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

Respiratory Failure Clinical Trial

— NEOKOFF22  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06401083
• Other study ID #: NEOKOFF22
• Secondary ID: 2022-003202-77
• Status: Recruiting
• Phase: Phase 4
• Start date: December 21, 2023
• Est. completion date: December 2028

Study information

• Verified date: April 2024
• Source: Semmelweis University
• Contact: Kinga Kovács, MD.
• Phone: +36206663718
• Email: kovacs.kinga1[@]semmelweis.hu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 226
• Est. completion date: December 2028
• Est. primary completion date: December 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Apnea of Prematurity
• Premature Birth
• Respiratory Failure
• Respiratory Insufficiency

Intervention

Drug:
• Caffeine citrate
20 mg/kg caffeine-citrate before the planned extubation.

Locations

Country	Name	City	State
Hungary	Department of Obstetrics and Gynecology, Semmelweis University	Budapest
Hungary	Pediatric Center, Semmelweis University	Budapest

Sponsors (1)

Lead Sponsor	Collaborator
Semmelweis University

Country where clinical trial is conducted

Hungary, 

References & Publications (12)

Bacci SLLDS, Johnston C, Hattori WT, Pereira JM, Azevedo VMGO. Mechanical ventilation weaning practices in neonatal and pediatric ICUs in Brazil: the Weaning Survey-Brazil. J Bras Pneumol. 2020 Mar 23;46(4):e20190005. doi: 10.36416/1806-3756/e20190005. eCollection 2020. — View Citation

Chavez L, Bancalari E. Caffeine: Some of the Evidence behind Its Use and Abuse in the Preterm Infant. Neonatology. 2022;119(4):428-432. doi: 10.1159/000525267. Epub 2022 Jun 10. — View Citation

Chen J, Jin L, Chen X. Efficacy and Safety of Different Maintenance Doses of Caffeine Citrate for Treatment of Apnea in Premature Infants: A Systematic Review and Meta-Analysis. Biomed Res Int. 2018 Dec 24;2018:9061234. doi: 10.1155/2018/9061234. eCollection 2018. — View Citation

Eichenwald EC. National and international guidelines for neonatal caffeine use: Are they evidenced-based? Semin Fetal Neonatal Med. 2020 Dec;25(6):101177. doi: 10.1016/j.siny.2020.101177. Epub 2020 Nov 4. — View Citation

Erickson G, Dobson NR, Hunt CE. Immature control of breathing and apnea of prematurity: the known and unknown. J Perinatol. 2021 Sep;41(9):2111-2123. doi: 10.1038/s41372-021-01010-z. Epub 2021 Mar 12. — View Citation

Kreutzer K, Bassler D. Caffeine for apnea of prematurity: a neonatal success story. Neonatology. 2014;105(4):332-6. doi: 10.1159/000360647. Epub 2014 May 30. — View Citation

Long JY, Guo HL, He X, Hu YH, Xia Y, Cheng R, Ding XS, Chen F, Xu J. Caffeine for the Pharmacological Treatment of Apnea of Prematurity in the NICU: Dose Selection Conundrum, Therapeutic Drug Monitoring and Genetic Factors. Front Pharmacol. 2021 Jul 26;12:681842. doi: 10.3389/fphar.2021.681842. eCollection 2021. — View Citation

McPherson C, Neil JJ, Tjoeng TH, Pineda R, Inder TE. A pilot randomized trial of high-dose caffeine therapy in preterm infants. Pediatr Res. 2015 Aug;78(2):198-204. doi: 10.1038/pr.2015.72. Epub 2015 Apr 9. — View Citation

Mohammed S, Nour I, Shabaan AE, Shouman B, Abdel-Hady H, Nasef N. High versus low-dose caffeine for apnea of prematurity: a randomized controlled trial. Eur J Pediatr. 2015 Jul;174(7):949-56. doi: 10.1007/s00431-015-2494-8. Epub 2015 Feb 3. — View Citation

Moschino L, Zivanovic S, Hartley C, Trevisanuto D, Baraldi E, Roehr CC. Caffeine in preterm infants: where are we in 2020? ERJ Open Res. 2020 Mar 2;6(1):00330-2019. doi: 10.1183/23120541.00330-2019. eCollection 2020 Jan. — View Citation

Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006 May 18;354(20):2112-21. doi: 10.1056/NEJMoa054065. — View Citation

Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity Trial Group. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med. 2007 Nov 8;357(19):1893-902. doi: 10.1056/NEJMoa073679. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of extubation failure	Reintubation. The discretion of the attending physician.	48 hours
Secondary	Frequency of apneas	Respiratory failure of 15-20 seconds or shorter duration associated with bradycardia or desaturation.	48 hours
Secondary	Change in the mean heart rate	Mean heart rate measured 24 hours before and 48 hours after intervention.	72 hours
Secondary	Tachycardia	The time interval when the heart rate >200 (min) during one day (1440 min) in percentage.	72 hours
Secondary	Volume of gastric residuals	Gastric residuals measured 24 hours before and 48 hours after intervention.	72 hours
Secondary	Reduction/Cessation of feeding	48 hours after intervention.	48hours
Secondary	Change in mean arterial blood pressure	Mean blood pressure measured 24 hours before and after intervention measured with non-invasive methods.	48 hours
Secondary	Mechanical ventilation (MV) days	MV days during the length of hospital stay	At discharge from participating centres, an average of one month.
Secondary	Non-invasive ventilation (NIV) days	NIV days during the length of hospital stay	At discharge from participating centres, an average of one month.
Secondary	Rate of necrotizing enterocolitis	Development of necrotizing enterocolitis according to Bell stages.	At discharge from participating centres, an average of one month.
Secondary	Rate of Intraventricular hemorrhage	Development or progression of intraventricular hemorrhage according to Papile stages diagnosed with cranial ultrasound.	At discharge from participating centres, an average of one month.
Secondary	Rate of periventricular leukomalacia	Development of periventricular leukomalacia, seen on cranial ultrasound.	At discharge from participating centres, an average of one month.
Secondary	Rate of late-onset sepsis	Culture proven sepsis after the first 72 hours of life.	At discharge from participating centres, an average of one month.
Secondary	Rate of patent ductus arteriosus	Pharmacological or surgical treatment was required.	At discharge from participating centres, an average of one month.
Secondary	Rate of bronchopulmonary dysplasia	Diagnosis of bronchopulmonary dysplasia.	36th postmenstrual age
Secondary	Rate of death before discharge		At discharge from participating centres, an average of one month.
Secondary	Required oxygen concentration	Required oxygen concentration before and after the intervention.	24 hours
Secondary	Long term neurodevelopmental outcome	Measured by Bayley score. The standardized mean score is 100 (SD 15), with scores lower than 85 indicating mild impairment, and lower than 70 indicating moderate or severe impairment.	At 2 years of corrected age
Secondary	Severity of sensoric or motoric impairment	Hearing or visual impairment, and cerebral palsy	At 2 years of corrected age