PubMed Health⌕ Search

Biomedical subjects

J A Widness

Publications and source records attributed to J A Widness.

At least 55 records · Page 3Linked to original sources
PubMed1996

Decreased fetal erythropoiesis and hemolysis in Kell hemolytic anemia.

OBJECTIVE: Lower changes in optical density (450 nm) measurements have been reported in fetuses with anti-Kell anemia compared with those anti-D anemia. The purpose of this investigation was to determine if hemolysis and erythropoiesis differ between anti-Kell and anti-D hemolytic disease. STUDY DESIGN: Ninety-three pregnancies complicated by either anti-D or anti-Kell alloimmunization were evaluated. Fetal blood samples obtained at the first cordocentesis were tested for the red blood cell antigen type, hemoglobin, hematocrit, reticulocyte count, nucleated red blood cells, total serum bilirubin concentration, umbilical venous respiratory blood gases, serum erythropoietin level, and strength of the direct Coombs test. To determine the evolution of hemolytic anemia in the two antigen groups, these laboratory parameters were repeated on the fetal blood samples triggering the decision to perform a fetal intravascular transfusion (hematocrit <30%). RESULTS: A total of 65 of 93 fetuses were antigen positive (11 for Kell and 54 for RhD). The mean gestational age and laboratory measurements of antigen- positive, nonanemic fetuses at first blood sampling did not differ significantly between groups. There was a strong inverse relationship observed between the hemoglobin concentration and reticulocyte count independent of gestational age in the anti-D group but not in the anti-Kell group. Eight (73%) fetuses with anti-Kell antibodies and 37 (69%) with anti-D antibodies underwent intravascular transfusion. At the cordocentesis when the decision for transfusion was made, anti-Kell anemic fetuses had lower reticulocyte counts and total bilirubin concentrations. The strong inverse relationship between the hemoglobin and reticulocyte count was again seen only in the anti-D group. In both groups, fetal erythropoietin increased significantly between the first and last blood samplings and in each group were negatively correlated with hemoglobin independent of gestational age. CONCLUSION: Anti-Kell anemic fetuses have lower reticulocyte counts and total serum bilirubin levels than do comparable anti-D anemic fetuses. This finding argues in favor of fetal blood sampling rather than amniotic fluid analyses for the management of fetal hemolytic disease resulting from Kell antibodies. Unlike RhD alloimmunized fetuses, these fetuses do not manifest an inverse relationship between hemoglobin concentration and reticulocyte count. We speculate that compared to anti-D fetal anemia, anti-Kell anemia is associated with increased hemolysis of nonhemoglobinized or incompletely hemoglobinized erythroid precursors.

Anemia, Hemolytic↗
PubMed1996

Changing patterns of red blood cell transfusion in very low birth weight infants.

OBJECTIVE: Anemia develops in increasing numbers of critically ill very low birth weight (VLBW) infants who survive the neonatal period, and they receive multiple red blood cell (RBC) transfusions. Despite their need for prolonged medical treatment, we hypothesized that VLBW infants presently receive fewer RBC transfusions as a result of the growing awareness of transfusion risks and improvement of neonatal care. METHODS: RBC transfusion practices and clinical outcomes in infants with birth weights of 1.5 kg or less were analyzed retrospectively in three selected years: 1982, before awareness of the human immunodeficiency virus; 1989, before surfactant availability; and 1993, before erythropoietin approval. RESULTS: Progressive declines in RBC transfusions, donor exposures, and transfusion volumes occurred concurrently with decreases in morbidity and mortality rates. Transfusions per infant (mean +/- SD) declined from 7.0 +/- 7.4 in 1982 to 5.0 +/- 5.8 in 1989 to 2.3 +/- 2.7 in 1993 (p < 0.001). This decline was associated with a decrease in pretransfusion hematocrit (33.6% +/- 2.8% in 1982, 34.2% +/- 3.7% in 1989, and 29.8% +/- 5.1% in 1993; p < 0.001). The distribution of RBC transfusions given by week of life among study years did not change; 70% of RBC transfusions were given within the first 4 weeks, when infants are sickest. Although the percentage of VLBW infants weighing more than 1 kg at birth and never receiving any RBC transfusions increased with time (17% in 1982, 33% in 1989, and 64% in 1993), more than 95% of infants weighing 1 kg or less in all years received transfusions. CONCLUSIONS: Overall administration of neonatal transfusions has decreased markedly, most likely because of multiple factors. Because most RBC transfusions are given to infants weighing 1 kg or less in the first weeks of life, therapeutic strategies should focus on this group of VLBW infants during this critical period. The temporal changes observed in transfusion patterns emphasize the importance of including concurrent controls in future studies evaluating transfusion interventions.

