No abstract

The dynamic pattern of fetal breathing was studied in 17 fetal lambs with chronically implanted electromyographic electrodes in the diaphragm. The instantaneous breathing rate time series appeared similar on different time scales, with clusters of faster breathing rates interspersed with periods of relative quiescience, suggesting self-similarity. Distribution histograms of the interbreath intervals (IBIs) showed log-normal distribution for IBIs less than 1 s and inverse power-law distribution for IBIs greater than 1 s. The ratio of log-normal distribution to power-law distribution varied from approximately 2 at 102 days to approximately 30 by 130 days of gestation. Fast Fourier transform of the breathing rate time series revealed 1/f beta power spectra for all animals, with beta increasing linearly from 0.43 to 0.88 between 102 and 139 days. Studies in the newborn lamb showed further maturation in both the distribution characteristics of the IBIs, as well as in the 1/f power spectra, with beta approaching 1.0 at 2 days after birth. The inverse power-law relationship in the distribution of the IBIs, together with the 1/f beta power spectra, indicate scale invariance and suggest that fractal mechanisms are involved in the regulation of fetal breathing.

Recent evidence suggests that administration of low doses of morphine causes respiratory stimulation, along with a more active electroencephalogram (EEG) in the fetal lamb. The present study used selective opioid agonists and antagonists to determine the role mu 1- and delta-opioid receptor subtypes play in the response as well as determine if endogenous opioid peptides exert a tonic influence at the mu 1- and delta-opioid receptors to maintain normal EEG and respiratory activity under control, physiological conditions. Both morphine (2.5 mg/h iv) and [D-Pen2,D-Pen5]enkephalin (DPDPE) (46 nmol/h icv) resulted in a significant activation of fetal EEG, which was blocked by naloxonazine (NALZ, mu 1-opioid antagonist) and naltrindole (NTI, delta-opioid antagonist), respectively. Administration of NALZ alone, but not NTI, resulted in a slowing of the EEG. Morphine and [D-Ala2]deltorphin I (0.36 nmol/h icv) significantly increased breath number and were blocked by NALZ and NTI respectively. Both NALZ and NTI alone resulted in a reduction in breath number. These results suggest that the activation of the delta- or mu 1-opioid receptors will stimulate fetal respiratory and EEG activity. Furthermore, the endogenous opioids play a tonic role at both the delta- and mu 1-opioid receptors in the regulation of respiratory timing and EEG activity.

The mechanism of action of low doses of morphine on breathing dynamics in the fetus was studied in 16 fetal lambs with chronically implanted electromyographic electrodes in the diaphragm. Morphine (0.15-2.5 mg/h) caused a significant dose-dependent increase in the number of diaphragmatic bursts per hour, with either an increase or no change in instantaneous breathing rate. There was also a significant dose-related increase in the continuity of the breathing pattern, as indicated by a decrease in the number of apneas per hour, and an increase in epoch duration. Morphine also had a significant effect on the stability of the breathing pattern, with an increase in the percentage of bursts that occurred in stable clusters. All of these effects were completely abolished by concurrent intracerebroventricular administration of either methylnaloxone or methylatropine or by pretreatment with intravenous naloxonazine. These results suggest that stimulation and stabilization of ventilatory activity in the fetal lamb by low doses of morphine are mediated via mu 1-receptors and involve central muscarinic pathways.

Developmental changes in the continuity and stability of fetal breathing patterns were studied in 27 fetal lambs with chronically implanted electromyographic electrodes in the diaphragm throughout the third trimester (102-140 days). The results showed that there was a progressive decrease in the incidence of fetal breathing movements throughout the third trimester (P less than 0.001). This reduction in incidence of fetal breathing movements was due, in part, to a 20% decrease in the total number of breathing bursts at approximately 125 days (P = 0.05). The breathing patterns in both immature (less than 120 days) and mature fetal lambs were fragmented by a large number of pauses (interburst interval 6-10 s) and apneas (interburst interval greater than 10 s). Increase in gestational age was associated with a decrease in the number of pauses and apneas but longer apnea durations. The breathing pattern in fetuses less than 120 days old was more continuous than that in those greater than 120 days old, as demonstrated by significantly longer epoch durations (P = 0.013). There was no significant change in the continuity of the breathing pattern after 120 days. However, there was a significant increase in the stability of the instantaneous breathing rates throughout the third trimester. This was indicated by a significant increase in the percent of breathing bursts that occurred in stable clusters (P = 0.046), the number of bursts per cluster (P = 0.013), and cluster duration (P = 0.018). Thus an increase in stability appears to be the major developmental change in breathing control in late gestation.