Management of apnea of prematurity

INTRODUCTION — Apnea of prematurity is a developmental disorder in preterm infants, which occurs as a direct consequence of immature respiratory control. Apneic spells are considered clinically significant if the episodes last >20 seconds or are accompanied by hypoxemia and/or bradycardia. The frequency and severity of symptoms is inversely proportional to gestational age (GA); almost all extremely preterm (EPT; GA <28 weeks) and extremely low birth weight (ELBW; BW <1000 g) infants 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 <35 weeks gestational age (GA) should be monitored for apnea because of the high prevalence of apnea in this group of patients [1]. (See "Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity", section on 'Incidence'.)

Monitoring for apnea of prematurity and associated bradycardia and hypoxemia generally includes all of the following:

●Continuous cardiac monitoring

●Continuous pulse oximetry (see "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Pulse oximetry')

●Impedance pneumography – The accuracy of pneumography is limited by movement artifacts and the inability to detect obstructive apnea episodes. For this reason, it is generally not used alone to detect apnea.

CLINICALLY SIGNIFICANT APNEA — Optimal thresholds to determine clinically significant apnea events have not been established. In our practice, we use the following threshold settings to detect clinically significant episodes of apnea (see "Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity", section on 'Diagnosis'):

●Apnea ≥15 or 20 seconds – The lower threshold may be used prior to discharge (see 'Discharge planning' below)

●Heart rate ≤70 or 80 beats per minute

●Oxygen saturation (SpO₂) <80 or 85 percent

Other centers may use different parameters.

MANAGEMENT OVERVIEW

Prevention — Prophylactic caffeine therapy is suggested for extremely preterm (EPT; gestational age <28 weeks) since apnea occurs in nearly all of these infants and treatment may reduce the need for intubation and mechanical ventilation. Caffeine therapy often is needed for several weeks until the apnea resolves as the respiratory control of the infant matures. (See 'Caffeine' below.)

In addition, early nasal continuous positive airway pressure (nCPAP) is often initiated in preterm infants <32 weeks gestation and almost all EPT infants who are at risk for neonatal respiratory distress. This is discussed separately. (See "Respiratory distress syndrome (RDS) in preterm infants: Management", section on 'Nasal continuous positive airway pressure (nCPAP)'.)

Other preventive measures that are applied to all neonates <35 weeks gestation include maintaining a stable thermal environment, ensuring proper head and neck position, and maintaining nasal patency. (See 'General measures' below.)

Treatment — Treatment of apnea of prematurity is instituted if:

●Apneic spells are frequent, prolonged, or associated with bradycardia or frequent oxygen desaturation. In our practice, we use an oxygen saturation (SpO₂) threshold of ≤85 percent. (See 'Clinically significant apnea' above.)

OR

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

Management is a combination of the following:

●General measures that reduce the risk of apnea or its associated hypoxemia (see 'General measures' below)

●Nasal continuous positive airway pressure (nCPAP) (see 'Nasal continuous positive airway pressure' below)

●Caffeine therapy (see 'Caffeine' below)

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. (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'.)

RESPIRATORY SUPPORT

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 "Respiratory distress syndrome (RDS) in preterm infants: Management", section on 'Nasal continuous positive airway pressure (nCPAP)'.)

nCPAP is typically applied using nasal prongs. In the smallest infants, a nasal mask or nasal cannula may be 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.

Nasal suctioning and/or frequent changing of the nCPAP prongs should be minimized to avoid irritation, unless nasal secretions are obstructing airflow.

nCPAP reduces the incidence of mixed and obstructive apnea, maintains functional residual capacity (FRC), and alters timing of breathing in preterm infants [3,4]. 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 [5]. CPAP also increases oxygenation by improving ventilation-perfusion matching and provides continuous distending pressure that optimizes FRC [4]. (See "Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity", section on 'Upper airway patency'.)

The efficacy of nCPAP for treating respiratory insufficiency in preterm neonates is described in greater detail separately. (See "Respiratory distress syndrome (RDS) in preterm infants: Management", section on 'Nasal continuous positive airway pressure (nCPAP)'.)

High flow nasal cannula — Humidified high flow nasal cannula (HFNC) has also been used to treat apnea of prematurity [6]. HFNC is an effective method to provide oxygen supplementation and deliver CPAP while minimizing patient discomfort, but the amount of positive end-expiratory pressure (PEEP) generated by HFNC is highly unpredictable. This modality and its limitations are discussed separately. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'High-flow nasal cannula'.)

Low flow nasal cannula — Low flow nasal cannula can be used with a blender to administer a low oxygen concentration at a flow rate of 1 to 2 L/min. This may provide a small amount of PEEP (approximately 1 to 3 cm H₂O) without exposing the neonate to high oxygen concentrations. However, like HFNC, the amount of PEEP generated is unpredictable. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Low-flow nasal cannula'.)

