Abstract
OBJECTIVE
Preterm infants often require caffeine for the treatment of apnea. While the maintenance dose of caffeine citrate is usually administered once daily per FDA labeling, many providers administer the maintenance dose in two divided doses. This study evaluated the effectiveness of a twice daily dosing regimen of caffeine for apnea of prematurity.
METHODS
This was a retrospective analysis conducted from 2013–2018 that included preterm infants who received caffeine that was dosed both once and twice daily respectively. The primary outcome of our study was a composite of the number of apneic and bradycardic events for five 24-hour periods prior to switching to twice daily dosing of caffeine and five 24-hour periods after switching to twice daily dosing of caffeine.
RESULTS
The median five-day average incidence of apnea and bradycardia during the once and twice daily dosing periods was 6.2 events and 6.4 events respectively (p=0.09).
CONCLUSIONS
There is little benefit of twice daily dosing of caffeine for apnea of prematurity.
Keywords: adverse drug reaction, apnea and bradycardia, caffeine, dosing, efficacy, prematurity, retrospective study
Introduction
Caffeine is frequently used in preterm neonates (<37 weeks' gestation) for the treatment of apnea of prematurity. Adequate treatment of apnea in neonates is critical because prolonged apnea can result in hypoxemia of the developing brain and other organs.1 While caffeine is a relatively benign medication with few side effects, there is still potential for harm with its use. Common adverse effects associated with caffeine use in neonates include tachycardia and feeding intolerance. Additionally, caffeine increases oxygen consumption in preterm infants, which can lead to diminished growth.2,3
The FDA labeled dose of caffeine for apnea of prematurity is a 20 mg/kg loading dose followed by a 5 mg/kg maintenance dose given once daily, though some authors4,5 have suggested that larger loading (i.e., 40 mg/kg) or maintenance (i.e., 10 mg/kg) doses may be beneficial. Caffeine is preferred for the treatment of apnea of prematurity because of its favorable pharmacokinetic profile, which allows for once-daily dosing and does not require routine therapeutic drug monitoring.1,2 To date, no studies have evaluated the efficacy of a twice-daily dosing regimen of caffeine for apnea of prematurity.
The data highlighting the pharmacokinetic profile of caffeine in preterm neonates do not appear to support a benefit with twice-daily administration. As postnatal age increases, the clearance of caffeine increases and the half-life decreases. At 27 weeks' gestation, the half-life of caffeine has been found to be 101 hours, decreasing to 65 hours in neonates born at 30 weeks' gestation.6 Some providers have reported anecdotal benefit with twice-daily caffeine dosing because of a perceived reduction in tachycardic events (peak effect) and more consistent coverage throughout the dosing interval (diminished therapeutic breakthrough toward the end of the dosing interval). The majority of infants at our institution use a regimen consisting of a 20 mg/kg load of caffeine followed by a 10 mg/kg once-daily maintenance dose. For patients having frequent, severe, or prolonged apneic events on the standard regimen, the 10 mg/kg/day maintenance dose is divided and administered twice a day. Because of a lack of evidence supporting twice-daily dosing of caffeine for apnea of prematurity, this study was conducted to evaluate the effectiveness of administering caffeine twice daily in infants who have failed traditional dosing.
Materials and Methods
This study was a retrospective analysis conducted to evaluate twice-daily administration of caffeine in preterm neonates from September 20, 2013, through September 20, 2018. Patients were included if they were delivered at or before 32 weeks in gestation; had documented administration of caffeine dosed both once and twice daily, respectively; and received each dosing regimen of caffeine for at least 5 consecutive days. Patients with diaphragmatic hernia, hydrops, or any congenital malformation that could affect the airway were excluded. Additionally, patients with documented mechanical ventilation during the study period and patients on non-standard doses of caffeine (i.e., maintenance doses of >10 mg/kg/day) were excluded.
The primary outcome of this study was the number of apneic and bradycardic events during the 5 days (24-hour periods) before and 5 days after transitioning from a once-daily to a twice-daily dosing regimen of caffeine. The same daily dose of caffeine was given in both study periods, and doses were given both intravenously and orally. Outcomes assessed included adverse effects of caffeine and efficacy of caffeine. Adverse effects included tachycardia and tachypnea. Tachycardia was defined as a heart rate greater than 180 beats per minute during the study period and tachypnea as a respiratory rate greater than 70 breaths per minute during the study period. Efficacy was determined via assessment of desaturation events.
Electronic data abstraction was used to pull information on baseline characteristics. Chart abstraction was performed to further identify our primary and secondary outcomes. Patient data were collected from electronic medical charts, both manually and using PowerInsight Explorer (Cerner, North Kansas City, MO).
