Incorporating pharmacodynamic considerations into caffeine therapeutic drug monitoring in preterm neonates
© Yu et al. 2016
Received: 7 November 2015
Accepted: 29 April 2016
Published: 7 June 2016
This study sought to assess the pharmacokinetic and pharmacodynamic relationships of caffeine citrate therapy in preterm neonates who had therapeutic drug monitoring (TDM) in the post-extubation period.
A retrospective observational study was conducted in preterm neonates who received caffeine citrate therapy for apnea of prematurity and had TDM done in the post-extubation period between January 2006 and October 2011. The relationships between pharmacodynamic effects (heart rate, respiratory rate, episodes of apnea, adverse events) and caffeine serum concentrations were explored.
A total of 177 blood samples were obtained from 115 preterm neonates with a median (range) gestational age of 29 (24 – 33) weeks and birth weight of 1230 (607 – 2304) kg. Caffeine citrate therapy was initiated at a median (interquartile range) postnatal age of 1 (1 – 3) day and TDM was performed at a postnatal age of 15 (10 – 24) days. No direct correlations were found between respiratory rate or apneic episodes and caffeine serum concentrations; however, heart rate and caffeine serum concentrations were significantly correlated (p < 0.05). Dosing regimen of 40/5 mg/kg q12h (loading dose/maintenance dose, time interval) led to similar endotracheal re-intubation rate but increased percentage of patients experiencing tachycardia compared to the standard regimen of 20/5 mg/kg q24h (44.7 % vs 10.2 %, p < 0.001).
Based on this retrospective study, no correlation between episodes of apnea and caffeine serum concentrations was found in neonates who had TDM of caffeine citrate therapy in the post-extubation period, whereas a significant association between tachycardia and concentrations existed. Notwithstanding the absence of severe adverse reactions, TDM should be considered in critically ill neonates with unexplained adverse effects, such as tachycardia.
KeywordsCaffeine Neonate Pharmacodynamics Therapeutic drug monitoring
Caffeine citrate is the first-line therapy for treatment of apnea of prematurity [1, 2]. The standard dosing regimen, approved by FDA in 1999 , is an intravenous loading dose of 20 mg/kg caffeine citrate followed by a maintenance dose of 5 mg/kg daily. Other dosing regimens exist, contingent upon the neonatologist’s decision based on the neonate’s disease status. The therapeutic range of 5 – 20 mg/L has been used to guide dosing in neonates and has its origin in early works by J. V. Aranda et al., which reported that optimizing ventilatory drive and control of apnea without toxicity were achievable with caffeine serum concentrations within this range . Clinical signs of toxicity have been observed with caffeine serum concentrations above 40 mg/L . However, therapeutic drug monitoring (TDM) is not routinely performed due to its benign safety profile when standard dosing is used [6, 7]. Since TDM usually requires blood sampling by heel prick and can contribute to anemia, it is important to understand if TDM is necessary during caffeine citrate therapy, especially with varied dosing regimens other than the FDA approved regimen.
Several studies did not support the practice of routine TDM of caffeine citrate therapy or indicated higher upper bound of therapeutic range (>20 mg/L) in preterm neonates [8–10]. An observational study of 101 preterm neonates revealed that standard maintenance dose led to serum concentrations within the recommended range (5 – 20 mg/L) independent of gestational age (GA), which also held true for patients with concomitant renal or hepatic dysfunction . A prospective study reported that caffeine serum concentrations from standard dosing were in a safe and therapeutic range of 11 – 33 mg/L by 14 postnatal days and were independent of neonatal demographics including GA, postmenstrual age (PMA), and weight, suggesting that routine TDM was not necessary without clinical signs of apnea or toxicity . A population pharmacokinetic (PK) study showed that the inter-occasion (day-to-day) variability of caffeine clearance was twice the inter-individual variability in preterm neonates, which implied that adjusting a maintenance dose based on previous serum concentrations of the individual neonate was not effective due to the marked day-to-day randomness in clearance . Gal suggested that the therapeutic concentrations could range from 10 to 40 mg/L and the likelihood of response and toxicity were specific to each individual [11, 12].
Our study examined cardiovascular/respiratory effects including heart rate, respiratory rate, episodes of apnea, and adverse events as major pharmacodynamic (PD) parameters and delineated their association with caffeine serum concentrations in preterm neonates. Clinical interventions and adverse events were also compared among various dosing regimens to illustrate the aggregated clinical outcomes resulting from different caffeine exposures. The aim of this study was to find the relationship between PD responses and caffeine serum concentrations to inform the use of TDM in neonates. This retrospective study was conducted to serve as a preliminary work for a future prospective study on caffeine citrate dosing regimen optimization in preterm neonates.
