Apnea In Preterm Infants Research Articles

193 Apnea of Prematurity: Association with Neurodevelopmental Outcome?

Background: Idiopathic apnea of prematurity is a very common problem in preterm infants that may require pharmacologic or respiratory intervention and delay hospital discharge. Several authors have shown that apneas, especially associated with hypoxemia and/or bradycardia, decrease cerebral blood flow which may induce brain injury.Aim: To investigate the association of apnea in preterm infants with subsequent neurodevelopmental outcome when compared with matched controls without apnea.Methods: 28 infants < 32 gestational weeks and / or < 1500g birth weight with recurrent apnea (> 3 per 24 hours) were matched with 28 infants the same gestational age without apnea. All infants were assessed at 24 months corrected for prematurity (Bayley II and neurological examination).Results: Gender distribution, mean gestational age, birth weight, days of mechanical ventilation, CPAP and days of oxygen were similar in both groups. The average length of hospital stay was longer in patients with apnea. There was no significant difference between the mean MDI and/or PDI of infants with apnea when compared with those of infants without apnea.Conclusion: Power analysis with alpha=0.05 and beta=0.2 reveals that the sample size of 56 suffices to exclude a possible difference of more than 11 points within the Bayley II scales (equivalent to 0.75 of a standard deviation of 15) when comparing infants with apnea to controls.

Gastroesophageal Reflux in the Preterm Neonate

After completing this article, readers should be able to: 1. Describe the epidemiology and pathophysiology of gastroesophageal reflux (GER) in preterm neonates. 2. Delineate the associations of GER with apnea, chronic lung disease, behavior, and growth of preterm infants. 3. Review the investigations used to evaluate GER in preterm infants. 4. Describe nonpharmacologic and pharmacologic therapies for GER. Gastroesophageal reflux (GER) is a normal physiologic event occurring across the age spectrum. It may contribute to a variety of disorders, including esophagitis, feeding problems, and airway disease in all age groups. (1) A large number of symptoms and signs have been purported to be caused by GER despite a lack of data showing a clear association between a specific symptom and GER. In preterm infants, empiric therapy often is administered using agents of unproven efficacy and safety to treat symptoms that likely are unrelated to GER. In a survey on management practices for GER in preterm infants, common treatment strategies included positioning (98%) and slopes (96%), histamine 2 (H 2) receptor antagonists (100%), feed thickeners (98%), antacids (96%), prokinetics (79%), proton pump inhibitors (PPIs) (65%), and dopamine receptor antagonists (53%). (2)(3) The safety, efficacy, and appropriate dosing recommendations for most medical therapies remain uncertain in neonates. In this review, we attempt to summarize the current literature regarding physiology, pathophysiology, and diagnostic and management strategies for GER pertinent to the neonate, with an emphasis on the preterm infant. GER describes the retrograde movement of stomach contents (air or feeding, liquid or semisolid, acid or alkaline, enzymes or bile salts) into the esophagus. GER disease (GERD) occurs when GER causes symptoms or signs such as pain, poor weight gain, esophagitis, hematemesis, and airway symptoms, including apnea, aspiration, recurrent pneumonia, chronic lung disease (CLD), or large airway inflammation. However, any of these symptoms or signs …

Enquête sur l'utilisation du doxapram dans les unités de néonatologie en France

Methylxanthines and doxapram have been used to stimulate breathing and to prevent apnea in preterm infants. The use of doxapram is controversial because the therapeutic index seems to be narrow and short-term adverse effects have been described. Objective. – To determine the use of doxapram in the French neonatal and intensive care units. Methods. – A structured postal questionnaire was sent to all the 236 neonatology and neonatal intensive care units of level IIa, IIb and III in France. The questionnaires were analysed after four months. Results. – Answers were obtained from 159 chiefs of department (67.4%), 102 used doxapram (64.1%). Doxapram was mainly used as a second step, if methylxanthines failed to reduce the frequency of apneic spells (102/159 units, 64.1%). Doxapram was usually administered intravenously (91/102 units, 89.2%). Only 57 respondents (35.8%) did not use doxapram, because they were aware of the potential adverse effects or they did not know the drug. Monitoring of drug plasma concentrations was rarely performed (11/102 services, 10.8%). Nevertheless, there was a significant interest in this monitoring. Conclusion. – Doxapram is frequently used in France to reduce apnea of prematurity if methylxanthine therapy fails. Further studies are needed to determine safety of doxapram at short and long-term. A multicenter, randomised, double-blinded clinical trial would be interesting to perform, similar to the ongoing caffeine for Apnoea of Prematurity trial (CAP) . The French setting seems appropriate for this kind of study.

