Caffeine for the Pharmacological Treatment of Apnea of Prematurity in the NICU: Dose Selection Conundrum, Therapeutic Drug Monitoring and Genetic Factors.
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SUBMITTER: Long JY
PROVIDER: S-EPMC8350115 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveCaffeine therapy for apnea of prematurity has been reported to improve brain white matter microstructure at term-equivalent age, but its long-term effects are unknown. This study aimed to investigate whether caffeine affects (1) brain structure at 11 years of age, and (2) brain development from term-equivalent age to 11 years of age, compared with placebo.MethodsPreterm infants born ?1250 g were randomly allocated to caffeine or placebo. Magnetic resonance imaging (MRI) was performed on 70 participants (33 caffeine, 37 placebo) at term-equivalent age and 117 participants (63 caffeine, 54 placebo) at 11 years of age. Global and regional brain volumes and white matter microstructure were measured at both time points.ResultsIn general, there was little evidence for differences between treatment groups in brain volumes or white matter microstructure at age 11 years. There was, however, evidence that the caffeine group had a smaller corpus callosum than the placebo group. Volumetric brain development from term-equivalent to 11 years of age was generally similar between treatment groups. However, there was evidence that caffeine was associated with slower growth of the corpus callosum, and slower decreases in axial, radial, and mean diffusivities in the white matter, particularly at the level of the centrum semiovale, over time than placebo.InterpretationThis study suggests any benefits of neonatal caffeine therapy on brain structure in preterm infants weaken over time and are not clearly detectable by MRI at age 11 years, although caffeine may have long-term effects on corpus callosum development.
| S-EPMC6144456 | biostudies-literature
Project description:Standard-dose caffeine citrate has been routinely prescribed for apnea of prematurity (AOP) management; however, some preterm infants respond well to the therapy while others do not. The AOP phenotype has been attributed solely to the immature control of the respiratory system consequent to preterm birth, but there are also important genetic influences. Based on our previous report, we tested the hypothesis that the human circadian locomotor output cycles kaput (CLOCK) gene polymorphisms play a role in the response to caffeine citrate therapy in preterm infants. We also studied the interactions of the circadian clock with aryl hydrocarbon receptor (AHR) signaling pathways in preterm babies who received caffeine citrate. This single-center study collected data from 112 preterm infants (<35 weeks gestational age) between July 2017 and July 2018, including apnea-free (n = 48) and apneic (n = 64) groups. Eighty-eight candidate single nucleotide polymorphisms (SNPs) were tested using the MassARRAY system. Association analysis was performed using the PLINK Whole Genome Data Analysis Toolset and SNPStats software. Linkage disequilibrium (LD) and haplotype analyses were performed using Hapview software. No significant intergroup differences in allele distributions or genotype frequencies of CYP1A2, CYP3A4, CYP3A5, and CYP3A7 were detected in our study on preterm babies. Two more SNPs in AHR were found to be associated with determining the response to caffeine citrate therapy in our pediatric patients. Of the 46 candidate SNPs in the CLOCK gene, 26 were found to be associated with determining the response to caffeine treatment in these babies. Interestingly, a significant association was retained for 18 SNPs in the CLOCK gene after false discovery rate correction. Moreover, strong LD formed in those variants in AHR, ADORA2A, and CLOCK genes was confirmed to be significantly associated with a better response to standard-dose caffeine therapy. In summary, CLOCK gene polymorphisms play a role in determining the response to caffeine therapy in premature neonates with AOP. However, whether the AHR and CLOCK signaling pathways crosstalk with each other during caffeine treatment remains largely unclear. Future clinical studies including more immature babies and basic research are needed to explore the mechanism by which circadian rhythms affect the response to caffeine therapy.
