The effect of change in sympatho-vagal balance on heart rate and blood pressure variability in the foetal lamb.

Cardiac and vascular function is mainly under autonomic nervous control within seconds to minutes, although the control is not mature at birth. We studied sympathovagal control of heart rate and blood pressure in chronically catheterized foetal lambs in the last trimester of gestation. Power spectral analysis was used to quantitate the frequency-specific heart rate variability (HRV) and blood pressure variability. We performed 15 experiments in seven foetal lambs. These preliminary studies showed that parasympathetic blockade by atropine (eight experiments) had no significant effect on the distribution of HRV to different frequencies. Beta-sympathetic blockade by propranolol (seven experiments) decreased the ratio of low and mid to high frequency (0.025-0.13 to 0.13-1.00 Hz) HRV (P = 0.02). The increased high frequency HRV in the absence of a similar increase in blood pressure variability and tracheal pressure variability suggests enhanced baroreflex responsiveness after propranolol administration. The frequency-specific sympathetic control of HRV in foetal lambs, the change in ratio of low and mid to high frequency HRV, might have clinical implications in estimating the level of foetal sympathetic activation in the follow-up of high-risk pregnancies.

Computer analysis of heart rate variation and breathing movements in fetal lambs.

A quantitative method for studying the frequency-specific relationships between heart rate (HR) and fetal breathing movements (FBM) was developed. The reactivity of periodic HR variation in relation to FBM was investigated by means of power spectral analysis. Seven fetal lambs were studied during the third trimester of gestation using a chronic animal model. HR variability increased at the rate of FBM, as shown by an increase of spectral density at > 0.35 Hz in the HR autospectrum and in the cross-spectrum of HR and respirogram, as well as by an increase in the short-term variability index CVS. FBM were associated with the increased HR variation in all but the lowest frequency bands (0.07-1.0 Hz). Although respiratory sinus arrhythmia was found, only 10 per cent of the total HR variability and 25 per cent of the joint-density of HR and respirogram appeared at > 0.35 Hz during FBM. The greatest variation in both the HR and respirogram spectra appeared at < 0.07 Hz. Although the low-frequency variability of HR and respirogram was simultaneous, it was on the whole not synchronised. The existence of multiple control systems that simultaneously link the cardiac and respiratory control mechanisms to each other in the fetal lamb is postulated.

Association of breathing movements to the variability of heart rate and blood pressure in foetal lambs.

Heart rate (HR) variability and arterial blood pressure (BP) variability were analysed as functions of foetal breathing movements (FBMs) by means of power spectral analysis in seven foetal lambs during the third trimester of gestation. No evidence of FBM-related changes, either in mean HR, mean systolic or diastolic arterial pressures, were found. Mean arterial pulse pressure, HR variability, and BP variability increased during FBMs. The increase in BP variability occurred at frequencies higher than 0.35 Hz, i.e. those of FBMs. The increase in HR variability occurred at 0.07-1.0 Hz, i.e. at every frequency band except the lowest one. Thus, the increase in HR variability was not frequency-specifically related to FBMs. During FBMs the periodic variability of HR at frequencies > 0.35 Hz was only 10% of total HR variability. We suggest that the FBM-related changes of BP variability may be mediated by direct peripheral, hydraulic mechanisms. HR changes involve autonomic control systems: the vagal component of baroreflex seems to be relatively insensitive, whereas the very slow vasomotor component of HR variability is dominant.

Do beta-adrenergic blockade and sleep state affect cardiorespiratory control in neonatal lambs? Multivariate autoregressive modeling approach.

Beta-Blockers are used in pregnancy-associated hypertension and in postnatal cardiac arrhythmias, and the neonate may get them in breast milk. We therefore studied the effects of beta-adrenergic medication on interrelations between heart rate (HR), respiration, and arterial blood pressure (aBP) in newborn lambs. The influence of sleep state on these cardiorespiratory interrelations was also examined. HR, aBP, and respiration (based on transthoracic electrical impedance) were recorded and the sleep state was visually documented in five healthy chronically instrumented newborn lambs before the age of 30 d. Propranolol was given (1 mg/kg). Two-min stationary segments of the three signals were analyzed using a multivariate autoregressive model, which yields oscillations of the signals and intersignal relationships as source contributions. The variabilities of aBP and HR were greatest at the low frequencies (less than 0.25 Hz) and so were their intersignal relationships (including baroreflex). The respiratory variability was greatest at the frequencies corresponding to the respiratory rate. During quiet sleep, the variabilities in HR, aBP, and respiration were lowest. The impact of respiratory oscillations on other signals increased but the impact of aBP variability decreased during quiet sleep. beta-Blockade and sleep state affected separately the cardiovascular and respiratory variables and their interrelations. beta-Blockade reduced HR and increased pulse pressure. The overall heart rate variability and the respiratory low-frequency contribution to heart rate variability decreased due to the beta-blockade. We postulate that the beta-adrenergic system is an important regulator of HR and HR variability in neonatal lambs and also of the low-frequency components of the respiratory sinus arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of heart rate variation by the autonomic nervous system in neonatal lambs.

