[Respiratory control: an esoteric zebra or a day-to-day workhorse?].
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Adult↗
Biomedical subjects
D Gozal
Publications and source records attributed to D Gozal.
Propofol does not modify the hemodynamic status of children with intracardiac shunts undergoing cardiac catheterization.
Immobility and cardiovascular stability are required for cardiac catheterization. Pediatric patients need a type of sedation that also allows spontaneous ventilation without supplemental oxygen. Propofol has been adequate in hemodynamically stable patients with congenital heart disease undergoing cardiac catheterization. However, mild systemic hypotension caused by propofol may increase a preexisting right-to-left shunt. The aim of this study is to evaluate, in pediatric patients scheduled for cardiac catheterization, the effects of propofol on systemic and pulmonic circulations. Fifteen patients aged 18 months to 9 years were studied. After a fast of 4-6 hours for solid food, the patient arrived at the cardiac catheterization suite, where an IV catheter was placed. Usual monitoring was used. For sedation, without supplemental oxygen, patients received 1 mg/kg of fentanyl followed by propofol (1-2 mg/kg) titrated to immobility during preparation of the groin. A continuous infusion of propofol (100 mg/kg/min) was also started to obtain immobility during the procedure. Hemodynamic data, including systemic venous, pulmonary artery and vein, aortic saturations, and pressures, were recorded; Qp and Qs were calculated. The same set of data was re-corded 4 minutes after discontinuation of propofol and when the patient was responding to tactile stimuli. Despite lower pressures during propofol infusion, as compared with those pressures measured after discontinuation of propofol, the extent of the intracardiac shunt remained unchanged. Propofol seems to be an adequate sedative agent for pediatric patients undergoing cardiac catheterization, including those with intracardiac shunts.
Anesthetics, Intravenous↗
S-nitrosothiols signal the ventilatory response to hypoxia.
Increased ventilation in response to hypoxia has been appreciated for over a century, but the biochemistry underlying this response remains poorly understood. Here we define a pathway in which increased minute ventilation (&Vdot;E ) is signalled by deoxyhaemoglobin-derived S-nitrosothiols (SNOs). Specifically, we demonstrate that S-nitrosocysteinyl glycine (CGSNO) and S-nitroso-l-cysteine (l-CSNO)-but not S-nitroso-d-cysteine (d-CSNO)-reproduce the ventilatory effects of hypoxia at the level of the nucleus tractus solitarius (NTS). We show that plasma from deoxygenated, but not from oxygenated, blood produces the ventilatory effect of both SNOs and hypoxia. Further, this activity is mediated by S-nitrosoglutathione (GSNO), and GSNO activation by gamma-glutamyl transpeptidase (gamma-GT) is required. The normal response to hypoxia is impaired in a knockout mouse lacking gamma-GT. These observations suggest that S-nitrosothiol biochemistry is of central importance to the regulation of breathing.
Animals↗
Excitotoxic preconditioning elicited by both glutamate and hypoxia and abolished by lactate transport inhibition in rat hippocampal slices.
Ischemic preconditioning (PC) of heart and brain is a well-documented phenomenon. However, the mechanism underlying the increased resistance to severe ischemia by a preceding mild ischemic exposure remains unclear. Over a decade ago, we demonstrated the existence of hypoxic PC in the hippocampal slice preparation. Here we report the ability of a short exposure to toxic levels of glutamate to heighten the tolerance of hippocampal slices to a subsequent, longer exposure to the excitotoxin. Glutamate PC could also be induced by a short hypoxic exposure, suggesting a common mechanistic pathway for all PC stimuli. Since glutamate receptor activation and hypoxia increase tissue lactate production, a-cyano-4-hydroxycinnamate was applied during the PC period to completely abolished PC. These results indicate that excitotoxic PC and hypoxic PC share similar mechanisms that possibly involve lactate production and its neuronal utilization.
Action Potentials↗
Evolving concepts of the maturation of central pathways underlying the hypoxic ventilatory response.
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Animals↗
Developmental differences in cortical and hippocampal vulnerability to intermittent hypoxia in the rat.