Nasal intermittent positive pressure ventilation — Nasal intermittent positive pressure ventilation (NIPPV) is an augmentation of 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]. It is discussed in greater detail separately. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Nasal intermittent positive pressure ventilation'.)

Mechanical ventilation — Infants who continue to have clinically significant apnea despite noninvasive respiratory support (CPAP or NIPPV) and caffeine therapy generally require intubation and mechanical ventilation, as discussed separately. (See "Approach to mechanical ventilation in very preterm neonates", section on 'Indications for invasive MV'.)

CAFFEINE — Methylxanthines 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 'Caffeine versus theophylline' below.)

Indications — Caffeine is appropriate in the following settings:

●For treatment of infants who have documented apneic spells that are frequent, prolonged, or associated with bradycardia and/or oxygen desaturation.

●For treatment in infants who have apneic spells that require intervention with bag and mask ventilation, or multiple episodes of tactile stimulation.

●As prophylactic therapy given to extremely preterm infants (EPT; gestational age <28 weeks) to reduce the need for intubation and mechanical ventilation, and to decrease associated morbidities.

●To facilitate extubation in EPT neonates who are intubated.

Dosing and monitoring

Initial and maintenance dosing — The dosing for caffeine, regardless of indication (treatment versus prophylaxis), is as follows [10,11]:

●A loading dose of 20 mg/kg of caffeine citrate (equivalent to 10 mg/kg caffeine base) is given intravenously (IV) or enterally.

●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 IV or orally.

●After the first weeks of therapy, increased dosing may be needed due to faster metabolism with advancing maturation [12].

The efficacy and safety of higher doses are uncertain. Limited clinical trial data suggest that high-dose caffeine may reduce the risk of bronchopulmonary dysplasia (BPD) compared with standard dosing [13,14]. However, the safety of high-dose caffeine has not been established.

Monitoring — Routine measurement of serum drug concentration is not necessary. This is because caffeine has a wide therapeutic index and serious adverse effects are uncommon [15]. In addition, the dose-response relationship is not established. Drug levels are usually only necessary in the rare patient who develops signs of toxicity.

Discontinuation of caffeine — Data are lacking on when to discontinue caffeine therapy. Our approach, which is based on our experience and the natural course of apnea of prematurity, is as follows (see "Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity", section on 'Natural history'):

●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.

●We then continue cardiorespiratory monitoring until discharge or for at least ten days after stopping caffeine, whichever is longer. The mean half-life of caffeine in preterm neonates is approximately 85 hours [16]. Thus, it takes up to seven days for caffeine to be eliminated.

●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.)

Limited data that suggest prolonged caffeine therapy beyond 35 weeks PMA may decrease the frequency and severity of intermittent hypoxemia [17,18]. Clinical studies are being conducted to further investigate the role of caffeine therapy in reducing intermittent hypoxemia.

Response failure — Infants who continue to have clinically significant apnea 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 "Overview of mechanical ventilation in neonates" and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Nasal intermittent positive pressure ventilation'.)

Efficacy of methylxanthines — The efficacy of methylxanthines for treating apnea of prematurity is supported by clinical trials and meta-analyses [10,19-22].

●Therapeutic use of caffeine – The major clinical trial that established the efficacy and safety of caffeine in this setting was the Caffeine for Apnea of Prematurity (CAP) trial [10]. It enrolled >2000 preterm infants (birth weight [BW] between 500 and 1250 g) and randomly assigned them to caffeine or placebo. In 41 percent of enrolled patients, the indication for caffeine therapy was to treat documented apnea, in 36 percent it was to facilitate extubation, and in the remaining 23 percent it was given to prevent apnea. In this trial, caffeine reduced the incidence of BPD (36 versus 47 percent; adjusted odds ratio [aOR] 0.63, 95% CI 0.52-0.76) and reduced the need for patent ductus arteriosus (PDA) ligation (4 versus 13 percent; RR 0.32, 95% CI 0.22-0.45). The reduction is BPD was attributed to reduced need for positive pressure ventilation (PPV) among caffeine-treated infants. Mortality was similar in both groups.

In a post-hoc subgroup analysis of the CAP trial, the benefit of caffeine in reducing BPD was greater among infants who were intubated or on noninvasive ventilation at the time of randomization compared with those who were not receiving PPV [20]. In addition, greater benefit was observed in infants started on caffeine on or before three days than between 4 and 10 days of age [20].

