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The Effect of an Additional Pre-extubational Loading Dose of Caffeine-citrate (NEOKOFF22)

S

Semmelweis University

Status and phase

Enrolling
Phase 4

Conditions

Respiratory Failure
Apnea of Prematurity
Premature Birth

Treatments

Drug: Caffeine citrate

Study type

Interventional

Funder types

Other

Identifiers

NCT06401083
NEOKOFF22
2022-003202-77 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment

226 estimated patients

Sex

All

Volunteers

No Healthy Volunteers

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.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

226 participants in 2 patient groups

Pre-extubational caffeine-citrate
Active Comparator group
Description:
Participants will receive 20 mg/kg loading dose of caffeine citrate on the first day of life and after that 5-10 mg/kg maintenance dose each day. On this arm, the participants will receive 20 mg/kg caffeine dose once again before the planned extubation.
Treatment:
Drug: Caffeine citrate
Routine care
No Intervention group
Description:
Participants will receive 20 mg/kg loading dose of caffeine citrate on the first day of life and after that 5-10 mg/kg maintenance dose each day, also on the day of the extubation.

Trial documents
1

Trial contacts and locations

2

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Central trial contact

Ákos Gasparics, MD.PhD; Kinga Kovács, MD.

Data sourced from clinicaltrials.gov

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