Clinical trial NCT06020495: Systematic Use of DDAVP to Prevent Serum Sodium Overcorrection in Severe Hyponatremia
Official title: Systematic Use of DDAVP to Prevent Serum Sodium Overcorrection in Severe Hyponatremia: a Multicenter Open-label Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Hyponatremia
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2023-08-31
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicentre, prospective, open-label randomized controlled superiority trial with stratification on the presence of neurological symptoms at inclusion and on the presence/absence of risk factors for central pontine myelinolysis (chronic alcohol abuse, malnutrition, serum potassium \< 3.0 mmol/L).
Primary purpose: TREATMENT

Brief summary: ICU patients with severe hyponatremia and a high risk of rapid SNa overcorrection.

Detailed description: Multicentre, prospective, open-label randomized controlled superiority trial with stratification on the presence of neurological symptoms at inclusion and on the presence/absence of risk factors for central pontine myelinolysis (chronic alcohol abuse, malnutrition, serum potassium \< 3.0 mmol/L).

Patients in ICU with severe hyponatremia defined by SNa \< 115 mmol/L or SNa \< 120 mmol/L in the presence of neurological symptoms (convulsions, stupor defined by a Glasgow score \<12 or signs of brain herniation) and a normal or decreased extracellular fluid volume will be included.

After written informed consent, they will be randomized (1:1), using a computer-generated randomization scheme of various-sized blocks, stratified by the presence of neurological symptoms at inclusion (seizures, stupor defined as Glasgow score \<12 or signs of brain herniation) and on the presence/absence of risk factors for central pontine myelinolysis (chronic alcohol abuse \[defined according to World Health Organization definition\], malnutrition \[BMI\<20.5 or weight loss \>5% in 3 months\], serum potassium \< 3.0 mmol/L), through a centralized 24-hour Internet service (CleanWEB™), to receive standard hyponatremic treatment alone or standard hyponatremic treatment and DDAVP 4 μg/ml IV, after randomisation and for a total duration of 48 hours. Since administration of DDAVP leads to an important decrease in urine output and increase in urine osmolarity which are clinically obvious very rapidly, a single or double blind trial is not appropriate. However, all investigators will be unaware of aggregate outcomes during the study and brain MRI imaging will be performed and analyzed blinded to the randomization group

Eligibility criteria: Inclusion Criteria:

* Adults ( ≥18 years)
* Current admission in ICU
* Severe hyponatremia defined by SNa \<120 mmol/L in the presence of neurological symptoms (seizures, stupor defined as Glasgow score \< 12, or signs of brain herniation) or by SNa \<115 mmol/L
* Normal or decreased extracellular fluid volume

Exclusion Criteria:

* Obvious increase of extracellular fluid volume (cirrhosis with ascites, congestive heart failure, nephrotic syndrome);
* Hyponatremia caused by hyperglycaemia (\> 30 mmol/L) or hypertriglyceridemia (10 g/L) or hyperproteinaemia (120 g/L)
* Severe acute kidney injury (KDIGO 3)
* Severe chronic kidney disease (eGFR \<20 ml/min)
* Coronary patients well stabilized with trinitrine-based medicines
* Recent neurosurgery or traumatic brain injury
* Previous DDAVP or hypertonic fluid administration for the current episode of severe hyponatremia
* SNa increased by 5 mmol or more between admission at hospital and randomisation (H0)
* Known contraindication to DDAVP

  * Allergy
  * Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
  * History of unstable angina and/or known or suspected heart failure.
  * Willebrand disease type IIB
* Severe previous neurologic disability (Glasgow Outcome Scale: GOS \< 3)
* Diabetes insipidus receiving DDAVP treatment
* Moribund state (patient likely to die within 24h)
* Need for invasive mechanic ventilation
* Enrolment to another interventional study (clinical trial on medicinal product, medical device and interventional research involving human participants not concerning health product)
* Pregnancy or breastfeeding
* Subject deprived of freedom, subject under a legal protective measure
* No affiliation to any health insurance system
* Refusal to participate to the study (patient or legal representative or family member or close relative if present)

