Archives ofDisease in Childhood 1992; 67: 425-428 425 Arch Dis Child: first published as 10.1136/adc.67.4_Spec_No.425 on 1 April 1992. Downloaded from Caffeine or theophylline for neonatal apnoea? J E M Scanlon, K C Chin, M E I Morgan, G M Durbin, K A Hale, S S Brown Abstract a higher dose of caffeine than that previously Caffeine, in the dose usualiy recommended recommended was required to treat effectively (12-5 mg/kg loading dose and 3 mg/kg daily infants of lower gestational age. This study was maintenance), and a higher dose regimen (25 therefore designed to compare the efficacy of mg/kg loading and 6 mg/kg daily maintenance), theophylline with that of caffeine administered was compared with theophylline (7.5 mg/kg in two different dose regimens to a group of loading and 3 mg/kg thrice daily maintenance). very preterm infants with frequent and clinically The study was a randomised controiled trial significant apnoeic attacks. in the treatment of a group of44 infants of less than 31 weeks' gestation (mean gestational age 28.3 weeks) who were suffering from Patients and methods frequent apnoeic attacks. AU three regimens PATIENT SELECTION produced a significant reduction in apnoeic Infants were included in our study if they were attacks within 24 hours, but only the higher less than 31 weeks' gestation at birth and if they dose caffeine and theophyfline groups showed had either 10 (or more) apnoeic attacks in eight a significant improvement in apnoea within hours or four apnoeas in one hour. Apnoea was eight hours. defined as a drop in heart rate of more than 40 The use of caffeine for the treatment of beats/minute (bpm) below the resting heart rate neonatal apnoea is recommended, because a in an infant who was not breathing, and who once daily dose is more easily administered, required stimulation to correct the problem. and because it was found that plasma concen- Infants prospectively entering the trial were trations were more predictable than those of randomly allocated (by random numbers in theophylline. If used in very preterm infants, sealed envelopes) to one of three treatment however, its is suggested that a higher dose groups. Group A ('standard dose caffeine')-a regimen than that previously recommended loading dose of 25 mg/kg caffeine citrate (12-5 be used to achieve a faster response. mg/kg caffeine) and a maintenance dose of 6 mg/kg caffeine citrate (3 mg/kg caffeine) once daily were given to produce a desired plasma http://adc.bmj.com/ Neonatal apnoea is a common problem: it concentration of 15 mg/l caffeine (range 13-20 occurs in 25% of infants under 2500 g and 80% mg/l). Group B ('higher dose caffeine')-a of infants under 1000 g.1 2 With smaller babies loading dose of 50 mg/kg caffeine citrate now forming a large percentage ofthe population (25 mg/kg caffeine) and maintenance dose of of neonatal intensive care units, the manage- 12 mg/kg (6 mg/kg caffeine) once daily were ment of neonatal apnoea is an important part of given to produce a desired plasma concentration the clinical workload. of 30 mg/l (range 26-40 mg/l). Group C ('theo- on September 26, 2021 by guest. Protected copyright. The methylxanthines-theophylline (and phylline')-a loading dose of 7.5 mg/kg theo- aminophylline) and caffeine-are widely used phylline and a maintenance dose of 3 mg/kg for the treatment of this condition.3 Theophyl- theophylline three times daily were given to to concentration of Regional Neonatal line has been the drug most commonly used produce a desired plasma Intensive Care Unit, treat neonatal apnoea in the UK.4 5 Caffeine, 15 mg/l (range 13-20 mg/l). Birmingham Maternity however, has many potential advantages: it has In all three treatment groups the maintenance Hospital, Institute of a therapeutic ratio, it is absorbed more dose of the drug was adjusted if the plasma Child Health, higher Birmingham reliably when administered enterally and has a concentrations were out of the desired range, J E M Scanlon longer half life, thus enabling the drug to be but in none of these patients were such adjust- K C Chin administered only once daily.6 Caffeine has also ments made within 48 hours of starting treat- M E I Morgan G M Durbin been shown to be effective in apnoeic infants ment. As theophylline is metabolised into the cumu- Regional Laboratory who are unresponsive to theophylline.7 caffeine in the premature infant," for Toxicology, Comparisons of the two drugs have been lated caffeine plus theophylline concentrations Dudley Road Hospital, reported before,"'0 but these studies have in this group were kept below 25 mg/l. Birmingham K A Hale either included a high proportion of more S S Brown mature infants (of 31 or 32 weeks' gestation), or DRUGS Correspondence to: excluded oxygen dependent infants included Dr J E M Scanlon, infants with as few as three apnoeas per day. The drugs were