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Written by | Medicine Chat Zhai. Chang Yiyong
Neonatal apnea refers to respiratory arrest for more than 20 seconds in preterm infants and respiratory arrest for more than 15 seconds in full-term infants, possibly accompanied by slowing of the heart rate. Neonates who usually develop apnea 24 hours after birth may have concurrent sepsis.
At present, neonatal apnea is clinically divided into primary and symptomatic, the former is mainly caused by respiratory center hypoplasia, and the latter may be related to hypoxia, infection, metabolic disorders, gastrointestinal diseases or central nervous system diseases.
If neonatal apnea is not treated effectively in time, repeated apnea can cause hypoxia and cause damage to the central nervous system of the child, and in severe cases, even disability or death, with serious consequences. This article summarizes the progress of pharmacotherapy for neonatal apnea for clinical reference.
aminophylline
At present, methylxanthines are still the main drugs for the clinical treatment of apnea (AOP) in preterm infants, including theophylline, aminophylline, and caffeine. These drugs are non-selective adenosine receptor antagonists that increase minute ventilation, improve the sensitivity of the respiratory center to CO2, reduce respiratory depression, enhance diaphragm activity, improve respiratory muscle contractility, and reduce periodic respiration.
The strong inhibitory reflex that occurs due to activation of throat receptors, swallowing activity, and closure of the upper trachea is called laryngeal chemoreflex (LCR) [1]. Physiological experimental animal models have shown that gastric contents reflux, uncoordinated swallowing breathing, or accumulation of pharyngeal secretions caused by some other factors can cause apnea through reflex suppression of breathing by the superior laryngeal nerve. In animal tests, aminophylline has been found to reduce AOP by preventing LCR in laboratory animals[2].
The first load of aminophylline was 5mg/kg, 20ml of 10% glucose injection was added to continuous intravenous drip, and the maintenance amount of 2.5mg/kg was given each time after 12 hours, 2 times/d, 8-12h apart. The half-life of aminophylline is 30-33h, and the therapeutic plasma concentration is 5-15mg/L.
The amount of aminophylline treatment is close to the toxic amount, premature infants have immature liver and kidney function, the half-life is 5-6 times longer than that of adults, and the blood concentration is unstable, even if the regular amount is given every day, some will appear irritability, tachycardia, hypotension, convulsions, nausea, vomiting, feeding intolerance, abdominal distension and gastrointestinal bleeding and other adverse reactions. Therefore, close observation should be made during the treatment process, and abnormalities should be treated in time.
caffeine
In a multicenter, randomized, double-blind trial study, foreign scholars [3,4] found that high doses of caffeine [20mg/(kg·d)] are beneficial to the extubation of children who have been on the machine for more than 48 hours, and significantly reduce the possibility of re-intubation, reduce the incidence of bronchial dysplasia, and significantly reduce the incidence of cerebral palsy and cognitive delay.
There were no significant differences in mortality, deafness, deafness, brain injury, and retinopathy compared with placebo. Caffeine produces a transient slowdown in weight gain, with the largest difference occurring at week 2 ( -32 g of caffeine group versus -13 g of control group, P<0. 01）。 After 3 weeks, there was no significant difference in weight gain.
Due to the good efficacy, safety and ease of use of caffeine, foreign countries have gradually replaced aminophylline. The half-life of caffeine is 72-96 hours, the basal load is 20 mg/kg, and the maintenance amount is given after 24 hours, 5 mg/kg each time, 1 time/day, intravenous drip. It is well absorbed after oral administration, and its bioavailability is close to 100%.
In neonates, a dose of 20 mg/kg of caffeine citrate yields a peak plasma concentration of 6-10 mg/ml with an average time of 30 min-2 h peak. It is absorbed by the body and is not affected by food, and has a safer therapeutic range than aminophylline. Domestic is mainly sodium benzoate caffeine, which can compete with bilirubin for albumin, so premature infants with severe jaundice should be used with caution [5].
In recent years, the clinical treatment of apnea in premature infants mostly uses caffeine citrate, this drug can stimulate the respiratory center, improve the sensitivity of chemoreceptors to CO2, relieve respiratory depression, and improve ventilation. At the same time, its safe dose range and long half-life can effectively improve the ventilation of children and reduce the occurrence of apnea [6].
The main component of caffeine citrate is caffeine, which contains about 50%. The clinical results showed that the number of apnea attacks in the caffeine citrate group was less than that in the control group (aminophylline), and the incidence of adverse reactions was lower than that in the control group.
The usual amount of caffeine citrate is 20 mg/kg per day for the loading dose and 5-10 mg/kg per day for the maintenance dose. Clinical studies have shown that caffeine citrate can reduce the frequency of apnea, shorten the duration of invasive respiratory support, continuous positive pressure ventilation, and atmospheric oxygen administration, and reduce the failure rate of extubation and the chance of re-entry [8].
Naloxone
AOP is very easy to cause hypoxia in the body, especially cerebral hypoxia. Promote the release of endogenous opioids into the blood, resulting in elevated plasma β-endorphins, acting on opioid receptors, inhibiting the central nervous system, respiratory, circulatory and other systems, and further aggravating hypoxia. Naloxone can pass through the blood-brain barrier, antagonize endogenous opioids, reverse their inhibition of the central nervous system, respiratory, and circulatory systems, thereby receiving the effect of treating AOP.
