Altered 5-HT2A/C receptor binding in the medulla oblongata in the sudden infant death syndrome (SIDS): Part II. Age-associated alterations in serotonin receptor binding profiles within medullary nuclei supporting cardiorespiratory homeostasis.

The failure of chemoreflexes, arousal, and/or autoresuscitation to asphyxia may underlie some sudden infant death syndrome (SIDS) cases. In Part I, we showed that some SIDS infants had altered 5-hydroxytryptamine (5-HT)2A/C receptor binding in medullary nuclei supporting chemoreflexes, arousal, and autoresuscitation. Here, using the same dataset, we tested the hypotheses that the prevalence of low 5-HT1A and/or 5-HT2A/C receptor binding (defined as levels below the 95% confidence interval of controls-a new approach), and the percentages of nuclei affected are greater in SIDS versus controls, and that the distribution of low binding varied with age of death.

Altered 5-HT2A/C receptor binding in the medulla oblongata in the sudden infant death syndrome (SIDS): Part I. Tissue-based evidence for serotonin receptor signaling abnormalities in cardiorespiratory- and arousal-related circuits.

The sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality in the United States, is typically associated with a sleep period. Previously, we showed evidence of serotonergic abnormalities in the medulla (e.g.

Does the RAM Cannula Provide Continuous Positive Airway Pressure as Effectively as the Hudson Prongs in Preterm Neonates?

Objective: To compare the level of continuous positive airway pressure (CPAP) delivered by the RAM cannula system (Neotech, Valencia, CA) with that delivered by a traditional CPAP nasal delivery interface (Hudson prongs; Hudson-RCI, Temecula, CA) in preterm infants with respiratory distress.

Methods: This was a crossover intervention study in a convenience sample of preterm infants with respiratory distress requiring treatment with CPAP. We measured the mean intraoral (pharyngeal) pressure, which approximates the applied CPAP level, using both the RAM cannula and Hudson prongs.

Does Diaphragmatic Electrical Activity in Preterm Infants Predict Extubation Success?

Background: Despite many advances in respiratory care and mechanical ventilation, neonatologists lack an objective tool to aid in decision making for timely extubation. Electrical activity of the diaphragm (EA), a measure of neural respiratory drive and inspiratory load, may be a useful predictor of extubation success in preterm neonates. The objective of this work was to investigate whether peak EA could distinguish successful versus failed extubation in mechanically ventilated preterm infants.

Caffeine decreases intermittent hypoxia in preterm infants nearing term-equivalent age.

Objective: To determine whether intermittent hypoxia (IH) persisting after 36 weeks postmenstrual age (PMA) can be attenuated using caffeine doses sufficient to maintain caffeine concentrations >20 μg ml.

Study Design: Twenty-seven infants born <32 weeks were started on caffeine citrate at 10 mg kg day when clinical caffeine was discontinued. At 36 weeks PMA, the dose was increased to 14 or 20 mg kg day divided twice a day (BID) to compensate for progressively increasing caffeine metabolism.

Early postnatal exposure to intermittent hypoxia in rodents is proinflammatory, impairs white matter integrity, and alters brain metabolism.

BackgroundPreterm infants are frequently exposed to intermittent hypoxia (IH) associated with apnea and periodic breathing that may result in inflammation and brain injury that later manifests as cognitive and executive function deficits. We used a rodent model to determine whether early postnatal exposure to IH would result in inflammation and brain injury.MethodsRat pups were exposed to IH from P2 to P12.

Salivary caffeine concentrations are comparable to plasma concentrations in preterm infants receiving extended caffeine therapy.

Aims: Caffeine concentrations in preterm infants are usually measured in the blood. However, salivary assays may provide a valid and practical alternative. The present study explored the validity and clinical utility of salivary caffeine concentrations as an alternative to blood concentrations and developed a novel plasma/salivary caffeine distribution model.

Eliminating medullary 5-HT neurons delays arousal and decreases the respiratory response to repeated episodes of hypoxia in neonatal rat pups.

Arousal from sleep is a critical defense mechanism when infants are exposed to hypoxia, and an arousal deficit has been postulated as contributing to the etiology of the sudden infant death syndrome (SIDS). The brainstems of SIDS infants are deficient in serotonin (5-HT) and tryptophan hydroxylase (TPH) and have decreased binding to 5-HT receptors. This study explores a possible connection between medullary 5-HT neuronal activity and arousal from sleep in response to hypoxia.

Impaired arousal in rat pups with prenatal alcohol exposure is modulated by GABAergic mechanisms.