Erythrocyte Transfusion↗
PubMed1996

Serum erythropoietin levels during infancy: associations with erythropoiesis.

OBJECTIVE: To determine plasma erythropoietin levels and their association with hemoglobin and reticulocyte counts in healthy term infants. DESIGN: We compared plasma erythropoietin levels measured in serial blood samples obtained every 4 weeks during the first 6 months of life with one another and with levels in term fetuses and healthy adults. Correlation analysis was applied to examine for associations of erythropoietin with hemoglobin and with reticulocyte count. RESULTS: Plasma erythropoietin levels were lowest in the first and highest in the second postnatal months, a pattern reciprocal to that observed for hemoglobin during the period of physiologic anemia. The erythropoietin level was negatively correlated with hemoglobin (p < 0.0001) and positively correlated with reticulocytes (p < 0.0001). The slope of the inverse relationship of hemoglobin and plasma erythropoietin in infants was similar to those previously reported for anemic fetuses and premature infants, but much less steep than for anemic children and adults. CONCLUSION: This study is the first to report simultaneous patterns of change observed in plasma erythropoietin, hemoglobin, and reticulocytes during normal infancy. These patterns are consistent with postnatal perturbations in tissue oxygenation and suggest a major role for erythropoietin in the regulation of erythropoiesis during normal infancy, but at a lower hemoglobin concentration than for older children and adults with pathologic anemia.

Adult↗
PubMed1996

Erythropoietin pharmacokinetics in premature infants: developmental, nonlinearity, and treatment effects.

Erythropoietin (EPO) pharmacokinetic studies were performed in premature infants (birth weight < 1.25 kg) and normal adults. Infants were divided into two subgroups on the basis of whether they received chronic treatment with recombinant human EPO (rhEPO; 500 IU.kg-1.wk-1 for 6 wk) beginning at 2-4 wk of life. Ten adults and seven rhEPO-treated infants underwent intravenous pharmacokinetic studies at escalating rhEPO doses: 10, 100, and 500 IU/kg. To test for pharmacokinetic developmental and treatment effects, an equal number of non-EPO- and EPO-treated infants were studied with 100 IU/kg on the last day of treatment. Compared with adults, very low birth weight infants demonstrated significantly greater plasma clearance and distribution volume and significantly shorter fractional elimination times (FET) and mean residence time (MRT) at all three rhEPO doses. Both infants and adults demonstrated nonlinear EPO elimination, i.e., increasing rhEPO dosing was associated with decreasing plasma clearance and increasing FET and MRT. In the absence of rhEPO treatment there were no pharmacokinetic differences between the two subgroups of infants studied 6 wk apart. In contrast, the rhEPO-treated infant subgroup demonstrated a significant increase in clearance and a decrease in FET and MRT following 6 wk of treatment. Enhancement of rhEPO efficacy in the prevention and treatment of anemia in premature infants may require higher doses administered in a progressively increasing fashion.

Adult↗
PubMed1996

Effect of chronic erythropoietin administration on plasma iron in newborn lambs.

Erythropoietin, the primary stimulator of erythropoiesis, represents an important potential therapy for the anemia of prematurity. Enhancement of the therapeutic benefit of recombinant human erythropoietin (rhEp) in very-low-birth-weight infants will require a better understanding of rhEp's pharmacodynamic effects including its interaction with iron in stimulating erythropoiesis. The purpose of this study was to determine the effects of chronic rhEp administration on plasma iron levels and hematopoiesis using a twin lamb model. Nine pairs of twin lambs in which one twin was randomized to receive rhEp, and the other saline, were studied during a 1-week baseline and a subsequent 4- to 5-week treatment period. The effects of therapy on plasma iron levels and erythropoiesis were measured by integrating the areas under the concentration-time curves (AUC) of the study variables. During the rhEp treatment period, significantly greater negative daily AUCs were observed in the rhEp-treated lambs for plasma iron concentration (p = 0.0008), while significantly greater positive daily AUCs were observed for hemoglobin concentration (p = 0.04) and reticulocyte count (p = 0.02). In the rhEp-treated group, pretreatment iron concentrations were directly associated with the magnitude of the iron response during treatment such that the greater the pretreatment iron, the greater the daily AUC below the plasma iron concentration-time plot (r = -0.66, p = 0.05). For the placebo-treated group, this association tended toward, but did not achieve, statistical significance (r = -0.52, p = n.s.). These observations suggest that treatment of rapidly growing newborn lambs with rhEp results in increased iron utilization due to increased erythropoiesis and depends on iron status at the initiation of rhEp treatment. Use of the term neonatal lamb model offers advantages over studies in human infants for more detailed or invasive examinations of the interaction of iron and rhEp treatment.

