47: Apnea and Bradycardia (“A's and B's”)

An infant has just had an apneic episode with bradycardia. Apnea is the absence of breathing for >20 seconds or a shorter pause (>10 seconds) associated with oxygen desaturation or bradycardia (<100 beats/min). Shorter apnea <10 seconds without hypoxemia or bradycardia is due to immaturity and is not clinically important. The incidence of apnea of prematurity (AOP) is inversely correlated with gestational age and birthweight. Apnea occurs in >50% of infants <1500 g and in 90% of infants <1000 g. Types of apnea with approximate incidence are:

1. Central apnea. Complete absence of the brainstem stimulus to breathe, resulting in no respiratory effort (40%).

2. Obstructive apnea. Infant breathes but no airflow is present because of an obstruction by mucus or airway collapse (10%).

3. Mixed apnea. Elements of both central and obstructive apnea. This is the type found in most preterm infants (>50%).

4. Periodic breathing. Three or more respiratory pauses lasting >3 seconds separated by normal respiratory intervals not >20 seconds and not associated with bradycardia. Periodic breathing can occur in 2–6% of healthy term neonates and in up to 25% of preterm infants.

5. Apnea of infancy (AOI). American Academy of Pediatrics (AAP) definition: “an unexplained episode of cessation of breathing for 20 seconds or longer or a shorter respiratory pause associated with bradycardia, cyanosis, pallor, and/or marked hypotonia” in an infant >37 weeks' gestational age.

6. Apnea of prematurity (AOP). Sudden absence of breathing that lasts at least 20 seconds or is associated with bradycardia or cyanosis (oxygen desaturation) in an infant <37 weeks' gestational age. It is most commonly central or mixed apnea. AOP is a developmental disorder usually of physiologic immaturity of respiratory control but other diseases may contribute. AOP may be hereditary. AOP usually presents on days 2–7. If apnea presents in the first 24 hours of life or after day 7, it is very unlikely to be AOP. Note: Apnea of prematurity is a diagnosis of exclusion.

7. Persistent apnea. Apnea persists in a neonate ≥37 weeks postmenstrual age. It usually occurs in infants born at <28 weeks' gestation.

8. Secondary causes of apnea. Apnea that has a specific cause (eg, sepsis, anemia, asphyxia, temperature instability, pneumonia, and others). Remember immaturity can worsen any apnea that is associated with a specific cause.

1. Did you observe the apnea? What was going on when the apnea occurred? Do you know what type of apnea it is? Try to distinguish the type; obstructive apnea is the easiest to detect visually while central and mixed are more difficult. A thorough history of the event may help differentiate the type of apnea. If it occurred during feeding with a naso- or orogastric tube, is the tube in proper position? (Stimulation of laryngeal receptors causes central apnea.) Did it occur with insertion of a naso-/orogastric tube? Think vagal response. (Stimulation of the vagal nerve resulting in central apnea.) Does it just occur with feeding? (Possible gastroesophageal reflux; mixed apnea.) If the infant has no respiratory effort on the monitor or on physical examination (absent breath sounds, chest wall not moving), think central apnea. What position was the infant in when it occurred? Neck flexion can obstruct the airway and cause obstructive apnea. Was the infant just suctioned when the apnea occurred? (Aggressive pharyngeal suctioning can cause central apnea.) Does the infant have excessive secretions? (Obstructive apnea.)

2. What is the gestational age of the infant? A's and B's are common in premature infants (∽70% experience apnea before 34 weeks' gestation) and uncommon in term infants In term infants apnea is usually associated with a serious disorder or related to a maternal condition (magnesium treatment or maternal exposure to narcotics). Apnea in a term infant is never physiologic; it requires a full workup to determine the cause.

3. Was significant stimulation needed to return the heart rate to normal? An infant requiring significant stimulation (eg, oxygen by bag-and-mask ventilation) usually needs an immediate evaluation. An infant who has had one episode of apnea and bradycardia not requiring oxygen supplementation may not need a full evaluation unless the infant is term.

