- Email: [email protected]
Controversies surrounding xanthine therapy
Seminars in Neonatology (2004) 9, 239e244
www.elsevierhealth.com/journals/siny
Controversies surrounding xanthine therapy David Millara, Barbara Schmidta, b,) a
Department of Paediatrics, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5 b Department of Clinical Epidemiology & Biostatistics, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada
KEYWORDS Methylxanthines; Apnoea of prematurity; Adenosine
Summary The methylxanthines aminophylline, theophylline and caffeine have been used for more than 30 years to treat apnoea of prematurity. Today, they are among the most commonly prescribed drugs in neonatal medicine. Methylxanthines reduce the frequency of idiopathic apnoea and the need for mechanical ventilation by acting as non-specific inhibitors of adenosine A1 and A2a receptors. However, recent and rapidly growing research into the actions of adenosine and its receptors raises concerns about the safety of methylxanthine therapy in very preterm infants. Possible adverse effects include impaired growth, lack of neuroprotection during acute hypoxiceischaemic episodes and abnormal behaviour. An international controlled clinical trial is underway to examine the long-term efficacy and safety of methylxanthine therapy in very low birth weight babies. ª 2003 Elsevier Ltd. All rights reserved.
Introduction ‘Caffeine is the only addictive psychoactive substance that has overcome resistance and disapproval around the world to the extent that it is freely available almost everywhere, unregulated, sold without licence, offered over the counter in tablet and capsule form, and even added to beverages intended for children’.1 The methylxanthines aminophylline, theophylline and caffeine are non-specific inhibitors of adenosine receptors.2 Adenosine is present in all tissues.2 In the neonatal medulla oblongata, aden) Corresponding author. Tel.: D1-905-521-2100x73243; fax: D1-905-521-5007. E-mail address: [email protected] (B. Schmidt).
osine depresses respiratory neuronal activity which is reversed by theophylline.3 Adenosine may also decrease respiration indirectly by reducing oxygen consumption.4 The methylxanthines increase oxygen consumption in the preterm infant.5e8 Theophylline and caffeine were used empirically to treat apnoea of prematurity long before the importance of adenosine as a modulator of neonatal respiratory activity had been discovered.9,10 Today, methylxanthines are among the most commonly prescribed drugs in neonatal medicine.11e13 However, extensive and ongoing research into the actions of adenosine and its receptors has raised concern about the safety of non-specific adenosine receptor blockade in very preterm infants. In this review, we will present evidence that prompts questions about the possible harmful effects of neonatal xanthine therapy on growth, neurological development and childhood behaviour.
1084-2756/$ - see front matter ª 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2003.11.008
240
Does xanthine therapy affect growth? ‘.caffeine adds additional efficacy to ephedrine in promoting weight loss.’14 Over 20 years ago, aminophylline and theophylline were shown to increase oxygen consumption in preterm infants by 20e25% when measured 24e48 h after the start of treatment for idiopathic apnoea.5,6 More recently, Carnielli et al.7 reported that a single loading dose of theophylline (5 mg/kg) increased energy expenditure by 15 kJ/kg/day. Similarly, Bauer et al. observed that oxygen consumption increased after 48 h of caffeine treatment for apnoea of prematurity.8 Moreover, compared with matched control infants, oxygen consumption remained elevated throughout a 4 week treatment period.8 Caffeine treatment was also associated with lower incubator temperatures to maintain a normal body temperature and with reduced weight gain. These findings have to be interpreted with caution, because caffeine was not randomly allocated to infants in the study. In adults, however, caffeine has been shown to promote weight loss.14 In summary, data obtained by four different groups of investigators suggest that methylxanthine therapy for apnoea of prematurity increases oxygen consumption, which may diminish growth. We could find only one study contradicting this conclusion.15
