Neonatal Apnea

REVIEW ARTICLE

Neonatal apnea

José Maria de Andrade Lopes*

Abstract Objective: to review medical literature related to apnea of prematurity. Sources: extensive literature search and clinical practice-oriented concepts. Summary of the findings: apnea is one of the most common respiratory disorders in the neonatal period. Immaturity of the central nervous system is associated with instability of respiration. Therefore, apnea manifests itself in other systems, causing problems such as hypoglycemia, hypothermia, infection, or patent ductus arteriosus. Apnea may be central, obstructive or mixed depending on the presence of air flow through the upper airways. Diagnosis should involve careful observation by unit personnel and the monitoring of heart rate, respiratory frequency or arterial oxygen saturation. Initially, the treatment consists of xanthines (caffeine and aminophylline). If respiratory failure occurs, then continuous positive airway pressure (CPAP), and mechanical ventilation should be used. Conclusions: preterm newborns are susceptible to respiratory problems, having apnea as a clinical manifestation of disorders in many organs and systems.

J Pediatr (Rio J) 2001; 77 (Supl.1): S97-S103:apnea, prematurity, respiration.

Introduction Apnea is the most frequent type of breathing disorder in In this paper, we will discuss basic concepts and practical the neonatal period.1 During the past few years, the use of aspects of the treatment of apnea in newborn infants. artificial surfactants, of new technologies, and the progress in neonatal care have allowed for a considerable increase in the survival of newborn infants with less than 1,500 grams Definition and concepts 2 and, consequently, in the population at risk for apnea. The definition of apnea has been changing in the past Most of the times, apnea is an isolated event, but that can put years due to new findings on its physiopathology. Initially, the newborn’s life at risk if not promptly diagnosed and apnea was defined in terms of respiratory movements. adequately treated. Exceptionally, severe apnea affects Cessation of respiratory movements of 5, 10, 20, or 30 term newborn infants, but it is common in newborns with seconds’ duration have been used to define apnea. Most less than 2,500 grams. authors agree that episodes of any duration followed by bradycardia and/or cyanosis are considered pathological.3,4 * Chief, Department of Neonatology, Instituto Fernandes Figueira, It is important to underscore that the more immature the FIOCRUZ. Member, Perinatology Committee, Brazilian Society of Pediatrics (SBP). newborn, the greater the irregularity of respiration and the

S97 S98 Jornal de Pediatria - Vol. 77, Supl.1, 2001 Neonatal apnea - Lopes JMA number of episodes of apnea without bradycardia and The response to hypoxia is paradoxal.6 While in adults cyanosis, and with spontaneous recovery. Particularly during patients hypoxemia stimulates breathing, in newborn patients REM (Rapid Eye Movement) sleep, apneic spells with 10 to the response is diphasic, initially with hyperventilation and 15 seconds’ duration are very frequent.5 Alternately with followed by ventilatory depression. One of the possible episodes of periodic respiration, others have also reported causes of post-hypoxia depression in newborns is the release apneic spells lasting 5 to 10 seconds without physiological of adenosine to the central nervous system. Adenosine is a consequences (see next section). nitrogen base produced with breakdown of adenosine The definition of apnea based on respiratory movements triphosphate (ATP) during hypoxia. Its effects can be is incomplete, and that is because even during active blocked by xanthines (caffeine and teophylline). Xanthines 7 respiratory movements there may be an obstruction of the are adenosine receptor antagonists. Lopes et al. studied the upper airways and a cessation of gas exchange. This condition role of adenosine in newborn piglets. The authors concluded is known as obstructive apnea (Figure 1). that pretreatment with xanthine abolished the ventilatory depression associated with hypoxia.7 The diphasic response to hypoxia can deteriorate cases of neonatal apnea because patients will enter an endless cycle of apnea-hypoxia-apnea, which leads to worsening of 6 Central apnea - total cessation of respiratory ventilatory depression. movements, and consequent The response to hypercapnia is still controversial. Some cessation of airflow in the upper authors consider that the response is similar to that of the airways. adult; whereas others insist that, at least during the first days Obstructive apnea - cessation of airflow in the upper of life, the response is depressed. In very low birth weight airways in the presence of active newborns (less than 1,500 g), studies have reported a respiratory movements. reduced sensitivity to CO2, which improved with increase 8 Mixed apnea - episode of central apnea in gestational age. followed by obstructive episode The most important aspect of respiration control is that (respiratory movements without there is a poor neuronal organization. The more immature airflow in the airways) or the newborn infant, the more immature the central nervous obstructive episode followed by system, with reduced synapses and dendritic