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We used novel 3'-monoiodothyronine sulfate (3'-T1S) and 3,3',5-triiodothyroacetic acid sulfate (TriacS) RIAs to characterize sulfation pathways in fetal thyroid hormone metabolism. 3'-T1S and TriacS levels were measured in serum samples obtained from fetal (n = 21, 94-145 d gestational age), newborn (NB, n = 5), and adult sheep (AD, n = 5) as well as from fetuses after total thyroidectomy (Tx), or sham-operated twin fetuses controls, conducted at gestational age 110-113 d (n = 5). Peak levels (expressed as ng/dL) of both 3'-T1S and TriacS occurred at 130 d gestation. These levels in fetuses were higher than those in NB and AD. In Tx fetuses, there was a significant decrease in the mean serum level of 3'-T1S, but not TriacS. The decrease in 3'-T1S in Tx is similar to that observed for thyroxine sulfate (T4S) and 3,3',5'-triiodothyronine sulfate (rT3S), whereas TriacS levels were not altered in the hypothyroid state, similarly to 3,3',5-triiodothyronine sulfate (T3S). These data demonstrate that 3'-T1S and TriacS are normal thyroid hormone metabolites in ovine serum and that TriacS is likely derived from T3S or from the same precursor(s) as T3S.

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Cortisol and thyroid hormones are critical to normal fetal development and neonatal transition, and baseline values and stimulation tests are abnormal after preterm birth. To evaluate cortisol and thyroxine (T4) responses that are not influenced by uncontrolled antenatal events associated with human preterm labor, we measured cortisol and T4 after standard-dose adrenocorticotropin (ACTH) and corticotropin-releasing hormone (CRH) stimulation tests, as well as high-dose CRH and thyrotropin-releasing hormone stimulation tests in baboons that were delivered for 3 separate protocols at 125 days of gestation (term is 186 days). The animals were surfactant treated and ventilated for up to 14 days. Some fetuses were exposed to fetal or maternal betamethasone, and some newborns were treated with 10 µg/kg T4 for 9 days after birth. Baseline cortisol levels were in a stress range of 30–60 µg/dl by day 5. Cortisol did not increase consistently until day 11 in response to a high CRH dose or ACTH. T4 treatment for 9 days after birth suppressed the cortisol responses and subsequent baseline T4 levels. The hypothalamic-pituitary-adrenal (HPA) axis was unresponsive to standard dose stimulation tests until 11 days of age in preterm baboons, indicating HPA immaturity.

We have shown that there is significant fetal-to-maternal transfer of sulfated metabolites of thyroid hormone after fetal infusion of a pharmacologic amount of 3,3',5-triiodothyronine (T(3)) or sulfated T(3) in late pregnancy in sheep (Am J Physiol 277:E915, 1999). The transferred iodothyronine sulfoconjugate, i.e. 3,3'-diiodothyronine sulfate (T(2)S), of fetal origin appears in maternal sheep urine. The present study was carried out to assess the contribution of T(2)S of fetal origin to the urinary pool in ewes. Eighteen date-bred ewes (mean gestational age of 115 d) and their twin fetuses were divided into four groups. In group I (control, n = 5), both ewes (M) and their fetuses (F) were sham operated for thyroidectomy (Tx). In group II, the ewes (MTx, n = 4) and, in group III, the fetuses (FTx, n = 4) were subjected to Tx. In group IV (MTx.FTx, n = 5), both the ewe and fetus had Tx. After 10-12 d, fetal and/or maternal hypothyroidism were confirmed by serum thyroxine (15 nmol/L) measurements. In addition, we infused radioactive T(3) without disturbing the T(3) pool in three singleton near-term fetuses and assessed the amount of radioactive iodothyronine that appeared in maternal urine (MU). After infusing [(125)I-3'],3,5-T(3) via fetal vein to the near-term normal fetuses, radioactive T(2)S was identified as the major metabolite in MU by HPLC and T(2)S-specific antibody. MU T(2)S excretion (pmol/mmol creatinine) was significantly reduced by FTx and MTx.FTx but not by MTx. In addition, positive correlations (p0.01) were found between MU T(2)S excretion and fetal serum thyroxine and T(3) concentrations but not with maternal serum thyroxine or T(3) levels. T(2)S of fetal origin contributes significantly to the MU pool.

Glucocorticoids are administered for preterm labor to improve postnatal adaptation. We assessed the effect of antenatal betamethasone (Beta) treatment on preterm newborn lamb neuroendocrine [catecholamine, arginine vasopressin (AVP)] and endocrine [triiodothyronine (T3), ANG II, and atrial natriuretic factor (ANF)] adaptive responses following delivery and a hypoxic challenge. Beta treatment included direct fetal injection at 0.2 (F0.2; n = 8) or 0.5 (F0.5; n = 7) mg/kg estimated fetal body weight or maternal injection with 0.2 ( n = 8) or 0.5 mg/kg (M0.5; n = 8). Control animals received fetal and maternal intramuscular injections of saline ( n = 8). After 24 h, lambs were delivered by cesarean section, surfactant treated, and ventilated for 4 h. Relative to the control lambs, 3 h after delivery, there was a marked suppression of plasma cortisol, epinephrine, norepinephrine, and ANG II levels and elevated plasma T3and ANF levels, systolic blood pressure, and left ventricular contractility (dP/d t; F0.5and M0.5) values in F0.5and both maternal Beta-treated groups. However, Beta treatment augmented the cardiac output, cortisol, norepinephrine, AVP, and ANF responses to 20 min of hypoxia (Po2= 25–30 mmHg). We concluded that short-term (24 h) antenatal glucocorticoid exposure 1) alters preterm newborn postnatal blood pressure regulation in the face of marked depression of plasma cortisol, catecholamine, and ANG II levels and 2) augments the postnatal neuroendocrine and endocrine responses to a hypoxic challenge.

