|Year : 2019 | Volume
| Issue : 3 | Page : 141-146
Does routine prophylaxis with caffeine prevent bronchopulmonary dysplasia in extremely low birth weight infants?
Varsha Bhatt-Mehta1, Todd Hershberger2, Julie Sturza3, Robert E Schumacher3
1 Department of Clinical Pharmacy, College of Pharmacy; Department of Pediatrics and Communicable Diseases, Michigan Medicine University of Michigan, Ann Arbor, Michigan, USA
2 Department of Clinical Pharmacy, College of Pharmacy, Michigan Medicine University of Michigan, Ann Arbor, Michigan, USA
3 Department of Pediatrics and Communicable Diseases, Michigan Medicine University of Michigan, Ann Arbor, Michigan, USA
|Date of Web Publication||6-Aug-2019|
Dr. Varsha Bhatt-Mehta
10-561A, C. S. Mott Children's Hospital, 1540 East Hospital Drive, Ann Arbor, Michigan
Source of Support: None, Conflict of Interest: None
Objective: The objective of the study was to determine the risk of developing bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants with and without caffeine prophylaxis. We hypothesized that there would be no difference in the risk of BPD between the two groups. Study Design: This was a comparative, single-center, retrospective cohort study comparing risk of BPD in ELBW infants (≤28-week gestation or ≤1001 g if gestational age [GA] unknown) receiving caffeine for BPD prophylaxis within the first 24 h of life to those with no prophylaxis. Materials and Methods: The risk of developing BPD in infants receiving caffeine for BPD prophylaxis was compared with a matched nonprophylaxis group. BPD was defined as the need for oxygen support at 36-week corrected GA (CGA). Secondary outcomes included total caffeine exposure, average weekly maintenance dose, and length of treatment and duration of mechanical ventilation. Results: One hundred and eight out of 153 infants (71%) received caffeine prophylaxis. The risk of developing BPD at 34–36-week CGA was not significantly different between the two groups (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.45–1.84). Infants in the prophylaxis group had higher total caffeine exposure and daily caffeine dose. There was no association between a patient's average daily dose of caffeine and risk of BPD (OR = 1.03, 95% CI: 0.91–1.18;P = 0.62). The duration of caffeine treatment was longer in the nonprophylaxis group. Infants in the prophylaxis group spent fewer days on mechanical ventilator (P = 0.03). Conclusion: The risk of BPD in infants receiving caffeine prophylaxis for BPD prevention was similar to a matched group of infants with no caffeine prophylaxis.
Keywords: Bronchopulmonary dysplasia, caffeine, extremely low birth weight, mechanical ventilation, prematurity, prophylaxis
|How to cite this article:|
Bhatt-Mehta V, Hershberger T, Sturza J, Schumacher RE. Does routine prophylaxis with caffeine prevent bronchopulmonary dysplasia in extremely low birth weight infants?. J Clin Neonatol 2019;8:141-6
|How to cite this URL:|
Bhatt-Mehta V, Hershberger T, Sturza J, Schumacher RE. Does routine prophylaxis with caffeine prevent bronchopulmonary dysplasia in extremely low birth weight infants?. J Clin Neonatol [serial online] 2019 [cited 2020 May 31];8:141-6. Available from: http://www.jcnonweb.com/text.asp?2019/8/3/141/264035
| Introduction|| |
Bronchopulmonary dysplasia (BPD) is a chronic respiratory disorder that is common among extremely premature neonates. Between 10,000 and 15,000 new cases of BPD are identified each year in the United States alone, making it the most common severe disorder of prematurity.,
In a 2006, a large multicenter study of caffeine citrate (referred to as caffeine from here on) for the treatment of apnea of prematurity (AOP) referred to as the Caffeine for Apnea of Prematurity (CAP) trial, caffeine showed beneficial effects by significantly reducing the incidence of BPD compared with placebo. This was a secondary finding in a study designed to evaluate caffeine in AOP. Several follow-up studies of the same patient population at various times over a decade have reported reduced rates of severe retinopathy of prematurity, cerebral palsy, and cognitive delay at 18 months and possibly improved gross motor function at 5 years of age. Some of these benefits did not sustain at an 11-year follow-up of a subpopulation from the original CAP trial. In this follow-up study designed to evaluate functional outcomes, caffeine therapy for AOP did not significantly reduce the combined rate of academic, motor, and behavioral impairments but was associated with a reduced risk of motor impairment in 11-year-old children with very low birth weight (BW). The authors concluded that at the doses used in the CAP trial, neonatal caffeine therapy was effective and safe into middle school age.,,
Evidence prior to the CAP trial suggested that the use of caffeine was potentially harmful to the development with significant side effects, and hence, a traditional randomized control trial was not ethically appropriate, while at the same time suggesting that in certain clinical situations (e.g., AOP and peri-extubation) using caffeine was beneficial.,,,, The CAP study design took advantage of this fact essentially asking the question “In select infants eligible to receive caffeine for other reasons (AOP), are the purported benefits worth the theoretical harm?” All medicines have the potential for harm (side effects) which is why clinicians prescribe medicines judiciously. This is why prior to the CAP study, prescribing of caffeine for AOP was often reserved for infants who were symptomatic due to AOP and not “prophylactically” for those “at risk” for apnea.
