Apnea of prematurity

Most drugs are administered to infants and children for the same therapeutic indications as for adults. However, a few drugs have found unique uses in children. Among these are theophylline and caffeine, which are used to treat apnea of prematurity indomethacin, which closes a patent ductus arteriosus and prostaglandin Ej, which maintains the patency of the ductus arteriosus. Paradoxically, drugs such as phenobarbital, which have a sedating action on adults, may produce hyperactivity in children, and some adult stimulant drugs, such as methyl-phenidate, are used to treat children with hyperactivity. 

Xanthines have been given to infants at the risk of sudden infant death sjmdrome or idiopathic apnea of prematurity (see monograph on Theophylline). About 50% of 30 infants treated with caffeine (and 12 of 18 infants treated with theophylline) had significant increases in episodes of gastroesophageal reflux (36). The authors stressed that screening for reflux should precede the administration of caffeine (and theophylline) to infants at the risk of sudden infant death syndrome. As expected, the frequency of adverse effects such as tachycardia and gastroesophageal reflux is lower with lower doses of caffeine for example 2.5 mg/kg qds (SEDA-17,1). 

Ten preterm infants receiving regular theophylline for apnea of prematurity, who subsequently received vancomycin and furosemide, have been studied (52). When vancomycin was introduced in the infants who were established on furosemide and theophylline, there was a consistent failure to achieve therapeutic concentrations. Starting furosemide in infants who were already receiving vancomycin resulted in falls in serum vancomycin to subtherapeutic concentrations in all but one case. Serum concentrations fell by a mean of 24% (range 12-43%), in the 24 hours after the start of furosemide treatment. Two of the 10 infants had persistence... 

Calhoun LK. Pharmacologic management of apnea of prematurity. J Perinat Neonatal Nnrs 1996 9(4) 56-62. 

Apnea in Premature Infants. Apnea of prematurity (AOP) occurs in about 90% of premature neonates weighing less than 1 kg at birth, and in 25%of infants with a weight of less than 2.5 kg (20). The first-line pharmacological therapies for the management of AOP,... 

Erenberg, A. Leff, R.D. Haack, D.G. Mosdell, K.W. Hicks, G.M. Wynne, B.A. Caffeine citrate study group. Caffeine citrate for the treatment of apnea of prematurity A double-blind, placebo-controlled study. Pharmacotherapy 2000, 20 (6), 644-652. 

Apnea of prematurity generally resolves as the neonate matures and approaches typical term age. Therefore, the PK/PD model must account for this trend with respect to time. Figure 27.2 showed the time course of apneic episode frequency. The number of daily episodes increased after birth with a peak between 1 and 2 weeks on average. A gradual decline was observed thereafter. A number of functional forms were considered to describe this profile, but two of the models evaluated are presented here. The first model, TCI (Eq. (27.15)), included a zero-order progression rate of episode frequency and a first-order resolution rate of episode frequency. In the second model, TC2 (Eq. (27.16)), the progression and resolution rates were both treated as first-order processes. Note that the use of resolution is meant to imply lessening of disease severity with maturity, not resolution of a specific apneic episode. 

C. Godfrey, The Population Pharmacokinetics and Pharmacodynamics of Theophylline in Neonates with Apnea of Prematurity. PhD Dissertation, University of Connecticut, 2001. 

Jamah F, Coutts RT, Malek F, Finer NN, Peliowski A. Lack of a pharmacokinetic interaction between doxapram and tiieophylline in apnea of prematurity. Dev Pharmacol 77ier(1991) 16, 78-82. 

The xanthines are readily absorbed by the oral and rectal routes. Although these agents can be administered by injection (aminophylline is a soluble salt of theophylline), intravascular administration is indicated only in status asthmaticus and apnea in premature infants. Intramuscular injection generally produces considerable pain at the injection site. 

Theophylline is frequently used as a bronchodilator in the treatment of asthma. The importance of the methylxanthines in the management of bronchial asthma is discussed more fully in Chapter 39. Caffeine as the citrate salt (Cafcit) is used for the short-term management of apnea in premature infants (28-33 weeks of gestational age). 

Caffeine has widespread therapeutic use. It is widely used in headache (migraine) remedies such as aspirin and other analgesics. Caffeine is a mild vasoconstrictor and its ability to constrict blood vessels serving the brain explains its use to relieve headache. Individuals who consume caffeine regularly through medications and food are susceptible to what is known as a rebound headache or caffeine rebound. This occurs when regular caffeine intake is suddenly reduced and the vessels dilate. Caffeine is a common substance in medications to treat apnea in premature infants. Apparently, the area of the brain controlling respiration in premature infants is not fully developed and caffeine helps to stimulate this portion of the... 