Thyroid hormones are important for both perinatal adaptation and long-term psychomotor development; however, there is limited information on the effects of extreme prematurity and antenatal TSH-releasing hormone (TRH) treatment on pituitary-thyroid function. In this study we assayed plasma triiodothyronine (T3) and TSH in infants who were part of a collaborative trial of antenatal maternal TRH therapy. Within the control population (n = 166), infants of 24-28-wk and 28-32-wk gestational age had comparable levels of T3 (0.94 and 1.06 nmol/L, respectively) and TSH (5.7 and 7.2 mU/L) at birth, but the increases at 2 h and subsequent T3 levels were less in the 24-28 wk versus 28-32-wk gestation infants. In the TRH-treated group (n = 131), T3 was lower in the first day for infants delivered 7-72 h after antenatal TRH compared with control infants. TSH at birth was approximately 3.5-fold greater for infants delivered at 0-6 h after the last TRH dose compared with the control group and was suppressed in infants delivering at 7-36 h. T3 and TSH levels were not different between control and TRH-treated groups at 3-28 d of age. In TRH stimulation tests on d 28, control and TRH-treated groups had similar peak levels of TSH and incidence of exaggerated response (TSH > or = 35 mU/L). We conclude that extremely premature infants have a reduced postnatal surge in TSH and T3 and maintain lower T3 concentrations, probably reflecting tertiary hypothyroidism. The stimulatory and suppressive effects of antenatal TRH treatment observed at birth are transient and do not affect pituitary-thyroid responsiveness at 28 d of age.

To assess effects of dose and duration of glucocorticoid exposure on maturation of the fetal lung, we administered single or multiple doses of betamethasone (0.5 mg/kg im) to pregnant sheep for 2 or 21 days before preterm delivery at 125 days of gestation. Lung function (compliance, lung volume at 40 cmH2O pressure, and ventilatory efficiency index) was increased after two to four weekly doses of glucocorticoid (2.5- to 4-fold increase) and after 48 h of exposure (1.4- to 2.3-fold). Total protein of lavage fluid decreased similarly with three doses, four doses, and 48 h of treatment. In lambs with long-term exposure to betamethasone, there was a similar, dose-dependent increase in concentrations of saturated phosphatidylcholine and surfactant proteins A (SP-A) and B (SP-B) (maximal 2- to 3-fold in tissue and 10- to 15-fold in lavage fluid). Levels of SP-A and SP-B were closely correlated in lavage fluid. In animals treated for 48 h, only tissue SP-B was increased (2.7-fold). We conclude that 48 h of glucocorticoid treatment improves lung function in the premature lamb without a detectable increase in lavage surfactant components and that longer exposure to antenatal glucocorticoid increases surfactant lipid and proteins in a coordinated fashion. The enhanced response with repetitive dosing indicates that the process of glucocorticoid-induced lung maturation is either reversible and/or gestational age dependent.

We evaluated the effects of multiple fetal exposures to glucocorticoids on postnatal lung function and growth. Ewes were randomized to receive 1 to 4 doses of 0.5 mg/kg betamethasone or saline placebo at 7 d intervals from 104 d to 118 d and at 124 d gestation. All lambs were delivered preterm at 125 d gestation, and postnatal lung function was evaluated. There were sequential improvements in compliance, ventilation efficiency, and lung volumes for two, three, and four doses of betamethasone. The maximal effect was a 150% increase in compliance and a 4-fold increase in lung volume after fetal exposure to four doses of betamethasone. However, birth weights decreased (15% after one dose, 19% after two doses, and 27% after three and four doses). There were no changes in lung to body weight ratios, lung dry to wet weight ratios, lung protein to body weight ratios, or lung hyaluronan content. Prenatal glucocorticoid exposure also altered postnatal cortisol, thyroid, and catecholamine plasma levels. Repetitive 7-d interval exposures of fetal lambs to glucocorticoids progressively enhanced postnatal lung function and resulted in growth and endocrine abnormalities.

Although antenatal corticosteroids improve outcomes for preterm newborns, negative effects could result if preterm delivery does not occur. We investigated whether betamethasone treatment of preterm fetal sheep would alter cardiovascular, renal, and lung function after delivery at term.Preterm fetal lambs were randomized at 126-128 days' gestation to receive single doses of saline (n = 6) or 0.5 mg/kg betamethasone (n = 7) by ultrasound-guided fetal intramuscular injection. The lambs were delivered by cesarean at term, 20 days after fetal treatment, then ventilated for 4 hours to evaluate lung, cardiovascular, renal, and endocrine newborn adaptive responses, as well as responses to mild hypoxia.Body and organ weights (brain, lung, heart, kidney, adrenal) were similar in the two groups. Values for blood gases and pH, mean arterial pressures, heart rates, glomerular filtration rates, renal osmolar clearance, and plasma cortisol, angiotensin II, epinephrine, and norepinephrine levels were similar between groups for 3 hours after delivery and before hypoxia. A 20-minute period of mild hypoxia resulted in increases in catecholamines, arginine vasopressin, and atrial natruretic factor in both betamethasone-treated and control lambs. However, hypoxia did not alter cardiovascular or lung function in either group. After reversal of hypoxia, measured physiologic parameters did not differ between groups. Kidney Na, K-adenosine triphosphatase activity was significantly higher for the betamethasone-treated lambs.Preterm fetal betamethasone administration does not alter neonatal pulmonary, cardiovascular, renal, or endocrine physiology after term delivery or in response to mild hypoxia.

OBJECTIVE: We hypothesized that fetal betamethasone exposure for

Although the benefits of antenatal hormone treatment are well accepted, most studies have reported only pulmonary effects. There is evidence of beneficial cardiovascular and metabolic effects in studies using chronically catheterized animals; however because of the route of administration, the results are not directly applicable to clinical strategies. We previously demonstrated significant pulmonary effects in animals treated antenatally with a single, direct fetal, intramuscular injection of glucocorticoids. This study was performed to determine the effects of a single fetal injection of betamethasone (BETA) alone or in combination with thyroxine (T4) on cardiovascular and metabolic responses after preterm birth. Hemodynamic and metabolic responses at birth were determined in fetuses (126-d gestation; term = 150 d) treated with ultrasound-guided intramuscular injections of 0.5 mg/kg BETA (n = 7), BETA plus 60 g/kg T4 (n = 7), or saline (SAL, n = 9). After 48 h, lambs were delivered by cesarean section and studied for 3 h. BETA treatment increased mean arterial blood pressure [56 +/- 6 (SEM) versus 42 +/- 3 mm Hg], heart rate (152 +/- 5 versus 123 +/- 4 beats/min), and cardiac output (467 +/- 17 versus 349 +/- 36 mL/min/kg) versus SAL. Responses of BETA+T4-treated animals were not different from animals treated with BETA alone. Glucose and FFA were similar among all groups. The increase in catecholamine levels normally seen at birth was significantly attenuated in both the BETA and BETA+T4-treated animals. A single, intramuscular injection of glucocorticoids 48 h before delivery improves cardiovascular responses to preterm birth. This effect is not augmented by concomitant administration of T4.

