Caffeine for preterm infants: Fixed standard dose, adjustments for age or high dose?

Saroha, Vivek; Patel, Ravi

doi:10.1016/j.siny.2020.101178

Cited by 27 publications

(25 citation statements)

References 42 publications

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“…While both doses of Caf reduced hemorrhage burden, Caf 20 mg/kg/day had a more robust effect. At this point, it should be taken into consideration that the doses used in this study (10 and 20 mg/kg/day) are in the range of previous studies using Caf in other models showing beneficial effects (Kaindl et al, 2008;Fan et al, 2011), but high-dose Caf treatment might have a negative impact on brain development and associated complications and therefore, Caf effects might entirely depend on the actual dose and pathologies under study (McPherson et al, 2015;Vesoulis et al, 2016;Saroha and Patel, 2020;Soontarapornchai et al, 2021). Importantly, Caf might not only have a positive effect in limiting the pathological complications associated, but it may also reduce the incidence of GM-IVH itself, when administered early to patients at risk (Borszewska-Kornacka et al, 2017;Helwich et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Caffeine Restores Neuronal Damage and Inflammatory Response in a Model of Intraventricular Hemorrhage of the Preterm Newborn

Alves-Martínez

Atienza-Navarro

Vargas-Soria

et al. 2022

Front. Cell Dev. Biol.

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Germinal matrix-intraventricular hemorrhage (GM-IVH) is the most frequent intracranial hemorrhage in the preterm infant (PT). Long-term GM-IVH-associated sequelae include cerebral palsy, sensory and motor impairment, learning disabilities, or neuropsychiatric disorders. The societal and health burden associated with GM-IVH is worsened by the fact that there is no successful treatment to limit or reduce brain damage and neurodevelopment disabilities. Caffeine (Caf) is a methylxanthine that binds to adenosine receptors, regularly used to treat the apnea of prematurity. While previous studies support the beneficial effects at the brain level of Caf in PT, there are no studies that specifically focus on the role of Caf in GM-IVH. Therefore, to further understand the role of Caf in GM-IVH, we have analyzed two doses of Caf (10 and 20 mg/kg) in a murine model of the disease. We have analyzed the short (P14) and long (P70) effects of the treatment on brain atrophy and neuron wellbeing, including density, curvature, and phospho-tau/total tau ratio. We have analyzed proliferation and neurogenesis, as well as microglia and hemorrhage burdens. We have also assessed the long-term effects of Caf treatment at cognitive level. To induce GM-IVH, we have administered intraventricular collagenase to P7 CD1 mice and have analyzed these animals in the short (P14) and long (P70) term. Caf showed a general neuroprotective effect in our model of GM-IVH of the PT. In our study, Caf administration diminishes brain atrophy and ventricle enlargement. Likewise, Caf limits neuronal damage, including neurite curvature and tau phosphorylation. It also contributes to maintaining neurogenesis in the subventricular zone, a neurogenic niche that is severely affected after GM-IVH. Furthermore, Caf ameliorates small vessel bleeding and inflammation in both the cortex and the subventricular zone. Observed mitigation of brain pathological features commonly associated with GM-IVH also results in a significant improvement of learning and memory abilities in the long term. Altogether, our data support the promising effects of Caf to reduce central nervous system complications associated with GM-IVH.

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Section: Discussionmentioning

confidence: 99%

Caffeine Restores Neuronal Damage and Inflammatory Response in a Model of Intraventricular Hemorrhage of the Preterm Newborn

Alves-Martínez

Atienza-Navarro

Vargas-Soria

et al. 2022

Front. Cell Dev. Biol.

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“…However, the recommended caffeine dosage does not vary with maturity as in other drugs in neonatology; only some pharmaceutical guide changes the dosage schedule in the more mature infants. Even in studies with mathematical pharmacokinetic simulation models, they suggest increasing the dose of caffeine at a rate of 1 mg / kg each week of life to maintain the levels in range, despite not being carried out in routine clinical practice [18,19]. We should also take into account the pharmacogenetics already described and the unknown information [20] about relevant polymorphisms for this drug related to clinical effects in the individualized prescription in neonates with immature metabolism of drugs, despite its renal elimination.…”

Section: Discussionmentioning

confidence: 99%

The Usefulness of Saliva in Therapeutic Drug Monitoring of Caffeine in Preterm Infants.

García-Robles

Solaz-García

Verdú‐Andrés

et al. 2021

Preprint

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Aim To verify if the concentrations of caffeine in saliva are comparable to the serum concentrations in preterm infants treated with caffeine for apnoea of prematurity. Methods Prospective observational study. Eligible patients were newborn infants < 37 weeks of gestational age treated with oral or intravenous caffeine for apnoea of prematurity. Two paired samples of saliva-blood were collected per patient. Tube solid phase microextraction coupled on-line to capillary liquid chromatography with diode array detection were used for analysis. Results A total of 47 newborns with a median gestational age 28 [26–30] weeks and mean of 1.11 ± 0.4 kg of birth weight. Median postmenstrual age, when samples were collected, was 31 [29–33] weeks. Serum caffeine median levels of 19.30 µg/mL [1.9–53.90]and salivary caffeine median levels of 16.36 µg/mL [2.20–56.90] were obtained. There was a strong positive Pearson’s correlation between the two variables r = 0.83 (p < 0.001). Conclusion The measurement of caffeine salivary concentrations after intravenous or oral administration offers an alternative to serum caffeine monitoring in apnoea of prematurity.

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“…Most importantly, failure in execution, as this step involves accurate patient/attendant performance of medication use according to the recommendations including right dose [20,21]. The chance of over and under medication was very high, which is the primary concern with caffeine therapy in neonates due to the high potential of adverse effects and failure to achieve desired results, respectively [8,22] Drug wastage and the high cost of the ampoule are other challenges and contributing factors to non-adherence to therapy and readmissions. The high cost of therapy per day (about Rs.2000 = 15USD/day) for the median 48 days (range 35-63days) is a significant economic burden on the family and possibly third parties that pay such as corporate groups and local health insurance companies.…”

Section: Challenges In the Usage Of Caffeine-our Local Experiencementioning

confidence: 99%

Evaluation of pharmaceutically compounded oral caffeine on the impact of medication adherence and risk of readmission among preterm neonates: A single-center quasi-experimental study

et al. 2022

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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.

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Caffeine for preterm infants: Fixed standard dose, adjustments for age or high dose?

Cited by 27 publications

References 42 publications

Caffeine Restores Neuronal Damage and Inflammatory Response in a Model of Intraventricular Hemorrhage of the Preterm Newborn

Caffeine Restores Neuronal Damage and Inflammatory Response in a Model of Intraventricular Hemorrhage of the Preterm Newborn

The Usefulness of Saliva in Therapeutic Drug Monitoring of Caffeine in Preterm Infants.

Evaluation of pharmaceutically compounded oral caffeine on the impact of medication adherence and risk of readmission among preterm neonates: A single-center quasi-experimental study

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