Iowa Neonatology Handbook: Pulmonary

Management of Neonatal Apnea

1. Definition:
   Apnea is a "pause in breathing of longer than 10 to 15 seconds, often associated with bradycardia, cyanosis, or both." (Martin et al). Apnea at UIHC is defined as cessation of breathing for 20 seconds with the above symptoms.
2. Sequelae:
   1. Apnea in premature infants can result in a failure of the mechanisms that protect cerebral blood flow, resulting in ischemia and eventually leukomalacia.
   2. During apneic episodes, in an attempt to protect cerebral blood flowcardiac output is diverted away from the mesenteric arteries resulting in intestinal ischemia and possibly necrotizing enterocolitis (NEC).
3. Etiology:
   The most common cause of apnea in the NICU is apnea of prematurity, but first ALWAYS investigate and rule out the following disorders:
   1. Infection - Sepsis, especially in the first day of life, and nosocomial infections and/or NEC in the first weeks of life
   2. Neurological - Intraventricular hemorrhage, intracranial hemorrhage, neonatal seizures, perinatal asphyxia, or other pathology which could lead to increased intracranial pressure
   3. Cardiovascular - Impairment of oxygenation from congestive heart failure and pulmonary edema (PDA, coarctation, etc.), or from shunting (cyanotic heart disease)
   4. Pulmonary - Impairment of oxygenation and ventilation from lung disease (surfactant deficiency disease, pneumonia, transient tachypnea of the newborn, meconium aspiration, etc.)
   5. Metabolic - Hypocalcemia, hypoglycemia, hyponatremia or acidosis
   6. Hematological - Anemia
   7. Gastrointestinal - NEC or gastroesophageal reflux
   8. Temperature Regulation - Hypothermia or hyperthermia
   9. Drugs - Prenatal exposure with transplacental transfer to the neonate of various drugs (narcotics, beta-blockers). Postnatal exposure to sedatives, hypnotics or narcotics.
4. Pathophysiology:
   Mechanisms of apnea of prematurity:
   1. Central Apnea - A pause in alveolar ventilation due to a lack of diaphragmatic activity. In other words, there is no signal to breathe being transmitted from the CNS to the respiratory muscles. This is due to immaturity of brainstem control of central respiratory drive. The premature infant also manifests an immature response to peripheral vagal stimulation. For example, stimulation of laryngeal receptors in the adult results in coughing. However, stimulation of these same receptors in the premature infant results in apnea. This reflex apnea can be induced by gavage feeds, aggressive pharyngeal suctioning and gastroesophageal reflux.
   2. Obstructive Apnea - A pause in alveolar ventilation due to obstruction of airflow within the upper airway, particularly at the level of the pharynx. The pharynx collapses from negative pressure generated during inspiration, because the muscles responsible for keeping the airway open, the genioglossus and geniohyoid are too weak in the premature infant. Once collapsed, mucosal adhesive forces tend to prevent the reopening of the airway during expiration. Neck flexion will worsen this form of apnea. Excessive secretions in the nasopharynx and hypopharynx may also cause obstructive apnea.
   3. Mixed Apnea - A combination of both types of apnea representing as much as 50% of all episodes.
5. Surveillance:
   All newborns less than 34 weeks gestational age, or less than 1800 grams birth weight, should be monitored for both apnea and bradycardia. This is done by applying ECG leads to the chest which are connected to a bedside respiratory and heart rate monitor. An alarm should sound if respiration ceases for more than 20 seconds, or if the heart rate drops below 100 bpm. Bradycardia by itself is often a sign of obstructive apnea. No apnea alarm is sounded because the chest wall is moving even through air flow is absent. Also reflex apnea can lead to bradycardia within 2 seconds of onset, thus setting off the cardiac alarm 10 to 15 seconds ahead of the apnea alarm.
6. Management:
   1. Acute - When the alarm sounds, the infant should immediately be observed for signs of breathing and skin color. If apneic, pale, cyanotic or bradycardic, then tactile stimulation needs to be given. If the infant does not respond, bag and mask ventilation, along with suctioning and airway positioning, may be needed.
   2. Chronic - The management of apnea of prematurity always involves diagnosing and correcting other potential etiologies, before attributing a specific neonate's apnea to prematurity alone. The decision to initiate chronic therapy is based on clinical judgment. Factors to be considered include the frequency and duration of the episodes along with the level of hypoxia and the degree of stimulation needed. Chronic management of apnea of prematurity involves three major therapies:
