Guidelines for diagnosis and management of congenital central hypoventilation syndrome.

BACKGROUND: Congenital Central Hypoventilation Syndrome (CCHS) is a rare condition characterized by an alveolar hypoventilation due to a deficient autonomic central control of ventilation and a global autonomic dysfunction. Paired-like homeobox 2B (PHOX2B) mutations are found in most of the patients with CCHS. In recent years, the condition has evolved from a life-threatening neonatal onset disorder to include broader and milder clinical presentations, affecting children, adults and families. Genes other than PHOX2B have been found responsible for CCHS in rare cases and there are as yet other unknown genes that may account for the disease. At present, management relies on lifelong ventilatory support and close follow up of dysautonomic progression. BODY: This paper provides a state-of-the-art comprehensive description of CCHS and of the components of diagnostic evaluation and multi-disciplinary management, as well as considerations for future research. CONCLUSION: Awareness and knowledge of the diagnosis and management of this rare disease should be brought to a large health community including adult physicians and health carers.

Updated Swedish advice on reducing the risk of sudden infant death syndrome.

UNLABELLED: This article reviews updated advice and factual material from the Swedish National Board of Health and Welfare on reducing the risk of sudden infant death syndrome. Issues covered by the guidance for parents and healthcare professionals include sleeping positions, smoking, breastfeeding, bed sharing and using pacifiers. CONCLUSION: The guidelines conclude that infants under three months of age are safest sleeping in their own cot and that a pacifier can be used when they are going to sleep.

Decreased heart rate variability in children born with low birth weight.

BACKGROUND: Low birth weight (LBW) is associated with cardiovascular morbidity in adulthood. Imbalance in the autonomic nervous system (ANS) has been implicated as a mechanism behind the developmental programming of cardiovascular function. We hypothesized that deviations in the ANS function are seen in children born with LBW. METHODS: Eighty-six children were included: 31 born preterm (<32 wk gestational age), 27 born at term but small for gestational age (SGA), and 28 born at term with normal birth weight (control). Twenty-four-hour Holter-electrocardiogram monitoring was performed at an average age of 9 y. Heart rate variability results were analyzed using frequency and time domain methods. RESULTS: All frequency components and both time domain parameters tested were significantly lower in the preterm and SGA children compared with controls. The low frequency/high frequency ratio was not significantly different between children born with LBW and controls. CONCLUSION: The autonomic control appears to be affected in children born with LBW despite gestational age at birth. Decreased total power, as an estimation of the ANS's global activity, rather than the balance between parasympathetic and sympathetic modulation might be an early marker of cardiovascular disease later on in life for LBW born children.

Obstructive pulmonary disease in old age among individuals born preterm.

There are only few studies of the association between preterm birth and risk of chronic lung disease in old age. The aim of this study was to assess the association between poor fetal growth, preterm birth, sex and risk of asthma and Chronic Obstructive Pulmonary Disease (COPD) in adulthood. We have followed up a cohort of all infants born preterm (<35 weeks) or with low birth weight (<2,000 and <2,100 g for girls and boys, respectively) and an equal number of controls in a source population of 250,000 individuals born from 1925 through 1949 in Sweden (6,425 subjects in total). Cases of asthma and COPD were identified through the Swedish Patient Register and we considered cohort subjects as cases if they had a main or additional discharge diagnosis of asthma or COPD. For any obstructive airways disease, there was a statistically significant increase in risk with decreasing birth weight and gestational duration among women but not among men. Compared to women born at term, women born before 32 weeks of gestation had a hazard ratio for any obstructive airways disease and asthma of 2.77 (95% CI 1.39-5.54) and 5.67 (1.73-18.6), respectively. Low birth weight and preterm birth are risk factors for obstructive airways disease also among the old, but the importance of these risk factors differs between the sexes.

A key circulatory defence against asphyxia in infancy--the heart of the matter!

