Neonatal Apnea

Apnea Pathophysiology

There are currently thought to be three mechanisms of apnea of prematurity:

Central Apnea

Obstructive Apnea

Mixed Apnea

In brief following are the pathophysiologic mechanisms responsible for different types of apnea:

Central 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

Obstructive Apnea:

Decreased or inhibitory upper afferent input to the central respiratory center.

Mixed Apnea:

• Decreased or inhibitory upper afferent input to the central respiratory center.

• Hypoxemia

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

Types

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 occurs 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.

Etiology (predisposing/triggering Factor)^2,3

The most common cause of apnea in the neonatal intensive care unit is apnea of prematurity, but it is necessary to initially investigate and rule out the following disorders:

• Infection: Sepsis especially in the first day of life and nosocomial infections and/or necrotizing enterocolitis in the first weeks of life.

• Temperature Regulation: Hypothermia or hyperthermia.

• Gastrointestinal: NEC or gastroesophageal reflux.

• Neurological: Intraventricular hemorrhage, intracranial hemorrhage, neonatal seizures, perinatal asphyxia or other pathology which could lead to increased intracranial pressure.

• Drugs: Prenatal exposure with transplacental transfer to the neonate of various drugs (narcotics, beta-blockers). Postnatal exposure to sedatives, hypnotics or narcotics.

• Metabolic: Hypercalcemia, hypoglycemia, hyponatremia or acidosis.

• Cardiovascular: Impairment of oxygenation from congestive heart failure and pulmonary edema (PDA, coarctation, etc.) or from shunting (cyanotic heart disease).

• Hematological: Anemia.

• Pulmonary: Impairment of oxygenation and ventilation from lung disease (surfactant deficiency, pneumonia, etc.).

Definition

Apnea is the most common problem of ventilatory control in premature infants frequently prolonging hospitalization and needing cardiopulmonary monitoring. The standard definition of apnea is the 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.

This must be distinguished from periodic breathing which is three or more respiratory pauses of greater than 3 seconds duration with less than 20 seconds respiration between the pauses. Such a pattern generally unaccompanied by hypoxemia is thought to be benign.

Incidence

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 the pharmacologic intervention or ventilatory support for recurrent prolonged apneic episodes. The peak incidence occurs between 5 and 7 days of postnatal age. Apnea of Prematurity is a specific diagnosis and usually resolves between 34 to 36 weeks postconceptual age.

The incidence of apnea and periodic breathing in the term infant has not been adequately determined. Approximately 50-60% of preterm infants have evidence of apnea: 35% present with central apnea, 5-10% with obstructive apnea, 15-20% with mixed apnea. Another 30% will have periodic breathing.¹

Evaluation of the Apneic Infant⁶

History:

• Perinatal complications and Apgar scores

• Gestational and postnatal age

• Drugs given to mother or infant

• Preceding infant and environmental temperatures

• Risk factors for infection

Electroencephalography:

Abnormal pneumogram: An abnormal pneumogram is defined as one in which one of the following patterns is demonstrated.

• Periods of prolonged apnea (cession of respiratory movement of >20 seconds).

• Short apnea (cessation of respiratory movement of <20 seconds) if accompanied by bradycardia.

• Episodes of periodic breathing lasting more than 5% of the total quiet or sleep time.

Four-channel pneumogram:

Pneumograms have been widely used as screening tests to predict SIDS or life-threatening apnea in asymptomatic preterm and term infants. However, no prospective controlled study has confirmed that these 12- to 24- hour recordings of heart rate and thoracic impedance are predictive of SIDS or life-threatening apnea. No studies to date have proved that the pneumogram has a predictive value that distinguishes who will survive from those who will die. However, pneumographs occasionally may be helpful in clinical management e.g. to distinguish false from true apnea monitor alarms.⁷

Polysomnography:

Monitoring

All preterm infants should be closely monitored for the development of this often life-threatening condition. Close attention should be paid to the type of monitoring that is given to infants in intensive care units. Preterm infants are commonly on heart rate monitors only, and they will be identified as having apnea only if the heart rate drops below the monitor alarm limit (usually set at 80 beats/min). In this case, these infants may suffer profound hypoxia before bradycardia develops, or they may have apnea with significant hypoxemia but without a drop in heart rate. In order to detect apnea, these infants should have continuous monitoring of respiratory activity or monitoring of oxygenation, or both, using either transcutaneous oximetry or pulse oximetry.¹

Principles of Therapy

Therapy for Apnea 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. The debate regarding risk of interventions persists, some authors advocating the 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)

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 ducts arteries

• 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 gastro esophageal reflux

Treatment Protocol

Institution of interventions should occur in the order of increasing invasiveness and risk.

• Diagnose and treat precipitating causes: respiratory diseases, hypertension, sepsis, anemia, hypoglycemia

• Initiate stimulation (cutaneous, vestibular)

• Initiate a trial of nasal prong air/oxygen airflow

• Initiate a trial of low-pressure nasal continuous positive airway pressure (CPAP)

• Initiate methylxanthine therapy

• Initiate mechanical ventilation

Pharmacologic therapy: The most common drugs used to treat apnea are the methylxanthines: Caffeine and Theophylline⁸. Aminophylline is Theophylline combined with Ethylenediamine to increase water solubility.

