Lupine Publishers | Journal paediatrics and neonatology
Abstract
Keywords:Apnoea of Prematurity; Premature Infant; Neurodevelopment; Methylxanthine Therapy
Introduction
Incidence
Fetal to Neonatal Transition
Ventilatory Response to Hypoxia
Ventilatory Response to Hypercapnia
Ventilatory Responses to Laryngeal Chemoreflex
Activation of the laryngeal mucosa in premature infants can lead to apnea, bradycardia, and hypotension. While this response is assumed to be a protective reflex, an exaggerated response may cause AOP. This reflex-induced apnea is termed the laryngeal chemoreflex and is mediated through superior laryngeal nerve afferents [9].Neurotransmitters and Apnoea
Enhanced sensitivity to inhibitory neurotransmitters, such as gamma-aminobutyric acid (GABA), adenosine has been postulated as a pathogenic mechanism. GABA is the major inhibitory neurotransmitter in the CNS. Adenosine is a product of adenosine triphosphate and is formed as a consequence of metabolic and neural activity in the brain, especially during hypoxia. Reports have found an interaction between adenosine and GABA in the regulation of breathing. This association is further strengthened by the observations that adenosine receptors are expressed in GABAcontaining neurons. The binding of adenosine to its receptor may be involved with the release of GABA and thus inhibit respiration leading to apnoea [10].Genetic Variability and Apnoea
Effects of Sleep State and Movements on Apnoea
Premature infants spend a large proportion of their time in rapid eye movement (REM) sleep, with a relatively smaller amount in wakefulness. During REM sleep, these infants have more paradoxical breathing with a less stable baseline of oxygen saturation. Therefore, apnoea occurs more frequently in REM sleep than in quiet sleep12. Arousal from REM sleep appears to be a precursor to apnoea associated with oxygen desaturation in premature infants since motor activities after arousal are typically associated with laryngeal closure. Therefore, movements frequently precede or occur simultaneously with apnoea, and arousal from sleep may cause the apnoea rather than terminate it [12,13].Other Factors Involved in Apnoea
While immature respiratory control is the primary cause of apnoea in the premature infant, many coexisting factors can potentiate or worsen apnoea. Apnoea is a common presenting sign of both local and systemic infection13. Apnoea can be secondary to central nervous system diseases like intracranial haemorrhage, hypoxic-ischemic encephalopathy, and seizures. Exposure to cooler temperatures decreased the duration and frequency of AOP, while elevated body temperature increased the incidence of AOP, suggesting that apnoea is related to metabolic state and environmental temperature [1,2]. Other factors that have been associated with apnoea in premature infants include glucose or electrolyte imbalance, presence of a hemodynamically significant patent ductus arteriosus (hs-PDA) [1,2]. Anaemia is also associated with apnoea because of lowered oxygen-carrying capacity of red blood cells that leads to hypoxia, resulting in respiratory depression. Drugs including narcotic analgesics and magnesium sulfate, can lead to apnea in infants. The role of Gastroesophageal reflux in causing apnoea is controversial also, there is no evidence to support the use of anti-reflux medications for the prevention of aponea [14].Interventions for Premature Infants with Apnoea
Interventions for AOP include efforts to reduce work of breathing and/or increase respiratory efforts.Non Pharmacological Therapies
Prone Position
Prone positioning can improve thoracoabdominal synchrony and stabilize the chest wall without affecting breathing pattern or SpO2. Several studies have demonstrated that prone position reduces AOP [15]. Extension of the neck 15° from the prone position is referred to as the head -tilt position, which has been found to decrease episodes of oxygen desaturation and it should be considered as a first-line intervention in infants with AOP However, head- tilt position has not been shown to work in combination with pharmacologic therapy.Continuous Positive Airway Pressure and Nasal Intermittent Positive Pressure Ventilation
Other Therapies
KMC
Maternal kangaroo care, also known as skin-to-skin care for premature infants, has calming effects on the baby’s clinical status and vital signs. It has shown to be effective in reducing the apnoea [18,19].Sensory Stimulation
Thermoneutral Range
Packed Cell Transfusion
Anemia can lead to AOP, and a proposed mechanism to treat AOP is transfusion of red blood cells to increase oxygen carrying capacity. However, data on the effect of blood transfusion on AOP is not clear. Because of the lack of clear cut evidence transfusion to treat AOP may not be recommended as a routine unless the neonate fulfils the recommened transfusion criteria for preterm neonates [24].Methylxanthine Therapy
Methylxanthine compounds such as caffeine, theophylline, and aminophylline have been administered to premature infants as respiratory stimulants to decrease AOP. These drugs are powerful central nervous system stimulants and are likely to reduce apnea by multiple physiological and pharmacological mechanisms [25,26].These drugs are antagonist of adenosine receptor and work by increasing the minute ventilation, improving the CO2 sensitivity and neural respiratory drive and decreasing the hypoxic respiratory depression. Other mechanisms include improved diaphragmatic contraction and improved respiratory muscle function [25]. Systematic reviews of caffeine therapy in AOP have shown that both caffeine and theophylline are effective in reducing apnoea. Caffeine is the preferred of the two drugs considering its wider therapeutic range and the plasma half-life making it ideal for once a day administration. Further studies have shown that the incidence bronchopulmonary dysplasia and neurodevelopment disabilities have decreased with the use of Caffeine. The potential mechanism of neuroprotection is not clearly understood but could be explained by the decrease of ventilator-induced lung injury (VILI) due to the use of caffeine [26-28]. Caffeine is usually available as caffeine citrate and the active component comprises of only 50% of the total dose. Caffine is generally given as a loading dose of 10 mg⁄kg caffeine (i.v. or orally) followed by a maintenance dose of 5 mg⁄kg once daily. Higher doses have been studied but have shown to be of little use except in cases of refractory AOP [27,28].
Theophylline is usually recommended at a loading dose of 5-6 mg/kg, followed by maintenance doses of 2-6 mg/kg/day in divided into two or three daily doses. Therapy with methylxanthines is associated with few adverse events. Toxic levels may produce tachycardia, cardiac dysrhythmias, and feeding intolerance or, at very high doses, may precipitate seizures. Mild diuresis and delayed gastric emptying can also be seen in very low birth weight infants on methyxanthine therapy. Methylxanthines also increase energy expenditure, possibly leading to diminished growth in premature infants hence a extra caloric requirement is necessary in infants treated with theophylline [26-28]. Doxapram is a potent respiratory stimulant previously used for the management of apnoea refractory to methylxanthine therapy. The use of doxapram is controversial because of its reported adverse effects with include irritability, elevated blood pressure, and gastric retention, increase in cerebral oxygen consumption and a decrease in oxygen delivery. This is probably mediated by a decrease of cerebral blood flow. Therefore, doxapram is not routinely recommended for AOP since its side effects and long-term benefits versus potential harm are concerning [29]. Drugs are generally stopped when the neonate is apnoea free for 7 days or has reached 34 weeks Corrected gestational age and it is generally advisable to stop the drugs 4 to 5 days prior to discharge of these neonates as the drugs have long half-life and premature discharge after stopping the drugs may lead to dire consequences.
Consequences of AOP
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