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The optimum caffeine dose in preterm infants has not been well investigated. We aimed to compare the efficacy and safety of high versus low-dose caffeine citrate on apnea of prematurity (AOP) and successful extubation of preterm infants from mechanical ventilation. We compared high-dose (loading 40 mg/kg/day and maintenance of 20 mg/kg/day) versus...
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... patients in high-dose caffeine group (23 %) experi- enced tachycardia compared to the low-dose group (23 vs 8 %, p<0.05). There was no significant difference in the incidence of hypertension or time to reach full enteral feeding (Table 4). Caffeine therapy was withheld, owing to a physician concern of a significant side effects, in 6 infants in the high-dose group and 2 infants in the low- dose group (p=0.27). ...
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The objective of the study is to determine if early high-dose caffeine (HD) therapy is associated with shorter duration of mechanical ventilation, bronchopulmonary dysplasia (BPD), or decreased need for mechanical ventilation. We conducted a single center, retrospective cohort study of 273 infants less than 32 weeks gestational age (GA). Infants re...
Introduction: Caffeine citrate is widely used for prevention of apnea of prematurity and helps in successful extubation from mechanical ventilation. The optimum caffeine dose in preterm infants with apnea of prematurity has been extensively investigated with varied results. The objective of our study was to compare the efficacy and safety of once v...
Objective:
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Methods:
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The present study was conducted to investigate the clinical significance of caffeine and aminophylline in the treatment of premature infants with apnea under varying conditions of oxygen (O2) delivery. The clinical data of 120 premature infants with apnea treated with oxygen therapy and either caffeine citrate (20 mg/kg/day; n=77) or aminophylline...
Citations
... Preterm neonates have immature respiratory control mechanisms and more than 85% of neonates born at gestational age (GA) ≤ 34 weeks, experience a developmental disorder known as apnea of prematurity (AOP) [1][2][3]. Preterm neonates have a higher probability of developing retinopathy of prematurity (ROP) and neurodevelopmental consequences due to apnea-associated intermittent hypoxemia [4,5]. Likewise, AOP and poor respiratory drive increase the risk of extubation failure and prolonged mechanical ventilation in newborns experiencing respiratory distress [6]. ...
... Apnea of prematurity might persist beyond 37 weeks postmenstrual age (PMA) in preterm neonates born at GA < 28 weeks [11]. Hence, CC is often prescribed for preterm neonates until they reach a PMA of 35-37 weeks in doses of 5-10 mg/kg in 24 h [3,5,7,12,13]. In this vulnerable population, the longer duration of CC-therapy and higher cumulative doses with potential catabolic response might affect the initial weight gain (WG) [14]. ...
... In addition, a recent randomized trial (RT) preferred the use of twice-daily caffeine dosage [49]. Another trial suggested that a higher daily CC-dose regimen possibly decreases the risk of extubation failure [3]. Though, a more recent RT has not demonstrated earlier extubation from earlier CC-therapy initiation [50]. ...
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 (β=-1.04; 95%CI:-1.62,-0.93) and > 7-10 mg/kg/day (β=-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 (β=-1.54; 95%CI:-1.66,-1.42). The GA ≤ 27weeks (β=-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.
... Preterm neonates have immature respiratory control mechanisms and more than 85% of neonates born at gestational age (GA) ≤34 weeks, experience a developmental disorder known as apnea of prematurity (AOP). [1][2][3] Preterm neonates have a higher probability of developing retinopathy of prematurity (ROP) and neurodevelopmental consequences due to apnea-associated intermittent hypoxemia. 4,5 Likewise, AOP and poor respiratory drive increase the risk of extubation failure (EF) and prolonged invasive mechanical ventilation (IMV) in newborns with respiratory distress. ...
... [16][17][18][19] Hence, CC is often prescribed for preterm neonates until they reach a PMA of 35 to 37 weeks in doses of 5 to 10 mg/ kg in 24 h. 3,5,7,20,21 The current standard CC-therapy involves a loading dose of 20mg/kg following a daily dose of 5 mg/kg/day. 22 However, with this regimen, EF was reported in a third of preterm neonates. ...
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.
... 26 In addition, a recent randomized trial (RT) preferred the use of twice-daily caffeine dosage. 27 Another trial suggested that a higher daily CC-dose regimen possibly decreases the risk of EF. 28 Though, a more recent RT has not demonstrated earlier extubation from earlier CC-therapy initiation. 29 A European trial reported about twenty-one CC-APSEs in premature neonates. ...
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.