4. If the patient is already receiving medication (eg, methylxanthine) for apnea and bradycardia, is the dosage adequate? Determine the serum drug level.

5. Did the episode occur during or after feeding? It has been stated that gastroesophageal reflux (GER) causes apnea and bradycardia because it was observed when regurgitation of formula into the pharynx occurred after feeding. This has been a source of much debate, with recent studies showing no temporal relationship. Consider aspiration in an infant who has been doing well and feeding. Insertion of a nasogastric (NG) tube may cause a vagal reflex, resulting in apnea and bradycardia.

6. How old is the infant? Apnea in the first 24 hours is usually pathologic. The peak incidence of apnea of prematurity occurs between 5 and 7 days postnatal age.

7. Is there a change in the frequency or increase in severity of episodes? Is this the first episode or has the pattern changed? If the pattern changes or the amount and severity of each episode increases, then something new may be going on and a workup should be done.

Causes of A's and B's can be classified according to diseases and disorders of various organ systems, gestational age, or postnatal age. Apnea of prematurity is a diagnosis of exclusion; therefore, it is important to diagnose and treat any secondary cause.

1. Diseases and disorders of various organ systems

   1. Head and central nervous system

      1. Perinatal asphyxia.

      2. Intraventricular/intracranial or subarachnoid hemorrhage.

      3. Meningitis.

      4. Hydrocephalus with increased intracranial pressure.

      5. Cerebral infarct with seizures.

      6. Seizures (apnea is an uncommon presentation of a subtle seizure). Consider a seizure if apnea occurs without bradycardia; tachycardia can be seen before or during the apneic attack.

      7. Birth trauma.

      8. Congenital myopathies or neuropathies.

      9. Congenital malformations.

      10. Congenital central hypoventilation syndrome.

      11. Encephalopathy.

   2. Respiratory system

      1. Hypoxia

      2. Airway obstruction/malformation

      3. Lung disease/pneumonia/respiratory distress syndrome (RDS)/aspiration

      4. Inadequate ventilation or performing extubation too early

      5. Surfactant deficiency

      6. Pulmonary hemorrhage

      7. Pneumothorax

      8. Hypercarbia

   3. Cardiovascular system

      1. Congestive heart failure.

      2. Patent ductus arteriosus.

      3. Cardiac disorders such as cyanotic congenital heart disease, congenital heart block, hypoplastic left heart syndrome, and transposition of the great vessels.

      4. Hypovolemia/hypotension/hypertension.

      5. Increased vagal tone. There is increased vagal tone in newborns especially in the postdelivery period. Vagal hyperreactivity has been described in sudden infant death syndrome (SIDS).

   4. Gastrointestinal (GI) tract

      1. Necrotizing enterocolitis (NEC). Apnea has been associated with the onset of NEC.

      2. Gastroesophageal reflux (GER). Thought by some investigators to be related to AOP; however, to date, no research has shown a relationship between the two. Some studies suggest that antireflux surgery can reduce apnea in preterm infants at highest risk. It is a rare/infrequent cause of apnea in a full-term infant.

      3. Feeding intolerance.

      4. Oral feeding.

      5. Abdominal distension.

      6. Bowel movement.

      7. Non-rotavirus infection causes apnea in a premature infant.

      8. Esophageal hematoma. Rare.

   5. Hematologic system

      1. Anemia. There is no specific hematocrit at which apnea and bradycardia occur and can be seen in infants with anemia of prematurity. These infants show improvement after transfusion; it has been shown that liberal blood transfusion may reduce apnea compared with more restrictive blood transfusion.

      2. Polycythemia. More common in term infants.

   6. Other diseases and disorders

      1. Temperature instability. Especially hyperthermia, but also hypothermia, can cause apnea and bradycardia. Note the incubator temperature; the infant may have a normal body temperature but may have a rise in incubator temperature (the infant is hypothermic) or may require a lower incubator temperature (the infant is hyperthermic). Any rapid fluctuation of temperature can cause apnea. Cold stress can occur after birth or during transport or a procedure, and it may produce apnea.