Does xanthine therapy affect neurological development? ‘.during exposure of the epaulette shark to anoxia, adenosine receptor activation had a pre-emptive role in maintaining brain ATP levels during oxidative stress in this anoxia tolerant shark.’ ‘Aminophylline-treated hypoxic epaulette sharks. had significantly lower brain ATP levels.’16 The role of adenosine as a neuromodulator under physiological and pathophysiological conditions is an area of intense investigation. A recent Pubmed search using the terms ‘adenosine’ and ‘receptor’ and ‘brain’ retrieved 3482 citations. We will highlight some of the current controversies in this field of research, but it is not our intention to review this rapidly expanding body of scientific literature systematically and comprehensively. Under physiological conditions, low levels of adenosine in the extracellular fluid of the brain activate adenosine A1 and A2a receptors.2 Both receptors
D. Millar, B. Schmidt are inhibited by methylxanthines.2 The other two known receptors, A2b and A3, have a substantially lower affinity for adenosine and are not probable targets for methylxanthines.2 Extracellular concentrations of adenosine in the brain increase when energy demand outstrips energy supply. Situations that cause such an imbalance between ATP synthesis and ATP breakdown include seizures, hypoxia, ischaemia and hypoglycaemia.17 Adenosine is involved in the regulation of sleep and arousal, susceptibility to seizures and analgesia.17 Adenosine has also been reported to mediate the effects of alcohol and opiates.17 Finally and importantly, adenosine has neuroprotective actions in a variety of experimental models of cerebral ischaemia.16,17 When paediatricians prescribe methylxanthines for apnoea of prematurity, they prescribe nonspecific adenosine receptor antagonists. What is known about the effects of methylxanthines in both the immature and mature brain? In 1978, Thurston and colleagues reported that aminophylline increased the cerebral metabolic rate and decreased anoxic survival in weanling mice.18 They advised caution in the use of methylxanthines in hypoxic human newborns.18 More recently, Kang et al. observed that caffeine caused neuronal death in the neonatal rat brain.19 In contrast, Bona et al. found that theophylline reduced rather than increased brain injury after hypoxiaeischaemia in 7-day old rats.20 In adult gerbils, pre-treatment with theophylline increased neuronal and vascular degeneration following carotid occlusion.21 Efforts to manipulate adenosine receptors in neonatal and adult animal models of hypoxice ischaemic brain injury with specific agonists and antagonists for the adenosine A1 and A2a receptors have yielded complex and occasionally contradictory results. Fig. 1 shows that acute inhibition of the adenosine A1 receptor increases hypoxice ischaemic brain injury while inhibition of the A2a receptor decreases brain injury, at least in mature animals. The functions of these two adenosine receptors have also been studied in A1 and A2a knockout mice. Because A1 and A2a receptors are both inhibited by methylxanthines, experiments in animals with targeted disruption of either the A1 or A2a receptor gene may shed some light on the possible effects of xanthine-induced adenosine receptor inhibition. Fig. 1 shows that deficiency of adenosine A1 and A2a receptors may lead to different responses in neonatal and adult animals. For example, 7-day old A2a knockout mice suffered more brain damage after cerebral hypoxic-ischaemia than wild-type mice.33 In contrast, adult A2a knockout mice appeared to be protected from
Controversies surrounding xanthine therapy
241 Decreased brain injury (Ref.22) No effect on brain injury (Ref.23)
Neonatal
Rat
Adult
Gerbil
Neonatal
Rat
No effect on brain injury (Ref.20)
Rat
Increased brain injury (Ref.26)
A1 Activation
A1 Inhibition
Decreased mortality (Refs.24,25) Decreased brain injury (Refs.24,25)
Adult Increased mortality (Ref.24) Increased brain injury (Refs.24,27)
Gerbil
Neonatal
No data
A1 Knockout Adult
Neonatal
Increased brain injury (Ref.28)
Mouse
No data
A2a Activation Adult
Gerbil
Decreased mortality (Ref.29) No effect on brain injury (Ref.29)
Neonatal
Rat
Decreased brain injury (Ref.20)
Rat
Decreased brain injury (Refs.30,31)
A2a Inhibition Adult
A2a Knockout
Gerbil
Decreased brain injury (Refs.27,29,32) No effect on mortality (Ref.29)
Neonatal
Mouse
Increased brain injury (Ref.33)
Adult
Mouse
Decreased brain injury (Ref.34)
Figure 1 Synopsis of the effects of experimental adenosine A1 and A2a receptor activation and inhibition in immature and mature animals on their ability to withstand an acute hypoxiceischaemic insult to the brain (Refs.20,22e34).
