Neonatal Respiration Research Articles

Effect of thyroid status in the perinatal period on oxidative capacities and mitochondrial respiration in porcine liver and skeletal muscle.

Regulatory thermogenesis is reduced in newborn piglets which have been made hypothyroid during late gestation by giving the sow a high glucosinolate rapeseed diet (test animals). Thereafter, the progressive increase in thermogenic capacity parallels the development of a marked postnatal hyperthyroid state. To explain these effects of thyroid hormones at the tissue and mitochondrial levels, we have examined both liver and skeletal muscle to determine possible underlying changes in (i) tissue oxidative capacities (cytochrome oxidase (CO) activity), between 80 d of gestation and 48 h after birth, and (ii) mitochondrial content and respiratory capacities at 24 h of life. In control piglets, CO activity increased sharply during late gestation and the first 2 d of life in liver and rhomboideus (RH) muscle (P < 0.01), whereas only a prenatal increase was observed in longissimus dorsi (LD) muscle. Test fetuses were hypothyroid and had lower CO activities than controls during late gestation in RH muscle (P < 0.06, at 110 d of gestation; P < 0.08, at birth) and in liver (P < 0.001, at birth). The postnatal increase in CO activity in RH muscle and liver was higher (P < 0.05) in test than in control piglets, and as a result the difference between the 2 groups was not significant by 24-48 h of life. There was no effect of treatment on LD muscle. At 24 h, hyperthyroid test piglets had lower amounts of mitochondrial proteins than controls (P < 0.05) in all three tissues, possibly reflecting reduced mitochondrial protein synthesis during fetal life and suggesting that high postnatal T3 levels did not bring about major increases in protein synthesis within 24 h. However, test piglets exhibited higher rates of mitochondrial respiration than controls in liver and RH muscle, as shown by increases in State III and FCCP-stimulated respirations (P < 0.05), and mitochondrial CO and creatine kinase activities (P < 0.05). In RH muscle, both subsarcolemmal and intermyofibrillar mitochondria showed the same trends. No changes were observed in LD muscle. Our results describe for the first time the effect of thyroid hormones on perinatal oxidative capacities and neonatal mitochondrial respiration in liver and skeletal muscle of the pig, through both the short-term regulation of mitochondrial respiration and the long-term control of mitochondrial biogenesis. The differential sensitivity of LD and RH muscles to thyroid hormones is discussed.

Opioid depression of respiration in neonatal rats.

1. The effects of opioid receptor agonists and antagonists on the breathing pattern of neonatal rats were studied. Three experimental approaches were taken. In the first approach, the effects of opioid agonists and antagonists on the spontaneous respiratory neural activity generated by brainstem-spinal cords isolated from neonatal rats aged 0-4 days postnatal (P0-4) maintained in vitro were studied. Secondly, similar studies were performed utilizing medullary slice preparations consisting of respiratory rhythm-generating regions (pre-Bötzinger complex). Thirdly, whole-body plethysmographic recordings were obtained from unanaesthetized neonatal (P0-18) rats before and after I.P. administration of opioid-receptor agonists and antagonists. 2. The mu-receptor agonists morphiceptin and DAGO (Tyr-D-Ala-Gly-[NMePhe]-Gly-ol), when added either to the solutions bathing the brainstems of neonatal rat brainstem-spinal cord preparations or bathing the medullary slice preparations, resulted in a naloxone-reversible, dose-dependent decrease in the frequency of respiratory rhythmic discharge. 3. The respiratory burst frequency and amplitude in vitro were unaffected by the addition of the delta-opioid receptor agonist DPDPE ([D-pen2,5]-enkephalin) and the kappa-opioid receptor agonist U50488 (trans-[+]-3,4-dichloro-N-methyl-N-(2-[1- pyrrolidinyl]cyclohexyl) benzene-acetamide) or the opioid receptor antagonist naloxone. 4. Intraperitoneal administration of the mu-opioid receptor agonist fentanyl resulted in a naloxone-reversible, dose-dependent decrease in the frequency and amplitude of breathing of unanaesthetized neonatal rats (P0-P10). I.P. administration of the delta-opioid receptor agonist DPDPE did not affect breathing of neonatal rats until the second week postnatally. 5. We conclude that opioids suppress the frequency of neonatal rat respiration by acting via mu-opioid receptors located within regions of the ventral medulla containing respiratory rhythm-generating centres (the pre-Bötzinger complex). delta-Opioid receptor activation does not affect breathing in neonatal rats until approximately the second week postnatally.

