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Understanding the physiology of neonatal respiratory control has served as an effective guide to common therapeutic approaches.
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Both the acute and longer-term consequences of intermittent hypoxia secondary to apnea of prematurity are subjects of intense interest.
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Intermittent hypoxemia may contribute to an inflammatory stress response.
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Although caffeine is the mainstay of apnea therapy, there remains considerable controversy regarding optimal treatment regimens.
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Innovative newer approaches to stabilizing respiratory control may hold promise as future interventions.
There are a multitude of reasons why immaturity in respiratory control is of interest to scientists and clinicians alike. From a biologic perspective it represents a unique link between the developing respiratory and central nervous systems. The resultant apnea precipitates repetitive oxygen desaturation and, hence, preterm infants serve as a novel biologic model for studying the consequences of such episodic desaturation. From a clinical perspective the combination of immature respiratory control, an immature lung, and the resultant therapeutic ventilatory support predispose these infants to chronic respiratory morbidity. Finally, there is a need to optimize and provide safe pharmacotherapy that enhances respiratory neural output in this high-risk population of neonates. These are some of the current high-profile issues and controversies that this chapter addresses.
Biologic Challenges in Characterizing Neonatal Respiratory Control
The ability to challenge respiratory neural output with hypoxic or hypercapnic exposures is quite limited in human infants. Therefore one must rely on older studies to better understand the maturation of peripheral and central components of chemoreception. We are also very dependent on neonatal animal models, particularly data derived from rodents, although, unfortunately, such models rarely exhibit long spontaneous apnea or periodic breathing as seen in preterm infants.
Central Respiratory Control
The neural circuitry that generates respiratory rhythm and governs inspiratory and expiratory motor patterns is distributed throughout the pons and medulla. The medulla contains a specialized region known as the pre-Bötzinger complex, which contains neurons that exhibit intrinsic pacemaker activity capable of producing rhythmic respiratory motor output without sensory feedback. Although a fundamental feature of this network is that it enables breathing to occur automatically, this systematic central rhythmicity may fail in preterm infants. Meanwhile, central and peripheral sensory inputs from multiple sources allow adjustments to the patterns of inspiratory and expiratory activity in response to changing metabolic conditions. For example, inhibitory sensory inputs from the upper airway may be particularly prominent in early postnatal life to serve a protective function, although this may trigger potentially clinically significant apnea.
A poorly understood concept is the relationship between periodic breathing—that is, repetitive cycles of respiratory output and pauses of approximately 5 to 10 seconds’ duration, and apneic episodes typically of 10 to 20 seconds’ duration that do not exhibit a cyclic pattern. Available data suggest that periodic breathing occurs predominantly in quiet sleep, whereas apnea is more common in active sleep. This would suggest a different central or peripheral biologic basis for those breathing patterns as discussed later.
Excitatory and inhibitory neurotransmitters and neuromodulators mediate the rhythmogenic synaptic communications between neurons of the medulla. Glutamate, acting on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N -methyl- d -aspartate receptors, is the major neurotransmitter mediating excitatory synaptic input to brainstem respiratory neurons. Gamma-aminobutyric acid (GABA) and glycine are the two primary inhibitory neurotransmitters in the network, mediating the waves of inhibitory postsynaptic potentials during the silent phase of respiratory neurons. Interestingly, during late embryonic and early postnatal development, GABA and glycine can mediate excitatory neurotransmission secondary to changes in the chloride gradient across the membrane. It is unclear how this phenomenon relates to the inhibition of respiratory output and resultant apnea seen in preterm infants. Neonatal rodent data suggest that caffeine, which is a nonselective adenosine receptor inhibitor, may block excitatory A 2A receptors at GABAergic neurons, and so inhibit GABA output and contribute to the ability of caffeine to enhance respiratory drive. Serotonin may be of particular importance in the modulation of respiratory function. Serotonergic neurons and their projections may represent the neuroanatomic substrate for the integration of cardiorespiratory responses. Defects in the medullary serotonergic system likely contribute importantly to the pathogenesis of sudden infant death syndrome. For future advances in the pharmacotherapy of neonatal apnea, greater understanding of the maturation of these neurotransmitters/neuromodulators is imperative.
Central and Peripheral Chemosensitivity
Responsiveness to carbon dioxide (CO 2 ) is the major chemical driver of respiratory neural output. This is apparent in fetal life where breathing movements increase under hypercapnic conditions in animal models. As in later life, CO 2 /hydrogen ion (H + ) responsiveness is predominantly based in the brainstem, although peripheral chemoreceptors contribute to the ventilatory response and respond more rapidly. The reduced ventilatory response to CO 2 in small preterm infants, especially those with apnea, is primarily the result of decreased central chemosensitivity; however, mechanical factors such as poor respiratory function and an unstable, compliant chest wall may contribute. It is difficult to distinguish the neural from mechanical factors that contribute to respiratory failure in this population.
