Predictors for poor daily weight gain in preterm neonates exposed to different dose regimens of caffeine in ICU- a retrospective cohort study.

BACKGROUND: With a wide therapeutic index, efficacy, ease of use, and other neuroprotective and respiratory benefits, caffeine citrate(CC) is currently the drug of choice for preterm neonates (PTNs). Caffeine-induced excessive energy expenditure, diuresis, natriuresis, and other CC-associated potential side-effects (CC-APSEs) result in lower daily-weight gain (WG) in premature neonates. This study aimed to evaluate the risk factors for daily-WG in neonates exposed to different dose regimens of caffeine in ICU. METHOD: This retrospective cohort study included neonates of ≤ 36weeks gestational age (GA) and received CC-therapy. The same participants were followed for data analysis in two postnatal phases: 15-28 and 29-42 days of life (DOL). Based on daily CC-dose, formed group-I (received; standard-doses = 5 mg/kg/day), group-II (received;>5-7 mg/kg/day), and group-III (received;>7 mg/kg/day). Prenatal and postnatal clinical characteristics, CC-regimen, daily-WG, CC-APSEs, and concomitant risk-factors, including daily-caloric intake, Parenteral-Nutrition duration, steroids, diuretics, and ibuprofen exposure, were analyzed separately for group-II and group-III using group-I as standard. Regression analysis was performed to evaluate the risk factors for daily-WG. RESULTS: Included 314 PTNs. During 15-28 DOL, the mean-daily-WG(MD-WG) was significantly higher in group-I than group-II [19.9 ± 0.70 g/kg/d vs. 17.7 ± 0.52 p = 0.036] and group-III [19.9 ± 0.70 g/kg/d vs. 16.8 ± 0.73 p < 0.001]. During 29-42 DOL the MD-WG of group-I was only significantly higher than group-III [21.7 ± 0.44 g/kg/d vs. 18.3 ± 0.41 g/kg/d p = 0.003] and comparable with group-II. During 15-28 DOL, observed CC-APSEs was significantly higher in group-II and III but during 29-42 DOL it was only significant in group-III. In the adjusted regression analysis for daily-WG during 15-28DOL, with respect to standard-dose, 5-7 mg/kg/day (ß=-1.04; 95%CI:-1.62,-0.93) and > 7-10 mg/kg/day (ß=-1.36; 95%CI:-1.56,-1.02) were associated with a lower daily-WG. However, during 29-42DOL, this association was present only for > 7-10 mg/kg/day (ß=-1.54; 95%CI:-1.66,-1.42). The GA ≤ 27weeks (ß=-1.03 95%CI:-1.24, -0.88) was associated with lower daily-WG only during 15-28DOL. During both periods of therapy, higher cumulative-caffeine dose and presence of culture proven sepsis, tachypnea, hyponatremia, and feeding intolerance were significantly associated with lower daily-WG. Conversely, daily kcal intake was found to be linked with an increase in daily-WG in both periods. CONCLUSION: In this study cohort exposure to higher caffeine daily and cumulative doses is associated with lower postnatal daily-WG in PTNs than standard-daily doses, which may be due to its catabolic effects and CC-APSEs.

Dose-Response Study of Caffeine on Postnatal Weight Gain in Premature Neonates-A Retrospective Cohort Study.

Background: Caffeine citrate (CC)-induced excessive energy expenditure, diuresis, natriuresis, and other CC-associated potential side effects (CC-APSEs) result in lower daily weight gain (WG) in premature neonates. This study aimed to assess higher CC-doses' effect on the mean daily-WG (MD-WG) and CC-APSE development, considering 5 mg/kg/day as the standard regimen. Method: This retrospective cohort study included neonates of ≤36 weeks gestational age and received CC-therapy. The same participants were followed for data analysis in two postnatal phases: 15-28 and 29-42 days of life (DOL). Based on daily CC-dose, formed group-I=(5 mg/kg/day), group-II=(>5-7 mg/kg/day), and group-III=(>7 mg/kg/day). Data was analyzed separately for group-II and group-III using group-I as the standard. Results: The study included 284 neonates. During phase-I, the MD-WG was significantly higher in group-I than group-II (19.9 ± .88 g/kg/d vs 17.5 ± .49, P = .031) and group-III (19.9 ± .88 g/kg/d vs 16.7 ± .71, P < .001). During 29-42 DOL, the MD-WG of group-I was only significantly higher than group-III (21.5 ± .42 g/kg/d vs 18.1 ± .39 g/kg/d, P = .003) and comparable with group-II. During 15-28 DOL, CC-APSEs were significantly higher in group-II and group-III but during 29-42 DOL was significant only in group-III. Conclusion: Exposure to higher caffeine doses in this study cohort is associated with lower postnatal WG in preterm neonates than standard daily doses may be due to its catabolic effects and CC-APSEs.