      1. Pharmacologic Therapy - The most common drugs used to treat apnea are the methylxanthines:
         Caffeine (1,3,7-trimethylxanthine) and
         Theophylline (1,3-dimethylxanthine)
         1. Mechanism of Action - Methylxanthines block adenosine receptors. Adenosine inhibits the respiratory drive, thus by blocking inhibition, the methylxanthines stimulate respiratory neurons resulting in an enhancement of minute ventilation.
         2. Dosages - The following is a guide to the initiation of medical therapy. Further dosing should be based on drug levels and clinical response.
         3. Caffeine Citrate - 20mg/ml containing the equivalent of 10 mg/ml of caffeine is available for either IV/po use.
            1. Loading Dose - 20 mg/kg/dose of caffeine citrate IV/po
            2. Maintenance Dose - 5 mg/kg/day of caffeine citrate given QD
            3. Plasma Half Life - 37-231 hrs
            4. Therapeutic Level - 8-20 ug/ml
            5. Toxic Level - >30 ug/ml
         4. Theophylline:
            1. Loading Dose - 6 mg/kg/dose IV/po
            2. Maintenance Dose - 6 mg/kg/day divided Q6H/Q8H/Q12H IV/po
            3. Plasma Half Life - 12-64 hrs
            4. Therapeutic Level - 6-12 ug/ml
            5. Toxic Level - >20 ug/ml
            6. Administration - ALWAYS INFUSE SLOWLY over a minimum of 20 minutes. Rapid IV pushes have been associated with SUDDEN DEATH from CARDIAC ARRHYTHMIAS
         5. Major side effects - tachycardia, vomiting, feeding intolerance, jitteriness and seizures.
         6. Choice of Methylxanthine - This decision depends on the clinical situation and should take into account the following factors. Caffeine has a longer half life (QD dosing) and is less toxic. At UIHC, caffeine is preferred for the routine management of apnea of prematurity. Theophylline is a bronchodilator and in neonates with BPD it offers the advantage of treating both apnea and bronchospasm.
      2. Continuous Positive Airway Pressure (CPAP) - CPAP is effective in treating both obstructive and mixed apnea, but not central apnea. CPAP is most commonly delivered by nasal prongs or by an endotracheal tube placed in the nasopharynx (see also separate section on CPAP).
         1. Mechanism of Action - Proposed mechanisms include alteration of the Hering-Breuer reflex (leading to higher lung volumes which minimize inspiratory duration and thus decrease the potential for airway collapse by prolonging expiratory time). Furthermore, CPAP increases stabilization of the chest wall musculature and decreases activity of the intercostal inspiratory inhibitory reflex. However, the most likely explanation is that CPAP splints the upper airway with positive pressure during both inspiration and expiration, thereby preventing pharyngeal collapse
         2. Initial Settings - Use either nasal prongs or a nasopharyngeal tube to deliver a CPAP of 5 cm H20. Further adjustments should be based on clinical response.
         3. Side Effects - Barotrauma, nasal irritation, abdominal distention and feeding intolerance. Feeding difficulties can be minimized by switching the patient to continuous drip feeds.
      3. Intermittent Mandatory Ventilation (IMV) - If significant apnea persists despite using both pharmaco-therapy and CPAP, the infant should be intubated and ventilated. Initial settings need to be clinically adjusted to prevent episodes of desaturation or cyanosis. In order to minimize barotrauma short inspiratory times should be used along with minimal peak inspiratory and expiratory pressures. The infant may need to remain on a minimal rate for a few weeks while the respiratory control system matures.
7. CONCLUSION:
   Apnea of prematurity is one of the most common and frustrating conditions that nurses, physicians and neonates face in the intensive care unit. A calm, rational team approach to this problem is beneficial for all involved.

References:

Higgins RD, Richter SE, Davis JM: Nasal continuous positive airway pressure facilities extubation of very low birth weight neonates. Pediatr 1991;88:999-1003.

Marchal F, Bairam A, Vert P. Neonatal apnea and apneic syndromes. Clin Perinatol 1987;14:509-529.

Hodson WA, Truog WE. Special techniques in managing respiratory problems. In: Avery GB, (ed). Neonatology: Pathophysiology and Management of the Newborn. 3rd ed., Philadelphia: JB Lippincott, 1987: 483-484.

Martin RJ, Miller MJ, Carlo WA. Pathogenesis of apnea in preterm infants. J Pediatr 1986;109:733-741.

Rall TW. Central nervous system stimulants. In: Gilman AG, Goodman LS, Rall TW, Murad F (eds): Goodman and Gilman's The Pharmacological Basis of Therapeutics, 7th ed., New York: Macmillan Publishing Company, 1985: 589-603.

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