Descriptive statistics were used to report baseline characteristics. The primary outcome was assessed in 2 ways: 1) The median number and interquartile range of apneic and bradycardic events for the study participants were reported for each of the 5-day periods pre- and post–dosing switch to allow visualization of the daily trend; and 2) The number of apneic and bradycardic events for each participant was summed for the 5 days pre- and 5 days post–dosing switch and were divided by 5 to report the measurement as an average count per day (total events per participant in 5 days divided by 5). The change in 5-day average values from pre- to post–dosing switch was evaluated using a Wilcoxon signed rank test and was reported through median values.
Differences in clinical characteristics between those who responded and did not respond to the change in twice-daily dosing were described. Participants were split into responders and non-responders based on their change in 5-day average apneic and bradycardic events pre- to post–dosing switch. We defined responders as those participants who had a 25% or more decrease in 5-day average apneic and bradycardic events. Non-responders were participants who did not have at least a 25% decrease in 5-day average apneic and bradycardic events. The 25% cutoff was chosen by providers at our institution as a clinically significant decrease in events. Clinical characteristics hypothesized to be associated with a change in response to the dosing regimen were compared between these groups using a Mann-Whitney U-test, Fisher's exact tests, and Chi-square tests, as appropriate.
Efficacy and potential adverse effects of caffeine were also assessed. The median number of tachycardic events, tachypneic events, and desaturation events were compared for the 5 days prior to and post–dosing switch. The median count difference for these events (with interquartile range) was quantified. Differences were evaluated using Wilcoxon signed rank tests. All statistical analysis was performed using SAS v9.4 (SAS Corporation, Cary, NC). Data collection and graphing were conducted using Excel (Microsoft Corporation, Seattle, WA).
Results
A total of 166 patients were evaluated in this study. Seventy-seven patients were excluded for the following reasons: mechanical ventilation required during the study period (n = 64); presence of diaphragmatic hernia (n = 1), congenital malformations (n = 3: cleft palates [n = 2], subglottic stenosis ([n = 1]), or hydrops (n = 1); and patients on maintenance doses of caffeine of >10 mg/kg/day (n = 8). Ultimately, 89 patients were included in the final analysis. Baseline patient characteristics of those included are shown in Table 1.
Table 1.
Baseline Characteristics
| Parameter | Value |
|---|---|
| Gestational age, median (IQR), wk | 27.2 (26–29) |
| Birth weight, median (IQR), kg | 1.0 (0.8–1.3) |
| Sex, n (%), female | 50 (56.2) |
| Race, n (%), white | 76 (85.4) |
| Age at switch to every 12-hr dosing, median (IQR), wk | 30.4 (26–32) |
| Apgar score at 1 min, median (IQR) | 5 (2–7) |
| Apgar score at 5 min, median (IQR) | 8 (7–9) |
| Singleton birth, n (%) | 66 (74.2) |
| Disorder, n (%) | |
| Patent ductus arteriosus, n (%) | 28 (31.5) |
| Intraventricular hemorrhage, n (%) | 15 (16.9) |
| Congenital heart defects, n (%) | 18 (20.2) |
| Bronchopulmonary dysplasia, n (%) | 48 (53.9) |
Primary Outcome. The median daily average incidence of apnea and bradycardia during the 5-day period for the once-daily dosing period was 6.2 events, and the average incidence was 6.4 events during the twice-daily dosing period. After switching from a once-daily to a twice-daily dosing regimen of caffeine, patients reduced their average daily incidence of apnea and bradycardia events by a median of 0.6 events (p = 0.09). A small increase in the daily median incidence of apnea and bradycardia for the study group is notable prior to the switch to the twice-daily dosage regimen, followed by a return to pre-switch counts in the 5 days following (Figure). The pre-switch median daily incidence of apnea and bradycardia was higher for participants who showed any improvement/reduction in events (pre-switch median = 7.2 events) than for those that did not show any improvement/reduction of events (pre-switch median = 4.7 events). Applying the predefined definition of responders to the twice-daily dosing regimen of caffeine, 35 (39.3%) participants were classified as responders and 54 (60.7%) patients as non-responders (Table 2).
Figure.
Incidence of apnea and bradycardia 5 days before and 5 days after switching from a once-daily to a twice-daily dosing schedule of caffeine.
Table 2.
