INTRODUCTION — Apnea of prematurity is a developmental disorder in preterm infants, which occurs as a direct consequence of immature respiratory control. In an infant less than 37 weeks gestational age (GA), apneic spells are considered clinically significant if the episodes are greater than 20-second duration or when shorter episodes are accompanied by hypoxemia and/or bradycardia [1]. The frequency and severity of symptoms is inversely proportional to GA, and almost all extremely low birth weight (ELBW) infants (BW below 1000 g) are affected.

The management of apnea of prematurity will be reviewed here. The pathogenesis, clinical features, and diagnosis of apnea of prematurity are discussed separately. (See "Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity".)

MONITORING — Preterm infants with a gestational age (GA) less than 35 weeks should be monitored for apnea because of the high prevalence of apnea in this group of patients. In most neonatal intensive care units (NICUs), cardiac monitors, pulse oximeters, and impedance pneumography are used to monitor for apnea of prematurity and its associated bradycardia and hypoxemia. The accuracy of pneumography is limited by movement artifacts and the inability to detect obstructive apnea episodes, and is generally not used as the sole technique. (See "Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity", section on 'Incidence' and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn" and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Pulse oximetry'.)

There are no data on the optimal threshold settings to determine significant apnea events. In our practice, we use the following threshold settings to detect episodes of apnea and its associated bradycardia and hypoxemia. The lower thresholds are used when the decision is being made to discontinue caffeine therapy or discharge the infant home. Other centers utilize different parameters.

●Apnea ≥15 or 20 seconds

●Heart rate ≤70 or 80 beats per minute

●Oxygen saturation (SpO₂) less than 80 or 85 percent

MANAGEMENT OVERVIEW — Treatment of apnea of prematurity is instituted if:

●Apneic spells are frequent, prolonged, or associated with bradycardia or frequent oxygen desaturation values. In our practice, we use oxygen saturation (SpO₂) threshold of 85 percent or less.

OR

●The infant requires intervention with bag and mask ventilation, or multiple episodes of tactile stimulation.

Therapy often is needed for several weeks until the apnea resolves as the respiratory control of the infant matures.

Management is a combination of the following:

●General measures that reduce the risk of apnea or its associated hypoxemia

●Nasal continuous positive airway pressure (nCPAP)

●Methylxanthine therapy

Patients who fail to respond to these interventions require intubation and mechanical ventilation or may be candidates for nasal intermittent positive pressure ventilation (NIPPV). (See 'Nasal intermittent positive pressure ventilation' below and "Overview of mechanical ventilation in neonates".)

GENERAL MEASURES — General measures are usually preventive in nature and are applied to all infants less than 35 weeks gestation who are at risk for apnea. These interventions are directed towards eliminating factors that increase the risk of apnea or reduce the prevalence of associated hypoxia.

●Environmental temperature control – A servo-controlled radiant warmer or incubator is used to provide a stable thermal environment, thereby eliminating temperature fluctuations that precipitate apneic episodes. (See "Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity", section on 'Pathogenesis'.)

●Consider underlying causes of new onset of apnea or increased severity, such as neonatal sepsis. Temperature instability may be a manifestation of sepsis. (See "Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity", section on 'Differential diagnosis'.)

●Head and neck position – Infants are positioned to avoid extreme flexion or extension of the neck, which decreases the patency of the upper airway. (See "Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity", section on 'Upper airway patency'.)

●Maintain nasal patency – Nasal patency is preserved by avoiding vigorous nasal suctioning or prolonged use of nasogastric tubes. (See "Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity", section on 'Upper airway patency'.)

●Oxygen supplementation to maintain oxygen saturation (SpO₂) at 90 to 95 percent – We provide oxygen supplementation to avoid baseline hypoxemia, which predisposes to episodes of severe oxygen desaturation. We use pulse oximetry to monitor SpO₂ in infants with apnea. (See "Neonatal target oxygen levels for preterm infants", section on 'Oxygen target levels'.)

