Early Human Development 90S2 (2014) S1–S2
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Editorial
Current management of apnea in premature infants: Is caffeine the magic bullet? Eduardo Bancalari* Department of Pediatrics, Division of Neonatology, University of Miami Miller School of Medicine, Miami, Florida, USA
article info Keywords: Respiratory control Hypoxia episodes Respiratory stimulants Respiratory support
Apnea of prematurity is one of the most common problems observed in premature infants and it is associated with other morbidities including worse neurodevelopmental outcome. The incidence is higher in the more immature infants and it occurs in up to 90% of infants born under 28 weeks of gestation. The pathogenesis of apnea is due to immaturity of the respiratory control systems characterized by an abnormal ventilatory response to carbon dioxide and hypoxia combined with immature reflex responses. Upper airway obstruction due to airway instability is also a frequent component in apnea of prematurity. These abnormalities frequently persist until the infants reach 32–36 weeks corrected age or longer in the more immature infants. Severe apneic episodes are frequently associated with hypoxia and bradycardia and because of this they can lead to increased risk of CNS damage and neurological sequelae [1]. Infants who are mechanically ventilated also present frequently with episodes of hypoxemia but the mechanisms for these episodes differ from those of apnea of prematurity. The management of the infant with apnea episodes should start by identifying and correcting known conditions that can increase their incidence. These include metabolic abnormalities such as hypoglycemia, hypocalcemia and metabolic alkalosis, anemia and arterial hypotension, and any condition that increases the work of breathing. Medications that depress CNS activity also favor apnea and should be avoided. The level of arterial oxygenation plays a critical role in control of breathing in premature infants and low arterial oxygen tension increases the incidence of periodic breathing and apnea episodes [2].
* Correspondence: Eduardo Bancalari, MD, Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine, PO Box 016960 R-131, Miami, FL 33101, USA. E-mail address: [email protected] (E. Bancalari). 0378-3782/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Respiratory stimulants When the apnea episodes are severe and persist, respiratory stimulants such as caffeine or aminophylline are usually effective in reducing the incidence of the episodes [3]. Although both drugs are similarly effective in reducing apnea episodes, caffeine has become the standard of care in the USA because it can be administered orally, has a longer half-life and a broader therapeutic range. Although these respiratory stimulants have been shown to reduce apnea incidence, the episodes are not completely eliminated until the infants develop a more mature respiratory control. These drugs increase the sensitivity of the respiratory center to CO2 and reduce periodic breathing and apnea. Recent evidence suggests that these drugs may also reduce the frequency of hypoxia episodes [4]. Use of respiratory stimulants is associated with increased metabolism and oxygen consumption and can reduce tolerance to hypoxia [5]. Caffeine has also been shown to reduce cerebral and mesenteric blood flow. Because of the potential side effects of caffeine, a large prospective randomized trial was carried out to evaluate the safety of this medication [6,7]. This study showed no significant side effects from the caffeine treatment and surprisingly revealed a reduced incidence of PDA, duration of mechanical ventilation and BPD and better neurodevelopmental outcome at two years of age in the treated infants. Recent retrospective studies have reported shorter duration of mechanical ventilation and lower incidence of BPD in infants that received caffeine earlier during their respiratory course [8]. These studies have raised the possibility of using caffeine earlier in mechanically ventilated infants to improve respiratory outcome but so far there is no clear evidence from prospective randomized studies supporting this more liberal use of caffeine. Based on the apparent safety of caffeine therapy some investigators have recently tested the effectiveness and safety of using higher doses of caffeine [9]. The results so far are promising, showing better control of apnea episodes and
S2
E. Bancalari / Early Human Development 90S2 (2014) S1–S2
improved long term neurodevelopmental outcome with the higher caffeine dose. All these promising results with caffeine therapy are resulting in a liberalization of its use with more infants being treated earlier and for longer periods of time [8]. However we should be reminded of the many therapeutic misadventures in the past because of adopting therapies before clear evidence of long term safety was established. Caffeine is a drug with broad multi systemic effects some of which can be detrimental in developing organs. Recent data from experimental animals has shown that caffeine therapy combined with hyperoxia in a murine model can have adverse effects on alveolarization and increase apoptosis in alveolar type II cells [10]. Another therapy that has been evaluated to manage apnea is an increase in inspired CO2 as a way of increasing respiratory drive [11]. This more physiologic intervention was shown to be effective in reducing periodic breathing and apnea but the practicalities of this therapy have prevented its routine use. 2. Mechanical respiratory support In the more severe cases of apnea that are unresponsive to pharmacological therapy the use of mechanical respiratory support such as nasal CPAP, nasal IPPV or invasive mechanical ventilation becomes necessary to reduce the occurrence of severe hypoxic episodes and its consequences. NCPAP is effective in reducing obstructive apnea and reducing respiratory failure after extubation. We have recently shown that in infants with residual lung disease the use of higher levels of CPAP, up to 8 cmH2 O is more effective in preventing respiratory failure and reintubation than the lower levels that have been used until now [12]. Recently the use of high flow nasal cannulas has also been shown to be effective in managing these infants. In infants that are unresponsive to CPAP the use of nasal ventilation can sometimes be more effective in avoiding respiratory failure and need for reintubation.
