Stillbirth: Genome-wide copy number variation profiling in archived placental umbilical cord samples with pathologic and clinical correlation.

INTRODUCTION: Stillbirth remains a devastating health issue with 26,000 stillbirths occurring annually in the United States. Formalin-fixed, paraffin-embedded (FFPE) umbilical cord samples are available for many stillbirths. Our aim was to validate the use of these samples in identifying genetic variations in stillbirth through microarray analysis. METHODS: This is a retrospective case-control study from a single institution of stillbirths ≥ 23 weeks gestational age and control liveborn infants. Fetal genomic DNA was extracted from FFPE umbilical cord samples of stillborn and control placentas, and genotyping was performed using the Illumina HumanOmniExpresss-12v1 Beadchip. Array results were verified with qPCR. RESULTS: 31 case-specific CNVs (17 deletions and 14 amplifications) with an average size of 294 kb for amplifications and 74 kb for deletions were identified among 94 FFPE samples (86 cases; 8 controls). In total 38 (44%) of the stillbirth samples had a CNV detected. Validation of a subset of microarray findings with qPCR confirmed deletions on 1p (2 cases), 11q (4 cases) and amplifications on 18 (1 case). Placental underperfusion changes were seen in stillborns with deletions on 1p, a region containing complement regulatory genes which have been shown to play a role in preeclampsia. DISCUSSION: This study validated the use of archived FFPE umbilical cord samples for genome-wide copy number profiling in stillbirths, and demonstrates specific CNV deletions and amplifications. Microarray analysis in an expanded cohort of stillbirth FFPE samples has the potential to identify biomarkers involved in stillbirth pathogenesis.

Anxiety and congenital central hypoventilation syndrome.

OBJECTIVE: It has been hypothesized that individuals who cannot perceive elevations of CO2 will be less anxious than individuals with intact CO2 perception. To test this hypothesis, children with congenital central hypoventilation syndrome, who have a potentially lethal chronic illness associated with lack of CO2 perception and thus provide a natural experimental group, were studied. METHOD: Rates of anxiety symptoms and disorders in children with congenital central hypoventilation syndrome (N = 13) were compared with rates in an age-matched, nonreferred group of community subjects (N = 292) that included subgroups of children with asthma (N = 15) and other chronic medical illnesses (N = 66). Anxiety symptoms were assessed with information obtained from structured interviews of the parents, which provided both total symptom scores and DSM-III-R diagnoses. RESULTS: The children with congenital central hypoventilation syndrome exhibited significantly fewer anxiety symptoms than all other comparison subjects. Two of these children (15%) met criteria for anxiety disorders, a rate lower than that of the whole community group (24%) and of the chronically ill comparison subgroups (32%-47%). The largest difference in the prevalence of disorder emerged between the children with congenital central hypoventilation syndrome (15%) and those with asthma (47%). In the comparison of children with congenital central hypoventilation syndrome and children with other chronic illnesses, a priori analysis showed that the former had significantly lower rates of disorders that have been linked to panic in the literature. CONCLUSIONS: This study supports theories of anxiety that implicate CO2 perception in the pathophysiology of panic and related anxiety states.

Infant polysomnography: reliability. Collaborative Home Infant Monitoring Evaluation (CHIME) Steering Committee.