      2. Infection (sepsis). Check for bacterial, fungal, and viral infections. Respiratory syncytial virus, Ureaplasma urealyticum, and botulism can all cause apnea in preterm infants.

      3. Metabolic/electrolyte imbalance and inborn errors of metabolism. Hypoglycemia, hypo-/hypernatremia, hypermagnesemia (during parenteral nutrition), hyperkalemia, hyperammonemia, and hypo-/hypercalcemia can cause apnea and bradycardia. Hypothyroidism and inborn errors of metabolism can also cause apnea and bradycardia.

      4. Vagal reflex. May occur secondary to nasogastric tube insertion, feeding, and suctioning.

      5. Acute/chronic pain.

      6. Head/body position (neck flexion).

      7. Drugs/drug withdrawal. Oversedation from maternal drugs such as magnesium sulfate, narcotics such as opiates, and general anesthesia can cause apnea in the newborn. Apnea can be seen in drug withdrawal of infants born to drug-addicted mothers. In the infant, high levels of phenobarbital or other narcotics or sedatives, such as diazepam and chloral hydrate, may cause apnea and bradycardia. Topical eye drops for routine eye examinations can sometimes cause changes in apnea pattern. Prostaglandin E₁, γ-aminobutyric acid (GABA), and adenosine therapy can cause apnea.

      8. Immunization. Apnea increases in preterm infants after immunization with the whole-cell pertussis component. New studies have shown an increase in apnea/bradycardia/desaturation after the DTaP-IPV-HIb and DTaP-IPV-HIb-HBV in premature infants with chronic disease. It is recommended to give these at 8 weeks if still hospitalized, with close observation. Infants with significant lung disease or sepsis can experience apnea after immunization. There is a risk of recurrence of apnea in premature infants who had apnea with their first immunization. Monitoring for a minimum of 24 hours after their next immunization is recommended.

      9. Kangaroo care. Early studies showed a relationship, but recent studies have found no adverse effects. Observe head positioning during holding.

      10. Surgery. This can cause postoperative apnea in premature infants.

      11. Retinopathy of prematurity (ROP). ROP examination has been reported as a cause.

2. Gestational age. See Table 47–1.

   1. Full-term infants. Usually do not have apnea and bradycardia from physiologic causes; the disease or disorder must be identified. The onset of apnea in a term infant at any time is a critical event that requires immediate investigation.

   2. Preterm infants. The most common cause is AOP, usually presenting between days 2 and 7 of life (usually <34 weeks' gestation, <1800 g, and no other identifiable cause) and is a diagnosis of exclusion.

3. Postnatal age can be a clue to the cause of apnea

   1. Onset within hours after birth. Oversedation from maternal drugs, asphyxia, seizures, hypermagnesemia.

   2. Apnea on day 1. Usually pathologic; consider sepsis or respiratory failure.

   3. Apnea on days 1–2. Sepsis, hypoglycemia, respiratory failure, polycythemia.

   4. Onset <1 week. Patent ductus arteriosus, periventricular-intraventricular hemorrhage, sepsis, respiratory failure, or AOP.

   5. Onset >1 week of age. Posthemorrhagic hydrocephalus with increased intracranial pressure or seizures, postextubation atelectasis, outgrown dose of caffeine or theophylline.

   6. Onset after 2 weeks in a previously well premature infant. Something new is going on that needs an immediate evaluation, usually indicative of a serious illness such as sepsis, meningitis, or other causes.

   7. Onset 4–6 weeks. Respiratory syncytial virus (RSV) infection.

   8. Variable onset. Sepsis, NEC, meningitis, aspiration, GER, cardiac disorder, pneumonia, cold stress, or fluctuations in temperature.

Determine any prenatal risk of sepsis. A history of feeding intolerance increases the suspicion of NEC.

1. Complete physical examination with attention to the following signs:

   1. Head. Signs of increased intracranial pressure, central nervous system (CNS) depression, or irritability.

   2. Nares. Pass a small-diameter feeding tube through the nares to rule out choanal atresia.

   3. Heart. Listen for a murmur or gallop.

   4. Lungs. Check for adequate movement of the chest if mechanical ventilation is being used. Check for signs of respiratory distress.