Air-flow sensor and humidity sensor application to neonatal infant respiration monitoring

A study is conducted on a newly designed neonatal infant respiration-monitoring system for detecting the respiratory situation of premature infants. Two kinds of tiny high-quality sensors, a humidity sensor and an air-flow sensor, and an MCS-51 (Intel) single-chip processor are used, which enable both the humidity values to be sensed and displayed quantitatively and the breathing rate monitored with user-settable alarms.

Neonatal lethality associated with respiratory distress in mice lacking cytochrome P450 1A2.

Cytochrome P450 1A2 (CYP1A2) is a constitutively expressed hepatic enzyme that is highly conserved among mammals. This protein is primarily involved in oxidative metabolism of xenobiotics and is capable of metabolically activating numerous procarcinogens including aflatoxin B1, arylamines, heterocyclic amine food mutagens, and polycylic aromatic hydrocarbons. Expression of CYP1A2 is induced after exposure to certain aromatic hydrocarbons (i.e., 2,3,7,8-tetrachlorodibenzo-p-dioxin). Direct evidence for a role of CYP1A2 in any physiological or developmental pathway has not been documented. We now demonstrate that mice homozygous for a targeted mutation in the Cyp1a-2 gene are nonviable. Lethality occurs shortly after birth with symptoms of severe respiratory distress. Mutant neonates display impaired respiratory function associated with histological signs of lung immaturity, lack of air in alveoli at birth, and changes in expression of surfactant apoprotein in alveolar type II cells. The penetrance of the phenotype is not complete (19 mutants survived to adulthood out of 599 mice). Surviving animals, although lacking expression of CYP1A2, appear to be normal and are able to reproduce. These findings establish that CYP1A2 is critical for neonatal survival by influencing the physiology of respiration in neonates, thus offering etiological insights for neonatal respiratory distress syndrome.

Multivariate autoregressive modelling combined with transcephalic electrical impedance: method to relate neonatal systemic circulation and respiration to cerebral circulation.

We studied the pulsatile component of cerebral circulation with transcephalic electrical impedance (delta Z) in six preterm newborns, three of whom had severe cerebral bleeding, peri-intraventricular haemorrhage (PIVH). The transcephalic electrical impedance delta Z signal, ECG, arterial blood pressure, (aBP) and respirogram were recorded on analogue magnetic tape for 30 min. Artefact-free stationary segments (lasting for 2 min) of the four signals were digitised. A digital multivariate autoregressive (MAR) model was used to study frequency-specific variability in the signals and to quantify interrelations between the variabilities of delta Z, HR, aBP and respiratory signals. MAR modelling describes a system where all the signals simultaneously explain each other. The inherent variability of delta Z was lower and the influences of respiration and aBP on delta Z significantly greater in infants with severe PIVH than in controls. These changes were observed at high frequencies corresponding to respiration and heart rate. This may be interpreted as a marker of pressure passivism in the cerebral circulation following PIVH. We conclude that in preterm babies the application of MAR modelling, together with transcephalic impedance, may be a new, helpful and quantitative method for the study of simultaneous interrelations between variables of cerebral and systemic circulations and respiration.

Sulfide-induced perturbations of the neuronal mechanisms controlling breathing in rats

The effects of sulfide on neonatal rat respiration were studied. Two in vitro experimental models were utilized: the isolated brain stem-spinal cord preparation and the medullary slice preparation containing respiratory rhythm-generating regions from neonatal rats. Plethysmographic measurements of the effects of sulfide on the breathing patterns of unanesthetized neonatal rats were also made to compare the sensitivities of neonatal and adult rats to sulfide toxicity. In vitro, sulfide acted at sites within the ventrolateral medulla to depress the frequency of respiratory rhythmic discharge by approximately 50-60%. However, the neuronal network underlying respiratory rhythmogenesis continued to function in the presence of concentrations of sulfide far beyond those deemed to be lethal in vivo. Intraperitoneal administration of sulfide caused a dose-dependent decrease in the frequency and amplitude of breathing of neonatal rats of all ages (0-19 days postnatal), although the sensitivity to sulfide increased with age. We hypothesize that the rapid suppression of breathing caused by sulfide is due to changes in neuronal excitability within respiratory rhythm-generating centers rather than, as previously hypothesized, to perturbations of cellular oxidative metabolism.