branches.9 central apnea. Physiologists tend to define the respiration of the newborn Figure 1 - Classification of neonatal apneas as a sensory and motor experience extremely dependent on the quantity and quality of sensory afferent stimulation. This concept is based on the facts that simple alterations of room temperature (hypo and hyperthermia) can, sometimes, cause apnea; physical or sensory stimulation are capable or reverting clinical status of apnea; hypoglycemia is frequently In this sense, apnea is currently defined as the cessation associated with apnea; and apnea itself is, at times, the most of airflow longer than 5 seconds in the upper airways. common symptom in the presence of infection, anemia, or Apnea is pathological and, independently of its duration, it metabolic disorders.10 is followed by bradycardia and cyanosis. It is interesting to underscore that as a general rule, Consequently, if, on the one hand, there are more obstructive apneas lead to earlier bradycardia. Central exciting stimuli than grating stimuli, breathing will continue. apnea rarely presents hemodynamic consequences if it lasts If, on the other hand, there are more grating stimuli, apnea less than 20 seconds. will occur.

Predisposing factors Sleep and alterations of the thoracic cavity We will discuss two of these factors, firstly, respiration control and, secondly, sleep and alterations of thoracic Sleep will determine important changes in the respiration cavity. of the newborn infant. There are basically two types of sleep, non-rapid eye movement (NREM) and rapid eye movement (REM). As soon as we fall asleep we enter the Respiration Control NREM stage. This stage is characterized by regular Respiration control in newborn infants is the focus of breathing, broadband waves, low-frequency EEG, and no extensive research projects carried out worldwide due to REM for a duration of 15 to 20 minutes (EEG indicating the differences in relation to adult patients. rapid, low-voltage waves). These two stages are repeated Neonatal apnea - Lopes JMA Jornal de Pediatria - Vol. 77, Supl.1 , 2001 S99 during sleep in the NREM-REM sequence. Adults will have Table 1 - Factors related to the occurrence of apnea, and some approximately 80% of their sleep in NREM. Conversely, possible physiological mechanisms involved premature newborn infants with less than 32 weeks will have approximately 80%of their sleep in REM.4,11 Factor Possible mechanism During sleep, the REM stage is characterized by irregular PDA Hypoxia and/or muscle fatigue breathing with intermittent respiratory pauses and apneas. Anemia Hypoxia During this period of sleep, there is a central inhibition of all postural muscles inducing a generalized muscle hypotonia. Hypoglycemia Central, lack of substrate to Among the muscles affected there are the inspiratory respiratory muscles intercostal muscles, which keep the thoracic cavity together. Hypocalcemia Central, lack of substrate to Near atonia of these muscles will lead, consequently, to respiratory muscles distortion of the rib cage during inspiration causing what is Infection Hypoxemia? Increased metabolic called paradoxical inspiratory motion of the abdomen rate, central inhibition (abdominal paradox). This distortion will result in an increase Prematurity CNS immaturity, muscle fatigue in the work done by the diaphragm, which will have to contract more in order to maintain adequate levels of Thermal instability Inhibitory afferent stimulation 12,13 ventilation (see below fatigue of the diaphragm). Intracranial pathology Direct effect on respiratory centers The lung volume at rest (functional residual capacity = Gastroesophageal reflux Inhibitory reflex concerning residual volume + expiratory reserve volume) is 30% lower upper airways in REM sleep in relation to that of NREM sleep.24 According Drugs CNS depression to some authors, this fact, in addition to the alterations to the thoracic cavity, is responsible for the fall of approximately 10 mmHg in TcPO2 (transcutaneous PO2) during REM sleep.14 It is a known fact that a small grade of hypoxia can be the cause of apnea; in this sense, this condition can be For a long time neonatologists and physiologist have easily reverted with the newborn being administered oxygen been in search for an explanation for occurrence of apnea. at 25%. It is neither understood why newborns stop breathing nor why once it has stopped most of these babies do not resume Another important aspect related to sleep is muscle regular breathing. These are classical factors reported in the tonus. It is understood that muscle tonus is reduced during literature as to the occurrence of apnea. Often, when the sleep and there is a near state of atonia in REM sleep. This related pathologies are treated, apnea will improve or hypotonia also affects the upper airway muscles, and it is disappear completely. However, there are many cases of responsible for a significant increase in lung resistance and newborn infants whose apnea does not present a related 15 in respiratory work. cause; these cases are called idiopathic apnea.1,10 Currently, it is understood that maintaining airways Recently, at the Instituto Fernandes Figueiras, a study permeable depends on a perfect respiratory, pharynx and was carried out on the risk factors for