Loading Dose Of Caffeine Citrate Research Articles

The Efficacy and Safety of Once Daily versus Twice Daily Dosing of Caffeine Citrate in Apnea of prematurity: a Randomised Control Tria

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

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.

Caffeine Citrate for Apnea of Prematurity: A Prospective, Open-Label, Single-Arm Study in Chinese Neonates

Background: Caffeine citrate has been approved in China for the management of apnea of prematurity. This clinical trial was conducted as a condition of regulatory approval. The aim was to confirm the efficacy of caffeine citrate in the treatment of recurrent intermittent hypoxia and bradycardia in preterm newborns with primary apnea.Objectives: The primary outcome was the change from baseline in the number of apnea events after loading dose administration of caffeine citrate. Secondary efficacy outcomes included the change from baseline in apnea events after 2 and 4 weeks of maintenance doses.Methods: This was a multicenter, prospective longitudinal open-label, single-arm study. Neonates who had experienced at least four apnea events during a 24 h period received a loading dose of caffeine citrate 20 mg/kg; those who required additional maintenance doses received 5 mg/kg/day (titrated up to 10 mg/kg/day in case of insufficient response). The number of apnea events was recorded for 6–12 h prior to the loading dose (baseline), and for 12 h post-dose, following the loading dose and at Weeks 2 and 4 (during maintenance).Results: A total of 247 neonates received the loading dose, who had a significant reduction from baseline of 3.9 events (p < 0.001) in the mean number of apnea events. The subset of neonates who required maintenance doses also had significant reductions in the number of events at all visits (p < 0.001 for all). A total of 79.4% of participants had at least one adverse event, but only one non-serious and no serious events were considered related to treatment.Conclusions: In this large, prospective, open-label study, premature infants with a history of apnea who received caffeine citrate were significantly less likely to experience further apnea events.

Effects of Caffeine on Splanchnic Oxygenation in Preterm Infants

The aim of this study is to assess the effects of administering 20 mg/kg loading dose of caffeine citrate intravenously on splanchnic oxygenation in preterm infants. The infants with a gestational age (GA) of <34 weeks who were administered with a 20 mg/kg intravenous loading dose of caffeine citrate within 48 hours after birth were investigated prospectively. Regional splanchnic oxygen saturation (rsSO2) and splanchnic fractional tissue oxygen extraction rate (sFTOE) were measured using near-infrared spectroscopy before caffeine infusion, immediately after caffeine infusion and 1, 2, 3, 4, and 6 hours (h) after dose completion; postdose values were compared with predose values. A total of 41 infants with a mean GA of 29.2 ± 1.6 weeks and birth weight of 1,315 ± 257 g as well as postnatal age of 32.2 ± 10.8 hours were included in the study. rsSO2 significantly reduced from 63.1 to 57.5% immediately after caffeine infusion, 55.1% after 1 hour, and 55.2% after 2 hours with partial recovery at 3-hour postdose. sFTOE increased correspondingly. Caffeine reduces splanchnic oxygenation and increases splanchnic oxygen extraction for at least 2 hours with partial recovery to predose levels at 3-hour postdose.

Electrical activity of the diaphragm following a loading dose of caffeine citrate in ventilated preterm infants.

Administration of caffeine citrate can facilitate extubation. Our aim was to determine whether a loading dose of caffeine citrate given to ventilated, preterm infants affected the diaphragm electrical activity. Infants <34 weeks of gestational age were recruited if requiring mechanical ventilation and prescribed a loading dose of caffeine citrate. Surface electrodes recorded the electrical activity of the diaphragm (dEMG) before and after administration of intravenous caffeine citrate. The mean amplitude of the EMG (dEMG) trace and the mean area under the EMG curve (aEMGc) were calculated. Thirty-two infants were assessed with a median gestational age of 29 (27-31) weeks. The dEMG amplitude increased, peaking at 25 min post administration (p = 0.006), and the increase in aEMGc (p = 0.004) peaked at 30 min; the differences were not significant after 60 min. At 20 min, there was an increase in minute volume (p = 0.034) and a reduction in the peak inspiratory pressure (p = 0.049). We have demonstrated a transient increase in both electrical activity of the diaphragm and respiratory function following an intravenous loading dose of caffeine citrate.