Obstructive sleep apnea is characterized by intermittent hypoxic events during sleep, and is associated with substantial neurocognitive morbidity, particularly in children. Intermittent hypoxia (IH) leads to increases in apoptosis in the cortex and hippocampus of the adult rat, peaking at 48 h of exposure. To examine whether the susceptibility to IH exhibits developmental differences, rats were exposed to 48 h of IH at ages 2, 5, 10, 15, 20, 25, 30, 60, and 120-day postnatally, and apoptosis was determined by terminal deoxy-nucleotidyl transferase-mediated in situ end labeling and immunohistochemical staining for single-stranded DNA. Although IH induced apoptosis at all postnatal ages, smaller increases were apparent in 2 and 5-day old (P < 0.01 vs. any other age) while peak apoptosis occurred at 10-25 days (P < 0.001 vs. 30, 60, and 120 days). We conclude that a unique window of vulnerability to IH is present in the cortex and hippocampus during post-natal maturation, and may underlie the high frequency of neurobehavioral deficits associated with obstructive sleep apnea in children.
Aging↗
Developmental patterns of NF-kappaB activation during acute hypoxia in the caudal brainstem of the rat.
NF-kappaB, an ubiquitous transcription factor which plays a major role in the regulation of stress-related genes, is activated during environmental hypoxia in the dorsocaudal brainstem of adult rats. To examine the developmental pattern of NF-kappaB basal activity in the brainstem and the response to hypoxia, electromobility shift assays and immunohistochemical staining for the P65 subunit of NF-kappaB were performed in caudal brainstem samples of rats at 2, 5, 10, 15, and 60 days postnatal age, following normoxic or hypoxic (1 h in 10% O2) exposures. In addition, the expression of IkappaB-alpha, and IkappaB kinases (ikk)-alpha and -beta was also examined using Western blots. Basal NF-kappaB nuclear activity and nuclear P65 immunoreactivity increased with maturation. In contrast, hypoxia induced enhanced activation of NF-kappaB and nuclear translocation of P65 in youngest animals. Expression of both IkappaB-alpha and ikk-alpha was highest in the more immature rats, and decreased with postnatal age. In contrast, ikk-beta expression was unchanged over time. We conclude that NF-kappaB activity in caudal brainstem is developmentally regulated, and that hypoxia-induced NF-kappaB activation is more prominent in youngest rats. We postulate that postnatal regulation of NF-kappaB complex expression and function may underlie fundamental genomic processes mediating developmental changes in neuronal hypoxic tolerance.
Acute Disease↗
Behavioral and anatomical correlates of chronic episodic hypoxia during sleep in the rat.
The role played by chronic episodic hypoxia (EHYP) in the neurocognitive morbidity of obstructive sleep apnea (OSA) is unknown. Sleep recordings, Morris water maze experiments, and immunohistochemistry for NMDA NR1 glutamate receptor, c-fos protein, and apoptosis [nuclear immunoreactivity for single-stranded DNA and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling assay] were conducted in EHYP-exposed Sprague Dawley male rats. Exposures consisted of up to14 d in an environmental chamber in which O(2) concentrations were cycled between 10 and 21% every 90 sec or 30 min during 12 hr of daylight. For the remaining 12 hr, EHYP rats breathed room air, while controls spent 14 d in room air. Although EHYP induced significant disruption of sleep architecture during the initial day of exposure, sleep patterns normalized thereafter. Marked increases in apoptosis occurred in the CA1 hippocampal region (sevenfold) and cortex (Cx; eightfold) after 1-2 d of EHYP but not in CA3 and were followed by decreases toward normoxic levels by 14 d. Double labeling for NMDA NR1 and c-fos revealed marked architectural disorganization in CA1 and Cx with increases in c-fos over time. Rats exposed to EHYP displayed significantly longer escape latencies and swim path lengths to escape a hidden platform during 12 training trials given over 2 d. Differences in the performances of EHYP and control rats, although reduced, persisted after 14 d of recovery. We conclude that EHYP is associated with marked cellular changes over time within neural regions associated with cognitive functions. Furthermore, EHYP impaired performance during acquisition of a cognitive spatial task without affecting sensorimotor function. Such changes may underlie components of the learning and memory impairments found in OSA.
Animals↗
Prenatal cigarette smoke exposure selectively alters protein kinase C and nitric oxide synthase expression within the neonatal rat brainstem.
