Apnea and Periodic Breathing

I. Introduction

Apnea is common in preterm neonates which is a significant clinical problem. It is manifested by an unstable respiratory rhythm, reflecting the immaturity of the respiratory control system. Apnea can also be secondary to other pathological conditions and needs to be excluded before diagnosis of apnea of prematurity is made. In contrast periodic breathing is a benign condition and does not merit any treatment.

II. Definition

A. Apnea is defined as cessation of breathing that lasts for at least 20 seconds and accompanied by bradycardia or oxygen desaturation (cyanosis).

B. Periodic breathing is normal breathing pattern followed by apnea for 5 to 10 seconds without change in heart rate or skin color.

III. Classification of apnea

A. Central apnea (40%): Characterized by total cessation of inspiratory effort with no evidence of obstruction.

B. Obstructive apnea (10%): Infant tries to breathe against an obstructed airway resulting in chest wall motion without airflow throughout the entire apneic episode.

C. Mixed apnea (50%): Consists of obstructed respiratory efforts usually followed by central apnea. Purely obstructive apnea in the absence of a positional problem is probably uncommon.

IV. Periodic breathing

Periodic breathing consists of breathing for 10 to 15 seconds followed by apnea for 5 t0 10 seconds without change in heart rate or skin color and the net effect may be hypoventilation. It is due to an imbalance between the peripheral and the central chemoreceptors effect on ventilator drive. Periodic breathing in premature infants is often due to excessive stimulation by the chemoreceptor promoting an imbalance. The peripheral chemoreceptors are inactive, reset and functional after 2 days, so periodic breathing does not occur during the first 2 days of life. Prevalence of periodic breathing approaches 100% in preterm infants <1000 grams. It is more frequent during active sleep. The prognosis is excellent and it is controversial whether periodic breathing is associated with high risk of apnea of prematurity.

V. Pathogenesis

Apnea of prematurity is a developmental disorder and reflects a “physiological” rather than “pathological” immature state of respiratory control. A. Fetal to neonatal transition: The postnatal rise in PaO2 effectively silences peripheral chemoreceptors, resulting in delayed onset of spontaneous breathing, especially when neonates are exposed to 100% oxygen during postnatal resuscitation. The immature respiratory pattern and chemoreceptor function in premature infants may delay this postnatal adjustment, given fewer synaptic connection and poor myelination of the immature brainstem.

B. Ventilatory response to hypoxia: Transient increase in respiratory rate and tidal volume that lasts for 1 - 2 minutes followed by late sustained decrease in spontaneous breathing that may last for several weeks in response to hypoxia after birth. This late hypoventilatory depression associated with delayed postnatal respiratory adjustment occurs in premature infants. Peripheral chemoreceptor stimulation secondary to hypocapnia after hyperventilation and decrease CO2 may cause apnea.

C. Ventilatory response to laryngeal chemoreflex: The laryngeal chemoreflex mediated through superior laryngeal nerve afferents assumed to be protective reflex, an exaggerated response may cause apnea.

D. Neurotransmitter and apnea: Increased sensitivity to inhibitory neurotransmitters such as GABA (gamma amino butyric acid), adenosine, serotonin and prostaglandins may cause apnea.

E. Genetic variability and apnea: Genetic and environmental factors may lead to apnea. Heritability of apnea of prematurity was 87% among same gender twins and genome studies may provide further information. Congenital hypoventilation syndrome defined by lack of CO2 responsiveness during sleep thought to occur due to the mutation of developmental transcription factor PhoX2B. Severe depletion of neurons of the respiratory group of muscles was observed in experimentation animals due to the above mutation.