A resumption of, and escalation in, breathing efforts (hyperpnoea) reflexively accelerates heart rate (HR) and may facilitate cardiac and circulatory recovery from apnoea. We analysed whether this mechanism can produce a sustained rise in HR (tachycardia) when a sleeping infant is confronted by mild, rapidly worsening asphyxia, simulating apnoea. Twenty-seven healthy term-born infants aged 1-8 days rebreathed the expired gas for 90 s during quiet sleep to stimulate breathing and heart rate. To discriminate cardio-excitatory effects of central respiratory drive, lung inflation, hypoxia, hypercapnia and asphyxia, we varied the inspired O(2) level and compared temporal changes in response profiles as respiratory sensitivity to hypoxia and asphyxia 'reset' after birth. We demonstrate that asphyxia-induced hyperpnoea and tachycardia strengthen dramatically over the first week with different time courses and via separate mechanisms. Cardiac excitation by hypercapnia improves first, followed by a slower improvement in respiratory hypoxic drive. A rise in CO(2) consequently elicits stronger, longer lasting tachycardia than moderate increases in respiratory drive or lung expansion. We suggest that without a strong facilitating action of CO(2) on the immature heart, respiratory manoeuvres may be unable to reflexively counteract strong vagal bradycardia. This may increase the vulnerability of some infants to apnoea-asphyxia.

Positional circulatory control in the sleeping infant and toddler: role of the inner ear and arterial pulse pressure.

Heart rate (HR) and arterial blood pressure (BP) are rapidly and reflexively adjusted as body position and the force/direction of gravity alters. Anomalies in these mechanisms may predispose to circulatory failure during sleep. We analysed the development of two key reflexes involved by undertaking a longitudinal (birth­1 year) comparison of instantaneous HR and BP changes evoked by abrupt upright, sideways or horizontal repositioning. Each manoeuvre triggered an identical rise in HR (tachycardia) followed by a slower rise in diastolic blood pressure (DBP)/systolic blood pressure (SBP) and variable pulse pressure (PP) change. We show that tachycardia is triggered by acceleration (vestibular) sensors located in the inner ear and slight changes in the pulsatile component of BP then signal to the arterial baroreceptors to reinforce or oppose these actions as needed. We also identified a PP anomaly in sleeping 1-year-olds of smokers that prematurely slows HR and is associated with mild positional hypotension. We conclude that positional circulatory compensation is initiated pre-emptively in a feed-forward manner and that feedback changes in vago-sympathetic drive to the heart (and perhaps blood vessels) by PP exert a slower but powerful modulating effect. An anomaly in either or both mechanisms may weaken positional compensation in some sleeping infants.

The effect of long term ventilatory support on hemodynamics in children with spinal muscle atrophy (SMA) type II.

BACKGROUND: Bi-level Positive Airway Pressure (Bi-PAP) treatment improves breathing efficiency and ventilation in children with SMA type II, but the effects of positive airway pressure swings on heart rate (HR) and blood pressure are not known. Here we studied children with SMA to determine whether Bi-PAP administered during sleep is associated with changes in hemodynamics. METHODS: Ten children aged 8-12 years on long term Bi-PAP therapy were evaluated during a routine overnight sleep study. We recorded HR, ECG, thoraco-abdominal movements and blood gases. Blood pressure was estimated indirectly from pulse transit time (PTT) and the efficiency ("work") of breathing from the phase angle between chest and abdominal movements. We compared periods of unsupported (spontaneous) and supported (i.e., on Bi-PAP) breathing during a split-night study. We also compared periods when Bi-PAP was judged optimal with periods that were sub-optimal due to mask leakage. RESULTS: HR and PTT during unsupported breathing and on optimal Bi-PAP were comparable (p=0.85 and 0.79, respectively), as were blood gases (SaO2, TcO2, TcCO2p=0.79, 0.88, 0.79, respectively). Breathing efficiency improved as expected when Bi-PAP was optimal (decrease in phase angle from 42 degrees to 22 degrees ). Sub-optimal Bi-PAP due to air leaking from the mask was associated with marked increases in breath-to-breath variability of HR, PTT and phase angle. CONCLUSIONS: Bi-PAP therapy does not appear to adversely influence hemodynamics in children with SMA if pressures are optimized and the mask is correctly applied and sealed.