Animals↗
PubMed1996

In vivo 125I-erythropoietin pharmacokinetics are unchanged after anesthesia, nephrectomy and hepatectomy in sheep.

Knowledge regarding the in vivo metabolic fate of the glycoprotein erythropoietin (EPO) is incomplete. To determine whether EPO pharmacokinetics are perturbed by ablation of the kidneys or liver or by anesthesia, EPO pharmacokinetic parameters were determined in adult sheep. Animals were studied in a paired manner, with and without deep barbiturate anesthesia and before and immediately after nephrectomy or hepatectomy accompanied by deep barbiturate anesthesia. Hepatectomy was accomplished with the liver left in situ, by occlusion of the arterial hepatic blood supply and diversion of portal venous flow to the jugular vein. After i.v. administration of tracer amounts of 125I-labeled recombinant human EPO, multiple blood samples were taken over 6 to 7 hr and analyzed for EPO immunoprecipitable radioactivity. EPO pharmacokinetic parameters were derived using a noncompartmental system analysis applied to the data on EPO immunoprecipitable radioactivity. No significant differences were detected for plasma clearance, distribution volume, mean residence time and alpha and beta half-lives examined under each of the three paired study conditions. Contrary to speculation by others, results of the present study make it highly unlikely that removal of the terminal sialic acid moieties of EPO contributes significantly to the metabolism of EPO. Because removal of the liver and kidney had no effect on EPO elimination, the metabolic degradation of EPO occurs in a tissue compartment that is yet to be defined. We speculate that the bone marrow is the most likely tissue with primary responsibility for the metabolism of EPO.

Anesthetics↗
PubMed1995

Kinetic evaluation of nonlinear drug elimination by a disposition decomposition analysis. Application to the analysis of the nonlinear elimination kinetics of erythropoietin in adult humans.

The disposition-decomposition analysis (DDA) methodology enables isolation of the overall elimination and distribution effects in pharmacokinetics and facilitates analysis which focuses on drug elimination kinetics and does not require a specific structured modeling of drug distribution processes. A computer algorithm enables a curve fitting and a kinetic estimation by integration of the convolution type integrodifferential equation in the DDA. The approach is demonstrated in an analysis of the nonlinear disposition kinetics of erythropoietin (Epo) in 10 healthy, adult human subjects who each received 10, 100, and 500 U/kg i.v. bolus doses of Epo. The nonlinearity is analyzed according to a Michaelis-Menten type nonlinear elimination function, considering simultaneous fitting to the data from all three doses in each subject. The simultaneous fittings produced estimates of the Michaelis-Menten parameters (mean, % cv) Vm (901 mU/mL/h, 19.4%) and km (4814 mU/mL, 24.6%). A linear clearance parameter is defined as the asymptotic clearance value approached when the drug level decreases toward zero. The degree of nonlinearity reached from various dosings was quantified in terms of a clearance ratio which is defined as the ratio between the linear clearance and the clearance estimated for the maximum drug concentration encountered at the given dose level. The subjects showed very little nonlinearity at the 10 U/kg dosing with a mean clearance ratio of 1.07 (2.1% CV) A statistically significant increase in the degree of nonlinearity was observed in the Epo elimination kinetics as the dosing level was increased to 100 and 500 U/kg, reaching clearance ratios of 1.66 (14% CV) and 4.33 (27% CV), respectively. A zero value for the global elimination rate parameter in all 30 dosings indicates that Epo's elimination is entirely accounted for by nonlinear pathway(s).

Adult↗
PubMed1995

The effect of regular maternal exercise on erythropoietin in cord blood and amniotic fluid.

OBJECTIVE: Our purpose was to test the hypothesis that continuing regular, high-intensity exercise until the onset of labor produces significant fetal hypoxemia, as evidenced by elevated erythropoietin levels in the fetal compartment. STUDY DESIGN: Erythropoietin levels were measured in samples of amniotic fluid and cord blood obtained from fetuses born to 31 exercising women and 29 matched controls. RESULTS: Erythropoietin levels (mean +/- SEM) in amniotic fluid obtained at the time of membrane rupture (9 +/- 2 vs 11 +/- 2 mU/ml) and in cord blood (38 +/- 6 vs 53 +/- 16 mU/ml) and amniotic fluid at delivery (9 +/- 1 vs 24 +/- 12 mU/ml) were no different in women who exercised regularly until the onset of labor. In both groups the majority of elevated cord blood levels (> 50 mU/ml) could be explained by labor events. Amniotic fluid erythropoietin levels correlated directly (r = 0.52) with cord blood hematocrit and increased slowly during labor. CONCLUSION: We conclude that the initial hypothesis is incorrect and speculate that cord blood erythropoietin reflects fetal oxygenation during labor, whereas amniotic fluid erythropoietin primarily reflects the adequacy of oxygenation before the onset of labor.