The effects of exogenous surfactant treatment combined with postnatal ventilation on surfactant protein (SP)-A, SP-B, and SP-C steady-state mRNA levels were evaluated in preterm sheep at 120, 132, and 139 days gestation. Three groups were studied at each gestation period: animals ventilated and treated with 100 mg/kg natural sheep surfactant, animals ventilated and not treated with surfactant, and a comparison group of lambs that were neither ventilated nor treated with surfactant. In unventilated lambs, SP-A and SP-C mRNA levels measured by densitometry from Northern blots increased between 120 and 132 days gestation (P < 0.05). At 120 days gestation, no differences in SP-A, SP-B, or SP-C mRNA levels were noted among the three groups. At 132 days gestation, SP-A mRNA levels increased in both ventilated groups (P < 0.01), but no additional surfactant effect on SP-A mRNA expression was detected. There were no changes in SP-B or SP-C mRNA levels among the groups at 132 days gestation. At 139 days gestation, mRNA levels for both SP-A and SP-B increased after ventilation, compared with the unventilated groups (P < 0.05). Furthermore, an additional effect of surfactant treatment to increase SP-A mRNA levels relative to animals undergoing ventilation alone was noted (P < 0.05). We conclude that postnatal changes in mRNA levels for the surfactant proteins are gestationally regulated and protein specific.

OBJECTIVE: We determined the effect of a single direct fetal injection of corticosteroid and thyroid hormones on postnatal pulmonary function in preterm lambs. STUDY DESIGN: Initially fetal sheep (126 days' gestation) randomly received saline solution, betamethasone (Celestone Soluspan, 0.5 mg/kg), betamethasone plus triiodothyronine (5 μg/kg), or betamethason plus thyroxine (15 μg/kg) as a single injection. Forty-eight hours later (128 days' gestation) the tetuses were delivered and ventilated for 50 minutes. In a second protocol fetuses were delivered at 128 days' gestation, after only 24 hours of hormone exposure. RESULTS: Betamethasone treatment improved compliance nearly twofold after 24 or 48 hours of exposure. Efficiency of ventilation also improved after steroid therapy; this effect was augmented 48 hours after thyroxine exposure (but not triiodothyronine). No thyroxine effect was noted after 24 hours of exposure. Maximal lung volume increased by 80% after steroid treatment and doubled in response to combination betamethasone and thyroxine therapy. Alveolar pool sizes of saturated phosphatidylcholine and surfactant protein A were comparable for all groups exposed for 48 hours. CONCLUSION: A single fetal exposure to betamethasone improves postnatal pulmonary function after 24 or 48 hours. Addition of thyroxine (but not triiodothyronine) augments this effect at 48 hours.

Three groups of sheep fetuses at 125 or 126 d gestational age randomly received a single ultrasound-guided intramuscular injection of saline, 0.5 mg/kg betamethasone, or 0.5 mg/kg betamethasone plus 50 micrograms/kg thyroxine (T4). Forty-eight hours later the fetuses were delivered, treated with a pulmonary surfactant preparation, and ventilated for 3 h. Corticosteroids alone and in combination with T4 increased FRC, compliance, and lung volumes, and decreased the protein leak into the airspace. Saturated phosphatidylcholine pool sizes recovered by alveolar washing were not changed after hormone treatment. To evaluate the function of surfactant recovered from the lambs in vivo, we treated preterm rabbits at 27 d gestational age with the large-aggregate surfactant from alveolar washes. Large-aggregate surfactants and the pulmonary surfactant preparation increased compliances and maximal lung volumes relative to those in untreated preterm rabbits. Large-aggregate surfactants improved compliance more than did the pulmonary surfactant preparation. We conclude that ultrasound-guided single fetal corticosteroid treatment followed by postnatal surfactant improved postnatal lung function in preterm lambs. Addition of T4 did not augment corticosteroid effects. The function of the exogenous surfactant was improved in premature lamb lungs independently of the fetal treatment modality.

Recent advances in the understanding of the normal process of maturation of fetal thyroid function now make possible the in utero diagnosis of fetal system abnormalities. The approach to the fetus at risk for altered thyroid function is discussed in the context of normal thyroid development and emphasis is given to the fetus presenting with goiter.

We studied the effect of a single-dose, corticosteroid treatment on preterm lambs (gestational age: 128 d). A low, medium, or high betamethasone dose (0.1, 0.5, and 2.0 mg/kg) or saline control was administered directly to the fetus by ultrasound-guided intramuscular injection 48 h before delivery. A second group received either the high dose of betamethasome or saline 24 h before delivery. The lambs were delivered at 128 d gestation, anesthetized with ketamine, and ventilated for 50 min. Respiratory system elastance and resistance were measured at 10-min intervals using multiple linear regression analysis of pressure, flow, and volume. Similarly, estimates of lung mechanics were calculated from transpulmonary pressure. The viscoelastic time constant (tau) was calculated by fitting an exponential to the pressure changes occurring after occluding the airway during expiration. Excised lung volume at 40 cm H2O and lung weight were used to calculate specific elastance and resistance correcting for lung size using volume or weight, respectively. Of the 13 lambs in the 48-h high-dose betamethasone group, five developed pulmonary interstitial emphysema (PIE) as did 3 of 11 animals in the high-dose group treated 24 h before delivery. These animals were analyzed separately. The lambs receiving medium- or high-dose (24 and 48 h predelivery) betamethasone had significantly lower elastance and a trend toward lower resistance when compared with the control groups. Ten minutes after delivery, the animals that developed PIE all had elastance values comparable to that of the control animals despite corticosteroid treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between cortisol infusion and time of fetal catheterization on postnatal lung function of prematurely delivered lambs was investigated with the hypothesis that the intervention of catheterization would alter fetal responsiveness to the maturational effects of corticosteroids. Fetal catheterization was performed on d 117 or on d 122 of gestation. Cortisol or saline control infusions were begun on d 126, with delivery 60 h later on d 128. The animals were ventilated for 1.25 h after delivery, and compliance, the ventilation efficiency index, labeled albumin leak into and out of the lungs, alveolar and lung saturated phosphatidylcholine and surfactant protein A were measured to evaluate lung performance and biochemical indicators of maturation. Cortisol improved compliance and ventilation efficiency and decreased labeled albumin recovery without changing alveolar saturated phosphatidylcholine or surfactant protein A in the animals catheterized at 122 d relative to 122-d saline-infused animals. However, the animals catheterized at 117 d and infused with saline were as mature as assessed by compliance and ventilation efficiency as the 122-d cortisol-treated animals. The 117-d cortisol-infused animals had significantly augmented lung function relative to either 117-d saline-infused or 122-d cortisol-treated lambs and were the only group that had increased alveolar surfactant protein A and lung saturated phosphatidylcholine pool sizes. This study demonstrates that the response of the fetal lung to a maturational agent such as cortisol is dependent on the history of previous fetal interventions.