Association of Caffeine Daily Dose With Respiratory Outcomes in Preterm Neonates: A Retrospective Cohort Study.

Apnea and poor respiratory drive increase the risk of extubation failure (EF) and prolonged invasive mechanical ventilation (IMV) in preterm neonates (pre-nates) with respiratory distress. Caffeine citrate (CC) is often prescribed for pre-nates in doses of 5-10 mg/kg in 24 h. This study aimed to evaluate the most effective dosage regimen (5 mg/kg/day vs >5-10 mg/kg/day) to prevent apnea and EF with minimal caffeine-associated potential side effects (CC-APSEs) in pre-nates. This one-year retrospective cohort study included all the eligible neonates admitted to NICU and received CC-therapy till 28 days of life (DOL) or discharge. Based on CC-daily dose formed LD-caffeine-group (5 mg/kg/day) and HD-caffeine-group (>5-10 mg/kg/day). Antenatal, prenatal, and postnatal characteristics, CC-regimen, comorbidities, and CC-APSEs were compared between the groups. Predictors of apnea and EF were analyzed through logistic regression. There were 181 and 72 neonates in the LD and HD-caffeine-groups respectively. In HD-caffeine-group daily CC-dose was 7 to 7.5 mg/kg/day in 93% of neonates and >7.5 to 10 mg/kg/day in only 7%. Significantly fewer neonates experienced apnea and EF in the HD-caffeine-group till 28DOL or discharge. This difference was even greater in the subgroup of ≤28 weeks GA (15.6% vs 40.0%; P < .01). In HD-caffeine-group the incidence of severe/moderate-BPD was significantly lower and the frequency of CC-APSEs was higher. Multivariate analysis showed that; the smaller the GA higher the risk of apnea (AOR = 0.510, 95% CI 0.483-0.999) and EF (AOR = 0.787, 95% CI 0.411-0.997). The HD-caffeine was inversely associated with developing apnea (AOR = 0.244, 95% CI 0.053-0.291) and EF (AOR = 0.103, 95% CI 0.098-2.976). IMV-duration before extubation (AOR = 2.229, 95% CI 1.672-2.498) and severe/moderate-BPD (AOR = 2.410, 95%CI 1.104-2.952) had a high risk of EF. Initiating early HD-caffeine may prevent apnea and extubation failure in preterm neonates. Optimization of caffeine initiation time and dosages can be a safe and feasible approach to decrease the burden of neonatal respiratory morbidities.

Physicochemical compatibility of caffeine citrate and caffeine base injections with parenteral medications used in neonatal intensive care settings.

PURPOSE: To investigate the physicochemical compatibility of caffeine citrate and caffeine base injections with 43 secondary intravenous (IV) drugs used in Neonatal Intensive Care Unit (NICU) settings. METHODS: Caffeine citrate (20 mg/mL or 10 mg/mL) or caffeine base injection (10 mg/mL) were mixed in a volume ratio of 1:1 with the secondary drug solution to simulate Y-site co-administration procedures in NICUs. Physical compatibility was evaluated based on visual observation for 2 h, against a black and white background and under polarised light, for changes in colour, precipitation, haze and evolution of gas. Chemical compatibility was determined from caffeine concentration measurements, using a validated high-performance liquid chromatography assay. RESULTS: Six of the 43 secondary drugs tested (aciclovir, amphotericin (liposomal), furosemide, hydrocortisone, ibuprofen and ibuprofen lysine) were physically incompatible with caffeine citrate undiluted injection (20 mg/mL), at their high-end, clinically relevant concentrations for NICU settings. However, when tested at lower concentrations, hydrocortisone (1 mg/mL) was physicochemically compatible, whereas furosemide (0.2 mg/mL) was physically incompatible with caffeine citrate. The six drugs which showed physical incompatibility with caffeine citrate 20 mg/mL injection were also physically incompatible with caffeine citrate 10 mg/mL solution. All 43 secondary drugs tested were physicochemically compatible with caffeine base injection. CONCLUSIONS: Most secondary test drugs, except aciclovir, amphotericin (liposomal), furosemide, hydrocortisone, ibuprofen and ibuprofen lysine, were physicochemically compatible with caffeine citrate injection. Caffeine base injection was physicochemically compatible with all 43 test drugs tested.

