J.

Arab Neonatal Forum 2005; 2:63-73

Apnea of prematurity: past, present and future

Jalal M Abu-Shaweesh, Richard J Martin Department of Pediatrics, Rainbow Babies and Childrens Hospital, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio _________________________________________________________________________________________ The transition from fetal to neonatal life requires infants to develop a stable respiratory pattern for successful gas exchange to occur. However, in preterm infants immaturity of respiratory control almost invariably results in respiratory pauses of variable duration that may require pharmacologic intervention or ventilatory support. Although the definition of apnea is inconsistent and varies between studies, apneic episodes often lead to multiple investigations to role out precipitating or associated disorders, and therapeutic interventions are common. The problem is compounded by the fact that apnea and the resultant combination of bradycardia and desaturation may not be benign, and the necessary therapeutic interventions may carry their own risks. Furthermore, apnea of prematurity has also been associated with poor developmental outcome in school age children, although a cause and effect relationship is difficult to establish. Definition and characteristics Apnea of prematurity has been defined as cessation of breathing of 10-30 seconds duration.1-7 However, this condition has been defined most widely as cessation of breathing in excess of 15 seconds duration, typically accompanied by desaturation and bradycardia. Shorter episodes of apnea may also be accompanied by significant bradycardia or hypoxia.8 Brief respiratory pauses of less than 10 seconds in duration can also occur in conjunction with startles, movement, defecation or swallowing during feeding. These short pauses are self limited and not typically associated with bradycardia or hypoxemia.9 Prolonged desaturation episodes have also been reported in the absence of apnea or bradycardia, both in healthy preterm infants,10-12 and more frequently in infants with chronic lung disease.13 These episodes might represent obstructive apnea, hypoventilation or intrapulmonary right-to-left shunting.14 The significance of such episodes is unclear, however, recurrent hypoxemia has been associated with retinopathy of prematurity,15 necrotizing 16 entercolitis, and periventricular leukomalacia.17 Apnea is traditionally classified into three categories based on the presence or absence of obstruction of ______________________________ Contact Address: Jalal M Abu-Shaweesh, MD, Division of Neonatology, Rainbow Babies & Childrens Hospital, 11100 Euclid Avenue, Cleveland, Ohio 44106-6010, Phone: 216-844-3387. Fax: 216-844-3380 the upper airways. These include central, obstructive and mixed apneas. Central apnea is characterized by total cessation of inspiratory efforts with no evidence of obstruction. In obstructive apnea, the infant tries to breathe against an obstructed upper airway resulting in chest wall motion without nasal airflow throughout the entire apnea. Mixed apnea consists of obstructed respiratory efforts usually following central pauses [Figure 1] and is probably the most common type of apnea followed in decreasing frequency by central and obstructive apnea. The contribution of obstruction to apnea was first described by Thach and Stark who observed that the frequency of apnea increased when the premature infants neck was flexed.9 Subsequently, upper airway obstruction was found to accompany apnea even in the absence of neck flexion.18,19 The site of obstruction in the upper airways is mostly in the pharynx, however, it may also occur at the larynx, and possibly both sites. The incidence of apnea of prematurity is inversely related to gestational age and occurs in the vast majority of extremely low birth weight infants.20,21 The onset of apnea seems to be related to the presence of lung disease as apnea may occur on day one of life in infants without respiratory distress syndrome but may be delayed to several days in infants with respiratory distress syndrome.22,23 The precise incidence of apnea obviously depends on the precise diagnostic criteria employed, nonetheless, both the frequency and duration of apnea decrease between 1 and 20 weeks postnatal age.24 However, apnea is not confined to preterm babies as healthy term infants were also found to have apnea exceeding 20 seconds on home monitoring.25 Physiological consequences of apnea A decrease in arterial PO2 and oxygen saturation is the typical response to apnea in preterm infants, although the extent of that fall varies between infants. Presumably the decrease in oxygenation is directly related to the duration of apnea and the initial level of PaO2, and is reportedly greater in obstructive than central apnea.26,27 The bradycardia that accompanies apnea and resultant desaturation has been attributed to hypoxic stimulation of the carotid body chemoreceptors,28 especially in the absence of lung inflation [Figure 2]. Bradycardia is also seen, however, to accompany apnea in the absence of desaturation. With more severe bradycardia, both systolic and diastolic blood pressures may fall and this has been associated with a decline in cerebral blood flow velocity usually to the extent that no or

63

Apnea of prematurity: past, present and future

Figure 1: Characteristic mixed apnea of approximately 20 seconds duration commencing with a central component and prolonged by obstructed inspiratory effort. In the absence of simultaneous measurement of rib cage and abdominal motion as occurs during routine impedance monitoring of chest wall motion, the obstructed inspiratory effort would not be recognized. Bradycardia and desaturation are secondary to the cessation of effective ventilation during mixed apnea. (Reproduced with permission from Miller, M.J., Fanaroff, A.A. and Martin, R.J. (2005) Respiratory disorders in preterm and term infants. In Fanaroff and Martins NeonatalPerinatal Medicine, Martin, R.J., Fanaroff, A.A and Walsh, M.W., eds, 8th Ed. Elsevier, Philadelphia, PA.). minimal diastolic flow could be detected.29 Therefore, in infants without adequate cerebrovascular autoregulation, cerebral perfusion may decrease to very low levels during prolonged apnea and might potentially exacerbate hypoxicischemic brain injury in susceptible premature infants. Pathophysiology Apnea of prematurity is thought to be secondary to immaturity of brainstem centers that regulate breathing. This immaturity in regulation of breathing is also manifested by immaturity in the respiratory responses to hypoxia, hypercapnia and an exaggerated inhibitory response to stimulation of airway receptors, as simplified in Figure 3. Although a cause and effect relationship has not been documented for disturbed control of breathing and the occurrence of apnea in preterm infants, strong associations are very well established. Histologically, immaturity of the preterm brain is manifested by a decrease number of synaptic connections, dendritic arborizations and poor mylenization.30,31 Functionally, infants with apnea expressed longer auditory-evoked responses than matched controls indicating a delay in brainstem conduction time.32 Furthermore, multiple inhibitory neurotransmitters and neuromodulators have been implicated in the pathogenesis of disturbances of breathing both at the peripheral and central chemoreceptors, including dopamine, adenosine, endorphins, -aminobutyric acid (GABA) and prostaglandins, and these may be upregulated in early life. Hypercapnic Responses The ventilatory response to CO2 has been clearly shown to increase with advancing postnatal and gestational age in preterm human infants. Therefore, the breathing response to CO2 in preterm infants and especially those with apnea is impaired when compared to term neonates or adults.33-35 This impairment is both quantitative and qualitative. Whereas term neonates and adults increase their ventilation through an increase in both tidal volume and frequency, preterm infants do not appear to increase frequency in response to CO2.34,36 This somewhat unique response of respiratory timing during hypercapnic exposure is associated with prolongation of expiratory duration.36 Physiologic studies employing various animal models such as rat