When should one prescribe caffeine (off-label) for infants at risk for BPD? Or when is the risk of BPD high enough to warrant caffeine? Despite the encouraging secondary findings from the CAP study, some theoretical risks of caffeine remain. Accordingly, in the absence of BPD, the risk/benefit ratio of caffeine can be considered speculative and the question of when to prescribe caffeine remains. Many enthusiastic clinicians have interpreted the results of the CAP trial to mean that prophylactic off-label administration of caffeine to premature infants will prevent BPD. Our neonatal intensive care unit (NICU) shared this enthusiasm. The present study was designed to gain insight into the potential benefits of this approach. In this study, we compared outcomes of infants who received “prophylactic” caffeine to those who received it for other reasons. In 2010, our institution adopted caffeine prophylaxis for BPD prevention as part of a systematic respiratory management protocol for premature infants based on the finding of the CAP trial. The purpose of this study is to evaluate the effect of prophylactic caffeine on the risk of developing BPD in extremely premature infants (≤28-week gestational age [GA], ≤1001 g if GA not known) as compared to a matched group of premature neonates who did not receive prophylactic caffeine for BPD prevention.
| Materials and Methods|| |
This study was approved by the Institutional Review Board at the University of Michigan. In this single-center, retrospective study of two cohorts of ELBW infants, one cohort received prophylactic caffeine (as the citrate salt) for the prevention of BPD according to a preestablished protocol at our institution wherein prophylactic caffeine administration was defined as initiation of caffeine treatment as soon as possible after birth but definitely by the first 24 h of life. A loading dose of caffeine was initiated at a dose of 10 mg/kg within the first 24 h of life, followed by a maintenance dose of 5 mg/kg every 24 h. The maintenance dose could be adjusted further at the discretion of the attending physician. Maintenance caffeine was continued for up to 36-week CGA with attempts made between 32 and 36 weeks to take it off. The second matched cohort of infants were those who were not on any prophylactic caffeine for BPD prevention. All patients were identified using the Vermont Oxford Network (VON) database using criteria of oxygen dependence at 36-week CGA as the presence of BPD.
All extremely premature (≤28-week GA or ≤1001 g BW if GA is not known) inborn neonates born between January 1, 2008, and June 30, 2015, were evaluated for inclusion in the study. Infants who received prophylactic caffeine for the prevention of BPD as part of respiratory distress syndrome (RDS) protocol introduced in our NICU in March 2010 were included in this study as the protocol group. Infants born prior to March 2010 who received caffeine at any time >24 h after birth for different indications such as peri-extubation or prevention/treatment of AOP were included in the nonprotocol (comparator) group. According to the RDS protocol, caffeine was to be initiated definitely by the first 24 h of life [Figure 1]. Infants in both the groups were excluded from the study if they lacked data on oxygen requirements at 36-week CGA used as a definition of BPD in the VON database or if they had missing caffeine or oxygen data.
|Figure 1: Ventilation guidelines for extremely low birth weight ≤28-week gestational age|
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The VON database was used to collect data on GA, postnatal age (PNA), total mechanical ventilation days, sex, oxygen dependence at 34–36-week CGA, and BW. Once oxygen-dependent patients were identified, all outborn infants were eliminated as the exact time of caffeine initiation (if transferred on caffeine) was difficult to ascertain. Inborn patients >28-week GA, those who died in the delivery room or at any time before 36-week CGA during intensive care admission or lacked caffeine data were also eliminated from the study. If outborn infants were transferred back to the home institution prior to 34-week CGA, they were also eliminated as procuring data were difficult due to patient privacy laws. These patients were typically sent back to level 2 nurseries to convalesce and hence at low probability for development of BPD. Electronic medical records were used to obtain data for total caffeine exposure expressed as mg/kg of caffeine exposure at 36 weeks and average maintenance dose of caffeine (collected as average dose per week since per standard practice doses are adjusted weekly for weight gain such that the mg/kg dose remains constant until intentionally increased to administer a higher dose).