This retrospective observational study consisted of preterm neonates who received caffeine citrate for apnea of prematurity at 8 sites of Intermountain Healthcare System in Utah (Utah Valley Hospital, Intermountain Medical Center, McKay-Dee Hospital, Primary Children’s Hospital, Dixie Regional Hospital, Latter-day Saints Hospital, American Fork Hospital, Logan Regional Hospital) between January 2006 and October 2011. Neonates who had been previously ventilated at birth, received at least 1 dose of intravenous caffeine citrate within 28 days of postnatal age (PNA), and had at least 1 blood sample taken for caffeine concentration measurement were included for analysis. Patients were excluded if they received caffeine citrate therapy for other indications (neonatal respiratory distress syndrome), apnea due to other causes (confirmed sepsis or pneumonia, diagnosed gastroesophageal reflux), or had no TDM. Preterm neonates with abnormalities in central nervous system were also excluded as the disease may affect the patient response to caffeine. Patient demographics including gender, birth weight, APGAR 1 min score, APGAR 5 min score, GA, PNA at dosing or sampling, PMA at dosing or sampling were recorded in enterprise data warehouse. This study was reviewed, approved, and granted a waiver of informed consent by the University of Utah Institutional Review Board.
Sample collection and measurement
The information on doses, dosing intervals, and TDM sample concentrations were obtained from enterprise data warehouse of Intermountain Healthcare System. In the clinical settings, a loading dose of either 40 mg/kg (20 mg/kg caffeine base equivalent) or 20 mg/kg caffeine citrate (10 mg/kg caffeine base equivalent) was administered by intravenous infusion over 15 min, followed by a maintenance dose of 5 mg/kg caffeine citrate (2.5 mg/kg caffeine base equivalent) every 12 or 24 h through intravenous or orogastric/nasogastric routes. The dosing regimen is denoted as loading dose/maintenance dose, dosing time interval throughout this paper. Decisions regarding caffeine citrate dosing regimen, use of TDM, and timing of blood sample acquisition were made by the clinical staff. The indication for TDM was inadequate responses such as repeated or severe apnea despite the continuation of caffeine therapy or symptoms of adverse events [13, 14]. The timing of sample collection post last dose was random and was at the discretion of the care providers. Total caffeine concentrations in serum were measured by quantitative enzyme multiplied immunoassay (EMIT caffeine assays, Siemens Healthcare, Pennsylvania, USA). The assay was accurate between 1 and 30 mg/L with between-day and within-day imprecision < 10 % across this range . Samples with caffeine concentration > 30 mg/L were diluted in drug-free serum and reanalyzed.
Clinical records identification and analysis
Intermountain HELP2 Clinical Desktop was searched to obtain clinical notes concurrent with sample collections using the patient’s enterprise master patient index number. The clinical notes included relevant critical care progress notes or discharge summaries. Vital signs (heart rate and respiratory rate) were recorded in the critical care progress notes on the date of sample collection along with the frequency of apnea and any adverse effects attributed to caffeine. The normal range of heart rate in neonates is 120 – 160 beats per minute (b · min−1) with toxicity associated with > 220 b · min−1. Episodes of heart rate > 170 b · min−1 were considered as tachycardia according to the clinical notes. The respiratory rate normal range in neonates is 30 – 60 breaths per minute (br · min−1) with toxicity defined as tachypnea > 80 br · min−1. Information on apnea or adverse events was screened in the notes. Apnea was cessation of breathing lasting > 20 seconds, and/or those that were shorter, but associated with hypoxia (oxygen saturation < 85 %) or bradycardia (heart rate < 100 b · min−1). Episodes of apnea (number) or onset of adverse events (yes/no) that happened on the same day of sample collection were recorded. If critical care progress notes concurrent with sample collections were not available, the apnea or adverse event records from the hospital discharge summary were searched to identify any information on apneic episodes or adverse events on the date of sample collection. Records from patients who were not on mechanical ventilators on the days of TDM were used to evaluate the relationships between vital signs/apnea episodes and caffeine serum concentrations. It is to note that vital signs were measured during the physical exam on the same day of TDM as dictated by the attending clinician, thus may not reflect the heart rate in a tachycardia event or respiratory rate in an apneic episode.