F. Sleep related apnea: Most apnea occurs during active sleep. Preterm infants are asleep 80% of time and 50% of sleep is active and the mature amount 20% is not reached until 6 months of age. During active sleep there is low voltage electrocortical state, decreased arousal from sleep, decreased muscular tone, absence of upper airway adductor activity, decreased respiratory drive. Irregular breathing and inspiratory chest wall distortion

associated with decreased ventilatory drive causes slight elevation in arterial PCO2. The ventilatory response to hypoxia and ventilatory sensitivity to CO2 is more depressed during active sleep. Activation of serotonin containing neurons which are part of arousal system of the brain stem decreases by nearly half during slow wave sleep and become nearly silent during REM sleep via activation of GABAnergic inputs. The respiratory center is depressed during active sleep as reflected in the slope of ventilatory response to

G. Siblings with SIDS: The collaborative home monitoring evaluation (CHIME) study showed that the incidence of apnea was same in siblings of SIDS and normal term infants.

H. GER and apnea: Studies have shown no temporal relation between GER and apnea. A decrease in LES tone and increased GER following apnea has been documented. Apnea occurs before reflux events and apnea with desaturation would lead to relaxation of gastroesophageal junction explain presence of formula often found in the pharynx of infants suctioned during an apneic event. Studies have shown that antireflux medications do not reduce apnea and bradycardia. It is common practice in many centers to treat methylxanthine resistant apnea of prematurity with antireflux medications. VI. Etiology of apnea

A. Physiologic (immaturity of respiratory center): This condition usually present after 1-2 days of life and within first 7 days also known as Apnea of prematurity.

B. Secondary causes:

B.1. Neurologic: Birth trauma, meningitis, ICH, seizures, perinatal asphyxia, congenital myopathies or neuropathies, placental transfer of narcotics, mgso4 or general anesthetics.

B.2. Pulmonary: Surfactant deficiency, pneumonia, pulmonary hemorrhage, obstructive airway lesions, pneumothorax, hypoxemia and hypercarbia.

B.3. Cardiac: Cyanotic CHD, hypo/hypotension, CHF, PDA, increased vagal tone and prostaglandins therapy.

B.4. Gastro intestinal: GE reflux and NEC.

B.5. Hematological: Anemia.

B.6. Hypothermia or hyperthermia.

B.7. Metabolic: Acidosis, hypoglycemia, hypocalcemia and hypo/hypernatremia.

B.8. Inborn errors of metabolism.

B.9. Sepsis.

VII. Diagnosis

A. History and physical examination: Review of maternal risk factors, medications, birth history and feeding intolerance. Examination including neurological examination and look for signs of sepsis.

B. Laboratory studies:

B.1. Complete sepsis workup, metabolic disorder workup if suspicious.

B.2. Imaging to look for atelectasis, pneumonia, airleak, NEC and Head ultrasound to detect IVH or other CNS abnormalities.

B.3. MRI and CAT study in infants with definitive signs of neurologic disorder.

B.4. EEG: to rule out seizures. Apnea as the sole presentation of seizures is uncommon.

B.5. Polysomnography: This study determines the type of apnea and can relate it to the sleep cycle of the infant. VIII. Treatment

Treatment strategies of apnea of prematurity should be based on modulating unstable respiratory rhythm into a more stable one.

A. Pharmacological management:

A.1. Methylxanthine therapy: Methylxanthine compounds such as caffeine, theophylline and aminophylline have been used as respiratory stimulants to decrease apnea of prematurity. Both caffeine and theophylline are effective treatment for AOP. Initially theophylline was the standard of treatment and required close monitoring of serum levels. Since FDA approval of caffeine, theophylline has been largely replaced by caffeine as the first line of management. Methylxanthines increase minute ventilation, improve CO2 sensitivity, decrease hypoxic depression, enhance diaphragmatic activity and decrease periodic breathing. How methylxanthine stabilize respiratory rhythm