| S-EPMC8822171 | biostudies-literature
Project description:Background: Caffeine citrate has been approved in China for the management of apnea of prematurity. This clinical trial was conducted as a condition of regulatory approval. The aim was to confirm the efficacy of caffeine citrate in the treatment of recurrent intermittent hypoxia and bradycardia in preterm newborns with primary apnea. Objectives: The primary outcome was the change from baseline in the number of apnea events after loading dose administration of caffeine citrate. Secondary efficacy outcomes included the change from baseline in apnea events after 2 and 4 weeks of maintenance doses. Methods: This was a multicenter, prospective longitudinal open-label, single-arm study. Neonates who had experienced at least four apnea events during a 24 h period received a loading dose of caffeine citrate 20 mg/kg; those who required additional maintenance doses received 5 mg/kg/day (titrated up to 10 mg/kg/day in case of insufficient response). The number of apnea events was recorded for 6-12 h prior to the loading dose (baseline), and for 12 h post-dose, following the loading dose and at Weeks 2 and 4 (during maintenance). Results: A total of 247 neonates received the loading dose, who had a significant reduction from baseline of 3.9 events (p < 0.001) in the mean number of apnea events. The subset of neonates who required maintenance doses also had significant reductions in the number of events at all visits (p < 0.001 for all). A total of 79.4% of participants had at least one adverse event, but only one non-serious and no serious events were considered related to treatment. Conclusions: In this large, prospective, open-label study, premature infants with a history of apnea who received caffeine citrate were significantly less likely to experience further apnea events.
| S-EPMC7078308 | biostudies-literature
Project description:BackgroundCircadian rhythms impact metabolism and the therapeutic effects of drugs. The purpose of this study was to determine the association between PER and CRY polymorphisms and caffeine citrate treatment response in infants with apnea of prematurity.MethodsA total of 221 preterm infants of gestational age <34 weeks were included in this study (160 in the response group and 61 in the non-response group). The propensity score matching method was used to perform a 1:1 matching for all premature infants, and the general characteristics and clinical outcomes of the two groups were compared. The association between polymorphisms of the circadian transcription repressors PER and CRY and caffeine citrate treatment response in infants with apnea of prematurity was analyzed with co-dominant, dominant, recessive, and over-dominant models, as well as analysis of alleles. Generalized multifactor dimensionality reduction (GMDR) analysis was used to analyze the interaction between the PER and CRY genes.ResultsAfter propensity score matching, 45 preterm infants were included in each of the response and non-response groups, and there were no statistically significant differences in general characteristics between the two groups (P > 0.05). Infants in the non-response groups had a higher incidence of moderate and severe bronchopulmonary dysplasia (BPD) (P = 0.043), retinopathy of prematurity (ROP) (P = 0.035), and invasive ventilation (P = 0.027), and their duration of oxygen use (P = 0.041) was longer. When corrected for false discovery rate, the PER3 rs228669 recessive model (P FDR = 0.045) and the over-dominant model (P FDR = 0.045) were both associated with caffeine citrate treatment response. Preterm infants with the rs228669 CC genotype had a significantly lower rate of caffeine citrate non-response in the recessive model (OR = 0.28, 95% CI = 0.12-0.66), which was significantly higher in preterm infants with the CT genotype in the over-dominant model (OR = 4.18, 95% CI = 1.64-10.66). GMDR analysis revealed an interaction between the PER and CRY genes (P < 0.05).ConclusionsCircadian rhythms may play a role in the response of premature infants to caffeine citrate, and polymorphisms of the PER and CRY genes may influence the effectiveness of caffeine citrate treatment for apnea of prematurity.
| S-EPMC11301747 | biostudies-literature
Project description:Background Methylxanthine, including caffeine citrate and aminophylline, is the most common pharmacologic treatment for apnea of prematurity. However, due to the lack of high-quality evidence, there are no clear recommendations or guidelines on how to choose between caffeine and aminophylline. Objective This meta-analysis aimed to assess the comparative efficacy and safety of caffeine and aminophylline for apnea of prematurity, and provide reliable evidence for clinical medication in the treatment for apnea of prematurity. Methods PubMed, Scopus, Embase, EBSCO, Web of Science, and Cochrane databases were systematically searched from May 1975 to June 2022. Results Ten studies including a total of 923 preterm infants were evaluated. Our results showed that there was no significant difference in the effective rate of 1-3days between caffeine and aminophylline (OR 1.05, 95%CI: 0.40–2.74, P = 0.914). However, for side effects such as tachycardia (OR 0.22, 95%CI: 0.13–0.37, P<0.001) and feeding intolerance (OR 0.40, 95%CI: 0.23–0.70, P = 0.001), the incidence rate was lower in the caffeine group compared with the aminophylline group. No significant difference was found in hyperglycemia (OR 0.45, 95%CI: 0.19–1.05, P = 0.064). Conclusion This meta-analysis reveals that caffeine citrate and aminophylline have similar therapeutic effectiveness on respiratory function, but caffeine has fewer side effects and should be considered first for treatment.