It has been known for many years that preterm infants respond to a fall in inspired oxygen concentration with a transient increase in ventilation over approximately 1 minute, followed by a return to baseline or even depression of ventilation. The characteristic response to low oxygen in infants appears to result from initial peripheral chemoreceptor stimulation, followed by overriding depression of the respiratory center as a result of hypoxemia. Such hypoxic respiratory depression may be useful in the hypoxic intrauterine environment where respiratory activity is only intermittent and not contributing to gas exchange. The nonsustained response to low inspired oxygen concentration may, however, be a disadvantage postnatally. It may play an important role in the origin of neonatal apnea, and offers a physiologic rationale for the decrease in incidence of apnea observed when a slightly increased concentration of inspired oxygen is administered to apneic infants who have a low baseline oxygen saturation. Decreased peripheral chemoreceptor responsiveness to oxygen or central hypoxic depression of respiratory neural output may impair recovery from apnea. In contrast, excessive peripheral chemosensitivity has also been shown to compromise ventilatory stability and predispose to periodic breathing and even apnea in preterm infants. Periodic breathing is thought to result from a combination of dominant peripheral chemosensitivity combined with a CO 2 level close to the apneic threshold, resulting in the characteristic cycles of breaths and pauses. These findings are consistent with the observed postnatal delay in onset of periodic breathing, as peripheral chemoreceptors may be silenced in the initial postnatal period.
Contribution from Inflammatory Mechanisms
It is well recognized that apnea may be the first indication of neonatal sepsis. There is also considerable current biologic interest in the role of inflammation on respiratory neural output at both central and peripheral levels. Although inflammatory cytokines probably do not readily cross the blood-brain barrier, systemic infection does upregulate inflammatory cytokines at the blood-brain barrier, resulting in activation of prostaglandin signaling and resultant inhibition of respiratory neural output. Chorioamnionitis is a major precipitant of preterm birth. It is possible that antenatal or postnatal exposure of the lung to a proinflammatory stimulus may activate brain circuits that destabilize respiratory neural output. In neonatal rodents there is a response of proinflammatory cytokine gene expression in the brainstem after intrapulmonary lipopolysaccharide exposure, which is partially vagally mediated. This is accompanied by significant ventilatory depression to hypoxic exposure. An interesting related line of investigation is the role of intermittent hypoxia (IH) and resultant oxidant stress on inflammatory pathways that regulate respiratory neural output. Much work is needed to explore these potential interrelationships between impaired respiratory neural output and inflammation, IH, and any resultant oxidant stress as discussed later.
Clinical Challenges in Defining Neonatal Apnea
During early postnatal life apneic events are ubiquitous; they can vary widely in duration and are often accompanied by bradycardia and/or intermittent hypoxemia. Accordingly, American Academy of Pediatrics guidelines have historically defined clinical apnea of prematurity as a respiratory pause of 20 seconds or shorter if accompanied by hypoxemia (<80%) and/or bradycardia (<80 beats/min). It should be noted that even short respiratory pauses, approximating 10 seconds or less, may be associated with desaturation and/or bradycardia. Apnea is categorized as (1) central with loss of central respiratory drive resulting in complete cessation of flow and absence of respiratory effort; (2) obstructive with absence of flow in the presence of respiratory efforts; and (3) mixed with both central and obstructive components. Mixed apnea accounts for approximately 40% to 50% of all events in preterm infants and is often initiated by a loss of central drive, followed by a delay in resolution owing to upper airway closure. However, airway narrowing and/or collapse, as measured by cardiac signal transmission on the flow waveform, can also occur during central apnea. Unfortunately, standard impedance monitoring, which reflects chest wall motion, may fail to differentiate obstructed versus unobstructed inspiratory efforts.
The true incidence of apnea during early postnatal life has been grossly underestimated because of the historical practice of using nursing documentation, shown to underreport the true frequency of clinical events by more than 50%. More accurate pneumogram recordings have revealed a high incidence of cardiorespiratory events even in convalescing infants. For example, in very low-birth-weight (VLBW) neonates, 91% of pneumograms performed within 72 hours of anticipated discharge revealed apnea accompanied by a fall in heart rate or oxygen saturation. This has been supported in a more recent expanded cohort of 1211 infants younger than 35 weeks’ gestation showing that preterm infants continue to experience short apnea with bradycardia and/or desaturation in the week before discharge. It is therefore not surprising that hospitalization is frequently prolonged owing to concern about persistent cardiorespiratory events. Neonatal intensive care unit (NICU) electronic medical record databases are beginning to incorporate automated detection of apnea/bradycardia/desaturation in contrast to manual entries by the nursing staff. Because hospital discharge is often driven by the presence (or absence) of events, it is unclear how the anticipated increased frequency of documentation with automated bedside monitoring may affect duration of hospitalization.