Metabolism during normoxia, hyperoxia, and recovery in newborn rats.

Aerobic metabolism (oxygen consumption, VO2, and carbon dioxide production, VCO2) has been measured in newborn rats at 2 days of age during normoxia, 30 min of hyperoxia (100% O2) and an additional 30 min of recovery in normoxia at ambient temperatures of 35 degrees C (thermoneutrality) or 30 degrees C. In normoxia, at 30 degrees C VO2 was higher than at 35 degrees C. With hyperoxia, VO2 increased in all cases, but more so at 30 degrees C (+20%) than at 35 degrees C (+9%). Upon return to normoxia, metabolism readily returned to the prehyperoxic value. The results support the concept that the normoxic metabolic rate of the newborn can be limited by the availability of oxygen. At temperatures below thermoneutrality the higher metabolic needs aggravate the limitation in oxygen availability, and the positive effects of hyperoxia on VO2 are therefore more apparent.

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.

Embryologic and Physiologic Basis of Neonatal Respiration

Development of the respiratory system requires the integration of anatomic, physiologic, and biochemical factors. This process is described from 5 weeks gestation until establishment of respirations after birth.

Disposition of Intrapartum Narcotic Analgesics in Monkeys

Maternal-fetal disposition and neonatal respiratory depressant effect of narcotic analgesics were studied by administration of meperidine (2 mg/kg, IV) or alfentanil (IV infusion, 0.1 mg/kg total dose) during labor in rhesus monkeys. Fetal/maternal plasma ratios were lower for alfentanil, the more highly protein-bound drug (fetal/maternal ratio 0.20 at birth versus 0.46 for meperidine). However, elimination of alfentanil was delayed in the neonate. Indeed, plasma concentrations of alfentanil increased during the first 2 postnatal hours, indicating a compartmental shift from tissues to circulation in the neonate. As regards respiratory depression, six of ten narcotic-treated monkeys had suboptimal (less than 60 breath/min) respiratory rates at birth. Respiratory rate was negatively correlated with cord vein normeperidine and meperidine levels; the strongest correlation was with normeperidine (r = -0.84, P less than 0.01). Neonatal normeperidine elimination in the postnatal period was prolonged, as has also been observed in humans. These studies serve as a basis for comparing the neonatal neurobehavioral effects of the two analgesics and support the use of the rhesus monkey as an animal model to further understanding of the effects of narcotic analgesics on neonatal respiration.

“Hypoxic depression” of respiration in neonates mediated by adenosine? : H. Lagercrantz, M. Rumold, I. Dahlin, B.B. Fredholm and I. Moss, Karolinska Institute, Stockholm, Sweden.

“Hypoxic depression” of respiration in neonates mediated by adenosine? : H. Lagercrantz, M. Rumold, I. Dahlin, B.B. Fredholm and I. Moss, Karolinska Institute, Stockholm, Sweden.

Ventilatory effect of an adenosine analogue in unanesthetized rabbits during development.

The effect of an adenosine analogue N6-L-(R-phenylisopropyl)adenosine (R-PIA) on respiration was studied in rabbit pups (1-8 days old). Respiration was monitored by a noninvasive barometric method during natural sleep. The adenosine analogue was given by an indwelling intraperitoneal catheter. R-PIA given in a dose of 0.1 mumol/kg (380 micrograms/kg) body wt caused a decrease of the ventilation. The respiratory decrease could be reversed or prevented by pretreatment with theophylline (10 mg/kg). R-PIA caused a considerably more pronounced effect in 1- to 3-day-old animals than in 8-day-old animals. This effect was seen both when the ambient temperature was held at 28 (P less than 0.01) and 32 degrees C (P less than 0.05). Determination of R-PIA receptors in whole brains of rabbit pups of various ages showed that R-PIA bound with higher affinity to membranes from newborn animals (Kd 0.53 nM) than older animals (Kd 0.7-1.26). Since adenosine is released during hypoxia, it may be involved in "hypoxic depression" of respiration in neonates and apnea of prematurity. This might also explain the potent therapeutic effect of the adenosine antagonist theophylline on recurrent apnea in preterm infants.