Naloxone has the following advantages over aminophylline [9]:
(1) It can antagonize opioids (β-endorphins, etc.) that significantly increase the central nervous system during apnea, thereby relieving respiratory depression, increasing respiratory rate, and improving ventilation.
(2) Increase cardiac output, improve coronary circulation, increase cerebral perfusion, and have a protective effect on the heart and brain.
(3) Fast onset, intravenous medication 1-3min after onset.
(4) The safety range is large (0. 01-0. 2mg/kg), neonatal dosage has been reported to reach 0. No adverse effects were found at 4 mg/kg [10].
(5) There is no need to monitor blood concentration. The clinical application of naloxone combined with aminophylline in the treatment of AOP has achieved satisfactory results.
Doxapram
Doxapram is thought to stimulate breathing and is used to treat apnea, especially when methylxanthines do not respond well. The main effect of doxapram at low doses is peripheral, and at larger doses, it acts on the center, can increase respiratory rate and ventilation per minute, can reduce arterial carbon dioxide partial pressure and increase arterial oxygen partial pressure. The drug requires continuous intravenous drip.
The initial dose is 0.5 mg/(kg·h), if the effect is not satisfactory, it can be gradually increased at a rate of 0.5mg/(kg·h) each time in 6-12 hours, and the maximum dose is 2. 0-2. 5mg /kg。 Its effect is often dose-dependent, with blood concentrations >3. 5mg/L can cause obvious adverse reactions.
Discontinuation should be reduced by 0 per dose. At a rate of 5 mg/kg, it was gradually withdrawn in 24-48 h. Foreign scholars [11] found that doxapram may reduce the onset of apnea in the first 48 hours of treatment, but in 48h-7 days, the failure rate is 80%, and its long-term efficacy and side effects have not been evaluated.
scopolamine
Methylxanthines increase oxygen consumption while stimulating breathing. As a cholinergic receptor blocker, scopolamine can not only directly stimulate the respiratory center, but also calm the cerebral cortex, and has the effect of reducing the body's oxygen consumption, relieving arteriolar spasm, improving the hypoxia state of brain tissue, and blocking the damage of multiple organ functions. Clinically[12] good results have been achieved in the clinical observation of naloxone combined with scopolamine in the treatment of AOP.
Ambroxol
The main causes of AOP are the immaturity of the central nervous system and respiratory organs. Drugs such as methylxanthines and naloxone have little effect on the development and maturation of respiratory organs.
Ambroxol is characterized by the promotion of mucus elimination and the dissolution of secretions, which can promote the synthesis and secretion of endogenous surfactant, thereby reducing the surface tension of the alveoli and refilling the collapsed alveoli.
At the same time, Ambroxol has a high degree of lung tissue affinity, which can improve lung function and lung tissue compliance, and promote lung maturation. Clinical [13] The use of low-dose aminophylline combined with ambroxol for the prevention and treatment of AOP effectively improved the clinical process of recurrent apnea in preterm infants and shortened the oxygen time.
Bibliography:
[1] St-Hilaire M，Samson N，Duvareille C，et al．Laryngeal stimulation by an acid solution in the preterm lamb［J］．Adv Exp Med Biol，2008，605：154-158．
[2] Wilson CG，Martin ＲJ，Jaber M，et al．Adenosine A2A receptors interact with GABAergic pathways to modulate respiration in neonatal piglets［J］．Ｒespir Physiol Neurobiol，2004，141（2）：201-211．
[3] Steer P，Flenady V，Shearman A，et al．High dose caffeine citrate for extubation of preterm infants：a randomised controlled trial［J］．Arch Dis Child Fetal Neonatal Ed，2004，89（6）：F499-F503．
[4] Schmidt B，Ｒoberts ＲS，Davis P，et al．Caffeine therapy for apnea of prematurity［J］．N Engl J Med，2006，354（20）：2112-2121．
[5] CHEN Chao. Prevention and treatment of apnea in premature infants[J].Pediatric Emergency Medicine,2003,10(4):204-206.)
[6] Shi Jinju, Zhang Huiyue. Clinical Rational Drug Use,2020,13(6):87-88.)
[7] Lin Jinwen. Clinical efficacy analysis of caffeine citrate on neonatal apnea[J].Chinese Medical Guide,2021,19(17):22-24.)
[8] HE Ting, LIAO Zhengchang, DING Ying, et al. Comparison of the efficacy of domestic and imported caffeine citrate in the treatment of apnea in preterm infants:a prospective randomized double-blind controlled study[J].Chinese Journal of Contemporary Pediatrics,2020,22(7):684-689.)
[9] CHENG Ling, LI Yuxi. Efficacy of naloxone combined with aminophylline in the treatment of apnea in preterm infants[J].Chinese Journal of Maternal and Child Health,2005,20(13):1610-1611.)
[10] ZHU Yimin. Application of naloxone in pediatric first aid[J].Chinese Journal of Practical Pediatrics,1999,14(11):643.)
[11] Henderson-Smart D，Steer P．Doxapram treatment for apnea in preterm infants［J］．Cochrane Database Syst Ｒev，2004，18 （ 4 ）：CD000074．
[12] LI Fengqi. Naloxone combined with scopolamine in the treatment of apnea of preterm infants in 48 cases[J].Clinical Journal of Practical Pediatrics,2005,20(4):363-364.)
[13] LI Meijuan. Low-dose aminophylline combined with ambroxol for the prevention and treatment of apnea in preterm infants[J].Journal of Pediatric Pharmacy,2010,16(5):19-20.)
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