Association Between Apnea of Prematurity, Intermittent Hypoxemia, and Bradycardia and Neonatal Outcomes
Multiple studies in preterm infants have shown an association between apnea of prematurity and morbidity. However, more recent data in neonatal models suggest that the accompanying desaturation and/or bradycardia may be the contributing factor(s) in initiating a pathologic cascade. In preterm infants, IH is almost always preceded by a respiratory pause and often occurs rapidly (∼10 seconds) after cessation of airflow. Factors that can influence the initiation, duration, and severity of IH include baseline oxygen saturation, oxygen uptake from the alveoli, pulmonary oxygen stores, total blood oxygen-carrying capacity, the slope of the hemoglobin oxygen dissociation curve, and metabolic oxygen consumption. In extremely preterm infants, IH events are pervasive and transient during early postnatal life with a relatively low incidence during the first week of life, followed by a rapid increase during the second and third weeks and a plateau or decrease thereafter. A significant challenge is that we are only beginning to understand the implications of patterns of IH events on morbidity ( Fig. 13.1 ).
Strong evidence in both animal and infant models suggests an association between cardiorespiratory events and impaired executive function. For example, in VLBW infants delayed resolution and increased event severity during early postnatal life are risk factors for severe handicap at 13 months of age. Apnea during hospitalization has also been shown as a predictor of neurodevelopmental impairment at 2 to 3 years of age and diminished adaptive behavior at early school age (Vineland Adaptive Behavior Scale composite score). Many of the infant studies relied on chart documentation of apnea, limiting the reliability of study findings, and do not address the question of whether it is the apnea or accompanying desaturation that initiates the pathologic sequelae. Unfortunately, it is very difficult to implicate causality as opposed to association when relating apnea and IH to outcome.
Long-term recordings have now allowed for more reliable and detailed analyses of oxygen saturation patterns and morbidity. For instance, continuous pulse oximetry monitoring over the first 2 months of life revealed an association between severe retinopathy of prematurity and a higher frequency of IH, of longer duration, and a distinct timing between IH events. A secondary analysis of infants enrolled in the Canadian Oxygen Trial has shown an association between increased time spent less than 80% during IH events and a greater probability of death or disability, cognitive or language delay, severe retinopathy of prematurity, and motor impairment at 18 months of age that was limited to IH events of 1 minute or longer in duration.
Association Between Apnea of Prematurity, Intermittent Hypoxemia, and Bradycardia and Longer-Term Outcomes
Interpretations of infant trial findings have been limited to associations between IH and morbidity in contrast to animal models that have been able to show direct causation. For example, in rodents, exposure to IH events during the first weeks of life causes impaired working memory, decreased brain weight, increased expression of caspase 3, locomotor hyperactivity, and alterations in dopamine signaling in adulthood, reinforcing long-term effects of IH exposure on brain development.
Sleep-disordered breathing is a relatively common condition in children and young adults. Former preterm infants are especially at risk, although the mechanisms are currently unknown. Early postnatal exposure to chronic intermittent exposure in rodents resulted in a blunted acute ventilatory response to hypoxia during adulthood, suggesting that early IH patterns can also have long-lasting effects on respiratory stability. This may be one explanation why former preterm infants have an approximately fourfold increase in the obstructive apnea hypopnea index at 8 to 11 years of age compared with former healthy term infants. A more recent trial in former preterm infants assessed the effect of early postnatal caffeine exposure on sleep architecture and breathing patterns at 5 to 12 years of age. Although there were no differences between caffeine groups, approximately 10% of the infants had obstructive sleep apnea, again suggesting former preterm birth is a risk factor for sleep-disordered breathing in later childhood.
Finally, IH may be one of many factors that contribute to growth trajectory in preterm infants. Data in neonatal rats have shown that IH induces both brain and body growth restrictions, which were followed by catch-up growth after a few weeks of recovery. Thus the effect of IH on growth restriction may be short term and reversible. In contrast, the effect of IH on cardiovascular control may be long-lasting and dependent on the pattern of IH exposure. For example, rat pups exposed to a clustered pattern of IH exhibited lower blood pressure that was sustained after 2 months of exposure. In contrast, an equally dispersed paradigm of IH had no effect on blood pressure.
