Youtaro Agata

Dopamine pharmacokinetics in critically ill newborn infants.

To compare clinical responses with plasma concentrations of dopamine and to compare dopamine pharmacokinetics in infants of different gestational age or clinical condition, dopamine was administered under carefully controlled conditions of dose and rate of infusion. The dose was increased stepwise from 1 to 2, to 2 to 4, and 4 to 8 micrograms/kg/min. Plasma concentrations of catecholamines, including dopamine, were compared with blood pressure, heart rate, and Doppler cardiac output. The data were analyzed to determine the threshold or minimal plasma concentration of dopamine necessary to produce discernible effects. Plasma clearance rate was calculated from steady-state plasma concentrations. The average threshold for increases in mean arterial pressure was 50% below that for increases in heart rate. Improvements in arterial pressure were noted before and at lower thresholds than for increases in heart rate. Serial echocardiographic data showed dose-dependent increases in cardiac output and stroke volume without significant change in heart rate or systemic vascular resistance. Thresholds and plasma clearance values were similar in infants of gestational age 27 to 42 weeks and birth weights 900 to 4300 g. Administration of dopamine at initial dosages lower than commonly recommended, followed by incremental increase in dose, may be associated with improved left ventricular performance with avoidance of undesirable tachycardia and arrhythmias.

Effect of fetal adrenalectomy on catecholamine release and physiologic adaptation at birth in sheep.

Plasma catecholamine levels increase dramatically at birth. To determine the contribution of adrenal catecholamine secretion to the surge in catecholamines at birth and the role in newborn adaptation, we performed surgical adrenalectomy or sham operation on near-term ovine fetuses. After recovery in utero, the animals were delivered and supported by mechanical ventilation. Plasma catecholamine levels, heart rate, blood pressure, cardiac output, pulmonary function, surfactant secretion, and release of free fatty acids (FFA) and glucose were compared in control and adrenalectomized animals. Plasma epinephrine increased rapidly at birth in controls but was undetectable in adrenalectomized animals. Norepinephrine levels were not statistically different. Heart rate, blood pressure, cardiac output and contractility increased abruptly after cord cutting in controls but did not increase in adrenalectomized animals. Lung compliance, pulmonary function, surfactant pool size, glucose and FFA levels were significantly decreased in adrenalectomized animals. These results suggest that adrenal epinephrine secretion is vital to many of the adaptive events at birth.

Regional blood flow distribution and left ventricular output during early neonatal life: A quantitative ultrasonographic assessment

ABSTRACT: To examine the serial changes of left ventricular output and regional blood flow distribution during the early neonatal period, we measured blood flow volume in the ascending aorta, middle cerebral artery, celiac artery, superior mesenteric artery, and renal artery in 23 normal term infants at 1, 4--8, 24, and 96 h after birth. The blood flow volume in each vessel was measured by the pulsed Doppler technique. In the middle cerebral artery, celiac artery, and superior mesenteric artery, the blood flow volume at 1 and 4--8 h of age was significantly lower than after 24 h of age. In contrast, renal artery blood flow volume did not change significantly throughout the study period. The reduced organ blood flow volume soon after birth was related to a low diastolic blood flow in the major vessels, and the percent diastolic integral of blood flow velocity in each vessel showed an inverse linear correlation with the diameter of the ductus arteriosus. The left ventricular output 1 h after birth was 365 ± 69 mL/kg/min, which was significantly higher than after 4-8 h of age. Left ventricular output gradually declined to 301 ± 63 mL/kg/min at 4—8 h of age (p < 0.05 versus 96 h), 272 ± 48 mL/kg/min at 24 h, and 258 ± 54 mL/kg/min at 96 h. There was a significant positive correlation between left ventricular output and the ductus arteriosus diameter. We concluded that 1) there were significant changes in organ blood flow during the period of ductal closure, 2) the high left ventricular output and reduced regional blood flow at 1 and 4—8 h after birth resulted from diastolic left-to-right shunting through the ductus arteriosus, and 3) left ventricular output and regional organ blood flow were not directly related to each other. Our findings on the changes in regional organ blood flow and left ventricular output may provide a useful basis for interpreting abnormal hemodynamics in the early postnatal period.

Pharmacokinetics of dopamine in critically ill newborn infants

Dopamine pharmacokinetics was investigated in 14 critically ill newborn infants ranging from 27 to 43 weeks of gestational age and from 0.9 to greater than 4 kg birth weight. Plasma clearance rate was determined from dopamine levels during controlled infusions under actual clinical conditions. Dopamine was administered in stepwise increasing doses up to 8 micrograms/kg/min. Dopamine concentration and dopamine clearance rate were determined from duplicate samples drawn during each infusion in each patient. Steady-state plasma dopamine concentrations and plasma clearance rates were observed within 20 minutes at each infusion. Plasma dopamine concentration ranged from 0.5 ng/ml before infusion to almost 70 ng/ml at an infusion rate of 4 to 8 micrograms/kg/min. There was a linear correlation between infusion rate and plasma dopamine concentration (r = 0.68, p less than 0.001). Neither plasma dopamine concentration nor infusion rate had a significant effect on clearance rate. These data are consistent with first-order kinetics for administered dopamine in critically ill neonates over the range of concentrations studied.