Conflict of interest statement The author has no conflicts of interest to declare. References 1. Janvier A, Khairy M, Kokkotis A, Cormier C, Messmer D, Barrington K. Apnea is associated with neurodevelopmental impairment in very low birth weight infants. J Perinatol 2004;24:763–8. 2. Weintraum Z, Alvaro R, Kwiatkowski K, Cates D, Rigatto H. Effects of inhaled oxygen (up to 40%) on periodic breathing and apnea in preterm infants. J Appl Physiol 1992;72:116–20. 3. Henderson-Smart DJ, De Paoli AG. Methylxanthine treatment for apnoea in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD000140. doi: 10.1002/14651858.CD000140.pub2. 4. Rhein LM, Dobson NR, Darnall RA, Corwin MJ, Heeren TC, Poets CF, et al. Effects of caffeine on intermittent hypoxia in infants born prematurely. JAMA Pediatr 2014;168:250–7. 5. 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;107:660–3. 6. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington K, Ohlsson A, et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006;354:2112–21. 7. Schmidt B. Methylxanthine therapy for apnea of prematurity: Evaluation of treatment benefits and risks at age 5 years in the international Caffeine for Apnea of Prematurity (CAP) trial. Biol Neonate 2005;88:208–13. 8. Dobson N, Patel R, Smith PB, Kuehn DR, Clark J, Vyas-Read S, et al. Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants. J Pediatr 2014;164:992–8. 9. Steer P, Flenady V, Shearman A, Charles B, Gray PH, Henderson-Smart D, et al. High dose caffeine citrate for extubation of preterm infants: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2004;89:F499–503. 10. Dayanim S, Lopez B, Maisonet TM, Grewal TM, Grewal S, Londhe VA. Caffeine induces alveolar apoptosis in the hyperoxia-exposed developing mouse lung. Pediatr Res 2014;75:395–402. 11. Alvaro RE, Khalil M, Qurashi M, Al-Saif S, Al-Matary A, Chiu A, et al. CO2 inhalation as a treatment for apnea of prematurity: a randomized double-blind controlled trial. J Pediatr 2012;160:252–7. 12. Buzzella B. Claure N, D’Ugard C, Bancalari E. A randomized controlled trial of two nasal continuous positive airway pressure levels after extubation in preterm infants. J Pediatr 2014;164:46–51.
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Editorial
Current management of apnea in premature infants: Is caffeine the magic bullet? Eduardo Bancalari* Department of Pediatrics, Division of Neonatology, University of Miami Miller School of Medicine, Miami, Florida, USA
article info Keywords: Respiratory control Hypoxia episodes Respiratory stimulants Respiratory support
Apnea of prematurity is one of the most common problems observed in premature infants and it is associated with other morbidities including worse neurodevelopmental outcome. The incidence is higher in the more immature infants and it occurs in up to 90% of infants born under 28 weeks of gestation. The pathogenesis of apnea is due to immaturity of the respiratory control systems characterized by an abnormal ventilatory response to carbon dioxide and hypoxia combined with immature reflex responses. Upper airway obstruction due to airway instability is also a frequent component in apnea of prematurity. These abnormalities frequently persist until the infants reach 32–36 weeks corrected age or longer in the more immature infants. Severe apneic episodes are frequently associated with hypoxia and bradycardia and because of this they can lead to increased risk of CNS damage and neurological sequelae [1]. Infants who are mechanically ventilated also present frequently with episodes of hypoxemia but the mechanisms for these episodes differ from those of apnea of prematurity. The management of the infant with apnea episodes should start by identifying and correcting known conditions that can increase their incidence. These include metabolic abnormalities such as hypoglycemia, hypocalcemia and metabolic alkalosis, anemia and arterial hypotension, and any condition that increases the work of breathing. Medications that depress CNS activity also favor apnea and should be avoided. The level of arterial oxygenation plays a critical role in control of breathing in premature infants and low arterial oxygen tension increases the incidence of periodic breathing and apnea episodes [2].