   5. Abdomen. Check for abdominal distention, which is one of the earliest signs of NEC. Other signs of NEC are decreased bowel sounds and visible bowel loops.

   6. Skin. An infant with polycythemia has a ruddy appearance. Pallor is associated with anemia.

   7. Neurologic examination. Do a complete neurologic examination and look for seizure activity. Is there hypotonia?

2. Laboratory studies

   1. Immediate studies

      1. Arterial blood gas. To rule out hypoxia and acidosis.

      2. Complete blood count (CBC) with differential. May suggest infection, anemia, or polycythemia.

      3. Cultures of the blood, urine, and cerebrospinal (CSF) fluid. If infection is suspected and tests indicated. C-reactive protein at 36–48 hours after birth may be useful as an infection screen. Polymerase chain reaction (PCR) analyses and viral cultures are appropriate if a viral infection is suspected. Lumbar puncture and CSF analysis if meningitis is suspected or if increased intracranial pressure from hydrocephalus is causing apnea and bradycardia.

      4. Serum electrolyte, calcium, magnesium, and glucose levels. To rule out metabolic abnormality.

      5. Serum phenobarbital and methylxanthine levels. To check levels if indicated.

   2. Additional studies

      1. If an inborn error of metabolism is suspected. Test for organic acid levels, amino acid profiles, ammonia, pyruvate, and lactate. Ketones in the urine may indicate an organic acidemia.

      2. Stool analysis. To rule out infant botulism or other organisms.

3. Imaging and other studies

   1. Immediate studies

      1. Chest radiograph. Should be performed immediately if there is any suspicion of heart or lung disease.

      2. Electrocardiogram (ECG). If cardiac disease is suspected.

      3. Abdominal radiograph. Should be performed immediately if indicated. It may detect signs of NEC (see Figure 11–23).

      4. Ultrasonography of the head. To rule out periventricular-intraventricular hemorrhage, hydrocephalus, or any congenital abnormalities.

   2. Additional studies

      1. Echocardiography and cardiac consultation. ECG can reveal changes in the R-wave amplitude and QRS duration, appearing at the onset and termination of apnea and bradycardia episodes. Also rules out prolonged QT syndrome.

      2. Electroencephalography. Apnea and bradycardia may be a manifestation of seizure activity.

      3. Computed tomography (CT) of the head. To detect cerebral infarction and subarachnoid hemorrhage. Use adjusted scanning protocol to limit radiation exposure. The American Academy of Pediatrics (AAP) recommends early noncontrast CT in term encephalopathic infants to rule out hemorrhage. Magnetic resonance imaging (MRI) may be indicated because of the concern for radiation exposure. Term infants may require an MRI for a more extensive workup.

      4. Abdominal sonography or gastric emptying study. Useful where GI motility disorder is suspected.

      5. Barium swallow. To rule out GER (only in cases of apnea and bradycardia associated with feeding). It is helpful if the infant has a swallowing dysfunction or you suspect tracheoesophageal (TE) fistula or esophageal web. A video-fluoroscopic swallow study (VFSS or VSS) is a modified barium swallow study.

      6. Esophageal pH probe testing (acid reflux test of Tuttle and Grossman). Useful in determining whether acidic GER is present. A small-caliber tube with a pH electrode is passed into the distal esophagus. Continuous monitoring can be carried out over 4–24 hours. If the pH is acidic, acidic GER is occurring. Most reflux in infants is not acidic. pH monitoring is of limited use in preemies because their gastric pH is >4 ∽90% of the time.

      7. Multichannel intraluminal impedance. Measures reflux from retrograde flow of liquid from the stomach through the esophagus going up to the oropharynx. It can detect as small as 0.1 mL of volume by changes in impedance. This technique allows for detection of pH-neutral reflux, which may be as much as 75% of reflux in an infant.

