OPTImized Restrictive Strategy Targeting Non-Resuscitative FLUIDs in Septic Shock: Pilot Study.

Septic Shock Clinical Trial

— OPTIFLUID  

Official title:

Impact on Fluid Balance of an Optimised Restrictive Strategy Targeting Non-Resuscitative Fluids in Intensive Care Patients Hospitalised for Septic Shock: an Open-label, Multi-Centre, Randomised, Controlled Pilot Study.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04947904
• Other study ID #: NIMAO/2019/SB-01
• Status: Completed
• Phase: N/A
• Start date: September 20, 2021
• Est. completion date: February 25, 2023

Study information

• Verified date: April 2023
• Source: Centre Hospitalier Universitaire de Nimes
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Intravenous fluids are one of the keystones in the initial management of patients with septic shock, but they inevitably lead to a fluid overload, which is associated with poor outcome.

So far no studies have evaluated the interest of a restrictive strategy for managing fluid intake targeting all non-resuscitative fluids (fluids for maintenance and drug dilution as well as nutrition) and especially the impact of this restrictive strategy on fluid overload.

The hypothesis of this research is that an optimised restrictive strategy targeting all non-resuscitative fluids in patients hospitalised in the intensive care unit for septic shock, will have an impact on fluid balance in these patients.

Description:

Sepsis and its most severe form, septic shock, are the cause of nearly 30% of admission in intensive care unit (ICU). The related mortality rate varies from 20 to 60% according to the studied population and the type of the study. With the concomitant and rapid treatment of the source of infection, hemodynamic optimization with fluid infusion (fluid resuscitation) is the cornerstone of management of patients in septic shock. Nevertheless, fluid overload has been shown to be associated with poor outcome. The negative effects of a positive fluid balance on ICU outcomes for septic patients has been well established.

In patients with acute respiratory distress syndrome, a restrictive fluid therapy has been associated with shorter use of mechanical ventilation. In patients with acute renal failure, fluid overload is associated with longer need of renal replacement therapy. In patients with septic shock numerous non-randomised studies reported that a positive fluid balance at Day 3, Day 5 was associated with an increased risk of mortality.

Actually, in patients with septic shock the part of resuscitation fluid is only the third of the total fluid input that can attain 25 liters at day 3. Some studies reported more specifically the role of the different types of fluid in the fluid balance at D3 and D5. In a retrospective single centre study including 14654 ICU patients over 10 years, the authors distinguished resuscitation, replacement and maintenance fluids, blood products, nutrition and fluid creep (to concentrate electrolytes, keep venous access and to infuse continuous medications). They reported that maintenance fluids and fluid creep represent more than 50% of fluid input during the first 5 ICU days with significant sodium and chloride loads. In a retrospective multi-centre study involving 400 patients mechanically ventilated > 24 h in 10 ICUs, the authors reported that maintenance and fluid creep represented more than 50% of the fluids infused during the first 3 ICU days. In this study, fluid balance at Day3 was an independent risk factor for 30-day mortality.

All these findings could lead to hypothesize that a restrictive strategy in fluid input for the maintenance of fluid and creep fluid could be associated with a better outcome without impairing the resuscitation phase.

To our knowledge, to date, no study has focused on a restrictive strategy targeting non-resuscitative fluid input to optimize fluid balance in patients with septic shock. OPTIFLUID will be the first randomised controlled trial with the objective of reducing fluid balance through a fluid restriction targeted at all fluids other than resuscitative fluids.

The only existing interventional studies on targeted restriction were limited to resuscitative intravenous fluids, and they failed showing a benefit.

By optimizing fluid therapy, our approach is likely to improve patient-centred outcomes, but in this pilot study we focus only on the fluid balance and the safety.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: February 25, 2023
• Est. primary completion date: January 27, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

• Patient suffering from an infection already documented or suspected

• Patient with organ dysfunction defined as an acute change in SOFA score = 2 points

• Patient with refractory hypotension requiring vasopressors to maintain a mean arterial pressure = 65 mm Hg in spite of resuscitation with an adequate volume of intravenous fluids (according to the recommendations of the Surviving Sepsis campaign). The treatment by vasopressor must have been started less than 24 hours before inclusion and randomization.

• Patient with hyperlactatemia (blood lactate > 2 mmol / L). This criterion must be fulfilled at least once for the purpose of the diagnosis within the 24 hours preceding inclusion and randomization.

• Patient or close relative / legal representative / family member / curator / tutor must have given written informed consent and signed the consent form for the patient included in an emergency situation

• Patient must be covered by a health insurance scheme.

• Adult patient (=18 years) under 85 years old (< 85).

Exclusion Criteria:

• Patient who has had a previous episode of septic shock requiring vasopressor administration or mechanical ventilation or renal replacement therapy during the current ICU stay.

• A patient whose life expectancy is shortened due to his/her initial health condition or a moribund patient whose life expectancy is less than 48 hours or whose decision to limit comprehensive care was made before including the patient.