We studied the role of the autonomic nervous system in the regulation of heart rate variation (HRV) in 12 chronically instrumented neonatal lambs. HRV was quantified from ECG tracings by computing periodic HRV distributions at frequencies of 0.02-1.00 Hz, using power spectral analysis of heart rate, and also by HRV indices. Heart rate declined more during the 1st than the 2nd mo after birth. Multiple regression analysis showed that the heart rate responses to vagal and to beta-adrenergic blockade had an independent negative association both with age and with the initial mean heart rate, whereas the overall HRV response had a positive association with age. Vagal blockade led to a 70-80% decrease in the beat-to-beat HRV in all lambs (p less than 0.001). The overall HRV indices decreased by 40-65% in lambs (less than 30 d old (p less than 0.001) and about 30% in those greater than 30 d old (p less than 0.05). In the power spectrum the greatest decrease was seen in the high-frequency components of HRV. beta-Blockade led to a decrease of about 50% in all HRV (p less than 0.001) in the younger lambs, without frequency selection. In the older lambs, it had no effect on the beat-to-beat HRV, but the overall HRV (coefficient of variance) decreased maximally by 40% (p less than 0.01), with a significant reduction in the low-frequency components of HRV. These results suggest that in the regulation of HRV after birth dual control via the autonomic nervous system is most important. In the older lambs, developmental changes result in precise regulation of the fast heart rate fluctuations mainly by the vagal division, whereas the slow fluctuations are partially regulated by the vagal and beta-adrenergic divisions.

Beta-adrenergic control and inter-relationships between heart rate and blood pressure in neonatal lambs.

Our aim was to develop a signal analysis method for revealing interrelationships between heart rate and blood pressure and for displaying the influence of autonomic nervous control on these signals in a chronic lamb model. A chronically instrumented neonatal lamb model was made to record ECG and direct arterial blood pressure (N = 15). Continuous two-minute recordings of blood pressure (BP) and ECG were digitised. The instantaneous heart rate signal (IHR) was derived from the ECG. The IHR and BP signals were bandpass filtered. Autospectra, cross-spectra, coherence spectra and phase spectra for the signals were computed to study the relative magnitudes and inter-relationships of the cardiovascular signals under normal conditions and during beta-adrenergic blockade. It was noted that both in the BP and IHR there were oscillations at the frequency of less than 0.1 Hz and also at the respiratory rate around 0.6 Hz. Beta-blockade reduced the oscillations of the IHR in less than 30-day-old lambs. It did not affect the coherence spectra or the phase lag between the signals. During quiet sleep the variability of blood pressure was decreased. In over-30-day-old-lambs the beta-blockade did not affect the variabilities of the cardiovascular parameters. These findings indicate that in neonatal lambs the sympathetic control system is a major regulator of cardiovascular interactions.

Multivariate autoregressive modeling of autonomic cardiovascular control in neonatal lamb.

The neonatal cardiovascular control system is a complicated interactive system which is under vigorous development at birth. From the measurement point of view the cardiovascular control is a closed-loop system. However, it can be examined on a beat-by-beat basis by analyzing circulatory-controlled variables with advanced signal analysis techniques. This paper proposes to use a multivariate autoregressive modeling technique in the analysis of several simultaneous physiological signals in order to examine interactions and inherent properties in the system. With the proposed multivariate autoregressive modeling technique, a signal is modeled as a linear combination of its own past and the past values of the other simultaneous signals plus a predictive error term of the model. The interactions in the system after the model identification are analyzed in frequency domain utilizing power spectrum estimates of the signals and signal contributions. The applicability of the proposed method was examined by a three-variable model between heart rate, blood pressure and respiration in the study of autonomic cardiovascular control in a chronic neonatal lamb model, in which the cardiovascular status was changed by using a beta-adrenergic autonomic nervous blockade. The study showed that the multivariate autoregressive modeling technique is a feasible technique in studying complicated interactions within the cardiovascular control system.

Changes in the concentration of ferritin in the serum during fetal life in singletons and twins.

