Caffeine Treatment and Apnoea Monitoring

 

Reviewed by Clinical Practice Committee
July 2015
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Apnoea of prematurity

Background

Apnoea of prematurity (AOP) is defined as cessation of breathing that lasts for more than 15 seconds and is accompanied by desaturation (SpO2 ≤80%) or bradycardia (HR ≤2/3 of baseline HR) lasting ≥ 4 seconds in infants born under 37 weeks’ gestation1, 2. The incidence of AOP is inversely correlated with gestational age and birth weight. Seven percent of neonates born at 34 to 35 weeks’ gestation, 15% at 32 to 33 weeks, 54% at 30 to 31 weeksc, and nearly all infants born at <29 weeks’ gestation or <1,000 g exhibit AOP4.Onset of AOP is usually between days 2 to 7 of life, peaking around day 3. AOP is due primarily to immaturity of respiratory homeostatic mechanisms and control of the upper airway (Table 1)5, but may be exacerbated by other complications of prematurity (see below). Most apnoeas in preterm infants are of mixed type, i.e., central and obstructive.
 

Table 1. Pathophysiologic mechanisms involved in AOP6
 

Central Mechanisms Peripheral reflex pathways Other
  • Decreased central chemosensitivity
  • Hypoxic ventilator depression
  • Upregulated inhibitor neurotransmitters (GABA, adenosine)
  • Impaired astrocyte development
  • Decreased carotid body activity

  • Increased carotid body activity

  • Laryngeal chemoreflex

  • Excessive bradycardic response to hypoxia

  • Genetic predisposition
  • Sepsis
  • Cytokines
  • Billirubin

Differential diagnosis of apnoea

A baby having apnoea needs a full assessment especially if the onset is before day 1 or after day 7. Potential causal or exacerbating factors need to be considered and excluded e.g. (this is not an exhaustive list).

Apnoea in a late preterm or term baby and late-onset apnoea or apnoea with onset on day1 would suggest the need to evaluate for other cause(s), predominantly sepsis.
 

Management of AOP

  1. Consider other causes of apnoea / treat accordingly – as above
  2. Positioning – Prone positioning can reduce frequency of AOP by improving thoracoabdominal synchrony and stabilising the chest wall7,8 .
  3. Optimise respiratory support. Consider starting or increasing positive pressure support, eg, CPAP at 6-8 cm H2O. CPAP enhances functional residual capacity, reduces the work of breathing, improves oxygenation and decreases bradycardia9. If the baby remains unstable on CPAP and caffeine citrate, consider NIPPV10. Intubation and mechanical ventilation should be considered if apnoeas require repeated IPPV via neopuff or significant stimulation (discuss with consultant).
  4. Caffeine citrate – Caffeine citrate treatment is effective in preventing or reducing AOP. In the CAP trial, caffeine citrate also reduced the incidence of BPD, severe ROP, use of postnatal steroids, cerebral palsy and cognitive delay at 18 to 21 months, especially if started within first 3 days in infants <1250g on positive pressure support11,12 . Benefits in motor function and visual perception persisted at 5 years of age13. Short-term use of high dose caffeine citrate (20 mg/kg) has been shown to reduce extubation failure in premature infants14
  5. Doxapram - Use of doxapram infusion can be considered if AOP continues to be a significant clinical problem despite high dose caffeine citrate and CPAP. The safety and efficacy of doxapram have only been studied in observational studies and caution should be exercised15,16.
  6. Transfusion may help increase O2 carrying capacity of the blood but the evidence is limited17 – consider in babies if obviously very anaemic.

There are no fixed guidelines on the initiation of any of these treatments, as the assessment of apnoea tends to be subjective, and each baby needs individual assessment. In general, exercise caution in giving caffeine citrate to babies with acute respiratory problems; apnoea often indicates respiratory deterioration needing respiratory support, not caffeine citrate, especially in the first 48-72 hours of life.

Monitoring babies with apnoea

Monitoring Caffeine Citrate Therapy

It is not necessary to do routine levels on stable babies20. Serum concentrations should be obtained if toxicity is suspected. Therapeutic range is: 26-150 micromol/L and toxicity is unlikely at <400 micromol/L. Testing is a send-away to Christchurch hospital.