Long-term reprogramming of cardiovascular function in infants of active smokers.

Newborn infants of smokers show symptoms of cardiovascular stress hyperreactivity. Persistent hyperreactivity could increase the risk of short- and/or long-term complications, such as hypertension. Here we determined whether incipient dysfunction in a smoker's infant persists or worsens with age, by comparing cardiovascular reflex function of control and tobacco-exposed infants longitudinally from birth to 1 year. We compared infants born at term to nonsmoking couples (controls; n=19) and mothers who smoked moderately (average consumption=15 cigarettes per day; n=17). All were tested at 1 to 3 weeks, 3 months, and 1 year during sleep. We recorded blood pressure and heart rate noninvasively during passive repositioning (60 degrees head-up tilt). Tilting control infants raised blood pressure slightly above baseline at 1 week (+2%) and much more at 1 year (+10%). This trend was reversed in the tobacco-exposed cohort (+10% at 1 week but only +4% at 1 year). At 3 months and 1 year, the heart rate response of tobacco-exposed infants to tilt was also abnormal (highly exaggerated). Our study reveals that maternal smoking leads to long-lasting "reprogramming" of infant blood pressure control mechanisms. The underlying dysfunction in a smoker's infant could plausibly be a precursor or early marker of long-term susceptibility to complications, such as raised blood pressure.

Obstructive lung disease in children with mild to severe BPD.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common cause of respiratory insufficiency in children born very premature. OBJECTIVES: The purpose of this study was to examine the impact of the severity of BPD on pulmonary morbidity at school age, as measured by conventional spirometry and impulse oscillometry. We also studied the association between changes in lung function and structural changes in the lungs of children with BPD via High-Resolution Computed Tomography (HRCT). Finally we studied the prevalence of atopy associated with BPD. METHODS: We studied 60 very low birth weight (VLBW) children, 28 with respiratory distress syndrome (RDS) who did not develop BPD ("preterm non-BPD") and 32 with RDS who developed BPD. The severity of BPD was graded as mild, moderate or severe. Follow-up at age 6-8 years consisted of spirometry, oscillometry, thoracic HRCT, allergy skin-prick test, blood samples and a questionnaire. RESULTS: All children with BPD showed some evidence of impaired lung function (more negative reactance, FEV1<80% predicted, greater reversibility), although less than half of these children were symptomatic. The majority of children with BPD (19/26) showed abnormalities on HRCT. There was no evidence that atopy was associated with BPD. CONCLUSIONS: Children with mild BPD exhibited similar impairments in respiratory mechanics and lung structure to those diagnosed with moderate BPD. The widespread involvement of the peripheral airways suggests that all children diagnosed with BPD are potentially at risk of developing chronic obstructive pulmonary disease later in life.

Cardiovascular stress hyperreactivity in babies of smokers and in babies born preterm.

BACKGROUND: Being born preterm, small, and to a mother who smokes are common perinatal complications with major public health implications. Evidence suggests that each affects the body's structure and function in ways that could increase susceptibility to cardiovascular dysfunction later in life. Here, we used 2 routine stress reactivity tests to identify incipient "silent" programming of cardiovascular dysfunction associated with adverse perinatal events. METHODS AND RESULTS: We studied 29 control babies born at term to nonsmokers, 18 term-born babies of mothers who smoked throughout pregnancy (mean, 15 cigarettes a day), and 31 babies born preterm to nonsmokers. All infants were compared at the same age after conception (ie, at 40 to 42 weeks), during sleep. We analyzed blood pressure (BP) and heart rate responses to breathing 4% CO(2) for 4 minutes or to passive head-up tilt to 60 degrees . BP was measured continuously from a wrist cuff. CO(2) exposure raised heart rate and BP in controls by 10%, and tilt increased their BP by 5%. CO(2) elicited the expected BP but no heart rate response from preterm infants but a much-greater-than-expected BP and heart rate response from babies of smokers. Tilt elicited a 3- to 4-fold greater rise in BP from preterm and tobacco-exposed babies. CONCLUSIONS: Vascular, cardiac, and blood pressure reactivity is heightened in babies born preterm or to smokers. The findings are consistent with in utero and early postnatal "programming" of human cardiovascular dysfunction by adverse circumstances. This incipient dysfunction may be an early manifestation of processes that lead to other problems or complications later on (eg, higher BP or sudden infant death syndrome).

