Persistence of the biphasic ventilatory response to hypoxia in preterm infants

Martin, Richard J.; DiFiore, Juliann M.; Jana, Laura A.; Davis, Rebecca; Miller, Martha J.; Coles, Sharon K.; Dick, Thomas E.

doi:10.1016/s0022-3476(98)70391-9

Cited by 96 publications

(65 citation statements)

References 25 publications

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“…The greater depression of respiratory frequency in response to hypoxia in the lesioned pups mimics what we see in preterm babies (15). It is known from fetal and neonatal sheep experiments that descending inhibition to the medulla contributes to this phenomenon (18,19).…”

Section: Discussionsupporting

confidence: 62%

“…Two days later, ventilatory responses to hypoxia (8% O 2 , 92% N 2 ), were tested. The responses were measured using plethysmography for unrestrained, unanesthetized small rodents (Buxco Electronics, Troy, NY, U.S.A.), which is a modification of the body-box technique (15). Briefly, in the body-box technique, pressure changes caused by differences in the temperature of inhaled or exhaled air are sensed by a sensitive pressure transducer and recorded as a pressure curve.…”

Section: Methodsmentioning

confidence: 99%

“…The PVN, in turn, regulates respiratory drive (12). Also, arcuate neurons project directly to the dorsal medulla, an area that strongly influences the activity of respiration-regulating neurons of the medullary pre-Bötzinger complex (13)(14)(15)(16). Finally, the arcuate nucleus contains numerous leptin-responsive neurons, and hence may be a major site of the influence of leptin upon respiratory control (7,9).…”

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confidence: 99%

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The Basomedial Hypothalamus Modulates the Ventilatory Response to Hypoxia in Neonatal Rats

et al. 2003

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We sought to examine the role of the basomedial hypothalamus in the regulation of breathing in neonatal rats. Small basomedial hypothalamic lesions were produced by a lesioning agent, goldthioglucose, in 5-d-old male rat pups, and 2 d later, baseline ventilation and the ventilatory responses to hypoxia and hypercapnia were examined. When compared with vehicleinjected controls, goldthioglucose-lesioned rat pups had a significantly slower respiratory rate and longer expiratory time at baseline. Lesioned rats displayed an impaired increase in breathing frequency in response to hypoxia, and augmented increases in tidal volume and respiratory drive (the ratio of tidal volume to inspiratory time) during hypoxia relative to controls. Hypercapnic responses were not affected. These data demonstrate that cells in a restricted area of the hypothalamus specifically influence the respiratory response to hypoxia. It is well established that ventilatory responses to hypoxia are mediated by discrete neural pathways involving peripheral chemoreceptors, primary afferents, and brainstem respiratoryrelated neurons. The characteristics of the response, however, depend on complex interactions at multiple levels of the neuraxis, including suprapontine structures. Several studies have suggested that the caudal hypothalamus modulates responses to hypoxia and hypercapnia (1, 2). For example, one study showed that 21% of hypothalamic units are activated by hypoxia and 31% by hypercapnic loading (3). Furthermore, hypoxia and hypercapnia stimulate neurons in various hypothalamic nuclei (paraventricular, supraoptic, and dorsomedial) to synthesize the transcription-regulating protein Fos (4 -6). Binding of the adipocyte hormone leptin to receptors in either the hypothalamus or area postrema modulates respiration and may underlie the respiratory abnormalities observed in genetically obese rodents (7-9). Finally, electrolytic lesions that destroy extensive amounts of perifornical cells in the posterior hypothalamus enhance the ventilatory response to hypoxia (10). However, the role of these structures in regulating ventilatory responses to chemical drive is not well understood.Functional effects of relatively large electrolytic lesions of the hypothalamus are instructive, but are less helpful in pinpointing the precise location of hypothalamic cells critical for respiratory control. Likewise, unit recording or examination of Fos expression throughout the hypothalamus during hypoxia does not identify cells initiating a hypothalamic response to hypoxia because of multisynaptic projections among activated neuronal pools. These techniques also do not determine the functional role of hypothalamic cells in the regulation of respiratory responses to changes in chemical drive. One approach to this problem is to examine the effects of relatively restricted hypothalamic damage. This can be achieved via the systemic administration of a toxin, GTG, which diffuses into the hypothalamus via the permeable capillaries of the median eminence and which damages o...

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Section: Discussionsupporting

confidence: 62%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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The Basomedial Hypothalamus Modulates the Ventilatory Response to Hypoxia in Neonatal Rats

et al. 2003

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“…The characteristic biphasic ventilatory response to hypoxia persists for 4 to 6 weeks in preterm infants. 15 The central respiratory depression because of hypoxia is believed to prolong apnea and delay its recovery.…”

Section: Peripheral Chemoreceptors and Impaired Hypoxic Ventilatory Rmentioning

confidence: 99%

Apnea of prematurity: pathogenesis and management strategies

Mathew

2010

J Perinatol

110

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Apnea of prematurity (AOP) is a significant clinical problem manifested by an unstable respiratory rhythm reflecting the immaturity of respiratory control systems. This review will address the pathogenesis of and treatment strategies for AOP. Although the neuronal mechanisms leading to apnea are still not well understood, recent decades have provided better insight into the generation of the respiratory rhythm and its modulation in the neonate. Ventilatory responses to hypoxia and hypercarbia are impaired and inhibitory reflexes are exaggerated in the neonate. These unique vulnerabilities predispose the neonate to the development of apnea. Treatment strategies attempt to stabilize the respiratory rhythm. Caffeine remains the primary pharmacological treatment modality and is presumed to work through blockade of adenosine receptors A 1 and A 2 . Recent evidences suggest that A 2A receptors may have a greater role than previously thought. AOP typically resolves with maturation suggesting increased myelination of the brainstem.