brain injury.34 However, Fig. 1 highlights some important gaps and also some contradictions in the existing knowledge about this complex receptor system. Furthermore, there is evidence that chronic administration of adenosine receptor ligands has different effects on hypoxiceischaemic brain injury than acute ligand administration.24 Methylxanthines are given to preterm infants both acutely (loading dose) and chronically, often for many weeks. This makes the effects of drug-induced blockade of adenosine receptors in the immature
brain even less predictable. Of note, chronic exposure of rat pups to a low dose of caffeine before a hypoxiceischaemic brain insult reduced brain damage, although high-dose caffeine did not.35 Finally, adenosine appears to influence the developing nervous system.36 Adenosine A1 receptors are among the earliest receptors found in the embryonic brain.36 During intrauterine stress, adenosine levels increase. The resulting activation of adenosine A1 receptors may impair nerve growth and cause periventricular leucomalacia.36 Turner et al. treated neonatal rats with an A1 adenosine
242 receptor agonist. Chronic activation of the A1 adenosine receptor inhibited the development of axons and produced white matter loss.37 In summary, the physiological and pathophysiological roles of the adenosine receptor system in the immature brain are complex and, as yet, incompletely understood. Therefore, one cannot, at present, predict the in vivo effects of non-specific adenosine receptor blockade with methylxanthine therapy, either during times of oxygen sufficiency or during the brief hypoxiceischaemic episodes that are so common in very preterm infants.
Does xanthine therapy affect behaviour? Mice lacking the adenosine A2a receptor ‘scored higher in anxiety tests, and male mice were much more aggressive towards intruders’.38 Similarly ‘mice lacking the adenosine A1 receptor are anxious and aggressive’.39 Children who were born preterm have an increased incidence of externalizing and internalizing behaviours.40 Externalizing behaviours include anger and aggression, while internalizing behaviours include fears and anxiety. A large number of preterm infants have been exposed to methylxanthines in an uncontrolled fashion over the past 20 years. Is it possible that neonatal xanthine therapy contributes to the behavioural problems of ex-preterm children? Several experimental observations suggest that this is not an unreasonable question. Firstly, limited neonatal exposure of rats to doses of caffeine that were similar to those used to treat idiopathic apnoea either increased or decreased the expression of A1 adenosine receptor, depending on the region of the rat brain that was examined.41 In contrast, much lower doses of caffeine, which mimicked the exposure of the foetus and newborn to maternal caffeine intake via the placenta or breast milk, had little effect on the ontogeny of the adenosine receptor system in the rat brain.42 Secondly, recent and intriguing laboratory studies have clearly established a link between the adenosine receptor system and behaviour. Mice lacking either the A1 or the A2a adenosine receptor are more anxious and aggressive than wild-type animals.28,38,39,43 Therefore, if xanthine therapy for idiopathic apnoea does indeed alter permanently the expression of adenosine receptors in the developing brain, this may have adverse consequences for later behaviour in childhood. In summary, the methylxanthines inhibit two adenosine receptors that have been convincingly
D. Millar, B. Schmidt linked to anxious and aggressive behaviour in mice with targeted deficiencies of each of these receptors. The relevance of this recent finding to the safety of xanthine therapy for apnoea of prematurity is presently unknown.
Evidence from neonatal randomized clinical trials Randomized trials of xanthine therapy in preterm infants have been surprisingly small and focused solely on very short-term benefits.44 Methylxanthines reduce the number of apnoeas and the use of mechanical ventilation in the 2e7 days after starting treatment.45 In view of its lower acute toxicity, caffeine is the preferred methylxanthine.45 Caffeine has the added advantage that routine measurements of blood levels are not needed.46 Since adenosine receptors are found in all tissues, methylxanthines may have beneficial or harmful effects on many clinically important outcomes. These include neonatal morbidities such as necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia and ultrasonographical evidence of brain injury as well as growth, neurological development and childhood behaviour. None of these outcomes has been examined in published trials of methylxanthine therapy for apnoea of prematurity.44,45 Therefore, in response to the uncertainty surrounding the efficacy and safety of neonatal xanthine therapy an international randomized placebo-controlled trial was launched in 2000.44 The Caffeine for Apnoea of Prematurity (CAP) trial will providedfor the first timed answers to the question of whether methylxanthine therapy affects growth, neurological development and childhood behaviour.
Practice points Methylxanthines (caffeine, theophylline, aminophylline) reduce the frequency of apnoea in preterm infants. Methylxanthines reduce the need for mechanical ventilation in preterm infants. Caffeine citrate is the methylxanthine of choice: it has a wider therapeutic range and routine measurements of blood concentrations are not needed. Methylxanthines are among the most commonly used drugs in neonatal medicine. The short-term and long-term safety of methylxanthine therapy in preterm infants is not sufficiently known.
Controversies surrounding xanthine therapy
Research directions Effects of methylxanthines on clinically important outcomes such as growth, neurological development and behaviour need to be investigated.