Effects of hyperoxia on ventilatory and metabolic rates of newborn mice

Newborn mammals of medium or large sized species have ventilatory rates, expressed per kg body weight, larger than adults of corresponding size, while newborns of the smallest species do not. We hypothesized that the oxygen consumption of the smallest newborns is limited by the supply of oxygen and reasoned that if this were the case, an increase in P O 2 of the inspired air should decrease their ventilation/oxygen consumption (V̇/V̇ O 2 ) ratio. We exposed 1–2 days old newborn mice for 5 min to 21% O 2 in N 2 or 100% O 2, then measured their breathing pattern, by flow plethysmography, and V̇ O 2 with an isovolume closed system. During hyperoxia the V̇ E/V̇ O 2 ratio dropped in average 36%, since V̇ E decreased in 14 out of 18 animals and V̇ O 2 increased in all the animals tested. The drop in V̇ E was due to a prolongation of the expiratory time, with no changes in inspiratory time or tidal volume. During expiration, interruptions of the expiratory flow and tendency to maintain the lung inflated, a characteristic of neonatal respiration, were more pronounced with 100% O 2 than 21% O 2 breathing. We conclude that the resting metabolic rate of newborn mice is limited by the supply of oxygen; when P O 2 is raised, metabolism increases and ventilatory rate decreases in favor of a breathing pattern aimed to preserve lung volume elevated.

1844 EFFECT OF PGE2 ON CONTROL OF BREATHING IN THE NEONATAL PIGTET

Prostaglandins (PG) and cyclo-oxygenase inhibitors influence fetal and neonatal respiration but the exact mechanism of this action is unknown. We evaluated the effects of PGE2 on control of breathing in 7 neonatal pigs (X ± SD; age 3.7±1.3 days; wt. 1.39±0.3 kg) sedated with PO Chloral Hydrate. Minute ventilation (VE) and airway occlusion pressure (Pocc) were measured in room air (RA), 5% CO2 and 10% O2 before and after 15-20 min. of PGE2 infusion ( 1 μug/kg/min.) Results were (X ± SD): PGE2 produced a depression of minute ventilation and ventilatory response to CO2 but did not alter the ventilatory response to 10 min. of hypoxia. Two animals developed apnea immediately after decreasing the FiO2 during PG infusion. Airway occlusion pressure with 5% CO2 was also lower during PG infusion than basal. Lung compliance and resistance did not change with PG. These results indicate that PGE2 reduces ventilation by central respiratory depression. While in some animals PGE2 may alter the immediate response to hypoxemia resulting in apnea, it does not change the ventilatory response to steady state hypoxemia.

1343 DETERMINANTS OF THE ONSET OF BREATHING AT BIRTH

We used mechanical ventilation of the fetal lung in utero to alter fetal bleed gases and thus separate the influences of PO2 and PCO2 on the onset of extrauterine breathing. Acute experiments: 7 pregnant sheep were operated under spinal anesthesia at 140-145 days' GA. An endotracheal tube, connecting tubes to the ventilator and a carotid artery catheter were placed in the fetus under local anesthesia, and the uterus was closed. Mechanical ventilation was started using O2, N2 and CO2 to achieve the desired bleed gas pattern. After 2 h the uterus was reopened, the fetus delivered, the umbilical cord clamped and the fetus placed either in a 40°C saline bath or on a cold table. Mechanical ventilation was stopped 2 min after delivery and the time to onset of breathing was observed. Chronic: Fetal electrodes, vascular catheters, endotracheal and ventilator tubes and an inflatable occluder on the umbilical cord were placed in 2 pregnant sheep at 127 days' GA. The fetuses were ventilated in utero 5 or irore days later with O2 or N2 ± CO2. The ventilator was stopped, the cord occluded, and the time to onset of breathing (diaphragm EMG) recorded: Results are given in the table. Conclusions: 1. Cold and hypercapnia are important stimuli for the onset of neonatal respiration. 2. Hypoxia depresses breathing at this time. 3. Cord clamping without change in bleed gases does not result in breathing.

