Apnea and bradycardia
Definition
Apnea of infancy is traditionally defined as the absence of breathing for 20 seconds or longer, or a shorter respiratory pause associated with bradycardia, cyanosis, pallor, and/or marked hypotonia.
The term apnea of prematurity generally refers to infants with gestational age of less than 37 weeks at the onset of apnea.
Apnea is further divided into central apnea (no respiratory effort), obstructive apnea (infant initiates breath but no airflow), and mixed apnea (central and obstructive, most common type in older preterm infants).
The definition of bradycardia should change in relationship to both gestational age and postconceptional age (PCA).
There is no standard definition for a significant cardiorespiratory event in preterm infants.
Incidence
Apnea and bradycardia are common problems that have plagued neonatologists for decades, primarily in high-risk preterm infants.
The problem may be more prevalent today than before the mid-1990s, given the increasing numbers of physiologically immature infants on less invasive forms of respiratory support (continuous positive airway pressure [CPAP], high-flow nasal cannula, and nasal intermittent positive pressure ventilation).
Pathophysiology
Immature respiratory system (Figure 8-1)
In the vast majority of otherwise healthy preterm infants who exhibit various combinations of central and obstructive apnea, bradycardia, and desaturation, the underlying problem is immature respiratory control.
Physiologic studies in both infants and immature animal models have demonstrated impaired ventilatory responses to hypercapnia, either decreased or increased hypoxic responses, exaggerated inhibitory responses to stimulation of airway (eg, laryngeal) receptors, and presumably an immaturity in the way these afferent pathways are integrated in the preterm brainstem.
Given that fetal breathing movements are only intermittent, function primarily to promote lung growth, and play no role in gas exchange, it is not surprising that postnatal respiratory activity is also often irregular in preterm infants.
Hypercapnia
Hypercapnia is the major chemical driver of ventilation and sensed primarily centrally by chemosensitive cells in the brainstem that respond to either H+, CO2, or both.
The impairment of central chemosensitivity in preterm neonates is evident by a diminished ventilatory response to CO2 when compared to term neonates or adults. This impairment of hypercapnic ventilatory responses is also more pronounced in preterm neonates with apnea when compared to their controls without apnea.
Baseline PaCO2 in both preterm and term infants is only 1 to 2 mm Hg above the apneic threshold, and the contribution of closeness of the apneic threshold to baseline CO2, together with excessive activation of the carotid body, might be an unstable combination that allows small oscillations of CO2 in response to mild hyperventilation to cause apnea.
Hypoxia
The peripheral chemoreceptors are located primarily in the carotid body and are responsible for stimulating breathing in response to hypoxia.
It is reasonable to assume that these chemoreceptors contribute to resolution of apnea and, if silenced (eg, by hyperoxic exposure), it may lead to prolongation of apnea.
After an initial excitation of breathing, preterm infants respond to hypoxia by a late depression in ventilation that is thought to be central in origin and might represent the effect of a descending pontine inhibitory tract.
Hypoxia-induced depression of respiration does not seem to contribute to the initiation of apnea as most infants are not hypoxic prior to apnea; however, once apnea occurs a hypoxic respiratory depression might prolong apnea and delay its recovery.
Repeated hypoxia may lead to excessive peripheral chemoreceptor sensitivity and destabilize breathing patterns in the face of significantly fluctuating levels of oxygenation.
This is consistent with findings in preterm infants that a greater hypoxia-induced increase in ventilation correlates with a higher number of apneic episodes.
Laryngeal chemoreflex (LCR)
Activation of laryngeal mucosa in preterm and term neonates results in apnea, bradycardia, hypotension, and closure of upper airways and swallowing movements.
While this strong inhibitory reflex, termed the laryngeal chemoreflex, is potentially protective of the airway, its contribution to apnea, bradycardia, and desaturation episodes in preterm infants is unclear.
Neurotransmitters
Role of central neurotransmitter and neuromodulator-mediated pathways in immature respiratory control:
Both adenosine and prostaglandins inhibit respiratory neural output in early life, and nonspecific blockade of receptors via xanthine therapy is standard neonatal therapy for apnea of prematurity.
γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS), and the interaction of GABA with adenosine appears to play a role in immaturity of neonatal respiratory control.
Which comes first?
While fall in HR can be reliably measured during impedance monitoring on a beat-by-beat basis, it is usually initiated by a prior respiratory pause or apnea.
Risk factors
Prematurity
Increased risk with lower gestational age
Comorbidities
The NICU patient with excessive or persistent cardiorespiratory events is often of very low birthweight and may suffer from a number of other comorbidities, including intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), BPD, anemia of prematurity, gastroesophageal reflux (GER), and feeding problems. Indeed, the presence of one or more of these conditions may overshadow concerns of respiratory control, further complicating and prolonging discharge.
Both IVH/PVL and BPD have been shown to impact the frequency, severity, and duration of cardiorespiratory events.
Medications, interventions, and procedures
Certain medications, ophthalmologic examinations or laser therapy, immunizations, and other interventions may precipitate apnea events and should be taken into consideration in the discharge planning process.
Clinical presentation
Documenting episodes
Nursing and physician records of apnea, based on charting by care providers, are unreliable largely due to the fact that standard impedance monitoring techniques will fail to identify mixed and obstructive events. This is important, as longer episodes of apnea are typically associated with a component of upper airway obstruction.
