Caffeine, a typical representative of methylxanthine, is world-widely used to manage apnea of prematurity (AOP) in neonatology. However, an appropriate medication regimen of caffeine has not been well defined until now. For example, in terms of the duration of caffeine, AAP guideline for AOP (2016) and British NICE guideline for neonatal respiratory care (2019) all recommended discontinuing caffeine when the infants reached a postmenstrual age (PMA) ≥33weeks and had a stable respiratory status, commonly manifested by weaning from non-invasive ventilation and free of apneic episodes for at least five consecutive days. Interestingly, the actual clinical settings seem to be not strictly following this recommendation. A survey of the neonatologist in North America revealed that a substantial variability existed among sites in the timing of caffeine discontinuation before discharge and the respiratory support at the time of caffeine discontinuation \[1\]. Another survey in Saudi Arabia also had a similar finding \[2\]. The optimal timing of discontinuing caffeine is still a conundrum in the field of neonatology. Ideally, the optimal timing of discontinuing caffeine should be individual-specific. Published work has indicated that AOP and intermittent hypoxemia (IH) were frequently observed beyond 36 weeks' PMA in all gestational age groups, particularly in the 24- to 27-week infants \[3, 4\]. In the clinical settings, intermittent hypoxic and AOP episodes is a predominant cause of oxygen supplement in premature infants and commonly prolong the hospital stay. Optimizing arterial saturation by oxygen supplement is essential to achieve a stable cardiorespiratory status because hypoxemia could induce hypoxic sensitivity of the carotid bodies in neonates, resulting in more pronounced ventilatory depression and more frequent apneic episodes. Some RCTs have shown that continuing caffeine administration beyond PMA 34 weeks could reduce the frequency of IH episodes in premature infants \[4, 5\]. Therefore, theoretically, a prolonged caffeine administration over the usual duration could shorten the duration of oxygen supplements in those infants at high risk of frequent late AOP or IH. Target weaning oxygen could be an opportunistic indicator of discontinuing caffeine. In light of the above considerations, a multicenter, retrospective, partially blinded, controlled trials will be conducted to verify the hypothesis that a novel caffeine regimen that weaning oxygen as the indicator of discontinuing caffeine could improve respiratory outcomes of very premature infants.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
310
after randomization, caffeine citrate will be contineously prescribed to those patients assigned to the "ongoing caffeine with oxygen supplement (group 2) with a medication regimen of 10mg/kg.dose, once daily, and weekly adjustment based on the working weight.
The First Affiliated Hospital of USTC（University of Science and Technology of China）
Hefei, Anhui, China
Peking Union Medical College Hospital
Beijing, Beijing Municipality, China
Yuan Shi
Chongqing, Chongqing Municipality, China
First Affiliated Hospital of Army Military Medical University
Chongqing, Chongqing Municipality, China
Fuling Central Hospital of Chongqing City
Fuling, Chongqing Municipality, China
recurrence of apnea of prematurity (RAP)
Either of the following condition is defined as a RAP event: 1. heart rate \<100 beats/min; 2. weak respiratory effort requiring mask-bag ventilation; 3. A high-flow nasal cannula (HFNC) and various noninvasive and invasive ventilation are dictated by the clinical condition, where HFNC is defined as the oxygen flow is ≥2L/min; 4. Restarted caffeine therapy is considered at the discretion of the healthcare team.
Time frame: from date of randomization until the date of discharge, assessed up to 100 days of life
duration of oxygen supplement after randomization
duration of oxygen supplement after randomization
Time frame: from date of randomization until the date of discharge, assessed up to 100 days of life
duration of hospital stay after randomization
duration of hospital stay after randomization
Time frame: from date of randomization until the date of discharge, assessed up to 100 days of life
postmenstrual age of discharging home
postmenstrual age at which the infants are discharged home
Time frame: from date of randomization until the date of discharge, assessed up to 100 days of life
onset of bronchopulmonary dysplasia
onset of bronchopulmonary dysplasia, defined by oxygen dependence at the postmenstrual age of 36 weeks.
Time frame: from date of randomization until the date of discharge, assessed up to 100 days of life
severity of bronchopulmonary dysplasia
evaluate the severity of bronchopulmonary dysplasia according to the 2016 NICHD proposed revision
Time frame: from date of randomization until the date of discharge, assessed up to 100 days of life
restart caffine therapy
either of the following condition considers restarting caffeine therapy: 1. RAP event requires additional interventions to positioning, suction, and tactile stimulation; 2. intermittent hypoxemia ≥ 5 episodes per day where intermittent hypoxemia is referred to as a transient desaturation with Saturation \<90%, but without bradycardia; 3. restart caffeine therapy at the discretion of the healthcare team.
Time frame: from date of randomization until the date of discharge, assessed up to 100 days of life
restart noninvasive ventilation
either of the following conditions considers restarting non-invasive ventilation: 1.patients exhibit severe respiratory distress, including but not limited to tachypnea, chest indrawing, and grunting; 2. In the setting of nasal cannula oxygen supplemental, PaO2\<50mmHg or SpO2\<90% at the effective FiO2≥30%； 3. In the setting of incubator oxygen or hood oxygen supplement, PaO2\<50mmHg or SpO2\<90% at effective FiO2≥30% at the measured FiO2≥30%；4. Restart non-invasive ventilation at the discretion of the healthcare team.
Time frame: from date of randomization until the date of discharge, assessed up to 100 days of life
reintubating the patients
Either of the following conditions considers reintubating the patients: 1. Severe respiratory acidosis with PaCO2\>65 mmHg and pH\<7.2; 2. Refractory hypoxemia at maximal setting in the non-invasive ventilation ( SpO2\< 90%, with FiO2=0.4，and PEEP reaching eight cmH2O in CPAP/NIPPV，or Paw reaching 16 cmH2O in NHFOV; 3. Severe pulmonary hemorrhage; 4. Frequent apneic episodes (≥3 episodes per hour), or at least one episode within the last 24hours requiring mask-bag ventilation, which does not respond well to methylxanthine; 5. Hemodynamic instability after a recent occurrence of neonatal resuscitation; 6. Reintubating the patients at the discretion of the healthcare team.
Time frame: from date of randomization until the date of discharge, assessed up to 100 days of life
hospitalization cost after randomization
hospitalization cost after randomization, which includes medicine cost (caffeine, and other medicine, respectively), and other healthcare cost
Time frame: from date of randomization until the date of discharge, assessed up to 100 days of life
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
The People's Hospital of Dazu
Longgang, Chongqing Municipality, China
Chongqing University Three Gorges Hospital
Wanzhou, Chongqing Municipality, China
Chongqing Wanzhou Health Center for Women And Children
Wanzhou, Chongqing Municipality, China
Fuzhou Children's Hospital of Fujian Medical University
Fuzhou, Fujian, China
Xiamen Children's Hospital
Xiamen, Fujian, China
...and 31 more locations