Maternal smoking is a major risk factor for sudden infant death syndrome. Protein kinase C (PKC) and neuronal nitric oxide synthase (NOS) activities within the dorsocaudal brainstem (DB) mediate critical components of respiratory drive and could be implicated in SIDS. Thus, exposure to smoking during fetal life could modify the expression of these kinases in the DB. Rats were exposed to cigarette smoke or room air (Sham) from day 2 to 22 of pregnancy. Immunoblots of DB lysates at 2 days postnatally revealed no differences in PKC-alpha, PKC-beta, and endothelial NOS expression. However, PKC-gamma, PKC-delta, and neuronal NOS immunoreactivities were reduced in the cigarette smoke group. We conclude that gestational smoking is associated with selective reductions in PKC and NOS isoforms within the DB, which could decrease respiratory drive and lead to enhanced hypoxic vulnerability in infants of smoking mothers.
Animals↗
In vivo PDGF beta receptor activation in the dorsocaudal brainstem of the rat prevents hypoxia-induced apoptosis via activation of Akt and BAD.
Activation of platelet-derived growth factor receptor beta (PDGFR) within the caudal brainstem modulates the hypoxic ventilatory response. Since hypoxia does not induce apoptosis in the caudal brainstem, PDGFR could underlie such protective mechanism via a PI3 kinase-dependent phosphorylation of both Akt and BAD pathways. To further study this issue, caudal brainstem lysates were harvested from Sprague--Dawley rats during hypoxia (10% O(2)) after treatment with either vehicle or CGP 57148B (100 mg/kg), a selective blood-brain barrier-permeable PDGFR antagonist. Time-dependent increases in phosphorylated Akt occurred during hypoxia, peaking at 45' and lasting for up to 6 h, without parallel changes in total Akt protein. CGP 57148B attenuated Akt activation at all time points. Similarly, phosphorylation of BAD at serine136 but not at serine 112 occurred in the caudal brainstem as early as 15' of hypoxia, and was completely blocked by CGP 57148B. Furthermore, CGP 57148B treatment elicited significant increases in single-stranded DNA, caspase-like activity, and cleaved caspase 3 after 24 h of hypoxia that were absent in the caudal brainstem of hypoxic vehicle-treated animals. We conclude that PDGFR-dependent in vivo activation of both Akt and BAD during hypoxia prevents induction of apoptosis, and may contribute to the increased hypoxic tolerance of brainstem neurons.
Animals↗
Percutaneous image-guided needle biopsy in children--summary of our experience with 57 children.
BACKGROUND: Percutaneous image-guided needle biopsy in children has been slower to gain acceptance than in adults where it is regarded as the standard clinical practice in screening suspicious masses. OBJECTIVES: To report our experience with percutaneous image-guided needle biopsy in the pediatric population and assess its clinical use, efficacy and limitations. MATERIAL AND METHODS: Sixty-nine percutaneous image-guided needle biopsies were performed in 57 children. The age of the children ranged from 4 days to 14 years (mean 5.6 years). We used 16- to-20-gauge cutting-edge needles. Sixty-two biopsies were core-needle biopsies and 7 fine-needle aspiration biopsies. RESULTS: There were 50 malignant lesions, 10 benign lesions and 2 infectious lesions. In 55 (88.7 %) lesions the needle biopsy was diagnostic. In 7 (11.3 %) the biopsy was non-diagnostic and the diagnosis was made by surgery. Core-needle biopsy was diagnostic in 47 of 50 (94 %) of the malignant solid tumors. In 3 out of 5 children with lymphoma, an accurate diagnosis was obtained with needle aspiration. Seven children underwent a repeated core-needle biopsy, (5 for Wilms' tumor and 2 for neuroblastoma) that was diagnostic in all cases. All the biopsies were performed without complications. CONCLUSION: Percutaneous image-guided needle biopsy is a simple, minimally invasive, safe and accurate method for the evaluation of children with suspicious masses. These data suggest that image-guided needle biopsy is an excellent tool for diagnosing solid tumors in the pediatric population. Negative studies should be considered nondiagnostic and followed by excisional surgical biopsies when clinical suspicion of malignancy is high.
Adolescent↗
Morbidity of obstructive sleep apnea in children: facts and theory.