Discontinuing Caffeine Citrate

When


Going home on Caffeine Citrate

Caffeine Citrate therapy in term infants

Caffeine citrate is sometimes prescribed in term infants with apnoeas or desaturation episodes. There is some observational data of its use in term infants with apnoea related to other reasons such as bronchiolitis21. Use for apnoea or desaturation in term infants is not very common and will usually be a consultant decision with or without the involvement of the respiratory team.

References

1 Barrington K, Finer N. THE NATURAL-HISTORY OF THE APPEARANCE OF APNEA OF PREMATURITY. Pediatr Res. 1991;29(4):372-5.
2 Moriette G, Lescure S, El Ayoubi M, Lopez E. [Apnea of prematurity: what's new?]. Arch Pediatr. 2010;17(2):186-90.
3 Martin RJ, Abu-Shaweesh JM, Baird TM. Apnoea of prematurity. Paediatr Respir Rev. 2004;5 Suppl A:S377-82.
4 Robertson CM, Watt MJ, Dinu IA. Outcomes for the extremely premature infant: what is new? And where are we going? Pediatr Neurol. 2009;40(3):189-96.
5 Abu-Shaweesh JM, Martin RJ. Neonatal Apnea: What's New? Pediatric Pulmonology. 2008;43(10):937-44.
6 Zhao J, Gonzalez F, Mu D. Apnea of prematurity: from cause to treatment. Eur J Pediatr. 2011;170(9):1097-105.
7 Oliveira TG, Rego MA, Pereira NC, Vaz LO, Franca DC, Vieira DS, et al. Prone position and reduced thoracoabdominal asynchrony in preterm newborns. J Pediatr (Rio J). 2009;85(5):443-8.
8 Bhat RY, Hannam S, Pressler R, Rafferty GF, Peacock JL, Greenough A. Effect of prone and supine position on sleep, apneas, and arousal in preterm infants. Pediatrics. 2006;118(1):101-7.
9 Pantalitschka T, Sievers J, Urschitz MS, Herberts T, Reher C, Poets CF. Randomised crossover trial of four nasal respiratory support systems for apnoea of prematurity in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 2009;94(4):F245-8.
10 Lemyre B, Davis PG, de Paoli AG. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for apnea of prematurity. Cochrane Database Syst Rev. 2002(1):CD002272.
11 Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Caffeine Therapy for Apnea of Prematurity. New England Journal of Medicine. 2006;354(20):2112-21.
12 Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Long-Term Effects of Caffeine Therapy for Apnea of Prematurity. New England Journal of Medicine. 2007;357(19):1893-902.
13 Schmidt B, Anderson PJ, Doyle LW, et al. SUrvival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. JAMA. 2012;307(3):275-82.
14 Steer P, Flenady V, Shearman A, Charles B, Gray P, Henderson-Smart D, et al. High dose caffeine citrate for extubation of preterm infants: a randomised controlled trial. Archives of Disease in Childhood-Fetal and Neonatal Edition. 2004;89(6):F499-F503.
15  Prins SA, Pans SJ, van Weissenbruch MM, Walther FJ, Simons SH. Doxapram use for apnoea of prematurity in neonatal intensive care. Int J Pediatr. 2013;2013:251047.
16 Henderson-Smart DJ, Steer P. Doxapram versus methylxanthine for apnea in preterm infants. Cochrane Database Syst Rev. 2000(2):CD000075.
17 Kirpalani H, Whyte RK, Andersen C, Asztalos EV, Heddle N, Blajchman MA, et al. The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. The Journal of pediatrics. 2006;149(3):301-7.
18 Weese-Mayer DE, Brouillette RT, Morrow AS, Conway LP, Klemka-Walden LM, Hunt CE. Assessing validity of infant monitor alarms with event recording. J Pediatr. 1989;115(5 Pt 1):702-8.
19 Nassi N, Piumelli R, Lombardi E, Landini L, Donzelli G, de Martino M. Comparison between pulse oximetry and transthoracic impedance alarm traces during home monitoring. Arch Dis Child. 2008;93(2):126-32.
20 Natarajan G, Botica M-L, Thomas R, Aranda JV. Therapeutic Drug Monitoring for Caffeine in Preterm Neonates: An Unnecessary Exercise? Pediatrics. 2007;119(5):936-40.
21  Cesar K, Iolster T, White D, Latifi S. Caffeine as treatment for bronchiolitis-related apnoea. J Paediatr Child Health. 2012;48(7):619.