The defining criteria for the diagnosis of BPD have been modified over the years. For purposes of this study, the VON definition of BPD was used to match the definition used for database entry. VON defines BPD as the need for oxygen at 28 days' PNA or at 36-week CGA. Recently, VON revised the definition of chronic lung disease or BPD to include any infant discharged home on oxygen at 34-week CGA. For the purpose of this study, we thus chose the BPD definition as oxygen dependence at 34–36-week CGA to capture low GA infants with oxygen dependence past 28-day PNA. These patients were also included in the study. The primary outcome of interest was to determine the risk of BPD defined as above in the prophylactic caffeine group compared to the nonprophylaxis group.
All analyses were conducted using SAS 9.4 (SAS Institute Inc., Cary, North Carolina, USA). Descriptive statistical procedures were used to describe the sample and check the normality of variables of interest. Independent sample t-test, Wilcoxon–Mann–Whitney test, and Chi-square test were used to check for group differences in demographics. Relative risk and odds ratio (OR) were determined using a nonmodeling approach with SAS PROC FREQ. Logistic regression was used to determine the association between average daily dose of caffeine and risk of BPD.
| Results|| |
A total of 153 infants who were inborn, ≤28-week gestation or ≤1001 g if GA was unknown, and dependent on oxygen at 34–36-week CGA were identified from the VON database as meeting criteria for entry into the study [Figure 2]. Of these study infants, 108 (71%) were in the protocol group and 45 (29%) in the nonprotocol group. Reasons for excluded infants are included in [Figure 2].
Demographic data and caffeine use comparison as well as risk of BPD is presented in [Table 1]. Infants in the nonprotocol group had significantly lower GA (average: 1 week) while median BW was similar between the two groups.
|Table 1: Characteristics of included infants and bronchopulmonary dysplasia outcome of infants in the protocol versus nonprotocol groups|
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The risk of developing BPD at 34–36-week CGA was not significantly different between the two groups (OR: 0.92, 95% confidence interval [CI]: 0.45–1.84).
Total caffeine exposure, daily caffeine dose, and total duration of caffeine treatment were significantly different between the groups. Infants in the protocol group (early caffeine) had a higher total caffeine exposure and higher daily caffeine dose. However, there was no association between a patient's average daily dose of caffeine and risk of BPD (OR = 1.03, 95% CI: 0.91–1.18; P = 0.62). The duration of caffeine treatment was longer in the nonprotocol (late caffeine) comparator group. Infants in the protocol group spent fewer days on mechanical ventilator compared to nonprotocol group (P = 0.03).
| Discussion|| |
The purpose of this study was to evaluate the effect of prophylactic caffeine on the risk of developing BPD in extremely premature infants (<28-week GA, <1001 g if GA not known) who received caffeine prophylaxis according to an institutional ventilation management protocol [Figure 1]. The protocol required initiation of caffeine treatment as soon as possible after birth according to the dosing regimen described in the protocol, but definitely by the first 24 h of life, in all eligible infants. Infants who received prophylactic caffeine were compared to a matched group of infants who did not receive such prophylaxis but received peri-extubation caffeine to facilitate successful extubation or for the treatment of AOP after the first 24 h of life.
Our intent was to evaluate a strictly regimented (in terms of start time and initial dose) caffeine utilization protocol and evaluate the risk of BPD as a singular outcome (vs. a composite of death or BPD). Our institution adopted caffeine prophylaxis for the prevention of BPD following the CAP trial. The reduction in the incidence of BPD reported in the CAP trial was a secondary finding from this study originally designed to evaluate the safety of caffeine in the treatment of AOP as used in various NICUs according to their standard of practice. Several follow-up studies from the same authors have shown reduced rates of BPD, severe retinopathy of prematurity, cerebral palsy, and cognitive delay at 18 months and possibly improved gross motor function at 5 years of age.,, In our study, although small but focused on a single outcome and following a strict caffeine prophylaxis protocol, the risk of BPD was not different between the two groups. We found higher total caffeine exposure in the prophylaxis group as caffeine was started much earlier and continued until 36-week CGA (and beyond in some cases), regardless of the type of respiratory support, resulting in higher total caffeine exposure. In many instances, infants who were on mechanical ventilation had doses adjusted upward. In some cases of severe BPD with ventilator or other respiratory dependencies with higher oxygen needs, caffeine was continued and doses adjusted upward with the thought that it was good for BPD. This was different from the nonprophylaxis group where caffeine was started later, mostly peri-extubation or after extubation for the treatment of AOP and only when needed, and continued to 34–36-week CGA once started. This observation is notable since the caffeine use was lower in the nonprophylaxis group despite this group being younger (average of 1 week) and hence had 1 more week for exposure to 36-week CGA. While the number of ventilator days between the two groups reached statistical significance, clinically this difference was not significant. This difference may also have been driven in part by a new unit guideline (with regular audits of clinician behavior) that encouraged earlier extubation.