Doxapram treatment for apnea in preterm infants.

Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Doxapram has been used to stimulate breathing and so prevent apnea and its consequences. In preterm infants with recurrent apnea, does treatment with Doxapram lead to a clinically important reduction in apnea and use of intermittent positive airways pressure (IPPV), without clinically important side effects? Searches were made of the Oxford Database of Perinatal trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2004), MEDLINE from 1966 - June 2004, EMBASE from 1980 - June 2001, CINAHL from 1982- June 2004. Text words 'doxapram', 'apnea or apnoea' and the MeSH term 'infant, premature' were used. Previous reviews including cross references, abstracts from conferences and symposia proceedings were also examined. Abstracts of the Society for Pediatric Research were searched from 1996 - 2004 inclusive. All trials utilising random or quasi-random patient allocation, in which doxapram was used for the treatment of apnea in preterm infants were included. Each author evaluated the papers for quality and inclusion criteria. Independent data extraction was carried out. Only one trial, which randomized 11 infants to intravenous doxapram and 10 infants to placebo, was found. There were fewer treatment failures after 48 hours in the group of preterm infants treated with doxapram (4/11) compared with the group treated with placebo (8/10). The wide confidence intervals made this result non-significant [RR 0.45 (0.20, 1.05)]. Only one infant, who was from the placebo group, was given IPPV. Of the seven responders by 48 hours in the group of 11 who received doxapram, five failed to respond between 48 hours and seven days after commencement of therapy. This gives a late failure rate of 9/11, similar to the short term failure rate in the placebo group of 8/10. It is not possible to evaluate the late responses of all those in the placebo group since they crossed over to a treatment arm. Although intravenous Doxapram might reduce apnea within the first 48 hours of treatment, there are insufficient data to evaluate the precision of this result or to assess potential adverse effects. No long term outcomes have been measured. Further studies are needed to determine the role of this treatment in clinical practice.

Apnea is associated with neurodevelopmental impairment in very low birth weight infants.

To determine whether apnea in preterm infants is associated with abnormal neurodevelopmental outcome. We determined the number of days that apnea and bradycardia spells were noted by the nursing staff, during the initial hospitalization of 175 preterm infants of less than <1250 g birth weight or <32 weeks gestation who had been enrolled in the follow-up program of the Royal Victoria Hospital. Multiple logistic and multiple linear regression models were constructed to determine the relationships between apnea days and neurodevelopmental impairment at 3 years of age, after correcting for gestation, sex, intrauterine growth restriction, intraventricular hemorrhage, periventricular leukomalacia, pre- and postnatal steroids, and maternal education. A total of 41 infants had neurodevelopmental impairment (Bayley MDI or PDI <70, cerebral palsy or blindness). By multiple logistic regression, an increasing number of days on which at least one apnea occurred, "total apnea days", and male sex were significantly associated with increasing probability of neurodevelopmental impairment, p<0.01, the sum of days of assisted ventilation and apnea days occurring after extubation was also associated with impairment in a separate regression model, p<0.001. Lower MDI at 3 years was significantly associated with postnatal steroid use, p=0.004. Lower PDI was associated with increasing apnea days, male sex, and postnatal steroid use, p<0.001. Functional impairment (a score on any one of the four dimensions of the Vineland scale <70), found in 17% of the infants, was associated with increasing apnea days, p<0.05. Caffeine treatment was not independently associated with any outcome. An increasing number of days that apnea was recorded during hospitalization was associated with a worse outcome. Among the potential explanations for this finding is the possibility that multiple recurrent hypoxic and bradycardic spells may cause brain injury.

