Caffeine Citrate Treatment Research Articles

The association of gene polymorphisms of adenosine and dopamine receptors with the response to caffeine citrate treatment in infants with apnea of prematurity: a prospective nested case-control study

BackgroundTo investigate the potential influence of adenosine and dopamine receptor genes polymorphisms in combination with clinical factors on the response of preterm infants to caffeine citrate treatment in apnea of prematurity (AOP).MethodsA prospective nested case-control study enrolled 221 preterm infants with gestational age < 34 weeks. These infants were divided into the response (n = 160) and the non-response groups (n = 61). 22 single-nucleotide polymorphisms in adenosine and dopamine receptor genes were genotyped. The basic characteristics and clinical outcomes of the two groups were compared. Univariate logistic regression analysis was performed to evaluate the differences in genotype distribution between the groups. Multivariable logistic regression analysis was performed to identify independent risk and protective factors and develop a nomogram to predict caffeine citrate response in preterm infants.ResultsPreterm infants in the non-response group had lower gestational age, lower birth weight, longer periods of oxygen supplementation and caffeine citrate use, and higher incidence of patent ductus arteriosus (PDA), bronchopulmonary dysplasia (BPD), neonatal respiratory distress syndrome (NRDS), retinopathy of prematurity (ROP), and brain injury (P < 0.05 for all). The ADORA1 rs10920573, ADORA2B rs2015353, ADORA3 rs10776728, DRD3 rs7625282, and DRD3 rs6280 gene polymorphisms were associated with caffeine citrate response in preterm infants (PFDR < 0.05 for all). The ADORA1 rs10920573 CC (aOR, 3.51; 95% CI, 1.34–9.25) and DRD3 rs6280 CT genotypes (aOR, 3.19; 95% CI, 1.53–6.65) were independent risk factors for non-response, whereas greater gestational age (aOR, 0.631; 95% CI, 0.53–0.75) was an independent protective factor for response. The concordance index of the nomogram was 0.764 (95% CI, 0.687–0.842), and the calibration and decision curve analysis indicated the nomogram had excellent predict performance.ConclusionsAdenosine receptor gene and dopamine receptor gene polymorphisms influence caffeine citrate treatment response in AOP. By combining genetic and clinical variables, it is possible to predict the response to caffeine citrate treatment in preterm infants.

Association between PER and CRY gene polymorphisms and the response to caffeine citrate treatment in infants with apnea of prematurity.

Circadian 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. A 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. After 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). Circadian 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.

Clinical effect of different maintenance doses of caffeine citrate in the treatment of preterm infants requiring assisted ventilation: a pilot multicenter study.

To explore the optimal maintenance dose of caffeine citrate for preterm infants requiring assisted ventilation and caffeine citrate treatment. A retrospective analysis was performed on the medical data of 566 preterm infants (gestational age ≤34 weeks) who were treated and required assisted ventilation and caffeine citrate treatment in the neonatal intensive care unit of 30 tertiary hospitals in Jiangsu Province of China between January 1 and December 31, 2019. The 405 preterm infants receiving high-dose (10 mg/kg per day) caffeine citrate after a loading dose of 20 mg/kg within 24 hours after birth were enrolled as the high-dose group. The 161 preterm infants receiving low-dose (5 mg/kg per day) caffeine citrate were enrolled as the low-dose group. Compared with the low-dose group, the high-dose group had significant reductions in the need for high-concentration oxygen during assisted ventilation (P=0.044), the duration of oxygen inhalation after weaning from noninvasive ventilation (P<0.01), total oxygen inhalation time during hospitalization (P<0.01), the proportion of preterm infants requiring noninvasive ventilation again (P<0.01), the rate of use of pulmonary surfactant and budesonide (P<0.05), and the incidence rates of apnea and bronchopulmonary dysplasia (P<0.01), but the high-dose group had a significantly increased incidence rate of feeding intolerance (P=0.032). There were no significant differences between the two groups in the body weight change, the incidence rates of retinopathy of prematurity, intraventricular hemorrhage or necrotizing enterocolitis, the mortality rate, and the duration of caffeine use (P>0.05). This pilot multicenter study shows that the high maintenance dose (10 mg/kg per day) is generally beneficial to preterm infants in China and does not increase the incidence rate of common adverse reactions. For the risk of feeding intolerance, further research is needed to eliminate the interference of confounding factors as far as possible.