Hemodynamic Adaptations at Birth and Neonates Delivered Vaginally and by Cesarean Section

In order to assess the possible influence of differences in delivery mode on cardiovascular adaptation at birth, we measured left ventricular output and its regional distribution in the major organs sequentially using an echographic technique during the first 96 h of life. We studied 27 normal newborns, of whom 15 were delivered vaginally and 12 by cesarean section. We also measured umbilical arterial and venous catecholamine concentrations. The umbilical arterial epinephrine and norepinephrine concentrations in the infants delivered vaginally were significantly greater than those in the infants delivered by cesarean section (epinephrine 1,195 +/- 208 vs. 565 +/- 81 pg/ml, p < 0.05; norepinephrine 11,832 +/- 3,819 vs. 5,153 +/- 1,400 pg/ml, p < 0.05). The left ventricular output and its regional distribution showed a similar pattern in the two groups, and there were no significant differences between them. These results indicate that the capacity of infants delivered by cesarean section to tolerate cardiovascular changes during the early neonatal period is comparable to that in infants delivered vaginally, even though there are significant differences in the catecholamine surge between these groups.

Neonatal Adaptation: Naloxone Increases the Catecholamine Surge at Birth

Abstract: A marked increase in plasma catecholamines at birth has been described in animals and man. Because the factors that regulate catecholamine secretion are incompletely understood and because it has recently been suggested that endogenous opiates are important in the regulation of catecholamine secretion, we designed studies to determine the influence of opiate receptor blockade prior to delivery on the increase in plasma catecholamines at birth. Term fetal sheep were delivered by cesarean section and randomly assigned to receive naloxone or vehicle. Naloxone was given just prior to umbilical cord cutting as a 2 mg/kg bolus followed by 2 mg/kg/h. Naloxone administration resulted in significantly greater peak levels of plasma norepinephrine (peak levels of 1.5 ± 0.4 versus 0.9 ± 0.1 ng/ml) and epinephrine (peak levels of 1.4 ± 0.7 versus 0.9 ± 0.3 ng/ml) and higher norepinephrine values throughout the study period. Naloxone administration was associated with significantly elevated heart rate (peak 184 ± 1 2 versus 207 ± 13 beats per min) and blood pressure (peak 95 ± 6 versus 88 ± 2 mm Hg). These studies demonstrate that opiate receptor blockade from birth markedly augments the neonatal sympathoadrenal response in the term newborn lamb.

The Effect of Chemical Sympathectomy on Catecholamine Release at Birth

ABSTRACT. The precise source of circulating catecholamine (CA) at birth and their role in circulatory adaptation is unclear. In order to determine the contribution of increased postganglionic sympathetic nerve activity to the CA surge at birth, we induced complete sympathectomy in near term fetal lambs prior to delivery by giving 6-hydroxydopamine. Chronically catheterized fetal sheep received either 6-hydroxydopamine (n=5) or control infusion (n=6). Chemical sympathectomy was verified by tyramine infusion. Lambs were delivered at 142 ± 1 days of gestation and serial plasma CA, heart rate, blood pressure, cardiac output, blood gases, blood glucose, and free fatty acids, were measured before and for 4 h after delivery. Myocardial ß-adrenergic receptors and tissue CA concentration were determined following sacrifice. Baseline circulating norepinephrine (NE) values were lower in sympathectomized animals (183 ± 45 versus 373 ± 125 pg/ml, p<0.05) and epinephrine values were slightly higher (118 ± 89 versus 48 ± 1 pg/ml, NS). There was only a 2-fold increase in NE after cord cutting in sympathectomized animals while control animals had a 4-fold increase (peak NE values 354 ±121 versus 1305 ± 363 pg/ml respectively, p<0.001). Epinephrine increased significantly in both groups and there were no significant differences between sympathectomized and control animals. Heart rate and blood pressure rose abruptly in both groups after cord cutting and there were no significant differences. Cardiac output was similar in both groups. Blood glucose in sympathectomized animals was significantly higher than control before (p<0.005) and after (p<0.001, peak values 66 ± 15 versus 35 ± 12 mg/dl). Plasma free fatty acid levels rose after cord cutting and were similar in both groups. Tissue NE content in the hearts of sympathectomized animals were less than 5% of control (mean 1.92 ± 0.5%), verifying the completeness of sympathectomy in this tissue. Myocardial ß-adrenergic receptors were 229 ± 21 versus 199 ± 26 fmol/mg protein in sympathectomized and control animals, respectively. These results suggest that the majority of circulating NE seen at birth arises from postganglionic sympathetic neurons rather than adrenal medullary secretion. The comparable hemodynamic and metabolic homeostasis of the two groups underscores the importance of increased circulating adrenal epinephrine at birth.