64

J. Arab Neonatal Forum 2005; 2:63-73

Fig. 2

IMMATURITY

Enhanced inhibitory reflexes

Altered hypercapnic responses

Hypoxic depression

APNEA

Figure 2: Proposed pathophysiologic mechanisms predisposing to or causing apnea of prematurity.

Fig. 3

Decreased Respiratory Drive

APNEA, HYPOVENTILATION incr. vagal tone

peak of phasic activity prior to corresponding events in the diaphragm. This presumably serves to ensure upper airway patency at peak inspiratory flow. In response to hypercapnic exposure in piglets, there is a relatively linear increase in diaphragm activation. In contrast, genioglossus and alae nasi exhibit a higher hypercapnic threshold with muscle activity increasing at a significantly higher level of CO2. It is possible that during hypercapnia, as might occur during apnea, an initial increase in diaphragmatic, but not upper airway, activity causes pharyngeal or laryngeal structures to collapse and leads to obstructed inspiratory efforts that characterize mixed apnea. Furthermore, decrease central neural output, as might occur during apnea and can be replicated experimentally by cooling at chemosensitive sites in the brainstem, preferentially inhibits neural output to upper airway muscles.41 However, at resolution of apnea, both diaphragm and upper airway activities are increased. Therefore, it appears that a decrease in diaphragm activity is common to both central and mixed apnea and delayed upper airway muscle activation may prolong the episode. Hypoxic Responses During exposure to hypoxia, neonates exhibit a biphasic ventilatory response that consists of an initial increase in ventilation that lasts 1-2 minutes, followed by a decline in breathing, often to below baseline ventilation. This late decline has been traditionally termed hypoxic ventilatory depression.43,44 The initial increase in ventilation is believed to be secondary to stimulation of peripheral chemoreceptors primarily in the carotid body. In preterm human infants, the late decrease in ventilation is due to a decrease in respiratory frequency; however, the tidal volume is relatively sustained. The origin of the late depression is not well understood, but it may persist for several weeks postnatally in preterm infants.45 Several theories have been postulated to explain hypoxic ventilatory depression, including a decrease in PaCO2 secondary to the initial hyperventilation and accompanying decrease in cerebral blood flow, a decrease in metabolism, and hypoxia-mediated central depression of ventilation, which represents the most likely primary mechanism. Multiple neurotransmitters have been implicated as mediators for hypoxic depression including adenosine, endorphins and GABA. The use of blockers for these neurotransmitters such as methylxanthines for adenosine, naloxone for endorphins, and bicuculline for GABA was successful in preventing the late hypoxic depression and caused a sustained ventilatory response. Furthermore, the depressive response to hypoxia is diminished by experimental lesions in the upper brainstem and midbrain of fetal lambs, implicating the presence of descending

decr. O2 decr. delivery BRADYCARDIA carotid body DESATURATION

Figure 3: Proposed physiologic mechanisms whereby apnea induces reflex bradycardia. This may occur secondary to hypoxemia in the absence of lung inflation or via stimulation of upper airway inhibitory afferents. (Reproduced with permission from Martin, R.J, Fanaroff, A.A. (1998) Neonatal apnea, bradycardia or desaturation: dose it matter? Journal of Pediatrics 132, 758.) pups and piglets have revealed that this prolongation of expiration associated with hypercapnia is centrally mediated at the brainstem level.37,38 Furthermore, the inhibitory neurotransmitter GABA appears to be implicated.38 Future studies will need to further substantiate the role of inhibitory neurotransmitters and neuromodulators such as GABA, opioids and adenosine in contributing to this predisposition to respiratory inhibition, as manifest by an impaired CO2 response, in early postnatal life. Other promising lines of investigation include maturational changes in distribution of CO2/H+ sensitivity among medullary chemosensory structures, and the role of second messenger systems in modulating ventilatory patterns and CO2 responses during early development.39 The prominence of mixed apnea has led to comparative analysis of upper airway versus chest wall muscle responses to chemoreceptor stimulation.40 Upper airway muscles, such as the alae nasi, genioglossus, and posterior cricoarytenoid (laryngeal abductor) typically have their onset and