Long-term non-invasive positive airway pressure ventilation in infants.

AIM: To evaluate the clinical application of long-term non-invasive ventilation (NIV) in infants with life-threatening ventilatory failure with regard to: diagnosis, age at initiation, indication for and duration of treatment, clinical outcome and mortality and adverse effects. PATIENTS AND METHODS: The medical records of 18 infants treated in a home setting during a 7-year period were reviewed. The criteria for ventilatory support were: (a) transcutaneous partial pressures of carbon dioxide (TcPCO(2)) >6.5 kPa and oxygen (TcPO(2)) < 8.5 kPa and (b) decreased cough ability and/or recurrent chest infections. RESULTS: The median age at initiation was 4 months (range 1-12). NIV was initiated because of hypoventilation in 12 infants and because of reduced cough ability and/or recurrent infections in six infants. Tracheotomy was eventually needed in two infants. The median duration of treatment was 24 months (range 1-84). NIV produced significant improvements, with median TcPCO(2) falling from 9.9 to 6.1 kPa, and median TcPO(2) rising from 9.8 to 11.1 kPa. CONCLUSION: NIV can be successfully and safely used in infants with prolonged life-threatening ventilatory failure, potentially avoiding intubation and tracheotomy.

Disturbances in cardiorespiratory function during day and night in Rett syndrome.

Rett syndrome causes severe autonomic dysregulation, probably due to brainstem dysfunction. Because the brainstem plays a decisive role in cardiorespiratory regulation during sleep, we investigated cardiorespiratory function in 12 girls with Rett syndrome, day and night, for 1 week in their home environment. Heart rate and breathing were recorded via standard three-lead electrocardiogram. Depth and frequency of respiratory movements were measured via changes in impedance. All children were scored clinically, and the association with cardiorespiratory function was examined. The total recording time for all patients was 1114 hours (535 during wakefulness; 579 during sleep), and 77 +/- 22 hours (median +/- standard error of the mean) per individual. All subjects manifested apnea, shallow breathing, or hypoventilation, when awake and during sleep. A majority had bradycardia or tachycardia. The frequencies of respiratory and heart alarms were similar during wakefulness and sleep. Bradycardia events predominated during sleep. The only significant correlation between clinical score and cardiorespiratory regulation was found for muscular-skeletal function and breathing abnormalities during wakefulness. We conclude that Rett syndrome is characterized by disturbed breathing and heart rate during sleep. The severity of cardiorespiratory dysfunction exhibited marked intra- and interindividual differences.

Abnormal circulatory stress responses of preterm graduates.

Preterm birth and chronic lung disease may increase the risk of hypertension and cardiovascular disease in infancy and adolescence. Here we looked for evidence of early circulatory dysfunction associated with these perinatal complications. We compared infants born at term (n = 12) with those born preterm with an uncomplicated neonatal course (n = 12) or diagnosed with bronchopulmonary dysplasia (BPD) (n = 10). We measured blood pressure (BP) (Finometer), and heart rate (HR) responses to 4 min of breathing 4% CO2 during quiet sleep. Hypercapnia accelerated HR and increased BP of term infants. Preterm infants either (i) had an exaggerated pressor but little or no HR response to CO2 (healthy or mild-moderate BPD) or (ii) had a diminished pressor response and accompanying decrease in HR (severe BPD). Short-term reflex cardiovascular control was consequently altered by premature birth, with potentially more serious aberrations associated with severe BPD. Most anomalies had not resolved by the time infants born preterm reached term age; some may be early signs of emerging long-term cardiovascular dysfunction.