Infant polysomnography (IPSG) is an increasingly important procedure for studying infants with sleep and breathing disorders. Since analyses of these IPSG data are subjective, an equally important issue is the reliability or strength of agreement among scorers (especially among experienced clinicians) of sleep parameters (SP) and sleep states (SS). One basic issue of this problem was examined by proposing and testing the hypothesis that infant SP and SS ratings can be reliably scored at substantial levels of agreement, that is, kappa (kappa) > or = 0.61. In light of the importance of IPSG reliability in the collaborative home infant monitoring evaluation (CHIME) study, a reliability training and evaluation process was developed and implemented. The bases for training on SP and SS scoring were CHIME criteria that were modifications and supplements to Anders, Emde, and Parmelee (10). The kappa statistic was adopted as the method for evaluating reliability between and among scorers. Scorers were three experienced investigators and four trainees. Inter- and intrarater reliabilities for SP codes and SSs were calculated for 408 randomly selected 30-second epochs of nocturnal IPSG recorded at five CHIME clinical sites from healthy full term (n = 5), preterm (n = 4), apnea of infancy (n = 2), and siblings of the sudden infant death syndrome (SIDS) (n = 4) enrolled subjects. Infant PSG data set 1 was scored by both experienced investigators and trained scorers and was used to assess initial interrater reliability. Infant PSG data set 2 was scored twice by the trained scorers and was used to reassess inter-rater reliability and to assess intrarater reliability. The kappa s for SS ranged from 0.45 to 0.58 for data set 1 and represented a moderate level of agreement. Therefore, rater disagreements were reviewed, and the scoring criteria were modified to clarify ambiguities. The kappa s and confidence intervals (CIs) computed for data set 2 yielded substantial inter-rater and intrarater agreements for the four trained scorers; for SS, the kappa = 0.68 and for SP the kappa s ranged from 0.62 to 0.76. Acceptance of the hypothesis supports the conclusion that the IPSG is a reliable source of clinical and research data when supported by significant kappa s and CIs. Reliability can be maximized with strictly detailed scoring guidelines and training.

Congenital central hypoventilation syndrome: inheritance and relation to sudden infant death syndrome.

We evaluated the families of 50 children with idiopathic congenital central hypoventilation syndrome (CCHS) to 1) test genetic hypotheses, 2) explore the relationship to Hirschsprung disease (HD), and 3) examine other clinical findings including sudden infant death syndrome (SIDS) in relatives of CCHS patients. A questionnaire was administered to parents of each proband to determine a detailed pedigree and medical history for 3 generations including 1,482 relatives. The data were analyzed under the unified mixed model method (assumes individual genotype composed of multifactorial [MF] and major locus [ML] components). Analysis was made of the Total dataset and on subdivided data sets: HIR1 = families of probands with HD (n = 8) vs. HIR2 = families of probands without HD; then under a premise that severe, chronic constipation may be a milder form of HD (i.e., ganglion cells present but dysfunctional), CON1 = families of probands with HD or constipation (n = 13) vs. CON2 = families of probands without HD or constipation. By statistical genetic analysis of the Total, HIR1, and CON1 datasets, the MF and ML hypotheses were about equally likely, with the MF model slightly more parsimonious. Although HIR2 and CON2 datasets indicated no familiality, statistical evidence of heterogeneity between the results of HIR1 and HIR2, or between CON1 and CON2 was lacking. A SIDS incidence of 11.2/1,000 was documented among the relatives of CON1 vs. 1.8/1,000 among relatives of CON2. Our results are consistent with familiality by either MF or ML models. Recurrence risk is likely < 5%. The relationship of CCHS to the high familial incidence of SIDS is intriguing and demands further investigation.

Congenital central hypoventilation syndrome: mutation analysis of the receptor tyrosine kinase RET.

Congenital central hypoventilation syndrome (CCHS) usually occurs as an isolated phenotype. However, 16% of the index cases are also affected with Hirschsprung disease (HSCR). Complex segregation analysis suggests that CCHS is familial and has the same inheritance pattern with or without HSCR. We postulate that alteration of normal function of the receptor tyrosine kinase, RET, may contribute to CCHS based on RET's expression pattern and the identification of RET mutations in HSCR patients. To further explore the nature of the inheritance of CCHS, we have undertaken two main routes of investigation: cytogenetic analysis and mutation detection. Cytogenetic analysis of metaphase chromosomes showed normal karyotypes in 13 of the 14 evaluated index cases; one index case carried a familial pericentric inversion on chromosome 2. Mutation analysis showed no sequence changes unique to index cases, as compared to control individuals, and as studied by single strand conformational polymorphism (SSCP) analysis of the coding region of RET. We conclude that point mutations in the RET coding region cannot account for a substantial fraction of CCHS in this patient population, and that other candidate genes involved in neural crest cell differentiation and development must be considered.

Genetic segregation analysis of autonomic nervous system dysfunction in families of probands with idiopathic congenital central hypoventilation syndrome.