65

Apnea of prematurity: past, present and future

inhibitory tracts that contribute to hypoxic ventilatory depression.46 Consistent with these findings is the observation that a progressive decrease in inspired oxygen concentration causes a significant flattening of carbon dioxide responsiveness in preterm infants.47 Hypoxic ventilatory depression has been implicated as underlying apnea of prematurity, however, hypoxia does not appear to precede episodes of apnea and, in most occasions, the infants start with a normal PaO2 prior to the occurrence of apnea.48 While the role of the biphasic ventilatory response to hypoxia in the genesis of neonatal apnea is unclear, once hypoxia occurs it would appear to aggravate apnea and result in delayed recovery of the infant. Upper Airway Afferents Stimulation of the laryngeal mucosa, either chemically or mechanically, causes inhibition of breathing and apnea in humans and animals.49 This reflex-induced apnea is mediated through the superior laryngeal nerve,50,51 and has been shown to be associated with contraction of the thyroarytenoid muscle, causing closure of the glottis and swallowing movements, signifying active stimulation of expiratory-related brainstem centers. There appears to be a maturational change in reflexinduced apnea.50,51 Chemical stimulation of the larynx in newborn piglets causes respiratory arrest, which is not seen in older piglets. Preterm infants have an exaggerated inhibitory reflex and they elicit prolonged apnea in response to instilling saline in the oropharynx. The precise mechanisms underlying the maturational change in reflex-induced apnea are not known, however, they do not seem to be related to either changes in laryngeal receptors, changes in central synaptic connections, or maturation of the carotid body. It has been shown that hypercapnia increases and hypocapnia decreases the threshold for superior laryngeal nerve stimulation-induced apnea.52,53 Cooling of the ventromedullary surface, a technique used to decrease central chemosensitivity by inhibiting synaptic transmission at this site, decreased the threshold for laryngeal stimulationinduced apnea. Theophylline, which stimulates respiratory neural output, has been shown to block laryngeal-induced apnea. It seems, therefore, that the exaggerated reflex-induced apnea seen in newborn infants and animals is related to a decrease in central neural output or a dominance of inhibitory pathways. Furthermore, blocking GABAA receptors resulted in complete abolition of superior laryngeal nerve stimulation-induced apnea in piglets.54 Reflex induced apnea has been implicated as an underlying mechanism in apnea of prematurity and gastro-esophageal reflux-induced apnea.55,56 This is further supported by the observations that swallowing movements, which are common in reflex

apnea, were found to be much more common during apnea than during comparable periods of interrupted sleep or periodic breathing.57,58 Furthermore, spontaneous apneas associated with contraction of the thyroarytenoid muscle and swallowing movements have been described in fetal and preterm lambs.59,60 These observations may suggest a common origin for apnea of prematurity and reflex induced apnea. Nonetheless, the role of laryngeal reflex-induced apnea as an underlying mechanism for apnea of prematurity is uncertain. Lung afferents play an important role in regulating respiratory timing and may play a role in apnea of prematurity. Stimulation of pulmonary stretch receptors through increasing lung volume causes shortening of inspiratory time, prolongation of expiratory time or both.61-63 This reflex, known as the Hering-Breuer reflex, is mediated through the vagus nerve and results in termination of respiration. In preterm infants the Hering-Breuer reflex is more active and contributes to their higher respiratory frequency.64 The purpose of such an exaggerated reflex is probably to prevent both overdistention and full emptying of the lung, so maintaining lung volume at end expiration. However, the HeringBreuer reflex was found to be weak in infants of 32 weeks gestation, increasing in strength at 36-38 weeks and decreasing thereafter.65 The HeringBreuer deflation reflex is also activated on deflation of the lung and results in inspiratory augmentation. Preterm infants, unlike term infants, respond to the deflation reflex by shortening inspiratory time and short apneas that were mostly central in origin. Furthermore, infants with apnea had even greater shortening of inspiratory time.66 Such data indicate that on deflation of the lung, as during apnea, preterm infants were less likely to initiate breathing and tended to have respiratory pauses, which further comprised their ability to recover from apnea. Management Strategies Clinical Associations Although apnea typically results from immaturity of the respiratory control system, it also may be the presenting sign of other diseases or pathophysiologic states frequently affecting preterm infants.67 A thorough consideration of possible causes is always warranted, especially when there is an unexpected increase in the frequency of episodes of apnea and/or bradycardia [Figure 4]. Central nervous system problems, particularly intracranial hemorrhage can precipitate apnea in the preterm infant. Asphyxia, including transient birth depression may cause either episodic or prolonged apnea. Malformations of the brain or less likely, the spinal cord should be considered in an otherwise healthy infant presenting with apnea at birth.

66

J. Arab Neonatal Forum 2005; 2:63-73

Fig. 4

PREMATURITY
Infection Thermal Instability Reflux, Inhibitory reflexes

Impaired Oxygenation

APNEA

Metabolic Disorders

CNS Pathology

reflux of gastric contents to the larynx induces reflex apnea, there is no clear evidence that treatment of reflux will affect frequency of apnea in most preterm infants. Therefore pharmacologic management for reflux with agents that decrease gastric acidity or enhance gastrointestinal motility should be generally reserved for the preterm infants who exhibit signs of emesis or regurgitation of feeds, regardless of whether apnea is present. Xanthine Therapy Methylxanthines have been the mainstay of pharmacologic treatment of apnea. There is now nearly 30-year history of their use in infants. Both theophylline and caffeine are used, and have multiple physiologic and pharmacologic mechanisms of action. Xanthine therapy has been shown to increase minute ventilation, improve CO2 sensitivity, decrease hypoxic depression of breathing, enhance diaphragmatic activity, and to decrease periodic breathing.72,73 The precise pharmacologic basis for these actions, which are mediated by an increase in respiratory neural output, is still under investigation. A likely major mechanism of action for xanthine therapy is through competitive antagonism of adenosine receptors, as adenosine acts as an inhibitory neuroregulator in the central nervous system. Treatment is usually initiated with a loading dose followed by maintenance therapy in the form of oral or intravenous preparations. Caffeine has some advantages when compared to theophylline. Because it has a higher therapeutic index, toxicity is less of a concern. Also, once a day dosing is possible due to its longer half-life.74 A Cochrane review of the use of methylxanthines concluded that both theophylline and caffeine are effective in reducing apnea episodes, and reducing the use of mechanical ventilation in preterm infants.75 In many centers xanthine therapy is routinely employed to enhance successful extubation of very low birth weight infants. The review further concluded that caffeine was the preferable drug, and that studies of the long-term effects of methylxanthine treatment on growth and development were needed. These issues are currently being addressed in a recently completed international trial in which preterm infants were randomized to caffeine versus placebo therapy, with neurodevelopmental outcome as a major endpoint.76 Elimination of methylxanthines is prolonged in infants when compared to children or adults, and is especially prolonged in preterm infants. The metabolic pathways for the elimination of theophylline are underdeveloped in the premature infant, and include conversion by methylation to caffeine. Serum concentrations of methylxanthines may vary considerably from infant to infant and are not entirely predictable based on dosage. Serum