Recently, we identified significant amounts of thyroxine sulfate (T4S) in fetal sheep serum, meconium, bile, and amniotic and allantoic fluids. Little is known, however, about sulfate conjugation of thyroxine in humans. In this study, we employed a novel, sensitive T4S RIA to address this question. The rabbit antiserum was quite specific; T4, T3, rT3, and 3,3'-T2 showed less than 0.002% cross-reactivity. Other analogs cross-reacted less than 0.0001%. Only rT3S and T3S cross-reacted significantly (9.9% and 2.0%, respectively). The mean serum T4S concentration (ng/dL) was 8.6 in euthyroid subjects, 14.4 in hyperthyroid subjects, 5.0 in hypothyroid subjects, 5.9 in pregnancy, and 4.5 in patients with nonthyroid illnesses. T4S concentration in amniotic fluid from women at 18-19 weeks of gestation (25.5 ng/dL) was higher than that at 14-15 weeks of gestation (14.3 ng/dL). A significant rise in serum T4S was detected in hyperthyroid patients 1 day after ingestion of 1 g of ipodate. These data suggest that T4S is a normal component of human serum and amniotic fluid, and it is mostly derived from T4 peripherally and accumulates when type I 5'-monodeiodinating activity is low in fetuses or inhibited by drugs, such as ipodate.

Four groups of twin sheep fetuses were catheterized at 121 days of gestational age and intravenously infused with saline, 0.75 mg.kg-1.h-1 cortisol for 60 h, five intermittent bolus injections of 5 micrograms/kg thyrotropin-releasing hormone (TRH) at 12-h intervals, or both hormones before delivery at 128 days. At birth, the lambs were randomized to receive surfactant or no treatment. Surfactant treatment improved lung function of all the groups. Corticosteroids alone and in combination with TRH improved compliance and gas exchange as well as pressure-volume curves. Corticosteroids alone dramatically decreased the recovery of intravenously administered radiolabeled albumin in the lung tissue and air space and improved the pulmonary response to surfactant treatment. There were no additional effects of TRH when given with corticosteroids on lung function or albumin leak. There were no changes in alveolar surfactant-saturated phosphatidylcholine pool sizes after any hormone treatment. The single significant effect of combined corticosteroid and TRH treatment was a fivefold increase in surfactant protein A in alveolar lavage fluid relative to all other groups.

The ontogenesis of hypothalamic and extrahypothalamic thyrotropin-releasing hormone (TRH) and the effect of altered thyroid status on tissue TRH levels were studied in fetal sheep. At 62 days gestation (term = 145 days) TRH was detectable in serum and in hypothalamic, placental, and pancreatic tissues; pancreatic, placental, and serum levels exceeded hypothalamic levels two- to fivefold. Analysis of tissues obtained from 88-day gestation fetuses were comparable: TRH levels in placenta (54 +/- 15 pg/mg tissue protein), pancreas (34 +/- 5 pg/mg protein), and serum (93 +/- 9 pg/ml) exceeded those in hypothalamic extracts (15 +/- 9 pg/mg protein). By 120 days gestation, TRH values in the hypothalamus (610 +/- 52 pg/mg protein) exceeded those in extrahypothalamic sites; values were comparable at 140 days gestation. Fetal thyroidectomy resulted in a 2-fold elevation of hypothalamic TRH concentrations (1,030 +/- 139 vs. 522 +/- 29 pg/mg protein) and 2 to 20-fold elevations of TRH in the placenta (147 +/- 23 vs. 42 +/- 8 pg/mg protein), pancreas (195 +/- 11 vs. 29 +/- 7 pg/mg protein), duodenum (363 +/- 97 vs. 29 +/- 7 pg/mg protein), and serum (2,563 +/- 212 vs. 131 +/- 16 pg/ml). 3, 5, 3'-Triiodothyronine (T3) infusion in thyroidectomized fetuses resulted in elevated serum T3 values (480 +/- 80 ng/dl) and suppressed hypothalamic TRH (249 +/- 68 vs. 522 +/- 29 pg/mg protein) and serum TRH concentrations (30 +/- 4 vs. 131 +/- 156 pg/ml). Placental, pancreatic, and duodenal TRH concentrations in thyroidectomized T3-infused animals were below the level of detection of the assay (5 pg/mg tissue protein).(ABSTRACT TRUNCATED AT 250 WORDS)

3,3'-Diiodothyronine sulfate (T2S) derived from T3 of fetal origin is transferred to the maternal circulation and contributes significantly to the maternal urinary pool. The present study quantitatively assesses the fetal to maternal transfer of T4 metabolites compared with those of T3. Labeled T4 or T3 was infused intravenously to four singleton fetuses in utero in each group at gestational age 138 +/- 3 d. Maternal and fetal serum and maternal urine samples were collected hourly for 4 h and at 24 h (serum) or in pooled 4-24 h samples (urine). Radioactive metabolites were identified by HPLC and by specific antibody in serum and urine extracts and expressed as percentage infusion dose per liter. The results demonstrate a rapid clearance of labeled T3 from fetal serum (disappearance T(1/2) of 0.7 h versus 2.4 h for T4 in the first 4 h). The metabolites found in fetal serum after labeled T3 infusion were T2S > T3 > T3S; in maternal urine, T2S > unconjugated iodothyronines (UI) > T3S > unknown metabolite (UM). After labeled T4 infusion, the metabolites in fetal serum were rT3 > T3 > T2S > T4S in the first 4 h, and rT3 = T3 = T4S = T2S > T3S at 24 h; in maternal urine we found T2S > UM > UI > T4S > T3S in the first 4 h and UM > T2S > UI in 4-24 h pooled sample. In conclusion, the conversion of T3 to T2S followed by fetal to maternal transfer of T2S and other iodothyronines appears to contribute importantly to maintaining low fetal T3 levels in late gestation.