Idiopathic congenital central hypoventilation syndrome (CCHS) is a very rare syndrome with major respiratory complications. Hypothesizing that CCHS is the most severe manifestation of general autonomic nervous system dysfunction (ANSD), we applied a case-control family study design to investigate the genetics of ANSD. Fifty-two probands with CCHS were identified, as well as 52 age-, race-, and gender-matched controls. ANSD phenotypic features were characterized in the cases, controls, and their family members. Our earlier studies found that most ANSD symptoms were more likely in CCHS cases and their relatives than in controls and their relatives (P < 0.05). The goal of the current study was to determine if the familiality of ANSD was consistent with a genetic pattern. We performed major locus segregation analysis of ANSD utilizing regressive models. CCHS probands were assumed to be affected; controls and relatives were designated as affected if they had two or more relevant symptoms. The hypothesis of "no transmission and no familial effects" was rejected in both case and control families. Case families were consistent with transmission of a major effect; control families were not (the difference in the pattern of results was significant, P < 0.0001). In the total data set, the best-fitting model was codominant Mendelian inheritance of a major gene for ANSD. These case-control family studies support our hypothesis that CCHS is the most severe manifestation of a general ANSD, with a family pattern consistent with Mendelian transmission, and demonstrate the potential utility of the approach to studies of other, similarly intractable disorders.

Case/control family study of autonomic nervous system dysfunction in idiopathic congenital central hypoventilation syndrome.

Children with idiopathic congenital central hypoventilation syndrome (CCHS) have a complex phenotype consistent with an imbalance of the autonomic nervous system (ANS). Since CCHS may be genetic in origin, we hypothesized that relatives of individuals with CCHS may exhibit symptoms of ANS dysfunction (ANSD), albeit in a milder form. We tested this hypothesis by assessing aspects of ANS function in relatives of CCHS cases vs. relatives of matched controls with a scripted questionnaire. Only those 35 symptoms of ANSD exhibited by > or =5% of the CCHS cases were included in the analysis as the basis for determining ANSD affection status. Two different arbitrary ANSD affection status definitions are presented in detail: any case, control, or relative with positive findings (1) in two or more symptoms, or (2) in two or more systems. The subjects included in the analysis totaled 2,353, including 56 CCHS cases, 56 age-, gender-, and race-matched controls, and their families. Under each of the two arbitrary ANSD affection statuses, CCHS cases and parents of cases were more likely to be affected than controls and parents of controls (P < 0.001 for both comparisons), 16% of the CCHS siblings had the ANSD phenotype with two or more symptoms, compared to 4% of control siblings (P = 0.03). Aunts and uncles of the CCHS cases were also significantly more likely to have two or more ANSD symptoms than were aunts and uncles of the controls (P= 0.009). These results support our hypothesis and also indicate that relatives of the CCHS cases tended to manifest a milder spectrum of ANSD, with fewer systems and/or fewer symptoms than the cases.

Risk factors associated with candidemia in the neonatal intensive care unit: a case-control study.

Systemic candidiasis, especially candidemia, is an increasing problem among high risk neonates. Although possible predisposing factors have been suggested, no case-control study has evaluated potential risk factors. By retrospective chart review we identified 21 infants admitted to the neonatal intensive care unit between 1976 and 1983 (0.9% of all admissions) who had documented nosocomial candidemia before 4 months of age. Twenty patients were matched to a control infant with similar birth weight and date of admission. We found that the median durations of exposure to the following risk factors were significantly longer in patients compared with controls: hyperalimentation; intravenous fat emulsion; endotracheal tubes; and/or tracheostomies and antibiotic therapy. However, by discriminant analysis, duration of antibiotic therapy remained the variable most strongly (and independently) associated with the development of candidemia. Treatment of the 22 episodes of candidemia was variable including catheter removal alone in 12 and a combination of catheter removal, amphotericin, 5-fluorocytosine and/or ketaconazole in the others. Although the overall mortality for the series was 5 of 20 cases (25%), no infant larger than 2000 g died. We conclude that development of candidemia in neonates is associated with, and possibly caused by, prolonged exposure to antibiotics (as documented by multivariate analysis), hyperalimentation, intravenous fat emulsion and tracheal intubation (as documented by univariate analysis). To the greatest extent possible consistent with good clinical care, exposure to these risk factors should be minimized in high risk neonates.

Uterine position determines the extent of dopamine reduction after chronic prenatal cocaine exposure.