A follow-up study of the CAP trial reported outcomes of survivors at 18 to 21 months corrected age [11]. Infants in the caffeine group had a lower incidence of cerebral palsy (CP) (4 versus 7 percent; aOR 0.58, 95% CI 0.39-0.87) and cognitive delay (34 versus 38 percent; aOR 0.81, 95% CI 0.66-0.99). At five-year follow-up, the difference between groups for these outcomes was no longer statistically significant (for CP: 1.6 versus 2.7 percent; aOR 0.59, 95 % CI 0.29-1.18; for cognitive delay: 4.9 versus 5.1 percent; aOR 0.97; 95% CI, 0.61-1.55) [23]. However, the study detected a difference in the incidence of any motor impairment at five years, including very mild impairment (9 versus 14 percent; aOR 0.66, 95% CI 0.48-0.91). Follow-up of the CAP cohort at 11 years of age reported that children in the caffeine group had better respiratory function compared with controls [24]. Additional data on long-term neurodevelopmental outcomes are discussed below. (See 'Long-term neurodevelopmental outcome' below.)

The results of the CAP trial support the use of caffeine in intubated preterm neonates as a means of facilitating extubation since this subgroup comprised over one-third of the trial population. In a post-hoc subgroup analysis of the CAP trial, the benefit of caffeine was similar in this subgroup of patients as it was for the overall trial population [20]. A subsequent small trial in which intubated preterm neonates were randomized to early caffeine treatment or placebo, the duration of mechanical ventilation was similar in both groups [25]. The trial was stopped early after enrolling only 82 patients due to a cautious decision of the data safety and monitoring board. As such, it is likely that the trial was underpowered to detect a difference between the two treatment arms.

●Prophylactic use – Prophylactic use of caffeine in EPT infants is supported by the CAP trial (discussed above), in which the indication for caffeine therapy for approximately one-quarter of the trial population was to prevent apnea [10]. In a post-hoc subgroup analysis of the CAP trial, the benefit of caffeine was consistent regardless of the indication [20].

Additional supporting evidence comes from observational studies [21,26]. In a large retrospective study from the Canadian Neonatal Network (CNN), 75 percent of EPT infants received caffeine within the first day after birth and the remaining patients received caffeine at a later time [21]. In a multivariate analysis, early caffeine was associated with lower risk of BPD (aOR 0.79, 95% CI 0.64-0.96) and lower likelihood of needing surgical ligation for PDA (aOR 0.58, 95% CI 0.42-0.8). A follow-up report of this observational cohort at 18 to 24 months corrected age reported that early caffeine use was associated with better neurodevelopment [22].

Similar findings were reported in a large cohort study using data from the Pediatrix Medical Group, in which early caffeine therapy before three days of life was associated with a lower incidence of BPD compared with later use (on or after three days of life) (23 versus 31 percent; OR 0.68, 95% CI, 0.63-0.73), shorter duration of mechanical ventilation (mean difference six days), and less need for treatment of PDA (OR 0.60; 95% CI, 0.55-0.65) [26].

However, another observational study did not detect a difference in the need for respiratory support between infants who received early caffeine therapy compared with later treatment [27].

Caffeine versus theophylline — We recommend caffeine as the preferred methylxanthine for the treatment of apnea of prematurity. Caffeine has the following therapeutic advantages over theophylline [15,28,29]:

●Longer half-life (65 to 100 hours), which means that caffeine can be administered once daily instead of the more frequent dosing required for theophylline.

●More reliable enteral absorption.

●Wide therapeutic index, which minimizes side effects.

●Less need for therapeutic monitoring – Caffeine levels are usually only measured if there are signs of toxicity, whereas theophylline therapy generally requires frequent monitoring of serum levels because of the smaller safety margin and greater variability in absorption [15]. (See 'Monitoring' above.)

In a meta-analysis of five small trials (108 infants) comparing caffeine with theophylline, both agents had similar efficacy for reducing episodes of apnea and bradycardia during the first week [29]. However, adverse reactions (ie, tachycardia and feeding intolerance) were considerably lower with caffeine (3 versus 31 percent; RR 0.17, 95% CI 0.04-0.72).

Side effects — The main adverse effects of methylxanthine treatment is tachycardia, which occurs less frequently with caffeine than with theophylline [30]. Theophylline can cause gastroesophageal reflux, perhaps because of delayed gastric emptying [31]; however, this does not present as a clinically significant problem.

Methylxanthines also increase metabolic rate [32]; 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 [33]. 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 — As noted above, based upon follow-up data from the CAP trial, caffeine appears to improve neurodevelopmental outcomes at 18 to 24 months corrected age, though it is uncertain whether the benefit is sustained in later childhood. (See 'Efficacy of methylxanthines' above.)

Other follow-up studies of the CAP trial reported similar overall cognitive outcome and academic performances between the two groups at 5 and 11 years of age [23,34,35] but neonatal caffeine therapy reduced rates of developmental coordination disorder at five years of age and motor impairment at 11 years of age [34,36]. 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 [35]. These data support the long-term safety and potential efficacy of caffeine therapy for apnea of prematurity.