We assessed renal and cardiovascular function in preterm newborn lambs after antenatal glucocorticoid exposure. Pregnant ewes were randomly assigned to receive betamethasone or saline via either direct fetal or maternal injection at 122 d gestation. Lambs were delivered 15 h later, and cardiovascular and renal function was assessed. Two hours after delivery, baseline urine flow, urinary sodium excretion, and urinary osmolar clearance were similar in all groups. Volume expansion (saline, 2.5% of body weight, for 10 min) increased values for urine flow (0.23 +/- 0.04 to 0.58 +/- 0.09 mL x min(-1) x kg(-1)), urinary sodium excretion (29.7 +/- 5.8 to 76.2 +/- 12.3 microEq x min(-1) x kg(-1)), and osmolar clearance (12.2 +/- 1.2 to 24.3 +/- 1.6 mL/100 mL GFR) in the fetal group. Increases in urine values were also observed in the maternal group, but control values did not change significantly. Mean arterial pressure was increased in both betamethasone-treated groups relative to controls. Short-term antenatal betamethasone exposure 1) augments preterm newborn kidney adaptive responses to acute volume expansion, and 2) increases postnatal blood pressure in preterm newborn lambs.

Earlier studies have shown that sulfoconjugation is a major pathway of thyroid hormone metabolism in fetal mammals. To assess the placental transfer of sulfoconjugates in the pregnant sheep model, we measured 3,3′,5-triiodothyronine (T3) sulfate (T3S), 3,3′-diiodothyronine sulfate (T2S), and T3 concentrations in fetal serum and in maternal serum and urine after T3S infusion to the fetus ( n = 5) or the ewe ( n = 6). Maternal infusion of T3S did not increase fetal serum T2S, T3S, or T3 concentrations. In contrast, fetal infusion of T3S produced significant increases in maternal serum T2S and T3S but not T3 concentrations. Fetal T3S infusion also increased maternal urine excretion of T3S. However, the 4-h cumulative maternal urinary excretion of T2S and T3S after fetal T3S infusion was less than the excretion observed after fetal infusion of equimolar amounts of T3 in our previous study. It is concluded that fetal serum T2S and T3S can be transferred to maternal compartments. However, compared with T3, these sulfoconjugates may be less readily transferred.

Maternal administration of TSH-releasing hormone (TRH) in the euthyroid mouse accelerates fetal lung ultrastructural maturation. However, the mechanism(s) of TRH in fetal lung development remains unclear; it could be due to its neuroendocrine and/or neurotransmitter effects. Although the neuroendocrine effect of TRH is mediated via stimulation of the fetal pituitary-thyroid axis, the neurotransmitter effect is mediated via stimulation of fetal autonomic nervous system activity. In the hyt/hyt mouse there is a point mutation in the beta subunit of the TSH receptor in the thyroid gland of the Balb-c mouse. In these mice TSH does not bind to its receptors, leading ultimately to the development of primary hypothyroidism, which is transmitted as an autosomal recessive trait. A maturational delay in the lung ultrastructure of the hyt/hyt mouse fetus has been observed. This investigation was undertaken to study the effect of maternal TRH treatment on lung ultrastructural maturation in the hyt/hyt mouse fetus. If the effect of TRH is mediated via stimulation of fetal pituitary-thyroid axis, TRH treatment should not enhance lung maturity in the hyt/hyt fetus and vice versa. Adult hyt/hyt mice made euthyroid by triiodothyronine supplementation were mated to carry hyt/hyt pups. Saline or TRH (0.4 or 0.6 mg/kg/dose) was administered to the mother (i.p.) on d 16 and 17 (b.i.d.) and on d 18 of pregnancy 1 h before killing (term, approximately 20 d). The fetal lung electron micrographs were subjected to ultrastructural morphometric analysis of the number of lamellar bodies and glycogen/nuclear ratio in type II cells, and the alveolar/parenchymal ratio by Chalkley point counting with an interactive computerized image analyzer (Optimas, Bioscan). Fetal lungs exposed to the lower dose of TRH (n = 7) showed no significant difference in their ultrastructural maturation when compared with saline-treated controls (n = 5). However, fetal lungs exposed to a higher dose of TRH (n = 6) showed increased numbers of lamellar bodies per type II cell, an increase in the alveolar/parenchymal ratio, larger air spaces, thinner alveolar septa, presence of tubular myelin, and increased numbers of air-blood barriers. We conclude that the effect of TRH in accelerating fetal mouse lung maturation is at least in part mediated via stimulation of extra thyroidal pathways.

Rebello, Celso M., Machiko Ikegami, M. Gore Ervin, Daniel H. Polk, and Alan H. Jobe. Postnatal lung function and protein permeability after fetal or maternal corticosteroids in preterm lambs. J. Appl. Physiol. 83(1): 213–218, 1997.—We evaluated postnatal lung function and intravascular albumin loss to tissues of 123-days-gestation preterm surfactant-treated and ventilated lambs 15 h after direct fetal ( n = 8) or maternal ( n = 9) betamethasone treatment or saline placebo ( n = 9). The betamethasone-treated groups had similar increases in dynamic compliances, ventilatory efficiency indexes, and lung volumes relative to controls ( P < 0.05). The losses of125I-labeled albumin from blood, a marker of intravascular integrity, and the recoveries of125I-albumin in muscle and brain were similar for control and betamethasone-exposed lambs. Betamethasone-treated lambs had lower recoveries of125I-albumin in lung tissues and in alveolar washes than did controls ( P < 0.01). Although blood pressures were higher for the treated groups ( P< 0.05), all groups had similar blood volumes, cardiac outputs, and organ blood flows. Maternal or fetal treatment with betamethasone 15 h before preterm delivery equivalently improved postnatal lung function, reduced albumin recoveries in lungs, and increased blood pressures. However, prenatal betamethasone had no effects on the systemic intravascular losses of albumin or did not change blood volumes.