Clinical intervention in terms of endotracheal re-intubation was used as a surrogate marker of treatment failure in this study. Patients requiring endotracheal re-intubation during the entire course of caffeine citrate therapy were identified in the clinical notes. The underlying indications for re-intubation were divided into two subgroups, one subgroup was re-intubation secondary to worsening symptoms of apnea of prematurity, the other subgroup was re-intubation secondary to other respiratory failure etiologies, such as significant periodic breathing, increased work of breathing, increased CO2 levels, significant episodes of bradycardia with desaturations, pleural effusions, pulmonary edema, and suspected infections (no culture confirmation).
Differences in caffeine serum concentrations between dosing regimen groups were determined by Mann–Whitney U test. Linear regression was used to evaluate the association between PD effects and caffeine serum concentrations. The relationships between treatment efficacy and patient demographics were also evaluated by linear regression. Predicted probabilities for adverse events as a function of caffeine serum concentrations were assessed by logistic regression analysis. The number of patients requiring re-intubation or experiencing adverse events was compared among various dosing regimens via a χ2 test of independence. Statistics were performed using SAS software (version 9.3) (SAS Inc. North Carolina, USA) and differences were considered significant at p < 0.05.
Demographics of preterm neonates included in this study
Median (Interquartile range)
60 male, 55 female
29 (28 – 30)
Birth weight (g)
Apgar score, 1 min
Apgar score, 5 min
PNA at initiation (day)
PMA at initiation (week)
PNA at sampling (day)
PMA at sampling (week)
Caffeine citrate dosing regimens and caffeine serum concentrations during TDM
Number of patients
Caffeine serum concentration (mg/L)
Summary of clinical interventions/adverse events in terms of re-intubation and tachycardia among dosing regimens
Number of patients going through re-intubation (%)
Number of patients having tachycardia (%)
Secondary to apnea of prematurity
Secondary to other respiratory etiologies
4 (8.5 %)
7 (14.9 %)
21*** (44.7 %)
4 (8.2 %)
8 (16.3 %)
5 (10.2 %)
1 (12.5 %)
4 (50.0 %)
2 (33.3 %)
1 (16.7 %)
1 (20.0 %)
The present study revealed that a correlation between number of apneic episodes and caffeine serum concentrations was not established under current dosing regimens. A significant association between heart rate and concentrations was found among the other PD parameters, consistent with the fact that the probability of tachycardia increased as caffeine serum concentration increased. A high dose regimen 40/5 mg/kg q12h led to similar re-intubation rate but significantly higher percentage of patients having tachycardia than standard regimen 20/5 mg/kg q24h, agreeing well with the PK/PD relationships found above. The total re-intubation rate of the standard regimen in our patients (24.5 %) was similar to that reported in the literature (24.0 %) .
The lack of correlation between efficacy and caffeine serum concentrations under current dosing regimens was in agreement with the trial that granted caffeine citrate label approval by FDA, which reported no association between success of ≥ 50 % reduction or elimination in apnea events and mean daily caffeine concentrations.3 Skouroliakou et al.’s study also revealed that methylxanthine concentrations were not significantly associated with number of apneic events per day in neonates with GA < 33 weeks . A previous study comparing 10 mg/kg and 5 mg/kg maintenance doses in neonates with GA < 32 weeks showed similar efficacy in reducing apnea spells despite significantly higher frequency of tachycardia in the 10 mg/kg group . It could be partially due to the underlying multifactorial etiology of apnea, with prematurity being a prerequisite for the indication . Apnea of prematurity is known to have an incidence inversely related to GA and could regress with the maturation of the newborn . This is echoed in our results that the number of apnea episodes reduced significantly as PMA increased as well as in patients with higher GA (Fig. 2).
The variable PK/PD response in neonates to caffeine citrate therapy is also likely to be attributed to variability in caffeine metabolism in individuals. Caffeine metabolism by hepatic enzymes is usually limited in neonates. Maturation of metabolic enzymes could lead to the improvement in metabolic function, which is significantly associated with the increase in PNA and varies extensively among individuals (range 1 %–41 %) . N7-demethylation, which produces theophylline, acts as the predominant metabolic pathway in premature neonates (range 1 %–37 %) . Theophylline is the active metabolite that is partially responsible for side effects such as tachycardia , the variable caffeine-theophylline conversion rate could lead to PD response variability. Several other factors, including genetic variation in hepatic metabolic enzymes and genetic variations in caffeine receptors may also contribute to the variability in PD responses [21–23]. Due to the variability in the caffeine metabolism and the resulting wide range of half-lives among individuals , the measurement of caffeine serum concentrations at a postnatal age of 15 (10–24) days in our study population may not necessarily reflect concentrations at steady state. Thus, caffeine concentrations may vary considerably and make it difficult to find other significant associations between PD responses and concentrations.