Resuscitation and ventilation strategies for extremely preterm infants: a comparison study between two neonatal centers in Boston and Stockholm.

AIM: To evaluate if different resuscitation and ventilatory styles exist between two neonatal units, and if the less aggressive approach has a beneficiary effect on BPD outcome. METHOD: Inborn infants delivered at a gestational age <28 weeks were retrospectively studied (Boston = 70 and Stockholm = 102). Data were collected from birth to discharge or to 40 weeks. RESULTS: The study groups were similar with regard to gestational age, birth weight, gender and CRIB score, whereas SNAPPE-II score was greater in Stockholm and prenatal steroids were given less frequently in Boston. In Stockholm, continuous positive airway pressure (CPAP) was applied in the delivery room for 56% of the infants and the prevalence of infants not requiring intubation or mechanical ventilation (MV) during the first week of life was 22%. In Boston all infants were initially intubated. Subsequently, CPAP was used less often, and higher mean airway pressures (MAWPs) were applied during the first 4 weeks of life. Mortality and moderate/severe BPD at 36 weeks were similar; however, at 40 weeks oxygen supplementation was more frequent in Boston. Site was a predictor for moderate/severe BPD or death at 40 weeks. CONCLUSION: Practice style differences exist and the less aggressive approach with more CPAP administration was successful. It did not decrease the risk for BPD at 36 weeks; however, at 40 weeks, fewer infants were on oxygen support, and a strong association was found between site, MAWP or MV with pulmonary morbidity indicating that CPAP could have a beneficiary role in outcome.

Development of chemoreceptor responses in infants.

This paper is devoted to the field of chemoreception and its role in the control of breathing in infants. We use "chemoreception" to refer to the capacity to sense and process changes in P(O2) and P(CO2), and also to react to these changes by adjusting ventilation in order to maintain homeostasis. Functional chemoreceptors are not essential to commence or even to sustain breathing efforts immediately at or after birth; the intense brain activation, which occurs at birth, is sufficient. Over subsequent days to weeks, however, this "neurogenic" drive weakens and drive from the chemoreceptors becomes critical for generating and maintaining a normal breathing rhythm. Failure of the chemoreceptors to develop normally, consequently, becomes an important underlying cause of breathing dysfunction, particularly during sleep. The paper deals with the methods available to study chemoreception in newborn infants and provide an overview of the early postnatal changes and interactions, which influence breathing at rest and under stress. The latter may be described in terms of the threshold and strength as well as the delay/speed with which ventilation changes in response to chemical stimulation. We conclude with a survey of disorders associated with chemoreceptor deficits in infancy.

Developmental risks and protective factors for influencing cognitive outcome at 5 1/2 years of age in very-low-birthweight children.

In a population-based follow-up study (the Stockholm Neonatal Project), 182 children with a birthweight of 1500 g or less (very-low birthweight: VLBW) and a control group of 125 children born healthy at term were examined with the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R) and a neuropsychological test battery (Nepsy) at 5 1/2 years of age. The WPPSI-R results of the VLBW children fell well within the normal range: WPPSI-R full-scale IQ 95.7, verbal subscale IQ 99.9, and performance subscale IQ 91.6. Nevertheless, the control group had significantly better results than the VLBW group which could be attributed to the greater variability of the VLBW group, with a larger proportion falling in the lower area of the IQ distribution, especially on the performance subscale. Likewise, the control group displayed better executive function (Nepsy). Paternal education was equal in the two groups and was the single most important predictor of IQ, possibly acting as a protective factor. The need for glasses or lenses was inversely associated with all IQ measures and severe retinopathy of prematurity (ROP) had the most negative impact on full-scale and performance IQ. These two IQ measures were also negatively associated with intrauterine growth retardation late in pregnancy. We conclude that VLBW children, in the absence of these identified risk factors, have normal cognitive development.