In summary, the potential consequences of apnea of prematurity are most likely associated with the accompanying fall in oxygenation. Pathologic cascades may be initiated by specific high-risk patterns of IH and have both short-term and long-lasting effects, including sleep-disordered breathing, growth restriction, retinopathy of prematurity, neurodevelopmental impairment, and alterations in cardiovascular regulation. Identification of high-risk patterns may provide insight on future intervention protocols in the NICU setting.
Mechanistic Insights Into Morbidity
Little information is known regarding the mechanism underlying morbidities associated with IH, although alterations in oxidative stress, inflammatory mediators, and trophic factors may be attributed to initiating a pathophysiologic cascade. Low levels of oxygenation alter transcriptional responses that are mediated by hypoxia-inducible factors (HIFs). In animal models, IH has been shown to initiate accumulation of HIF-1α and reactive oxygen species generation during the onset of reoxygenation. At the same time, IH exposure initiates degradation of HIF-2α and downregulation of superoxide dismutase. The net result is overall prooxidant signaling leading to pathophysiology. These effects are supported by data in healthy volunteers demonstrating that CIH increases oxidative stress by increasing production of reactive oxygen species without a compensatory increase in antioxidant activity. Future therapeutic interventions could include inhibition of oxidative stress associated with resolution of IH.
The increase in IH events during early postnatal life in extremely preterm infants may also play a role in enhancing inflammatory cytokine levels. In animal models IH initiates an inflammatory response during early postnatal life with increments in tumor necrosis factor α, interleukin (IL)-8 and IL-6 from onset of IH exposure. Correspondingly, in ELBW infants recurrent or persistent elevations of serum inflammatory proteins during the first 2 weeks of life have been associated with attention deficit behavior at 2 years of age. Therefore it is reasonable to suggest that IH during early postnatal life may play a role in the inflammatory response associated with later neurodevelopmental dysfunction. This may be one possible explanation why caffeine, a known antiinflammatory, improves the rate of survival of VLBW infants without neurodevelopmental impairment (NDI) at 18 to 21 months.
Controversies in Therapy
There are various pharmacologic and nonpharmacologic therapies for apnea of prematurity. Therapies are initiated depending on variations in NICU clinical practice, nursing documentation of events, clinical status, and infant respiratory requirements. Some therapies are shown to be beneficial in larger trials; however, other treatments are controversial and require further investigation.
Accepted Treatments
Caffeine
Caffeine is the most common therapy used to treat apnea and intermittent hypoxemia. Caffeine and other methylxanthines have been prescribed in preterm infants for the past 40 years and have been shown to reduce apnea and the need for ventilation. In a recent study Rhein et al. demonstrated that caffeine therapy, administered to infants of 25 to 32 weeks’ gestation, decreased the number of intermittent hypoxemic events and time with hypoxemia at 35 and 36 weeks’ postmenstrual age.
The largest trial of caffeine (Caffeine for Apnea of Prematurity Trial) randomly assigned 2006 infants with birth weights between 500 and 1250 g to caffeine or placebo in the first 10 days of life. Although apnea of prematurity was not measured in this clinical trial, caffeine administration was associated with a reduction in the duration of positive-pressure support, oxygen supplementation, and the incidence of bronchopulmonary dysplasia. Caffeine also significantly improved survival without neurodevelopmental disability at 18 to 21 months, although the two treatment groups were no longer statistically different at 5 years of age.
There are various pharmacologic effects of caffeine in apnea of prematurity. Most importantly, it stimulates the respiratory center in the brainstem and increases sensitivity to CO 2 . Mechanisms of action include blockade of adenosine A 1 and A 2A receptor subtypes resulting in excitation of respiration neural output. Caffeine has also been shown to enhance peripheral chemoreceptor activation. A loading dose of caffeine showed a rapid (within 5 min) and prolonged (2-hour) increase in diaphragmatic activity that was associated with an increase in tidal volume. Lastly, caffeine may have antiinflammatory properties in the lung. For example, rat pups exposed prenatally to lipopolysaccharide had improved lung resistance and cytokine profiles after caffeine treatment.
Optimal strategies of caffeine therapy have yet to be determined ( Box 13.1 ). For example, common practice entails a caffeine citrate loading dose of 20 mg/kg followed by 5 to 10 mg/kg per day with potential side effects including tachycardia, dysrhythmia, feeding intolerance, gastroesophageal reflux disease, jitteriness, irritability, or rarely observed seizures. However, higher doses of 80 mg/kg have been associated with an increased incidence of cerebellar hemorrhage and should most likely be avoided.