... We identified 15 eligible RCTs enrolling a total of 3530 premature infants. Most trials enrolled infants born at <32 weeks' PMA [22][23][24][25][26][27][28][29][30], although some included infants up to 35 [31] or 36 [32] weeks, or defined eligibility based on birthweight [24,[33][34][35] or clinical decision to treat with caffeine [36]. Eight trials compared caffeine to placebo or no treatment [22-25, 31, 33-35]. ...
... High-dose vs. low-dose caffeine Primary outcome: Neonatal/infancy: For the primary outcome of apnea (continuous), evidence of very low certainty from four trials showed possible benefit from receiving high-dose caffeine compared to low-dose caffeine, although the effect size was small (mean difference [MD] −0.2, 95% CI −0.3, −0.2, 560 infants) (Table 4) [27,28,30,36]. There was statistical heterogeneity (I 2 = 87%) among trials, although the direction of effect consistently favored high-dose caffeine (Fig. 2). ...
... d OIS criteria not met (total population less than half of OIS, resulting in downgrading by two steps). e One included study (Scanlon [28]) was judged to have high overall risk of bias for this outcome, two (Steer [36] & Zhao [30]) were judged to have some concerns overall for this outcome and one (Mohammed [27]) was judged to have a low overall risk of bias for this outcome. f I 2 = 87%. ...
This systematic review and meta-analysis evaluated the evidence for dose and effectiveness of caffeine in preterm infants. MEDLINE, EMBASE, CINHAL Plus, CENTRAL, and trial databases were searched to July 2022 for trials randomizing preterm infants to caffeine vs. placebo/no treatment, or low (≤10 mg·kg ⁻¹ ) vs. high dose (>10 mg·kg ⁻¹ caffeine citrate equivalent). Two researchers extracted data and assessed risk of bias using RoB; GRADE evaluation was completed by all authors. Meta-analysis of 15 studies (3530 infants) was performed in REVMAN across four epochs: neonatal/infant (birth-1 year), early childhood (1–5 years), middle childhood (6–11 years) and adolescence (12–19 years). Caffeine reduced apnea (RR 0.59; 95%CI 0.46,0.75; very low certainty) and bronchopulmonary dysplasia (0.77; 0.69,0.86; moderate certainty), with higher doses more effective. Caffeine had no effect on neurocognitive impairment in early childhood but possible benefit on motor function in middle childhood (0.72; 0.57,0.91; moderate certainty). The optimal dose remains unknown; further long-term studies, are needed.
... Concerns for caffeine use have arisen with one high dose trial reporting statistically significant increases in abnormal neurological outcomes compared with standard dose (96). Results from a randomised double-blind placebo controlled study showed the initiation of early caffeine did not reduce the age of first successful extubation, rates of BPD, or the duration of need for supplemental oxygen when compared with the placebo group and this trial was halted due to a non-significant trend towards an increased mortality rate in the caffeine group (97). ...
Neonatal brain injury and associated inflammation is more common in males. There is a well-recognised difference in incidence and outcome of neonatal encephalopathy according to sex with a pronounced male disadvantage. Neurodevelopmental differences manifest from an early age in infancy with females having a lower incidence of developmental delay and learning difficulties in comparison with males and male sex has consistently been identified as a risk factor for cerebral palsy in epidemiological studies. Important neurobiological differences exist between the sexes with respect to neuronal injury which are especially pronounced in preterm neonates. There are many potential reasons for these sex differences including genetic, immunological and hormonal differences but there are limited studies of neonatal immune response. Animal models with induced neonatal hypoxia have shown various sex differences including an upregulated immune response and increased microglial activation in males. Male sex is recognized to be a risk factor for neonatal hypoxic ischemic encephalopathy (HIE) during the perinatal period and this review discusses in detail the sex differences in brain injury in preterm and term neonates and some of the potential new therapies with possible sex affects.
... Compared to the literature and clinical standard dosing regimens in neonates, our dosing was higher. However, studies in preterm infants have shown that higher doses of caffeine are effective without reporting significant side effects when compared to the standard treatment [27][28][29] . In our study, we did not note any adverse effects, like increased seizure rates, weight loss or death, in the animals treated with caffeine when we used a dose of 40 mg/kg/dose. ...