References 1. Weinberg BA, Bealer BK. The world of caffeine: the science and culture of the world’s most popular drug. New York and London: Routledge, Taylor & Francis Group; 2002. 2. Fredholm BB. Adenosine, adenosine receptors and the actions of caffeine. Pharmacol Toxicol 1995;76:93e101. 3. Herlenius E, Lagercrantz H, Yamamoto Y. Adenosine modulates inspiratory neurons and the respiratory pattern in the brainstem of neonatal rats. Pediatr Res 1997;42:46e53. 4. Lagercrantz H, Runold M, Yamamoto Y, Fredholm BB. Adenosine: a putative mediator of the hypoxic ventilatory response of the neonate. In: Euler H, Lagercrantz H, editors. Neurobiology of the control of breathing. New York: Raven Press; 1986. p. 133e9. 5. Gerhardt T, McCarthy J, Bancalari E. Effect of aminophylline on respiratory center activity and metabolic rate in premature infants with idiopathic apnea. Pediatrics 1979; 63:537e42. 6. Milsap RL, Krauss AN, Auld PAM. Oxygen consumption in apneic premature infants after low-dose theophylline. Clin Pharmacol Ther 1980;28:536e40. 7. Carnielli VP, Verlato G, Benini F, Rossi K, Cavedagni M, Filippone M, et al. Metabolic and respiratory effects of theophylline in the preterm infant. Arch Dis Child Fetal Neonatal Ed 2000;83:F39e43. 8. Bauer J, Maier K, Linderkamp O, Hentschel R. Effect of caffeine on oxygen consumption and metabolic rate in very low birth weight infants with idiopathic apnea. Pediatrics 2001;107:660e3. 9. Koppe JG, de Bruijne JI, de Boer P. Apneic spells and transcutaneous PO2: treatment with caffeine, 19-year follow-up. Birth Defects Orig Artic Ser 1979;15:437e45. 10. Kuzemko JA, Paala J. Apnoeic attacks in the newborn treated with aminophylline. Arch Dis Child 1973;48:404e6. 11. Conroy S, McIntyre J, Choonara I. Unlicensed and off label drug use in neonates. Arch Dis Child Fetal Neonatal Ed 1999;80:F142e5. 12. ’t Jong GW, Vulto AG, de Hoog M, Schimmel KJ, Tibboel D, van den Anker JN. A survey of the use of off-label and unlicensed drugs in a Dutch children’s hospital. Pediatrics 2001;108:1089e93. 13. O’Donnell CP, Stone RJ, Morley CJ. Unlicensed and off-label drug use in an Australian neonatal intensive care unit. Pediatrics 2002;110:e52. Available from: http://www. pediatrics.org/cgi/content/full/110/5/e52. 14. Shekelle PG, Hardy ML, Morton SC, Maglione M, Mojica WA, Suttorp MJ, et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a metaanalysis. J Am Med Assoc 2003;289:1537e45. 15. Fjeld CR, Cole FS, Bier DM. Energy expenditure, lipolysis, and glucose production in preterm infants treated with theophylline. Pediatr Res 1992;32:693e8. 16. Renshaw GM, Kerrisk CB, Nilsson GE. The role of adenosine in the anoxic survival of the epaulette shark, Hemiscyllium ocellatum. Comp Biochem Physiol B Biochem Mol Biol 2002;131:133e41.
243 17. Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 2001;24:31e55. 18. Thurston JH, Hauhard RE, Dirgo JA. Aminophylline increases cerebral metabolic rate and decreases anoxic survival in young mice. Science 1978;201:649e51. 19. Kang SH, Lee YA, Won SJ, Rhee KH, Gwag BJ. Caffeineinduced neuronal death in neonatal rat brain and cortical cell cultures. Neuroreport 2002;13:1945e50. 20. Bona E, Aden U, Gilland E, Fredholm BB, Hagberg H. Neonatal cerebral hypoxiaeischemia: the effect of adenosine receptor antagonists. Neuropharmacology 1997;36:1327e38. 21. Dux E, Fastbom J, Ungerstedt U, Rudolphi K, Fredholm BB. Protective effect of adenosine and a novel xanthine derivative propentofylline on the cell damage after bilateral carotid occlusion in the gerbil hippocampus. Brain Res 1990;516:248e56. 22. Halle JN, Kasper CE, Gidday JM, Koos BJ. Enhancing adenosine A1 receptor binding reduces hypoxiceischemic brain injury in newborn rats. Brain Res 1997;759:309e12. 23. Aden U, Leverin AL, Hagberg H, Fredholm BB. Adenosine A(1) receptor agonism in the immature rat brain and heart. Eur J Pharmacol 2001;426:185e92. 24. Von Lubitz DK, Lin RC, Melman N, Ji XD, Carter MF, Jacobson KA. Chronic administration of selective adenosine A1 receptor agonist or antagonist in cerebral ischemia. Eur J Pharmacol 1994;256:161e7. 