Relationship of the ventilatory response to hypoxia with neonatal apnea in preterm infants

Objective Correlate the ventilatory response of preterm infants to hypoxic exposure with incidence of neonatal apnea. Study design Seventeen stable convalescing premature infants underwent bedside cardiorespiratory monitoring of respiration using respiratory inductance plethysmography, heart rate, and oxygen saturation (SaO 2) for a 12-hour period. These studies were scored for number of apneas ≥15 and ≥20 seconds. Infants then underwent a 3-minute hypoxic exposure. Minute ventilation (V E) was calculated for 30-second epochs from the time inspired oxygen reached 15%. Linear regression analysis was used to correlate the change in V E normalized for decrease in SaO 2 (ΔV E/ΔSaO 2) during the first and third minutes of hypoxic exposure with the number of apneic episodes during the 12-hour study. Results The majority of infants exhibited an anticipated biphasic ventilatory response to hypoxia. There was a significant positive correlation between ΔV E/ΔSaO 2 during the first and third minutes of hypoxic exposure and number of apneic episodes ≥15 and ≥20 seconds during the preceding 12 hours. Conclusions Preterm infants with a greater number of apneic episodes exhibit an increased ventilatory response to hypoxic exposure, suggesting that apnea of prematurity may be associated with enhanced peripheral chemoreceptor activity.

Detection of Oxygen Sensing During Intermittent Hypoxia

Publisher Summary This chapter discusses the detection of oxygen sensing during intermittent hypoxia. Intermittent hypoxia is associated with a number of clinical conditions, including sleep apneas, apneas in premature infants, asthma, and pulmonary fibrosis. Epidemiologic and cross-sectional studies on recurrent apnea patients have identified a strong association between apneas and serious cardiovascular disturbances, including the development of hypertension. Peripheral chemoreceptors, especially carotid bodies, sense the changes in arterial oxygen. Carotid bodies are located at the bifurcation of the common carotid artery and receive sensory innervation from the carotid sinus nerve, a branch of the 12th cranial nerve. Hypoxemia augments the sensory discharge of the carotid bodies, which in turn stimulates breathing and increases sympathetic nerve activity as well as blood pressure via reflex mechanisms, involving the central nervous system (CNS).. In this study, the rat model of intermittent hypoxia is presented. Experimental methods for exposure of rats to chronic intermittent hypoxia, the recording of carotid body sensory activity in vivo , the carotid body slice preparation and recording of ionic currents from glomus cells are described. Concepts related to membrane current recordings from rat carotid body tissue slices and monitoring of transmitter changes in carotid bodies are discussed as well.

Impact of bradycardia on cerebral oxygenation and cerebral blood volume during apnoea in preterm infants

Apnoea in prematurity is a common problem in neonatology; and it is the impaired oxygen delivery during apnoea, which can harm the brain. The aim of this study was to evaluate the effect of bradycardia (below 80 beats min−1) on ‘cerebral haemoglobin oxygenation index’ (cHbD) and cerebral blood volume (CBV) during apnoea in stable preterm infants measured by means of near infrared spectroscopy. Twenty-six episodes of mixed and central apnoea with bradycardia (bradycardia group) in 20 preterm infants were compared to 26 episodes of mixed and central apnoea without bradycardia (non-bradycardia group) in 19 preterm infants. cHbD decreased significantly more in the bradycardia group (−11.33 µmol l−1 after 30 s) than in the non-bradycardia group (−6.36 µmol l−1 after 30 s) (p < 0.05). CBV decreased significantly in the bradycardia group (p < 0.05), whereas CBV did not change significantly in the non-bradycardia group. Peripheral oxygen saturation (SaO2) decreased similarly in both groups. The aggravation of decrease of cHbD and the decrease of CBV during bradycardia in association with apnoea could be explained by decrease in cerebral blood flow, which caused decrease in cerebral oxygen delivery. This decrease of oxygen delivery during bradycardia might worsen long-term neurodevelopmental outcome in preterm infants with apnoea.