The Babyccino: The Role of Caffeine in the Prevention of Acute Kidney Injury in Neonates-A Literature Review.

Acute kidney injury (AKI) in neonates is associated with increased morbidity and mortality. Theophylline (a methylxanthine) has been shown to prevent neonatal AKI but is seldom used due to its unfavorable profile. Caffeine, another methylxanthine, is utilized ubiquitously to treat apnea of prematurity, but there are no randomized trials evaluating its efficacy in preventing neonatal AKI. This literature review aims to summarize the existing research pertaining to the relationship between caffeine and neonatal AKI. The review was conducted using Pubmed, Embase, Google Scholar, and Cochrane. Inclusion criteria incorporated empirical studies, being published in English, and being available electronically. All eight studies identified were included. Seven studies found caffeine-exposed premature neonates had lower rates of AKI than caffeine-unexposed neonates. Four found reduced AKI severity with caffeine exposure. One study included term neonates and did not find a difference in the AKI rate between caffeine-exposed and non-exposed babies. Limitations include exclusively observational studies, short study periods, heterogenous definitions of prematurity, and a lack of assessment of dose-effect relationships. In conclusion, premature neonates exposed to caffeine appear to have lower rates and potentially less severe AKI. Further research is needed before caffeine can be considered for use in the primary prevention of neonatal AKI.

Effect of early preventive use of caffeine citrate on prevention together with treatment of BPD within premature infants and its influence on inflammatory factors.

OBJECTIVE: To explore caffeine citrate prophylactic and therapeutic influences upon broncho-pulmonary dysplasia (BPD) within premature infants and its influence on inflammatory factors. METHODS: A total of 128 premature infants from January 2021 to June 2022 were investigated, segregated within control group and observation group through randomized number table protocol, having 64 cases per group. RESULTS: Effective rate of observation group was elevated in comparison to control group (95.31% versus 84.38%, P < 0.05). The number of apnea of prematurity (AOP) in observation group was reduced in comparison to control group, while duration of auxiliary ventilation together with hospitalization days were reduced in comparison to control group (P < 0.05). Post-therapy, matrix metalloproteinase-9 (MMP-9), tumor necrosis factor (TNF-α) and Toll-like receptor-4 (TLR-4) were downregulated within observation group, while scorings for psychomotor development index (PDI) and mental development index (MDI) in observation group were elevated in comparison to control group (P < 0.05). Weight-gain rate and growth rate of body length within observation group was elevated in comparison to control group (P < 0.05). Post-therapy, work of breathing (WOB) and airway resistance (Raw) within observation group were lower compared to control group, while respiratory system compliance (Crs) was elevated in comparison to control group (P < 0.05). Occurrences of broncho-pulmonary dysplasia (BPD) within observation group was reduced in comparison to control group (P < 0.05). CONCLUSION: Early prophylactic use of caffeine citrate can effectively reduce the incidence of BPD in premature infants.

Caffeine - Essentials for anaesthesiologists: A narrative review.

Caffeine has a multitude of uses in anaesthesia, and numerous studies have evaluated its efficacy and usefulness in various aspects of anaesthesia and medical practice. Its various applications in anaesthesia include its role in awakening from anaesthesia, managing post-dural puncture headache, managing post-sedation paradoxical hyper-activity in children, post-operative bowel paralysis, and apnoea in paediatric populations, that is, apnoea in infancy, paediatric obstructive apnoea, and post-anaesthetic apnoea in pre-mature infants. Though the effects of caffeine on bronchial smooth muscle, neurological, and cardio-vascular systems are well known, the relatively little-known effects on the endocrine and gastro-intestinal (GI) system have been recently taking primacy for eliciting its therapeutic benefits. The literature shows encouraging evidence in favour of caffeine, but unambiguous evidence of caffeine benefits for patients is lacking and needs further investigation. In this narrative review of literature, we summarise the available literature to provide insights into the pharmacokinetics, pharmacodynamics, clinical application of caffeine in modern anaesthetic practice, and evidence available in this field to date. An awareness of the various physiological effects, adverse effects, reported applications, and their evidence will widen the horizon for anaesthesiologists to increase its rational use and advance research in this field. Well-designed randomised controlled trials regarding the various outcomes related to caffeine use in anaesthesia should be planned to generate sound evidence and formulate recommendations to guide clinicians.