Prenatal alcohol exposure (PAE) increases the risk for The Sudden Infant Death Syndrome (SIDS) in human infants. In rat pups, the arousal response to hypoxia is modulated by medullary raphe GABAergic mechanisms. We hypothesized that arousal to hypoxia is impaired by PAE, and is associated with an increase in medullary GABA and enhanced GABAergic activity.

Assigning cause for sudden unexpected infant death.

We have reached a conundrum in assigning cause of death for sudden unexpected infant deaths. We summarize the discordant perspectives and approaches and how they have occurred, and recommend a pathway toward improved consistency. This lack of consistency affects pediatricians and other health care professionals, scientific investigators, medical examiners and coroners, law enforcement agencies, families, and support or advocacy groups.

Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial.

Importance: Preterm infants have immature respiratory control and resulting intermittent hypoxia (IH). The extent of IH after stopping routine caffeine treatment and the potential for reducing IH with extended caffeine treatment are unknown.

Objectives: To determine (1) the frequency of IH in premature infants after discontinuation of routine caffeine treatment and (2) whether extending caffeine treatment to 40 weeks' postmenstrual age (PMA) reduces IH.

The carotid body and arousal in the fetus and neonate.

Arousal from sleep is a major defense mechanism in infants against hypoxia and/or hypercapnia. Arousal failure may be an important contributor to SIDS. Areas of the brainstem that have been found to be abnormal in a majority of SIDS infants are involved in the arousal process.

Developmental profiles of infant EEG: overlap with transient cortical circuits.

Objective: To quantify spectral power in frequency specific bands and commonly observed types of bursting activities in the EEG during early human development.

Methods: An extensive archive of EEG data from human infants from 35 to 52 weeks postmenstrual age obtained in a prior multi-center study was analyzed using power spectrum analyses and a high frequency burst detection algorithm.

Results: Low frequency power increased with age; however, high frequency power decreased from 35 to 45 weeks.

Arousal from sleep in response to intermittent hypoxia in rat pups is modulated by medullary raphe GABAergic mechanisms.

Arousal is an important defense against hypoxia during sleep. Rat pups exhibit progressive arousal impairment (habituation) with multiple hypoxia exposures. The mechanisms are unknown.

Reversible blunting of arousal from sleep in response to intermittent hypoxia in the developing rat.

Arousal is an important survival mechanism when infants are confronted with hypoxia during sleep. Many sudden infant death syndrome (SIDS) infants are exposed to repeated episodes of hypoxia before death and have impaired arousal mechanisms. We hypothesized that repeated exposures to hypoxia would cause a progressive blunting of arousal, and that a reversal of this process would occur if the hypoxia was terminated at the time of arousal.

The role of CO(2) and central chemoreception in the control of breathing in the fetus and the neonate.

Central chemoreception is active early in development and likely drives fetal breathing movements, which are influenced by a combination of behavioral state and powerful inhibition. In the premature human infant and newborn rat ventilation increases in response to CO(2); in the rat the sensitivity of the response increases steadily after ∼P12. The premature human infant is more vulnerable to instability than the newborn rat and exhibits periodic breathing that is augmented by hypoxia and eliminated by breathing oxygen or CO(2) or the administration of respiratory stimulants.

The brainstem and serotonin in the sudden infant death syndrome.

The sudden infant death syndrome (SIDS) is the sudden death of an infant under one year of age that is typically associated with sleep and that remains unexplained after a complete autopsy and death scene investigation. A leading hypothesis about its pathogenesis is that many cases result from defects in brainstem-mediated protective responses to homeostatic stressors occurring during sleep in a critical developmental period. Here we review the evidence for the brainstem hypothesis in SIDS with a focus upon abnormalities related to the neurotransmitter serotonin in the medulla oblongata, as these are the most robust pathologic findings to date.

5-HT2A receptors are concentrated in regions of the human infant medulla involved in respiratory and autonomic control.

The serotonergic (5-HT) system in the human medulla oblongata is well-recognized to play an important role in the regulation of respiratory and autonomic function. In this study, using both immunocytochemistry (n=5) and tissue section autoradiography with the radioligand (125)I-1-(2,5-dimethoxy-4-iodo-phenyl)2-aminopropane (n=7), we examine the normative development and distribution of the 5-HT(2A) receptor in the human medulla during the last part of gestation and first postnatal year when dramatic changes are known to occur in respiratory and autonomic control, in part mediated by the 5-HT(2A) receptor. High 5-HT(2A) receptor binding was observed in the dorsal motor nucleus of the vagus (preganglionic parasympathetic output) and hypoglossal nucleus (airway patency); intermediate binding was present in the nucleus of the solitary tract (visceral sensory input), gigantocellularis, intermediate reticular zone, and paragigantocellularis lateralis.