2. GARRETT S. LEVIN, M.D. DEPARTMENT OF PEDIATRICS DIVISION OF NEONATOLOGY APNEA OFPREMATURITY APNEA OF PREMATURITY

3. Definition of Apnea Apnea is the most common problem of ventilatory control in the premature infant frequently prolonging hospitalization and the need for cardiopulmonary monitoring. The standard definition of apnea is cessation of inspiratory gas flow for 20 seconds, or for a shorter period of time if accompanied by bradycardia (heart rate less than 100 beats per minute), cyanosis, or pallor.

4. Incidence of Apnea versus Gestational Age Although there is considerable variation in incidence and severity of apnea in premature infants, both are inversely related to gestational age. Approximately 50% of infants less than 1500 grams birth weight require either pharmacologic intervention or ventilatory support for recurrent prolonged apneic episodes. The peak incidence occurs between 5 and 7 days postnatal age. Apnea of Prematurity is a specific diagnosis and usually resolves between 34 to 36 weeks postconceptual age. ONSET USUALLY BY THIRD DAY OF LIFE!

11. The more hypoxic, the flatter the response to carbon dioxide.

21. Proposed Pathogenic Mechanisms of Apnea Primary central respiratory center depression Decreased or inhibitory upper afferent input to the central respiratory center Abnormal or hyperactive reflexes Decreased or inhibitory lower afferent input to the central respiratory center Hypoxemia

22. Primary central respiratory center depression - likely to result in central apnea Fewer neuronal synapses Decreased carbon dioxide (CO2) sensitivity Decreased neurotransmitter levels Metabolic disorders Sepsis Suppression by drugs Decreased or inhibitory upper afferent input to the central respiratory center - likely to result in obstructive, central, or mixed apnea Less cortical traffic Sleep state, especially REM sleep Seizures Metabolic disorders Sepsis Suppression by drugs

23. Abnormal or hyperactive reflexes - likely to result in central apnea Head's paradoxical reflex (gasp and apnea following lung inflation) Laryngeal receptors (taste buds) acting through superior laryngeal nerves Posterior pharyngeal reflex (apnea induced by deep repeated suctioning) Vascular receptors (apnea induced by large vessel distension) Decreased or inhibitory lower afferent input to the central respiratory center - likely to result in central apnea Sensory receptors (temperature receptors on face) Chemoreceptor immaturity Hypoxemia - likely to result in central or mixed apnea Immature ventilatory response to hypoxemia Presence of lung disease Decreased lung volume Patent ductus arteriosus Anemia Hypotension with decreased oxygen delivery to the brain

24. Physiologic Effects of Apnea Decrease in arterial oxygen tension Decrease in heart rate Decrease in peripheral blood flow EEG changes suggesting CNS depression if apnea is severe Increase in venous pressure Decrease in muscle tone

25. Diseases Associated with Apnea Apnea is only a symptom and frequently occurs secondary to other disease processes. However, 'Apnea of Prematurity' is a specific diagnosis and also one of exclusion. Other causes of apneic spells should be pursued if the apnea progresses in severity, fails to respond to appropriate therapy, severe episodes occur on the first day of life, or it appears at a gestational age where it should not occur. Apnea should be treated with simultaneous attention focused on the primary disease. Treatment of these associated problems may result in a decrease in the frequency and severity of apneic spells. These causes include: Respiratory Distress Syndrome Pulmonary mechanical problems such as Airleak, or Atelectasis Infectious causes such as Sepsis, Meningitis, or Pneumonia Intracranial Hemorrhage Seizures Anemia Gastroesophageal Reflux Necrotizing Enterocolitis Patent Ductus Arteriosus Hemorrhagic Shock Metabolic disturbances such as Hypoglycemia, Acidosis, Hyponatremia, Hypocalcemia Maternal Drugs Inappropriate Thermal Environment - Hyperthermia

26. Types of Apnea Apnea has been classified into three types depending on whether inspiratory muscle activity is present. If inspiratory muscle activity fails following an exhalation, it is termed Central Apnea. If inspiratory muscle activity is present without airflow, this is termed Obstructive Apnea.If both central and obstructive apnea occur during the same episode, this is termed Mixed Apnea. It is important to characterize a patient's apnea episodes into one or more types for treatment consideration.