Clinical Characteristics of Responders Versus Non-Responders to Twice-Daily Caffeine Dosing
| Clinical Characteristic | Responders* (n = 35) | Non-Responders† (n = 54) | p value |
|---|---|---|---|
| Birth weight, n (%) | |||
| ≤1500 g | 31 (88.6) | 52 (96.3) | 0.21 |
| >1500 g | 4 (11.4) | 2 (3.7) | |
| Gestational age, n (%), wk | |||
| 23–25.6 | 7 (20) | 8 (14.8) | 0.73 |
| 26–28.6 | 18 (51.4) | 32 (59.3) | |
| 29–32 | 10 (28.6) | 14 (25.9) | |
| Disorder, n (%) | |||
| Anemia, n (%) | 3 (8.6) | 3 (5.6) | 0.68 |
| Sepsis, n (%) | 14 (40) | 25 (46.3) | 0.56 |
| Gastroesophageal reflux disease, n (%) | 9 (25.7) | 12 (22.2) | 0.70 |
| Necrotizing enterocolitis, n (%) | 2 (5.7) | 4 (7.4) | 1.00 |
| Bronchopulmonary dysplasia, n (%) | 19 (54.3) | 29 (53.7) | 0.96 |
| Patent ductus arteriosus, n (%) | 13 (37.1) | 15 (27.8) | 0.35 |
* Response was defined as a ≥25% decrease in 5-day average apneic and bradycardic events.
† Numbers do not add up 100% because patients may have more than one disorder.
Secondary Outcomes. During the twice-daily dosing period of caffeine, participants had a statistically significant median increase of one more tachycardia event compared with during the once-daily dosing period (p = 0.04). There was no statistically significant difference in tachypnea events observed between the 2 dosing periods. Efficacy, as determined by the incidence of desaturation events, was similar between the 2 dosing periods, but there was high variability in the study group (Table 3).
Table 3.
Adverse Effects and Efficacy Assessed During the Study Period
| Adverse Effect | 24-hr Dosing* Period | 12-hr Dosing† Period | Difference | p value |
|---|---|---|---|---|
| Adverse effect | ||||
| Tachycardia,‡ median (IQR) | 3 (1–7) | 5 (2–8) | 1 (−1 to 3) | 0.04 |
| Tachypnea,§ median (IQR) | 3 (1–6) | 3 (1–7) | 0 (−2 to 2) | 0.56 |
| Efficacy | ||||
| Desaturation,¶ median (IQR) | 40 (10–66) | 34 (13–76) | 1 (−9 to 21) | 0.09 |
* Data represents 5 days of once-daily dosing of caffeine prior to a change to every 12-hr dosing with the same dose.
† Five days of twice-daily dosing of caffeine after a change from once-daily administration with the same dose.
‡ Tachycardia event, heart rate > 180 beats/min.
§ Tachypnea event, respiratory rate > 70 breaths/min.
¶ Desaturation event, SpO2 < 88%.
Subgroup Analysis. A subgroup analysis of baseline characteristics of responders (25% drop in apnea/bradycardia events) versus non-responders was performed to determine whether certain groups of patients might benefit from a twice-daily dosing regimen of caffeine. As seen in Table 2, no assessed factors showed different representation within the responder and non-responder subgroups.
Discussion
The results of this study suggest that there is little benefit to twice-daily dosing of caffeine for apnea of prematurity. The median average daily incidence of apnea and bradycardia on twice-daily caffeine was similar to that on once-daily caffeine. It was observed that prior to switching to twice-daily caffeine, the pre-switch average incidence of apnea and bradycardia was higher for participants who showed any improvement (a decrease in events) compared with those who showed no improvement. This suggests that observed decreases in apneic and bradycardic events could be because of regression to the mean, such that patients with higher-than-average incidence on one day are likely to fall closer to the mean on the following day.7 A prospective, controlled study would be required to fully assess this finding. Study participants had a statistically significant median increase of one more tachycardia event during the twice-daily dosing period. While this contradicts the belief that split caffeine dosing can reduce tachycardia, there is no way to correlate the tachycardia events with the caffeine itself because no concentrations were drawn in this study. Additionally, we were unable to rule out other causes of tachycardia (e.g., sepsis, respiratory distress) at the time of the events, making an association with caffeine even more difficult. Limitations to this study include its retrospective design and the manual charting of apneic and bradycardic events, which left room for inaccurate and possible underrecording of events during the study period. Selection bias may have occurred because patients were only included if they had previously failed to respond to a once-daily caffeine regimen. It is possible the study group represents truly refractory patients, which may be refractory to all currently accepted approaches, and this hypothesis requires further investigation.
Conclusions
This analysis did not support use of a twice-daily dosing schedule of caffeine for apnea of prematurity. A prospective, controlled trial is needed to determine whether or not twice-daily caffeine dosing is beneficial for apnea of prematurity.
Acknowledgments
We thank Ryan Tilton, PharmD, for data curation. Preliminary results were presented at the American Society of Health System Pharmacist Midyear Clinical Meeting in Anaheim, CA on December 5, 2018, and at the Southeastern Residency Conference Annual Meeting in Athens, GA, on April 25, 2019.
ABBREVIATIONS
- FDA
US Food and Drug Administration
Footnotes
Disclosure. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Ethical Approval and Informed Consent. The Institutional Review Board of Mission Hospital approved the study. Given the nature of this study, informed consent was not obtained.
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