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-1ß 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-1ß 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.

Research progress on caffeine citrate in the treatment of neonatal respiratory distress syndrome / 中国小儿急救医学

Neonatal respiratory distress syndrome is typically characterized by progressive exacerbation of respiratory distress shortly after birth, which is more common in preterm infants and has a high disability and mortality rate.Caffeine citrate has been used in the treatment of premature infants with respiratory distress syndrome to enhance the contraction of the diaphragm and optimize the function of respiratory muscles to accelerate the recovery of spontaneous breathing.This review summarized the use of caffeine citrate in premature infants with respiratory distress syndrome.

Research progress on caffeine citrate in the treatment of neonatal respiratory distress syndrome / 中国小儿急救医学

Neonatal respiratory distress syndrome is typically characterized by progressive exacerbation of respiratory distress shortly after birth, which is more common in preterm infants and has a high disability and mortality rate.Caffeine citrate has been used in the treatment of premature infants with respiratory distress syndrome to enhance the contraction of the diaphragm and optimize the function of respiratory muscles to accelerate the recovery of spontaneous breathing.This review summarized the use of caffeine citrate in premature infants with respiratory distress syndrome.

The timing of withdrawal from caffeine citrate in very preterm infants. / æžæ—©æ—©äº§å„¿æž¸æ©¼é ¸å’–å•¡å› åœç”¨æ—¶æœºçš„ä¸´åºŠç ”ç©¶.

OBJECTIVES: To study the clinical features and outcome of very preterm infants withdrawn from caffeine citrate at different time points. METHODS: 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. RESULTS: 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). CONCLUSIONS: A relatively long course of caffeine citrate treatment is more beneficial to the short-term clinical outcome of very preterm infants.

Effect of different maintenance doses of caffeine citrate on ventilator weaning in very preterm infants with respiratory distress syndrome: a prospective randomized controlled trial. / ä¸åŒç»´æŒå‰‚é‡æž¸æ©¼é ¸å’–å•¡å› å¯¹æžæ—©äº§å„¿å‘¼å¸çª˜è¿«ç»¼åˆå¾æ’¤æœºå½±å“ï¼šå‰çž»æ€§éšæœºå¯¹ç §ç ”ç©¶.

OBJECTIVES: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

The timing of withdrawal from caffeine citrate in very preterm infants / 中国当代儿科杂志

OBJECTIVES@#To study the clinical features and outcome of very preterm infants withdrawn from caffeine citrate at different time points.@*METHODS@#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.@*RESULTS@#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 (@*CONCLUSIONS@#A relatively long course of caffeine citrate treatment is more beneficial to the short-term clinical outcome of very preterm infants.

Effect of different maintenance doses of caffeine citrate on ventilator weaning in very preterm infants with respiratory distress syndrome: a prospective randomized controlled trial / 中国当代儿科杂志

OBJECTIVES@#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).@*METHODS@#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.@*RESULTS@#The high-dose caffeine group had a significantly lower re-intubation rate within 48 hours after ventilator weaning than the low-dose caffeine group (@*CONCLUSIONS@#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.

Is caffeine available and affordable in low and middle-income countries? A survey in sub-Saharan Africa.

Caffeine is the preferred pharmacologic treatment for apnea of prematurity. Little is known about the availability and affordability of caffeine in the low and middle-income countries of sub-Saharan Africa (SSA). We conducted an online survey in 2020 of newborn physicians in SSA to determine their access to caffeine. Of 90 invited participants, 55 responded (61%). They worked in 13 SSA countries and 48 hospitals. Caffeine was used in 6 countries. In 5 of these countries, the price of caffeine was reported and ranged from US $1.73 in Ghana to US $73.63 in Kenya per 3 mL vial. High drug prices and lack of drug availability for purchase were identified most frequently as primary barriers. Some respondents believed that other methylxanthines are adequate substitutes for caffeine. Only 31 of 53 (58%) respondents knew that caffeine is included in the essential drug list of the World Health Organization (WHO).