Apnea associated with hypoxia in preterm infants: impact on cerebral blood volume

The present study analyzed changes in cerebral blood volume (CBV) during apnea associated with hypoxia compared to apnea without hypoxia. Hypoxia was defined as pulsoxymetric oxygen saturation <80%>10 s. The employed technique was near infrared spectroscopy combined with electrocardiogram, electroocologram, pulsoxymetry, sidestream capnography and two respiratory effort sensors. In 24 preterm infants 44 incidences of apnea were analyzed. Two main patterns were observed: a significant decrease or a significant increase of CBV. In the ‘CBV decrease’ group ΔCBV was −55 μl/100 g brain in hypoxic apnea, and −62 μl/100 g brain in non-hypoxic apnea. In the ‘CBV increase’ group the rise of CBV above preapneic values was +50 μl/100 g brain in hypoxic apnea, and +47 μl/100 g brain in non-hypoxic apnea. Heart rate showed a significant decrease only in the ‘CBV decrease’ group. Endexpiratory CO 2 increased significantly 1 min after apnea. In conclusion, this study observed significant changes of CBV during apnea in preterm infants, but no difference in CBV behavior regarding whether incidents of apnea were associated with hypoxia or not. It remains unclear which regulatory mechanisms are responsible for the two observed patterns of ΔCBV during apnea.

Neonatal intermittent hypoxia impairs dopamine signaling and executive functioning.

Mesotelencephalic dopamine (DA) pathways are exquisitely vulnerable to ischemic-anoxic insult. These insults are known to produce long-term derangements in DA signaling and have been hypothesized to contribute, at least in part, to pathologic behaviors such as cerebral palsy, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Whether modest intermittent hypoxia, such as that encountered with repetitive apneas in premature infants, contributes to clinically significant impairments in DA signaling, and how these impairments manifest at a systems level, is unknown. To address these voids there is a need to develop animal models emulating features of a common disorder of prematurity, namely, apnea with hypoxia. Behavioral traits exhibited by such models include disturbed sleep-wake architecture, excessive locomotion, and impaired working memory persisting 1 to 2 months post-insult. Western-blot analysis of expression patterns of proteins involved in DA signaling (e.g., DA and vesicular monoamine transporters, tyrosine hydroxylase, and D1 receptors) are consistent with that which might be expected from hyper- or hypodopaminergic functioning in DA-responsive prefrontal cortex and striatal circuits, respectively. These novel observations suggest that intermittent hypoxia occurring during a period of critical brain development disrupts development of those mesotelencephalic pathways modulating the expression of sleep and wakefulness, locomotion, and executive functioning.

Kinesthetic stimulation for preventing apnea in preterm infants.

Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia, which may be severe enough to require resuscitation including use of positive pressure ventilation or other treatments. Physical stimulation is often used to restart breathing and it is possible that repeated stimulation, such as with an oscillating mattress (kinesthetic stimulation), might prevent apnea and its consequences. In preterm infants at risk for apnea, does prophylactic use of kinesthetic stimulation lead to a clinically important reduction in apnea and bradycardia, and use of intemittent positive preswsure ventilation (IPPV). The standard search strategy of the Neonatal Review Group was used. This included searches of the Oxford Database of Perinatal trials, Cochrane Controlled Trials Register, MEDLINE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal handsearching mainly in the English language. All trials in preterm infants at risk of developing clinical apnea which utilised random or quasi-random allocation to treatment with an oscillating mattress or control, were eligible. Standard methods of the Cochrane Collaboration and its Neonatal Review Group were used with separate evaluation of trial quality and data extraction by each author and synthesis of the data using relative risk. There were no differences in short term effects (apnea /bradycardia, IVH, use of IPPV, sleep/wake cycles and neurological status at discharge) or longterm effects (in one trial - growth and development to one year). Implications for practice. Prophylactic use of kinesthetic stimulation cannot be recommended to reduce apnea/bradycardia in preterm infants. Implications for research. There are currently no clear research questions regarding prophylactic use of kinesthetic stimulation to prevent apnea in preterm infants.