neonatal apnea in larynx muscles coordination. These muscle groups contract newborns with less than 1,500 g. Out of a total 63 newborns in synchrony during inspiration. The generation of negative who survived until 1 year of age, 32 presented apnea at some airway pressure by the respiratory muscles, in normal point and that required treatment, and 10 presented severe situations, should be counteracted by contraction of upper and recurring apnea. The average weight of newborns with airway muscles. One of these muscles, which is widely apnea was of 1,124 g, whereas in those without apnea it was studied even in newborn patients, is the genioglossus (GG). of 1,270 g. The incidence of apnea was inversely proportional Contraction of the GG will set the tongue in the anterior to gestational age/weight. Results indicated an incidence of position, avoiding contact with the posterior wall of the 90% in patients with less than 1,000 g and of 43% in those pharynx. Lack of contraction of this muscle, consequently, between 1,000 and 1,500 g. The relative risk for apnea did will almost always result in obstructive apnea. In 1987, not differ for type of delivery, sex, sepsis, intracranial Carlo et al. detected obstructive episodes related to hemorrhage, and bronchopulmonary dysplasia. However, unsynchronized GG and diaphragm.17 results also indicated that the relative risk for apnea was of 1.73 (1.13 - 2.66) in patients with weight appropriate for gestational age as compared to those small for gestational age; and of 2.58 (1.16 - 5.74) in patients with hyaline Etiology membrane disease as compared to those without hyaline The mechanisms through which different factors are membrane. These data corroborate the international literature related to the occurrence of apnea are not entirely established. in the sense that risk for apnea is greater in small, appropriate Table 1 presents a relationship between some of the possible for gestational age newborns and in situations of post- physiological mechanisms involved. hyaline membrane disease.18 S100 Jornal de Pediatria - Vol. 77, Supl.1, 2001 Neonatal apnea - Lopes JMA

In a different study carried out in Canada, we indicated In a different study with a population of 20 newborns that approximately 30% of the so-called idiopathic apneas with apnea, we showed the predominance of central episodes may actually be a consequence of respiratory muscle in newborn infants without intracranial hemorrhage.13 12 failure. The increase in respiratory work associated with As to what concerns the etiology of episodes of apnea, increased rib cage compliance will put the premature it is necessary to be on the look for the related factors, as newborn infant at risk for muscular fatigue. Moreover, the described above. Figure 2 presents the general diagnostic respiratory muscles (especially the diaphragm) of these guidelines. babies are not well-developed, and present poor differentiation and low enzymatic capacity. Keens et al. showed that the percentage of muscle fibers with great oxidizing capacity (type 1 fibers) in the diaphragm is reduced at 32 weeks. Adult percentage levels are attained only at approximately one year of age.19 During the 1980s, studies with adult patients provided information on the possible occurrence of diaphragm fatigue 1. In-depth clinical examination(auscultation of the in premature newborns. Chronic alcoholic, phosphorus- heart, and pulse rate); depleted patients with serum levels below 40 mg% were 2. Environmental conditions(temperature, necessity of removed from the ventilator as soon as plasmatic phosphorus oxygen therapy, and positioning of the newborn); 20 was corrected. In this sense, it is known that hypophos- 3. Dextrostix, Multistix, Hematocrit; phatemia is common in premature newborns, especially in 4. Sodium, potassium, calcium, magnesium; those with birth weight less than 1,500 g and with history of respiratory disease and parenteral nutrition. Human milk 5. Hemogram + mini VHS (Screening for sepsis, as lacks adequate phosphorus (P) content. Parenteral feeding indicated); of P usually follows a fixed calcium:P ratio which affects 6. Blood gas analysis; the intake of P. Currently, at various centers worldwide, the 7. Chest x-ray; administered intake of calcium and phosphorus is much 8. pHmetry of the esophagus or radiological screening higher than that provided by human milk. The for reflux; supplementation with calcium and P is aimed at preventing 9. Transfontanelle ultrasonography. rickets of prematurity. The increased intake of these minerals will certainly bring benefits to the respiratory muscle function Figure 2 - General guidelines for the diagnosis of apnea if normal levels of P are delivered to the patient. Another mechanism of apnea - which is not widely- discussed in the literature but is frequent in very low birth weight newborns - is the reduction of functional residual capacity. Newborns with birth weight less than 1,000 grams, and who do not present severe pulmonary disease on the first days of life can frequently maintain a regular respiratory Treatment rhythm in the first few days of life. In this case, apnea General guidelines appears, in general, after the third day of life. Based on Most services adopt a criterion for the beginning of indirect evidence only, it