The optimal dose, route of administration, and treatment-to-delivery interval necessary to induce beneficial extrapulmonary effects of glucocorticoids are not known. Pregnant ewes (127 days gestation) were randomized to receive maternal or fetal intramuscular injections of betamethasone (0.2 or 0.5 mg/kg body wt) or saline 24 h before cesarean delivery of their lambs. Three hours after delivery, low-dose maternal vs. control lamb mean arterial pressure [64 +/- 4 vs. 47 +/- 2 (SE) mmHg], glomerular filtration rate (1.7 +/- 0.2 vs. 0.7 +/- 0.1 ml.min-1.kg-1), and total renal sodium reabsorption (219 +/- 31 vs. 85 +/- 12 mueq.min-1.kg-1) were increased. Comparable increases were observed in the high-dose maternal and fetal groups without effects in the low-dose fetal group. This study provides the first quantitative data demonstrating that even short-term (24-h) antenatal betamethasone exposure alters preterm newborn cardiovascular and renal functions. These responses are route and dose dependent and are comparable to glucocorticoid-induced maturational effects after longer-term antenatal exposure.

OBJECTIVE: We hypothesized that two doses of betamethasone administered 1 week apart would further enhance postnatal pulmonary function in preterm lambs (compared with a single dose). STUDY DESIGN: Fetal sheep (121 days' gestation) randomly received saline solution or betamethasone (0.5 mg/kg) as a single injection. Six days later fetal sheep were retreated with either saline solution or corticosteroid, and postnatal lung function was evaluated 1 day later. RESULTS: Betamethasone improved compliance and ventilation efficiency index nearly 50%, and total lung volume increased twofold. No effects of treatment-to-delivery interval (1 vs 7 days) or corticosteroid retreatment on pulmonary function were apparent. Although surfactant pool sizes increased as a function of duration of exposure, no additional effect of corticosteroid retreatment was noted. Antenatal betamethasone increased messenger ribonucleic acid levels for the surfactant proteins A and C, and retreatment augmented surfactant protein B messenger ribonucleic acid levels but suppressed surfactant protein A and C messenger ribonucleic acid. CONCLUSION: Improved postnatal lung function resulting from antenatal betamethasone was not augmented by retreatment.

We asked whether a single-dose fetal treatment strategy using betamethasone plus either a long-acting beta2 agonist (formoterol) or betamethasone plus agents that elevate intracellular cyclic adenosine monophosphate (isobutyl methylxanthine and dibutyryl-cyclic adenosine monophosphate) would augment the effects of prenatal betamethasone on postnatal lung function. Preterm lambs were treated with 0.5 mg/kg betamethasone or betamethasone plus the other agents and delivered 48 h after treatment. The postnatal lung function as assessed by compliance, ventilatory efficiency, and lung volumes at 40 min of age was improved by prenatal betamethasone and improved further by combination treatment, although the augmented responses were not significantly greater than with betamethasone alone. Fatty acid synthase protein and enzymatic activity were not increased by betamethasone or combined treatments, in contrast to responses reported for other animal models. There were no effects of glucocorticoids or the combined treatments on surfactant. Stimulation of the beta2 agonist system did not augment postnatal lung function significantly above that noted for betamethasone alone with the agents, doses, and duration of exposures tested.

To determine the circulatory response of the preterm fetus to a sustained hypoxic insult, regional blood flow was measured (microsphere technique) in 12 unanesthetized fetal sheep (0.75 gestation) during a normoxic control period, after 1 h and 8 h of sustained hypoxemia, and after a 1-h recovery period. Associated endocrine changes which might relate to organ-specific changes in blood flow were also assessed. Myocardial and cerebral blood flow were increased by 240 and 90%, respectively, such that oxygen delivery to the heart was well maintained throughout the study, whereas that to the brain was significantly decreased by 8 h of hypoxic study. Regional blood flows for all structures within the brain showed similar percent increases, except that for the pituitary gland, where the increase was much smaller, and that for the choroid plexus, where blood flow actually fell. Whereas blood flow to upper body muscle showed no significant change throughout the study, that to the thyroid was increased by 70% by 1 h of hypoxic study but fell thereafter. Adrenal cortical blood flow relative to that of the medulla was increased 3-fold by 8 h of hypoxic study, indicating a differential effect of sustained hypoxia on these vascular beds. Although pituitary and thyroid blood flows showed no relationship to respective trophic and/or secretory hormones measured, values for adrenal cortical flow relative to medullary flow were well correlated with plasma concentrations of ACTH. It is concluded that the "centralization" of blood flow to vital organs in response to a sustained hypoxic insult is qualitatively similar for both the preterm and near term ovine fetus and that hypoxic regulatory mechanisms may be better protective of the heart. Additionally, a role for the functional activation of the adrenal gland in its blood flow response to sustained hypoxemia is suggested.

To evaluate the effect of dose and route of administration of betamethasone on subsequent postnatal lung function, pregnant ewes were randomized at 127 days gestation to receive maternal or fetal intramuscular doses of 0.2 or 0.5 mg/kg body wt betamethasone or saline. At delivery 24 h later, preterm lambs were treated with surfactant and ventilated for 4 h. The lambs exposed to 0.5 mg/kg betamethasone by either the maternal or fetal route had higher Po2 values, lung volumes, dynamic compliances, and ventilatory efficiency indexes, as well as lower ventilatory pressure requirements, than did control animals (P < 0.05). There were no consistent improvements in postnatal lung function for the 0.2 mg/kg dose given to the fetus or ewe. However, measurements of radiolabeled protein in the total lung were decreased in all treatment groups (P < 0.01). Surfactant that was recovered from all groups of lambs and fractionated to isolate the large-aggregate fraction improved lung volumes in preterm rabbits to a greater degree than the surfactant used to treat the lambs (P < 0.05). Surfactant recovered from both groups treated with 0.5 mg/kg betamethasone was less sensitive to inactivation by plasma than was surfactant from the 0.2 mg/kg groups or the controls (P < 0.01). Fetal or maternal treatment with 0.5 mg/kg betamethasone improved postnatal lung function and increased the resistance of surfactant to inactivation.