Concentration of serum ferritin was analyzed in cord blood samples of 34 preterm and 24 full-term subjects, 10 fetuses which were aborted by laparotomy at 14-20 weeks of gestation, and 20 pairs of twins. The findings indicated that the fetal amount of storage iron gradually increases as the gestational age increases, it is similar in singletons and twins, within the pairs of twins, and slightly lower in some small-for-dates newborns. There was no correlation between fetal ferritin and maternal iron status. Our data suggest that the accumulation of fetal iron stores is not regulated by the fetus itself, or by maternal iron metabolism. Thus, we speculate that the placenta may have a role in this regulation.

Heart rate variation in relation to age and sleep state in neonatal lambs.

The heart rate (HR), heart rate variation (HRV) and the power spectrum of the HR were studied in 1 to 10-week-old neonatal lambs. The average HR was highest and the indices of the HRV were lowest at the age of 1 to 3 weeks. However, there was a decreasing trend in the overall HRV with advancing age when it was normalized in relation to the average HR. The absolute beat-to-beat HRV increased after the age of 3 weeks; it remained the same when normalized in relation to the HR. The overall HRV was highest during waking and active sleep; it was lowest during quiet sleep. The beat-to-beat HRV was lower during quiet sleep than during active sleep. Three major peaks of HRV power were detected in the spectra of all lambs. During active sleep the HRV power increased at all frequencies ranging from 0 to 1.0 Hz. During waking the low-frequency HRV power was primarily increased. The high-frequency HRV was pronounced during quiet sleep and the state of sleepy waking, especially at the age of 4 to 6 weeks. Our study indicates that developmental factors and the sleep state have to be considered when HR patterns are experimentally investigated. Many similarities between the HR control of neonatal lambs and that of human neonates make it feasible to study the mechanisms of clinical HRV patterns by lamb experiments.

Amniotic fluid zinc in risk pregnancies.

The zinc concentration of amniotic fluid (AF) of 129 pregnant women was analyzed by the flame atomic absorption spectrometry. This prospective study was performed in order to find out whether the determination of the AF zinc concentration can be used to monitor the growth and development of the fetus. There were two groups of patients: early stage (15th-19th gestation wk) in which the amniocentesis was performed as a prenatal genetic examination, and late stage (26th-40th wk) in which the amniocentesis was performed due to obstetric reasons. The average AF zinc concentrations were 1.2 and 1.0 µmol/L in the early and late gestation group, respectively. The AF zinc concentration did not correlate with the weight, height, or Apgar scores of the newborn nor with the maternal diseases, age, or parity. The AF zinc concentration in the late gestation group was significantly lower if the fetus was male than if it was female. If the AF was greenish the zinc concentration was elevated. One malformation, congenital nephrosis, with an exceptionally high zinc concentration (9.0 µmol/L), was found.

Plasma renin substrate in the prediction of pregnancy outcome in threatened abortion.

Concentrations of plasma renin substrate, serum oestradiol-17 beta, human chorionic gonadotrophin, sex-hormone binding globulin and plasma renin activity were measured in 77 samples from 74 patients with uterine bleeding during the first and second trimesters of pregnancy and in a control group of 29 normal pregnant women (51 samples). Mean concentrations of these substances were lower than control values in patients with an abnormal outcome of pregnancy. In patients with a normal outcome after uterine bleeding, concentrations were mostly within the control range. Serum oestradiol-17 beta concentration was superior to the other variables in predicting fetal outcome in the whole group. In patients with a live fetus at the time of blood sampling but who subsequently aborted, serum oestradiol-17 beta concentration was mostly normal, whereas plasma renin substrate was decreased. Our results suggest that plasma renin substrate may provide additional prognostic information to that given by serum oestradiol-17 beta measurement or ultrasonography in threatened abortion.

Plasma renin substrate and oestrogens in normal pregnancy.

Relationship between concentrations of serum oestrogens, plasma renin substrate and plasma renin activity were studied in six women throughout pregnancy. There was a significant positive correlation between serum oestradiol-17 beta and plasma renin substrate concentrations (r=0.60). Serum oestriol concentrations also correlated significantly with plasma renin substrate concentrations (r = 0.68). Correlation coefficients calculated separately for each subject throughout pregnancy were higher than those for the whole group. Also, there was much individual variation in dose-response of serum oestrogens to plasma renin substrate concentrations. There was no significant correlation between serum oestrogens and plasma renin activity. Our results support the view that oestrogens cause the increase in plasma renin substrate concentration during pregnancy, and emphasize the individual variation in response of renin substrate concentration to serum level of oestrogens.

Antepartal analysis of fetal heart rate variability by abdominal electrocardiography.