Most studying the consequences of prenatal cocaine (COC) exposure employ rodents or other multiparous organisms in their models. We have previously shown that when pregnant Sprague-Dawley albino rats are administered a 30 mg/kg subcutaneous (s.c.) injection on embryonic day 15 (E15), fetal brain COC levels show a proximal-to-distal (in relation to the cervix) gradient that can vary by as much as 350%. The present study sought to determine whether this gradient translated into a similar gradient in brain dopamine (DA) levels. Pregnant rats were administered COC or saline (SAL) (30 mg/kg COC or 1 ml/kg SAL, b.i.d., E7-E19). On E20, dams were anesthetized with halothane, the fetuses immediately removed, their brains excised, frozen and subsequently processed for DA, dihydroxyphenylacetic acid (DOPAC) or homovanillic acid (HVA). High-performance liquid chromatography (HPLC) analysis revealed a proximal-to-distal gradient for DA in both COC- and SAL-exposed fetuses. Average fetal DA levels per litter were significantly lower in COC-exposed litters (57.39 +/- 3.67 ng/hemibrain SAL; 48.29 +/- 3.87 ng/hemibrain COC F7,1 = 11.66, p < 0.05). The gradients for DA were in opposite directions such that COC litters showed the lowest levels of DA in the most distal uterine positions, whereas SAL-exposed litters showed the highest DA levels in the same location. These data suggest that a gradient in brain dopamine normally exists for fetuses based upon uterine position, and that cocaine can have selectively greater effects on this level as a function of fetal location.

Effects of almitrine on genioglossal and diaphragmatic electromyograms.

We previously demonstrated dose-dependent increases in both hypoglossal and phrenic electroneurograms after almitrine in anesthetized, paralyzed, and vagotomized cats. We have now investigated the effect of this peripheral chemoreceptor stimulant on diaphragmatic and genioglossal (GG, an upper airway-maintaining muscle) electromyograms in five unanesthetized, chronically instrumented, spontaneously breathing adult cats during slow-wave sleep. In 12 studies almitrine doses of 1.0-6.0 mg/kg increased inspired minute ventilation (VI), frequency (f), and tidal volume (VT) and decreased expiratory time (TE). However, almitrine doses as high as 6.0 mg/kg failed to augment phasic inspiratory GG activity. To determine why almitrine induced phasic inspiratory upper airway activity in anesthetized, vagotomized cats but not in sleeping cats, additional studies were performed. In four dose-response studies in three pentobarbital-anesthetized cats, almitrine, 1.0-6.0 mg/kg, did not produce phasic inspiratory GG activity. Almitrine did induce phasic inspiratory GG activity in two of three studies in three vagotomized, tracheostomized, alpha-chloralose-urethan-anesthetized cats. These results suggest that almitrine would not be useful in obstructive sleep apnea, yet because almitrine markedly increased VI, f, and VT and decreased TE in unanesthetized sleeping cats the drug may be effective in patients who lack normal central neural respiratory drive, such as the preterm infant.

Effects of almitrine on respiration in unanesthetized newborn rabbits.

We previously demonstrated that almitrine, a peripheral chemoreceptor stimulant, increased tidal volume (VT), expired minute ventilation (VE), and respiratory frequency (f) and decreased inspiratory (TI) and expiratory time (TE) in sleeping adult cats. We now hypothesized that almitrine would induce an increase in ventilation in a young animal model. Respiration was studied by the barometric method in 11 unanesthetized New Zealand White rabbit pups between 3 and 6 days of age. Recordings were made in 0.21 FIO2 at base line and after cumulative intraperitoneal infusions of almitrine (2.5, 5.0, and 7.5 mg/kg). The chamber pressure deflection (proportional to VT after appropriate calculation) was computer sampled at 200 Hz. At least 100 breaths for each dose in each animal were analyzed. We found that a 7.5-mg/kg intraperitoneal dose of almitrine increased f to 135 +/- 9% (SE) of base line and decreased TE and TI to 72 +/- 8% and 79 +/- 8% of base line, respectively. Changes in VE, VT/TI, and VT were not significant. Recognizing that apnea is associated with inadequate ventilation and a prolonged TE (failure of the "inspiratory on-switch"), these results, particularly the increase in f and decrease in TE, suggest that almitrine might be useful in treating apnea in preterm infants.

Effects of almitrine on hypoglossal and phrenic electroneurograms.