Clinical Associations, Treatment, and Outcome of Apnea of Prematurity

After completing this article, readers should be able to: 1. Identify common neonatal problems that may present with apnea. 2. Describe the role of pharmacologic and nonpharmacologic treatment of apnea. 3. Characterize the findings of long-term follow-up of infants who have apnea. Although apnea typically results from immaturity of the respiratory control system (see accompanying article in this issue), it also may be the presenting sign of other diseases or pathophysiologic states that frequently affect preterm infants. A thorough consideration of possible causes is always warranted, especially when there is an unexpected increase in the frequency of episodes of apnea or bradycardia (Fig. 1). Figure 1. Multiple etiologic factors that may contribute to apnea in preterm infants. IVH=intraventricular hemorrhage. Central nervous system problems, particularly intracranial hemorrhage, can precipitate apnea in the preterm infant. Asphyxia, including transient birth depression, may cause either episodic or prolonged apnea. Malformations of the brain or less likely, the spinal cord, should be considered in an otherwise healthy infant who presents with apnea at birth. Infections (bacteremia possibly accompanied by meningitis) may cause unstable breathing patterns and should prompt the appropriate evaluation and possibly antibiotic therapy. In the older infant, the onset of a viral illness such as respiratory syncytial virus (RSV) infection sometimes is heralded by apnea, although the precise mechanism whereby RSV presents with apnea is unclear. Anemia, another frequent problem in preterm infants, whether iatrogenic or due to bleeding, is a potential precipitating factor. Blood transfusions have been demonstrated to improve irregular breathing patterns in preterm infants, although the risk of blood transfusion has limited its use as treatment for apnea. It has been assumed, although unproven, that enhanced oxygen-carrying capacity, as with red blood cell transfusion, may decrease the likelihood of hypoxia-induced respiratory depression. Other disease states that may precipitate apnea include metabolic disorders such as …

Pathophysiologic Mechanisms Underlying Apnea of Prematurity

After completing this article, readers should be able to: 1. Characterize the unique features of neonatal respiratory control mechanisms. 2. Clarify how immature respiratory control contributes to neonatal apnea. 3. Identify the contribution of upper airway obstruction to episodes of mixed apnea. Idiopathic apnea of prematurity is a common disorder that requires therapeutic intervention to avoid potential morbidity in preterm infants who require neonatal intensive care. Severe, recurrent apneic episodes may lead to multiple investigations to rule out secondary disorders leading to apnea (see accompanying article in this issue). Although the incidence of neonatal apnea is inversely related to gestational age and is probably as high as 100% in the most immature preterm infants, the onset may be delayed by the presence of lung disease in the first days of life. Apnea of prematurity, especially if severe or persistent, has been associated with poor developmental outcome in school-age children, although a cause-and-effect relationship is difficult to establish. The definition of apnea varies among studies. Apnea of prematurity has been defined most widely as cessation of breathing in excess of 15 seconds’ duration, typically accompanied by desaturation and bradycardia. However, shorter episodes of apnea, and even periodic breathing, may be accompanied by bradycardia or hypoxemia. Prolonged desaturation episodes also have been reported in the absence of apnea or bradycardia, both in healthy preterm infants and in infants who have chronic lung disease. These episodes might represent obstructive apnea, hypoventilation, or possibly intrapulmonary right-to-left shunting, although episodes of desaturation and bradycardia almost always are preceded by apnea or hypoventilation. Apnea is classified traditionally into three categories based on the presence or absence of upper airway obstruction: central, obstructive, and mixed apneas. Central apnea is characterized by total cessation of inspiratory efforts with no evidence of obstruction. In obstructed apnea, the infant tries to breathe against …

Doxapram treatment for apnea in preterm infants.

Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Doxapram has been used to stimulate breathing and so prevent apnea and its consequences. In preterm infants with recurrent apnea, does treatment with doxapram lead to a clinically important reduction in apnea and use of Intermittent positive airways pressure (IPPV), without clinically important side effects? Searches were made of the Oxford Database of Perinatal trials, the Cochrane Collaboration Clinical Trials Register, MEDLINE (using text words 'doxapram', 'apnea or apnoea' and Mesh term 'infant, premature') previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, mainly in the English language. Also an expert informant's search in the Japanese language was made by Prof. Y. Ogawa in 1996. All trials utilising random or quasi-random patient allocation, in which doxapram was used for the treatment of apnea in preterm infants were included. Each author evaluated the papers for quality and inclusion criteria. Independent data extraction was carried out. Only one trial, which randomized 11 infants to intravenous doxapram and 10 infants to placebo, was found. There were fewer treatment failures after 48 hours in the group of preterm infants treated with doxapram (4/11) compared with the group treated with placebo (8/10). The wide confidence intervals made this result non-significant [RR 0.45 (0.20, 1.05)]. Only one infant, who was from the placebo group, was given IPPV. Of the seven responders by 48 hours in the group of 11 who received doxapram, five failed to respond between 48 hours and seven days after commencement of therapy. This gives a late failure rate of 9/11, similar to the short term failure rate in the placebo group of 8/10. It is not possible to evaluate the late responses of all those in the placebo group since they crossed over to a treatment arm. Although intravenous doxapram might reduce apnea within the first 48 hours of treatment, there are insufficient data to evaluate the precision of this result or to assess potential adverse effects. No longterm outcomes have been measured. Further studies are needed to determine the role of this treatment in clinical practice.