Effect of a single breath of 100% oxygen on respiration in neonates during sleep

To determine the effect of a single breath of 100% O2 on ventilation, 10 full-term [body wt 3,360 +/- 110 (SE) g, gestational age 39 +/- 0.4 wk, postnatal age 3 +/- 0.6 days] and 10 preterm neonates (body wt 2,020 +/- 60 g, gestational age 34 +/- 2 wk, postnatal age 9 +/- 2 days) were studied during active and quiet sleep states. The single-breath method was used to measure peripheral chemoreceptor response. To enhance response and standardize the control period for all infants, fractional inspired O2 concentration was adjusted to 16 +/- 0.6% for a control O2 saturation of 83 +/- 1%. After 1 min of control in each sleep state, each infant was given a single breath of O2 followed by 21% O2. Minute ventilation (VE), tidal volume (VT), breathing frequency (f), alveolar O2 and CO2 tension, O2 saturation (ear oximeter), and transcutaneous O2 tension were measured. VE always decreased with inhalation of O2 (P less than 0.01). In quiet sleep, the decrease in VE was less in full-term (14%) than in preterm (40%) infants (P less than 0.001). Decrease in VE was due primarily to a drop in VT in full-term infants as opposed to a fall in f and VT in preterm infants (P less than 0.05). Apnea, as part of the response, was more prevalent in preterm than in full-term infants. In active sleep the decrease in VE was similar both among full-term (19%) and preterm (21%) infants (P greater than 0.5). These results suggest greater peripheral chemoreceptor response in preterm than in full-term infants, reflected by a more pronounced decrease in VE with O2. The results are compatible with a more powerful peripheral chemoreceptor contribution to breathing in preterm than in full-term infants.

Clinical Significance of Fetal Breathing Movement and Neonatal Respiration Detected by impedance Method

Clinical Significance of Fetal Breathing Movement and Neonatal Respiration Detected by impedance Method

Systemic Analgesia During Labor

Investigators in the fields of neonatology, obstetrics, and anesthesiology have increasingly directed their efforts to identifying the effects of analgesic agents administered to parturients in labor. This article examines the recent literature on the effects of systemic analgesia on the uterus, fetus, and neonate when these agents are administered to the mother during labor. Special attention is paid to the distribution and disposition of drugs administered to the parturient and to the effects of these drugs on maternal uterine activity, fetal heart rate variability, acid-base balance, neonatal respiration, and neurobehavior.

Neonatal respiration, feeding and neurobehavioural state

The effects on mature newborn have been compared at 0.5, 4, 8 12 24 and 48 hr after birth, of maternally administered epidural bupivacaine (11 babies) or pethidine (18 babies) or pethidine reversed by naloxone administered intramuscularly to the newborn (15 babies). Bupivacaine (mean dose 130 mg) had less effect that pethidine (mean dose 183.3 mg) on alveolar carbon dioxide tension (PACO2) at 0.5 hr after birth, but had a similar effect to pethidine on feeding, elicited reflexes and produced more depression of muscle tone up to 48 hr. Bupivacaine had more effect on PACO2 feeding measures, elicited reflexes and muscle tone at almost all examination periods than pethidine (mean dose 157.0 mg) reversed by naloxone (200 micrograms intramuscularly). Except at delivery, the effects of bupivacaine or pethidine on respiration and feeding up to 48 hr after birth were similar. There were more signs of depression with both drugs than when pethidine had been reversed by naloxone.

Fetal and maternal metabolism of prostaglandin F 2α in the guinea pig

Metabolism of prostaglandin F 2α (PGF 2α was studied with both qualitative and quantitative techniques in liver, kidney and lung of fetal and maternal guinea pigs at term. In the pregnant guinea pigs 15-hydroxyprostaglandin dehydrogenase (PGDH) activities were highest in the kidney, followed by the lung and then by the liver. In fetuses PGDH activity was highest in the liver, followed in decreasing order by kidney and lung. The kidneys and lungs of the mothers showed a 6- to 10-fold higher PGDH activity than those of the litter ( P < 0.005), but the mean PGDH activity of liver was lower in the mothers than in the fetuses. It is suggested that the liver may play a major role in prostaglandin metabolism during fetal life, and may fulfil part of the function reserved to the lung during adult life. Maternal and fetal lungs differed greatly in their handling of PGF 2α. This was not due to a difference in aeration, for the differences in the metabolism of PGF 2α between mother and litter increased when well-aerated neonatal lungs were considered instead of non-aerated fetal lungs. The observed differences in enzyme activity between fetal and neonatal lungs add yet another dimension to the role of prostaglandins in the establishment of neonatal respiration.