Intrapartum hypoxia–ischemia leading to neonatal encephalopathy (NE) results in significant neonatal mortality and morbidity worldwide, with > 85% of cases occurring in low- and middle-income countries (LMIC). Therapeutic hypothermia (HT) is currently the only available safe and effective treatment of HIE in high-income countries (HIC); however, it has shown limited safety or efficacy in LMIC. Therefore, other therapies are urgently required. We aimed to compare the treatment effects of putative neuroprotective drug candidates following neonatal hypoxic-ischemic (HI) brain injury in an established P7 rat Vannucci model. We conducted the first multi-drug randomized controlled preclinical screening trial, investigating 25 potential therapeutic agents using a standardized experimental setting in which P7 rat pups were exposed to unilateral HI brain injury. The brains were analysed for unilateral hemispheric brain area loss after 7 days survival. Twenty animal experiments were performed. Eight of the 25 therapeutic agents significantly reduced brain area loss with the strongest treatment effect for Caffeine, Sonic Hedgehog Agonist (SAG) and Allopurinol, followed by Melatonin, Clemastine, ß-Hydroxybutyrate, Omegaven, and Iodide. The probability of efficacy was superior to that of HT for Caffeine, SAG, Allopurinol, Melatonin, Clemastine, ß-hydroxybutyrate, and Omegaven. We provide the results of the first systematic preclinical screening of potential neuroprotective treatments and present alternative single therapies that may be promising treatment options for HT in LMIC.
... As consequence, a very small number of drugs are approved for neonates and data supporting the safety and efficacy are limited. Quite recently, considerable attention has been paid to clinical trials of caffeine citrate treatment for apnea of prematurity, the prevention of extubation failure, bronchopulmonary dysplasia, and the need for mechanical ventilation [3][4][5][6][7][8][9][10]. Current research focusses on effects on the central nervous system for apnea prevention. ...
Since 2000, caffeine is used as citrate salt of caffeine for treatment of apnea of prematurity. However, it remained elusive if caffeine citrate has a direct function in the respiratory epithelium, potentially as modulator for ciliary beat frequency (CBF) regulation in human respiratory cells (hRECs). Here, we studied the mechanism of action of caffeine citrate on the respiratory epithelium on hRECs derived from healthy donors and individuals with cystic fibrosis (CF) cultured under air-liquid-interface (ALI) conditions. CBF analyses of hRECs were performed by high-speed video microscopy. In the presence of caffeine, hRECs show a significant increase in CBF over ciliary base frequency (CBFb), demonstrating a direct influence of caffeine on ciliary function. We also demonstrate a specific action of caffeine at ryanodine receptor (RYR) channels, mediating calcium efflux from intracellular stores to increase CBF. We describe a novel pharmacological effect of caffeine citrate - direct increase of CBF of primary hRECs cultured at ALI. Caffeine citrate has certain advantages over other methylxanthines: it was shown to have stable plasma concentration, longer half-life, and is better tolerated than e.g. theophylline. We conclude that caffeine citrate therapy might be suitable strategy to treat respiratory diseases with compromised mucociliary clearance.
... Gestational age, sex, and birthweight are known to significantly affect LOS (Briere et al., 2016;Brumbaugh et al., 2018;Lau et al., 2015;Lee et al., 2016;Maier et al., 2018;Sahiledengle et al., 2020;Seaton et al., 2016;Sullivan et al., 2022). Additionally, respiratory conditions such as apnea of prematurity, a complication often treated with prescribed caffeine (Mohammed et al., 2015), prolongs NICU admission (Kumar and Lipshultz, 2019;Ma et al., 2020) and contributes to delays in oral feeding (Sullivan et al., 2022). Length of stay may also be extended in infants who require supplemental oxygen, are diagnosed with infections, or who undergo complex surgical procedures further into their admission (Seaton et al., 2016). ...
... There are heterogeneous reports on the optimal loading and maintenance dose of caffeine in several studies in terms of benefits and risks. [9][10][11] Our study showed that those babies receiving twice daily divided dose of caffeine had 50% reduction in apneic episodes from baseline within two median days compared to 3.5 median days in babies receiving single daily dose and the results were statistically significant. In our study the median number of apneic episodes on consecutive days was significantly lower in group 1 (BD) achieving a median of zero episodes by day five compared to group 2 (OD) and the results were statistically significant. ...
... 12 A study done by Mohammed S et al comparing highdose (Loading 40 mg / kg / day and maintenance of 20 mg / kg / day) versus low-dose (Loading 20 mg / kg / day and maintenance of 10 mg / kg / day) caffeine citrate in preterm infants < 32 weeks with AOP showed that high-dose caffeine was associated with a significant reduction in extubation failure in mechanically ventilated preterm infants (P < 0.05), the frequency of apnea (p < 0.001), and days of documented apnea (p < 0.001). 10 In this study, the neonates receiving twice daily dose of caffeine achieved full feeds significantly earlier (Median days: 2 vs 4) than those receiving once a day caffeine. Caffeine is generally well tolerated with lower rate of adverse effects. ...