Two other smaller studies have aimed to compare the effects of early and late (routine) initiation of caffeine on BPD or death or non-BPD-related outcomes in nonintubated preterm neonates., The first, an observational trial, was conducted to determine the power needed to reduce the need for endotracheal intubation by 12 h of age. Incidence of BPD was not reported as an outcome in this study. The second was a large retrospective study of neonates who initiated caffeine within the first 2 days after birth (early) and on or after the 3rd day following birth (late). This study evaluated a composite outcome of death or BPD. In this study, neonates in the early group had decreased odds of a composite outcome of death or BPD and patent ductus arteriosus, but there was no difference between the groups in mortality, BPD alone defined as oxygen dependence at 28 days, necrotizing enterocolitis, severe neurological injury, or severe retinopathy of prematurity. This study also did not provide information on indication for caffeine use.
The variability in the definition of caffeine initiation (“early” vs. “late”), study of either combined outcome of BPD or death, and evaluation of BPD as a secondary outcome or outcomes unrelated to BPD when studying the effects of “early” versus “late” caffeine have caused significant confusion regarding the true value of caffeine for the prevention of BPD. This confusion may contribute to an overuse of caffeine in premature neonates.
Caffeine is a central nervous system stimulant. Most data regarding pharmacologic and adverse effects stem from mature animal models or adult humans. The impact of caffeine exposure on the developing immature brain is not well understood. Caffeine mobilizes intracellular calcium and inhibits specific phosphodiesterase at high nonphysiological concentrations. What constitutes a high concentration in premature neonates is not known. Its main mechanism of action is through adenosine receptor antagonism. Caffeine increases energy metabolism throughout the brain but decreases cerebral blood flow at the same time, inducing relative brain hypoperfusion. Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. In large amounts, it can have a significant effect on blood pressure, systemic circulation, and heart rate. The methylxanthine induces dose–response increases in locomotor activity in animals is known. Caffeine exerts obvious effects on anxiety and sleep which vary according to individual sensitivity to the methylxanthine. The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are possible., Caffeine has been shown to influence the activity of many neurotransmitters and enzymes in the brain. The long-term impact of such changes in the developing brain due to caffeine exposure is unknown. The stimulant effects of caffeine may be counter productive in mechanically ventilated infants where higher levels of sedation may be needed to counter its stimulant effects. Because of these observations, we continue to be concerned about unnecessary exposure to caffeine. Prophylactic use of caffeine can expose a number of newborns who would not otherwise have developed BPD (exposure without benefit) to effects of caffeine.
Schmidt et al. have reported that caffeine therapy for AOP did not significantly reduce the combined rate of academic, motor, and behavioral impairments but was associated with a reduced risk of motor impairment in 11-year-old children with very low BW treated with caffeine for AOP. At the doses used (prescriber discretion) in the original CAP trial of which this study was a follow-up, neonatal caffeine therapy was effective and safe into middle school age. However, there was a significant variability in caffeine dosing in the CAP trial. The CAP trial was designed to determine whether caffeine therapy for AOP alters the rate of survival without neurodevelopmental disability at a corrected age of 18–21 months in infants at a high risk of apneic attacks. Forty percent of the patients assigned to caffeine in the first 10 days of life (median age: 3 days) died or survived with a neurodevelopmental disability compared with 46% assigned to placebo (OR: 0.77, 95% CI: 0.64–0.93). In this study where neonatologists were asked to start caffeine based on their standard of practice, the indication for caffeine was peri-extubation use or prevention or treatment of AOP. Only a quarter of the neonatologists started caffeine to prevent apnea. Thus, the risk–benefit ratio of caffeine administered exclusively for prophylaxis of BPD earlier remains unclear, although infants who received caffeine on or before 3 days of life had a greater reduction in the duration of mechanical ventilation than those started after 3 days of life. The CAP trial also had broad and pragmatic eligibility criteria.,
| Conclusion|| |
We have not been able to demonstrate a difference in the risk of BPD in our study between a matched group of infants with and without caffeine prophylaxis for the prevention of BPD. We acknowledge the small sample size in the nonprotocol group. This leaves open the question of whether caffeine should be used for BPD prevention and if so what is the ideal time to initiate such prophylaxis. Targeting caffeine for BPD prophylaxis in the relatively high-risk group seems a rational approach. A prospective study targeting caffeine prophylaxis in various well-defined risk value categories may provide helpful insight into answers to some of these questions. Our data suggest that despite the benefits demonstrated in the CAP trial, it may be prudent to minimize caffeine exposure in the premature developing brain through thoughtful use of caffeine.
This manuscript has been read and approved by all the authors. The requirements for authorship have been met, and each author believes that the manuscript represents honest work.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]