25. Von Lubitz DK, Beenhakker M, Lin RC, Carter MF, Paul IA, Bischofberger N, et al. Reduction of postischemic brain damage and memory deficits following treatment with the selective adenosine A1 receptor agonist. Eur J Pharmacol 1996;302:43e8. 26. Boissard CG, Lindner MD, Gribkoff VK. Hypoxia produces cell death in the rat hippocampus in the presence of an A1 adenosine receptor antagonist: an anatomical and behavioral study. Neuroscience 1992;48:807e12. 27. Phillis JW. The effects of selective A1 and A2a adenosine receptor antagonists on cerebral ischemic injury in the gerbil. Brain Res 1995;705:79e84. 28. Johansson B, Halldner L, Dunwiddie TV, Masino SA, Poelchen W, Giminez-Llort L, et al. Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor. Proc Natl Acad Sci USA 2001; 98:9407e12. 29. Von Lubitz DK, Lin RC, Jacobson KA. Cerebral ischemia in gerbils: effects of acute and chronic treatment with adenosine A2A receptor agonist and antagonist. Eur J Pharmacol 1995;287:295e302. 30. Monopoli A, Lozza G, Forlani A, Mattavelli A, Ongini E. Blockade of adenosine A2A receptors by SCH 58261 results in neuroprotective effects in cerebral ischaemia in rats. Neuroreport 1998;9:3955e9. 31. Melani A, Pantoni L, Bordoni F, Gianfriddo M, Bianchi L, Vannucchi MG, et al. The selective A2A receptor antagonist SCH 58261 reduces striatal transmitter outflow, turning behavior and ischemic brain damage induced by permanent focal ischemia in the rat. Brain Res 2003; 959:243e50. 32. Gao Y, Phillis JW. CGS 15943, an adenosine A2 receptor antagonist, reduces cerebral ischemic injury in the Mongolian gerbil. Life Sci 1994;55:PL61e5. 33. Aden U, Halldner L, Lagercrantz H, Dalmau I, Ledent C, Fredholm BB. Aggravated brain damage after hypoxic ischemia in immature adenosine A2A knockout mice. Stroke 2003;34:739e44. 34. Chen JF, Huang Z, Ma J, Zhu J, Moratella R, Standaert D, et al. A(2A) adenosine receptor deficiency attenuates brain
244
35.
36.
37.
38.
39.
40.
injury induced by transient focal ischemia in mice. J Neurosci 1999;19:9192e200. Bona E, Aden U, Fredholm BB, Hagberg H. The effect of long term caffeine treatment on hypoxiceischemic brain damage in the neonate. Pediatr Res 1995;38:312e8. Rivkees SA, Zhao Z, Porter G, Turner C. Influences of adenosine on the fetus and newborn. Mol Genet Metab 2001;74:160e71. Turner CP, Yan H, Schwartz M, Othman T, Rivkees SA. A1 adenosine receptor activation induces ventriculomegaly and white matter loss. Neuroreport 2002;13:1199e204. Ledent C, Vaugeois JM, Schiffmann SN, Pedrazzini T, El Yacoubi M, Vanderhaeghen JJ, et al. Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature 1997;388:674e8. Gimenez-Llort L, Fernandez-Teruel A, Escorihuela RM, Fredholm BB, Tobena A, Pekny M, et al. Mice lacking the adenosine A1 receptor are anxious and aggressive, but are normal learners with reduced muscle strength and survival rate. Eur J Neurosci 2002;16:547e50. Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ. Cognitive and behavioral outcomes of school-aged children
D. Millar, B. Schmidt
41.
42.
43.
44.
45.
46.
who were born preterm: a meta-analysis. J Am Med Assoc 2002;288:728e37. Etzel BA, Guillet R. Effects of neonatal exposure to caffeine on adenosine A1 receptor ontogeny using autoradiography. Brain Res Dev Brain Res 1994;82:223e30. Aden U, Herlenius E, Tang LQ, Fredholm BB. Maternal caffeine intake has minor effects on adenosine receptor ontogeny in the rat brain. Pediatr Res 2000;48: 177e83. Deckert J. The adenosine A(2A) receptor knockout mouse: a model for anxiety? Int J Neuropsychopharmcol 1998; 1:187e90. Schmidt B. Methylxanthine therapy in premature infants: sound practice, disaster, or fruitless byway? J Pediatr 1999; 135:526e8. Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants. Cochrane Database Syst Rev 2001;3:CD000140. Pesce AJ, Rashkin M, Kotagal U. Standards of laboratory practice: theophylline and caffeine monitoring. National Academy of Clinical Biochemistry. Clin Chem 1998;44: 1124e8.