Sleep-disordered breathing (SDB) is a frequent, albeit underdiagnosed, problem in children. If left untreated, SDB may lead to substantial morbidities affecting multiple target organs and systems. This review provides a detailed and current description of the current status of our understanding of SDB-associated morbidity in children, and provides recommendations of future research directions necessary for increasing our knowledge and awareness on the short- and long-term consequences of SDB during childhood.
Adenoids↗
Chemoreceptive mechanisms elucidated by studies of congenital central hypoventilation syndrome.
Humans born with the condition of central hypoventilation during non-rapid eye movement sleep, termed congenital central hypoventilation syndrome (CCHS), invariably have absent or greatly diminished central hypercapnic ventilatory chemosensitivity. Genetic and pathological studies of CCHS may enable identification of the genes or areas of the central nervous system involved in the syndrome and thus implicated in central hypercapnic ventilatory chemosensitivity. Functional studies of CCHS permit a more quantitative assessment of the importance of ventilatory chemosensitivity in the regulation of breathing during wakefulness and sleep. The experimental evidence suggests that central hypercapnic ventilatory chemosensitivity is crucial in regulating alveolar ventilation during non-rapid eye movement sleep but not during rapid eye movement sleep or during many of the behaviors occurring during wakefulness. Presumably, other neural drives to breathe supervene to enable adequate ventilation. However, although physiological studies in CCHS subjects have been greatly instructive, their accurate interpretation will have to await future determination of the potential genetic and/or neuroanatomic basis of the syndrome.
Chemoreceptor Cells↗
Respiratory plasticity following intermittent hypoxia: developmental interactions.
Intermittent hypoxia (IH) is the most frequent form of hypoxia occurring in the developing mammal. On one hand, the maturational process of neural, mechanical, pulmonary, and sleep state-dependent factors will favor the occurrence of IH during early postnatal life. On the other hand, it has also become clear that hypoxia, even when short lasting, can modify subsequent respiratory responses to hypoxia and induce a variety of genes whose consequences will persist for much longer periods than the duration of the hypoxic stimulus itself, i.e., functional and adaptive plasticities. The dynamic interactions between the overall duration and recurring frequency of IH, the severity of IH, and the level of neural maturity at the time of IH will modify the ventilatory, metabolic, and cardiovascular responses to hypoxia. We propose that the earlier IH will occur in the developmental course the more likely that the physiological responses to an ulterior hypoxic challenge will be altered even into adulthood. At this point in time, a critical examination of the field would suggest that the short-term alterations of the hypoxic ventilatory response (HVR) of the developing mammal to IH are qualitatively similar to those of the adult and display a biphasic pattern, namely, initial enhancement of the HVR followed by a reduction in HVR. However, the short- and long-term effects of IH on the modulation of neurotransmitter release, receptor binding and expression, intracellular signaling cascades, transcriptional regulation, and gene expression as a function of animal maturity are almost completely unknown. Further delineation of such complex responses to IH may permit the formulation of interventional strategies aiming at reducing the overall vulnerability of the young infant and child to apnea and sudden death.
Animals↗
Brainstem nitric oxide tissue levels correlate with anoxia-induced gasping activity in the developing rat.
Gasping is an important mechanism for survival that appears to be developmentally modulated by the glutamate-nitric oxide (NO) pathway. However, the temporal characteristics of NO brain tissue levels during gasping are unknown. We hypothesized that during anoxia-induced gasping, the gasping frequency would be closely correlated with caudal brainstem tissue NO concentrations in developing rats. Brainstem and cortical tissue NO levels were measured during anoxia using a voltammetric electrode in adult rats and 5-day-old pups during control conditions and following pretreatment with the NMDA receptor antagonist MK-801 (1 mg/kg) or the neuronal NO synthase inhibitor 7-nitro-indazole (7-NI; 100 mg/kg). In young animals, NO tissue levels followed a triphasic trajectory coincident with gasp frequency which was markedly altered by MK-801 and 7-NI, albeit with preservation of gasp frequency-NO tissue level relationships. In adult rats, 40-fold higher NO tissue levels occurred and followed a monophasic trajectory coincident with gasp patterning. In the cortex, monophasic increases in NO levels occurred at all ages. We conclude that anoxia-induced gasping neurogenesis is modulated via NMDA-NO mechanisms in the developing rat. We postulate that higher NO brainstem concentrations may favor early autoresuscitation, but limit anoxic tolerance.