Comparative Efficacy and Safety of Caffeine and Aminophylline for Apnea of Prematurity in Preterm (≤34 weeks) Neonates: A Randomized Controlled Trial.

To compare the efficacy and safety of standard doses of Caffeine and Aminophylline for Apnea of prematurity. Randomized controlled trial. Tertiary-care referral centre and a teaching institution in Southern India. Trial was conducted from February 2012 to January 2015. 240 preterm (≤34 wk) neonates with apnea of prematurity. Neonates randomized into two groups: Caffeine group received loading dose of caffeine citrate (20 mg/kg) followed by 5 mg/kg/day maintenance dose every 24 hour. Aminophylline group received loading dose of Aminophylline - 5 mg/kg and maintenance dose of 1.5 mg/kg 8-hourly. Difference in apneic spells, associated respiratory morbidity, and acute adverse events were assessed. Association of efficacy with therapeutic drug levels was also evaluated. Infants on aminophylline experienced less apnea spells in 4-7 days of therapy (P=0.03). Mean apnea rate and isolated desaturations were similar in 1-3, 4-7 and 8-14 days of therapy. No difference was noted in duration of Neonatal Intensive Care Unit stay and hospital stay. Mean heart rate was significantly high in Aminophylline group (P<0.001). Risk of developing tachycardia was less (RR 0.30; 95% CI range 0.15 to 0.60; P<0.001) in Caffeine- over Aminophylline-treated infants. Aminophylline is as effective as caffeine for prevention of apneic spells in preterm neonates; however, dosage optimization needs to be done to reduce toxicity.

A pilot randomized trial of high-dose caffeine therapy in preterm infants

BackgroundStandard-dose caffeine improves white matter microstructural development assessed by diffusion MRI. We hypothesized that early high-dose caffeine would result in further improvement in white matter microstructural development.MethodsSeventy-four preterm infants (≤30 weeks gestational age) were randomly assigned to either a high (80 mg/kg IV) or standard (20 mg/kg IV) loading dose of caffeine citrate in the first 24 hours of life. MRI and neurobehavioral testing were undertaken at term equivalent age. Infants returned at 2 years of age for developmental testing.ResultsClinical characteristics were similar between groups, with the exception of higher maternal age in the high-dose caffeine group. There was an increased incidence of cerebellar hemorrhage in infants randomized to high-dose caffeine (36% vs. 10%, p=0.03). Infants in the high-dose caffeine group also demonstrated more hypertonicity (p=0.02) and more deviant neurologic signs (p=0.04) at term equivalent age. Diffusion measures at term equivalent age and developmental outcomes at two years of age did not differ between groups.ConclusionsPreterm infants randomized to early high-dose caffeine had a higher incidence of cerebellar injury with subsequent alterations in early motor performance. The results of this pilot trial discourage a larger randomized controlled trial.

NPC-11 Phase III Trial Concerning Apnea of Prematurity in Japanese Neonates: A Study of Safety, Efficacy and Pharmacokinetics