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

WHAT IS KNOWN AND OBJECTIVES: 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. METHODS: A total of 88 serum concentration measurements from 46 preterm patients (median gestational age 29 weeks) 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. RESULTS: 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 0.268 L/h and 109 L per 70 kg, 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. WHAT IS NEW AND CONCLUSION: 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 Citrate for the Prevention of Apnea Associated With Alprostadil Infusions.

OBJECTIVE: To evaluate the incidence of apnea and requirement for positive pressure ventilation in patients who received caffeine for prevention while receiving alprostadil compared with those who did not receive caffeine. METHODS: This was a single-center, retrospective study of patients who received alprostadil over a 7-year time frame. Patients were divided into 2 groups based on whether they received caffeine for prevention of apnea while receiving alprostadil. The incidence of apnea and requirements for positive pressure ventilation were recorded. RESULTS: A total of 64 patients who received alprostadil were included for review. Thirty-two patients received caffeine for the prevention of apnea, and 32 patients received alprostadil only. Alprostadil doses were similar between the 2 groups (0.04-0.05 mcg/kg/min). Seven patients had a documented apneic event; 3 in the group given caffeine and 4 in the control group. One patient in each group required intubation because of apnea. All patients with documented apnea were on low-dose alprostadil therapy (<0.05 mcg/kg/min). Three patients had apnea after dose reductions had been made. Six out of the seven patients experienced apnea within the first 24 hours after the infusion. Only 1 patient experienced multiple apneic events. CONCLUSIONS: In this small sample, there was no difference in incidence of apnea between patients on low-dose alprostadil who received caffeine for prevention and those who did not. Despite the use of low-dose alprostadil therapy and dose reductions, the incidence of apnea remains low, and most patients did not have repeated apneic events or require intubation.

Comparison of the effects of caffeine citrate administering at different time on outcome and neuro-development of premature infants / 中国小儿急救医学

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.

Caffeine citrate enhanced cisplatin antitumor effects in osteosarcoma and fibrosarcoma in vitro and in vivo.

BACKGROUND: While multiagent chemotherapy has dramatically improved the prognosis of sarcoma, the novel chemotherapeutics have hardly developed over the past 30 years. Caffeine can induce apoptosis, delays in cell cycle progression and can enhance the cytocidal effects of anti-cancer agents. Citrate has been reported to enhance the cytocidal effect of cisplatin in gastric cancer in vitro. However its effect in sarcoma cells had not been reported. METHODS: This study was designed to evaluate whether the addition of caffeine, citrate, or caffeine citrate to cisplatin improved its cytocidal effect (cell survival, proliferation, and apoptosis) on human osteosarcoma (HOS), human fibrosarcoma (HT1080) and murine osteosarcoma (LM8) cell lines. We also tested the various combinations in a mouse heterotopic transplantation model in vivo. In cell survival assay, combination index (CI) of caffeine citrate was calculated as a combination of anhydrous caffeine and citric acid, and the synergy was evaluated (CI < 1.0). RESULTS: In all cell lines, cisplatin combined with caffeine citrate significantly reinforced the anticancer effect compared with cisplatin alone, combination of cisplatin and anhydrous caffeine, and combination of cisplatin and citric acid. Moreover, CI was < 1.0 in all conditions. The anticancer agent reinforcement effect of caffeine citrate was synergy of anhydrous caffeine and citric acid. In cell proliferation and cell cycle assay revealed that caffeine citrate had most strong effect as a combination drug than caffeine and citric acid in inducing G0/G1 cell-cycle arrest with subsequent suppressed cell proliferation. In mitochondrial depolarization and caspase 3/7 activity assay revealed that caffeine citrate had most strong effect as a combination drug than caffeine and citric acid in apoptosis associated with decreased mitochondrial membrane potential. In vivo, three different drug concentrations were tested, and cisplatin combined with caffeine citrate was found to have the strongest antitumor effect. CONCLUSIONS: This is the first report demonstrating that caffeine citrate has a significantly greater potentiating effect on cisplatin than adding either caffeine or citric acid. The combination of cisplatin with caffeine citrate is a novel treatment that might hold promise for improving the outcome of osteosarcoma and fibrosarcoma, which up till now has generally not responded well to chemotherapy.