Neonatal apnea is defined as the cessation of respiratory airflow for ≥20 seconds, with or without bradycardia, or for <15 seconds accompanied by bradycardia. In premature infants, respiratory pauses lasting 10–15 seconds without bradycardia are referred to as periodic breathing, which is a normal phenomenon. Types of neonatal apnea include: (1) Central—cessation of airflow due to lack of respiratory effort caused by central nervous system factors; (2) Obstructive—respiratory effort is present but airflow in the respiratory tract is absent; (3) Mixed.

bubble_chart Etiology

The causes of apnea are classified into:

1. Primary – premature labor infants solely due to underdeveloped respiratory centers;

2. Symptomatic (1) Hypoxia: asphyxia, pneumonia, hyaline membrane disease, congenital heart disease, anemia, etc.; (2) Infection: sepsis, meningitis, etc.; (3) Central nervous system disorders: intraventricular hemorrhage and hypoxic-ischemic encephalopathy, etc.; (4) Excessively high or low environmental temperatures; (5) Metabolic disturbances: hypoglycemia, hyponatremia, hypocalcemia, hyperammonemia, etc.; (6) Gastroesophageal reflux, necrotizing small intestine colitis; (7) Airway obstruction caused by excessive neck flexion. Apnea is more common in premature labor infants, with an incidence rate as high as 50–60%, and the incidence increases with decreasing gestational age.

bubble_chart Clinical Manifestations

Diagnosing apnea based on the above definition is not difficult; the key lies in distinguishing between primary and symptomatic cases. Therefore, a thorough and comprehensive physical examination should be conducted for children with apnea, paying special attention to abnormalities in body temperature, cyanosis, heart, lungs, and the nervous system. Infants who develop apnea within 24 hours after birth may often have sepsis. For premature infants who experience apnea between 3 days and 1 week after birth, primary apnea can only be considered after ruling out other diseases. Premature infants who develop apnea after 1 week of birth should be evaluated for underlying disease causes to exclude symptomatic cases. All full-term infants who experience apnea are symptomatic.

1. Complete blood count (CBC), hematocrit, and blood culture can identify anemia and sepsis. Blood generation and transformation tests can rule out electrolyte and metabolic disorders.

2. Imaging studies

(1) X-ray examination: Chest X-ray can detect pulmonary diseases such as pneumonia and hyaline membrane disease, and also provides some assistance in diagnosing congenital heart disease. Abdominal radiography can exclude necrotizing enterocolitis.

(2) Head CT: Helps diagnose neonatal intracranial hemorrhage and central nervous system disorders.

(3) Ultrasound examination: Cranial ultrasound can rule out intraventricular hemorrhage. Cardiac ultrasound aids in the diagnosis of congenital heart disease.

3. Polysomnography: By monitoring electroencephalography (EEG) and muscle movements, it not only distinguishes different types of apnea but also identifies the relationship between apnea and sleep phases, aiding in the diagnosis of the underlying causes of apnea.

bubble_chart Diagnosis

(1) Medical History The following are high-risk infants prone to apnea:

1. Premature infants with a birth weight ≤1800g (32 weeks gestation);

2. Infants whose siblings have sudden death syndrome;

3. Infants with neurological disorders or the aforementioned diseases.

(2) Clinical Manifestations: See Clinical Manifestations

Diagnosing apnea based on the above definition is not difficult; the key is differentiating between primary and symptomatic cases. Therefore, a detailed and comprehensive physical examination should be conducted for infants with apnea, with particular attention to hypothermia, cyanosis, and abnormal manifestations of the heart, lungs, and nervous system. Infants who develop apnea within 24 hours after birth may often have sepsis; premature infants who develop apnea between 3 days and 1 week after birth should be considered primary only after other diseases are ruled out; premature infants who develop apnea after 1 week of birth should be evaluated for disease causes to exclude symptomatic cases. All full-term infants with apnea are symptomatic.

(4) Monitoring High-risk infants prone to apnea should be admitted to the ICU. Relying solely on clinical observation is often insufficient, and the use of monitors can promptly diagnose apnea. Recent data indicate that cardiopulmonary monitors alone can only detect central apnea. Some infants may develop apnea and already have hypoxemia without a drop in heart rate. Therefore, units with the necessary resources should use four-channel monitoring, including ECG, respiratory monitoring, pulse oximetry, and a thermal sensor under the external nostrils. The thermal sensor under the nostrils can record changes in airway airflow, aiding in the diagnosis of obstructive apnea.

bubble_chart Treatment Measures

(1) Treatment of the Primary Disease

If the cause of apnea can be identified, aggressive treatment of the primary disease is essential. For example, correcting anemia, hypoglycemia, etc.