www.elsevierhealth.com/journals/siny
Controversies surrounding xanthine therapy David Millara, Barbara Schmidta, b,) a
Department of Paediatrics, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5 b Department of Clinical Epidemiology & Biostatistics, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada
KEYWORDS Methylxanthines; Apnoea of prematurity; Adenosine
Summary The methylxanthines aminophylline, theophylline and caffeine have been used for more than 30 years to treat apnoea of prematurity. Today, they are among the most commonly prescribed drugs in neonatal medicine. Methylxanthines reduce the frequency of idiopathic apnoea and the need for mechanical ventilation by acting as non-specific inhibitors of adenosine A1 and A2a receptors. However, recent and rapidly growing research into the actions of adenosine and its receptors raises concerns about the safety of methylxanthine therapy in very preterm infants. Possible adverse effects include impaired growth, lack of neuroprotection during acute hypoxiceischaemic episodes and abnormal behaviour. An international controlled clinical trial is underway to examine the long-term efficacy and safety of methylxanthine therapy in very low birth weight babies. ª 2003 Elsevier Ltd. All rights reserved.
Introduction ‘Caffeine is the only addictive psychoactive substance that has overcome resistance and disapproval around the world to the extent that it is freely available almost everywhere, unregulated, sold without licence, offered over the counter in tablet and capsule form, and even added to beverages intended for children’.1 The methylxanthines aminophylline, theophylline and caffeine are non-specific inhibitors of adenosine receptors.2 Adenosine is present in all tissues.2 In the neonatal medulla oblongata, aden) Corresponding author. Tel.: D1-905-521-2100x73243; fax: D1-905-521-5007. E-mail address: [email protected] (B. Schmidt).
osine depresses respiratory neuronal activity which is reversed by theophylline.3 Adenosine may also decrease respiration indirectly by reducing oxygen consumption.4 The methylxanthines increase oxygen consumption in the preterm infant.5e8 Theophylline and caffeine were used empirically to treat apnoea of prematurity long before the importance of adenosine as a modulator of neonatal respiratory activity had been discovered.9,10 Today, methylxanthines are among the most commonly prescribed drugs in neonatal medicine.11e13 However, extensive and ongoing research into the actions of adenosine and its receptors has raised concern about the safety of non-specific adenosine receptor blockade in very preterm infants. In this review, we will present evidence that prompts questions about the possible harmful effects of neonatal xanthine therapy on growth, neurological development and childhood behaviour.
1084-2756/$ - see front matter ª 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2003.11.008
240
Does xanthine therapy affect growth? ‘.caffeine adds additional efficacy to ephedrine in promoting weight loss.’14 Over 20 years ago, aminophylline and theophylline were shown to increase oxygen consumption in preterm infants by 20e25% when measured 24e48 h after the start of treatment for idiopathic apnoea.5,6 More recently, Carnielli et al.7 reported that a single loading dose of theophylline (5 mg/kg) increased energy expenditure by 15 kJ/kg/day. Similarly, Bauer et al. observed that oxygen consumption increased after 48 h of caffeine treatment for apnoea of prematurity.8 Moreover, compared with matched control infants, oxygen consumption remained elevated throughout a 4 week treatment period.8 Caffeine treatment was also associated with lower incubator temperatures to maintain a normal body temperature and with reduced weight gain. These findings have to be interpreted with caution, because caffeine was not randomly allocated to infants in the study. In adults, however, caffeine has been shown to promote weight loss.14 In summary, data obtained by four different groups of investigators suggest that methylxanthine therapy for apnoea of prematurity increases oxygen consumption, which may diminish growth. We could find only one study contradicting this conclusion.15