| S-EPMC9484669 | biostudies-literature
Project description:Fluconazole has been associated with higher mortality compared with the echinocandins in patients treated for invasive candida infections. Underexposure from current fluconazole dosing regimens may contribute to these worse outcomes, so alternative dosing strategies require study. The objective of this study was to evaluate fluconazole drug exposure in critically ill patients comparing a novel model-optimized dose selection method with established approaches over a standard 14-day (336-h) treatment course. Target attainment was evaluated in a representative population of 1,000 critically ill adult patients for (i) guideline dosing (800-mg loading and 400-mg maintenance dosing adjusted to renal function), (ii) guideline dosing followed by therapeutic drug monitoring (TDM)-guided dose adjustment, and (iii) model-optimized dose selection based on patient factors (without TDM). Assuming a MIC of 2 mg/liter, free fluconazole 24-h area under the curve (fAUC24) targets of ≥200 mg · h/liter and <800 mg · h/liter were used for assessment of target attainment. Guideline dosing resulted in underexposure in 21% of patients at 48 h and in 23% of patients at 336 h. The TDM-guided strategy did not influence 0- to 48-h target attainment due to inherent procedural delays but resulted in 37% of patients being underexposed at 336 h. Model-optimized dosing resulted in ≥98% of patients meeting efficacy targets throughout the treatment course, while resulting in less overexposure compared with guideline dosing (7% versus 14%) at 336 h. Model-optimized dose selection enables fluconazole dose individualization in critical illness from the outset of therapy and should enable reevaluation of the comparative effectiveness of this drug in patients with severe fungal infections.
| S-EPMC8092533 | biostudies-literature
Project description:Background and objectivePharmacokinetic models can inform drug dosing of vancomycin in neonates to optimize therapy. However, the model selected needs to describe the intended population to provide appropriate dose recommendations. Our study aims to identify the population pharmacokinetic (PopPK) model(s) with the best performance to predict vancomycin exposure in neonates in our hospital.MethodsRelevant published PopPK models for vancomycin in neonates were selected based on demographics and vancomycin dosing strategy. The predictive performance of the models was evaluated in Tucuxi using a local cohort of 69 neonates. Mean absolute error (MAE), relative bias (rBias) and relative root mean square error (rRMSE) were used to quantify the accuracy and precision of the predictive performance of each model for three different approaches: a priori, a posteriori, and Bayesian forecasting for the next course of therapy based on the previous course predictions. A PopPK model was considered clinically acceptable if rBias was between ± 20 and 95% confidence intervals included zero.ResultsA total of 25 PopPK models were identified and nine were considered suitable for further evaluation. The model of De Cock et al. 2014 was the only clinically acceptable model based on a priori [MAE 0.35 mg/L, rBias 0.8 % (95% confidence interval (CI) - 7.5, 9.1%), and rRMSE 8.9%], a posteriori [MAE 0.037 mg/L, rBias - 0.23% (95% CI - 1.3, 0.88%), and rRMSE 6.02%] and Bayesian forecasting for the next courses [MAE 0.89 mg/L, rBias 5.45% (95% CI - 8.2, 19.1%), and rRMSE 38.3%) approaches.ConclusionsThe De Cock model was selected based on a comprehensive approach of model selection to individualize vancomycin dosing in our neonates.
| S-EPMC10954945 | biostudies-literature
Project description:OBJECTIVE:To determine the association between human milk (HM) dose and health care utilization at one and 2 years of life in very low birth weight (birth weight?<?1500?g; VLBW) infants. STUDY DESIGN:This study included 345 VLBW infants enrolled in a prospective observational cohort study (2008-2012) who completed a neonatal high-risk follow-up clinic visit. Subsequent health care utilization included hospitalizations, emergency department visits, pediatric subspecialists, and specialized therapies. RESULTS:Each 10?mL/kg/day increase in HM in the first 14 days of life was associated with 0.26 fewer hospitalizations (p?=?0.04) at 1 year and 0.21 fewer pediatric subspecialist types (p?=?0.04) and 0.20 fewer specialized therapy types (p?=?0.04) at 2 years. CONCLUSION:HM dose in early life for VLBW infants was an independent predictor of the number of hospitalizations at 1 year and types of pediatric subspecialists and specialized therapies at 2 years of life.