Continuous positive airway pressure versus theophylline for apnea in preterm infants.

Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Theophylline and continuous positive airways pressure (CPAP) are two treatments that have have been used to prevent apnea and its consequences. The main objective was to determine in preterm infants with recurrent apnea, if treatment with CPAP compared with treatment with theophylline leads to a clinically important reduction in apnea or use of mechanical ventilation, without clinically important side effects. Searches were made of the Oxford Database of Perinatal trials, the Cochrane Collaboration Clinical Trials Register, MEDLINE 1966 - July 2001, EMBASE 1980 - July 2001, CINAHL 1982 - July 2001(using text words 'theophylline', 'caffeine', 'CPAP', 'CDAP', 'positive pressure', 'apnea or apnoea' and MeSH term 'infant, premature'), previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, mainly in the English language. Abstracts of the Society for Pediatric Research were searched from 1996 - 2001 inclusive. All trials using random or quasi-random allocation to CPAP or theophylline in preterm infants with clinical recurrent apnea/bradycardia were eligible. Data were extracted using standard methods of the Cochrane Collaboration and its Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author and synthesis of data using relative risk. Only one eligible trial was found. The use of mask CPAP is associated with a higher treatment failure rate as measured by less than a 50% reduction in apnea or use of an alternative treatment [RR 2.89 (95% CI 1.12, 7.47); RD 0.42 (95% CI 0.11, 0.74)]. For every 2.4 infants (95% CI 1.4, 9.5) treated with mask CPAP rather than theophylline, there results one treatment failure. In the mask CPAP group there is more use of IPPV [RR 3.09 (1.42, 6.70); RD 0.58 (95% CI 0.30, 0.86). For every 1.7 infants (95% CI 1.2, 3.3) treated with mask CPAP rather than theophylline, one infant is intubated for IPPV. In the mask CPAP group, there are trends towards more deaths in the first year, and in death or major disability in survivors at follow up, which do not reach significance. There are no differences in rates of necrotizing enterocolitis or major disability in survivors at follow up. Theophylline is more effective than mask CPAP for preterm infants with apnea. Since CPAP is no longer administered by mask, the results of this review have limited importance for current clinical practice. Further evaluation of the benefits and harms of CPAP vs theophylline for preterm infants with apnea requires further trials in which CPAP is administered by current methods.

Body position-dependent changes in cerebral hemodynamics during apnea in preterm infants

The objective of the present study was to evaluate sleeping position-dependent effects on cerebral hemodynamics during apnea in preterm infants. To this end, polygraphic studies were performed on 15 stable preterm infants lying prone and lying supine. Changes in cerebral blood volume (ΔCBV) and in cerebral hemoglobin oxygenation (ΔcHbD) in association with apnea were measured by near infrared spectroscopy. For comparison, apnea in the prone position was matched for duration to apnea in the supine position. A total number of 98 pairs of apnea were compared. The mean duration of apnea was 8.2±3 s. In both positions there was a predominance of decrease in CBV and cHbD in association with apnea. The mean decrease of cHbD (−1.57±1.82 μmol/l) and of CBV (−0.120±0.137 ml/100g brain) in the supine position was significantly pronounced compared to prone position (ΔcHbD: −1.18±1.77 μmol/l, ΔCBV: −0.080±0.095 ml/100 g brain). The degree of ΔCBV and ΔHbD did not correlate with postconceptional or postnatal age ( r 2<0.01). In both positions there was a similar small decrease of SaO 2 in association with apnea. In the supine position heart rate decreased slightly during apnea, whereas in the prone position no change in heart rate could be observed. The present study revealed a position-dependent different impact of apnea on cerebral hemodynamics. With regard to cerebral blood volume and oxygenation in association with apnea no negative effects of prone sleeping position could be observed in preterm infants.