Does xanthine therapy affect neurological development? ‘.during exposure of the epaulette shark to anoxia, adenosine receptor activation had a pre-emptive role in maintaining brain ATP levels during oxidative stress in this anoxia tolerant shark.’ ‘Aminophylline-treated hypoxic epaulette sharks. had significantly lower brain ATP levels.’16 The role of adenosine as a neuromodulator under physiological and pathophysiological conditions is an area of intense investigation. A recent Pubmed search using the terms ‘adenosine’ and ‘receptor’ and ‘brain’ retrieved 3482 citations. We will highlight some of the current controversies in this field of research, but it is not our intention to review this rapidly expanding body of scientific literature systematically and comprehensively. Under physiological conditions, low levels of adenosine in the extracellular fluid of the brain activate adenosine A1 and A2a receptors.2 Both receptors
D. Millar, B. Schmidt are inhibited by methylxanthines.2 The other two known receptors, A2b and A3, have a substantially lower affinity for adenosine and are not probable targets for methylxanthines.2 Extracellular concentrations of adenosine in the brain increase when energy demand outstrips energy supply. Situations that cause such an imbalance between ATP synthesis and ATP breakdown include seizures, hypoxia, ischaemia and hypoglycaemia.17 Adenosine is involved in the regulation of sleep and arousal, susceptibility to seizures and analgesia.17 Adenosine has also been reported to mediate the effects of alcohol and opiates.17 Finally and importantly, adenosine has neuroprotective actions in a variety of experimental models of cerebral ischaemia.16,17 When paediatricians prescribe methylxanthines for apnoea of prematurity, they prescribe nonspecific adenosine receptor antagonists. What is known about the effects of methylxanthines in both the immature and mature brain? In 1978, Thurston and colleagues reported that aminophylline increased the cerebral metabolic rate and decreased anoxic survival in weanling mice.18 They advised caution in the use of methylxanthines in hypoxic human newborns.18 More recently, Kang et al. observed that caffeine caused neuronal death in the neonatal rat brain.19 In contrast, Bona et al. found that theophylline reduced rather than increased brain injury after hypoxiaeischaemia in 7-day old rats.20 In adult gerbils, pre-treatment with theophylline increased neuronal and vascular degeneration following carotid occlusion.21 Efforts to manipulate adenosine receptors in neonatal and adult animal models of hypoxice ischaemic brain injury with specific agonists and antagonists for the adenosine A1 and A2a receptors have yielded complex and occasionally contradictory results. Fig. 1 shows that acute inhibition of the adenosine A1 receptor increases hypoxice ischaemic brain injury while inhibition of the A2a receptor decreases brain injury, at least in mature animals. The functions of these two adenosine receptors have also been studied in A1 and A2a knockout mice. Because A1 and A2a receptors are both inhibited by methylxanthines, experiments in animals with targeted disruption of either the A1 or A2a receptor gene may shed some light on the possible effects of xanthine-induced adenosine receptor inhibition. Fig. 1 shows that deficiency of adenosine A1 and A2a receptors may lead to different responses in neonatal and adult animals. For example, 7-day old A2a knockout mice suffered more brain damage after cerebral hypoxic-ischaemia than wild-type mice.33 In contrast, adult A2a knockout mice appeared to be protected from
Controversies surrounding xanthine therapy
241 Decreased brain injury (Ref.22) No effect on brain injury (Ref.23)
Neonatal
Rat
Adult
Gerbil
Neonatal
Rat
No effect on brain injury (Ref.20)
Rat
Increased brain injury (Ref.26)
A1 Activation
A1 Inhibition
Decreased mortality (Refs.24,25) Decreased brain injury (Refs.24,25)
Adult Increased mortality (Ref.24) Increased brain injury (Refs.24,27)
Gerbil
Neonatal
No data
A1 Knockout Adult
Neonatal
Increased brain injury (Ref.28)
Mouse
No data
A2a Activation Adult
Gerbil
Decreased mortality (Ref.29) No effect on brain injury (Ref.29)
Neonatal
Rat
Decreased brain injury (Ref.20)
Rat
Decreased brain injury (Refs.30,31)
A2a Inhibition Adult
A2a Knockout
Gerbil
Decreased brain injury (Refs.27,29,32) No effect on mortality (Ref.29)
Neonatal
Mouse
Increased brain injury (Ref.33)
Adult
Mouse
Decreased brain injury (Ref.34)
Figure 1 Synopsis of the effects of experimental adenosine A1 and A2a receptor activation and inhibition in immature and mature animals on their ability to withstand an acute hypoxiceischaemic insult to the brain (Refs.20,22e34).
