Clinical trial NCT06401083: The Effect of an Additional Pre-extubational Loading Dose of Caffeine-citrate
Official title: The Effect of an Additional Pre-extubational Loading Dose of Caffeine-citrate
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Apnea of Prematurity
Premature Birth
Respiratory Failure
Keywords: prematurity
caffeine
methylxanthine
apnea of prematurity
extubation failure
Lead sponsor: Semmelweis University
Sponsor class: OTHER
First posted: 2024-05-06
Enrollment: 226
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to answer whether the use of a single loading dose (20 mg/kg) of caffeine citrate one hour before extubation has an impact on the success rate of extubation among preterm neonates. In addition, the investigators would like to assess the frequency of apneas and side effects of the intervention, as well as the development of NEC, BPD, IVH, PVL, and long-term neurodevelopmental outcomes in the investigated populations.

According to institutional protocol, preterm infants born before the 32nd week of gestation receive a standard dose of caffeine citrate therapy. This covers a maintenance dose of 5-10 mg/kg of caffeine citrate administered intravenously once or twice daily after a loading dose of 20 mg/kg on the first day of life. In this trial, preterm infants born before the 32nd gestational week and who had been mechanically ventilated for at least 48 hours before planned extubation are planned to be randomly allocated into intervention and control groups. The intervention group will receive an additional loading dose of caffeine citrate 60 minutes before extubation. The control group will receive standard dosing regimens.

Detailed description: The most common cause of the failure of non-invasive ventilatory support is poor spontaneous respiratory activity in preterm infants and recurrent respiratory arrest (apnea) due to the immature nervous system. The national and international literature has extensively studied apnea in preterm infants. Apnea is a respiratory failure of 15-20 seconds or shorter duration associated with bradycardia or desaturation. Apneas develop in preterm infants due to prematurity of the respiratory center and chemoreceptors and reduced patency of the upper airway. Apnea in preterm infants is the most common indication for intubation and reintubation.

The apnea-reducing effects of the respiratory center stimulant methylxanthines have been known for more than 40 years. Based on current knowledge, caffeine is the drug of choice for the medical treatment of apnea. Caffeine has the narrowest spectrum of side effects, the broadest therapeutic range, and the most prolonged half-life among methylxanthines.

Caffeine is currently one of the most commonly used drugs in premature neonatal intensive care units. The most common dosing recommendation is a maintenance dose of 5-10 mg/kg daily after a loading dose of 20 mg/kg of caffeine citrate. Higher saturating and maintenance doses have been used in some studies, with some reports suggesting that higher doses of caffeine increase the chance of successful extubation. However, other studies have reported more frequent adverse effects at higher doses. Conflicting literature suggests that caffeine dosing may vary between institutions. Further basic research and clinical studies are needed to determine the optimal dose.

The investigators seek to answer whether the use of a single loading dose of caffeine citrate one hour before extubation impacts the success rate of extubation. In addition, the investigators would like to assess the frequency and severity of side effects and the development of necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia, and bronchopulmonary dysplasia.

To investigate the effect of a pre-extubational loading dose of caffeine-citrate, the investigators plan to carry out a two-armed randomized clinical trial, including preterm neonates being treated in one of the tertiary neonatal intensive care units of Semmelweis University. A total of 226 patients are planned to be enrolled. According to institutional protocol, preterm infants born before the 32nd week of gestation receive a standard dose of caffeine therapy. This covers a maintenance dose of 5-10 mg/kg of caffeine citrate administered intravenously once or twice daily after a loading dose of 20 mg/kg on the first day of life.

Preterm infants who have been on mechanical ventilation for at least 48 hours before planned extubation will be randomly allocated into intervention and control groups. Stratification of the randomization will be based on gestational age and antenatal steroid prophylaxis. Intervention is an additional loading dose (20 mg/kg) of intravenous caffeine citrate 60 minutes before extubation. The control group will receive routine dosing regimens as mentioned above. Before extubation, the parents will be informed and asked for consent. Pre-interventional, the investigators plan to collect baseline characteristics and oxygen requirements. After extubation, the need for reintubation within the next 48 hours will be assessed. This timeframe was chosen because most of reintubation due to respiratory reasons happens within the next 48 hours after extubation, and the caffeine half-life ranges from 40 to 230 hours.

The investigators will also assess the frequency of side effects such as gastric residuals, frequency of apneas, need for supplementary oxygen, elevated heart rate, or blood pressure. Data will be collected about adverse outcomes of prematurity, e.g., necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia, and bronchopulmonary dysplasia.

Eligibility criteria: Inclusion Criteria:

* Premature infant born before 32nd week of gestation is completed;
* Had been mechanically ventilated for at least 48 hours;
* Before the first planned extubation.

Exclusion Criteria:

* Lack of informed consent, refusal to participate in the study;
* Major congenital anomaly;
* Had not received surfactant treatment;
* Hydrops foetalis;
* Persistent tachycardia before extubation, fetal/neonatal arrhythmia;
* Asphyxia.

Primary outcomes:
measure: Rate of extubation failure
timeFrame: 48 hours
Secondary outcomes:
measure: Frequency of apneas
timeFrame: 48 hours
measure: Change in the mean heart rate
timeFrame: 72 hours
measure: Tachycardia
timeFrame: 72 hours
measure: Volume of gastric residuals
timeFrame: 72 hours
measure: Reduction/Cessation of feeding
timeFrame: 48hours
measure: Change in mean arterial blood pressure
timeFrame: 48 hours
measure: Mechanical ventilation (MV) days
timeFrame: At discharge from participating centres, an average of one month.
measure: Non-invasive ventilation (NIV) days
timeFrame: At discharge from participating centres, an average of one month.
measure: Rate of necrotizing enterocolitis
timeFrame: At discharge from participating centres, an average of one month.
measure: Rate of Intraventricular hemorrhage
timeFrame: At discharge from participating centres, an average of one month.
measure: Rate of periventricular leukomalacia
timeFrame: At discharge from participating centres, an average of one month.
measure: Rate of late-onset sepsis
timeFrame: At discharge from participating centres, an average of one month.
measure: Rate of patent ductus arteriosus
timeFrame: At discharge from participating centres, an average of one month.
measure: Rate of bronchopulmonary dysplasia
timeFrame: 36th postmenstrual age
measure: Rate of death before discharge
timeFrame: At discharge from participating centres, an average of one month.
measure: Required oxygen concentration
timeFrame: 24 hours
measure: Long term neurodevelopmental outcome
timeFrame: At 2 years of corrected age
measure: Severity of sensoric or motoric impairment
timeFrame: At 2 years of corrected age
Other outcomes:
Locations:
city: Budapest
country: Hungary
facility: Pediatric Center, Semmelweis University
city: Budapest
country: Hungary
facility: Department of Obstetrics and Gynecology, Semmelweis University
Study officials:
affiliation: Semmelweis University, Department of Obstetrics and Gynecology
name: Ákos Gasparics, MD.PhD
role: PRINCIPAL_INVESTIGATOR
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