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“…One factor potentially involved is the socalled hypoxic ventilatory depression, the fetal response to hypoxia that persists until ϳ36 weeks' gestation. 3 The exact pathophysiology mediating this fetal response is unknown, but 1 substance likely involved is creatine, which is a substrate in the regeneration of adenosine diphosphate to adenosine triphosphate via the creatine kinase reaction (phosphocreatine [PCr] ϩ adenosine 5Ј-diphosphate ϩ H ϩ 7 creatine ϩ adenosine 5Ј-triphosphate) during nonoxidative phosphorylation. 4,5 Neonatal mice whose dams were fed creatine (2 g/kg per day for 20 days) before delivery showed significant increases in amplitude and duration of hypoglossal bursts and in synaptic drive currents of single respiratory neurons during anoxia 6 and a reduced decrease in minute ventilation during exposure to Fio 2 of 0.1.…”

mentioning

confidence: 99%

Randomized, Controlled Trial of Oral Creatine Supplementation (Not Effective) for Apnea of Prematurity

et al. 2004

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ABSTRACT. Background. Hypoxic ventilatory depression in mice and muscle fatigue in adult humans are improved by creatine supplementation (CS). Because these issues may be operative in apnea of prematurity (AOP), we hypothesized that CS reduces episodes of hypoxemia and bradycardia in infants with AOP.Methods. Infants were eligible for this double-blind, controlled trial if gestational age was <32 weeks and AOP was severe enough to require treatment with caffeine. If they had >1 desaturation (pulse oximeter saturation [SpO 2 ] < 80%) or bradycardia (heart rate < two thirds of baseline) per hour in an initial 6-hour recording, they were randomized to a 2-week course of oral CS (200 mg/kg per day) or placebo (P). Infants then underwent 2 additional 6-hour recordings of breathing movements, nasal airflow, heart rate, pulse oximeter saturation (SpO 2 ) and pulse waveforms after 7 and 14 days of treatment. Urinary creatine excretion was measured also. Recordings were analyzed for the frequency of bradycardia and desaturation, the primary outcome parameter, as well as for apnea (>10 seconds), baseline heart and respiratory rate, and SpO 2 .Results. Of 38 infants enrolled, 34 completed the study (17 in each group). Median (range) gestational age at birth was 27 (25-30) vs 27 (25-30) weeks, and at study 29 (26 -36) vs 29 (27-33) weeks. Oral CS was well tolerated; no side effects were noted. Urinary creatine excretion was low in the P group (median: 27 mmol/mol of creatinine; range: 18 -102) and increased in the CS group (6949 mmol/mol of creatinine; range: 1427-11807). CS, however, had no effect on the combined rate of bradycardia and desaturation W ith decreasing use of mechanical ventilation in extremely low birth weight infants, apnea of prematurity (AOP) has become one of the most common problems in neonatal intensive care. AOP is defined as the recurrence of a variable combination of apnea, bradycardia, and desaturation, with the latter 2 components posing a potential risk to neurodevelopment. 1 Current therapy including methylxanthines, nasal continuous positive airway pressure (CPAP), and doxapram often fails to eradicate symptoms. 2 The pathophysiology of AOP is incompletely understood. One factor potentially involved is the socalled hypoxic ventilatory depression, the fetal response to hypoxia that persists until ϳ36 weeks' gestation. 3 The exact pathophysiology mediating this fetal response is unknown, but 1 substance likely involved is creatine, which is a substrate in the regeneration of adenosine diphosphate to adenosine triphosphate via the creatine kinase reaction (phosphocreatine [PCr] ϩ adenosine 5Ј-diphosphate ϩ H ϩ 7 creatine ϩ adenosine 5Ј-triphosphate) during nonoxidative phosphorylation. 4,5 Neonatal mice whose dams were fed creatine (2 g/kg per day for 20 days) before delivery showed significant increases in amplitude and duration of hypoglossal bursts and in synaptic drive currents of single respiratory neurons during anoxia 6 and a reduced decrease in minute ventilation during exposure to Fio 2 o...

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Persistence of the biphasic ventilatory response to hypoxia in preterm infants

Cited by 96 publications

References 25 publications

The Basomedial Hypothalamus Modulates the Ventilatory Response to Hypoxia in Neonatal Rats

The Basomedial Hypothalamus Modulates the Ventilatory Response to Hypoxia in Neonatal Rats

Apnea of prematurity: pathogenesis and management strategies

Randomized, Controlled Trial of Oral Creatine Supplementation (Not Effective) for Apnea of Prematurity

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