The timing of withdrawal from caffeine citrate in very preterm infants.

To study the clinical features and outcome of very preterm infants withdrawn from caffeine citrate at different time points. A retrospective analysis was performed on the medical data of the preterm infants with a gestational age of <32 weeks, who were hospitalized in the Division of Neonatology, the Second Xiangya Hospital of Central South University, from January 1, 2016 to November 30, 2020. According to the time of withdrawal from caffeine citrate, the infants who met the study criteria were divided into the group with withdrawal before the last week of hospitalization and the group with withdrawal within the last week of hospitalization. The two groups were compared in terms of clinical features, features of citric caffeine use, length of hospital stay and hospital costs, change in the intensity of respiratory support, and preterm complications. A total of 403 preterm infants were enrolled, with 285 infants in the group with withdrawal before the last week of hospitalization and 118 infants in the group with withdrawal within the last week of hospitalization. There were no significant differences in clinical features between the two groups (P>0.05). Compared with the group with withdrawal before the last week of hospitalization, the group with withdrawal within the last week of hospitalization had a significantly longer duration of the use of caffeine citrate, a significantly shorter length of hospital stay, a significantly lower rate of increased intensity of respiratory support after withdrawal, and a significantly lower incidence rate of moderate or severe bronchopulmonary dysplasia (P<0.05). A relatively long course of caffeine citrate treatment is more beneficial to the short-term clinical outcome of very preterm infants.

Caffeine citrate for apnea of prematurity-One dose does not fit all a prospective study.

Caffeine citrate is the most frequently used medication in preterm neonates for the prevention of apnea of prematurity. There is no accepted consensus regarding the optimal caffeine citrate dosing. In this study, we evaluate clinical responses of premature neonates to standard-dose caffeine citrate treatment. A prospective observational study conducted at the NICU at Sheba Medical Center (3/2016-2/2017). The study population included preterm neonates born at a gestational age (GA) < 33 weeks and treated with caffeine citrate according to the local NICU protocol. The study cohort included 66 preterm neonates of GA < 33 weeks. Thirty infants were defined as responders and 36 as nonresponders to 7.5 mg/kg caffeine citrate treatment, and they required a further dose increase to 10 mg/kg. Infants in the nonresponders group were born at earlier GA than responders (29 vs. 31 weeks, respectively, P = 0.004). The nonresponders required a significantly longer hospital stay (56 vs. 46 days, P = 0.014), and longer supplemental oxygen support (18 vs 2 days, P = 0.008). Caffeine citrate initiation at higher doses is safe and does not require routine serum levels monitoring. It might be more effective for controlling apnea of prematurity in preterm neonates born ≤29 weeks of gestation.

Clinical audit on management of apnea of prematurity in neonatal intensive care unit

Introduction Apnea of prematurity (AOP) is one of the most common diagnoses in the neonatal intensive care unit (NICU). An apneic spell is usually defined as a cessation of breathing for 20 s or longer or a shorter pause accompanied by bradycardia, cyanosis, or pallor. The incidence of AOP increased with decreasing gestational age. Essentially, all infants born at less than or equal to 28 weeks of gestation were diagnosed with apnea. Apnea may be obstructive, central, or mixed. Idiopathic AOP is mostly of mixed etiology (50–75). The physiopathological mechanism underlying AOP is not fully clear, but is certainly linked to the immaturity of the central nervous system of the preterm neonate. Apnea is a diagnosis of exclusion. It usually resolves by 36–37 weeks' corrected age without long-term sequelae. Patients and methods The study includes all preterms at NICU in Assiut University Children Hospital with idiopathic apnea of prematurity in a period of 1 year (March 2018–March 2019). The study included 50 preterm neonates admitted to the NICU with idiopathic AOP. Their ages ranged from 27 to 34 weeks, 27 male and 23 female. The study is a clinical audit to detect the adherence of physicians to the Protocol for Management of AOP at NICU in Assiut University Children Hospital. Results A total of 54% were males whereas 46% were females. Gestational age of the studied cases range from 27 to 34 weeks with a mean age of 30.4 ± 1.99 weeks. Caffeine citrate treatment was given in 100% of the studied cases; 68% of them showed good response to caffeine citrate therapy. A total of 86% of the studied cases improved and discharged without further attacks of apnea; 14% of the studied cases died during the study due to complications and sequela of the disease. Conclusion Stark's 2016 Guidelines have been followed in the management of idiopathic pnea of prematurity in the studied cases but there were some defects that can affect the outcome of management of idiopathic apnea of prematurity. The study recommends avoiding these defects.

