Do β-Adrenergic Blockade and Sleep State Affect Cardiorespiratory Control in Neonatal Lambs? Multivariate Autoregressive Modeling Approach

003 1-3998191 /2903-0272$03.00/0 PEDIATRIC RESEARCH Copyright O 1991 International Pediatric Research Foundation, Inc. Vol. 29, No. 3, 1991 Printed in U.S.A. Do 8-Adrenergic Blockade and Sleep State Affect Cardiorespiratory Control in Neonatal Lambs? Multivariate Autoregressive Modeling Approach J. U. GRONLUND, S. T. KALLI, A. S. I. SIIMES, M. SYDANMAA, K. J. ANTILA, I. A. T. VALIMAKI CardiorespiraforyResearch Unif [J. U.G., A.S.I.S., K.J.A., I.A. T . V.], Universifyof Turktr, T~rrku,Finland and Technical Research Cenfreof Finland [S.T.K., M.S.], Tampere, Finland ABSTRACT. @-Blockersare 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 @-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 mglkg). 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 ( ~ 0 . 2 5Hz) 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. 0Blockade and sleep state affected separately the cardiovascular and respiratory variables and their interrelations. 8Blockade 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 @-blockade. We postulate that the @-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. However, inasmuch as the interrelations between HR and aBP were not altered by the @-blockade,even high doses of propranolol do not seem hazardous for the cardiovascular system in neonatal lambs. (Pediatr Res 29: 272-277,1991) Abbreviations aBP, arterial blood pressure aBPV, arterial blood pressure variability AR, autoregressive HR, heart rate HRV, heart rate variability MAR, multivariate autoregressive model RSA, respiratory sinus arrhythmia Received August 23, 1989; accepted September 25, 1990. Correspondence: Juhani Gronlund, M.D., Cardiorespiratory Research Unit, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland. Supported by the Academy of Finland, Sigrid Juselius Foundation, and Lydia Marja Julin Fund. TEZ, transthoracic electrical impedance respirogram The central and autonomic nervous control of the heart and respiration are under vigorous development at birth and yet many cardiovascular reflex mechanisms are operational in the neonate. Many adaptive changes are necessary in the cardiovascular system during the neonatal period. In neonatal animals (l3) and newborn infants (4), some maturation of this control takes place during the first weeks of life. Also, the baroreceptor sensitivity has been found to be lower in newborn lambs than in adult sheep (5). Disturbances in this adaption may be hazardous for the infant's well-being. The control system of arterial blood pressure comprises a negative feedback loop and a time delay. As a consequence, spontaneous oscillations occur in HR and aBP. In addition, respiratory activity is a physiologic "disturbance factor" of the system, and in part respiratory control is linked to the nervous control of the heart. P-Blockers are used in the treatment of hypertension during pregnancy, e.g. in acute preeclampsia. P-Blockers can cross the placenta (6),and the neonate may receive considerable amounts of these compounds also in breast milk (7). Hypotension, bradycardia, and respiratory problems have been reported in newborns whose mothers have been receiving antihypertensive @-blocker treatment (8,9). Also, propranolol has been found to be a strong inhibitor of vasoconstrictive thromboxane A1 production in newborns (10). This drug can therefore affect both the work of the heart and the peripheral vascular bed in newborns and potentially influence the cardiovascular control. Although changes of circulatory variables and respiratory activity have been studied separately during the neonatal period, quantitative information about the fairly complicated relationships between HR, respiration, and blood pressure is still very limited and somewhat controversial. We examined the role of Padrenergic medication on the interrelations between HR, aBP, and respiration in a chronic newborn lamb model using a new multivariate AR signal analysis technique. We have previously shown that this technique provides quantitative frequency-selective information on complex interactions between the cardiac and respiratory control systems ( 1 1). We also examined whether changes in the sleep state alter relationships between cardiovascular variables and respiration and whether sleep state changes the effect of the P-blockade or vice versa. MATERIALS AND METHODS Surgical procedures. Five newborn lambs were Operated on at the age of 3 d. Two silver ECG electrodes were @-BLOCKERS A N D NEONATAL LAMBS 273 implanted bilaterally in the chest wall and polyvinyl catheters includes inherent signal sources related to the measured signals. were inserted into the carotid artery and jugular vein, tunneled Energy, i.e. external disturbances, are fed to the closed-loop s.c., and guided into a nylon pocket attached to the skin. The system through these signal sources. A novel method to analyze catheters were filled with heparin solution and flushed daily with such a closed-loop system is an AR model technique (I I). saline. The lambs were allowed to recover for at least 3 d. A MAR was computed for the analysis of 2-min periods of Cephalosporin and gentamicin were given for 4 d. The body HR, aBP, and TEZ signals (I I). The MAR model describes a weight was regularly assessed to confirm normal growth. The system where all signals are related to each other. Within the blood gases were examined several times a week, as well as before MAR model, each signal is modeled as a linear combination of and 10 min after each blockade, and found to be normal. A its own past values and the past values of the other signals plus detailed description of the surgical procedures has been published a predictive modeling term. The multivariat (...truncated)