Almitrine increases breathing by stimulating peripheral chemoreceptors. Previous studies suggest clinical usefulness in the adult with chronic obstructive pulmonary disease, but little data are available to decide whether almitrine would be helpful in diseases involving pharyngeal airway obstruction, such as apnea of prematurity or obstructive sleep apnea. We investigated the effect of intravenous almitrine on hypoglossal (HG), an upper airway nerve, and phrenic (PHR) neural activity in eight alpha-chloralose-urethan anesthetized, paralyzed, vagotomized, and artificially ventilated cats. Recordings were made of raw and integrated HG and PHR electroneurograms (ENGs), alveolar PCO2, arterial PO2, arterial blood pressure, and rectal temperature. A dose-response study of cumulative almitrine doses ranging from 0.1 to 4.0 mg/kg was performed in three cats. The interactive effects of almitrine and hypoxic stimulation were investigated in four cats. The interactive effects of almitrine and hypercapnic stimulation were investigated in five cats. The interactive effects of almitrine and ventilatory timing were investigated in six cats. We found that 1) almitrine doses as low as 0.1 mg/kg iv increased both HG and PHR ENG activity, with a maximum effect at approximately 1.0 mg/kg; 2) almitrine markedly increased HG and PHR ENG activity at all arterial PO2 values from 35-175 Torr; 3) almitrine increased HG and PHR ENG activity at all arterial PCO2 values from 30-70 Torr; and 4) almitrine increased the ratio of tidal volume to inspiratory time and decreased the inspiratory muscle duty cycle at normoxia and eucapnia.

Effects of continuous low-frequency pacing on immature canine diaphragm.

Although diaphragm pacing has been shown to be a practical method of supporting ventilation in children, its usefulness has been limited because of concern that continuous (24 h/day) diaphragm pacing would fatigue and damage the diaphragm. We examined the functional and structural effects of continuous low-frequency diaphragm pacing on the left hemidiaphragm of five immature dogs aged 65 +/- 2 (SD) days at onset of pacing. Stimulus parameters approximated those required to pace infants: frequency 11.1 Hz, inspiratory time 810 ms, and respiratory rate 20 breaths/min. Animals were paced 24 h/day for 24-28 days. Paced tidal volumes and airway occlusion pressures were unchanged at low (less than 15 Hz) stimulus frequencies but were reduced at high (greater than 20 Hz) stimulus frequencies. Although histologically the paced hemidiaphragms appeared normal, histochemical studies showed a conversion from a mixture of type I (54%) and type II (46%) fibers to a uniform population of type I fibers with high oxidative enzyme activity. Transformation of muscle type was also demonstrated by pyrophosphate gel electrophoresis; fast and slow isomyosin bands were noted in control specimens, whereas only slow isomyosin was identified in paced specimens. Thus, in immature dogs, continuous low-frequency pacing affects both function and structure of the diaphragm.

Prenatal cocaine exposure reduces glial cell line-derived neurotrophic factor (GDNF) in the striatum and the carotid body of the rat: implications for DA neurodevelopment.

Glial cell line-derived neurotrophic factor (GDNF) is a glycosylated, disulfide-bonded homodimer, and a member of the transforming growth factor-beta superfamily. GDNF has been shown to promote the survival and morphological differentiation of dopamine (DA) neurons and increase their high-affinity dopamine uptake. In order to determine whether the mechanism for our previously observed cocaine-induced DA reductions in brain and carotid body were GDNF-mediated, we exposed Sprague-Dawley rat fetuses to cocaine via maternal subcutaneous injections (30 mg/kg b.i.d., E7-E19). Brains and carotid bodies of fetuses were excised and processed for assessment of GDNF levels using an Enzyme-Linked ImmunoadSorbent Assay (ELISA). ANOVA indicated that cocaine reduced carotid body GDNF by 36% (F((1,5))=28. 11, p<0.05) and striatal GDNF by 41% (F((1,5))=41.77, p<0.01). Although there was no interaction between drug exposure and fetal uterine position, post-hoc pairwise comparisons indicated that reductions in GDNF in the cocaine groups were due to differences at more distal positions (positions 4-8). The magnitude of the reductions in striatal GDNF (but not carotid body GDNF) in both cocaine-exposed and control fetuses followed a cervical (smallest GDNF reductions) to ovarian (greatest GDNF reductions) uterine position gradient. This pattern was similar to that which we observed in prior studies examining DA reductions in brain following prenatal cocaine exposure. The finding that cocaine reduces GDNF levels in striatum and carotid body support the hypothesis that cocaine's ability to reduce striatal and carotid body DA may be indirect through its ability to reduce GDNF. These data along with previous findings support the hypothesis that cocaine's effects on DA neurons are at least partially due to its indirect effects on trophic activity. The possible mechanisms whereby cocaine affects trophic activity are discussed.