• Patient who has had a recent cardiac arrest (during current hospital stay)

• Patient requiring emergency renal-replacement therapy (hyperkalemia [potassium > 6.5 mmol/l] refractory to medical treatment and/or metabolic acidosis [pH <7.15 and partial pressure of carbon dioxide (pCO2) <45 mmHg] refractory to medical treatment and/or pulmonary edema in anuric patients who do not respond to diuretic therapy).

• Patient with KDIGO 3 acute kidney injury and likely to require renal-replacement therapy within the next 24 hours, as determined by the patient's clinician in charge

• Patients with end-stage chronic renal failure or patients already undergoing chronic dialysis

• Severely malnourished patient in whom nutritional support is an emergency procedure (body mass index <18 kg / m2)

• Patient participating in or having participated in an interventional study with similar patient outcome in the previous 3 months.

• Patient in an exclusion period determined by another study.

• Patient under legal protection.

• Pregnant patient (positive serum pregnancy test).

Related Conditions & MeSH terms

• Electrolyte and Fluid Balance Conditions
• Septic Shock
• Shock
• Shock, Septic

Intervention

Other:
• Reduction of the patient's fluid intake during the first 7 days
The volume of fluids infused to the patient will be reduced by the doctor in charge of the patient for the first 7 days of the patient's stay in the intensive care unit according to a protocol with instructions to reduce fluid intake as far as possible in terms of maintenance fluids, dilution of medication and artificial nutrition. This protocol will be begun immediately following the patient's inclusion on Day 1 and pursued for 7 days after inclusion (i.e. from Day 1 - to Day 7). The fluid restriction strategy does not involve the administration of any medication (i.e. diuretics). A clinical pharmacist will help the intensive care teams apply the fluid restriction protocol with a daily check. If the restrictive strategy leads to hypovolemia and / or a electrolyte anomaly (sodium, potassium, chloride, etc.), the physician in charge will be authorised to treat these anomalies in conformance with the protocol recommendations.

Locations

Country	Name	City	State
France	Centre Hospitalier d'Alès	Alès
France	CHU de DIJON	Dijon
France	CHU de Montpellier	Montpellier
France	Nimes University Hospital	Nîmes

Sponsors (3)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Nimes	Centre Hospitalier Universitaire Dijon, University Hospital, Montpellier

