Neonatal Intensive Care Drug Manual

1. 
   Treatment of apnoea of prematurity.
   
2. 
   Weaning from mechanical ventilation.
   
3. 
   Prevention of post-operative apnoea.
   

Caffeine citrate oral 25 mg/5 mL solution

Caffeine base

Oral

Caffeine citrate

Draw up 1 mL (20 mg) of caffeine citrate and add 4 mL sodium chloride 0.9% or glucose 5% to make a final volume of 5 mL with a concentration of 4 mg/mL.

Caffeine base

Draw up 2 mL caffeine base (20 mg) and add 8 mL sodium chloride 0.9% or glucose 5% to make a final volume of 10 mL with a concentration of 2 mg/mL.

ORAL: Solution may be administered without regard to feeds, however consider giving with feeds to reduce gastric irritation.

Consider withholding dose if HR > 180 bpm.

Cardiorespiratory monitoring should continue for at least 5-7 days after the cessation of

caffeine treatment for apnoea.

Therapeutic drug monitoring is usually not necessary. [2] Trough concentrations may be

taken one hour before the next dose is due but should only be done if using high doses or

toxicity is suspected. Monitoring of serum drug concentration should be determined on

approximately day 5 of therapy.

Standard caffeine dosing of a 20 mg/kg load followed by 5 mg/kg once daily results in serum

concentrations of 5–20 mg/L (26-103 micromol/L).

Supratherapeutic levels 20-60 mg/L (103 – 308 micromol/L) offer potential increased effect.

Levels >60 mg/L (>308 micromol/L) are considered the toxic range. [3]

Y-site: Dopamine, fentanyl, heparin, amino acid solutions and fat emulsions.

Y-site: Aciclovir, frusemide, glyceryl trinitrate and ibuprofen lysine.

Time to peak serum concentration: Within 30 minutes to 2 hours in oral administration.

Caffeine may not reach subtherapeutic levels until 11 to 12 days post cessation [6].

In a subgroup analysis of the CAP 2016 trial [7], use of caffeine citrate (20mg/kg loading dose followed by 5 mg/kg maintenance) versus placebo for extubation of preterm infants born 500 to 1250g found a reduction in PDA ligation (717 infants; RR 0.32 [95%CI 0.20, 0.52]), PMA at last oxygen therapy (666 infants; MD -1.5 [-2.25, -0.75] days), PMA at last endotracheal tube (668 infants; MD -0.90 [-1.42, -0.38] weeks), PMA at last positive pressure ventilation (667 infants; MD -1.10 [-1.64, -0.56] weeks) and bronchopulmonary dysplasia at term age (672 infants; RR 0.81 [0.70, 0.93]). Caffeine was associated with a reduction cerebral palsy (644 infants; RR 0.54 [0.32, 0.92]) and death or major disability by 18-21 months (676 infants; RR 0.85 [0.73, 0.99]) [8]. At age 11 years the caffeine-treated children had better respiratory function and reduced risk of motor impairment [9].

Prevention of apnea in preterm infants

In two trials including 104 preterm infants comparing caffeine versus placebo for prevention of apnea reported no significant difference in apnoea, bradycardia, hypoxaemic episodes, use of IPPV or side effects. Meta-analysis found no significant difference in use of IPPV or tachycardia. [10] In a subgroup analysis of the CAP 2006 trial [7], infants treated with prophylactic caffeine had a reduction in PDA (453 infants; RR 0.41, 95%CI 0.20, 0.84) and PMA at last positive pressure ventilation (432 infants; MD -1.00, 95%CI -1.62, -0.38 weeks]. There was no reported difference in PMA at last oxygen therapy, PMA at last endotracheal tube, bronchopulmonary dysplasia (437 infants; RR 0.83, 95%CI 0.67, 1.05), cognitive delay (396 infants; RR 1.08, 95%CI 0.83, 1.40), cerebral palsy (415 infants; RR 1.03, 95%CI 0.43, 2.49) or death or major disability (423 infants; RR 1.00, 95%CI 0.80, 1.24).