NASAL CONTINUOUS POSITIVE AIRWAY PRESSURE — For preterm infants with clinically significant apnea (ie, respiratory pauses >20 seconds or a shorter duration accompanied by oxygen desaturation and/or bradycardia), we suggest nasal continuous positive airway pressure (nCPAP) [2]. Many preterm infants may have other indications for nCPAP. For example, nCPAP is often initiated in preterm infants <32 weeks gestation and almost all extremely preterm (gestational age <28 weeks) who are at risk for neonatal respiratory distress. (See "Prevention and treatment of respiratory distress syndrome in preterm infants", section on 'Nasal continuous positive airway pressure (nCPAP)'.)

nCPAP is applied using nasal prongs or, in the smallest infants, a nasal mask or nasal cannula is used to minimize nasal trauma. In our practice, nCPAP is initiated at 4 to 6 cm H₂O pressure. Although data are lacking, some clinicians may increase nCPAP pressure in an attempt to optimize FRC based on estimating lung volume on chest radiography. However, many of these infants have good lung compliance, and pressures above 8 cm H₂O may overdistend the lungs or impair circulatory function. Changing prongs and nasal suctioning are minimized to avoid irritation, unless increased secretions obstruct nasal airflow.

Humidified high flow nasal cannulas have also been used to treat apnea of prematurity [3]. Nasal cannulae are an effective method to provide oxygen supplementation and deliver CPAP while minimizing patient discomfort, but high flow through nasal cannulas may provide unpredictable levels of CPAP. This technique and its limitations are discussed separately. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'High-flow'.)

nCPAP reduces the incidence of mixed and obstructive apnea, maintains functional residual capacity (FRC), and alters timing of breathing in preterm infants [4,5]. nCPAP is thought to be effective by splinting the pharyngeal airway with positive pressure, thereby reducing the risk of upper airway collapse and obstruction. nCPAP decreases respiratory frequency, primarily by prolongation of expiratory time, without altering ventilatory response to CO₂ [6]. CPAP also increases oxygenation by improving ventilation-perfusion matching and provides continuous distending pressure that optimizes FRC [5]. (See "Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity", section on 'Upper airway patency'.)

NASAL INTERMITTENT POSITIVE PRESSURE VENTILATION — Nasal intermittent positive pressure ventilation (NIPPV) is an augmentation of continuous positive airway pressure (CPAP), which superimposes inflations set to a peak pressure delivered through nasal prongs or mask. NIPPV may be a useful tool to augment the beneficial effects of CPAP in preterm infants with apnea [7,8]. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Nasal intermittent positive pressure ventilation'.)

METHYLXANTHINE THERAPY — Methylxanthines cause stimulation of respiratory neural output, presumably by inhibiting adenosine receptors, and are the primary pharmacologic therapy used to treat apnea of prematurity. The two methylxanthines used in apnea of prematurity are caffeine and theophylline. Caffeine is the preferred agent because of its longer half-life, wider margin of safety, and lower frequency of adverse effects [1,9]. (See 'Mechanism of action' below and 'Caffeine versus theophylline' below.)

Efficacy — Several trials have established that methylxanthines are effective in the treatment of apnea of prematurity.

In a 2010 systematic review, results from five trials that studied short-term effects of methylxanthine therapy demonstrated that patients treated with methylxanthine compared with those who received placebo were less likely to have apneic episodes (relative risk [RR] 0.44, 95% CI 0.32-0.60) and require assisted ventilation (RR 0.34, 95% CI 0.12-0.97) [10].

A sixth trial, the Caffeine for Apnea of Prematurity (CAP) trial of2006 preterm infants (birth weight [BW] between 500 and 1250 g), reported no difference in the rate of death, abnormal brain ultrasound, or necrotizing enterocolitis (NEC) between the treated and control groups [11] . However, caffeine therapy was associated with reduced risk of patent ductus arteriosus (PDA) ligation (RR 0.37, 95% CI 0.21-0.66) and bronchopulmonary dysplasia (BPD) (RR 0.72, 95% CI 0.58-0.89), earlier discontinuation of supplemental oxygen, and a lower age at the time of last endotracheal tube use.

In a subsequent report of the CAP trial, for infants who required positive pressure ventilation, caffeine benefit was associated with shorter duration of mechanical ventilation compared with placebo [12]. The earlier discontinuation of positive airway pressure support with caffeine indirectly suggests a decrease in the frequency of apnea [13], and the reduction of BPD suggests that caffeine might have a preventive role in the development of this disorder. (See "Bronchopulmonary dysplasia: Management".)

Prophylactic use — We and other centers administer prophylactic caffeine therapy in extremely preterm (EPT) infants born at gestational age <28 weeks (table 1)to avoid intubation and mechanical ventilation, or to enhance extubation [14].