27. Principles of Therapy for Apnea of Prematurity Therapy for Apnea of Prematurity can be divided arbitrarily into four groupings based on proposed pathogenic mechanisms that might result in apnea. Institution of interventions should occur in the order of increasing invasiveness and risk. Debate regarding risk of interventions persists, some authors advocating use of methylxanthines prior to CPAP therapy. Increase Afferent Input into the Respiratory Centers Cutaneous or vestibular stimulation Avoid hyperoxia Treatment of Primary Depression of Respiratory Center Treat infection Correct metabolic disturbances Administer central nervous system stimulants (aminophylline, theophylline, caffeine, doxapram)

28. Treatment of Hypoxemia Treat HMD, pneumonia,aspiration, etc. Increase inspired oxygen Apply continuous positive airway pressure (CPAP) Prone positioning Treat congestive heart failure Close patent ductus arteriosus Transfuse with packed red blood cells Avoidance of Triggering Reflexes Beware of suction catheters Avoid nipple feedings (feed by tube or intravenously) Avoid hyperinflation and hyperventilation during bagging Avoid cold stimuli to the face Place infant in the prone position Avoid severe flexion of neck Treat gastroesophageal reflux

29. Suggested Treatment Protocol for Apnea of Prematurity Institution of interventions should occur in the order of increasing invasiveness and risk. 1.Diagnose and treat precipitating causes respiratory diseases hypotension sepsis anemia hypoglycemia 2.Initiate stimulation (cutaneous, vestibular) 3.Initiate a trial of nasal prong air/oxygen airflow 4.Initiate a trial of low-pressure nasal continuous positive airway pressure (CPAP) 5.Initiate methylxanthine therapy 6.Initiate mechanical ventilation

30. When to Initiate a CPAP Trial Apnea that continues in spite of optimum methylxanthine treatment may respond to low level CPAP. Accordingly, a trial of CPAP (4-5 cmH2O) is warranted in addition to or as an alternative to ineffective methylxanthine treatment. Frequent apnea associated with marked bradycardia and/or arterial oxygen desaturation refractory to methylxanthines and/or CPAP should be treated with positive pressure ventilation.

31. Methylxanthine Therapy The exact mechanism by which methylxanthines exert their beneficial effect in apnea is not known. Proposed mechanisms include increased respiratory drive secondary to increased carbon dioxide sensitivity and increased oxygen consumption. Other mechanisms postulated include adenosine antagonism, enhanced diaphragmatic contractility, and increased cyclic 3', 5' -cyclic AMP. Desaturation spells not associated with apnea are not benefited by methylxanthine therapy. Caffeine is recommended over aminophylline due to it's wider margin of safety and ease of administration (once daily).

32. Initiation of Methylxanthines Apnea Type Type of InterventionTreatment Indication Spontan eous No intervention required Frequent episodes associated with desaturations (SaO2 <80%) and/or bradycardia (HR <90); e.g., one or more per hour over a long period of time such as 12-24 hours Mild Light touch, stroke back Associated with desaturations <80% and bradycardia <90 Multiple episodes; more than 6 over a 12 hour period or 12 over a 24 hour period Moderate Move infant, i.e. roll over, reposition, etc. Oxygen administered More than 2 episodes in a 24 hour period Severe Prolonged vigorous stimulation PPV with or without oxygen More than 1 episode in a 24 hour period Note: Apnea, bradycardia, and/or cyanotic spells associated with feeding, handling,suctioning,mucus plugging, etc. should not be counted when determining whether to initiate methylxanthine therapy.

33. Methylxanthine Dosing Guidelines Caffeine: 10mg/kg IV or PO loading dose of caffeine base (20mg/kg caffeine citrate) of 20 mg/mL solution, then 2.5 mg/kg in one daily dose. Plasma level 8-20 micrograms/mL. Mean caffeine half-life in low birth weight infants - 102 hours. Aminophylline: 5 mg/kg IV loading dose, then 1-2 mg/kg IV q8-12 hours: Metabolized to theophylline. Plasma level (theophylline) 5-15 micrograms/mL Mean half-life in low birth weight infants - 30.2 hours. Reminder-Premature infants metabolize up to 15% of administered theophylline to caffeine. Apparent methylxanthine toxicity can occur despite therapeutic plasma theophylline levels.

34. Adverse Effects of Methylxanthine Therapy Excessive diuresis Increased cerebral metabolic rate (X2-3) Decreased anoxic survival in animal studies Increased cardiac output Decreased cerebral blood flow Increased blood sugar levels Increased plasma glycerol Increased lung glycogen metabolism Decrease cholesterol synthesis in glial cells Decreased cerebral cell growth and division Decreased retinal blood flow

36. References Miller MJ and Martin RJ. Apnea of Prematurity. Clinics in Perinatology. 19:789-808, 1992. Schmidt B. Methylxanthine therapy in premature infants: Sound practice, disaster, or fruitless byway? J Pediatr 135:526-528, 1999. Lagercrantz H. What does the preterm infant breathe for? Controversies on apnea of prematurity. Acta Paediatr81:733-736, 1992. Bucher HU and Duc G. Does caffiene prevent hypoxaemic episodes in premature infants? Eur J Pediatr 147:288-291, 1988. Martin RJ. Neonatal apnea, bradycardia, or desaturation: Does it matter? J Pediatr 132:758-759, 1998. National Institutes of Health Concensus Development Conference on Infantile Apnea and Home Monitoring. Pediatrics 79:292-299, 1987.