Population pharmacokinetic study of caffeine citrate in Chinese premature infants with apnea.

Caffeine citrate is a commonly used methylxanthine for pharmacologic treatment of apnea of prematurity. The aim of this study was to develop and verify a population pharmacokinetic (PPK) model, which can provide a reference for individualized caffeine citrate treatment of apnea in Chinese premature infants. A total of 88 serum concentration measurements from 46 preterm patients (median gestational age 29weeks) were retrospectively collected and the relevant clinical data of patients were recorded. The PPK analysis was performed by non-linear mixed-effect modelling method using NONMEM. Allometric scaling was applied in the PPK analysis, and the final model was evaluated by graphic and statistical methods, including goodness-of-fit plots, normalized prediction distribution errors plots and bootstrap procedures. A one-compartment model with first-order elimination was successfully fitted to the data. The typical scaled values for the parameters clearance and volume of distribution (V) were 0.268L/h and 109L per 70kg, respectively. The weight at the time of blood collection (CW) and post-natal age were identified as important predictors for pharmacokinetic parameters of caffeine. The evaluation process showed good stability and predictability of the final PPK model. This is a complete PPK study of caffeine citrate in Chinese premature infants with apnea, which complements caffeine pharmacokinetic data of the premature from China. A final PPK model was developed which may serve as a beneficial tool for the use of caffeine citrate in the treatment of apnea in Chinese preterm infants.

Caffeine preserves quiet sleep in preterm neonates.

Caffeine is widely used in preterm neonates suffering from apnea of prematurity (AOP), and it has become one of the most frequently prescribed medications in neonatal intensive care units. Goal of this study is to investigate how caffeine citrate treatment affects sleep‐wake behavior in preterm neonates. The observational study consists of 64 preterm neonates during their first 5 days of life with gestational age (GA) <32 weeks or very low birthweight of < 1500 g. A total of 52 patients treated with caffeine citrate and 12 patients without caffeine citrate were included. Sleep‐wake behavior was scored in three stages: active sleep, quiet sleep, and wakefulness. Individual caffeine concentration of every neonate was simulated with a pharmacokinetic model. In neonates with GA ≥ 28 weeks, wakefulness increased and active sleep decreased with increasing caffeine concentrations, whereas quiet sleep remained unchanged. In neonates with GA < 28 weeks, no clear caffeine effects on sleep‐wake behavior could be demonstrated. Caffeine increases fraction of wakefulness, alertness, and most probably also arousability at cost of active but not quiet sleep in preterm neonates. As such, caffeine should therefore not affect time for physical and cerebral regeneration during sleep in preterm neonates.

Comparison of the effects of caffeine citrate administering at different time on outcome and neuro-development of premature infants

Objective To investigate the effect of caffeine citrate administering at different time on outcome and neurodevelopment of premature infants. Methods A total of 113 preterm infants with gestational age less than 32 weeks and birth weight less than 1 500 g who were hospitalized and treated in the neonatal intensive care unit from January 2018 to June 2018 were enrolled.According to the time when caffeine citrate treatment was started, they were divided into early treatment group(≤1 days) with 53 infants and late treatment group(1 to 10 days) with 60 infants.A retrospective analysis was performed for their clinical data.The perinatal conditions, treatment process and clinical outcomes of the two groups were compared and the neurological development was followed up at 12 months old. Results Compared with the late treatment group, the early treatment group had a significantly shorter durations of mechanical ventilation time, oxygen therapy time, hospitalization days and a significantly lower incidence of bronchopulmonary dysplasia, patent ductus arteriosusand intraventricular hemorrhage or periventricular leukomalacia, and there were significant differences between two groups(P<0.05, respectively). The neonatal behavioral neurological assessment score in the early treatment group was higher than that in the late treatment group at 40 weeks of gestational age, and there was significant difference between two groups(P<0.05). The mental developmental index at 3 months of corrected age, the mental developmental index and psychomotor developmental index at 12 months were significantly better in the early treatment group than those in the late treatment group, and there were significant differences between two groups(P<0.05, respectively). Conclusion Early use of caffeine citrate can improve the outcome of premature infants and improve the prognosis of nervous system. Key words: Caffeine citrate; Premature infant; Very low birth weight infant; Neural development

Clinical effect and safety of different maintenance doses of caffeine citrate in treatment of apnea in very low birth weight preterm infants: a prospective randomized controlled trial

To study the clinical effect and safety of different maintenance doses of caffeine citrate in the treatment of apnea in very low birth weight preterm infants. A total of 78 very low birth weight preterm infants with primary apnea were enrolled who were admitted from January 2016 to January 2018. They were randomly divided into high-dose caffeine group with 38 children and low-dose caffeine group with 40 children. Both groups received a loading dose of 20 mg/kg caffeine citrate, and 24 hours later, the children in the high-dose caffeine group were given a maintenance dose of 10 mg/kg, and those in the low-dose caffeine group were given a maintenance dose of 5 mg/kg. The two groups were compared in terms of response rate and incidence rate of adverse events. The high-dose caffeine group had a significantly higher response rate than the low-dose caffeine group (71% vs 48%; P<0.05). Compared with the low-dose caffeine group, the high-dose caffeine group had significantly shorter duration of apnea and time of caffeine treatment (P<0.05). There were no significant differences between the two groups in length of hospital stay and incidence rates of tachycardia, feeding intolerance, bronchopulmonary dysplasia, necrotizing enterocolitis, and intracranial hemorrhage (P>0.05). There was no significant difference in the mortality rate between the two groups (P>0.05). Higher maintenance dose of caffeine citrate has a better clinical effect than lower maintenance dose of caffeine citrate in the treatment of apnea in very low birth weight preterm infants, without increasing the incidence rates of adverse drug reactions and serious complications in preterm infants.

Influence of prevention of caffeine citrate on cytokine profile and bronchopulmonary dysplasia in preterm infants with apnea.

This study aims to investigate the preventive effects of caffeine citrate on cytokine profile and bronchopulmonary dysplasia (BPD) in preterm infants with apnea. Preterm infants with apnea who were born at less than 32 weeks of gestational age and birth weight ≤1500 g were randomly divided into caffeine citrate prevention group and caffeine citrate treatment group. Preterm infants in caffeine citrate prevention group who were at risk of developing recurrent apnea were given to caffeine citrate within 8 h after birth. Those in caffeine citrate treatment group experienced apnea after birth were given to caffeine citrate for treatment. Preterm infants in both groups were treated with the same respiratory management and other conventional therapy. After drug discontinuation, levels of cytokine profile, and incidence of BPD were compared between two groups. A total of 56 preterm infants were enrolled. Differences in gestational age (P=0.11) and birth weight (P=0.251) were not statistically significant. Differences in application time of caffeine citrate (P=0.356), hour of ventilator use (P=0.152), length of stay (P=0.416) and BPD morbidity (P=1.00) between two groups were not statistically significant. At birth, there were no statistically significant in levels of IL-6 (P=0.063) and IL-8 (P=0.125) between two groups. After conventional therapy, levels of IL-6 (P=0.001) and IL-8 (P=0.001) significantly decreased in caffeine citrate prevention group compared with those in caffeine citrate treatment group. Prevention usage of caffeine citrate in preterm infants with apnea could reduce the level of cytokine profile and the incidence of BPD.

Risk Factors for Nephrocalcinosis in Very Low Birth Weight Infants

Objective: The objective was to identify risk factors for nephrocalcinosis in very low birth weight (VLBW) infants. Methods: Prospective study has done between 2014 and 2017. The study included 81 VLBW infants in the neonatal intensive care unit (NICU). Renal ultrasonography was performed at four weeks and 3 months. Baseline characteristics, complications and medication during NICU admission were collected. 25-(OH)-vitamin D, calcium, phosphorous, alkaline phosphatase, urine calcium to creatinine ratio were serially measured. Results: The incidence of nephrocalcinosis was 16.9%. On univariate analysis, gestational age, lower birth weight, maternal pregnancy-induced hypertension, neonatal sepsis, and frequency of vancomycin and caffeine citrate treatment were significantly associated with nephrocalcinosis. In addition, preterm infants with nephrocalcinosis had lower cord blood 25-(OH)-vitamin D and serum calcium levels and higher serum alkaline phosphatase levels at 2 weeks of life. Multivariate analysis showed that gestational age (P=0.042), birth weight (P=0.019), sepsis (P=0.046), small for gestational age (P=0.015), and maternal pregnancy-induced hypertension (P=0.024) were significant risk factors for nephrocalcinosis. Conclusion: This study suggests that neonatal sepsis and maternal pregnancy-induced hypertension, in addition to gestational age and birth weight are important perinatal risk factors for nephrocalcinosis.

Association between adenosine receptor gene polymorphism and response to caffeine citrate treatment in apnea of prematurity; An Egyptian single-center study

BackgroundCaffeine citrate is the methyl-xanthine of choice used in controlling apnea of prematurity (AOP). Caffeine central effect is mediated via non-selective (A1) and selective (A2a) adenosine receptors antagonism. Variability in caffeine response had been frequently noticed in AOP, suggesting underlying genetic predisposition. Aim of the studyWe evaluated the role of adenosine receptor A1 [ADORA1] and adenosine receptor A2a [ADORA2a] gene polymorphisms in the variability of caffeine response among Egyptian preemies with AOP. Patient and methodsIn this case-control study, 43 preterm neonates with AOP were eligible as cases and 43 preterm babies free from apnea were taken as controls. Preterm neonates with AOP were further divided according to response to caffeine treatment into caffeine responder (n = 18) and caffeine non-responders (n = 25). ADORA1 [716 T > G] and ADORA2a [1976C > T] gene polymorphisms were genotyped by mean of PCR-based RFLP-assay. ResultsThere were significant increase in frequency distribution of ADORA2a [1976C > T] CT (62.7% vs 23.3%), TT (14% vs 4.7%) genotypes and T allele (34.3% vs 16.3%) in cases compared to controls with significant increased risk of AOP development with OR (95%CI); P-value of 8.37(3.03–23.1), P = 0.000; 9.3(1.61–53.61), P = 0.005 and 4.27(2.09–8.70), P = 0.000 respectively. Further, caffeine non-responders were associated with significant increase frequency of ADORA2a CT (80% vs 38.9%) and TT (16% vs 11.1%) genotypes and T allele (56% vs 30.6%) with OR (95%CI) and P-value of 21.38 (2.31–197.8), P = 0.001; 18 (1.24–260.9); P = 0.005 and 2.89(1.17–7.13), P = 0.019 respectively, when compared to caffeine responders. Patients with AOP who had ADORA2a CT and TT genotypes were associated with significant increase in duration of hospital stay and poor outcome. Genotype distribution frequency of studied polymorphisms did not deviate from Hardy Weinberg (HW) equilibrium among controls. ConclusionADORA2a [1976C > T] polymorphism has a significant role in AOP development and variation in caffeine response among preterm babies.

Effects of different doses of caffeine in the treatment of neonatal apnea

Objective To investigate the therapeutic effect of different doses of caffeine on premature apnea. Methods 80 patients with apnea were divided into observation group and control group, each group in 40cases.The two groups applicated caffeine citrate. The control group received the basal dose, first application of 20 mg/kg, intravenous injection, intravenous injection of 5 mg/kg after 24 h. The observation group was treated with intravenous injection of 10 mg/kg after 24 h. The treatment period was 7 d. The therapeutic effect, blood gas and oxygenation index and adverse reactions were observed in the two groups. Results The effective rate of the observation group was 92.5%, which was significantly higher than 75.0% of the control group(χ2=4.501, P 0.05). Conclusion In the treatment of premature apnea, advanced caffeine citrate treatment can better improve the clinical symptoms and blood gas index, the curative effect is reliable. Key words: Apnea; Caffeine; Infant, premature