Drugs

Figure 4: Multiple etiologic factors that may contribute to apnea in preterm infants. Infections (bacteremia possibly accompanied by meningitis) may cause unstable breathing patterns, and should prompt the appropriate work-up and possibly antibiotic therapy. In the older infant, the onset of a viral illness such as RSV is sometimes heralded by apnea, although the precise mechanism whereby RSV presents with apnea is unclear. Anemia, another frequent problem in preterm infants, whether iatrogenic or secondary to bleeding, is a potential precipitating factor. Blood transfusions have been demonstrated to improve irregular breathing patterns in preterm infants,68 although the potential risk of blood transfusion has limited its use as treatment for apnea. It has been assumed, although unproven, that enhanced oxygen carrying capacity as with red cell transfusion may decrease the likelihood of hypoxia-induced respiratory depression. Other disease states that may precipitate apnea include metabolic disorders such as hypoglycemia or electrolyte imbalance. Temperature instability may be associated with apnea, however, there is always the risk that sepsis is the underlying precipitant. Medications that produce sedation, such as the opiates, and drugs that depress muscle function (e.g., magnesium) can produce apnea, as can prostaglandin (PGE1) infusion to maintain ductal patency in infants with suspected cardiac lesions. Gastroesophageal reflux (GER) is often incriminated in causing neonatal apnea.69 However, caution should be exercised when attributing apnea to reflux.70 Despite the frequent co-existence of apnea and GER in preterm infants, investigations into the timing of reflux in relation to apneic events indicate that they are not commonly temporally related. Monitoring studies demonstrate that when a relationship between reflux and apnea is observed, apnea may precede rather than follow reflux. This suggests that loss of respiratory neural output may be accompanied by a decrease in lower esophageal tone and resultant reflux in some infants. Furthermore, we have also recently documented that when these events coincide, there is no evidence that GER prolongs the concurrent apnea.71 Although physiologic experiments in animal models reveal that

67

Apnea of prematurity: past, present and future

Fig. 5

Therapeutic Approaches
Accepted Interventions
!Xanthine therapy !CPAP !Ventilator

Interventions Needing Further Study

!Kangaroo care !Enrichment of sensory environment !Change in baseline SaO2, hematocrit, or CO2 !Antireflux medication

Figure 5: A partial summary of therapeutic approaches that are used, or have been proposed, to benefit apnea of prematurity.
Fig. 6

Neonatal Apnea and SIDS

Relative Incidence Apnea of Prematurity
24 wks GA

followed at the beginning of treatment. Cessation of xanthine therapy is to be encouraged at least one to two weeks prior to discharge and this is especially relevant for caffeine with its longer half-life. Toxic levels may produce tachycardia, cardiac dysrhythmias, feeding intolerance, diuresis, and infrequently seizures, although these side effects are less commonly seen with caffeine at the usual therapeutic doses. Drug-drug interactions requires special attention when dosing methylxanthines; medications that affect liver function and those whose clearance depend on cytochrome P-450 should alert the clinician to the need for close monitoring of therapeutic and toxic side effects. The observation that xanthine therapy causes an increase in metabolic rate and oxygen consumption of approximately 20% suggests that caloric demands may be increased with this therapy at a time when nutritional intake is already compromised.77 Role of CPAP Among non-pharmacologic strategies widely used in the treatment of apnea, continuous positive airway pressure (CPAP) at 4-6 cm H2O is relatively safe and effective. Because longer episodes of apnea frequently involve an obstructive component, CPAP appears to be effective by splinting the upper airway with positive pressure and decreasing the risk of pharyngeal or laryngeal obstruction.67 CPAP probably also benefits apnea by increasing functional residual capacity (FRC) and so improving oxygenation status. It has been shown that at higher FRC, time from cessation of breathing to desaturation and resultant bradycardia is prolonged. High-flow nasal cannula therapy has been suggested as an equivalent treatment modality that may allow CPAP delivery while enhancing mobility of the infant for parents and caretakers.78 This approach is widely employed, although it has not been well studied. For severe or refractory episodes, endotracheal intubation and artificial ventilation may be needed. Minimal ventilator settings should be used to allow for spontaneous ventilatory efforts, and to minimize the risk of barotrauma. Other Approaches Any approach to nursing care that optimizes the infants well being is clearly highly desirable. Kangaroo care, or skin-to-skin nursing, has achieved widespread acceptance for stable infants, and provides an opportunity for greater parental involvement. Although the advocates of this approach have suggested a decrease in apnea rates, recent data have not supported this impression.79 This needs further study as any environmental change that has the potential to enhance patient well-being in the NICU is clearly desirable. A recent novel suggestion is the introduction of pleasant odors and preliminary evidence suggests that such olfactory stimulation

40 wks GA

}
6 mo

SIDS (mSD)

Pre-term

Term

3 mo

Age

Figure 6: Relative incidence of apnea episodes in preterm infants. The typical ages for SIDS deaths are shown by the horizontal bars (meanSD) that include most SIDS deaths. The typical age for SIDS in the most immature infants (24 week gestational age) is shifted to the left, but not into the zone of relatively higher incidence of apnea episodes.
Fig. 7

Resolution of Apnea in Preterm Infants

Resolved:
Apneic episodes may persist beyond discharge in preterm infants After 43-44 weeks corrected age, apnea rate is comparable to that of term infants Apnea of prematurity is not a documented risk factor for SIDS

Unresolved:
Is apnea of prematurity and associated hypoxemia of pathophysiologic significance? Is persistent apnea implicated in impaired neurodevelopmental outcome or later sleep disordered breathing? Will insights derived from the genetics of congenital central hypoventilation syndrome shed light on the apnea of prematurity phenotype?