Data supportive of prophylactic use was provided by a large retrospective study from the Canadian Neonatal Network (CNN) of preterm infants (gestational age <29 weeks) that compared early administration of caffeine within the first two days of life with late administration on or after the third day of life [14]. In this cohort, 75 percent were given early caffeine, and the remaining patients received late administration of caffeine. In a multivariate analysis, neonates in the early caffeine group had a small but statistically significant lower risk of a composite outcome of death or BPD (31.5 versus 31.1 percent; odds ratio [OR] 0.81, 95% CI 0.67-0.98). However, most of this effect was due to a reduction in the incidence of BPD, as there was no difference in mortality (5.7 versus 5.8; OR 0.98, 95% CI 0.7-1.37). In addition, the early caffeine group was less likely to develop PDA or undergo surgical intervention for PDA. There were no differences in other secondary outcomes including NEC, severe neurological injury, or severe retinopathy of prematurity (ROP). A follow-up report of this observational cohort at 18 to 24 months corrected age reported better neurodevelopmental outcome with early versus late administration providing additional support for the early use of caffeine [15].

However, two other studies showed no additional benefit of prophylactic caffeine for infants who are initially treated with CPAP or required mechanical ventilation [16,17].

Mechanism of action — Methylxanthines are competitive inhibitors of adenosine receptors. Because adenosine is an inhibitory neuromodulator of respiratory drive, blockage of its receptors by methylxanthines results in increased ventilatory responsiveness to carbon dioxide, reversal of central hypoxic depression of breathing, enhanced force of diaphragmatic contraction, and improved pharyngeal muscle tone [18]. Respiratory neural output is increased within five minutes after administration an intravenous loading dose of caffeine [19].

In one study of 51 preterm infants (median gestational age [GA] 29 weeks), increased cerebral cortical activity, decreased transcutaneous carbon dioxide partial pressure, and an increase in mean arterial pressure were observed during the two-hour period after caffeine administration [20]. Caffeine may also reduce the effects of hypoxia on perinatal white matter injury [18]. Some of the effects of caffeine may be due to its ability to inhibit pro- and anti-inflammatory mechanisms, which are mediated by the various adenosine receptor subtypes [21-23].

Side effects — The main adverse effects of methylxanthine treatment is tachycardia, which occurs less frequently with caffeine than with theophylline [24]. Theophylline can cause gastroesophageal reflux, perhaps because of delayed gastric emptying [25]; however, this does not present as a clinically significant problem.

Methylxanthines also increase metabolic rate [20]; however, the long-term impact of these effects is not known. In a study of metabolic rate and oxygen consumption, caffeine significantly increased oxygen consumption (7 to 8.8 mL/kg per min) and energy expenditure (2.1 to 3 kcal/kg per hour) compared with baseline measurements [26]. During the four-week study period, treated infants required a lower incubator temperature to maintain normal body temperature and had less weight gain with similar caloric intake than untreated infants (21 versus 42 g/day).

Long-term neurodevelopmental outcome — Limited initial data from the CAP trial suggest overall neurobehavioral outcome is not affected by neonatal caffeine therapy and that there may be some benefit from caffeine compared with placebo [27]. Follow-up studies reported similar overall cognitive outcome and academic performances between the two groups at 5 and 11 years of age [28-30] but neonatal caffeine therapy reduced rates of developmental coordination disorder at five years of age and motor impairment at 11 years of age [29,31]. In addition, the caffeine-treated group at 11 years of age performed better than the control group on tests for fine motor coordination, visuomotor integration, visual perception, and visuospatial organization [30]. These data support the long-term safety and potential efficacy of caffeine therapy for apnea of prematurity.

As noted above, neurodevelopmental outcome at 18 to 24 months corrected age is better with early versus late administration of caffeine [15].

Caffeine versus theophylline — Caffeine has therapeutic advantages over theophylline including its longer half-life, ranging from 65 to 100 hours [32]. As a result, caffeine can be administered once daily instead of the more frequent dosing required for theophylline. In addition, enteral absorption of caffeine is more reliable, and the wide therapeutic index of caffeine minimizes side effects [33]. Finally, monitoring serum levels is generally required in patients treated with theophylline because of the smaller margin of safety and greater variability of absorption, whereas caffeine levels are usually only measured if there are signs of toxicity [34].

A systematic review of the literature that included five trials reported similar rates of reduction of apnea and bradycardia during the first week between caffeine and theophylline [33]. However, adverse reactions (ie, tachycardia and feeding intolerance) were lower in the group treated with caffeine compared with theophylline (RR 0.17, 95% CI 0.04-0.72).

Based upon these data and the need to administer theophylline on a more frequent basis and obtain serum levels, we recommend caffeine as the preferred methylxanthine for the treatment of apnea of prematurity.