Congenital central hypoventilation syndrome: cardiorespiratory responses to moderate exercise, simulating daily activity.

Children with congenital central hypoventilation syndrome (CCHS) lack normal awake ventilatory responses to hypoxia and hypercarbia, yet engage in daily activities typical of similarly aged children. Our patients with CCHS are assessed annually with a walking treadmill protocol to assess physiologic responses to different levels of simulated daily activity. We hypothesized that children with CCHS (compared with age- and sex-matched healthy controls) would 1) exercise for shorter durations and reach lower peak speed and incline on the treadmill; 2) become more hypoxemic, more hypercarbic, and develop less tachycardia during activity; and 3) take longer to return to baseline oxygenation, ventilation, and heart rate than normal children. Seven children with CCHS [mean age, 6.9 +/- 3.0 (SD) years] who required 24 h/day ventilatory support (diaphragm pacers while awake and mechanical ventilation asleep) and 7 controls performed a walking protocol on a treadmill with progressive increments in speed and incline. Hemoglobin saturations (SaO2), end-tidal carbon dioxide concentrations (ETCO2), and heart rates (HR) were recorded at baseline conditions, during activity and during recovery. There were no significant differences between children with CCHS and controls in baseline values, duration of activity, peak speed, and incline achieved during walking and recovery time to baseline once the treadmill had stopped. However, children with CCHS became significantly more hypoxemic and hypercarbic during activity (P < 0.05), and they had a lower percent increase in HR during treadmill walking than controls (P < 0.05). These results offer the clinician an opportunity to adjust clinical management in children with CCHS by providing specific recommendations to parents about appropriate levels of activity for their children with CCHS.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of prenatal cocaine on respiration, heart rate, and sudden infant death syndrome.

We studied 114 neonates by pneumocardiogram recordings in order to examine the effects of cocaine with and without opiate exposure on neonatal respiration, heart rate, apparent life threatening events (ALTE), and sudden infant death syndrome (SIDS). In full-term infants exposed to cocaine without opiates we found increased longest apnea duration and more episodes of bradycardia, but decreased periodic breathing and average heart rate than in control full-term infants. Term infants prenatally exposed to cocaine with opiates also had less periodic breathing. Preterm infants exposed to cocaine with and without opiates had decreased apnea density and periodic breathing compared with preterm controls. Discriminant analysis to determine whether perinatal asphyxia or exposure to other drugs could predict cardiorespiratory abnormalities showed no consistent relationship. In 72 of 114 infants available for follow-up, no ALTE occurred but two were lost to SIDS. Our data support the hypothesis that prenatal cocaine exposure may perturb, albeit subtly, the maturation of respiratory control, resulting in disruption of postnatal respiration.

Comparison of transthoracic impedance/heart rate monitoring and pulse oximetry for patients using diaphragm pacemakers.

Patients using diaphragm pacemakers have several respiratory-related problems placing them at high risk for death during sleep, including central hypoventilation, abnormal arousal responses, upper airway and/or tracheostomy obstruction, and, in the case of high quadriplegia, lack of motor response to airway obstruction. The recent death from airway obstruction of a patient using diaphragm pacemakers prompted us to re-evaluate both the need for home monitoring and the type of monitor to prescribe. We compared the performance of a transthoracic impedance/heart rate (TI/HR) monitor with that of a pulse oximeter in six patients with central hypoventilation syndrome whose treatment included diaphragm pacing. Polygraphic recordings of airflow, ECG, SaO2, transthoracic impedance, heart rate, and breath detection were obtained during brief tracheostomy occlusion during patient sleep. Although none of 13 occlusions was detected by the TI/HR monitor, the pulse oximeter identified 13 of 13 occlusions. Three reasons for TI/HR monitor failure included 1) the breath detection circuit consistently registered a breath with each obstructed, paced diaphragmatic contraction; 2) bradycardia did not occur during any airway occlusion; and 3) pacemaker stimuli were misinterpreted as additional heart beats, increasing apparent heart rate. Thus, pulse oximetry, but not TI/HR monitoring, can detect life-threatening airway obstruction in children using diaphragm pacemakers.