Metabolic Clearance and Plasma Appearance Rates of Catecholamines in Preterm and Term Fetal Sheep

Abstract: Plasma catecholamines increase markedly during labor and delivery. Moreover we have noted greater increases at birth in preterm than term lambs. It was unclear whether these differences were due to differences in secretion or clearance. We therefore designed experiments to compare the metabolic clearance rates (MCR) and plasma appearance rates of norepinephrine (NE) and epinephrine (E) in chronically catheterized term (143 ± 1 days) and preterm (131 ± 1 days) fetal sheep. Two different techniques, radioisotope tracer techniques and infusion of cold hormones for estimation of clearance rates, were compared systematically in the same group of animals. The results demonstrate that MCR of NE in term fetuses (178 ± 28 ml·kg−1 min−1) is similar to preterm fetuses (205 ± 22 ml·kg−1 min−1) as is MCR for E (193 ± 28 versus 170 ± 33 ml·kg−1 min−1, respectively). Estimates of MCR from cold hormone infusion were highly dependent on infusion rate with estimtes as much as 150% above that determined by isotope tracer infusions. Plasma appearance rates for both NE and E in term and preterm animals were similar. There were no detectable physiologic alterations during the tracer isotope infusions whereas infusions of cold hormone were associated with marked alterations in heart rate and blood pressure. These results suggest: 1) there are no differences in MCR or plasma appearance rates of NE or E between 130 days gestational age and term fetal sheep; 2) cold hormone infusions overestimate MCR and plasma appearance rates of both NE and E when compared to radioisotope tracer infusions; 3) differences in catecholamine concentrations at birth between term and preterm animals appear to be due to differences in secretion rather than clearance.

Catecholamine and endorphin responses to delivery in term and preterm lambs

A marked increase in catecholamines and endorphins at birth has been described in animals and man. Because the factors which regulate catecholamine secretion are incompletely understood and because it has been suggested that endogenous opiates are important in the regulation of catecholamine secretion, we designed studies to compare changes in plasma catecholamines at birth with simultaneously measured endorphins. Catecholamines and beta-endorphin-like immunoreactivity (beta-ELI) were measured at birth in term (145 days) and preterm (130 days) lambs. Preterm lambs were given natural sheep surfactant intratracheally to prevent respiration failure. Following umbilical cord cutting, there was a marked increase in circulating norepinephrine (NE) and epinephrine (E) levels. The peak preterm NE (2.2 +/- 0.3 ng/ml at 1 h) was greater than the peak term NE (1.0 +/- 0.2 ng/ml at 5 min). The peak preterm E occurred later and also was greater than the peak term E (4.0 +/- 0.5 ng/ml at 1 h vs. 1.3 +/- 0.4 ng/ml at 15 min, respectively, p less than 0.01). Baseline beta-ELI in term animals (767 +/- 15 pg/ml) was greater than preterm (456 +/- 12 pg/ml). Following cord cutting peak beta-ELI in term animals rose to 867 +/- 201 pg/ml compared to a peak beta-ELI in preterm animals of 1,866 +/- 450 pg/ml. These results and their significance for neonatal adaptation to extrauterine life are discussed.

Hemodynamic and neuroendocrine adaptations of the preterm lamb left ventricle to acutely increased afterload

ABSTRACT: The birth process is associated with dramatic alterations of left ventricular (LV) volume loading, pressure loading, and contractile state. The preterm LV has considerable volume loading reserve. We have assessed neuroendocrine and related hemodynamic responses of the preterm lamb LV at 0.8 gestation during acute pressure loading within the first 2-4 h after birth. We measured plasma catecholamines and hemodynamic and cineangiocardiographic parameters of LV pump performance and contractility at basal levels and during rapid LV pressure loading by partial balloon obstruction of the ascending aorta before and after propranolol. A relatively high level of propranolol (3 mg/kg) was required to produce β -adrenoceptor blockade associated with reduction of heart rate and blood pressure, but after atrial pacing there was no detectable difference of basal LV pump performance or contractility at comparable heart rate, preload, and afterload. The LV pump performance was maintained and plasma catecholamines and LV contractility were increased when aortic systolic pressure was augmented 60% over baseline. The increased contractile state at greater afterload was minimally blunted by propranolol. Thus the preterm LV is relatively hypercontractile soon after birth and is capable of an integrated augmentation of pump performance and contractile state during pressure loading. These findings are relevant to the maintenance of adequate LV performance and successful adaptation to the acute alterations of afterload associated with the transitional circulation at birth.