A single combined intramuscular dose of betamethasone and l-thyroxine (T4) or placebo was injected into the shoulder of fetal lambs 48 hours prior to delivery at days 121 (n = 14), 128 (n = 25) or 135 (n = 20) of gestation. Respiratory mechanics were calculated using multiple linear regression analysis. Both respiratory system resistance (R(RS)) and elastance (E(RS)) decreased approximately 4 fold between gestational days 121 (D121) and 135 (D135). Both variables were also reduced by hormone treatment. Reduction in E(RS) was due to a reduction in both lung (E(L)) and chest wall (E(W)) components. In absolute terms E(W) decreased with gestational age; however, E(W) as a proportion of total elastance (% E(W)) increased. Inclusion of a volume-dependent elastance term in the multiple linear regression model enabled us to separate total elastance into volume-independent (E1) and volume-dependent (E2V) components. E1 decreased almost 8-fold compared with only a 2.5-fold fall in E2V between D121 and D135. %E2, the proportion of E(RS) which is volume-dependent and which provides an index of overventilation, doubled over this time period. Hormone treatment affected E1 and E2V components equally hence %E2 was not altered. Both excised lung volume and end expiratory alveolar volume increased with gestational age and with treatment. The response to treatment was qualitatively similar at each of the gestational ages examined, however, for all mechanics variables, except resistance and E1, the magnitude of response to treatment was significantly smaller in D135 animals compared with other age groups.

The effect of altering the interval from treatment to delivery on postnatal lung function of the preterm lamb is unknown. We treated groups of 8-10 singleton fetal sheep with 0.5 mg/kg betamethasone by fetal injection and evaluated postnatal lung function 40 min after preterm delivery at 123 days gestation 2 days after treatment or at 128 days gestation 2, 4, and 7 days after treatment relative to groups of 4-8 saline-injected control animals. At 123 days, betamethasone significantly improved arterial PCO2, dynamic thoracic compliance, and ventilatory efficiency index and doubled lung gas volume relative to a control group. Fetal treatment with betamethasone 2, 4, or 7 days before delivery at 128 days also improved these same indicators of lung function relative to controls, and the magnitude of the improvements was the same for all indicators and independent of treatment-to-delivery interval. Betamethasone suppressed the normal postnatal increase in plasma cortisol after 2 and 4 days of exposure but not after 7 days of exposure. Betamethasone also increased fetal and postnatal triiodothyronine concentrations after 2 days of exposure but not at 4 or 7 days of exposure. Although the hormone effects were transient, postnatal lung functional responses to betamethasone persisted over the 2- to 7-day interval from treatment to delivery.

Effects of prenatal corticosteroid on the properties of surfactant have not previously been evaluated. A single ultrasound-guided fetal injection with 0.5 mg/kg betamethasone 48 h before delivery of preterm lambs at 134- to 135-days gestation improved oxygenation, lowered the ventilatory pressures required to maintain arterial PCO2 between 30 and 40 Torr and decreased the protein leak of albumin from the intravascular to the alveolar space. This dose of glucocorticoid did not alter surfactant-saturated phosphatidylcholine pool sizes in the airspaces of preterm lambs. However, the treatment changed the characteristics of the surfactant recovered from the ventilated preterm lambs. The in vitro conversion from heavy to light subtype surfactant decreased from 59% for the saline-treated lambs to 37% for the corticosteroid-treated lambs after 180 min of surface area cycling (P < 0.02). Surfactant from the corticosteroid-treated lambs also increased the dynamic compliance of preterm surfactant-deficient rabbits more than did surfactant from the saline-treated lambs (P < 0.05). Prenatal treatment of preterm lambs with betamethasone improved the functional characteristics of surfactant without significant effects on the alveolar surfactant pool sizes.

Objective: The purpose of this study was to investigate the fetal catecholamine and arterial blood gas responses to ultrasonographically guided percutaneous needle aspiration of blood from a fetal cardiac ventricle. Study Design: A crossover trial design was used. Nine pregnant sheep of 120 to 130 days' gestation were stratified to either percutaneous fetal blood sampling or a sham experiment performed on the first day, and the alternative study on the following day. Arterial blood samples were withdrawn from chronically implanted catheters. Results: Percutaneous fetal blood sampling caused small but statistically significant increases in mean plasma epinephrine and norepinephrine levels 5 seconds after the procedure. Levels thereafter were similar to baseline values. Arterial pH and P CO 2 values were unaltered except in one fetus, where blood sampling was followed by bradycardia with acidosis and elevated catecholamine levels. Conclusions: Ultrasonographically guided percutaneous fetal blood sampling from a cardiac ventricle in sheep produces a rise in catecholamine levels that return to baseline values within 5 minutes. This technique provides an alternative to chronic catheterization for some experiments in which blood sampling or drug injection is required. The results also indicate that needle insertion produces only a modest and transient stress response in the fetus.

Maternal corticosteroid treatments augment lung function in the human preterm infant. However, not all fetuses respond, the response requires > or = 48 h of exposure, and multiple maternal doses expose the mother to potential risks. To evaluate the potential of direct fetal therapy, we used ultrasound to direct fetal intramuscular or intravascular injections of corticosteroids or saline in sheep and subsequently delivered the preterm lambs at 128 days gestational age to assess postnatal lung function. Relative to saline-injected controls, 0.5 or 2 mg/kg betamethasone given as a single intramuscular dose 48 h before delivery increased compliance and the efficiency of ventilation (as measured by an indicator that included ventilatory pressures and CO2 values) nearly twofold (P < 0.05). Lung volumes, measured from deflation pressure-volume curves, also increased (P < 0.05). However, the 2 mg/kg dose caused severe pulmonary interstitial emphysema in 5 of 13 lambs, suggesting adverse effects. An intravascular fetal dose of 12.5 mg/kg hydrocortisone or an intramuscular dose of 0.1 mg/kg betamethasone had no effect on postnatal lung function. In separate studies, the 2 mg/kg dose improved all indicators of lung function almost twofold after only 24 h of fetal exposure and delivery at 128 days gestational age (P < 0.01). There was a dose-dependent suppression of the postnatal cortisol surge in treated animals, although fetal treatment did not alter cord cortisol levels. Single-dose fetal hormone treatments can cause large and rapid improvements in postnatal lung function in preterm lambs.