Primary outcomes:
measure: reduced occurrence of overcorrection of serum sodium concentration (SNa) in the first 48 hours after randomization
timeFrame: 48 hours after the randomization
Secondary outcomes:
measure: the reversal of acute neurological symptoms in patients with neurological symptoms at inclusion
timeFrame: 6 hours after the randomization
measure: ICU and hospital length of stay
timeFrame: ICU or hospital discharge
measure: survival
timeFrame: death after randomization
measure: the occurrence of central pontine myelinolysis diagnosed on clinical and MRI criteria
timeFrame: 15 days after randomization
measure: the occurrence of any (pontine or extrapontine) osmotic demyelination as assessed by brain MRI
timeFrame: 15 days after randomization
measure: on the percentage of patients with neurological symptoms at inclusion and reaching the initial goal of rapid partial pre-defined correction of SNa level
timeFrame: 6 hours after the randomization
measure: the urine output between H0 and H6
timeFrame: 6 hours after the randomization
measure: the urine output between H6 and H12
timeFrame: 12 hours after the randomization
measure: the urine output between H12 and H24
timeFrame: 24 hours after the randomization
measure: the urine output between H24 and H48
timeFrame: 48 hours after the randomization
measure: the urine osmolality between H0 and H6
timeFrame: 6 hours after the randomization
measure: the urine osmolality between H6 and H12
timeFrame: 12 hours after the randomization
measure: the urine osmolality between H12 and H24
timeFrame: 24 hours after the randomization
measure: the urine osmolality between H24 and H48
timeFrame: 48 hours after the randomization
measure: SNa level correction rate between H0 and H24
timeFrame: 24 hours after the randomization
measure: SNa level correction rate between H0 and H48
timeFrame: 48 hours after the randomization
measure: the maximal change of SNa level between H0 and H24
timeFrame: 24 hours after the randomization
measure: the maximal change of SNa level between H0 and H48
timeFrame: 48 hours after the randomization
measure: amount of hypotonic fluids administration
timeFrame: 24 hours after the randomization
measure: amount of hypotonic fluids administration
timeFrame: 48 hours after the randomization
measure: amount of sodium and potassium administered between H0 and H24
timeFrame: 24 hours after the randomization
measure: amount of sodium and potassium administered between H0 and H48
timeFrame: 48 hours after the randomization
measure: the occurrence of any new neurological sign in relation with hyponatremia in patients with a normal neurological exam at inclusion or on the reappearance of any neurological sign in relation with hyponatremia after inclusion
timeFrame: 28 days after randomization
measure: the occurrence of excessive re-lowering of sodium
timeFrame: 48 hours after the randomization
Other outcomes:
Locations:
city: Amiens
country: France
facility: Médecine Intensive et Réanimation - Centre Hospitalier Universitaire Amiens-Picardie
city: Bobigny
country: France
facility: Médecine Intensive et Réanimation - Hôpital Avicenne
city: Bondy
country: France
facility: Réanimation Polyvalente - Hôpital Jean Verdier
city: Colombes
country: France
facility: Médecine Intensive et Réanimation - Hôpital Louis Mourier
city: Corbeil-Essonnes
country: France
facility: Réanimation Polyvalente et Surveillance continue - Centre Hospitalier Sud Francilien
city: Créteil
country: France
facility: Médecine Intensive et Réanimation - Hôpital Henri Mondor
city: Dijon
country: France
facility: Médecine Intensive et Réanimation - Hôpital François Mitterand
city: La Roche-sur-Yon
country: France
facility: Réanimation Polyvalente - Centre Hospitalier Départemental Vendée
city: Longjumeau
country: France
facility: Réanimation Médicale - Hôpital de Longjumeau
city: Paris
country: France
facility: Médecine Intensive et Réanimation - Hôpital de la Pitié Salpêtrière
city: Saint-Denis
country: France
facility: Médecine Intensive Réanimation - Hôpital Delafontaine
city: Suresnes
country: France
facility: Réanimation Polyvalente - Hôpital Foch
Study officials:
References: