Caffeine Citrate Research Articles

0822 Caffeine as a treatment option for primary central sleep apnea of infancy in term infants

Abstract Introduction Primary central sleep apnea of infancy tends to improve over weeks with supportive care. No established treatments exist; however, infants with this condition remain at risk from sequelae of intermittent hypoxemia. We present a term infant with primary central sleep apnea of infancy treated with caffeine citrate resulting in clinical and polysomnographic improvement. Report of Cases: A 7-day-old male infant born at 37 weeks gestation (gestational age confirmed by early first trimester prenatal ultrasound) was hospitalized following an episode of hypotonia and decreased responsiveness. Infectious studies, chest radiograph, and echocardiogram were normal. During the hospitalization, oxygen desaturations during sleep were observed and capillary blood gas during sleep showed a pH of 7.36 and a partial pressure of carbon dioxide of 54 mmHg. Polysomnography on room air showed central sleep apnea [central apnea hypopnea index (AHI) of 58, obstructive AHI of 4, hypoxemia, hypoventilation with transcutaneous carbon dioxide greater than 50 mmHg for 89% of sleep time, and periodic breathing for 21.7% of sleep time]. Brain MRI and paired-like homeobox2B (PHOX2B) genetic testing were normal. A trial of caffeine citrate was initiated with prompt resolution of oxygen desaturations during sleep. Serial capillary blood gases showed improvement with partial pressure of carbon dioxide between 39-44 mmHg. Polysomnography on room air three days after caffeine initiation demonstrated resolved hypoxemia, hypoventilation, periodic breathing, obstructive sleep apnea, and central sleep apnea (central AHI of 6.8). The patient was discharged home on caffeine and continuous pulse oximetry during sleep. At follow-up six weeks later, the patient had no oxygen desaturations and was successfully weaned off caffeine. Conclusion To our knowledge, there are no prior reports of term infants being treated with caffeine citrate for primary central sleep apnea of infancy. While caffeine is an established therapy for apnea of prematurity, it is typically discontinued at a postmenstrual age of 32 - 34 weeks. Our case demonstrates that in term infants with no underlying medical conditions and primary central sleep apnea of infancy, immature regulation of respiration should be suspected, and a trial of caffeine may be considered. Support (If Any) None.

Caffeine Citrate Protects Against Sepsis-Associated Encephalopathy and Inhibits the UCP2/NLRP3 Axis in Astrocytes.

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction without overt central nervous system infection. Caffeine citrate has therapeutic effect on different brain diseases, while its role in SAE remains unclear. The expression levels of interleukin (IL)-18 and IL-1β were upregulated in the cerebrospinal fluid of the subjects. In this study, a rat model of SAE was established by cecal ligation and puncture. Caffeine citrate inhibited SAE-induced neuronal apoptosis and astrocytic activation, decreased reactive oxygen species (ROS) generation, and elevated mitochondrial membrane potential (MMP) level in the cerebral cortex. In vitro, primary astrocytes were isolated from rat cerebral cortex and incubated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Caffeine citrate reduced ROS and MMP levels and mitochondrial complex enzyme activities in LPS plus IFN-γ-induced astrocytes. Moreover, caffeine citrate inhibited the activation of nucleotide-binding and oligomerization domain (NOD)-like receptor (NLRP3) inflammasome and decreased the production of IL-1β and IL-18 in vivo and in vitro. Notably, caffeine citrate promoted UCP2 expression in astrocytes. The neuroprotective role of UCP2 has been reported in several experimental brain diseases. These results suggest that caffeine citrate inhibits neuronal apoptosis, astrocytic activation, mitochondrial dysfunction in rat cerebral cortex, thereby alleviating SAE. The protection of caffeine citrate against SAE may be achieved by the UCP2-mediated NLRP3 pathway inhibition in astrocytes.

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.

1: Comparison of the effect of caffeine and aminophylline on recovery from total intravenous anaesthesia with propofol and fentanyl in laparoscopic hysterectomy: A randomised controlled trial

Background and Aims:During extubation, the loss of consciousness (LOC) after general anaesthesia (GA) is reversed by stopping the administration of anaesthetic agents. It is a passive process and it is affected by many factors like age, sex, weight, temperature, duration of surgery, and type of anaesthetic agent used. This study is conducted to find whether caffeine and aminophylline hasten the emergence and reversal of LOC caused by propofol.To evaluate recovery time [time to Bispectral(BIS) index 90] from total intravenous anaesthesia (TIVA) in patients receiving caffeine and aminophylline in comparison to saline/placebo.Methods:This study was conducted on 75 American Society of Anesthesiologists (ASA) I and II female patients undergoing laparoscopic hysterectomy, aged between 18 to 60 years. The patients were divided into three equal groups (Group C: Caffeine citrate, Group A: aminophylline, and Group S: saline) of 25 each by random number computer table. The allocation was concealed by the sealed envelope method which was opened after giving GA. GA was induced with propofol, fentanyl, and rocuronium followed by endotracheal intubation and was maintained with propofol infusion. On completion of surgery, infusion of propofol was stopped. The study drug was administered intravenously when a BIS of 60 was achieved. Time to achieve BIS 90, time to the return of regular breathing with adequate tidal volume, to the return of first gag reflex, time to eye-opening on verbal command, handgrip on verbal command, and time to extubation after study drug administration were noted.Haemodynamic and respiratory parameters were also monitored. The Modified Aldrete score was recorded in all patients.Results:The time for BIS 60 to 90 was 10.6±3.9 min in the caffeine group, 12.6± 2.9 min in the aminophylline group, and 24.8 ± 4.8 min in the saline group. Thus, time to recovery was decreased by 57% and 49% in caffeine and aminophylline groups respectively and is statistically significant. The time to return of adequate tidal volume was least in the aminophylline group while it was highest in the control group. The difference was statistically significant when the aminophylline group was compared to the control group while it was insignificant for others. Time to return of gag reflex and time to extubation were statistically significant between aminophylline and saline group, and between caffeine and saline group. Haemodynamic parameters after infusion of the study drug were comparable in all three groups. Modified Aldrete score was higher in both caffeine and aminophylline group than in the control group and the difference was statistically significantTimeGroup S Median (IQR) (min)Group C Median (IQR) (min)Group A Median (IQR) (min) P Return of adequate tidal volume5.0 (3.25)4.0 (2.10)3.8 (2.75)P=0.035Return of gag reflex6.0 (2.85)3.6 (2.6)4.0 (3.5)P=0.005Return of eye opening6 (2.85)5.0 (3.85)4.6 (3.88)P=0.044Return of hand grip6.0 (3.35)4.0 (3.25)5.0 (4.5)P=0.05Extubation time7.0 (2.75)5.5 (3.0)5.0 (3.8)P=0.006Conclusion:Caffeine hastens the recovery from TIVA with propofol and fentanyl in laparoscopic hysterectomy as effectively as aminophylline. The recovery is significantly earlier with either of the drugs compared to when none of the drugs is given

Validation and application of a simple and rapid stability-indicating liquid chromatographic assay for the quantification of caffeine from human saliva

A clinical trial is currently underway to examine the efficacy of using caffeine citrate to prevent intermittent hypoxemia in late preterm neonates. Determining caffeine concentration using saliva in this population would be preferable as it is less invasive than plasma sampling, but a suitable method of analysis is required. This paper presents the development and validation of a rapid, efficient and reproducible stability-indicating high-performance liquid chromatography (HPLC) method and extraction protocol for the quantification of caffeine present in saliva. The stability of extemporaneously prepared caffeine citrate solutions (at 20–25 °C) was determined, along with the stability of caffeine spiked saliva samples (at 20–25 and 2–8 °C), to ensure the suitability of the developed method in the analysis of clinical trial samples. Protein precipitation using acetonitrile ensured the complete removal of salivary proteins and resulted in extraction recovery of ≥95% for all samples. The HPLC assay following extraction was linear (R 2>0.99) over the range 0.3–50 µg/mL (lower limit of quantification 0.3 µg/mL). The accuracy of the quality control samples was 94–100% and the relative standard deviation (RSD) was <7% for all samples. Caffeine-spiked saliva samples were stable for three freeze-and-thaw cycles pre-extraction and up to 72 hr post-extraction. The extraction and HPLC methods described were thus suitable for the analysis of clinical trial samples from the Latte Dosage Trial. All caffeine solutions were physically and chemically stable, with concentrations at the end of the three-month test period being within 4% of the baseline concentrations, indicating appropriateness for use as clinical trial medications.

Five-year outcomes of premature infants randomized to high or standard loading dose caffeine.

Objective:To examine five-year outcomes in children enrolled in a pilot randomized controlled trial of a high loading dose of caffeine after preterm birthStudy design:Seventy-four very low birth weight neonates were randomized within the first 24 hours of life to receive a high (80 mg/kg) or standard (20 mg/kg) loading dose of caffeine citrate. At five years of age, we conducted standardized neurodevelopmental tests and collected parent reports of child socioemotional problems.Result:Seventy-four percent of survivors returned for follow up. Children obtained similar scores on neurodevelopmental and socioemotional evaluations. There was no difference in the incidence of any neurodevelopmental delay after controlling for confounding factors.Conclusion:Five year follow up of a pilot trial of high loading dose caffeine citrate documented no profound impacts on childhood neurodevelopment or socioemotional outcome.

Treating Apnea of Prematurity.

Premature babies often suffer apnea of prematurity as a physiological consequence of an immature respiratory system. Hypercapnia may develop, and neonates with apnea of prematurity are at an increased risk of morbidity and mortality. The long-term effects of apnea of prematurity or their treatments are less clear. While a number of treatment options exist for apnea of prematurity, there is no clear-cut “first-line” approach or gold standard of care. Effective treatments, such as caffeine citrate, carbon dioxide inhalation, nasal continuous positive airway pressure, nasal intermittent positive pressure ventilation, and others, may be associated with safety concerns. More conservative treatments are available, such as kangaroo care, postural changes, and sensory stimulation, but they may not be effective. While apnea of prematurity resolves spontaneously as the respiratory system matures, it can complicate neonatal care and may have both short-term and long-term consequences. The role, if any, that apnea of prematurity may play in mortality of preterm neonates is not clear.

Caffeine Therapy for Apnea of Prematurity: Role of the Circadian CLOCK Gene Polymorphism.

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.

The Use of Off-Label Medications in Newborn Infants Despite an Approved Alternative Being Available-Results of a National Survey.

Neonates continue to be treated with off-label or unlicensed drugs while in hospital. However, some medications that have previously been used in adults underwent clinical testing and licensure for use with a different indication in the neonatal and pediatric population. Almost always, the marketing of these newly approved substances in a niche indication is accompanied by a steep increase in the price of the compound. We investigated the use of the approved formulation or the cheaper off-label alternative of Ibuprofen (Pedea®), Propanolol (Hemangiol®) and Caffeine Citrate (Peyona®) in neonatal clinical practice by conducting a National Survey of 214 Perinatal Centers in Germany. We also assessed price differences between on- and off-label alternatives and the extend of the clinical development program of the on-label medication in the neonatal population. On-label medication was more frequently used than the off-label alternative in all indications (PDA: on-label to off-label ratio 1:0.26, Apnea: 1:0.56, Hemangioma 1:0.76). All sponsors did conduct placebo-controlled Phase III trials with efficacy and safety endpoints in the target population and the number of participants in the target population varied between 82 and 497. Costs for the three drugs in their approved and marketed formulations increased in median 405-fold compared with the corresponding off-label alternative. Overall, about one out of three neonatologists prescribed an off-label or non-approved drug to patients despite an alternative medication that is approved for the indication in the target population being available.

Effect of Caffeine on Time to Anesthetic Emergence after Laparoscopic Cholecystectomy: Randomized-Controlled Trial

Background: The aim of this study was to examine the effect of caffeine on the time to emerge from sevoflurane anesthesia for laparoscopic cholecystectomy. Methods: Prospective, randomized, double-blind study conducted between July 2021 and October 2021. ASA I and II patients proposed for laparoscopic cholecystectomy were included and randomized into 2 groups at the end of the surgery to receive either 300mg of caffeine citrate infusion (C) or saline infusion (S). The main endpoint was to compare anesthetic recovery times. The secondary endpoints were recovery scales, postoperative pain, time to the first flatus, fatigue, occurrence of cardiovascular adverse events, and plasma caffeine levels one and twenty-four hours after intravenous infusion. Results: Sixty patients were included. Both groups were comparable regarding demographic characteristics and anesthesia parameters. All average times to emergence were shorter in group C with significant differences (p &lt;0.05) for time to spontaneous ventilation (p= 0.002, -2.86 min) and time to extubation (P= 0.004, -3.51 min). In group C the modified Aldrete scale and the Richmond agitation-sedation scale were significantly higher. Fatigue was significantly lower 4 hours postoperatively with caffeine (p = 0.049). There was no difference regarding postoperative pain, headache incidence, nausea and vomiting, time to the first flatus and satisfaction at discharge from hospital. Plasma levels of caffeine were well below the toxicity threshold. Conclusion: Caffeine administration following laparoscopic cholecystectomy reduced the time to emergence and sedation. Cardiovascular adverse events were not reported and plasma levels were well below the toxicity threshold.

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.

The effect of sensory stimulation on apnea of prematurity

ObjectivesThe study aims to assess the effect of sensory stimulation on apnoea among premature newborns. MethodsThirty preterm newborns that were diagnosed with apnoea of prematurity, had a gestational age between 32 and 34 weeks, had low birth weight, and were appropriate for gestational age from 1200 to 2000 g were included in this prospective randomized study. Subjects were divided into two equivalent groups: a control group that received the standard care including nasal oxygen (one litre per minute) and caffeine citrate, and a study group that received the same care plus sensory stimulation (tactile, proprioceptive, and kinaesthetic). Participants’ heart rate, oxygen saturation, and apnoea frequency were measured by the neonatal intensive care unit team using a pulse-oximeter. The sensory stimulation sessions were 10 min, 3 times per day, totalling 30 min over a 7 day period. ResultsThere was a significant decrease in heart rate within both groups after receiving treatment from before treatment (p < 0.05), with no significant differences between the two groups. Furthermore, there was no significant difference in oxygen saturation within the groups after treatment compared with the levels before treatment, with no significant differences between the two groups (p > 0.05). Before treatment, there was a non-significant difference in the apnoea rate between both groups (p = 0.464), whereas there was a significant decrease in the apnoea rate of the study group after treatment compared with the control group (p = 0.031). ConclusionSensory stimulation applied with standard respiratory care can decrease the frequency of apnoea of prematurity.

Effects of caffeine citrate on respiratory mechanics and pulmonary function during peri-extubation in premature infants with low body weight.

article: Effects of caffeine citrate on respiratory mechanics and pulmonary function during peri-extubation in premature infants with low body weight - Minerva Pediatrics 2022 August;74(4):493-5 - Minerva Medica - Journals

Effect of different maintenance doses of caffeine citrate on ventilator weaning in very preterm infants with respiratory distress syndrome: a prospective randomized controlled trial.

To study the effect of different maintenance doses of caffeine citrate on the success rate of ventilator weaning in very preterm infants (gestational age of ≤32 weeks) with respiratory distress syndrome (RDS). A total of 162 preterm infants with RDS who were admitted to the hospital from January 2016 to December 2018 were enrolled in this prospective trial. These infants had a gestational age of ≤32 weeks and required invasive mechanical ventilation. They were randomly divided into a high-dose caffeine group and a low-dose caffeine group, with 81 infants in each group. Within 6 hours after birth, both groups were given caffeine at a dose of 20 mg/kg. After 24 hours, the high- and low-dose caffeine groups were given caffeine at a maintenance dose of 10 mg/kg and 5 mg/kg, respectively. The two groups were compared in terms of re-intubation rate within 48 hours after ventilator weaning, durations of ventilation and oxygen therapy, enteral feeding, weight gain, and the incidence rates of complications and adverse reactions during hospitalization. The high-dose caffeine group had a significantly lower re-intubation rate within 48 hours after ventilator weaning than the low-dose caffeine group (P<0.05), with frequent apnea as the main reason for failed ventilator weaning in both groups. The high-dose caffeine group had significantly shorter durations of mechanical ventilation and oxygen therapy than the low-dose caffeine group (P<0.05). There were no significant differences between the two groups in the time to total enteral feeding, average daily weight gain, body weight at discharge, and the incidence rates of complications (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and intracranial hemorrhage) and adverse reactions (tachycardia, hypertension, and feeding intolerance) (P>0.05). A high maintenance dose of caffeine can safely and effectively reduce the incidence rate of apnea after ventilator weaning and the failure rate of ventilator weaning in RDS preterm infants with a gestational age of ≤32 weeks, and therefore, it holds promise for clinical application.

The limited management options for apnoea of prematurity.

About 10% of all infants are born prematurely. Almost all of those of gestational age less than about 30weeks, and about half of those of gestational age up to about 35weeks, are subject to unpredictable interruptions of breathing-known as "apnoea of prematurity" (AOP). We present a synopsis of the problem and point out the limited management options. A basal rate for spontaneous breathing is normally maintained by integrated action of generator cells in the brainstem and feedback from central and peripheral chemosensors. In AOP, there are intermittent periods (seconds) lacking spontaneous firing, which results in hypoxia and hypercapnia. The long-term consequences of these interruptions in oxygen supply to tissues are not known. Although many treatment modalities are used, including drug therapy, nonpharmacologic care and mechanical intervention, there is no universally effective first-line management for AOP. Caffeine citrate is generally the most frequently used pharmacotherapeutic agent, but its side effect profile narrows with higher doses and the upper limit is still being investigated to discern the greatest benefit-to-risk ratio; thus, most infants do not achieve complete resolution of apnoeas. Given the widespread and serious nature of the problem of AOP, there is a surprising lack of treatment options. A more consistent and effective treatment, alone or as adjunct, would be welcome.

Development of Protein-Specific Analytical Methodologies to Evaluate Compatibility of Recombinant Human (rh)IGF-1/rhIGFBP-3 with Intravenous Medications Co-Administered to Neonates

The protein complex of recombinant human insulin-like growth factor-1 and insulin‑like growth factor binding protein‑3 (rhIGF-1/rhIGFBP-3; mecasermin rinfabate), is an investigational product for the prevention of complications of prematurity. Delivery of rhIGF-1/rhIGFBP-3 is by continuous central line intravenous infusion in preterm infants until endogenous IGF-1 production begins. Protein-specific analytical methodologies were developed to evaluate the compatibility of rhIGF-1/rhIGFBP-3 at low protein concentrations (∼2.5-10 μg/mL) expected when co-administered with other required medications in the NICU. Highly sensitive detection of the biologic potential degradants (fragments) and/or molecular modifications (oxidized species, aggregates) required the use of reversed-phase high-performance liquid chromatography and size-exclusion ultra-performance liquid chromatography coupled with mass spectrometric detection. We report on the quantification of rhIGF-1/rhIGFBP-3, its components and degradants, to a limit of quantitation of 3.1 μg/mL upon mixing with 24 commonly administered neonatal medications. Methods developed for the rhIGF-1/rhIGFBP-3 admixtures, optimized in studies with furosemide, caffeine citrate and ampicillin, demonstrated good reproducibility, linearity, and limit of detection/quantitation. Using these methods, no increase in degradation of rhIGF-1/rhIGFBP-3 components and no increase in oxidation or aggregation level was observed with caffeine citrate, while admixtures of rhIGF-1/rhIGFBP-3 with ampicillin yielded lower mass recovery of rhIGF-1/rhIGFBP-3 components, which likely resulted from adduct formation. Furosemide was found to be physically incompatible with rhIGF-1/rhIGFBP-3. Our findings support the use of these methodologies for detection of protein modifications under various clinical administration conditions, and additionally supplement physical compatibility data studies of ultra-low concentrations of rhIGF-1/rhIGFBP-3 post co-administration to preterm infants with other medications (manuscript in-preparation).

Effect of very early use of caffeine citrate in preterm neonates needing respiratory support

Abstract Background Caffeine citrate is one of the most widely used medications in neonatal intensive care units. It is a respiratory stimulant which has well established therapeutic effects in apnea and extubation. Little is known about the very early use of caffeine citrate in preterm neonates. We aim to explore the effectiveness of its very early use in reducing the duration of the respiratory support used and not just extubation. Objectives to study the effect of the very early use of caffeine citrate in preterm neonates on morbidity and short-term neonatal outcomes. Subjects and Methods A prospective phase 3 clinical trial was carried out on 54 preterm neonates less than 34 weeks of gestation who require respiratory support and were given caffeine citrate in two different settings, over a period of one year. Patients were randomly allocated to one of two groups, the first group was given caffeine citrate at initiation of respiratory support(CPAP, NIPPV and IPPV). The second group received caffeine citrate 6 hours before weaning of the respiratory support used. Caffeine citrate was stopped after complete removal of the respiratory support used. Both groups were compared as regard the duration of each respiratory support used separately and the total duration of respiratory support needed for each patient. Results The duration of IPPV used in patients was significantly lower in the patients that received early caffeine citrate. Total duration of the respiratory support needed for each patient was significantly lower in the early group. There was no significant difference in the development of complications related to the drug use between both groups. The total duration of NICU stay was significantly lower in the early group than the other group. Conclusion The Early initiation of caffeine citrate has effectively and safely decreased duration of respiratory support used and NICU stay without the development of any complications. Key words early caffeine citrate, preterm neonates, respiratory support. *CPAP: Continuous positive airway pressure NIPPV: Non invasive positive pressure ventilation IPPV: Intermittent positive pressure ventilation NICU: Neonatal Intensive care unit

Medication Use in the Neonatal Intensive Care Unit and Changes from 2010 to 2018

To provide up-to-date medication prescribing patterns in US neonatal intensive care units (NICUs) and to examine trends in prescribing patterns over time. We performed a cohort study of 799 016 infants treated in NICUs managed by the Pediatrix Medical Group from 2010 to 2018. We used 3 different methods to report counts of medication: exposure, courses, and days of use. We defined the change in frequency of medication administration by absolute change and relative change. We examined the Food and Drug Administration (FDA) package insert for each medication to determine whether a medication was labeled for use in infants and used PubMed to search for pharmacokinetics (PK) studies. The most frequently prescribed medications included ampicillin, gentamicin, caffeine citrate, poractant alfa, morphine, vancomycin, furosemide, fentanyl, midazolam, and acetaminophen. Of the top 50 medications used in infants with extremely low birth weight, only 20 (40%) are FDA-labeled for use in infants; of the 30 that are not labeled for use in infants, 13 (43%) had at least 2 published PK studies. The medications with the greatest relative increase in use from 2010 to 2018 included dexmedetomidine, clonidine, rocuronium, levetiracetam, atropine, and diazoxide. The medications with the greatest relative decrease in use included tromethamine acetate, pancuronium, chloral hydrate, imipenem+cilastatin, and amikacin. Trends of medication use in the NICU change substantially over time. It is imperative to identify changes in medication use in the NICU to better inform further prospective studies.

The risk of development of acute kidney injury in full-term infants with administration of methylxanthines

Exploring new possibilities for the use of methylxanthines to prevent the development of acute kidney injury (AKI) in full-term infants with perinatal asphyxia. Aim: to evaluate the efficacy and safety of methylxanthines in full-term infants for the prevention and conservative treatment of acute kidney injury. Materials and methods. To test the effectiveness of the proposed method of AKI treatment, 38 infants were chosen and divided into 2 groups by random selection. Nursing and intensive care were according to current legislation (Order of the Ministry of Health of Ukraine No. 225 of March 28, 2014). The main group (n = 20) received therapy with caffeine citrate, the comparison group (n = 18) – theophylline. Both of these drugs were used to prevent the development of acute kidney injury – stage II and III according to KDIGO. Results. A significant difference in serum creatinine was found in the main group - the level of serum creatinine was higher than in the comparison group, but did not exceed the physiological norm. GFR on the 3rd day of life was higher with administration of theophylline, but in the group of caffeine did not exceed the reference values of the norm. No differences between urea levels and diuresis rates were found in the groups. The initial results indicate the lack of statistical significance when using various drugs of the methylxanthine group, namely theophylline and caffeine citrate. This is explained by the fact that in the main group 65.00 % (n = 13) of patients had AKI stage 0 according to KDIGO, and 35.00 % (n = 7) had stage I. In the comparison group, 55.56 % (n = 10) and 44.44 % (n = 8), respectively. Stages II and III in both groups of the study did not develop, the obtained data are equivalent – U = 163,00; P = 0,6296. However, the use of caffeine citrate may become a priority due to a better safety profile compared to theophylline. Caffeine is less likely to cause adverse effects in the form of non-pathological bile vomiting and has significantly lower relative risk of non-pathological bile vomiting in infants (RR 0.26 (95 % CI 0.10; 0.66)). Conclusions. Conservative methylxanthine therapy in full-term infants with perinatal asphyxia prevents the development of stages II and III of AKI according to KDIGO. However, it is necessary to continue the collection of material to increase the statistical significance, as well as to study the early and long-term consequences of this therapy.

Evaluation of the Use of Caffeine Citrate Maintenance Doses >5 mg/kg/day in Preterm Neonates for Apnea of Prematurity.

Caffeine citrate doses >5 mg/kg/day are frequently used for apnea of prematurity. The primary objective was identification of patients maintained on 5 mg/kg/day (Group 1). Secondary objectives included identification of patients requiring dose increases: 7.5 mg/kg every 24 hours (Group 2), 10 mg/kg every 24 hours (Group 3), and 5 mg/kg every 12 hours (Group 4); comparison of demographics and clinical characteristics; and identification of patients requiring dose adjustments owing to caffeine-associated tachycardia. Retrospective study of neonates born between 23 to <31 weeks' gestation, receiving caffeine between January 1, 2015, and July 31, 2019. Patients receiving caffeine <1 week, initial maintenance dose >5 mg/kg/day, or with congenital abnormalities were excluded. Descriptive and inferential statistics were performed, with a p < 0.05. Overall, 281 patients were included, with 99 (35.2%) in Group 1; 56 (19.9%) in Group 2; 47 (16.7%) in Group 3; and 79 (28.1%) in Group 4. Significant differences in gestational age were noted, with Group 3 and 4 patients being more premature than Groups 1 and 2 (p < 0.001). Dose increases occurred at a median postnatal age and postmenstrual age of 13.0 days and 31.4 weeks in Group 2; 17.0 days and 30.3 weeks in Group 3; and 16.0 days and 30.1 weeks in Group 4. Significant differences were noted for development of tachycardia requiring dose adjustment, with Groups 3 and 4 having the highest percentage (p < 0.001). Two-thirds received caffeine citrate doses >5 mg/kg/day, with 44% receiving 10 mg/kg/day. Further exploration is necessary to determine the optimal PNA or PMA for dose adjustments.