Figure 7: A Summary of some of the consequence of apnea in preterm infants, many of which remain unresolved. measurement of theophylline should be monitored whenever aminophylline or theophylline is used. Caffeine levels are less critical but may also be

68

J. Arab Neonatal Forum 2005; 2:63-73 may diminish apnea.80 Meanwhile, research on the biologic basis of sleep and awake states needs to be translated into preventive strategies for apnea.81 Another novel approach is supplementation of inspired air with a very low concentration of supplemental CO2 to increase respiratory drive.82 While likely to be successful in decreasing apnea, it is doubtful that this would gain widespread acceptance (Figure 5). Resolution and Outcome Apnea of prematurity generally resolves by about 3640 weeks postconceptional age. However, in the most premature infants (24 to 28 weeks gestation) apnea frequently persists beyond 36 weeks postpostconceptional age, and may persist beyond 40 weeks post- postconceptional age. Cardiorespiratory events in such infants return to the baseline normal level at about 43 to 44 weeks postconceptional age.25 In other words, beyond 43-44 weeks postconceptional age, the incidence of cardiorespiratory events in preterm infants does not significantly exceed that in term babies [Figure 6]. Many preterm infants have resolved their apnea and bradycardia by the time they are ready for hospital discharge as determined by maturation of temperature control and feeding pattern. An apneafree observation period, usually ranging from five to seven days is utilized as a criterion for determining discharge date. For a subset of infants, however, the persistence of cardiorespiratory events may delay discharge from the hospital. In these infants, apnea longer than 20 seconds is rare, rather they exhibit frequent bradycardia to less than 70 or 80 beats per minute with short respiratory pauses.83 The reason that some infants exhibit marked bradycardia with short pauses is unclear. For a few of these infants home cardiorespiratory monitoring until 43 to 44 weeks post-conceptional age may offer an alternative to a prolonged hospital stay. Diagnostic pneumograms prior to discharge are of limited value in deciding who needs a home monitor, however, when used in a selective manner, they may aid in the characterization of events (i.e. central vs obstructive apnea) and serve a useful educational role. The apparent lack of a relationship between persistent apnea of prematurity and sudden infant death syndrome (SIDS) has become clearer.84,85 Significant progress in reducing the rate of SIDS was made with the Back to Sleep program for both full term and preterm infants. This effort was based on the observation that decreasing the incidence of prone sleeping (in conjunction with avoidance of cigarette smoke exposure and overheating an infant) reduced the rate of SIDS.86 The finding of an intervention that decreased SIDS rates helped remove

some of the mystery surrounding these deaths that are by definition unexplained. Apnea and SIDS remain linked epidemiologically because they both occur in certain population groups, e.g., preterm infants. While early case reports seemed to indicate that children who had apnea were at risk to die of SIDS, careful analysis of a large cohort of infants failed to find any relationship between apnea and later deaths. Currently, no clinical evidence reliably links a ventilatory control abnormality to SIDS. Because idiopathic apnea is most often seen in highrisk preterm infants, separating the consequences of premature birth from the effects of apnea of prematurity has proven difficult. Infants born prematurely often have multiple problems during their NICU stay, and many of these conditions, particularly periventricular leukomalacia and intraventricular hemorrhage, may contribute to poor neurodevelopmental outcome. Additionally, studies that assess improvement in long-term outcome as a result of treating apnea of prematurity are few, and confounded by these same issues. Reports of long term follow-up of these at-risk infants have attempted to address this problem.87,88 In preterm infants followed to early school age, factors that predicted poor neurodevelopmental outcomes included apnea of prematurity, however, other series of case comparisons have reported no difference in outcome of infants with apnea (Figure 7). Future studies might better focus on the incidence and severity of desaturation events, as techniques for long term collection of pulse oximeter data are more advanced. Furthermore, it is likely that recurrent hypoxia is the detrimental feature of the breathing abnormalities exhibited by preterm infants. Recurrent intermittent hypoxia might lead to excessive peripheral chemoreceptor sensitivity and thereby destabilize breathing patterns in the face of significantly fluctuating levels of oxygenation.89 This is consistent with the recent finding in preterm infants that a greater hypoxia-induced increase in ventilation correlates with a higher number of apneic episodes.90 Clearly, much remains to be learned about both the short and long term consequences of intermittent hypoxic episodes during early development.91,92 Finally, there are no available data on a link between apnea of prematurity and sleep disordered breathing in children, although former preterm infants appear to be at greater risk of later sleep disordered breathing.93 Recurrent episodes of desaturation during early life and resultant effects on neuronal plasticity related to peripheral and/or central respiratory control mechanisms may serve as the underlying mechanisms for such a putative relationship.