      8. Reflux scintiscan (termed “milk scan” if used with milk or formula). This test is used to document GER. It is comparable to the pH probe and superior to the barium swallow. Technetium-99m–labeled pertechnetate is put in a water-based solution or milk (milk scan) and is instilled in the stomach. The patient is scanned in the supine position for 2 hours with the gamma camera. Positive scintigraphy has no correlation with symptoms.

      9. Lateral neck radiography, head and neck tomography (3 dimensional), and otolaryngology evaluation. May help to evaluate the upper airway in obstructive apnea.

      10. Polygraphic recording. (Usually multichannel, which can include many physiologic parameters.) Continuous recordings for up to 24 hours may help in the differential diagnosis of apnea. There are many different types of devices used.

          1. Polysomnography. This is the collective process of monitoring and recording physiologic data during sleep. It includes respiration, perioral electromyography, oxygen saturation, heart rate, electroencephalography, electrocardiography, and electrooculography.

          2. Thermistor pneumocardiogram. This incorporates a thermistor, which detects the changes in nasal and mouth airflow. It incorporates a pH probe to study the acidity in the esophagus.

          3. Impedance pneumography. This measures chest wall movements, oronasal flow, heart rate, and O₂ saturation by a multichannel recorder to help identify different types of apnea.

See also Chapter 83.

1. Prophylactic therapy and recommended monitoring

   1. At-risk infants. Cochrane review does not support prophylactic caffeine for premature infants at risk of apnea, bradycardia, or hypoxemic episodes.

   2. Postoperative apnea/bradycardia. Caffeine can be used to prevent postoperative apnea/bradycardia and oxygen desaturation in preterm infants. Infants <46 weeks postconceptional age should be monitored a minimum of 12 hours postoperatively.

   3. Postimmunization of preemies. Infants who had apnea after their first immunization should receive cardiorespiratory monitoring for a minimum of 24 hours after immunization.

   4. Cobedding of preterm twins. A decrease in central apnea occurs with cobedding of preterm twins.

2. General plan

   1. Emergency treatment. Tactile stimulation, oxygen if the infant is hypoxic, bag-and-mask ventilation, and intubation may be necessary if the infant is not responding. Once the infant is stabilized, evaluation should begin. Send stat labs, get a chest x-ray (CXR) and possible abdominal radiograph. Rule out simple causes: Is temperature okay in isolette? Is the NG tube, endotracheal tube (ETT) in the correct position? Is the position of the infant okay?

   2. Determine the cause of apnea and bradycardia and treat if possible. Sepsis is a cause that cannot be overlooked because antibiotics need to be started. Rule out sepsis/infection and other treatable causes (such as intraventricular hemorrhage [IVH], seizures, PDA, anemia, NEC, and others) before diagnosing and treating the infant with apnea of prematurity.

   3. Apnea of prematurity (AOP)

      1. Nonpharmacologic treatments

         1. Environmental temperature. Overheating may play a role in apnea. Keep the environmental thermoneutral or at the lower end of the range; a specific environmental temperature cannot be recommended. Some recommend humidification of warm gas.

         2. Infant positioning. In infants receiving other treatments, these positions did not result in a further decrease of AOP. Remember that the infant needs to be transitioned to be on the back before discharge.

            • (a) Prone position. Avoid neck flexion or extension, which can decrease the patency of the airway. Prone position reduces apnea, improves oxygenation and ventilation, decreases GER, and reduces energy expenditure in respiration. Only recommended for infants with apnea in the neonatal intensive care unit (NICU). Nursing in the prone position is also done.

            • (b) Head elevated tilt position (“HETP”). The bed is tilted in an inclined position of 15 degrees so the head and neck are elevated 15 degrees from the prone position; this position reduces episodes of hypoxia.

            • (c) Three stair position (“TSP”). The head and abdomen are maintained at horizontal position. The head is on 3 blankets, the thorax is on 2 blankets, and the pelvis is on one. Airway obstruction and neck inclination do not occur. This position was shown to improve apnea, bradycardia, and desaturation.