and decrease apnea is not entirely clear. Enhancing the CO2 sensitivity may be an important component of its effectiveness. Animal studies have shown that adenosine protects brain cells during experimental hypoxic ischemic episodes. Methylxanthines are inhibitors of adenosine receptors and reducing apnea may be through blockade of A2 receptors on GABAnergic neurons. The common side effects include tachycardia, feeding intolerance, emesis, jitteriness, restlessness and irritability. Toxic effects may produce arrhythmias and seizures. Methylxanthines increase metabolic rate and oxygen consumption and have mild diuretic effect. Caffeine has much less side effects, is better tolerated and has a high therapeutic index when compared to theophylline. Caffeine has a long half life which makes convenient once a day dosing regimen and monitoring of caffeine levels at the recommended dosing is seldom necessary. Methylxanthine also increase metabolic rate and decrease cerebral blood flow, studies have shown that caffeine therapy for AOP reduce the incidence of BPD and improves survival without neurodevelopmental disabilities in VLBW infants. Caffeine at a loading dose of 10 mg/kg/day followed by 5 mg/kg/day maintenance may be adequate starting dose. High dose of caffeine may be considered for refractory apnea.

A.2. Doxapram: Doxapram is a potent non specific respiratory stimulant. It stimulates peripheral chemoreceptors at low dose and central chemoreceptor at high dose. Small dose is used for the treatment of AOP. Doxapram increases tidal volume and minute ventilation. Studies have shown effectiveness of doxapram in reducing apnea when refractory to methylxanthines. As a result of poor absorption, it is used as a continuous intravenous infusion. Side effects are increase in blood pressure, abdominal distension, irritability, jitteriness, increased gastric residue and emesis. Concern about benzyl alcohol, a preservative used in doxapram has limited its use in the United States.

B. Non pharmacological management:

B.1. Evidence based:

B.1.a. Prone head elevated positioning: the chest wall is stabilized and thoraco-abdominal asynchrony is reduced in prone position. Prone position along with head elevated tilt position showed reduction in apnea and bradycardia. The effect of head position on bradycardia and intermittent hypoxia is less pronounced in infants already receiving other treatment for apnea of prematurity. The prone, head tilt positioning may therefore be considered as a first line intervention, but will offer little benefit in infants treated with caffeine or CPAP.

B.1.b. Continuous positive airway pressure (CPAP): CPAP at 4-6 cm H2O has proven a safe and effective therapy of apnea of prematurity. It is effective in obstructive apnea rather than central apnea. Primary effect of CPAP is on airway patency or its splinting effects. CPAP delivers a continuous distending pressure via the infant’s pharynx to the airway to prevent both pharyngeal collapse and alveolar atelectasis, thereby enhances functional residual capacity, reduce work of breathing, improving oxygenation and decreasing bradycardia. During active sleep, functional residual capacity decreases because of reduction in tonic and post inspiratory activity of the diaphragm. CPAP increases functional residual capacity; thereby decrease periodic breathing and apnea. Another potential mechanism is through laryngeal mechanoreceptors; inhibitory feedback from mechanoreceptors in upper airway is reduced by CPAP. This decrease in inhibitory influence may translate into more stable respiratory rhythm and less apnea.

B.1.c. Flow through nasal cannula: Both high and low flow through nasal cannula can be a useful adjunct therapy in some infants with apnea who are already receiving methylxanthines. High flow produces a distending pressure especially in VLBW infants, which depends on factors such as flow rate, nasal leak and mouth closure. The airway pressure is not monitored while on flow.

B.1.d. Synchronized nasal ventilation: An extension of CPAP is administration of nasal intermittent positive pressure ventilation (N- IPPV). It has a high effectiveness over CPAP in preventing extubation failure.

B.2. Other interventions with unclear efficacy:

B.2.a. Orogastric versus nasogastric feeding tube placement: A nasogastric tube increase nasal resistance by 50%, therefore orogastric feeding tube are sometimes preferred in preterm infants with apnea. Studies have shown that no benefit using oral instead of a nasogastric tube for feeding infants with AOP. In one retrospective study showed that transpyloric human milk feeding have shown to be safe and reduce episodes of apnea and bradycardia in preterm infants with suspected GE reflux.