The 2-fold higher-than-standard dosing regimen led to similar re-intubation rate but significantly higher percentage of patients having tachycardia than standard regimen. This is similar to Steer et al.’s findings on the use of 3–6 fold higher maintenance doses for a course of 7 days in neonates of similar GA range (<32 weeks) to our study’s (<33 weeks) . A significant reduction in re-ventilation was shown when 4-fold higher maintenance doses were used for the duration of averagely 1 month in neonates with GA < 30 weeks . This effect was more evident in the stratified subgroup of neonates with GA < 28 weeks that a significant reduction in the days on mechanical ventilator (average 8 days) was observed . A retrospective study in neonates < 28 weeks GA revealed that patients receiving caffeine citrate > 7.9 mg/kg/day were associated with a decreased need for clinical interventions in terms of dose adjustments compared to those receiving ≤ 7.9 mg/kg/day doses . It suggests that neonates with lower GA, especially extremely low-gestational-age neonates (GA < 28 weeks), could benefit more from high doses of caffeine citrate. Dosing regimens stratified by GA is warranted for more systematic trial evaluation.
None of the neonates died or had a severe reaction under current dosing regimens, however, TDM may be helpful in suspected toxicity to diagnose caffeine-related adverse events, based on our findings on a significant association between tachycardia and caffeine serum concentrations. The use of high dose caffeine citrate inevitably increases the risk of tachycardia in neonates, this need to be taken into consideration combined with other elements of therapy, such as efficacy and requirement for respiratory support, to determine treatment priority in lieu of medical cost and facility resources available. Caffeine TDM is valuable in the setting of clinically-significant tachycardia to assist differential diagnosis with respect to other potential etiologies.
This study has several limitations associated with its nature of retrospective chart evaluation. First, the TDM was done at the discretion of the medical team and may have patient selection bias towards sicker patients or patients who had adverse events. Second, vital signs were measured during the physical exam in the day of TDM, thus, they were the approximate rather than the exact values at TDM sampling time. Third, the records were physician notes that were not verified by audits of electronic monitoring, however, they are the critical information used by clinicians for patient management and decision making.
Based on our analysis on the retrospective dataset, little correlation between episodes of apnea and caffeine serum concentrations was observed in neonates who had TDM in the post-extubation period under current dosing regimens, whereas a significant association between tachycardia and concentrations existed. Notwithstanding the absence of severe adverse reactions, TDM should be considered in critically ill neonates with unexplained adverse effects, such as tachycardia. Future prospective study is warranted to establish the linked PK/PD relationship to optimize dosing regimen in preterm neonates.
Availability of supporting data
Supporting data are available in the form of an extended study report to the ethics committee of the University of Utah Institutional Review Board. This report is available upon request, which should be addressed to the corresponding author.
therapeutic drug monitoring
This project was supported in part by a Primary Children’s Hospital Foundation Early Career Development Research Grant for Catherine M. T. Sherwin. Authors would like to thank Chris R. Stockmann for assistance with clinical note information.
