1. Definition of Apnea of Prematurity
2. Types of Apnea
3. Incidence of Apnea versus Gestational Age
4. Physiologic Effects of Apnea
5. Diseases Associated with Apnea
6. Proposed Pathogenesis of Apnea
7. Principles of Therapy for Apnea of Prematurity
8. Suggested Treatment Protocol for Apnea of Prematurity
9. Methylxanthine Therapy
10. Methylxanthine Toxicity

Apnea is the most common anomaly of respiratory control in the premature infant frequently resulting in prolonged hospitalization and the need for cardiopulmonary monitoring. Apnea of prematurity usually resolves between 34 to 36 weeks postconceptual age. The standardized definition is cessation of inspiratory activity for 20 seconds, or for a shorter period if accompanied by bradycardia (heart rate less than 100 beats per minute), cyanosis, or pallor.

Apnea has been classified into three groups depending on whether inspiratory muscle activity is present. If inspiratory muscle acitivity fails to continue following an exhalation, it is termed Central Apnea. If inspiratory muscle activity is present, but no airflow accompanies the activity, the apnea is termed Obstructive Apnea. If both of these types of apnea spells occur during the same episode, this type of apnea is termed Mixed Apnea. It is handy to characterize a patient's apnea spells into one or more types for purposes of treatment.

Although there is considerable variation in incidence and severity of apnea in premature infants, both appear to be inversely related to gestational age. Approximately 50% of infants less than 1500 grams birth weight require either respiratory support or pharmacologic intervention for recurrent prolonged apneic episodes. The peak incidence occurs between 5 and 7 days postnatal age.

• Decrease in arterial oxygenation
• Decrease in heart rate
• Decrease in perpheral blood flow
• EEG changes
• Increase in venous pressure
• Decrease in muscle tone

Apnea of prematurity is ofen a symptom of some other primary disorder and should be treated with simultaneous attention focused on the primary disease. Treatment of these associated diseases may result in a decrease in the frequency and severity of apnea spells. Apnea of Prematurity is a diagnosis of exclusion. Other causes of apnea spells should be pursued if the apnea progresses in severity, fails to respond to appropriate therapy, severe episodes occur on first day of life, or appears at a gestational age where it should not occur. 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
• Patent Ductus Arteriosus
• Hemorrhagic Shock
• Metabolic disturbances such as Hypoglycemia, Acidosis, Hyponatremia, Hypocalcemia
• Maternal Drug Administration
• Inappropriate Thermal Environment
• Apnea of prematurity (Idiopathic Apnea)

• Primary central respiratory center depression
  • 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
  • Less cortical traffic
  • Sleep state, especially REM sleep
  • Seizures
  • Metabolic disorders
  • Sepsis
  • Suppression by drugs
• Abnormal or hyperactive reflexes
  • 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 deeping repeated suctioning)
  • Vascular receptors (apnea induced by large vessel distension)
• Decreased or inhibitory lower afferent input to the central respiratory center
  • Sensory receptors (temperature receptors on face)
  • Chemoreceptor immaturity
• Hypoxemia
  • Immature ventilatory response to hypoxemia
  • Presence of lung disease
  • Decreased lung volume
  • Patent ductus arteriosus
  • Anemia
  • Hypotension with decreased oxygen delivery to the brain

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.

Increase Afferent Input into the Respiratory Centers

• Cutaneous or vestibular stimulation
• Avoid hyperoxia

Treatment of Primary Depression of Respiratory Center

• Treat infection
• Treat metabolic disturbances
• Administer drug antagonists (naloxone)
• Administer CNS stimulants (theophylline, caffeine)

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 blood

Avoidance of Triggering Reflexes

• Beware of suction catheters
• Avoid nipple feedings (feed by tube or intravenously)
• Avoid hyperinflation/hyperventilation during bagging
• Avoid cold stimulus to the face
• Place infant in the prone position
• Avoid flexion of neck

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. Start low-pressure nasal CPAP
4. Start methylxanthine therapy
5. Start mechanical ventilation

The exact mechanism by which methylxanthines exert their beneficial effect in apnea is not known. Proposed mechanisms include increased increase 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.

----------------------------------------Dosing Guidelines--------------------------------------------------------
Theophylline: 5-6 mg/kg loading dose, then 1-2 mg/kg q8-12 hours: plasma level 5-15 micrograms/mL; Reminder-Premature infants can metabolize theophylline into caffeine. Toxicity can occur despite therapeutic plasma theophylline levels. Mean half-life in low birth weight infants - 30.2 hours.

Aminophylline: 5 mg/kg loading dose, then 1-2 mg/kg q8-12 hours: plasma level (theophylline) 5-15 micrograms/mL; Reminder-Premature infants can metabolize theophylline into caffeine. Toxicity can occur despite therapeutic plasma theophylline levels. Mean half-life in low birth weight infants - 30.2 hours.

Caffeine: 10mg/kg loading dose (20mg/kg caffeine citrate), then 2.5 mg/kg in one daily dose: plasma level 8-20 micrograms/mL. Mean half-life in low birth weight infants - 102 hours.

• Excessive diuresis
• Increased cerebral metabolic rate (X2-3)
• Decreased anoxic survival
• 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

• Dennis Mayock, M.D., Associate Professor
• EMAIL feedback to primary author