Adult↗
PubMed1995

Effect of recombinant human erythropoietin on the switchover from fetal to adult hemoglobin synthesis in preterm infants.

To determine whether recombinant erythropoietin (r-HuEpo) administered to very low birth weight infants could increase hemoglobin F synthesis, or delay its developmentally programmed decline, we determined serially the synthesis of hemoglobins A and F in 15 preterm infants receiving either a placebo or r-HuEpo. There was no difference between the two groups in the proportion of hemoglobin F being synthesized in relation to postconceptional age.

Analysis of Variance↗
PubMed1995

The proportions of G gamma- and A gamma-globins in the fetal hemoglobin synthesized in preterm and term infants.

The change in G gamma to A gamma ratio in relation to the switchover of fetal HB (HbF) to adult Hb (alpha 2 beta 2) synthesis has not been well defined. The gamma-globins of HbF (alpha 2 gamma 2) have either glycine (G gamma) or alanine (A gamma) at position 136. During fetal life the G gamma makes up 70% of the gamma-globins, although they are 40% of the small amounts of HbF in the adult. To further the understanding of this switchover, globin chain synthesis was determined sequentially in eight preterm and 20 full-term infants postnatally. To complete the study, single analysis was also carried out in eight term infants at birth and six preterm infants at the postconceptional age equivalent to term. Blood samples were incubated in an amino acid mixture containing 3H-leucine and subjected to reversed-phase liquid chromatography. The results demonstrated that the fetal proportions of G gamma to A gamma are rigidly controlled according to postconceptional age and not affected by postnatal age after preterm birth. During the early postconceptional age switchover from HbF to adult Hb synthesis, an equal repression of the G gamma and A gamma chains was found. However, based on the values obtained from the term infants, after a postconceptional age of 44 wk, the levels of G gamma to total gamma synthesis begin to decrease and become more variable.

Fetal Hemoglobin↗
PubMed1995

Circulatory and metabolic effects of hypoxia in the hyperinsulinemic ovine fetus.

Fetuses of women whose diabetes is poorly controlled often exhibit hypoxemia and elevated catecholamine concentrations at birth. In the ovine fetus, experimental hyperinsulinemia results in hypoxemia, elevated catecholamine concentrations, and hemodynamic changes. Limited oxygen availability occurring during pregnancy-related complications and/or delivery may present an additional risk to the hyperinsulinemic fetus. In this study, we tested the hypothesis that hypoxia induced via acutely limiting oxygen availability compromises the hemodynamically and metabolically stressed but compensated hyperinsulinemic ovine fetus. Fetuses receiving insulin (n = 8) or placebo (n = 5) for 48 h were exposed to maternally induced hypoxia. Hypoxic hypoxia was associated with a surge in catecholamines in the hyperinsulinemic fetuses. During hypoxia, this group exhibited insulin-related sustained increases in the combined ventricular output and fetal body blood flow, accentuation of the prior insulin-related increase in blood flow to the heart, decreased systemic oxygen delivery, accentuation of the insulin-related increased oxygen extraction, reductions in the insulin-related increased systemic oxygen uptake, sustained increases in regional oxygen delivery to the heart and adrenal glands, reductions in the insulin-related increased delivery to the carcass, and decreased oxygen delivery to the kidneys and gastrointestinal tract. We conclude that, in the hyperinsulinemic ovine fetus, hypoxic hypoxia attenuates the hyperinsulinemia-mediated increased systemic oxygen uptake. Regional oxygen transport is preserved to vital regions (brain, heart, and adrenal glands) by increased perfusion and compromised to certain other regions (kidneys and gastrointestinal tract), because the increases in perfusion are insufficient to offset the limited oxygen availability.

Animals↗
PubMed1995

Erythropoietin transplacental passage--review of animal studies.