Caffeine — Caffeine is the preferred prophylactic agent to prevent apnea of prematurity because of its longer half-life, wider margin of safety, and lower frequency of adverse effects.

Initial and maintenance dosing — In preterm infants with apnea of prematurity, a loading dose of 20 mg/kg of caffeine citrate (equivalent to 10 mg/kg caffeine base) is given intravenously, or enterally [11,27]. A daily maintenance dose of 5 to 10 mg/kg per dose (equivalent to 2.5 to 5 mg/kg caffeine base) is started 24 hours after the loading dose, which can also be administered either intravenously or orally. The efficacy and safety of higher doses are unknown, although there are low-quality data that suggest the risk of BPD or death may be reduced [35]. Additional postnatal increased dosing after the first weeks of therapy may be needed due to faster metabolism with advancing maturation [36].

Routine measurement of serum drug concentration is not necessary. Drug levels are usually only measured if there are signs of toxicity because there is a wide therapeutic index and the dose-response relationship is not established. Steady state concentrations of caffeine are attained five to seven days after the drug is started. The therapeutic trough serum concentration is 5 to 25 mg/L. In an observational study of 101 preterm infants, the median caffeine citrate dose was 5 mg/kg (range 2.5 to 10.9 mg/kg) that resulted in levels from 3 to 23.8 mg/L [34]. In 95 percent of samples, the level was between 5 and 20 mg/L. Comparable results were seen in the 23 patients with renal dysfunction (elevated serum creatinine or blood urea nitrogen [BUN] levels) and in the 13 patients with elevated liver function studies.

Discontinuation of caffeine — Data are lacking on when to discontinue caffeine therapy. Based on our experience and the natural course of apnea of prematurity, we discontinue caffeine when the infant reaches a postmenstrual age (PMA) between 32 and 34 weeks and there have been no apneic episodes requiring intervention for approximately five days. [37]. It takes up to seven days for caffeine to be eliminated from the neonate.

However, there are limited data that suggest prolonged caffeine therapy beyond 35 weeks PMA decreases the frequency and severity of intermittent hypoxemia [38,39]. An ongoing clinical study is being conducted to further investigate the role of caffeine therapy in reducing intermittent hypoxemia.

Whenever caffeine is discontinued, cardiorespiratory monitoring is continued and performed until the infant is discharged home, because the mean half-life of caffeine is approximately 87 hours in patients who are 35 weeks PMA [40]. Caffeine rarely needs to be reinstituted, but if there are frequent episodes of apnea, bradycardia, or oxygen desaturation, or if the infant requires intervention with a bag and mask, caffeine therapy may be restarted. (See 'Management overview' above.)

Response failure — As noted above, infants who remain apneic despite caffeine therapy and continuous positive airway pressure (CPAP) require intubation and mechanical ventilation or may be candidates for nasal intermittent positive pressure ventilation (NIPPV). (See 'Management overview' above and 'Nasal intermittent positive pressure ventilation' above and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Nasal intermittent positive pressure ventilation' and "Overview of mechanical ventilation in neonates".)

OTHER THERAPIES

Possible role of transfusion — We consider packed RBC transfusion in infants with hematocrits less than 25 to 30 percent who have frequent and/or severe apnea despite administration of caffeine therapy. The indications for transfusion in the preterm infants are discussed separately. (See "Red blood cell transfusions in the newborn", section on 'Indications'.)

The frequency and severity of apnea occasionally are increased in preterm infants who develop significant anemia at one to two months of age. It appears that transfusion reduces the frequency of apnea. This was best illustrated in a study of very low birth weight (VLBW) infants (BW <1500 g) that demonstrated a decreased apnea rate after transfusion based on data from continuous computer monitoring of chest impedance and electrocardiographic and oximetry signals, and bedside nursing records [41]. In a study of extremely low birth weight (ELBW) infants (BW <1000 g), red blood cell (RBC) transfusions reduced the frequency and severity of episodes of intermittent hypoxemia (defined as oxygen saturation ≤80 percent for ≥4 seconds and ≤3 minutes) up to 48 hours after transfusion in infants who were one week of age or older [42]. However, there was no effect on the frequency or severity of hypoxemic events in patients less than seven days of age.