         3. Stimulation

            • (a) Tactile stimulation. Provides excitatory activity in the brainstem to stimulate respiratory activity. This is the most common intervention. Provide tactile stimulation (eg, rubbing the skin, stroking the back, patting the infant, tapping or tickling the feet).

            • (b) Olfactory stimulation. Introducing a pleasant odor (vanillin) into the incubator decreased apnea (study only 24 hours) in infants who were unresponsive to caffeine or doxapram (see Chapter 20).

            • (c) Kangaroo care. Conflicting results: effect is similar to prone positioning.

            • (d) Kinesthetic stimulation (oscillating mattress). Not effective in clinically significant apnea. Stochastic mechanosensory stimulation has been shown to decrease the duration of oxygen desaturation and potentially decrease apnea.

         4. Maintain nasal patency. Because nasogastric tubes increase nasal airway resistance and an increase in upper airway resistance may increase apnea of prematurity, orogastric tubes have been preferred in premature infants with apnea. Recent studies show that there is no difference in the two for feeding infants with AOP. The placement of the oral versus nasal feeding tubes also had no effect on hypoxia and bradycardia. Transpyloric feedings (especially when only human milk is used) may reduce apnea and bradycardia in preemies with suspected GER.

3. Management. Deciding on which infants to treat usually depends on how many episodes of apnea are occurring, the severity of each episode, and the required intervention to stop the episode of apnea. If there are multiple or severe apneic episodes, medical treatment may be necessary. Different institutions have different guidelines on when to start treatment. Some recommendations are: >6 apneic episodes every 12 hours requiring only minimal stimulation, or >2 apneic episodes per hour requiring minimal stimulation over a couple of hours, or >1–2 apneic episodes in 24 hours requiring vigorous stimulation, or any episode that the infant does not respond to tactile stimulation, or when the infant requires bag-and-mask ventilation with oxygen.

   1. Respiratory support. Maintain adequate oxygen saturation with supplemental oxygen (indicated if there is desaturation or bradycardia). Avoid vigorous suctioning.

      1. Low-flow oxygen. This may decrease the rate of intermittent hypoxia and apnea. Avoid hyperoxia.

      2. Nasal cannula oxygen This is a small, tapered cannula that is used to deliver oxygen or blended oxygen. It can cause nasal irritation, causing arousal, and may help to prevent apnea.

         1. Low-flow nasal cannula (<1 L/min) can be used as an adjunct for apnea. Low-flow oxygen does decrease the rate of intermittent hypoxia and apnea.

         2. High-flow nasal cannula (HFNC) can provide high concentrations of oxygen and also deliver a positive end-expiratory pressure and can be used as an alternative to nasal continuous positive airway pressure (NCPAP). The rates are 1–6 L/min. One study showed that nasal cannula oxygen was just as effective as nasal CPAP (NCPAP). HHHFNC (heated humidified high-flow nasal cannula) is preferred over HFNC.

      3. Continuous positive airway pressure (CPAP). CPAP via nasal prongs reduces apneic spells. (Note: Different sources cite different CPAP parameters. Ranges reported: 2–4, 3–6, 4–6, and 5–8 cm H₂O.) A range of 4–6 cm H₂O seems to be cited frequently and is safe. Use the settings recommended by your institution. It can be used in conjunction with medication (after a therapeutic level has been obtained). Side effects of CPAP include bowel distension, nasal trauma, barotrauma, and pneumothorax.

      4. Noninvasive ventilation (NIV). NIV is a method of ventilation without tracheal intubation that uses constant or variable pressure to provide ventilatory support. It is often used with CPAP. Nasal intermittent positive pressure ventilation (NIPPV) is a type of noninvasive ventilation that combines nCPAP with superimposed positive pressure breaths. Cochrane review states that NIPPV reduced the frequency of apneas more effectively than NCPAP. NIPPV via nasal prongs is more effective than NCPAP alone in apnea of prematurity. NIPPV also reduces the incidence of extubation failure more effectively when compared with NCPAP. More research is recommended.