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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Bhatt-Mehta V, Schumacher RE. Treatment of apnea of prematurity. Paediatr Drugs. 2003;5:195–210.View ArticlePubMedGoogle Scholar
- Schoen K, Yu T, Stockmann C, Spigarelli MG, Sherwin CM. Use of methylxanthine therapies for the treatment and prevention of apnea of prematurity. Paediatr Drugs. 2014;16:169–77.View ArticlePubMedGoogle Scholar
- Erenberg A, Leff RD, Haack DG, Mosdell KW, Hicks GM, Wynne BA. Caffeine citrate for the treatment of apnea of prematurity: a double-blind, placebo-controlled study. Pharmacotherapy. 2000;20:644–52.View ArticlePubMedGoogle Scholar
- Aranda JV, Gorman W, Bergsteinsson H, Gunn T. Efficacy of caffeine in treatment of apnea in the low-birth-weight infant. J Pediatr. 1977;90:467–72.View ArticlePubMedGoogle Scholar
- Kulkarni PB, Dorand RD. Caffeine toxicity in a neonate. Pediatrics. 1979;64:254–5.PubMedGoogle Scholar
- Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006;354:2112–21.View ArticlePubMedGoogle Scholar
- Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med. 2007;357:1893–902.View ArticlePubMedGoogle Scholar
- Natarajan G, Botica ML, Thomas R, Aranda JV. Therapeutic drug monitoring for caffeine in preterm neonates: an unnecessary exercise? Pediatrics. 2007;119:936–40.View ArticlePubMedGoogle Scholar
- Leon AE, Michienzi K, Ma CX, Hutchison AA. Serum caffeine concentrations in preterm neonates. Am J Perinatol. 2007;24:39–47.View ArticlePubMedGoogle Scholar
- Charles BG, Townsend SR, Steer PA, Flenady VJ, Gray PH, Shearman A. Caffeine citrate treatment for extremely premature infants with apnea: population pharmacokinetics, absolute bioavailability, and implications for therapeutic drug monitoring. Ther Drug Monit. 2008;30:709–16.View ArticlePubMedGoogle Scholar
- Gal P. Caffeine Therapeutic Drug Monitoring Is Necessary and Cost-effective. J Pediatr Pharmacol Ther. 2007;12:212–5.PubMedPubMed CentralGoogle Scholar
- Gal P. Optimum use of therapeutic drug monitoring and pharmacokinetics-pharmacodynamics in the NICU. J Pediatr Pharmacol Ther. 2009;14:66–74.PubMedPubMed CentralGoogle Scholar
- Ward RM, Lugo RA. Drug therapy in the newborn. In: MacDonald MG, Seshia MMK, Mullett MD, editors. Avery’s neonatology: pathophysiology & management of the newborn. 6th ed. Philadelphia PA: Lippincott Williams & Wilkins; 2005. p. 1507–56.Google Scholar
- Spector R, Park GD, Johnson GF, Vesell ES. Therapeutic drug monitoring. Clin Pharmacol Ther. 1988;43:345–53.View ArticlePubMedGoogle Scholar
- Pesce AJ, Rashkin M, Kotagal U. Standards of laboratory practice: theophylline and caffeine monitoring. National Academy of Clinical Biochemistry. Clin Chem. 1998;44:1124–8.PubMedGoogle Scholar
- Steer P, Flenady V, Shearman A, Charles B, Gray PH, Henderson-Smart D, et al. High dose caffeine citrate for extubation of preterm infants: a randomised controlled trial. Arch Dis Child. Fetal Neonatal Ed. 2004;89:499–503.View ArticleGoogle Scholar
- Skouroliakou M, Bacopoulou F, Markantonis SL. Caffeine versus theophylline for apnea of prematurity: a randomised controlled trial. J Paediatr Child Health. 2009;45:587–92.View ArticlePubMedGoogle Scholar
- Romagnoli C, De Carolis MP, Muzii U, Zecca E, Tortorolo G, Chiarotti M, et al. Effectiveness and side effects of two different doses of caffeine in preventing apnea in premature infants. Ther Drug Monit. 1992;14:14–9.View ArticlePubMedGoogle Scholar
- Paolillo P, Picone S. Apnea of prematurity. J Pediatr Neonatal Individ Med. 2013;2:1–7.Google Scholar
- Al-Alaiyan S, Al-Rawithi S, Raines D, Yusuf A, Legayada E, Shoukri MM, et al. Caffeine metabolism in premature infants. J Clin Pharmacol. 2001;41:620–7.View ArticlePubMedGoogle Scholar
- Bloch-Salisbury E, Hall MH, Sharma P, Boyd T, Bednarek F, Paydarfar D. Heritability of apnea of prematurity: a retrospective twin study. Pediatrics. 2010;126:779–87.View ArticleGoogle Scholar
- Kumral A, Tuzun F, Yesilirmak DC, Duman N, Ozkan H. Genetic basis of apnoea of prematurity and caffeine treatment response: role of adenosine receptor polymorphisms: genetic basis of apnoea of prematurity. Acta Paediatr. 2012;101:299–303.View ArticleGoogle Scholar
- Pacifici GM. Clinical pharmacology of caffeine citrate in preterm infants. Med expr. 2014;1:243–50.Google Scholar
- Steer PA, Flenady VJ, Shearman A, Lee TC, Tudehope DI, Charles BG. Periextubation caffeine in preterm neonates: a randomized dose response trial. J Paediatr Child Health. 2003;39:511–5.View ArticlePubMedGoogle Scholar
- Francart SJ, Allen MK, Stegall-Zanation J. Apnea of prematurity: caffeine dose optimization. J Pediatr Pharmacol Ther. 2013;18:45–52.PubMedPubMed CentralGoogle Scholar