Polysomnography in obese children with a history of sleep-associated breathing disorders.

We hypothesized that obese children with a history of breathing difficulty during sleep would demonstrate (1) evidence of complete and partial obstructive sleep apnea (OSA) with hypercarbia and/or hypoxemia; and (2) correlation between symptoms, degree of obesity, adenoid and tonsil size, and polysomnography (PSG) results. We evaluated 32 obese children [% ideal body weight (IBW), 196 +/- 45%] with a sleep history questionnaire, airway radiographs, electrocardiograms (ECG), and PSG. By history, we found snoring (100%), difficulty breathing (59%), sweating (44%), restlessness (53%), arousals (41%), apnea (50%), worsening with upper respiratory infection (URI) (81%), hypersomnolence (59%), and mouth breathing (59%). We found adenoid and/or tonsil enlargement on 75% of airway x-ray pictures. ECGs were abnormal in 5 patients. Among all patients, mean sleep study oxyhemoglobin saturation (SaO2) was 85 +/- 16% and mean end-tidal CO2 (PetCO2) was 51 +/- 7 torr; 84% had paradoxical inward movement of the chest on inspiration, 59% had OSA, and 66% had partial OSA. In those with > or = 200% IBW and adenotonsillar enlargement, elevated PetCO2 and the presence of hypoxemia (SaO2 < 90%) for > or = 5% of the total sleep time (TST) were correlated, unlike in patients of similar weight but without adenotonsillar enlargement. Individuals symptoms did not correlate with the severity of PSG abnormalities. By discriminant analysis, using three variables (IBW, presence of adenotonsillar tissue, and presence of > or = 5 symptoms), we could predict PSG abnormalities with up to 81% reliability. Our findings indicate that in obese children, particularly those with %IBW > or = 200 and adenotonsillar hypertrophy, with sleep-disordered breathing evaluation by polysomnography should be considered.

Cardiac rhythm disturbances among children with idiopathic congenital central hypoventilation syndrome.

The objective of this study was to determine whether subjects with congenital central hypoventilation syndrome (CCHS) had an increased frequency of cardiac arrhythmias and decreased heart rate variability when compared to subjects without a known deficit in control of breathing, and that these abnormalities would be exaggerated by anesthesia. Continuous ambulatory Holter recordings were obtained in patients with CCHS and compared to two otherwise healthy control groups without a deficit in control of breathing: one with an intact airway (n = 11) and a second group with a tracheostomy (n = 6). Holter recordings were obtained before, during (under general anesthesia), and after bronchoscopy. Fourteen children with CCHS (age: 9.3 +/- 4.4 years mean +/- S.D.) were studied, and 7 underwent bronchoscopy. Seventeen control children were studied (age 6.6 +/- 3.6 years): 11 without a tracheostomy, and 6 with a tracheostomy who also underwent bronchoscopy. Maximum heart rate during baseline recording was significantly lower in the CCHS subjects as compared to controls (P = 0.0001). At baseline the difference in the number of arrhythmias/24 hr/subject in all CCHS vs. all control subjects was significant (P = 0.0002); for the subjects who had bronchoscopy, CCHS vs. control, the difference was also significant (P = 0.03). In addition, there was a significant decrease in the number of events/24 hr/subject among the CCHS subjects between baseline and post-bronchoscopy (P = 0.0288). The predominant arrhythmias were sinus bradycardia and transient asystole. The longest asystole in a CCHS subject was 6.50 sec, and in a control subject, 1.42 sec (at baseline the means of the longest asystole were 2.69 +/- 1.4 vs. 1.24 +/- 0.13; P = 0.003 in the CCHS vs. control groups). Other indices of heart rate variability were significantly reduced in the CCHS subjects (P < 0.05). These results substantiate our hypothesis that subjects with CCHS have more arrhythmias than controls, an increased frequency of bradyarrhythmias, and decreased cyclical sinus arrhythmia.