DISCHARGE PLANNING — At discharge, home cardiorespiratory monitoring is not needed for infants who are otherwise ready for discharge and remain free of any episode of apnea, bradycardia, or oxygen desaturation for five to seven days, as the risk of a subsequent clinically significant apnea event is very low [43]. However if a preterm infant is ready for discharge, but mild apnea continues to be a concern, it remains uncertain what is the optimal approach [1]. Many of these infants have persistent mild bradycardia and/or desaturation events that are detected by cardiorespiratory monitoring, which are associated with short undetected respiratory pauses as they remain below the apnea alarm threshold. These events are probably of no prognostic significance. If caffeine has only recently been discontinued, we generally advise that the infant not be discharged home unless there is an event-free period of seven (as opposed to five) days to allow caffeine to be either eliminated or reach low subtherapeutic levels. (See 'Monitoring' above.)

Discharge criteria vary. Most centers wait until infants are free of apnea and off caffeine therapy before discharge, while some may discharge infants home with cardiorespiratory monitoring, and on or off caffeine therapy. If the infant is to be monitored at home, prior to discharge the parents or primary home care provider must demonstrate proficiency in managing the monitor, providing stimulation, and performing cardiorespiratory resuscitation. Such home monitoring can almost always be discontinued at around 43 to 44 weeks postmenstrual age (PMA). Implementation of home cardiorespiratory monitoring in infants, including discontinuation, is discussed separately. (See "Use of home cardiorespiratory monitors in infants", section on 'Preterm infants with persistent symptoms related to apnea of prematurity'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Apnea of prematurity".)

SUMMARY AND RECOMMENDATIONS

●Initial cardiorespiratory monitoring is provided for all preterm infants admitted to a neonatal intensive care unit (NICU), as they are at risk for apnea. (See 'Monitoring' above and "Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity", section on 'Incidence'.)

●Supportive care is focused on eliminating factors that increase the risk of apnea. It includes maintenance of a stable thermal environment and nasal patency, avoidance of extreme neck flexion and extension, and identifying any other underlying condition associated with apnea (eg, sepsis). (See 'General measures' above and "Neonatal target oxygen levels for preterm infants", section on 'Oxygen target levels'.)

●In preterm infants with apnea, we suggest the use of nasal continuous positive airway pressure (nCPAP) (Grade 2C). Positive airway pressure reduces the risk of upper airway collapse and obstruction, and increases oxygenation. In these patients, positive airway pressure is begun at a pressure between 4 and 6 cm H₂O via nasal prongs or mask. (See 'Nasal continuous positive airway pressure' above.)

●For infants with apnea of prematurity who require repeated tactile stimulation or ventilatory support, we recommend additional treatment with methylxanthine therapy versus general measures alone (Grade 1B). We recommend the use of caffeine rather than theophylline as the preferred methylxanthine for infants with apnea of prematurity (Grade 1B). Caffeine is the preferred agent because of its longer half-life and wider safety margin associated with a lower incidence of adverse effects. (See 'Caffeine versus theophylline' above and 'Efficacy' above.)

●For extremely low birth weight (ELBW) infants (BW <1000 g), we suggest early prophylactic caffeine therapy within the first two days of life (Grade 2C). Apnea occurs in nearly all of these infants and prophylactic caffeine is provided with the aim of avoiding intubation and mechanical ventilation, or facilitating early extubation. (See 'Prophylactic use' above.)

●Caffeine is given as a loading dose of 20 mg/kg of caffeine citrate (equivalent to 10 mg/kg caffeine base). It is followed in 24 hours by a daily maintenance dose of 5 to 10 mg/kg per dose (equivalent to 2.5 to 5 mg/kg caffeine base). Both the loading and maintenance doses can be administered intravenously or orally. (See 'Initial and maintenance dosing' above.)

●We suggest red blood cell (RBC) transfusions for infants with hematocrits of less than 25 to 30 percent who have frequent and/or severe apnea requiring intervention (Grade 2C). (See 'Possible role of transfusion' above.)

●In our center, discontinuation of caffeine is considered for infants at a postmenstrual age (PMA) between 32 and 34 weeks who have a five-day period that is free of any apnea, bradycardia, or desaturation alarm event episode. (See 'Discontinuation of caffeine' above.)

●If an infant is ready for discharge, but mild apnea (ie, apneic episodes greater than 15 seconds that do not require intervention or are not accompanied with bradycardia and desaturation) continues to be a concern, home cardiorespiratory monitoring may be considered until the infant is 43 to 44 weeks PMA. Prior to discharge, the parents or primary home care provider must demonstrate proficiency in managing the monitor, providing stimulation, and performing cardiorespiratory resuscitation. Infants still exhibiting apnea with associated bradycardia or oxygen desaturation are not candidates for discharge and home monitoring. (See "Use of home cardiorespiratory monitors in infants", section on 'Implementation'.)