The success rate of some methodological factors influencing the antepartal analysis of fetal heart rate variability (FHRV) by abdominal electrocardiography (aFECG) were studied in 80 normal and 554 high risk pregnancies. The success rate of FHRV analysis was found to be dependent on the gestational age with virtually 100% success at 22 to 25 weeks and at 40 to 41 weeks of gestation. The lowest rate of success, 50% was found around the 30th week of gestation (Fig. 1). The fifteen-degree lateral tilt and the supine position of the mother were found to be equal respecting the success rate and the test results, while the 90-degree lateral tilt was found to be less favorable for the analysis. FHRV analysis succeeded more often with electrode paste than it did with tap water moistening or with dry electrodes. The rejection limit of maximum interval differences in FHRV analysis was found to be an important factor influencing the test results. The variability indices should be compared only if they have been measured with the same rejection logic. Differential index, of short-term variability, can be measured from short samples of aFECG, having a good correlation between DIs measured using 1-minute, 5-minute and 20-minute samples (Figs. 3, 4). On the other hand, interval index measuring the long-term variability should be measured using longer samples of aFECG.

Maternal and fetal metabolic responses to ritodrine in the sheep.

Ritodrine hydrochloride was infused intravenously for 60 minutes into pregnant ewes or for 29 minutes into fetal lambs, during the last third of gestation. The maternal and fetal acid-base balance and carbohydrate status was determined prior to, during, and after the ritodrine infusions. Ritodrine was also infused into pregnant sheep in labor until no further inhibition of uterine activity could be achieved. In these studies, acid-base balance was frequently assessed. The maternal or fetal infusion of ritodrine resulted in no major changes in maternal or fetal acid-base balance during the periods of study. Lactate and pyruvate concentrations in mother and fetus rose during the infusion. The lactate/pyruvate ratio remained stable, suggesting an increase in both aerobic and anaerobic glycolysis. Maternal glucose concentrations were significantly elevated after one hour of the ritodrine infusions to the ewes, but minimally elevated in the fetus. Fructose concentrations were unchanged. The possible role as fetal fuels of increased metabolic products of glycolysis caused by beta-adrenergic stimulation is discussed.

Cardiac and uterine hemodynamic responses to ritodrine hydrochloride administration in pregnant sheep.

The changes in the maternal circulation following administration of ritodrine hydrochloride were investigated in chronically prepared pregnant sheep. Low infusion rates of ritodrine (see text) elevated the maternal heart rate and cardiac output and decreased peripheral vascular resistance. Stroke work fell while minute work increased. The distribution of uterine blood flow did not change, as measured with microspheres. Simultaneously measured fetal cardiac output and umbilical blood flow were not altered. When ritodrine infusion rates (see text) were increased there was a slight but significant decrease in uterine perfusion pressure, and an increase in uterine vascular resistance with uterine blood flow decreasing. These changes were observed when the ewes were not in labor, and similar changes were again recovered with ewes in labor despite the simultaneous inhibition of uterine contractions. Selective beta blockade with practolol during ritodrine administration decreased the maternal tachycardia without affecting cardiac output, peripheral vascular resistance, or uterine vascular resistance.

Cardiac output and its distribution and organ blood flow in the fetal lamb during ritodrine administration.

The response of the fetal circulation to beta adrenergic stimulation with ritodrine hydrochloride has been investigated by long-term monitoring of the fetal lamb in utero. Ritodrine was infused intravenously either into the ewe or directly into the fetus, and cardiovascular and acid-base responses were measured. Fetal cardiac output and its distribution were measured with the use of radionuclide-labeled microspheres. The output of each ventricle also was measured by means of long-standing implanted electromagnetic flow transducers around the ascending aorta or pulmonary trunk during infusion of ritodrine at various rates into the fetus. Infusion of ritodrine (1.9 mcg. per kilogram per minute) into the ewe caused no change in fetal heart rate, blood pressure, cardiac output, or umbilical blood flow, but did cause an increase in fetal adrenal and myocardial blood flow. Ritodrine infused directly into the fetus produced a marked increase in fetal heart rate and a minimal change in cardiac output. There were no significant changes in fetal or maternal acid-base balance during the ritodrine infusions.

Effect of ritodrine on uterine activity, heart rate, and blood pressure in the pregnant sheep: combined use of alpha or beta blockade.

Ritodrine hydrochloride was administered parenterally to pregnant ewes during spontaneous or oxytocin-induced uterine activity. The effects of ritodrine on the uterus and cardiovasculature were assessed both with and without simultaneous administration of either alpha or beta blockade. Ritodrine was found to be an effective inhibitor of both spontaneous and induced uterine activity. Ritodrine did cause maternal tachycardia but no significant hypotension. Alpha-adrenergic blockade did not influence the effects of ritodrine. Beta blockade with propranolol reversed the uterine and cardiovascular effects of ritodrine, whereas beta blockade with practolol reversed the cardiovascular effects without interfering with the inhibition of uterine activity produced by ritodrine.