is believed that functional residual treatment for apnea. We indicate intervention when three or capacity decreases progressively with repetitive collapse more episodes requiring resuscitation and bag-mask and reexpansion (this can be verified with chest X-rays). ventilation occur within 24 hours. Mild apneas with slight This situation will lead the newborn patient to hypo- cardiovascular complications and that require only physical ventilation, increase in oxygen requirements, and apnea. stimulation are usually directly observable. In these cases, Usually, these cases of apnea are severe enough to require the most important measure is to monitor the newborn and intubation and assisted ventilation. adequately register the number, the duration, and the types of episodes. Before beginning the treatment it is important to try to Diagnosis establish an etiologic factor according to the discussion Apnea can be diagnosed as obstructive, mixed, or central above. When an etiologic factor is not identified, the apnea and also according to the etiology. In order to correctly is idiopathic and there is no question whether treatment diagnose the type of apnea, it is necessary to use a polygraph should be started. But if the diagnosis of apnea is related to to register movements of the thorax and abdomen, and to neonatal infection, the anti-infection therapy will not bring, register airflow in the upper airways. In turn, direct and as a rule, immediate results. The question that remains is careful observation by doctors and nurses for periods of 15 whether it would be best to start pharmacological treatment to 20 minutes can allow for an approximate clinical diagnosis. even considering that it is a case of infection; or whether it Neonatal apnea - Lopes JMA Jornal de Pediatria - Vol. 77, Supl.1 , 2001 S101 would be best to submit the patient to mechanical ventilation of diet and episodes of apnea, which can be verified with until the infection gets better. This question is still to be continuous esophageal pH-metry. In other cases, the pH- answered. The routine procedure at the Instituto Fernandes metry will indicate the reflux and the newborn will have an Figueira is to treat only non-idiopathic apneas if the clinical episode of apnea, but the two episodes are not time-related. status of the patient is suggestive of rapid reversal of the In cases of apnea provenly related to reflux, it is symptomatology. Newborn infants with apnea following recommended that specific treatment observing posture, intracranial hemorrhage or with apnea following severe diet, and administration of prokynetic drugs be carried out. infection require, first and foremost, that the baseline disease be treated. Registering episodes of apnea Following the indication of an episode of apnea, it is Treatment - basic principles important to characterize and register episodes adequately. a) correct metabolic disorders or other intercurrent It is important to register the number of episodes that pathologies and check environmental conditions occurred within a 24-hour period, the duration of each b) eliminate neonatal infections episode, the complications (bradycardia or cyanosis) and if c) register episodes appropriately, indicating duration, type, they were related to any procedure (airway aspiration or frequency, and physiological consequences feeding) or to position of the baby, and the maneuvers d) establish treatment criteria - 3 episodes in 24 hours that required to reverse the situation. Careful observation of the require bag-mask ventilation newborn in the incubator may not indicate the type of apnea. Bradycardia can be often observed in newborns who are apparently breathing normally (active thoracic movements); hence, this is clearly an obstructive episode. If the episodes Metabolic disorders and environment can be reverted with adequate positioning of the baby or Considering what we presented in the above section, it changing decubitus, this indicates that they may be related is important to note that careful screening should be carried to upper airway obstruction. out in order to correct the most frequent metabolic disorders. Control of temperature is also critical in these situations. Criteria for beginning treatment Hypo- and hyperthermia can be easily corrected with adequate temperature adjustments of the newborn’s We apply the criterion of occurrence of 3 or more surrounding environment. It is recommended to register the episodes, within 24 hours, requiring resuscitation and bag- thermal curve simultaneously with the temperature of the mask ventilation for the indication of intervention. Usually, newborn and of the incubator in order to check the efficacy patients with apneas with 20 seconds duration or less, that of these measures. Together with the assessment of revert spontaneously or with slight physical stimulation, environmental conditions, it is also important to check the and with mild cardiovascular complications can be simply position and the neck flexion of the newborn (cause of indicated for observation. In these cases, the most important obstructive apnea). Moreover, it is also important to check measure is to monitor the newborn and register the number, for upper airway obstruction and to ensure patent airways. duration, and type of episodes.