| S-EPMC6298834 | biostudies-literature
Project description:OBJECTIVE:To evaluate the efficacy and safety of caffeine citrate in the treatment of apnea in bronchiolitis. STUDY DESIGN:Eligible infants aged ?4 months presenting to the main pediatric emergency service with apnea associated bronchiolitis were stratified by gestational age (<34 weeks or longer) and randomized to receive a single dose of intravenous 25 mg/kg caffeine citrate or saline placebo. The primary efficacy outcome was a 24-hour apnea-free period beginning after completion of the blinded study drug infusion. Secondary outcomes were frequency of apnea by 24, 48, and 72 hours after study medication, need for noninvasive/invasive ventilation, and length of stay in the hospital's pediatric intensive care/step-down unit. RESULTS:A total of 90 infants diagnosed with viral bronchiolitis associated with apnea (median age, 38 days) were enrolled. The rate of respiratory virus panel positivity was similar in the 2 groups (78% for the placebo group vs 84% for the caffeine group). The geometric mean duration to a 24-hour apnea-free period was 28.1 hours (95% CI, 25.6-32.3 hours) for the caffeine group and 29.1 hours (95% CI, 25.7-32.9 hours) for the placebo group (P = .88; OR, 0.99; 95% CI, 0.83-1.17). The frequency of apnea at 24 hours, 24-48 hours, and 48-72 hours after enrollment and the need for noninvasive and invasive ventilation were similar in the 2 groups. No safety issues were reported. CONCLUSIONS:A single dose of caffeine citrate did not significantly reduce apnea episodes associated with bronchiolitis. TRIAL REGISTRATION:Clinicaltrials.gov: NCT01435486.
| S-EPMC7126124 | biostudies-literature
Project description:BackgroundCaffeine is a routinely prescribed pharmacological active compound in neonatal intensive care units (NICU) for treating apnea of prematurity (AOP), which also decreases the risk of bronchopulmonary dysplasia and cerebral palsy in neonates. Caffeine-induced excessive calcium loss can promote the development of metabolic bone disease (MBD) in preterm neonates. This study aimed to evaluate the effect of the caffeine regimen on the development of osteopenia of prematurity (OOP), using serum alkaline phosphatase (serum-ALP) concentrations as a surrogate marker at the 4th week of life.MethodsThis retrospective cohort study was conducted including neonates of < 32 weeks gestational age (GA) and birth weight < 1500 g, admitted to NICU from April-2017 to December-2018 and received caffeine therapy till 28 days of life for AOP. Based on serum-ALP levels, formed the high and low-ALP groups. Neonatal characteristics, caffeine regimen, risk factors for OOP, including duration of parenteral nutrition (PN), exposure to medicines associated with MBD, and intake of essential vitamins and minerals, were compared in both groups. Predictors of OOP were analyzed through logistic regression.ResultsFrom the total of 268 participants, 52 (19%) developed OOP, mostly female (61.5%). In the high ALP group, the serum-ALP levels were significantly higher than in the low-ALP group (725.0 ± 143.8 vs 273.6 ± 55.0 units/L, p < 0.001). The high-ALP group received significantly (p < 0.001) higher daily and cumulative caffeine doses and were associated with a higher likelihood of developing OOP in this study cohort [cumulative dose (mg) (AOR = 1.082 95% CI 1.011 to 1.157) and daily dose (mg/kg/day) (AOR = 2.892 95% CI 1.392 to 6.007)]. Smaller GA was found directly related to OOP. Among the other medical risk factors, phosphorus intake was significantly low in the high-ALP group. No, significant relationship between duration of PN and use of steroids and diuretics, and intake of vitamins and minerals were identified.ConclusionThe daily and cumulative doses of caffeine and smaller GA are associated with the development of OOP in this study cohort. Clinical randomized control studies are needed to validate the outcomes and determine the range of safest and most effective caffeine doses for treating AOP in preterm neonates.
| S-EPMC9306044 | biostudies-literature