Episodes of apnea, bradycardia, and/or desaturation should be both quantified and qualified in order to understand its significance.
Setting alarm limits
Most neonatal intensive care units in the United States set low HR alarms to 80 or 100 beats/min and infants remain on monitoring until the time of discharge.
Any fall in HR below that threshold is recorded in an infant’s medical record as a bradycardia, interpreted as abnormal, and a “brady watch” is reset until the infant is deemed ready for discharge.
One appropriate strategy would be to use 100 and 70 bpm as the low HR limit in the NICU and step-down unit, respectively, to account for gestational age. Lower heart rate alarm limits of 60 or 70 within the week of discharge may be preferable in this regard for older infants.
Another approach in documentation is to focus on desaturation episodes.
Since bradycardia and hypoxemia may be the primary variables contributing to neurodevelopmental morbidity, a focus on desaturations may be appropriate (Figure 8-2).
Like bradycardia, desaturation episodes (hypoxemia) lack a standard definition. Thresholds of 90%, 85%, and 80% have all been used to define hypoxemia in the recent literature.
The magnitude of desaturation associated with cessation of breathing will depend on baseline levels of oxygenation and pulmonary oxygen stores. Therefore, infants with residual lung disease exhibiting impaired pulmonary function, reduced functional residual capacity (FRC), and perhaps lower baseline oxygen levels, as in BPD, will be most vulnerable to episodic desaturation.
Recurrent apnea in both preterm infants and adults can cause rapid and profound decreases in oxygen saturation.
There is marked change in intermittent hypoxemic events in ELBW infants over time with relatively few hypoxemic episodes occurring during the first week of life, then a progressive increase in weeks 2 to 4, and finally a decrease in weeks 6 to 8, consistent with previous observations that apnea of prematurity is less common in the first postnatal days.
Also, the remarkably high incidence of intermittent hypoxic episodes in the ELBW population (eg, 50 to 100/day) would likely be underestimated by conventional pulse oximeter settings employing prolonged averaging times. These data provide a basis for evaluating potential morbidity associated with such episodes. They are also relevant to current controversy concerning optimal baseline oxygen saturation targets in acute and convalescing preterm infants.
Diagnosis
(As earlier, Clinical Presentation)
Management
“Normal”
The approach to the treatment of apnea in preterm infants should be with the basic understanding that apnea is, to an extent, physiologic.
Diligent management, not eradication, should be the goal.
When the frequency or severity of events becomes clinically significant, some form of further evaluation or therapy is instituted.
What qualify for significant or pathologic apnea events are generally at the discretion of the clinician; however, events requiring the following usually meet criteria for treatment.
Vigorous stimulation
Positive pressure ventilation
Chest compressions
Those resulting in heart rate and oxygen saturation alarms several times a day
Medical treatment
Medications
Methylxanthines, specifically caffeine, remain the first line of therapy. The Caffeine for Apnea of Prematurity (CAP) Trial provides substantial evidence that caffeine is both effective and safe.
Theophylline, although equally effective, has significant side effects that include tachycardia, feeding intolerance, jitteriness, and seizures, and is used only in situations where caffeine is not available.
Respiratory support
In infants with apnea refractory to pharmacotherapy, various forms of respiratory support may be added. These include
Nasal continuous positive airway pressure (NCPAP): The variable flow NCPAP device is the most effective in treating apnea of prematurity.
Biphasic CPAP.
Nasal intermittent positive pressure ventilation (NIPPV).
High-flow nasal cannula (HFNC): The use of humidified or nonhumidified HFNC, especially at flows exceeding 2 L/min, remains controversial. A recent Cochrane Review concluded that there is insufficient evidence to establish the safety of this form of respiratory support.
Intubation and mechanical ventilation.
Any one of these approaches may have beneficial effects by stabilizing the airway, increasing FRC, and improving oxygenation.
Early developmental/therapeutic interventions
Respiratory support for a prolonged duration, beyond 34 weeks’ PCA, may negatively impact early developmental processes, including feeding and motor skills.
Intermittent apnea and bradycardia spells should not prevent the infant from continuing to work on oral feeding skills or appropriate developmental care.
Kangaroo care and nonnutritive feeding practice is recommended for stable infants, with close attention to head positioning.
Attention to positioning is important in infants on respiratory support.
Prognosis
Although the natural history of cardiorespiratory instability in preterm infants is resolution over time, characterization of other risk factors, as well as frequency and severity of events, is essential in order to determine their potential relationship with various aspects of neurodevelopmental outcome.
The persistence and severity of apnea, bradycardia, and desaturation have been linked to unfavorable neurodevelopmental outcomes. However, this association does not imply cause and effect.
Newer technologies that incorporate continuous and reliable quantification of cardiorespiratory events (eg, episodic desaturation or bradycardia), coupled with the impact of various interventions (eg, caffeine and/or CPAP), may help unravel the long-term consequences of cardiorespiratory events.
Figure 8-1
Various pathways contributing to apnea of prematurity. With hypoxic responses, upregulation of peripheral chemosensitivity may destabilize breathing and predispose to apnea, while impaired hypoxic chemosensitivity may contribute to failure of apnea resolution. Central apnea with upper airway closure (mixed apnea) and diminished pulmonary oxygen stores may predispose to desaturation and bradycardia with short episodes of apnea.
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