Neonatal infection Unfortunately, neonatal infection is still very common. Therapeutics Hence, all efforts should also be directed towards eliminating or treating this type of infection, if it is the case. Apneas are Physical stimulation frequent and difficult to revert in cases of severe infection, Physical stimulation or repeated stimulation (kinesthetic thus compromising the overall clinical status of the newborn. stimulation) are recommended in cases of mild apnea. According to our experience, infection/sepsis has been the Other services have reported the use of oscillating mattress most frequent cause for indication of mechanical ventilation as a form of repeated stimulation. This method was carried in premature newborn infants. At our services, mechanical out placing a disposable glove under the mattress and ventilation is indicated in these cases since we know that connecting the glove to a ventilator, which is set at a low clinical status of severe infections last 48 to 72 hours, and frequency (5 to 10 minutes) for slight and intermittent that apneas rarely improve before 72 hours. stimulation. This method has been reported efficient in a number of cases.23,24 For severe, frequent apnea, we present 3 alternatives to be considered: Apnea and gastroesophageal reflux The occurrence of apnea related with gastroesophageal – pharmacological treatment; reflux is still a focus of discussion in the literature.21,22 In – continuous positive airway pressure - CPAP; some cases, there is a clear relation between administration – mechanical ventilation. S102 Jornal de Pediatria - Vol. 77, Supl.1, 2001 Neonatal apnea - Lopes JMA

Pharmacological treatment A common endotracheal tube can be used for CPAP. The drug of choice is the teophylline. An initial dosage The tube is inserted through the nose and located at the of 6 mg/kg followed by a maintenance dosage of 4 mg/kg/ hypopharynx. Positive pressure can be administered day divided in three doses is indicated. Dosages can be following Gregory’s classical circuit or with a mechanical administered either orally or endovenously since the ventilator. The administration of nasal CPAP can prevent absorption of the drug is excellent. Thirty minutes after tracheal intubation in many newborn infants with apnea. administration of the drug, adequate plasmatic levels can be The action of CPAP is still being discussed. It is known detected, which can produce a therapeutic response. It is that there is an increase in functional residual capacity, important to monitor plasmatic levels 2 or 3 days after especially in newborns with less than 1,500 g. However, it treatment because the half-life of teophylline in newborns is not established that this is the reason for the efficacy of 23 varies considerably. Collection of blood samples pre- and CPAP. In some newborn infants, the action of CPAP is postxanthine treatment (30 minutes before and after) will basically that of maintaining a patent airway, which is provide good information on minimum and maximum probably a case of obstructive apnea. plasmatic levels in blood. Levels between 5.0 and 15 mg/l are considered adequate. Finally, it is still necessary to consider the action described as afferent stimulation. Positive pressure in the One of the problems with teophylline is that treatment hypopharynx and distention of the airways (trachea and levels are very near the toxic levels. Clinically, tachycardia bronchi) can lead to stimulation of peripheral receptors. In is an early sign of toxicity. If the newborn presents turn, these receptors would support the activity of respiratory tachycardia before administering a dose of the drug centers, thus allowing for regular breathing. (obviously excluding other possible reasons), the next dose should not be given. Next, plasmatic dosage should be carried out in order to adjust blood levels. The drug causes other undesirable effects such as upper digestive hemorrhage, Mechanical ventilation increase in