brain injury.34 However, Fig. 1 highlights some important gaps and also some contradictions in the existing knowledge about this complex receptor system. Furthermore, there is evidence that chronic administration of adenosine receptor ligands has different effects on hypoxiceischaemic brain injury than acute ligand administration.24 Methylxanthines are given to preterm infants both acutely (loading dose) and chronically, often for many weeks. This makes the effects of drug-induced blockade of adenosine receptors in the immature
brain even less predictable. Of note, chronic exposure of rat pups to a low dose of caffeine before a hypoxiceischaemic brain insult reduced brain damage, although high-dose caffeine did not.35 Finally, adenosine appears to influence the developing nervous system.36 Adenosine A1 receptors are among the earliest receptors found in the embryonic brain.36 During intrauterine stress, adenosine levels increase. The resulting activation of adenosine A1 receptors may impair nerve growth and cause periventricular leucomalacia.36 Turner et al. treated neonatal rats with an A1 adenosine
242 receptor agonist. Chronic activation of the A1 adenosine receptor inhibited the development of axons and produced white matter loss.37 In summary, the physiological and pathophysiological roles of the adenosine receptor system in the immature brain are complex and, as yet, incompletely understood. Therefore, one cannot, at present, predict the in vivo effects of non-specific adenosine receptor blockade with methylxanthine therapy, either during times of oxygen sufficiency or during the brief hypoxiceischaemic episodes that are so common in very preterm infants.
Does xanthine therapy affect behaviour? Mice lacking the adenosine A2a receptor ‘scored higher in anxiety tests, and male mice were much more aggressive towards intruders’.38 Similarly ‘mice lacking the adenosine A1 receptor are anxious and aggressive’.39 Children who were born preterm have an increased incidence of externalizing and internalizing behaviours.40 Externalizing behaviours include anger and aggression, while internalizing behaviours include fears and anxiety. A large number of preterm infants have been exposed to methylxanthines in an uncontrolled fashion over the past 20 years. Is it possible that neonatal xanthine therapy contributes to the behavioural problems of ex-preterm children? Several experimental observations suggest that this is not an unreasonable question. Firstly, limited neonatal exposure of rats to doses of caffeine that were similar to those used to treat idiopathic apnoea either increased or decreased the expression of A1 adenosine receptor, depending on the region of the rat brain that was examined.41 In contrast, much lower doses of caffeine, which mimicked the exposure of the foetus and newborn to maternal caffeine intake via the placenta or breast milk, had little effect on the ontogeny of the adenosine receptor system in the rat brain.42 Secondly, recent and intriguing laboratory studies have clearly established a link between the adenosine receptor system and behaviour. Mice lacking either the A1 or the A2a adenosine receptor are more anxious and aggressive than wild-type animals.28,38,39,43 Therefore, if xanthine therapy for idiopathic apnoea does indeed alter permanently the expression of adenosine receptors in the developing brain, this may have adverse consequences for later behaviour in childhood. In summary, the methylxanthines inhibit two adenosine receptors that have been convincingly
D. Millar, B. Schmidt linked to anxious and aggressive behaviour in mice with targeted deficiencies of each of these receptors. The relevance of this recent finding to the safety of xanthine therapy for apnoea of prematurity is presently unknown.
Evidence from neonatal randomized clinical trials Randomized trials of xanthine therapy in preterm infants have been surprisingly small and focused solely on very short-term benefits.44 Methylxanthines reduce the number of apnoeas and the use of mechanical ventilation in the 2e7 days after starting treatment.45 In view of its lower acute toxicity, caffeine is the preferred methylxanthine.45 Caffeine has the added advantage that routine measurements of blood levels are not needed.46 Since adenosine receptors are found in all tissues, methylxanthines may have beneficial or harmful effects on many clinically important outcomes. These include neonatal morbidities such as necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia and ultrasonographical evidence of brain injury as well as growth, neurological development and childhood behaviour. None of these outcomes has been examined in published trials of methylxanthine therapy for apnoea of prematurity.44,45 Therefore, in response to the uncertainty surrounding the efficacy and safety of neonatal xanthine therapy an international randomized placebo-controlled trial was launched in 2000.44 The Caffeine for Apnoea of Prematurity (CAP) trial will providedfor the first timed answers to the question of whether methylxanthine therapy affects growth, neurological development and childhood behaviour.
Practice points Methylxanthines (caffeine, theophylline, aminophylline) reduce the frequency of apnoea in preterm infants. Methylxanthines reduce the need for mechanical ventilation in preterm infants. Caffeine citrate is the methylxanthine of choice: it has a wider therapeutic range and routine measurements of blood concentrations are not needed. Methylxanthines are among the most commonly used drugs in neonatal medicine. The short-term and long-term safety of methylxanthine therapy in preterm infants is not sufficiently known.
Controversies surrounding xanthine therapy
Research directions Effects of methylxanthines on clinically important outcomes such as growth, neurological development and behaviour need to be investigated.
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