69

Apnea of prematurity: past, present and future

Acknowledgment Supported by the National Institute of Health Grants No. HL62527 and HL073240-01A1. References 1. Aranda JV, Turmen T. Methylxanthines in apnea of prematurity. Clin Perinatol 1979; 6: 87-108. 2. Grisemer AN. Apnea of prematurity; current management and nursing implications. Pediatric Nursing 1990; 16: 606-611. 3. Jones RAK. Apnoea of immaturity. 1. Controlled trial of theophylline and face mask continous positive airways pressure. Arch Dis Child 1982;57: 761-765. 4. Hiatt IM, Hegyi T, Indyk L, Dangman BC, James LS. Continuous monitoring of PO2 during apnea of prematurity. J. Pediatr 1981;98: 288291. 5. Boros SJ, Reynolds JW. Prolonged apnea of prematurity: treatment with continuous distending pressure delivered by nasopharyngeal tube. Clin Pediatr (phila) 1976;15: 123-134. 6. Gerhardt T, Bancalari E. Apnea of prematurity: 1. Lung function and regulation of breathing. Pediatrics 1984;74: 58-62. 7. Lagercrantz H, Rane A, Tunell R. Plasma concentration-effect relationship of theophylline in treatment of apnea in preterm infants. Eur J Clin Pharmacol 1980;18: 65-68. 8. Barrington K, Finer N. The natural history of the appearance of apnea of prematurity. Ped Res 1991;29(4): 372-75. 9. Thach BT, Stark AR. Spontaneous neck flexion and airway obstruction during apneic spells in preterm infants. J Pediatr 1979;94: 275. 10. Poets CF, Stebbens VA, Richard D, Southall DP. Prolonged episodes of hypoxemia in preterm infants undetectable by cardiorespiratory monitors. Pediatrics 1995;95(6): 860-863. 11. Peabody JL, Gregory GA, Willis MM, Philip AGS, Lucey JF. Failure of conventional monitoring to detect apnea resulting in hypoxemia. Birth defects 1979;15: 276-284. 12. Spear ML, Stefano JL, Spitzer AR. Prolonged apnea and oxyhemoglobin desaturation in asymptomatic premature infants. Pediatr Pulmonol 1992;13: 151-154. 13. Singer L, Martin RJ, Hawkins SW, BensonSzekely LJ, Yamashita TS, Carlo WA. Oxygen desaturation complicates feedings in infants with bronchopulmonary dysplasia after discharge. Pediatrics 1992;90: 380-384. 14. Poets CF, Samuels MP, Southall DP. The potential role of intrapulmonary shunting in the pathogenesis of hypoxemic episodes in infants and young children. Pediatrics 1992;90: 385391. 15. Avery GB, Glass P. Retinopathy of prematurity: what causes it? Clin Perinatol 1988;15: 917-928.

16. Beeby PJ, Jeffery H. Risk factors for necrotizing enterocolitis: the influence of gestational age. Arch Dis Child 1992;67: 432-435. 17. Volpe JJ. Brain injury in the premature infant current concepts of pathogenesis and prevention. Biol Neonate 1992;62:231-242. 18. Dransfield DA, Fox WW. High incidence of apnea with airway obstruction in recovering premature infants. Pediatr Res 1980;14:595. 19. Milner AD, Boon AW, Saunders RA, et al. Upper airway obstruction and apnea in preterm infants. Arch Dis Child 1980;55:22. 20. Miller H., Behrle F, Smull N. Severe apnea and irregular respiratory rhythms among premature infants. A clinical and laboratory study. Pediatrics 1959;23(4): 676-685. 21. Alden ER, Mandelkorn T, Woodrum DE, Wennberg RP, Parks CR, Hodson WA. Morbidity and mortality of infants weighing less than 1000 grams in an intensive care nursery. Pediatrics 1972;50(1): 40-49. 22. Carlo WA, Miller MJ, Versteegh Fg, et al. the effect of respiratory distress syndrome on chest wll movements and respiratory pauses in preterm infants. Am Rev Resp Dis 1982;126: 103. 23. Barrington K, Finer N. The natural history of the appearance of apnea of prematurity. Pediatr Res 1991;29(4):372-375. 24. Lee D, Caces R, Kiatkowski K, et al. Developmental study on types and frequency distribution of short apnea (3 to 15 seconds) in term and preterm infants. Pediatr Res 1987;22:344. 25. Ramanathan R, Corwin M, Hunt C, et al (the CHIME Study Group). Cardiorespiratory Events recorded on Home Monitors: Comparison of Healthy Infants with those at increased risk for SIDS. JAMA 2001;285 (17):2199-2207. 26. Hiatt IM, Hegyi T, Indyk L, Dangman BC, James LS. Continuous monitoring of PO2 during apnea of prematurity. J Pediatr 1981;98(2): 288291. 27. Kahn A, Blum D, Waterschoot P, Engelman E, Smets P. Effects of obstructive sleep apneas on transcutaneous oxygen pressure in control infants, siblings of sudden infant death syndrome victims and near miss infants: comparison with the effects of central sleep apneas. Pediatrics 1982;70: 852-857. 28. Vyas H, Milner AD, Hopkin IE. Relationship between apnea and bradycardia in preterm infants. Acta Pediatr Scand 1981;70: 785-790. 29. Perlman JM, Volpe JJ. Episodes of apnea and bradycardia in the preterm newborn: impact on cerebral circulation. Pediatrics 1985;76:333. 30. Kattwinkel J. Neonatal apnea: Pathogenesis and therapy. J Pediatr 1977;90:342-347. 31. Schulte FJ. Apnea. Clin Perinatol 1977;4:65-76.