      5. Mechanical ventilation. Should only be used if apnea and bradycardia cannot be controlled by other interventions (drug therapy or nasal CPAP or NIPPV). Low pressures (minimal peak inspiratory pressure) are used at the rate necessary to prevent apnea.

   2. Pharmacotherapy. See doses in Chapter 148.

      1. Caffeine is the drug of choice for apnea. Theophylline and caffeine seem to have equal efficacy (both reduce apnea within 2–7 days of beginning treatment), but caffeine offers benefits (fewer side effects, once-daily dosing, and increased CSF penetration). Caffeine therapy is associated with improved neurodevelopmental outcome and survival at 18–21 months in infants 500–1250 g and a reduction in death, incidence of cerebral palsy, cognitive delay, and severe ROP. Therapy can usually be discontinued by postconceptional age, usually 35–37 weeks, depending on the weight of the infant (usually 1800–2000 g) or if the infant has been free of apnea for 5–7 days.

      2. If apnea persists, begin doxapram. (Controversial, not recommended as routine therapy.) Doxapram appears to be efficacious when theophylline, caffeine, and CPAP have failed; it can reduce apnea within 48 hours after other methods have failed. There are concerns with side effects: risk of reduced cerebral blood flow with mental delay later; increased QTc interval, second-degree heart block, lower mental developmental index at 18 months; irritability, gastric retention, hypertension, seizures, and GI disturbance; metabolic acidosis (has benzyl alcohol preservative). If acidosis occurs, consider stopping the medication.

4. Specific treatment

   1. Anemia. Transfusion is not routinely recommended as data are conflicting and evidence is insufficient. Most institutions do not treat anemia if the infant is asymptomatic, the infant is feeding and growing, and the reticulocyte count is >5–6%. If the hematocrit (Hct) is low (<21–25% based on institutional guidelines), transfusion may be indicated. If the infant is symptomatic (significant apnea and bradycardia, defined as >9 episodes in 12 hours or >2 episodes in 24 hours requiring bag-and-mask ventilation), on therapeutic doses of methylxanthines, not feeding well, or on oxygen or respiratory support and the reticulocyte count is not appropriate for the low hematocrit (ie, reticulocyte count <2–3%), transfusion may be indicated to a Hct level of ≥30% or higher (controversial). Some data suggest that blood transfusion in extremely low birthweight infants is associated with an increase risk in bronchopulmonary dysplasia/chronic lung disease (BPD/CLD) and NEC. The use of recombinant human erythropoietin (rHuEPO) with iron for anemia of prematurity, decreasing the need for transfusions, is controversial and may increase the incidence of progression of ROP.

   2. Gastroesophageal reflux (GER). Common in premature infants. Apnea is unrelated to GER in most studies. The impression that apnea and bradycardia are more prevalent after feeding is not supported by the literature. Most institutions treat GER because of the possible association. Non-acid GER is responsible for a variable number of AOPs after GER. If clinical assessment (significant reflux or emesis with feeds) warrants intervention, then treatment options include:

      1. Feedings. Consider a change in feeding volume, method of feeding, or type of feeding. Overfeeding can aggravate reflux, so small volumes more frequently are recommended. Continuous tube feedings may help. Thickened feedings are recommended but controversial because randomized trials are inconclusive (starch thickening may be associated with an increase in human milk osmolality, which may make GER worse). Small-volume, thickened milk is preferred. A change in formula may be necessary if a food allergy is suspected. A diet change for the mother with a breast-feeding infant may be necessary. Transpyloric feedings with human milk may reduce apnea and bradycardia in preterm infants with GER.

      2. Position. Hold the infant upright in your arms at least 30 minutes after feeding. Prone head-elevated positioning showed a reduction in apnea and bradycardia and is preferred in infants with GER, but it has become controversial because of its association with SIDS. Infants with GER should sleep on their backs. Prone or left lateral position in the postprandial period limits GER.

