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Apnoea monitoring and caffeine treatment

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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 (this is not an exhaustive list). For example:

  • Mechanical or obstructive reasons 
  • Local or systemic infection 
  • Respiratory causes such as atelectasis, RDS, pneumothorax etc. 
  • CNS disease including IVH and seizures 
  • Issues with thermoregulation and environmental temperature 
  • Presence of a PDA 
  • Electrolyte imbalance 
  • Hypoglycaemia 
  • Drugs such as opiates, prostin, phenobarbitone, or neonatal abstinence syndrome 
  • Anaemia 
  • Gastro-oesophageal reflux 

Apnoea in a late preterm or term baby and late-onset apnoea or apnoea with onset on day 1 would suggest the need to evaluate for other cause(s), predominantly sepsis.

Apnoea of prematurity (AOP)

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 weeks, 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 below)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

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 NIPPV 10. 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

Babies with apnoea severe enough to consider treatment should be monitored by a cardio-respiratory monitor and pulse oximeter. Once the baby becomes more stable, discuss changing to an apnoea mattress on the ward round.  Usually this is at >32 weeks gestation.

Apnoea alarms are useful adjuncts to monitoring. However, 87% of alarms are false when using a combination of SpO2 monitoring and apnoea alarm, with the rate being higher (92-94%) when using apnoea alarms alone18,19. As these machines are movement sensitive they might detect periods of disconnection or hypoventilation rather than a true apnoea.

Current NICU apnoea mattresses can be programmed to respond to either 15 or 20 seconds of lack of impulses from the probe.

Caffeine Citrate therapy

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

  • In most babies it will be possible to "grow-out" of the caffeine citrate dose (i.e., do not increase the dose of caffeine citrate with weight gain so that the mg/kg dose of caffeine citrate is slowly weaned prior to stopping).
  • Caffeine citrate can usually be stopped between 32 and 34 weeks' gestation if they have not had an apnoea, bradycardia or desaturation episode requiring intervention for approximately five days. At the latest, it should be discontinued at least 5 days before the baby goes home. Continue apnoea monitoring for a minimum of 4 days after stopping caffeine citrate. Depending on the clinical situation, this can be either by an apnoea mattress or cardio-respiratory monitor plus pulse oximetry.
  • For babies about to go home, monitoring is usually for 4 days, with a further day off an apnoea monitor before discharge.

Going home on Caffeine Citrate

This will usually be a consultant decision with or without the involvement of respiratory team. The indications might be borderline overnight saturation monitoring that is not severe enough to warrant home O2 therapy or ongoing desaturation episodes in an infant otherwise ready for discharge and other diagnoses have been ruled out.

  • Homecare nurses should be made aware of a baby being discharged on caffeine citrate. These infants will usually have a home apnoea mattress.
  • A script should be arranged at least 3-4 days prior to the anticipated discharge date. Local pharmacy should be notified by the PIN registrar or FLN of the caffeine citrate prescription as caffeine citrate solution only lasts 1 week and frequent supplies will be needed.
  • Baby's primary consultant should be made aware of the discharge on caffeine citrate and follow-up arrangements with the appropriate clinic (Neonatal Fellow/Neonatologist/Respiratory Paediatrician).
  • A weaning / stopping plan should be discussed and put in the discharge letter. Usually, these babies will be allowed to grow out of the caffeine citrate dose prior to stopping. The plan is likely to include home oximetry prior to stopping caffeine citrate completely.
  • Parents will have completed neonatal CPR training prior to discharge

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.

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Document Control

  • Date last published: 01 August 2015
  • Document type: Clinical Guideline
  • Services responsible: Neonatology
  • Owner: Newborn Services Clinical Practice Committee
  • Editor: Sarah Bellhouse
  • Review frequency: 2 years