70

J. Arab Neonatal Forum 2005; 2:63-73

32. Henderson-Smart DJ, Pettigrew AG, Campbell DJ. Clinical apnea and brainstem neural function in preterm infants. N Engl J Med 1983;308:353357. 33. Rigatto H., Brady JP, Verduzco RT. Chemoreceptor reflexes in preterm infants II. The effects of gestational and postnatal age on the ventilatory response to inhaled carbon dioxide. Pediatrics 1975;55: 614-620. 34. Krauss AN, Klain DB, Wldman S, Auld PAM. Ventilatory response to carbon dioxide in newborn infants. Pediatr Res 1965:9:46-50. 35. Gerhardt T, Bancalari E. Apnea of prematurity: 1. Lung function and regulation of breathing. Pediatrics 1984; 74:58-62. 36. Noble LM, Carlo WA, Miller MJ, DiFiore JM, Martin RJ. Transient changes in expiratory time during hypercapnia in premature infants. J Appl. Physiol 1987;62(3): 1010-1013. 37. Abu-Shaweesh JM, Dreshaj IA, Thomas AJ, Haxhiu MA, Strohl KP, Martin RJ. Changes in respiratory timing induced by hypercapnia in maturing rats. J Appl Physiol 1999;87:484-490. 38. Dreshaj IA, Haxhiu MA, Abu-Shaweesh J, Carey RE, Martin RJ. CO2-induced prolongation of expiratory time during early development. Respir Physiol 1999; 116:125-132. 39. Dreshaj IA, Haxhiu MA, Martin RJ. Role of the medullary raph nuclei in the respiratory response to CO2. Respir Physiol 1998; 111:1523. 40. Bandla HPR, Simakajornboon N, Graff GR, Gozal D. Protein kinase C modulates ventilatory patterning in the developing rat. Am J Respir Crit Care Med 1999; 159:968-973. 41. Carlo WA, Martin RJ, DiFiore JM. Differences in CO2 threshold of respiratory muscles in preterm infants. J Appl Physiol 1988; 65:24342439. 42. Gauda EB, Miller MJ, Carlo WA, DiFiore JM, Martin RJ. Genioglossus and diaphragm activity during obstructive apnea and airway occlusion in infants. Pediatr Res 1989;26:583-587. 43. Cross KW, Oppe TE. The effect of inhalation of high and low concentration of oxygen on the respiration of the premature infant. J. Physiol 1952;117: 38. 44. Rigatto H, Brady JP, Verduzco R de la T. Chemoreceptor reflexes in preterm infants: 1. The effect of gestational and postnatal age on the ventilatory response to inhalation of 100% and 15% oxygen. Pediatrics 1975;55(4): 604-613. 45. Martin RJ, DiFiore JM, Jana L, Davis RL, Miller MJ, Coles SK, Dick TE. Persistence of the biphasic ventilatory response to hypoxia in preterm infants. J Pediatr 1998;132:960-964. 46. Gluckman PDD, Johnston BM. Lesions in the upper lateral pons abolish the hypoxic

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

depression of breathing in unanesthetized fetal lambs in utero. J Physiol 1987; 382:373-383. Rigatto H, de la Torre Verdizco R, Gates DB. Effects of O2 on the ventilatory response to CO2 in preterm infants. J Appl Physiol 1975; 39:896899. Hiatt IM, Hegyi T, Indyk L, Dangman BC, James LS. Continuous monitoring of PO2 during apnea of prematurity. J. Pediatr 1981;98(2): 288291. Pickens DL, Schefft D, Thach BT. Prolonged apnea associated with upper airway protective reflexes in apnea of prematurity. Am Rev Resp Dis 1988; 137:113-118. Goding GS, Richardson MA, and Trachy RE. Laryngeal chemoreflex: anatomic and physiologic study by use of the superior laryngeal nerve in piglet. Otolaryngology- Head & Neck surgery 1987;97(1): 28-38. Lee JC, Stoll BG, Downing SE. Properties of the laryngeal chemoreflex in neonatal piglets. Am. J. Physiol 1977;233(1): R30-36. Lawson EE. Recovery from central apnea: effect of stimulus duration and end-tidal CO2 partial pressure. J Appl Physiol 1982; 53:105-109. Litmanowitz I, Dreshaj I, Miller MJ, Haxhiu MA, Martin RJ. Central chemosensitivity affects respiratory muscle responses to laryngeal stimulation in the piglet. J Appl Physiol 1994; 76:403-408. Abu-Shaweesh JM, Dreshaj IA, Haxhiu MA, Martin RJ. Central GABAergic mechanisms are involved in apnea induced by superior laryngeal nerve stimulation in piglets. J Appl Physiol 2001; 90:1570-1576. Leape LL, Holder TM, Franklin JD, Amoury RA, Ashcraft KW. Respiratory arrest in infants secondary to gastro-esophageal reflux. Pediatrics 1977;60(6): 924-928. Menon AP, Schefft GL, Thach BT. Apnea associated with regurgitation in infants. J Pediatr 1985;106:625-629. Menon AP, Schefft GL, Thach BT. Frequency and significance of swallowing during prolonged apnea in infants. Am Rev Respir Dis 1984;130:969-973. Miller MJ, Difiore JM. A comparison of swallowing during apnea and periodic breathing in premature infants. Pediatr Res 1995;37: 796799. Kianicka I, Diaz V, Dorian D, Praud JP. Coordination between glottic adductor muscle and diaphragm EMG activity in fetal lambs in utero. J Appl Physiol 1998;84(2):669-675. Renolleau S, Letourneau P, Niyonsenga T, Praud JP, Gagne B. Thyroarytenoid muscle electrical activity during spontaneous apneas in preterm lambs. Am. J. Respir. Crit. Care Med 1999;159(5 Pt 1): 1396-404.