Objective: To study the safety, efficacy, and pharmacokinetics of caffeine citrate in the treatment of apnea of prematurity in Japanese neonates. Study design: A non-blind, uncontrolled, multicenter, collaborative clinical trial. Setting: Three neonatal intensive care units in Japan Patient inclusion criteria: Neonates at the post conceptional age of 28 weeks to 33 weeks who were diagnosed with apnea of prematurity. Main outcome measures: 50% or greater reduction in apneic episodes, adverse effects, and pharmacokinetics. Method: Day 1 - Intravenous (IV) administration of caffeine citrate loading dose of 20 mg/kg, administered over 30 minutes. From day 2 onward - Commencement of administration of maintenance dose (caffeine citrate dose of 5 mg/kg) once daily intravenously over 10 minutes or orally. In the case that event incidence was reduced, the maintenance dose continued to be administered until day 10. If the doctor judged the initial maintenance dose to be ineffective, or its efficacy to be insufficient, the maintenance dose was raised to 10 mg/kg/day. Results: 23 patients fitting the specifications were found, and dosing was commenced. The reduction rate in apneic episodes during the trial was from 43.5% to 60.9%. Severe adverse effects were not noted. Mean serum concentration was maintained within the therapeutic range, between 11.87 and 18.82 mg/L. Data from clinical trials (Study OPR-001) in the United States, which were similar in methodology to this trial, were used when analyzing population pharmacokinetics. No difference due to race Conclusion: Caffeine citrate dosing for treatment of apnea of prematurity was effective, produced no safety problems, and showed good tolerability. Additionally, no differences between Japanese and Americans with regard to efficacy, safety and pharmacokinetics were observed Identifier of this clinical trial: NCT01408173

Evidence behind the WHO Guidelines: Hospital Care for Children: Is Caffeine Useful in the Prevention of Apnoea of Prematurity?

The World Health Organization has produced guidelines for the management of common illnesses in hospitals with limited resources. This series reviews the scientific evidence behind WHO’s recommendations. The WHO guidelines, and more reviews are available at http://www.ichrc.org. This review addresses the question: The WHO Pocketbook of Hospital Care for Children recommends caffeine citrate and aminophylline to prevent apnoea in premature babies, caffeine is preferred if it is available. The loading dose of caffeine citrate is 20mg/kg orally or i.v., a maintenance dose should be prescribed. If an apnoea monitor is available, this should be used.

Low‐dose doxapram for treatment of apnoea following early weaning in very low birthweight infants: a randomized, double‐blind study

The effects of low‐dose doxapram (0.5 mg kg−1 h−1) in combination with caffeine were evaluated on apnoea frequency following weaning from mechanical ventilation, and on blood pressure, in very low birthweight (BW) premature infants. Twenty‐nine infants with BW &lt;1250 g, gestational age at birth (GA) &lt;34 weeks and postnatal age &lt;5 d, who required minimal respiratory support, were included. Following randomization, they received a loading dose of caffeine citrate and a continuous infusion of doxapram (doxapram, n= 14) or placebo (n= 15) was started. They were extubated 8 h after starting the infusion, which was continued for 5 d. During this period, weaning was well tolerated in both groups, apnoeas occurred less frequently and there was a greater increase in systolic blood pressure in infants treated with doxapram than in controls. Plasma doxapram levels were also higher than expected. It is therefore suggested that doxapram, even at low doses, should not be used during the first few days of life. Careful monitoring of blood pressure is required if doxapram is used later.

Effect of Caffeine on Cerebral Blood Flow Velocity in Preterm Infants

A continuous-wave form Doppler monitor was used to examine the effect of caffeine on cerebral blood flow velocity (CBFV) in 7 clinically stable preterm neonates suffering from apnea. Caffeine, in the form of caffeine citrate, or saline were given intravenously at loading doses of 20 mg/kg. Every subject was his own control. Placebo (saline) was systematically injected prior to caffeine citrate. Simultaneous recording of heart rate, arterial blood pressure, respiratory rate, TcPO2, TcPCO2 were made before, then at the end of the injection, and 30, 60 and 120 min after the end of each administration of either placebo or caffeine. Compared with placebo, caffeine injection was not associated with significant changes in CBFV. An increase was found in both heart-rate and respiratory rate (p less than 0.05). Mean arterial blood pressure, TcPCO2 and TcPO2 did not change significantly. Our data suggest that a caffeine citrate loading dose of 20 mg/kg as currently used at the beginning of treatment of apnea in preterm neonates has no effect on CBFV.