diuresis, hyperglycemia, and hypercalciuria. It Mechanical ventilation is indicated in the treatment for is recommended to test periodically for blood glucose and apnea refractory to clinical and pharmacological treatment occult blood in feces.25 or to CPAP. There are two major groups of patients who In the late 1980s, studies described the efficacy of usually require mechanical ventilation: doxapram in the treatment of apnea refractory to therapeutic – newborns of all birth weights and gestational age with levels of aminophylline. The treatment required continuous severe infection; infusion of the drug due to its short half-life. The therapeutic – newborns with very low birth weight (less than 1,000 g). regimen did not become widely used due to its complications, such as hypertension and even intestinal hypoperfusion with increased risk for enterocolitis. Before indicating In septic newborns, the metabolic requirements are doxapram, it is necessary to better understand the increased and situations of coma are not infrequent. In these pharmacokinetics of the drug in newborns, as well as the cases it is indicated that early mechanical ventilation be possible short- and long-term side-effects.26-28 administered with the objective of reducing respiratory work and improving prognosis. In newborns with this Still in relation to treatment, it is important to comment clinical status, especially in septic newborns, on the use of caffeine, which is the drug of choice at other pharmacological treatment is indicated. In cases of good 29 centers. The advantage of caffeine over teophylline is its response to antibiotictherapy, ventilatory assistance is longer half-life, which allows for timed 24-hour usually carried out for shorter periods of time. administration of the drug with less side-effects. In Brazil, the caffeine citrate is not available for endovenous Mechanical ventilation is indicated for newborns with administration. In turn, caffeine citrate for oral administration less than 1,000 g when, as a result of apnea, the baby is is commercially available. Different authors have labile, incapable of maintaining adequate oral intake, and recommended administration of caffeine in newborns who incapable of maintaining good lung volume (functional despite the use of teophylline still present apnea. residual capacity). When carrying out ventilatory assistance with very low birth weight newborns, it is important to monitor minimal Use of CPAP ventilator settings. Usually, there are no pulmonary diseases Newborn infants with recurring apnea require a more and mechanical ventilation is indicated due to insufficient aggressive treatment despite administration of drive or muscle fatigue. FiO2 (concentration of oxygen in aminophylline, caffeine, or other drugs. Apneas followed inspired air) should be monitored with frequency. Oxygen by bradycardia and cyanosis frequently require bag-mask should be used in amounts as low as possible to maintain ventilation. CPAP is indicated in cases of long and/or arterial PO2 between 50 and 60 mmHg in order to minimize frequent episodes of apnea. risks for bronchopulmonary dysplasia and retrolental Neonatal apnea - Lopes JMA Jornal de Pediatria - Vol. 77, Supl.1 , 2001 S103 fibroplasia. Ventilator frequency settings should be as low 18. Lopes JMA, Carvalho M, Moreira MEL, et al. Análise dos as possible in order not to inhibit spontaneous breathing of fatores de risco para apnéia neonatal no recém-nascido com peso the newborn and, thus, prevent atrophy of respiratory inferior a 1.500g. Trabalho apresentado no Congresso Brasileiro muscles. de Perinatologia. Belo Horizonte;1996. 19. Keens TGA, Bryan AC, Bryan MH. Developmental pattern of muscle fiber types in human ventilatory muscles. J App Physiol 1978;44:909-13. 20. Aubier M, Marciano D, Lecognic Y, Viires N, Jaquens Y, Squara P, et al. Effect of hypophosphatemia on diaphragmatic References contractility in adults with acute respiratory failure. N Engl J Med 1985;313:420-4. 