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 [37].

Physiologic changes that occur shortly after administering intravenous caffeine in preterm neonates include increases in cerebral cortical activity, respiratory neural output, and diaphragmatic contraction; decreased carbon dioxide partial pressure; and increased arterial blood pressure [32,38]. Caffeine may also reduce the effects of hypoxia on perinatal white matter injury [37]. 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 [39-41].

ROLE OF TRANSFUSION — Red blood cell (RBC) transfusion may be warranted in neonates with anemia (hematocrit <25 to 30 percent) who have frequent and/or severe apnea despite caffeine therapy. Indications for transfusion in the preterm infants are discussed in detail separately. (See "Red blood cell (RBC) transfusions in the neonate", section on 'Indications for transfusion' and "Anemia of prematurity (AOP)", section on 'Transfusion'.)

The frequency and severity of apnea occasionally are increased in preterm infants who develop significant anemia at one to two months of age. Observational studies have demonstrated improvements in apneic and/or desaturation episodes temporally associated with RBC transfusion [42-44].

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 [45].

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 clinical 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 10 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, the parents/caregivers or primary home care provider must receive training in cardiorespiratory resuscitation prior to discharge and must demonstrate proficiency in managing the monitor and providing stimulation. 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

●Monitoring – 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 – 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'.)

●Management approach – Our approach to managing preterm infants with documented apnea and those at high risk of apnea (eg, extremely low birth weight [ELBW] infants [BW <1000 g] and/or extremely preterm [EPT] infants [gestational age <28 weeks]) is as follows:

•nCPAP – 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) rather than other respiratory modalities or supportive care alone (Grade 2C). Many preterm infants may have other indications for nCPAP (eg, nCPAP is commonly used for management of respiratory distress syndrome and it is used routinely in most EPT infants). nCPAP is typically started at a pressure between 4 and 6 cm H₂O via nasal prongs or mask. (See 'Nasal continuous positive airway pressure' above and "Respiratory distress syndrome (RDS) in preterm infants: Management", section on 'Nasal continuous positive airway pressure (nCPAP)'.)

•Indications for caffeine – For infants with apnea of prematurity who require repeated tactile stimulation or ventilatory support, we recommend caffeine rather than theophylline or supportive care alone (Grade 1B). Caffeine and theophylline appear to have similar efficacy for reducing episodes of apnea and bradycardia in preterm infants; however, the risk of adverse effects is substantially lower with caffeine. In addition, caffeine has the advantage of more reliable enteral absorption, and it does not require routine therapeutic monitoring. (See 'Caffeine versus theophylline' above and 'Efficacy of methylxanthines' above.)

In addition, we suggest early prophylactic caffeine therapy for ELBW or EPT infants (Grade 2C). Caffeine is typically started within the first two days after birth. Apnea occurs in nearly all of these infants and the available evidence suggests that prophylactic caffeine reduces the need for intubation and mechanical ventilation and may facilitate earlier extubation. (See 'Indications' above and 'Efficacy of methylxanthines' above.)

•Caffeine dosing and maintenance – Caffeine is given as a loading dose of 20 mg/kg of caffeine citrate (equivalent to 10 mg/kg caffeine base), 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. Routine measurement of serum drug concentration is not necessary unless there are signs of toxicity. (See 'Initial and maintenance dosing' above.)

•Stopping caffeine – In our center, discontinuation of caffeine can be discontinued when the infant is at a postmenstrual age postmenstrual age (PMA) between 32 and 34 weeks and has had a five-day period free of any apnea, bradycardia, or desaturation alarm events. (See 'Discontinuation of caffeine' above.)

•Transfusion – Red blood cell (RBC) transfusion is often warranted for infants who are anemic (eg, hematocrit <25 percent) and have frequent and/or severe apnea requiring intervention despite caffeine therapy. This is discussed separately. (See "Red blood cell (RBC) transfusions in the neonate", section on 'Indications for transfusion' and "Anemia of prematurity (AOP)", section on 'Transfusion'.)

●Discharge planning – At discharge, home cardiorespiratory monitoring is not necessary 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. (See 'Discharge planning' above.)

If an infant is ready for discharge, but mild apnea (ie, apneic episodes >15 seconds that do not require intervention and 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/caregivers or primary home care provider must receive training in cardiorespiratory resuscitation and must demonstrate proficiency in managing the monitor and providing stimulation. (See "Use of home cardiorespiratory monitors in infants", section on 'Implementation'.)

Infants still exhibiting apnea with associated bradycardia or oxygen desaturation are not candidates for discharge and home monitoring.