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Fluid balance at day 5	Fluid intakes are noted on a daily basis (parenteral, enteral, and oral routes) and all outgoing fluids (diuresis, depletion on renal-replacement therapy, drainage, diarrhoea (if the volume is measurable). The difference between these daily fluid intakes and outgoing fluids is the daily fluid balance. Fluid balance on Day 5 is the sum total of the fluid balances from Days 1 to 5 and is measured in millilitres per kgs of patient's weight at baseline.	Day 5
Secondary	Change from baseline in fluid balance at day 7	Fluid intakes are noted on a daily basis (parenteral, enteral, and oral routes) and all outgoing fluids (diuresis, depletion on renal-replacement therapy, drainage, diarrhoea (if the volume is measurable). The difference between these daily fluid intakes and outgoing fluids is the daily fluid balance. Fluid balance on Day 5 is the sum total of the fluid balances from Days 1 to 7 and is measured in millilitres per kgs of patient's weight at baseline.	Day 1 to 7
Secondary	Change from baseline in patient's weight at day 5	The patient's weight will be recorded every day in kgs. The difference in the patient's weight between Day 1 and Day 5 will be recorded in kgs.	Day 1 to 5
Secondary	Change from baseline in patient's weight at day 7	The patient's weight will be recorded every day in kgs. The difference in the patient's weight between Day 1 and Day 7 will be recorded in kgs.	Day 1 to 7
Secondary	Change from baseline in central venous pressure at day 5	Central venous pressure will be recorded every day in mmHg	Day 1 to 5
Secondary	Change from baseline in central venous pressure at day 7	Central venous pressure will be recorded every day in mmHg	Day 1 to 7
Secondary	Vital status at Day 7	The number of patients still alive on Day 7 will be recorded	Day 7
Secondary	Vital status at Day 28	The number of patients still alive on Day 28 will be recorded	Day 28
Secondary	Proportion of patients alive without organ failure at Day 7	The Sequential Organ Failure Assessment (SOFA) score will be used will be used to record the patient's condition. The score ranges from 0 to 3 points : one point for each of Low blood pressure (SBP = 100 mmHg), High respiratory rate (= 22 breaths/min) and Altered mentation (GCS = 14).The presence of 2 or more SOFA points near the onset of infection was associated with a greater risk of death or prolonged intensive care unit stay. These are outcomes that are more common in infected patients who may be septic than those with uncomplicated infection. The number of patients with a SOFA score = 0 will be recorded.	Day 7
Secondary	Proportion of patients alive without organ failure at Day 28	The Sequential Organ Failure Assessment (SOFA) score will be used to record the patient's condition. The score ranges from 0 to 3 points : one point for each of Low blood pressure (SBP = 100 mmHg), High respiratory rate (= 22 breaths/min) and Altered mentation (GCS = 14).The presence of 2 or more SOFA points near the onset of infection was associated with a greater risk of death or prolonged intensive care unit stay. These are outcomes that are more common in infected patients who may be septic than those with uncomplicated infection. The number of patients with a SOFA score = 0 will be recorded.	Day 28
Secondary	Vasopressors free days	The number of days the patient has survived without the use of vasopressors will be recorded.	Day 28
Secondary	Invasive mechanical ventilation free days	The number of days the patient has survived without the use of invasive mechanical ventilation will be recorded.	Day 28
Secondary	Renal-Replacement Therapy free days	The number of days the patient has survived without the use of renal-replacement therapy will be recorded.	Day 28
Secondary	Intensive Care Unit Length of stay	The total number of days spent in the ICU will be recorded.	Day 28
Secondary	Intensive Care Unit Free Days	The number of days spent in hospital outside the intensive care unit will be recorded.	Day 28
Secondary	Hospital Length of stay	The total number of days spent in hospital will be recorded.	Day 28
Secondary	Frequency of metabolic disorders - moderate hypernatremia	The frequency of moderate hypernatremia will be recorded to evaluate the safety and tolerance of adverse events associated with the optimal restrictive strategy. Moderate hypernatremia = natremia between 146 and 150 mmol/l.	Day 7
Secondary	Frequency of metabolic disorders - severe hypernatremia	The frequency of severe hypernatremia will be recorded to evaluate the safety and tolerance of adverse events associated with the optimal restrictive strategy. Severe hypernatremia = natremia over 150 mmol/l.	Day 7
Secondary	Frequency of metabolic disorders - hyponatremia	The frequency of hyponatremia will be recorded to evaluate the safety and tolerance of adverse events associated with the optimal restrictive strategy. Hyponatremia = natremia below 130 mmol/l	Day 7
Secondary	Frequency of metabolic disorders - hyperkalemia	The frequency of hyperkalemia will be recorded to evaluate the safety and tolerance of adverse events associated with the optimal restrictive strategy (hyperkalemia over 6 mmol/l	Day 7
Secondary	Frequency of metabolic disorders - hypoglycemia	The frequency of hypoglycemia < 0.6g/l will be recorded to evaluate the safety and tolerance of adverse events associated with the optimal restrictive strategy.	Day 7
Secondary	Insulin cumulative dose at Day 7	The cumulative dose of insulin administered over 7 days will be recorded.	Day 7
Secondary	Frequency of moderate acute kidney injury	The frequency of moderate acute kidney injury defined by the Kidney Disease Improving Global Outcomes (KDIGO) score 2 will be recorded.	Day 7
Secondary	Frequency of severe acute kidney injury	The frequency of severe acute kidney injury defined by the Kidney Disease Improving Global Outcomes (KDIGO) score 3 will be recorded.	Day 7
Secondary	Cumulative dose of diuretics at day 7	The cumulative dose of diuretics administered over 7 days will be recorded.	Day 7
Secondary	Frequency of Stage 3 pressure sores	The frequency of Stage 3 pressure sores acquired in the resuscitation unit will be recorded.	Day 7
Secondary	Daily fluid intake: Resuscitation Fluids	The daily volume of crystalloids and colloids supplied to the patient will be recorded daily in milliliters per kilograms of patient's weight	Day 1 to 7
Secondary	Daily fluids intake: Blood Transfusions and Blood Derivatives	The daily volume of blood transfusions, Blood Derivatives and plasma-derived products supplied to the patient will be recorded daily in milliliters per kilograms of patient's weight	Day 1 to 7
Secondary	Daily fluids intake: Maintenance Fluids	The amount of Maintenance fluids (prescribed to provide water and electrolytes when patients are unable to ingest food or fluids) will be recorded daily in milliliters per kilograms of patient's weight	Day 1 to 7
Secondary	Daily fluids intake: Fluid Creep	The volume of fluids administered unintentionally as a vehicle for intravenous, oral, or enteral medication will be recorded daily in milliliters per kilograms of patient's weight	Day 1 to 7
Secondary	Daily fluids intake : Enteral Nutrition	The amount of fluid in terms of enteral nutrition will be recorded daily in milliliters per kilograms of patient's weight	Day 1 to 7
Secondary	Daily fluids intake : Parenteral Nutrition	The amount of fluid in terms of parenteral nutrition will be recorded daily in milliliters per kilograms of patient's weight	Day 1 to 7
Secondary	Daily fluids intake : Water	The volume of water in terms of oral intake and the volume administered in the nasogastric tube will be recorded daily in milliliters per kilograms of patient's weight	Day 1 to 7
Secondary	Daily fluids intake : intravenous fluids to treat hypernatremia	The amount of fluids given intravenously to treat hypernatremia (intravenous hydration with a 2.5% glucose solution) will be recorded daily in milliliters per kilograms of patient's weight	Day 1 to 7