Higher versus lower dosage caffeine

Several systematic reviews [1, 11, 12] have assessed the effects of higher (loading dose >20 mg/kg and maintenance >10 mg/kg/day) versus lower dose caffeine citrate in preterm infants. Loading and maintenance caffeine citrate doses varied in trials between 20 and 80 mg/kg/day and 3 and 20 mg/kg/day, respectively.[1] In the largest review, 13 RCTs reporting

1515 infants compared low-dose 5-10 mg/kg daily versus high-dose group (10-20 mg/kg daily) caffeine citrate. The high-dose group had a lower extubation failure rate (RR: 0.5, 95%CI: 0.35 to 0.71, P=0.0001), frequency of apnea (MD: -1.55, 95%CI: -2.72 to -0.39, P=0.009), apnea duration (MD: -4.85, 95%CI: -8.29 to -1.40, P=0.006), and incidence of bronchopulmonary dysplasia (RR: 0.79, 95%CI: 0.68 to 0.91, P=0.002), but higher incidence of tachycardia (RR: 2.02, 5%CI: 1.30 to 3.12, P=0.002). There were no significant group differences in other adverse events including in-hospital death (P>0.05). [12] Higher maintenance doses of caffeine citrate was more effective and safer than low maintenance

doses for treatment of premature apnea, despite a higher incidence of tachycardia. [LOE I GOR C]

Prevention of post-operative apnoea.

Prophylactic caffeine for prevention of postoperative apnea following general anaesthesia in preterm infants reduced postoperative apnoea/bradycardia (3 trials, 78 infants; RR 0.09 [0.02, 0.34] and postoperative oxygen desaturations (2 trials, 58 infants; RR 0.13 [0.03, 0.63].[13] Caffeine can be used to prevent postoperative apnea/bradycardia and episodes of oxygen desaturation in preterm infants at risk [14] undergoing general anaesthesia for

surgery. [LOE I GOR B]

Safety

incidence of tachycardia (RR: 2.02, 5%CI: 1.30 to 3.12, P=0.002) [12]. Despite the increased incidence of tachycardia, growth was not adversely affected in infants in the CAP trial assessed at 18 to 24 months [8]. A trial of caffeine versus aminophylline reported similar growth parameters at 18 to 24 months [19]. Although higher maintenance doses of up to 20 mg/kg/day may be even more effective] [11], it is recommended [20] this needs further testing in randomised trials as higher doses (80 mg/kg loading dose) were reported in a clinical trial to be associated with increased risk of cerebellar haemorrhage, hypertonicity and possibly seizure burden [21, 22], a concern not completely addressed by the reporting of a retrospective cohort which did not find an association [23, 24].

Pharmacokinetics and pharmacodynamics

Caffeine has a long elimination half-life in preterm infants of 72–96 hours (range 40–230 hours) [4, 5], necessitating a loading dose to rapidly achieve therapeutic concentrations and allowing for once-daily dosing. In contrast, the half-life of caffeine in adults is 4–5 hours. Caffeine is metabolized in the liver by cytochrome P450 1A2 before rapid renal elimination of metabolites. This pathway is limited in preterm infants because of immaturity of hepatic enzyme system, therefore, most of a caffeine dose is eliminated unchanged in infancy, with 86 percent of the dose excreted in the urine at a slow rate. In contrast, only 1 percent of a caffeine dose is excreted unchanged by the kidneys in adults. The time to peak concentration from an oral dose is 30 minutes to two hours. The volume of distribution in infants is 0.8–0.9

L/kg.[3, 5] Loading doses of caffeine citrate produce relatively predictable serum concentrations. Caffeine citrate is 50 percent caffeine base; therefore, a loading dose of caffeine citrate 20 mg/kg produces a serum concentration of approximately 10 mg/L. Loading doses ranging from 6 to 60 mg/kg with daily maintenance doses ranging from 3 to

30 mg/kg examined in clinical trials and resulted in serum levels ranging from 6.7 to 59.9 mg/L. Standard caffeine dosing of a 20 mg/kg load followed by 5 mg/kg once daily results in serum concentrations of 5–20 mg/L. Supratherapeutic levels 20-60 mg/L offer potential increased therapeutic effect, whereas levels >60 mg/L are considered the toxic range.[3] Following cessation of caffeine at a mean postmenstrual age of 35 weeks, caffeine levels decreased from 13.3 ± 3.8 to 4.3 ± 2 mg/L (n = 50) at 24 and 168 hours respectively (P<0.01). The mean caffeine half-life was 87 ± 25 hours. Seven days after discontinuation of caffeine, 64% of the infants had pathologic apnea. Caffeine may not reach subtherapeutic levels until 11–12 days post cessation [6].

Caffeine should be used to facilitate weaning from MV (High quality; Strong recommendation for using intervention). Early caffeine should be considered for babies at high risk of needing MV such as those on non-invasive respiratory support (Low qualityStrong recommendation for using intervention). [20]