* Correspondence: Eduardo Bancalari, MD, Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine, PO Box 016960 R-131, Miami, FL 33101, USA. E-mail address: [email protected] (E. Bancalari). 0378-3782/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Respiratory stimulants When the apnea episodes are severe and persist, respiratory stimulants such as caffeine or aminophylline are usually effective in reducing the incidence of the episodes [3]. Although both drugs are similarly effective in reducing apnea episodes, caffeine has become the standard of care in the USA because it can be administered orally, has a longer half-life and a broader therapeutic range. Although these respiratory stimulants have been shown to reduce apnea incidence, the episodes are not completely eliminated until the infants develop a more mature respiratory control. These drugs increase the sensitivity of the respiratory center to CO2 and reduce periodic breathing and apnea. Recent evidence suggests that these drugs may also reduce the frequency of hypoxia episodes [4]. Use of respiratory stimulants is associated with increased metabolism and oxygen consumption and can reduce tolerance to hypoxia [5]. Caffeine has also been shown to reduce cerebral and mesenteric blood flow. Because of the potential side effects of caffeine, a large prospective randomized trial was carried out to evaluate the safety of this medication [6,7]. This study showed no significant side effects from the caffeine treatment and surprisingly revealed a reduced incidence of PDA, duration of mechanical ventilation and BPD and better neurodevelopmental outcome at two years of age in the treated infants. Recent retrospective studies have reported shorter duration of mechanical ventilation and lower incidence of BPD in infants that received caffeine earlier during their respiratory course [8]. These studies have raised the possibility of using caffeine earlier in mechanically ventilated infants to improve respiratory outcome but so far there is no clear evidence from prospective randomized studies supporting this more liberal use of caffeine. Based on the apparent safety of caffeine therapy some investigators have recently tested the effectiveness and safety of using higher doses of caffeine [9]. The results so far are promising, showing better control of apnea episodes and
S2
E. Bancalari / Early Human Development 90S2 (2014) S1–S2
improved long term neurodevelopmental outcome with the higher caffeine dose. All these promising results with caffeine therapy are resulting in a liberalization of its use with more infants being treated earlier and for longer periods of time [8]. However we should be reminded of the many therapeutic misadventures in the past because of adopting therapies before clear evidence of long term safety was established. Caffeine is a drug with broad multi systemic effects some of which can be detrimental in developing organs. Recent data from experimental animals has shown that caffeine therapy combined with hyperoxia in a murine model can have adverse effects on alveolarization and increase apoptosis in alveolar type II cells [10]. Another therapy that has been evaluated to manage apnea is an increase in inspired CO2 as a way of increasing respiratory drive [11]. This more physiologic intervention was shown to be effective in reducing periodic breathing and apnea but the practicalities of this therapy have prevented its routine use. 2. Mechanical respiratory support In the more severe cases of apnea that are unresponsive to pharmacological therapy the use of mechanical respiratory support such as nasal CPAP, nasal IPPV or invasive mechanical ventilation becomes necessary to reduce the occurrence of severe hypoxic episodes and its consequences. NCPAP is effective in reducing obstructive apnea and reducing respiratory failure after extubation. We have recently shown that in infants with residual lung disease the use of higher levels of CPAP, up to 8 cmH2 O is more effective in preventing respiratory failure and reintubation than the lower levels that have been used until now [12]. Recently the use of high flow nasal cannulas has also been shown to be effective in managing these infants. In infants that are unresponsive to CPAP the use of nasal ventilation can sometimes be more effective in avoiding respiratory failure and need for reintubation.
Conflict of interest statement The author has no conflicts of interest to declare. References 1. Janvier A, Khairy M, Kokkotis A, Cormier C, Messmer D, Barrington K. Apnea is associated with neurodevelopmental impairment in very low birth weight infants. J Perinatol 2004;24:763–8. 2. Weintraum Z, Alvaro R, Kwiatkowski K, Cates D, Rigatto H. Effects of inhaled oxygen (up to 40%) on periodic breathing and apnea in preterm infants. J Appl Physiol 1992;72:116–20. 3. Henderson-Smart DJ, De Paoli AG. Methylxanthine treatment for apnoea in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD000140. doi: 10.1002/14651858.CD000140.pub2. 4. Rhein LM, Dobson NR, Darnall RA, Corwin MJ, Heeren TC, Poets CF, et al. Effects of caffeine on intermittent hypoxia in infants born prematurely. JAMA Pediatr 2014;168:250–7. 5. 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;107:660–3. 6. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington K, Ohlsson A, et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006;354:2112–21. 7. Schmidt B. Methylxanthine therapy for apnea of prematurity: Evaluation of treatment benefits and risks at age 5 years in the international Caffeine for Apnea of Prematurity (CAP) trial. Biol Neonate 2005;88:208–13. 8. Dobson N, Patel R, Smith PB, Kuehn DR, Clark J, Vyas-Read S, et al. Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants. J Pediatr 2014;164:992–8. 9. Steer P, Flenady V, Shearman A, Charles B, Gray PH, Henderson-Smart D, et al. High dose caffeine citrate for extubation of preterm infants: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2004;89:F499–503. 10. Dayanim S, Lopez B, Maisonet TM, Grewal TM, Grewal S, Londhe VA. Caffeine induces alveolar apoptosis in the hyperoxia-exposed developing mouse lung. Pediatr Res 2014;75:395–402. 11. Alvaro RE, Khalil M, Qurashi M, Al-Saif S, Al-Matary A, Chiu A, et al. CO2 inhalation as a treatment for apnea of prematurity: a randomized double-blind controlled trial. J Pediatr 2012;160:252–7. 12. Buzzella B. Claure N, D’Ugard C, Bancalari E. A randomized controlled trial of two nasal continuous positive airway pressure levels after extubation in preterm infants. J Pediatr 2014;164:46–51.