71

Apnea of prematurity: past, present and future

61. Hering E, Breuer J. Die Selbststeurung der Athmung durch den nervus vagus. Sitzber Deut Akad Wiss Wein 1868;57:672-677. 62. Cross KW, Klaus M, Tooley WH, Weisser K. The response of the newborn baby to inflation of the lung. J Physiol 1960;151:551-565. 63. Martin RJ, Okken A, Katona PG, Klaus MH. The effect of lung volume on expiratory time in the newborn infant. J Appl Physiol 1978;45:1823. 64. Olinsky A, Bran MH, Bryan C. Influence of lung inflation on respiratory control in neonates. J Appl. Physiol 1974;36(4): 426-429. 65. Bodegard G, Schwieler GH, Skoglund S, Zetterstorm R. Control of respiration in newborn babies. Acta Paediatr Scand 1969;58: 567-571. 66. Hannam S, Ingram DM, and Milner AD. Apossible role for the Hering-Breuer deflation reflex in apnea of prematurity. J Pediatr. 132(1):35-39, 1998. 67. Miller MJ, Martin RJ. Pathophysiology of apnea of prematurity. In: Polin RA and Fox WW [eds]: Fetal and Neonatal Physiology. Philadelphia: WB Saunders Co., 1129-1143. 68. Joshi A, Gerhardt T, Shandloff P, Bancalari E. Blood Transfusion Effect on the Respiratory Pattern of Preterm Infants. Pediatrics 1987;80:79-84. 69. de Ajuriaguerra M, Radvanyi-Bouvet MF, Huon C, Moriette G. Gastroesophageal reflux and apnea in prematurely born infants during wakefulness and sleep. Am J Dis Child 1991; 145:1132-1136. 70. Kimball AL, Carlton DP. Gastroesophageal reflux medication in the treatment of apnea in premature infants. J Pediatr 2001; 138:355-360. 71. DiFiore JM, Arko M, Whitehouse M, Kimball A, Martin RJ. Apnea is not prolonged by acid gastroesophageal reflux (GER) in preterm infants. Pediatrics, in press, 2005. 72. Gerhardt T, McCarthey J, Bancalari E. Effect of Aminophylline on respiratory Center Activity and Metabolic Rate in Premature infants with Idiopathic Apnea. Pediatrics 1979;63:537-42. 73. Aubier M, DeTroyer A, Sampson M, Macklem PT, Roussos C. Aminophylline improves diaphragmatic contractility. N Engl J Med 1981;305:249-252. 74. Aranda JV, Cook CE, Gorman W, et al. Pharmacokinetic profile of caffeine in the premature newborn infant with apnea. J Pediatr 1979;94: 664-668. 75. Steer PA, Henderson-Smart DJ. Caffeine versus theophylline for apnea in preterm infants. Cochrane Database Syst Rev 2000; 2:CD000273. 76. Schmidt B. Methylxanthine therapy in premature infants: Sound practice, disaster, or fruitless byway? J Pediatr 1999; 135:526-528.

77. Bauer J, Maier K, Linderkamp O, Hentschel R. Effect of caffeine on oxygen consumption and metabolic rate in very low birth weight infants with idiopathic apnea. Pediatrics 2001; 107:660663. 78. Sreenan C, Lemke RP, Hudson-Mason A, Osiovich H. High-flow nasal cannulae in the management of apnea of prematurity: a comparison with conventional nasal continuous positive airway pressure. Pediatrics 2001; 107:1081-1083. 79. Bohnhorst B, Gill D, Dordelmann M, Peter CS, Poets CF. Bradycardia and desaturation during skin-to-skin care: no relationship to hyperthermia. J Pediatr 2004; 145:499-502. 80. Marlier L, Gaugler C, Messer J. Olfactory stimulation prevents apnea in premature newborns. Pediatrics 2005; 115:83-88. 81. Lehtonen L, Martin RJ. Ontogeny of sleep and awake states in relation to breathing in preterm infants. Semin Neonatol 2004; 9:229-238. 82. Al-Aif S, Alvaro R, Manfreda J, Kwiatkowski K, Cates D, Rigatto H. Inhalation of low (0.5% 1.5 %) CO2 as a potential treatment for apnea of prematurity. Semin Perinatol 2001;25(2): 100106. 83. DiFiore JM, Arko MK, Miller MJ, et al. Cardiorespiratory events in preterm infants referred for apnea monitoring studies. Pediatrics 2001; 108:1304-1308. 84. Southall DP, Richards JM, Rhoden KJ, Alexander JR et al. Prolonged apnea and cardiac arrhythmias in infants discharged from neonatal intensive care units: failure to predict an increase risk for sudden infant death syndrome. Pediatrics 1982; 70(6): 844-51. 85. Meny RG, Carroll JL, Carbone MT, and Kelly DH. Cardiorespiratory recordings from infants dying suddenly and unexpectedly at home. Pediatrics 1994;93:43 - 49. 86. Willinger M, Hoffman HJ, Wu K-T, et al. Factors associated with the transition to nonprone sleep positions of infants in the United States: the National Infant Sleep Position Study. JAMA 1998;280:329 - 335. 87. Taylor HG, Klein N, Schatschneider C, Hack M. Predictors of early school age outcomes in very low birth weight infants. J Dev Behav Pediatr 1998; 19:235-243. 88. Cheung P, Barrington KJ, Finer NN, Robertson CMT. Early childhood neurodevelopment in very low birth weight infants with predischarge apnea. Pediatr Pulmonol 1999; 27:14-20. 89. Peng Y-J, Rennison J, Prabhakar NR. Intermittent hypoxia augments carotid body and ventilatory response to hypoxia in neonatal rat pups. J Appl Physiol 2004; 97:2020-2025.

72

J. Arab Neonatal Forum 2005; 2:63-73

90. Nock ML, Di Fiore JM, Arko MK, Martin RJ. Relationship of the ventilatory response to hypoxia with neonatal apnea in preterm infants. J Pediatr 2004; 144:291-295. 91. Mitchell GS, Baker TL, Nanda SA, et al. Intermittent hypoxia and respiratory plasticity. J Appl Physiol 2001; 90:2466-2475. 92. Gozal D, Reeves SR, Row BW, Neville JJ, Guo

93. SZ, Lipton AJ. Respiratory effects of gestational intermittent hypoxia in the developing rat. Am J Respir Crit Care Med 2003; 167:1540-1547. 94. Rosen CL, Larken EK, Kirchner HL, et al. Prevalence and risk factors for sleep-disordered breathing in 8-to 11-year-old children: Association with race and prematurity. J Pediatr 2003; 142:383-389.

73