1. Apnea of prematurity – Introduction and management with Caffeine Harish Narayanan MD Surgery Intern – R1 Seattle Children’s Hospital 07/10/2014

2. Case Presentation HPI: M.R. is a 12 week old male with s/p ileostomy closure with short segment ileal resection following reduction of stoma prolapse under anesthesia, POD # 0. – Admitted to the surgical floor in stable condition. PMH/PSH: – Extreme prematurity: 25 weeks 3/7 gestation – Isolated ileal perforation: repaired and ileostomy placed 4/2 – Patent Ductus Arteriosus: ligated 4/23 – Apnea of prematurity: on caffeine therapy – Adrenal insufficiency – Bronchopulmonary Displasia

3. Case Presentation O: – T(max) – 37.2 C; – HR – 125-154; RR: 23-70; SBP: 86-103 DBP: 48-62 – O2 (% RA) – 94-100% Hospital course: – Post-operatively the patient was afebrile, with stable vital signs. – The patient was transferred from a outside hospital and outside records were not available. – Sign out obtained from nurse mentioned, patient getting caffeine at midnight for apnea of prematurity. – Mom was present in the room but was a poor historian.

4. Case Presentation Hospital course (cont.): – After discussion with pharmacist and hospital records from previous NICU visit during birth, she was ordered for 5 mg/kg of caffeine at midnight. – At 11PM, patient started desaturating to 55% x 2 before being 100% after receiving blow by oxygen for couple of minutes. – Patient continued to cycle between desaturation in the next hour with associated tachycardia in 200s. – CBG showed significant respiratory acidosis (ph~7.1) and rapid response team was activated and the patient was transferred to the NICU. Patient received 1 dose of caffeine at 11:20 PM. – In the NICU, patient required bag-valve ventilation and required intubation – Patient condition was likely secondary to combination of underlying prematurity, residual general anesthesia post-surgery and supplemental opioids for pain control.

5. Apnea of prematurity – Introduction [1][2] Definition: Developmental disorder in premature infants secondary to immature respiratory control – Infants 20 seconds or accompanied by bradycardia (<70-80 bpm) Frequency/Severity of symptoms are related to decreased gestational age and low birth weight (<1000g).

6. Apnea of prematurity – Management [1] Treatment is necessary if: – Frequent apneic spells (<85%) with or without associated bradycardia – Requirement of bag-valve-mask or frequent stimulation. Management: – Monitoring (cardiac and pulse ox) – Continuous positive air pressure – Methylxanthine therapy Caffeine Theophylline

7. Continuous positive airway pressure [4] Reduces the incidence of mixed and obstructive apnea while optimizing functional residual capacity (FRC). High flow nasal cannula is initiated at 3-5 mm Hg but must not exceed 8 mm Hg. Humidified air can also be used with the high flow NC.

8. Methylxanthine therapy Competitively blocks adenosine receptors  stimulation of respiratory neural output Two treatment options: – Theophylline – Caffeine Preferred due to longer half life (65-100 hours) and better safety profile.

9. RCT evaluating 2006 infants for short term benefits of caffeine by comparing it to placebo group Findings found that infants in placebo required positive airway pressure with supplemental oxygen a week longer than infants that received caffeine had the potentially adverse effect of diminishing weight gain for the first three weeks after the start of therapy but had no significant effects on the rates of deaths Source [3] : NEJM

10. - In addition, Systematic review (2010) showed that patients treated with methylxanthine compared with those who received placebo were less likely to have apneic episodes (relative risk [RR] 0.44, 95% CI 0.32-0.60) and require assisted ventilation (RR 0.34, 95% CI 0.12-0.97) [5]

11. Caffeine Administration [6] Preterm infants: – Start with a loading dose of 20 mg/kg – Transition to maintanence dose of 5-10 mg/kg after 24 hours Prophylaxis (premies): – Mixed data on its efficacy for preventing intubation and mechanical ventilation but is used commonly for infants < 1000g

12. Caffeine Administration Discontinuation: – 32 and 34 weeks postmenstrual age and there have been no apneic episodes requiring intervention for approximately five days. – Some studies have shown decreased events up till 36 weeks but no differences beyond that date. Persistent apnea – Defined as premature infants (<28 weeks) who have persistent spells beyond 37 weeks in spite of treatment

13. Discharge from hospital [8] Home CR monitoring is not necessary if the infant is free of apneic spells for 5-7 days. [7] If caffeine is discontinued, it is recommended to monitor for 7 days for apneic spells before the infant is safe for discharge Home monitoring can be considered for infants with mild apnea – Can be dc/ed after 44 weeks since control of breathing matures around that time

14. Summary Management of apnea of prematurity typically includes supportive care, positive airway pressure (CPAP), and caffeine therapy. Caffeine therapy is usually continued until 32-34 weeks post-menstrual age. No benefit is seen past 36 weeks PMA. Home monitoring is usually not necessary during discharge if infant has no apneic spells for 5-7 days. Wait for 7 days after discontinuing caffeine before discharge. No further monitoring is necessary after 44 weeks since respiratory control is established during that time.

15. References 1.UpToDate. Management of apnea of prematurity 2.National Institutes of Health Consensus Development Conference on Infantile Apnea and Home Monitoring, Sept 29 to Oct 1, 1986. Pediatrics 1987; 79:292. 3.Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006; 354:2112. 4.Miller MJ, Carlo WA, Martin RJ. Continuous positive airway pressure selectively reduces obstructive apnea in preterm infants. J Pediatr 1985; 106:91. 5.Henderson-Smart DJ, De Paoli AG. Prophylactic methylxanthine for prevention of apnoea in preterm infants. Cochrane Database Syst Rev 2010; :CD000432. 6.Rhein LM, Dobson NR, Darnall RA, et al. Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial. JAMA Pediatr 2014; 168:250. 7.Ramanathan R, Corwin MJ, Hunt CE, et al. Cardiorespiratory events recorded on home monitors: Comparison of healthy infants with those at increased risk for SIDS. JAMA 2001; 285:2199. 8.Lorch SA, Srinivasan L, Escobar GJ. Epidemiology of apnea and bradycardia resolution in premature infants. Pediatrics 2011; 128:e366.