Aging↗
PDGF-beta receptor expression in the dorsocaudal brainstem parallels hypoxic ventilatory depression in the developing rat.
The temporal trajectory of platelet-derived growth factor (PDGF)-beta receptor activation within the dorsocaudal brainstem parallels that of the mild hypoxic ventilatory depression (HVD) seen in adult rats. We hypothesized that enhanced PDGF-beta receptor activity may account for the particularly prominent HVD of developing mammals. To study this issue, 2-, 5-, 10-, and 20-d-old rats underwent hypoxic challenges (10% O(2) for 30 min) after pretreatment with either vehicle (Veh) or the selective PDGF-beta receptor antagonist CGP57148B (intraperitoneal 100 mg/kg). The developmental characteristics and magnitude of the peak hypoxic ventilatory response (HVR) were not modified by the PDGF-beta receptor blocker. However, HVD was markedly attenuated by CGP57148B, and such effect, although still present, gradually abated with increasing postnatal age [p < 0.001, analysis of variance (ANOVA)]. Hypercapnic ventilatory responses were not affected by CGP57148B. The expression of PDGF-beta receptor in the dorsocaudal brainstem was assessed by immunoblotting and confirmed progressively decreasing expression with maturation. We conclude that PDGF-beta receptor activation during hypoxia is an important contributor to HVD at all postnatal ages but more particularly in the immature rat.
Animals↗
Snoring during early childhood and academic performance at ages thirteen to fourteen years.
OBJECTIVES: Obstructive sleep apnea syndrome in young children is associated with an adverse effect on learning. However, the long-term impact of sleep-disordered breathing (SDB) during early childhood on learning remains unknown. METHODS: Questionnaires were mailed to seventh and eighth graders attending public schools whose class ranking was either in the top 25% (high performance [HP]) or bottom 25% of their class (low performance [LP]), and who were matched for age, gender, race, school, and street of residence. Snoring frequency and loudness at 2 to 6 years of age, tonsillectomy and adenoidectomy (T&A) for snoring or recurrent infection, school grades, and parental smoking and snoring were assessed. RESULTS: The questionnaire response rate was 82.8%. Because of ongoing ring, 13 responders were excluded, such that 1588 questionnaires could be analyzed (797 in LP and 791 in HP group). Frequent and loud snoring during early childhood was reported in 103 LP children (12.9%) compared with 40 HP children (5.1%; odds ratio: 2.79; confidence interval: 1.88-4.15). Furthermore, 24 LP and 7 HP children underwent T&A for snoring (odds ratio: 3.40; confidence interval: 1.47-7.84), while 21 LP and 19 HP children required surgery for recurrent tonsillitis. CONCLUSIONS: Children with lower academic performance in middle school are more likely to have snored during early childhood and to require T&A for snoring compared with better performing schoolmates. These findings support the concept that SDB-associated neurocognitive morbidity may be only partially reversible or that a "learning debt" may develop with SDB during early childhood and hamper subsequent school performance.
Achievement↗
Objective sleepiness measures in pediatric obstructive sleep apnea.
OBJECTIVES: Excessive daytime sleepiness (EDS) occurs frequently in adult patients with obstructive sleep apnea (OSA). However, the incidence of EDS in children with OSA is unknown. METHODS: To determine overall daytime sleepiness in pediatric OSA, 54 children with OSA, 14 children with primary snoring (PS), and 24 controls (C) underwent an overnight diagnostic polysomnogram followed the next day by a multiple sleep latency test. RESULTS: The mean apnea index was 15.1 +/- 9.5 standard deviation in OSA, 1.1 +/- 0.5 in PS, and 0.1 +/- 0.3 in C. Mean sleep latencies were 23.7 +/- 3.0 minutes in C, 23.7 +/- 3.1 minute in PS, and 20.0 +/- 7.1 minute in OSA patients. However, only 7 children with OSA had mean sleep latencies <10 minutes. In addition, shorter sleep latencies were more likely to occur in more obese OSA patients and those with more severe apnea index, and oxyhemoglobin desaturation. CONCLUSIONS: Shortened sleep latencies occur in children with OSA, but EDS is infrequent and tends to develop among more severe and/or obese patients.
Case-Control Studies↗