We assayed TSH, triiodothyronine, free thyroxine, and prolactin (PRL) in plasma of women and infants participating in a trial of prenatal thyrotropin-releasing hormone (TRH) treatment for prevention of newborn lung disease. Women in labor at 26-34 wk of gestation received 400 micrograms of TRH i.v. every 8 h (one to four doses) plus 12 mg betamethasone (one or two doses); controls received saline plus betamethasone. Mean cord concentrations in control infants were TSH 9.7 mU/L, triiodothyronine 0.6 nmol/L (40.2 ng/dL), free thyroxine 14.4 pmol/L (1.13 ng/dL), and PRL 67.6 micrograms/L. TRH increased maternal plasma TSH by 100% at 2-4 h after treatment and decreased levels by 28-34% at 5-36 h. In cord blood of treated infants delivered at 2-6 h, TSH, triiodothyronine, and PRL were all increased about 2-fold versus control, and free thyroxine was increased 19%; the response was similar after one, two, three, or four doses of TRH. In treated infants delivered at 13-36 h, cord TSH and triiodothyronine levels were decreased 62 and 54%, respectively, and all thyroid hormones were lower after birth at 2 h of age versus control. We conclude that prenatal TRH administration increases thyroid hormones and PRL in preterm fetuses to levels similar to those normally occurring at term. Pituitary-thyroid function is transiently suppressed after treatment to a greater extent in fetus than mother, and infants born during the early phase of suppression do not have the normal postnatal surge in thyroid hormones.

Many hormones and several growth factors are present in significant concentrations in breast milk. That these substances are of physiologic significance has been suggested by many investigators. This review summarizes the biological roels of thyroid hormones and epidermal growth factor (EGF) derived from breast milk in a variety of developing mammals.

Forty-three twin lamb fetuses of 121 +/- 1 d gestation were catheterized and received i.v. saline (n = 8), 0.75 mg/kg/h cortisol for 60 h (n = 15), 5 micrograms/kg thyrotropin-releasing hormone (TRH) every 12 h for five doses (n = 9), or cortisol and TRH (n = 11) before delivery at 128 +/- 1 d. After delivery, the lambs were randomized for natural sheep surfactant treatment or sham treatment, ventilated for 75 min, and killed. Superoxide dismutase, catalase, and glutathione peroxidase activities were measured in fetal lung tissue. Superoxide dismutase and catalase activities were increased in both the corticosteroid (p less than 0.001) and the corticosteroid with TRH (p less than 0.01) groups. Glutathione peroxidase activity was higher after prenatal corticosteroid treatment, but statistical significance was not reached (p = 0.06). Although prenatal exposure to corticosteroids increased superoxide dismutase, catalase, and glutathione peroxidase activities, TRH alone or TRH added to corticosteroids provided no additional benefit. Lambs treated with surfactant had higher lung catalase activities than lambs that did not receive surfactant, probably secondary to the presence of catalase activity in the surfactant preparation. Increased pulmonary antioxidant enzyme activity may be an additional feature of the overall beneficial effect of corticosteroids on fetal lung development.

Thyrotropin releasing hormone (TRH) and its precursor peptide pGlu-His-Pro-Gly (TRH-Gly) were measured in serum and in a variety of tissues of developing rats using specific RIA. TRH and TRH-Gly immunoreactivities were detected in most tissues. TRH concentrations were highest in pancreas, in which mean (± SEM) TRH concentrations were 138 ± 20 pmol/g wet tissue 2 d before birth and 644 ± 80 and 586 ± 86 pmol/g, respectively, 2 and 5 d after birth. Hypothalamic TRH levels gradually increased from 4 d before birth (12 ± 2.5 pmol/g) to 77 d of postnatal age (348 ± 33 pmol/g). Hypothalamic concentrations were lower than levels in pancreas until 13 d of age. The mean serum TRH level at 2 d was 80 ± 20 pmol/L and fell to the adult range by 21 d. TRH-Gly concentrations were highest in small gut (371 ± 64 pmol/g) during the neonatal period, falling gradually to adult levels (33 ± 4.8 pmol/g) by 35 d. Mean hypothalamic TRH-Gly concentrations increased to a peak of 62 ± 4.5 pmol/g at 13 d, falling thereafter. High TRH-Gly concentrations (>100 pmol/g) also were observed in pancreas (at d 2), kidney, and pituitary gland (at d 21). Serum TRH-Gly concentrations were highest (mean 417 ± 26 pniol/L) on the 2nd postnatal day and gradually decreased to the adult level by 35 d. Changes in the TRH-Gly/TRH ratio were inversely correlated with tissue TRH concentrations in hypothalamus, pancreas, and liver. Our results suggest that 1) tissue levels of TRH-Gly and TRH are developmentally regulated, 2) the conversion of TRH-Gly to TRH varies among tissues, and 3) the major tissue site of TRH biosynthesis changes during development from liver during fetal life to pancreas in the neonatal period and to hypothalamus in the adult. The consistently high TRH-Gly/TRH ratio in serum suggests that the circulating peptides are derived from multiple and predominantly non-hypothalamic tissue sources.

TRH (pGlu-His-Pro-NH2) arises from the post-translational processing of a larger precursor peptide containing multiple copies of the TRH progenitor sequence, Gln-His-Pro-Gly. Concentrations of TRH and its precursor peptide (TRH-Gly) were determined in serum and a variety of tissues of the rat using specific RIA systems. TRH and TRH-Gly immunoreactivities were detectable in almost all tissues studied. TRH was distributed mainly in neural tissues, with the highest mean concentration (126 pg/mg tissue) in hypothalamus. In extra-neural tissues, mean TRH levels ranged from 0.6-4.8 pg/mg tissue; the mean serum concentration was 12.4 pg/ml. In contrast to the distribution of TRH, relatively higher mean TRH-Gly concentrations were observed in serum (76.5 pg/ml) and in extraneural tissues, including prostate (83.3 pg/mg tissue), spleen (19.0 pg/mg), adrenal (16.2 pg/mg), kidney (13.3 pg/mg), and gastrointestinal tract (6.3-19.8 pg/mg). Among brain tissues, the TRH-Gly concentration was highest in pituitary gland (13.1 pg/mg). The mean ratio of TRH-Gly/TRH concentrations was less than 1 in neural tissues and pancreas. The lowest ratio (0.04) was observed in hypothalamus, and the highest ratio (66) in prostate gland. Assuming that tissue TRH-Gly levels reflect TRH synthesis, these results suggest that 1) the processing of TRH-Gly to TRH varies among tissues, 2) TRH-Gly to TRH conversion occurs most efficiently in neural tissues, and 3) TRH-Gly to TRH conversion may be a rate-limiting step in TRH biosynthesis.

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.

Plasma Thyroid Hormone Concentrations in Premature Infants and Effect of Thyrotropin Releasing Hormone (TRH) † 954