Definition of ApneaApnea is the most common problem of ventilatory control in the premature infantfrequently prolonging hospitalization and the need for cardiopulmonarymonitoring. The standard definition of apnea is cessation of inspiratory gas flowfor 20 seconds, or for a shorter period of time if accompanied by bradycardia(heart rate less than 100 beats per minute), cyanosis, or pallor.
Incidence of Apnea versus Gestational AgeAlthough there is considerable variation in incidence and severity of apnea inpremature infants, both are inversely related to gestational age. Approximately50% of infants less than 1500 grams birth weight require either pharmacologicintervention or ventilatory support for recurrent prolonged apneic episodes. Thepeak incidence occurs between 5 and 7 days postnatal age. Apnea of Prematurityis a specific diagnosis and usually resolves between 34 to 36 weeks postconceptualage. ONSET USUALLY BY THIRD DAY OF LIFE!
The more hypoxic, the flatterthe response to carbon dioxide.
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
•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 centralrespiratory 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
•Abnormal or hyperactive reflexes•- likely to result in central apnea •Heads 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 centralrespiratory 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
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 issevere•Increase in venous pressure•Decrease in muscle tone
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 apneicspells 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
Types of ApneaApnea has been classified into three types depending on whetherinspiratory muscle activity is present. If inspiratory muscle activityfails following an exhalation, it is termed Central Apnea. If inspiratorymuscle activity is present without airflow, this is termed ObstructiveApnea.If both central and obstructive apnea occur during the sameepisode, this is termed Mixed Apnea. It is important to characterize apatients apnea episodes into one or more types for treatmentconsideration.
Principles of Therapy for Apnea of PrematurityTherapy for Apnea of Prematurity can be divided arbitrarily into four groupings based on proposedpathogenic mechanisms that might result in apnea. Institution of interventions should occur in theorder of increasing invasiveness and risk. Debate regarding risk of interventions persists, some authorsadvocating use of methylxanthines prior to CPAP therapy.Increase Afferent Input into the Respiratory Centers •Cutaneous or vestibular stimulation •Avoid hyperoxiaTreatment of Primary Depression of Respiratory Center •Treat infection •Correct metabolic disturbances •Administer central nervous system stimulants (aminophylline, theophylline, caffeine, doxapram)
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 cellsAvoidance 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
Suggested Treatment Protocol for Apnea of PrematurityInstitution of interventions should occur in the order of increasinginvasiveness 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
When to Initiate a CPAP TrialApnea that continues in spite of optimum methylxanthine treatment may respondto low level CPAP. Accordingly, a trial of CPAP (4-5 cmH2O) is warranted inaddition to or as an alternative to ineffective methylxanthine treatment. Frequentapnea associated with marked bradycardia and/or arterial oxygen desaturationrefractory to methylxanthines and/or CPAP should be treated with positivepressure ventilation.
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 methylxanthinetherapy. Caffeine is recommended over aminophylline due to its wider margin of safety and ease of administration (once daily).
Initiation of Methylxanthines Apnea Type of Intervention Treatment Indication Type Frequent episodes associated with desaturations Spontan (SaO2 <80%) and/or bradycardia (HR <90); e.g., one No intervention required eous or more per hour over a long period of time such as 12-24 hours Light touch, stroke back Multiple episodes; more than 6 over a 12 hour period Mild Associated with desaturations <80% and or 12 over a 24 hour period bradycardia <90 Move infant, i.e. roll over, reposition, etc. Moderate More than 2 episodes in a 24 hour period Oxygen administered Prolonged vigorous stimulation Severe More than 1 episode in a 24 hour period PPV with or without oxygenNote: 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.
Methylxanthine Dosing GuidelinesCaffeine: 10mg/kg IV or PO loading dose of caffeine base (20mg/kg caffeinecitrate) 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/mLMean half-life in low birth weight infants - 30.2 hours.Reminder-Premature infants metabolize up to 15% of administered theophyllineto caffeine. Apparent methylxanthine toxicity can occur despite therapeuticplasma theophylline levels.
ReferencesMiller MJ and Martin RJ. Apnea of Prematurity. Clinics in Perinatology. 19:789-808, 1992.Schmidt B. Methylxanthine therapy in premature infants: Sound practice, disaster, orfruitless byway? J Pediatr 135:526-528, 1999.Lagercrantz H. What does the preterm infant breathe for? Controversies on apnea ofprematurity. 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 Pediatr132:758-759, 1998.National Institutes of Health Concensus Development Conference on Infantile Apnea andHome Monitoring. Pediatrics 79:292-299, 1987.