usually given orally or via a Department of Paediatrics, Southampton General They therefore failed to reflect the day to day nasogastric tube. The preparations used for oral Hospital, Tremona Road, problems in most neonatal intensive care units administration were caffeine citrate in chloro- Southampton S09 4XY. in their management of very preterm infants form water (20 mg caffeine citrate/ml) and Accepted 13 December 1991 with apnoeic attacks. theophylline hydrate in 90% alcohol diluted No reprints available. In a pilot study we formed an impression that with water (3 mg theophylline/ml). Although 426 Scanlon, Chin, Morgan, Durbin, Hale, Brown these are the preparations that we are still using, chromatography on 100 tl of plasma (minimum Arch Dis Child: first published as 10.1136/adc.67.4_Spec_No.425 on 1 April 1992. Downloaded from recent work has shown that the preservatives in 50 ,ul plasma). these mixtures (that is, chloroform water and 90% alcohol) are not essential, and that caffeine and theophylline are pharmacologically stable STATISTICS and microbiologically safe for a period of one Statistical analysis of results was performed week having been made up in purified water using Fisher's exact test and Student's paired and stored in a refrigerator (Tina Crook, Royal t test as appropriate. Berkshire Hospital, pharmacy department- This project was approved by the ethical personal communication). committee of Central Birmingham Health When using the 'higher dose caffeine' regi- Authority. men the loading dose was administered in two separate doses of 25 mg/kg caffeine citrate given orally one hour apart, in order to avoid the Results possibility of the infant vomiting because of the Over a two year period 44 infants were entered volume load. into the study. Of the 44 infants, 32 (73%) had Caffeine citrate 0-99% (caffeine citrate 10 previously been ventilated and 43 (98%) were mg/ml)-both loading dose and maintenance still oxygen dependent at the time of entry to doses infused daily over half an hour-and the study. Twenty six infants (59%) were boys aminophylline injection (aminophylline 25 and 37 (84%) were white. mg/ml)-administered as a continuous in- Although every attempt was made to exclude fusion-were available as alternatives to oral or other causes of apnoea, eight infants were nasogastric treatment in our trial. None of the subsequently found to have other problems and infants in group B (higher dose caffeine) or it became clear that their apnoeic attacks were group C (theophylline) received intravenous secondary to these other diagnoses: four infants treatment. Only two infants in group A (stan- had proven infection (pneumonia and septi- dard dose caffeine)receivedintravenous caffeine, caemia with positive blood cultures), two and neither their clinical response nor the infants had significant neurological abnormality plasma concentrations of caffeine different (bilateral periventricular leucomalacia with appreciably from the other infants in that subsequent abnormal neurological development) group. We have treated large numbers of other and two had severe oesophageal reflux (as infants with both caffeine citrate and amino- demonstrated by an intraoesophageal pH phylline administered intravenously, and have probe. 12 observed no differences, clinically or with Table 1 shows the characteristics of the plasma concentrations, related to route of infants in the trial. There were no significant administration. differences between the groups in weight, gesta- tional age, or postnatal age and the sex distribu- tion of the infants within the groups showed an MEASUREMENTS OF PLASMA CONCENTRATIONS OF approximately equal male to female ratio. THE DRUGS http://adc.bmj.com/ Blood samples for measurement of drug concen- trations were obtained at the same time as blood RESPONSE TO TREATMENT sampling for other routine tests: all were The number of apnoeas (over a 24 hour period) heparinised capillary samples taken from the decreased dramatically over two days from the heel. They were obtained daily for five days, start of treatment in all three groups, but was starting the day after the loading dose, and most significant in the high dose caffeine and twice during the course of the next week. theophylline groups. on September 26, 2021 by guest. Protected copyright. Plasma theophylline and caffeine concentrations As can be seen in table 2, which includes the were determined by high performance liquid results from all infants entered, the number of apnoeas/day was reduced by a third within 24 hours by treatment with standard dose Table I Characteristics of infants entering the trial (n=44). Weight and age figures are caffeine. It was, however, reduced by over 50% mean (SD) by the higher dose caffeine and theophylline No of Birth weight Gestational Postnatal M:F treatments within the same time period.