      3. Medications for reflux have limitations based on inconclusive effectiveness and concern for side effects. If needed, the following can be used. Some clinicians advocate a prokinetic agent (eg, metoclopramide). If there is true acid reflux (documented by esophageal pH probe studies), then an H₂ blocker or proton pump inhibitor is used. Acid suppression therapy has been associated with an increase in lower respiratory infections and an increase in gram-negative infections due to the potential for GI colonization. See doses in Chapter 148.

         1. Prokinetic agents increase the muscle tone of the digestive tract.

            • (a) Metoclopramide (Reglan). Improves GI motility and reduces feeding intolerance. In GER of prematurity it is commonly used but controversial. (See Chapter 148 for dosing and other information.) Effectiveness is inconclusive and side effects are a concern: drowsiness, restlessness, extrapyramidal symptoms.

            • (b) Erythromycin. A prokinetic agent; it increases gastric motility and has been used in GER. Cochrane review states that there is insufficient evidence to recommend low or high doses of erythromycin for feeding intolerance in preterm infants. Studies in infants >32 weeks using high-dose erythromycin did show improvement in feeding intolerance.

         2. Antacids (Maalox and Mylanta). Neutralize acid but their use increases the risk of infection and feeding intolerance in infants receiving gavage feedings, and there is a risk of concretion formation. Side effects include diarrhea or constipation. If used, the dosage is 0.5–1 mL/kg by mouth every 4 hours by nasogastric tube. Alginate-based formulations (sodium alginate, Gaviscon dose 0.25 mL/kg per dose QID) was shown to decrease the degree and acidity of GER but had no effect on non-acid GER. It doesn't reduce the total number of apneas or gastroesophageal apneas. Side effects have included bezoar formation and adverse effects from the aluminum content. Further studies need to be done.

         3. H₂ blockers. Inhibit gastric acid production in neonates and are usually recommended. Of the 4 H₂ blockers available, ranitidine and famotidine are most commonly used in infants. They are preferred because of fewer side effects. H₂-blocker therapy is associated with higher rates of NEC in very low birthweight (VLBW) infants and an increased risk of Candida infections with H₂ blockers (predisposes to gastric colonization and increases the risk of bacteremia). They may also increase the risk of gram-negative sepsis. Ranitidine is associated with increased infections, increased NEC, and an increase in fatal outcome in VLBW infants and should be used with caution in newborns <1500 g.

         4. Proton pump inhibitors (PPIs). Found not to be effective in reducing GER symptoms in infants. Physicians should use caution when prescribing PPIs in infants and only use them if there is documented disease with strict monitoring. The studies show that evidence is lacking supporting the safety of PPIs in infants. Lansoprazole (Prevacid) and omeprazole (Prilosec) have been used the most in infants (only U.S. Food and Drug Administration [FDA] approved for infants >1 year). Like the H₂ blockers, they also increase the risk of Candida infections. There is also an increase in the risk of gram-negative sepsis.

5. Persistent apnea. Apnea of prematurity usually resolves by 36 weeks. Persistent apnea is apnea that persists ≥37 weeks postmenstrual age. It usually occurs in infants born <28 weeks' gestation. These infants are usually ready to go home except they continue to have apnea. These infants can be at risk for serious episodes of apnea, bradycardia, and cyanosis for several months. How to manage these infants at home is not well studied and recommendations are lacking.

   1. A comprehensive polygraphic recording is sometimes done before discharge. This does not predict the risk of SIDS or a severe cardiopulmonary event. It may give a more detailed explanation of the apnea and help in the decision process.

   2. Medication is continued. Decision when to stop depends on institutional guidelines.

   3. Apnea home monitoring. Cardiorespiratory monitoring at home with an event recorder can be recommended. Parents need to be instructed in the use of the monitor and be trained in cardiopulmonary resuscitation (CPR). Home monitoring does not prevent SIDS. AAP recommendations on home monitoring: may be justified in premature infants who are at high risk for recurrent apnea, bradycardia, and hypoxemia; infants with symptomatic BPD/CLD; infants who are respiratory technology dependent; and infants with medical conditions affecting their breathing. Use is limited after episodes stop or ∽43 weeks postmenstrual age.