Alma Martinez

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.

The effects of corticosteroids and thyrotropin-releasing hormone on newborn adaptation and sympathoadrenal mechanisms in preterm sheep

OBJECTIVES We examined the effect of prenatal corticosteroids and thyrotropin-releasing hormone on postnatal adaptation and sympathoadrenal function in preterm lambs. STUDY DESIGN Catheterized fetal lambs received saline solution (n = 6), corticosteroids alone (n = 8), or corticosteroids plus thyrotropin-releasing hormone (n = 6) for 60 hours. The lambs were delivered by cesarean section at a gestational age of 130 +/- 1 days. Ventilatory, cardiovascular, and metabolic responses and plasma catecholamine concentrations were measured for 2 hours after birth. Statistical analysis was performed by use of independent t tests or analysis of variance. RESULTS Ventilatory function and cardiac contractility were significantly improved in both corticosteroid and corticosteroid plus thyrotropin-releasing hormone animals. Lambs treated with corticosteroid plus thyrotropin-releasing hormone had significantly higher aortic pressure and left ventricular blood pressure than either of the other groups. The postnatal norepinephrine and epinephrine surge was blunted in response to corticosteroid and corticosteroid plus thyrotropin-releasing hormone treatment. There were no differences in metabolic responses among the three groups. CONCLUSIONS In premature lambs prenatal exposure to corticosteroids and thyrotropin-releasing hormone improves postnatal cardiovascular adaptation more than corticosteroids alone.

The effects of hypoxia on (methionine) enkephalin peptide and catecholamine release in fetal sheep

ABSTRACT: The effect of hypoxia on plasma met-enkephalin and catecholamine levels was studied in chronically catheterized fetal sheep. Maternal and fetal hypoxia was maintained for 20 min. We found hypoxia significantly increased the plasma levels of large mol wt met-enkephalin containing peptides from 1755 ± 229 pg/mL during baseline to 4408 ± 1426 pg/mL by 15 minutes of hypoxia. The levels of the met-enkephalin pentapeptide were unchanged during hypoxia from a baseline value of 168 ± 56 pg/mL. Norepinephrine and epinephrine levels increased 5- and 10-fold, respectively, by 15 min of hypoxia. These observations suggest cosecretion of the large mol wt met-enkephalin peptides with catecholamines during stress in developing animals.

Neonatal Adaptation: Cardiac Adrenergic Effector Mechanisms after Birth in Newborn Sheep

ABSTRACT: At birth, there is a marked increase in circulating plasma catecholamine concentrations. This increase is critical to many of the physiologic adjustments to postnatal life. Because the levels observed are higher than those seen in most other physiologic conditions in adults, previous investigators have suggested that the newborn is less sensitive to adrenergic stimulation or that desensitization to adrenergic stimulation occurs rapidly. To investigate this question, we designed experiments to measure myocardial β-adrenergic receptor density and sensitivity before and after exposure to the catecholamine surge at birth in term newborn sheep. We also measured the status of sympathetic innervation, reflected by myocardial norepinephrine content. At birth, plasma catecholamines increased 4- to 6-fold with associated increases in heart rate, blood pressure, and cardiac output. Myocardial β-adrenergic receptor at birth (135 fmol/mg protein) did not change significantly by 6 h of life (157 fmol/mg protein). Myocardial adenyl cyclase activity, reflecting receptor sensitivity, and myocardial sympathetic innervation also did not change. These results suggest that, despite exposure to sustained adrenergic stimulation, myocardial adrenergic effector mechanisms do not change in the newborn sheep at birth.

Naloxone potentiates epinephrine release during hypoxia in fetal sheep: dose response and cardiovascular effects

ABSTRACT: The effect of opiate receptor blockade on the plasma catecholamine response to hypoxemia was studied in seven chronically catheterized fetal lambs in utero. All animals underwent treatment with hypoxia alone, naloxone infusion alone (2 mg/kg) and hypoxia with naloxone at four different dosages (0.1, 0.5, 1.0, and 2.0 mg/kg). Maternal and fetal hypoxia was maintained for 20 min. There were no differences noted in the degree of hypoxemia or acidemia between the different hypoxia treatment groups. Hypoxia increased both norepinephrine and epinephrine plasma levels in all fetal sheep studied. We found a dose-dependent increase in plasma epinephrine levels in response to naloxone infusion during hypoxia. Plasma epinephrine level by 20 min of hypoxia with the 0.1 mg/kg naloxone dose (geometric mean 5366 pg/ml) was significantly more than with hypoxia alone (997 pg/ml). Naloxone at the other doses did not alter the epinephrine responses. There was no augmentation of plasma norepinephrine levels by naloxone at any dose studied. Thus, naloxone augmented the plasma epinephrine response to hypoxia in fetal sheep suggesting that the opiate peptides act as modulators of the sympathoadrenal system. The naloxone dose response differences observed in this study suggest this modulation is largely by antagonism of μ-receptors.

Plasma methionine enkephalin levels in the human newborn at birth.

Plasma met-enkephalin immunoreactivity (MET-ENKi) and catecholamine levels were measured in umbilibal cord blood from 46 healthy newborn infants. Clinical data including Apgar scores, birth weight, gestational age, route of delivery, fetal heart tracings and arterial blood gas values were also obtained. Thirty-nine infants were delivered by the vaginal route. All but 1 infant delivered by cesarian section had undergone a trial of labor. Plasma MET-ENKi in the newborn infants was markedly greater than levels found in healthy adult volunteers: 360 +/- 25 versus 25 +/- 2 pg/ml, respectively. MET-ENKi levels were similar in umbilical arterial and umbilical venous blood, and in infants delivered vaginally or by cesarian section.

Maturational changes in expression of enkephalin peptides in adrenal and extra-adrenal tissue of fetal and adult rabbits

Met-enkephalin immunoreactivity (MET-ENKi), total enkephalin immunoreactivity (TOTAL MET-ENKi) and catecholamines were measured in adrenal and extra-adrenal tissue of fetal, newborn and adult rabbits. Met-enkephalin peptides were detected in adrenal and extra-adrenal tissue by 29 days of gestation. There were progressive increases in TOTAL MET-ENKi in both the adrenal and extra-adrenal tissue during development. In 29-day-old fetuses, MET-ENKi represented 43 and 50% of the peptide content in adrenal and extra-adrenal tissues respectively. By 3 days after birth, MET-ENKi represented only 15 and 7% of the peptide content in the same tissues. In the adult adrenals, 10% of enkephalin peptides were found as MET-ENKi. There were progressive increases in adrenal and extra-adrenal catecholamine content in the fetal and newborn rabbits throughout development. The changes in the ratio of MET-ENKi to TOTAL MET-ENKi peptides suggest differences in posttranslational processing of proenkephalin peptide during maturation. We speculate that enkephalin peptides derived from proenkephalin A are important during fetal and early newborn life and that extra-adrenal tissue may be an important source of these peptides during development.

Cardiovascular effects of SKF 104078 in lambs.

We studied the effects of SKF 104078 in anesthetized, newborn lambs and compared it to nonspecific alpha-receptor blockade by tolazoline. SKF 104078 infusion decreased pulmonary and systemic arterial pressures in newborn lambs when infused during normoxic ventilation. When infused during hypoxia, SKF 104078 decreased cardiac output and systemic blood pressure without affecting pulmonary pressure. Due to the predominance of systemic effects, the usefulness of SKF 104078 in states of hypoxic pulmonary vasoconstriction is limited.