Percutaneous absorption may be increased substantially in newborns because of an underdeveloped epidermal barrier (stratum comeum) and increased skin hydration. The increased permeability can produce toxic effects after the topical use of hexachlorophene soaps and powders, salicyhc acid ointment, and rubbing alcohol. Interestingly, a study has shown that a therapeutic serum concentration of theophylline can be achieved to control apnea in premature infants of less than 30 weeks gestation after a topical apphcation of gel containing a standard dose of theophylline. " The use of this route of administration may minimize the unpredictability of oral and intramuscular absorption and complications of intravenous drug administration for certain drugs. 

More importantly, the effects of theophylline are not limited to bronchodila-tion, bnt also include immunomodulatory, anti-inflammatory, and bronchoprotec-tive activity that substantially contribute to its usefulness as a prophylactic drug in asthma and other respiratory diseases. Additional effects include an increase in mucociliary clearance, a decrease of microvascular leakage into the airways, and an improvement of respiratory mnscle fatigue, especially that of the diaphragm. Theophylline fnrthermore acts centrally, blocking the decrease in ventilation that occurs with sustained hypoxia. While some of these effects are the rationale for its use in asthma, others form the basis for its effectiveness in chronic obstructive pulmonary disease (COPD) or in the treatment of apnea in premature newborns. 

Yazd 1 Kissling GE, Tran TH, Gottschalk K, Schuth CR Phenobarbital increases the theq>hylline requirement of premature infants being treated for apnea. AmJDis Child ( 9Z7) 141,97-9. 

The total and ionic maternal serum calcium levels of 54 women with normal uncomplicated pregnancies were each significantly less than in normal cord serum collected from several umbilical cords and prior to placental separation. This is accounted for in terms of simple diffusion rather than increased protein binding [121]. The calcium ion-selective electrode has also established the existence of hypocalcaemia during normal uncomplicated pregnancies [122], the ionic serum calcium being 1.11 0.03,1.10 0.02 and 1.05 0.01 mmol dm", respectively, during the first, second, and third trimesters. Hypocalcaemia has also been studied in relation to recurrent apnea in premature infants [124]. 

M. Boutroy, P. Vert, R. Royer, P. Monin, and M. Royer-Morrot, Caffeine, a metabolite of theophylline during treatment of apnea in the premature infant, J. Pediatr., 94, 996 (1979). 

Labor and delivery - May produce fetal bradycardia, respiratory depression, apnea, cyanosis, and hypotonia in the neonate. Maternal administration of naloxone during labor has normalized these effects in some cases. Use with caution in women delivering premature infants. 

This section demonstrates aspects of the application of a nonlinear mixed effects modehng approach to the analysis of count data using the premature neonate apnea data described in Section 27.2. The objective is to draw attention to key features the pharmacometrician should be aware of and provide methods for model diagnostics and general considerations. Selected results presented here are excerpted and adapted from the complete analysis (3). A subset of the analysis data set is provided in the appendix. 

The use of a biexponential equation with postnatal age as the time scale permits some practical interpretation of the time course component of the final PD model. Table 27.2 presents the peak spell frequency, the time to achieve peak frequency, and the model predicted resolution half-time of apnea in absence of therapy. The resolution half-time defines the number of days of postnatal maturation that transpire before the daily spell frequency is reduced by one-half. The influence of hyaline membrane disease on resolution half-time is readily apparent. The most premature neonates with HMD have the slowest time to maximum episode counts and have the highest frequency of apnea. A 24 week gestational age infant with HMD requires an additional 7 days for a maturational reduction in spell count of one-half. The half-time of apnea onset is approximately 2.5 days. On average, the greatest severity of apnea would occur at approximately 1 postnatal week. Figure 27.10 depicts the baseline apneic episode frequency versus postnatal age for each gestational age in the present study. The predictions of daily spell count are population predictions, calculated using the final parameter estimates for PRE, and... 

Methylxanthines have a few valid therapeutic uses, including treatment of asthma and relief of dyspnea (see Antiasthmatic agents). The CNS stimulatory effects are also utilized for the treatment of the prolonged apnea that may be observed in premature infants. Theophylline may be combined with doxapram (13) for this use (20). The methylxanthine most widely used therapeutically is theophylline, although caffeine may also be used. For parenteral administration, a salt of theophylline is employed. There are several salts available, including theophylline ethylenediamine (aminophylline [317-34-0]) and oxtriphylline (choline theophyllinate). Other synthetic xanthines that are used include dyphylline [479-18-5] and enprofylline [410784)2-8] (21). Caffeine is obtained in pure form from tea waste, from the manufacture of caffeine coffee, and by total synthesis (22,23). 

Theophylline is a methylated xanthine which exemplifies a clinically useful drug with a narrow margin of safety. Theophylline is used to treat bronchial asthma as well as apnea and bradycardia in premature infants. Serum concentrations must be maintained between 10 and 20 lg/ ml because it is ineffective at lower concentrations and it produces undesirable effects at higher concentrations. 

---