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, chemoreceptor sensitivity to CO2, and cardiac output.

Dosages: The following is a guide to the initiation of medical therapy. Further dosing should be based on drug levels and clinical responses.^9,10

Aminophylline:

Loading dose: 6 mg/kg PO or IV infusion over 30 min

Maintenance dose: 1.5-3 mg/kg/dose IV or PO given q8-12 hr started 8-12 hours after loading dose.

Plasma half-life: 20-30 hours

Therapeutic level: 6-13 mcg/ml. Obtain trough 48-72 hours after the loading dose.

Toxic level: >20 mcg/ml

Caffeine:

Loading dose: 10 mg/kg PO

Maintenance dose: 2.5 mg/kg per dose PO Q24 hours, started 24 hours after the loading dose. Note that doses for caffeine citrate are higher: Use 2X the caffeine base dose.

Plasma half-life: 40-230 hrs.

Therapeutic level: 5-25 mcg/ml. Obtain trough level on day 5 or 6 after loading dose.

Toxic level: >40-50 mcg/ml

Initiation of Methylxanthines¹¹

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.

Adverse Effects of Methylxanthine Therapy:¹¹

• Excessive diuresis

• Increased blood sugar levels

• Increased cerebral metabolic rate (X2-3)

• Increased plasma glycerol

• Decreased anoxic survival in animal studies

• Increased lung glycogen metabolism

• Increased cardiac output

• Decrease cholesterol synthesis in glial cells

• Decreased cerebral blood flow

• Decreased cerebral cell growth and division

• Decreased retinal blood flow

Doxapram

If theophylline therapy fails to reduce the frequency of apneic spells, a trial of the respiratory stimulant doxapram may be considered¹². Doxapram is administered only as a continuous infusion, initially at a rate of 1.0 to 1.5 mg/kg per hour. Once control is obtained, the infusion is decreased. Although increased doses up to 2.5 mg/kg per hour may be effective in infants who continue to have apnea at lower doses, the risk of toxicity is considerably increased.

Toxicity includes hyperactivity, jitteriness, seizure, hyperglycemia, mild liver dysfunction, and hypertension. Although these abnormalities resolve following discontinuation of the drug, toxicity and the need for continuous parenteral administration limit is widespread use.

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. Candidates for NCPAP consideration would be infants with moderate to severe apnea i.e. >8 episodes in a 12 hour period or 2 episodes in 24 hours requiring bag and mask ventilation.

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.

Intermittent Mandatory Ventilation (IMV)

If significant apnea persists despite using both pharmacotherapy 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.

Discharge Planning & Follow Up¹

A major issue in the management of infants with apnea is deciding when to stop administration of theophylline and whether or not the infant needs to be discharged on theophylline, a home monitor, or both.

Discontinuing medications: Consider stopping theophylline therapy when the apnea has resolved and the infant weighs between 1800 and 2000 g. If the infants remain asymptomatic following the discontinuation of theophylline therapy, the child may be discharged without further therapy.

Reinstituting medication: If symptomatic apnea recurs after discontinuing therapy, theophylline therapy should be reinstituted and a decision made to discharge the infant on this medication or to keep the infant hospitalized longer. The use of home monitors in addition to theophylline therapy is controversial. Therapeutic theophylline levels are maintained until the child reaches 52 weeks of post-conception age; then theophylline therapy is discontinued and pneumography is performed. If the pneumogram is normal, therapy can be stopped. If the pneumogram is abnormal, the infant needs to be restarted on theophylline, and monitoring continued. Another attempt can be made to discontinue theophylline in 4 weeks

Home Monitors: Preterm infants who continue to exhibit symptomatic apnea when they would otherwise be ready for hospital discharge should have their oxygenation carefully evaluated, because hypoxia can cause apnea in preterm infants, and relieving it may resolve the problem. Chronic lung disease is frequently associated with apnea in preterm infants, In the absence of any identified underlying cause, preterm infants who are still having clinically apparent episodes of apnea can be discharged on home apnea-bradycardia monitoring. If theophylline or caffeine reduces the frequency of these episodes, then these infants can be treated in addition to the home monitor.¹³ Routine monitoring of asymptomatic preterm infants, as a group, is not warranted. An additional indication for home monitoring is a positive history of an apparent life-threatening event (ALTE) during the infant's hospital course.

Sequelae

Although the ultimate significance of apnea of prematurity for the long-term neurodevelopment of infants remains uncertain^14,3, prolonged apnea in association with falls in oxygen saturation must be considered an adverse event in view of the necessary decline in tissue oxygen delivery.

Apnea in premature infants can result in a failure of the mechanisms that protect cerebral blood flow resulting in ischemia and eventually leukomalacia. During apneic episodes, in an attempt to protect cerebral blood flow, cardiac output is diverted away from the mesenteric arteries resulting in intestinal ischemia and possibly necrotizing enterocolitis¹⁵.