Clinical effectiveness of different doses of caffeine for primary apnea in preterm infants

To evaluate the effectiveness and safety of different doses of caffeine in treatment of primary apnea in preterm infants. A total of 164 preterm infants (<32 weeks gestation), presented with primary apnea, were recruited in Tianjin Central Hospital of Gynecology and Obstetrics from October 2013 to December 2014. The patients were prospectively allocated into low-dose (loading 20 mg/kg and maintenance of 5 mg/(kg·d) after 24 h, n=82) and high-dose (loading 20 mg/kg and maintenance of 15 mg/(kg·d) after 24 h, n=82) groups of caffeine citrate treatment by using a random number table. The treatment effects, side effects of caffeine, and the clinical outcome of the preterm infants were compared between groups by χ(2) test or nonparametric test. The patients in low-dose group had birth weight of (1,237 ± 338) g, male gender of 43 (52%) and gestational age of (29.8 ± 3.4) weeks. The patients in high-dose group had birth weight of (1 262 ± 296) g, male gender of 45 (55%) and gestational age of (29.9 ± 2.7) weeks. The baseline characteristics including birth weight, gender and gestational age were comparable between the two groups. Frequency of apnea was significantly lower in high-dose group compared with low-dose group (10 (8, 15) vs.18 (13, 22), Z = -2.610, P = 0.009), and the success rate of removal of the ventilator was significantly higher in high-dose group compared with low-dose group (85% (70/82) vs.70% (57/82), χ(2) = 5.898, P = 0.015). The effective rate of caffeine treatment was significantly higher in high-dose group compared with low-dose group (82% (67/82) vs.61% (50/82), χ(2)=8.619, P = 0.003). No significant differences were observed concerning the incidence of caffeine-associated side effects including tachycardia, irritability, difficulty in feeding, hyperglycemia, hypertension, digestive disorders and electrolyte disturbances between two groups (P all > 0.05). There were no significant differences in the clinical outcomes of the preterm infants including death during hospitalization, chronic lung disease, other complications and duration of hospital stay between two groups (P all > 0.05). A therapeutic regimen consisting of a loading dose of 20 mg/kg and maintenance dose of 15 mg/(kg·d) of caffeine citrate could improve the treatment effects and keep safety for primary apnea in preterm infants, and will not cause more adverse events.

The Influence of Dosage and Timing of Caffeine Administration on Neurodevelopmental Outcome of Very Preterm Infants

Objective: To analyze starting time (early versus late) and duration of caffeine treatment and its possible influence on neurodevelopmental (ND) outcome in very preterm infants. Hypothesis: Early initiation of caffeine treatment with longer duration of treatment may significantly improve ND outcome in very preterm infants. Design: Retrospective cohort study. Setting: Level III Neonatal Intensive care Unit (NICU) and out-patient NICU follow-up clinic of an academic medical center in New York City. Participants: A total of 146 inborn infants with gestational ages (GA) of 23-32 weeks who received caffeine treatment were included in this study with the following exclusion criteria: incomplete clinical data, insufficient ND follow-up and transfer of infants to other facilities. Interventions: Information on the administration of Caffeine Citrate injection USP and Caffeine Citrate oral solution (20 mg/ml equivalent to 10 mg caffeine base) including duration of treatment were obtained from individual chart reviews. Primary outcome measure: Normal and adverse (mild/moderate, severe) ND outcome. Results: Duration and starting point (early versus late) of caffeine treatment were not associated with ND outcome; adjusted for GA, head ultrasound (HUS) results and gender. The only significant predictor of ND outcome was GA. Conclusion: Gestational age (GA) seems to have more of an influence on ND outcome than caffeine citrate treatment regardless of duration (i.e., dose) and onset (early versus late) of such treatment.