Methylxanthine treatment for apnea in preterm infants.

Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Methylxanthines have been used to stimulate breathing and prevent apnea and its consequences. The objective of this review is to determine if methylxanthine treatment in preterm infants with recurrent apnea leads to a clinically important reduction in apnea and use of intermittent positive pressure ventilation (IPPV), without clinically important side effects. Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts of conferences and symposia proceedings, expert informants, journal handsearching mainly in the English language. All trials utilising random or quasi-random patient allocation, in which methylxanthine (theophylline or caffeine) was compared with placebo or no treatment for apnea in preterm infants, were included. Methodological quality was assessed independently by the two authors. Data were extracted independently by the two authors. Treatment effects were expressed as relative risk (RR) and risk difference (RD) and their 95% confidence intervals, using a fixed effect model. For significant results, the inverse of the risk difference (1/RD) was used to calculate the number needed to treat (NNT). The results of four trials which enrolled a total of 110 preterm infants with apnea indicate that methylxanthine therapy leads to a reduction in apnea and use of IPPV in the first 2 - 7 days. There are insufficient data to evaluate side effects and no data to examine effects within different gestational age groups. There are no trial data which examine long term effects. Methylxanthines are effective in reducing the number of apneic attacks and the use of mechanical ventilation in the two to seven days after starting treatment. In view of its lower toxicity, caffeine would be the preferred drug. Although the safety of methylxanthine therapy has been suggested in cohort studies, there are no trial data on longterm outcome. In order to indicate which infants are likely to benefit from treatment, there is a need for stratification by gestation and/or other risk factors in future studies. In any future studies the longer term effects of treatment on growth and development should be evaluated.

Highlighted Topics series: Physiological and Genomic Consequences of Intermittent Hypoxia

This issue of the Journal of Applied Physiology introduces a new Highlighted Topics series, “Physiological and Genomic Consequences of Intermittent Hypoxia.” The physiological responses to acute and chronic (continuous) hypoxia have been the focus of numerous studies that have produced valuable

Gastroesophageal reflux medications in the treatment of apnea in premature infants

Objective: To determine whether medications commonly used in the management of gastroesophageal reflux reduce the frequency of apnea in premature infants. Study design: We reviewed the medical records of all infants ≤36 weeks’ gestational age at birth who were treated in 2 neonatal intensive care units from 1990 through 1999 and identified those who received the antireflux medications cisapride or metoclopramide in association with apnea. We averaged the frequency of apnea during the 5 days before and the 5 days after antireflux treatment was started and compared these 2 periods by paired analysis. Results: There were 164 separate courses of treatment with either cisapride or metoclopramide in 132 patients. There were 3.6 ± 3.2 apneic episodes per day during the 5 days before treatment and 4.0 ± 3.4 apneic episodes per day during the 5 days after treatment (P =.048). When evaluated separately, neither cisapride nor metoclopramide reduced the frequency of apnea. Stratification for documented reflux (by radiographic contrast or by pH probe analysis), concomitant use of methylxanthines or ranitidine, developmental age, feeding volume, and respiratory support did not identify a subgroup of patients whose apnea improved with antireflux treatment. Conclusion: Antireflux medications do not reduce the frequency of apnea in premature infants. (J Pediatr 2001;138:355-60)

Chronic intermittent hypoxia enhances carotid body chemoreceptor response to low oxygen.

Episodic or intermittent hypoxia occurs in many pathophysiological situations, including sleep apneas and recurrent apneas in premature infants. In addition, intermittent hypoxia is not all uncommon in humans who have lung diseases such as chronic obstructive pulmonary disease (COPD), asthma or pulmonary fibrosis. Thus mammals experience episodic hypoxia, often in life, even perhaps more so than sustained hypoxia that occurs in situations like high altitude.