... 12 However in the study by Mohammed S et al more patients in highdose caffeine group (23%) experienced tachycardia compared to the low-dose group (23 vs 8 %, p < 0.05) with no significant difference in the incidence of hypertension or time to reach full enteral feeding. 10 Through this study we have highlighted the beneficial effects of twice daily divided dose of caffeine citrate, using the standard dose regimen in the treatment of AOP. The limitations of our study is that the sample size was not calculated statistically. ...
Introduction: Caffeine citrate is widely used for prevention of apnea of prematurity and helps in successful extubation from mechanical ventilation. The optimum caffeine dose in preterm infants with apnea of prematurity has been extensively investigated with varied results. The objective of our study was to compare the efficacy and safety of once versus twice daily maintenance dose of caffeine citrate in premature infants with apnea. Methods: In this study, preterm neonates with gestational age of 28 to 34 weeks, with evidence of apnea of prematurity were included. Both groups received a 20 mg / kg loading dose of caffeine citrate followed by a maintenance dose of 2.5 mg / kg every 12-hour-interval in group 1 and 5 mg / kg every 24-hour-interval in group 2, either orally or by intravenous infusion. Response to treatment, duration to achieve full feeds, possible adverse reactions were evaluated and compared among the two groups. Results: Among two groups, group 1 had early reduction in number of apneic episodes on five consecutive days after loading dose, which was statistically significant. Time taken to establish full feeds following treatment initiation was lower in group 1 compared to group 2 (median: Two vs four days) which was statistically significant. Conclusions: In this study, neonates who received twice daily maintenance dose of caffeine citrate had better outcomes in terms of early reduction in number of apneic episodes and early feed establishment when co
... Apnea of prematurity (AOP) is a developmental disorder in preterm neonates due to immature respiratory control mechanisms [1,2]. It occurs in almost all neonates born at gestational age (GA)<29 weeks or birth weight (BW) <1000 g [3], in about 50% of the neonates with GA 30 to 32 weeks, and 7% neonates with GA 34-35 weeks [4]. AOP is associated with intermittent hypoxemia, therefore reported to affect the neurodevelopmental consequences and increased risk of retinopathy of prematurity (ROP) [5,6]. ...
... In most neonates, apneic episodes cease by term gestation [11], though apnea might persist beyond the term in infants born < 28 weeks' gestation [12]. Therefore, caffeine is used for preterm neonates for a longer duration in doses of 5-10 mg/kg/day once daily [4,6,8]. ...
Background
Caffeine is available in an ampoule, used via parenteral and enteral routes in preterm neonates to treat apnea of prematurity (AOP) in neonates of gestational age ≥ 35–40 weeks. A longer duration of therapy has a higher risk of medication non-adherence due to higher costs and inappropriate dosage forms. Pharmaceutically compounded oral caffeine (PCC) could be an appropriate alternate dosage form. The researchers aimed to determine the impact of PCC on medication-related factors influencing medication adherence (MA) and the frequency of hospital readmission with apnea (HRA) in preterm neonates.
Methods
We conducted a single-center quasi-experimental study for this quality improvement project using PCC among the preterm neonates admitted in a tertiary care level-III NICU at the Aga Khan University Hospital Karachi, Pakistan, received caffeine therapy, and survived at discharge. The researchers compared pre-PCC data (April-December 2017) with post-PCC data (April-Dec 2018) each for nine months, with three months intervals (January-March 2018) of PCC formulation and implementation phase. The study was conducted according to the SQUIRE2.0 guidelines. The Data were collated on factors influencing MA, including the cost of therapy, medication refill rates, and parental complaints as primary outcome measures. The Risk factors of HRA were included as secondary outcomes.
Results
After PCC implementation cost of therapy was reduced significantly from Rs. 97000.0 (729.0 USD) to Rs. 24500.0 (185.0 USD) (p<0.001), significantly higher (p<0.001) number of patients completed remaining refills (77.6% pre-phase vs 97.5% post-phase). The number of parental complaints about cost, ampoule usage, medication drawing issue, wastage, inappropriate dosage form, and longer duration of therapy reduced significantly in post-phase. HRA reduced from 25% to 6.6% (p<0.001). Post-implementation of PCC (RR 0.14; 95% CI: 0.07–0.27) was a significant independent risk factor for reducing HRA using a multivariate analysis model. Longer duration of caffeine therapy after discharge (RR 1.05; 95% CI: 1.04–1.04), those who were born in multiple births (RR 1.15; 95% CI: 1.15–1.15), and those who had higher number of siblings were other significant independent risk factors for HRA.
Conclusions
PCC dispensation in the appropriate dosage form at discharge effectively reduced cost, non-adherence to therapy, and risk of hospital readmissions. This neonatal clinical and compounding pharmacist-led model can be replicated in other resource-limiting setting.