Caffeine Citrate Treatment for Extremely Premature Infants With Apnea: Population Pharmacokinetics, Absolute Bioavailability, and Implications for Therapeutic Drug Monitoring

The objective of this study was to develop a population model of the pharmacokinetics (PK) of caffeine after orogastric or intravenous administration to extremely premature neonates with apnea of prematurity who were to undergo extubation from ventilation. Infants of gestational age <30 weeks were randomly allocated to receive maintenance caffeine citrate dosing of either 5 or 20 mg/kg/d. Four blood samples were drawn at prerandomized times from each infant during caffeine treatment. Serum caffeine was assayed by enzyme-multiplied immunoassay technique. Concentration data (431 samples, median: 4 per subject) were obtained from 110 (52 male) infants of mean birth weight of 1009 g, current mean weight (WT) of 992 g, mean gestational age of 27.6 weeks, and mean postnatal age (PNA) of 12 days. Of 1022 doses given, 145 were orogastric, permitting estimation of absolute bioavailability. A 1-compartment model with first-order absorption was fitted to the data in NONMEM. Patient characteristics were screened (P < 0.01) in nested models for pharmacokinetic influence. Model stability was assessed by nonparametric bootstrapping. Clearance (CL) increased nonlinearly with increasing PNA, whereas volume of distribution (Vd) increased linearly with WT, according to the following allometric models: CL (L/h) = 0.167 (WT/70) (PNA/12); Vd (L) = 58.7 (WT/70). The mean elimination half-life was 101. Interindividual variability (IIV) of CL and Vd was 18.8 % and 22.3 %, respectively. Interoccasion variability (IOV) of CL and Vd was 35.1% and 11.1%, respectively. This study established that the elimination of caffeine was severely depressed in extremely premature infants but increased nonlinearly after birth up to age 6 weeks. Caffeine was completely absorbed, which has favorable implications for switching between intravenous and orogastric routes. The interoccasion variability about CL was twice the interindividual variability, which, among other factors, indicates that routine serum concentration monitoring of caffeine in these patients is not warranted.

Apnées tardives du prématuré : facteurs de risque, traitement ambulatoire par citrate de caféine

Introduction Apnea of prematurity develop during the first days of life and usually resolve by the time the infant reaches 36-37 weeks postmenstrual age. In a few cases, they persist beyond term, especially in infants delivered at the youngest gestational ages (24–28 GA), and require specific care. In our unit, those preterm babies are discharged home with caffeine citrate treatment. Discontinuing the treatment is performed in hospital when they achieve a postmenstrual age of at least 42 weeks. Objective To identify predictive factors of persistent apnea in preterm babies. Material and methods Retrospective study comparing a population of 41 preterm infants discharged with treatment to 123 preterm babies discharged without treatment to identify predictors of persistent apnea. Results Factors significantly associated were: birth weight < 1500 g, initial hypotension, gastroesophageal reflux, need for continuous positive airway pressure and multiparity. At home, no infant died and no adverse effect was reported by parents. Conclusion Persistent apnea can be responsible for prolonged hospitalization. Risk factors can be identified in some children. Discharging with treatment can be an alternative to their hospitalization.

Utilisation du citrate de caféine pour le traitement des apnées idiopathiques du prématuré dans les équipes françaises de médecine néonatale

Caffeine citrate is commonly used for prophylaxis and treatment of apnea in preterm babies. Objective To evaluate the use of caffeine citrate in french neonatal units. Materials and methods Postal survey in 100 neonatal units. Results Answers were obtained from 81 units. Sixty-three units use systematic prophylactic treatment and the threshold of gestationnal age (weeks gestation) for this systematic treatment is 32 weeks. Caffeine citrate is administered as a loading dose of 20 mg/kg followed by a maintenance dose of 5 mg/kg in 95% of the units. Discontinuing the treatment occurs between 33 and 35 weeks in 37% of the units and between 35 and 37 weeks in 53%. Two third of neonatologits describe recurrent apnea beyond 37 weeks, with the need to continue treatment. Fourteen units sometimes discharge babies at home with ambulatory caffeine citrate treatment and discontinue treatment by 42 to 46 weeks'gestation. A mean duration of 5 days without apnea is required before discharge. Conclusion French teams respect “recommendations” concerning doses and duration without apnea before discharge. Indication of treatment, threshold for systematic treatment, duration of treatment and ambulatory treatment differ among teams.