(2) Treatment of Apnea

If the cause of apnea cannot be determined or no specific treatment is available after the cause is identified (e.g., intraventricular hemorrhage), the following methods may be used:

1. Oxygen Supply: All infants with apnea require oxygen therapy. Often, correcting unrecognized hypoxemia can reduce the frequency of apnea episodes. Generally, a mask or head hood can be used. During oxygen administration, oxygenation must be monitored to maintain PaO₂ at 6.65–10.76 kPa (50–80 mmHg) and pulse oxygen saturation around 90% to prevent hyperoxemia.

2. Increasing Afferent Stimulation: During an episode, measures such as tapping the infant’s back or soles of the feet or providing other tactile stimuli can often relieve apnea. However, the drawback is that it requires dedicated monitoring. Placing the infant on a vibrating waterbed can increase vestibular proprioceptive stimulation, enhancing sensory nerve impulses to the respiratory center and reducing apnea episodes.

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(1) Theophylline or Aminophylline: The most commonly used medications, belonging to the methylxanthine class. Theophylline may directly stimulate the respiratory center or increase its sensitivity to CO₂, thereby increasing respiratory rate and reducing apnea episodes. Its mechanism involves inhibiting phosphodiesterase, increasing cAMP and catecholamine levels. The dosage regimen is as follows: a loading dose of 5 mg/kg, diluted with an appropriate amount of 10% glucose and administered intravenously over 15–20 minutes. The maintenance dose is 1–1.5 mg/kg every 8–12 hours, given intravenously or orally.

Side effects of theophylline include tachycardia, hypotension, dysphoria, convulsions, hyperglycemia, and gastrointestinal bleeding. The occurrence of side effects is related to drug blood concentration. At concentrations above 15–20 mg/L, the first manifestation is tachycardia (≥180 beats/min), followed by tremors, irritability, abdominal distension and fullness, vomiting, and feeding difficulties. At concentrations >50 mg/L, convulsions and arrhythmias may occur.

(2) Caffeine Citrate: Its mechanism of action is similar to theophylline, but it has a longer half-life and lower toxicity. The recommended clinical dose is: a loading dose of 20 mg/kg (equivalent to 10 mg of caffeine base), administered intravenously or orally, followed by a maintenance dose of 5 mg/(kg·d) after 24–48 hours, given once daily intravenously or orally. The effective blood concentration is 8–20 mg/L, measured every 3–4 days. At concentrations >50 mg/L, nausea, vomiting, tachycardia, arrhythmias, diuresis, dysphoria, and even convulsions may occur.

Sodium benzoate caffeine is not used for apnea in premature infants because sodium benzoate competes with bilirubin for albumin binding sites, increasing the risk of kernicterus.

(3) Doxapram: A respiratory stimulant. Literature reports that it is effective when theophylline and caffeine fail. Dosage: 1–1.5 mg/(kg·h) via continuous intravenous infusion. After apnea is controlled, reduce the dose to 0.5–0.8 mg/(kg·h), with a maximum dose of up to 2.5 mg/(kg·h). The typical treatment course is 5 days, which may be extended if necessary. The effective blood concentration is <5 mg/L. Toxic effects include tremors, spasms, increased heart rate, hyperglycemia, abdominal distension and fullness, vomiting, grade I liver dysfunction, and hypertension, which resolve after discontinuation. It is contraindicated in patients with cardiovascular disease or spasms. Due to the need for continuous intravenous infusion and its toxic effects, the use of this drug is limited.

4. Continuous Positive Airway Pressure (CPAP) CPAP can be used when general oxygen supply fails to alleviate apnea, commonly administered via bilateral nasal prongs or endotracheal intubation with a pressure range of 0.3-0.5 kPa. The mechanism may be related to correcting hypoxia.

5. Mechanical Ventilation Some infants may still experience frequent apnea episodes accompanied by hypoxemia or significant bradycardia despite the aforementioned treatments. In such cases, mechanical ventilation can be employed. For patients without lung disease, the ventilator preset parameters are as follows: FiO₂0.25–0.3 or the oxygen concentration prior to ventilation. PIP 1.4–1.9 kPa (15–20 cmH₂O), respiratory rate 15–25 breaths/min, and inspiratory time 0.5–0.6 s.

6. Medication Withdrawal and Home Monitoring Once apnea is alleviated, theophylline can be considered for discontinuation. If apnea recurs after stopping the medication, theophylline therapy should be resumed, and if necessary, maintained until 52 weeks post-pregnancy or 4 weeks after birth.