B.2.b. Kangaroo mother care: Studies have shown that infants receiving KMC had decreased episodes of apnea and bradycardia. The effect of KMC in improvement of apnea and bradycardia is same as that seen with prone positioning. The use of KMC for treatment of AOP still requires further study.

B.2.c. Keeping environmental temperature at the lower end of the thermoneutral range: Increase in body temperature in infants enhances the instability of the breathing pattern. Overheating should be avoided but there is no significant data to recommend a specific environmental temperature that may be used to reduce the incidence of AOP. B.2.d. Oscillating waterbed and tactile stimulation: Synchronization of respiration may be achieved between infants own breathing rhythm and an external rhythm generator (eg:-an inflatable mattress connected to a respirator). This synchronization is better beyond 35 weeks GA when AOP is no longer a major issue, so this intervention was largely abandoned. Recently stochastic mechanosensory stimulation using actuators embedded in a specially designed mattress for subcutaneous stimulation have shown to decrease in duration of oxygen desaturation. Confirmation of this approach in a large sample and over longer study duration is necessary.

B.2.e. Olfactory stimulation: Olfactory stimulation modulate infants respiratory pattern particularly during active sleep when apnea is more common. Introduction of a pleasant odor into the incubator reduce the incidence of apnea and bradycardia. Study was done in smaller group for a period of 24 hours. A large trial is needed to test this mode of treatment, but the lack of side effects is encouraging.

B.2.f. Inhaled Co2 (Increased inspiratory concentration): respiratory drive depends on CO2, if CO2 levels fall below a baseline level, apnea occurs. Inhaled Co2 reduces apnea and periodic breathing by regularizing respiration and was not associated with any adverse side effects. However it is likely that infant will quickly adjust to a higher

inspiratory CO2 concentration and the effectiveness of long term exposure is not known.

B.2.g. Red blood cell transfusion: An increase in respiratory drive resulting from an increased tissue oxygenation is one of the proposed mechanisms for red cell transfusion to ameliorate AOP. There is insignificant evidence to recommend transfusion to treat AOP in anemic infants. Data on the effect of blood transfusion in treating AOP is conflicting, though it was not associated with apnea frequency but was associated with increased risk of BPD and NEC.

B.2.h. Oxygen administration: application of low flow oxygen results in reduced rate of intermittent hypoxia and apnea. Oxygen toxicity should be considered while using this modality of treatment.

i. Branch chain amino acid supplementation: Preterm babies have increased work of breathing which may lead to muscle fatigue contributing to AOP. Thus improving diaphragmatic strength should theoretically be beneficial. Total parenteral nutrition solution enriched with branched chain amino acids which improve diaphragmatic function in vitro was associated with decrease in apneic episodes. This treatment needs further investigation. Another approach that has been tried in this regard is creatine supplementation which also potentially increase muscle endurance, but existing data are not encouraging.

IX. Discharge planning and follow up

A. Consider stopping caffeine at 34 weeks postmenstrual age. B. More aggressive approach is to stop when infant is apnea free for a period of 7 days irrespective of age. C. If asymptomatic for 5 days after stopping methylxanthines, the child may be discharged without further therapy. D. Considerations for home apnea monitoring: 1. Persistent, symptomatic apnea at >36 weeks postmenstrual age. 2. History of severe apparent life threatening event and abnormal Polysomnography. 3. Technology dependent infant (eg, home mechanical ventilation) 4. Home oxygen administration. 5. Central hypoventilation syndromes.

X. Prognosis

Apnea of prematurity resolves with maturation. Physiological basis for resolution of apnea is believed to be myelination of the brainstem. Poor neurodevelopmental outcome is associated with delayed in myelination in infants with apnea of prematurity. Otherwise in most infants apnea resolves without the occurrence of long term deficiencies.