. when the ventricle operates on the steep part of the Frank-Starling's curve). Moreover, giving fluids to a non-volume-responsive patient (preload independency) can result in detrimental pulmonary and interstitial oedema. Fluid responsiveness (i.e., increase in stroke volume, SV, after fluid challenge, FC, administration) can be detected in 35-50% of both critically ill and surgical patients. The FC consists in assessing the hemodynamic effects of giving a small amount of fluid in a short period of time. The FC allows restoring fluid depletion when indicated, while minimizing the risk of overloading, which makes it the gold standard for assessing fluid depletion in patients undergoing surgery.
Then, FC administration should be based on predictors of fluid responsiveness. Static indexes, such as the central venous pressure, do not seem appropriate, whereas dynamic indexes, such as pulse pressure variation (PPV) and stroke volume variation (SVV), reliably predict the effect of FC administration during controlled mechanical ventilation only in case of a tidal volume (VT) of at least 8 mL/kg, which unfortunately are rarely found in both critically ill and surgical patients.
To overcome this VT-related limitation of PPV and SVV, the prediction of fluid responsiveness can be also achieved by applying functional hemodynamic tests aiming at increasing venous return and enhancing right ventricle preload dependence.
For example, when a FC is performed using a rapid infusion rate and a relatively "small" dose, its effect is sufficient to test whether the patient is on the ascending part of the cardiac function curve, hence showing an increase in cardiac output (CO).
The role of this small-dose (the so called mini-FC) has been recently tested to assess if the infusion of a small amount of fluids (100 ml in 1 minute) could predict the final effect of the residual aliquot (i.e., 250 ml of FC test subdivided as follows: 100 ml in 1 minute and 150 ml in 9 minutes). Both the sudden increase in the stroke volume and the reduction of PPV and SVV after a bolus of 100 ml of crystalloids administered in 1 minute showed high sensitivity and specificity in predicting the final outcome of the FC. However, the mini-FC has been tested, insofar, only in small-sized studies, needing further investigations to be confirmed.
Moreover, the response to the FC is transitory, and as such also its clinical effect. The study of Aya et al. pointed out that the effect of the FC is dissipated in about 10 minutes in both responders and non-responders and that a dose of 4 ml/kg of crystalloids is the lowest one to evocate a significant hemodynamic effect. It remains unclear, however, what the best approach to FC administration should be and, in fact, wide variability exists at this regard among studies performed both in the perioperative setting and in the intensive care unit (ICU). In fact, the rate of fluid administration is not fixed. A recent systematic review showed a significant heterogeneity. In a subgroup of 35 studies three (8.6%) reported an infusion rate of 1 ml/kg/min. In another group of 32 studies, the FC was administered in 30 minutes in 7 (21.8%) studies, in 20 minutes in 2 (6.2%) studies, in 13 minutes in 1 (3.1%) study, in 10 minutes in 15 studies (46.8%), in 5 minutes in 4 (12.5%) studies, in 3 minutes in 1 (3.1%) study, and in 2 minutes in 2 (6.2%) studies. The median (IQR) time of infusion was 10 (5-20) minutes.
After the indication of Aya et al., 4 ml/kg of crystalloids is the standard dose for the FC in our center. However, it is unclear if the rate of administration could affect the rate of fluid responsiveness. We, therefore, will perform a study to address this issue in a sample of neurosurgical patients.
The primary aim of the present study is assess whether the does the rate of infusion of fluid challenge affect fluid responsiveness in neurosurgical patients.
The secondary aim is to assess the reliability of the changes in SV, PPV and SVV after a mini-FC test in predicting the final fluid responsiveness.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- A single group of patient will receive 4 ml/kg fluid challenge in either 10 or 20 minutes
| Arm | Type | Receives |
|---|---|---|
| Treatment | Experimental | Diagnostic Test: fluid challengeAll the enrolled patients will receive the same mini-fluid challenge test of 100ml and then will complete the 4 ml/kg fluid challenge in either 10 or 20 minutes |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Adult patients aged ≥ 18 years;
- Scheduled for elective supine neurosurgery and requiring invasive arterial monitoring;
- Glasgow coma scale 15 at recruitment
Key exclusion criteria (4 listed)
- Any recurrent cardiac arrhythmias;
- Reduced left (ejection fraction <30%) or right (systolic peak velocity of tricuspid annular motion <0.17 m/s) ventricular systolic function;
- Intra-operative use of vasopressors or inotropes before FC administration or between the first and the second bolus of fluids.
- Chronic use beta-blocking agents.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| fluid challenge4 ml/kg fluid challenge infused over in either 10 or 20 minutes | Diagnostic test | Treatment |
Primary outcome
Percentage of fluid responders
Time frame: 10 or 20 minutes from the start
Percentage of patients showing an increase in the stroke volume above the predefined threshold of fluid responsiveness after the infusion of the fluid challenge (>10%).
Pharmacodynamic effect of the FC
Time frame: 10 or 20 minutes from the start
AUC
Pharmacodynamic effect of the FC
Time frame: 10 or 20 minutes from the start
dmax
Pharmacodynamic effect of the FC
Time frame: 10 or 20 minutes from the start
Tmax
Pharmacodynamic effect of the FC
Time frame: 10 or 20 minutes from the start
d1
Pharmacodynamic effect of the FC
Time frame: 10 or 20 minutes from the start
d5
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 May 2020.
- Results publication: PubMed 24374504Mahjoub Y, Lejeune V, Muller L, Perbet S, Zieleskiewicz L, Bart F, Veber B, Paugam-Burtz C, Jaber S, Ayham A, Zogheib E, Lasocki S, Vieillard-Baron A, Quintard H, Joannes-Boyau O, Plantefeve G, Montravers P, Duperret S, Lakhdari M, Ammenouche N, Lorne E, Slama M, Dupont H. Evaluation of pulse pressure variation validity criteria in critically ill patients: a prospective observational multicentre point-prevalence study. Br J Anaesth. 2014 Apr;112(4):681-5. doi: 10.1093/bja/aet442. Epub 2013 Dec 29.
- Results publication: PubMed 28640019Biais M, de Courson H, Lanchon R, Pereira B, Bardonneau G, Griton M, Sesay M, Nouette-Gaulain K. Mini-fluid Challenge of 100 ml of Crystalloid Predicts Fluid Responsiveness in the Operating Room. Anesthesiology. 2017 Sep;127(3):450-456. doi: 10.1097/ALN.0000000000001753.
- Results publication: PubMed 21792056Muller L, Toumi M, Bousquet PJ, Riu-Poulenc B, Louart G, Candela D, Zoric L, Suehs C, de La Coussaye JE, Molinari N, Lefrant JY; AzuRea Group. An increase in aortic blood flow after an infusion of 100 ml colloid over 1 minute can predict fluid responsiveness: the mini-fluid challenge study. Anesthesiology. 2011 Sep;115(3):541-7. doi: 10.1097/ALN.0b013e318229a500.
- Results publication: PubMed 26683506Aya HD, Ster IC, Fletcher N, Grounds RM, Rhodes A, Cecconi M. Pharmacodynamic Analysis of a Fluid Challenge. Crit Care Med. 2016 May;44(5):880-91. doi: 10.1097/CCM.0000000000001517.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing fluid challenge in people with Neurosurgery and Cardiovascular System, run by Humanitas Clinical and Research Center at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 May 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of fluid responders (time frame: 10 or 20 minutes from the start). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03810118, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 May 2020.