1. Kattwinkel J. Neonatal apnea: Pathogenesis and therapy. J Pediatrics 1977;90:342-7. 21. Kinball AL, Carlton DP. Gastroesophageal reflux medications in the treatment of apnea in premature infants. J Pediatric 2. Vohr RB. Survival of the extremely preterm infant in North 2001;138:355-60. America in the 1990s. Clin Perinatol 2000;27:255-62. 22. Wenzl TG, Schenke S, Peschgens T, Silny J, Heimann G, 3. Martha M, Martin RJ. Apnea of prematurity. Clin Perinatol Skopnik H. Association of apnea and non-acid gastroesophageal 1992;19:789-808. reflux in infants: Investigations with intraluminal impedance 4. Harthorn MK. The rate and depth of breathing in newborn infants technique. Pediatric Pulmonol 2001;31:144-9. during different sleep states. J Physiol 1974;243:101-13. 23. Henderson-Smart DJ, Steer P. Kinesthetic stimulation for 5. Gabriel M, Albani MD, Schulte FJ. Apneic spells and sleep states preventing apnea of preterm infants (Cochrane review) Cochrane in preterm infants. Pediatrics 1976;57:142-7. Database Syst Review 2000:000373. 6. Rigatto H, Brady JP. Periodic breathing and apnea in preterm 24. Konner AF, Guillerminault G, Van den Hoed J, Baldwin RB. infants. II. Hypoxia as a primary event. Pediatrics 1972;50:219-28. Reduction of sleep apnea and bradycardia in preterm infants on 7. Lopes JMA, Aranda JV, Davies GM, Mullahoo K. The role of oscillating waterbeds: a controlled polygraphic study. Pediatrics adenosine in the hypoxic response of the newborn piglet. Pediatric 1978;61:528-33. Pulmonol 1994;17:50-5. 25. Zanardo V, Dani C, Trevisanuto D, Menegethi S, et al. 8. Rigatto H, Brady JP, De La Torre Verduzco R. Chemoreceptor Methylxanthines increase renal calcium excretion in preterm reflexes in the preterm infant II. The effect of gestational and post infants. Biol Neonate 1995;68:169-74. neonatal age on the ventilatory response to carbon dioxide. 26. Barrington KJ, Finer NN, Torok-Both GR, et al. Dose response Pediatrics 1975;55:614-20. relationship of doxapran in the therapy for refractory idiopathic 9. Langercrantz H. Improved understanding of respiratory control apnea of prematurity. Pediatrics 1987;80:22-7. implications for the treatment of apnea. Eur J Pediatr 27. Colonna F, Pahor T, de Vonderweid U, Radillo L, Tamaro G. 1995;154(suppl):s10-2. Metabolic, hormonal and nutritional effects of long term 10. Schulte FJ. Apnea. Clin Perinatol 1977;4:65-79. theophylline therapy in preterm infants: a case control study. 11. Curzi-Dascalova L. Development of sleep and autonomic nervous Pediatr Med Chir 1995;17:345-8. system control in premature and full-term newborn infants. Arch 28. Henderson-Smart DJ, Steer P. Doxapram vs methylxanthine for Pediatr 1995;2:255-62. apnea in preterm infants (Cochrane Review). Cochrane Database 12. Lopes JMA, Bryan AC, et al. Synergistic behaviour of inspiratory Syst Rev 2000(4):000075. muscles after diaphragmatic fatigue in the newborn. J App 29. Henderson-Smart DJ, Steer PA. Prophylactic methylxanthine Physiol 1981;51:447-551. for preventing apnea of preterm infants. Cochrane Database Syst 13. Lopes JMA. Respiratory muscle function during sleep [thesis]. Rev 2000(2):000432. Review - 000273. Toronto: University of Toronto; 1982. 14. Martin RJ, Okken A, Rubin D. Arterial oxygen tension during active and quiet sleep in the normal neonate. J Pediatrics 1979;94:271-4. Correspondence: 15. Phillipson EA. Control of breathing during sleep. Am Rev Resp Dr. José Maria de Andrade Lopes Dis 1978;118:909-39. Fundação Oswaldo Cruz 16. Jeffries B, Brouilette RT, Hunt C. Electromyographic study of some accessory muscles of respiration in children with obstructive Av. Rui Barbosa, 716 - Flamengo sleep apnea. Am Rev Respir Dis 1984;129:696-702. CEP 22250-020 – Rio de Janeiro, RJ, Brazil 17. Carlo WA, Di Fiori JM, Martin RJ, et al. Differences in CO2 Phone: + 55 21 558.1434 – Fax: + 55 21 558.1780 threshold of respiratory muscles in preterm infants. J App Physiol E mail: [email protected] 1988;65:2434-9.