Animal studies addressing the question does erythropoietin (EPO) cross the placenta are reviewed in a historical context. The majority of early studies using impure EPO preparations and assays of EPO's biologic activity concluded that EPO did not cross the placenta in biologically meaningful quantities. With the availability of pure recombinant EPO, direct measurement of EPO passage using radiolabeled tracers confirmed these findings in near term sheep and monkeys, but not in mice and rats. In the latter species, fetal plasma EPO levels were 7-10% of maternal plasma levels. Although not proven, it is likely that in murine species maternal EPO reaches the fetal circulation via a receptor mediated process. Even though EPO receptors have not been found in late gestation ovine and human placental tissue, this does not eliminate the possibility that EPO could traverse the placenta earlier in gestation during organogenesis. Thus while treatment of anemic women during pregnancy may have desirable maternal physiologic effects and eliminate maternal and fetal risks associated with erythrocyte transfusion, the potential for as yet unrecognized untoward fetal effects of EPO remains. In addition to future animal studies, ethically acceptable and scientifically sound studies in appropriately selected high risk groups of anemic women are needed to address this concern.

Animals↗
PubMed1995

Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants.

DESIGN AND METHODS: We hypothesized that treatment with recombinant human erythropoietin (r-HuEPO) would stimulate erythropoiesis and would thereby reduce the need for erythrocyte transfusions in preterm infants. We treated 157 preterm infants born at 26.9 +/- 1.6 weeks of gestation who weighed 924 +/- 183 g at birth with either subcutaneous r-HuEPO (100 U/kg/d, 5 days per week) or placebo for 6 weeks in a randomized, double-blind, controlled clinical trial. All patients received oral iron and were managed according to uniform conservative transfusion guidelines. RESULTS: Treatment with r-HuEPO was associated with fewer erythrocyte transfusions (1.1 +/- 1.5 per infant in the r-HuEPO group versus 1.6 +/- 1.7 per infant in the placebo group; P = .046) and with a reduction in the volume of packed erythrocytes transfused (16.5 +/- 23.0 mL versus 23.9 +/- 25.7 mL per infant; P = .023). Overall, 43% of the infants in the r-HuEPO group and 31% of placebo-treated infants were transfusion-free during the study (P = .18). The volume of blood removed for laboratory tests and the need for respiratory support at the start of treatment had major effects on transfusion requirements independent of r-HuEPO. Reticulocyte counts were higher during treatment in the r-HuEPO group (P = .0001), and r-HuEPO-treated infants had higher hematocrit values at the end of the study (32% versus 27.3% in the placebo group; P = .0001). We found no differences in the incidence of major complications of prematurity between the treatment groups. CONCLUSION: We conclude that treatment with r-HuEPO at a weekly dose of 500 U/kg stimulates erythropoiesis, moderates the course of anemia, is associated with a reduction in erythrocyte transfusions, and appears safe in very low birth weight preterm infants who are receiving iron supplements. Conservative transfusion criteria, minimization of phlebotomy losses, and treatment with r-HuEPO are complementary strategies to reduce erythrocyte transfusions in these infants.

Anemia↗
PubMed1994

Recombinant human erythropoietin vs transfusions in the treatment of anemia of prematurity. A cost-benefit analysis.

OBJECTIVE: To evaluate the costs relative to the benefits of using recombinant human erythropoietin (rHuEPO) therapy as an alternative to red blood cell (RBC) transfusions in infants with anemia of prematurity. DESIGN: A cost-benefit analysis of rHuEPO therapy was performed based on its use in very-low-birth-weight premature infants. SETTING AND PATIENTS: Data were drawn from published studies or were provided by the University of Iowa Hospitals and Clinics, Iowa City. MAIN OUTCOME MEASURES: Costs and benefits were analyzed as a comparison of incurred costs to averted costs. Incurred and averted costs of rHuEPO therapy and RBC transfusions included direct product costs and estimates of costs of adverse events. The analysis was viewed in terms of net savings. Sensitivity analysis was performed. RESULTS: The base case analysis yielded a net loss of $299.48 per infant. A 54% reduction in the direct product costs of rHuEPO therapy yielded a break-even point. No other variations in the sensitivity analysis resulted in a net savings. CONCLUSION: Using assumptions based on the current state of clinical research, it appears that routine use of rHuEPO with supplemental RBC transfusions would not generate any cost savings as an alternative to RBC transfusions alone. As further evidence is compiled on the efficacy of rHuEPO therapy in very-low-birth-weight premature infants, the true costs may be better established.

Anemia, Neonatal↗
PubMed1994

Myocardial, erythropoietic, and metabolic adaptations to anemia of prematurity.

We determined the effects of anemia of prematurity on myocardial, metabolic, and erythropoietic functions. Twelve anemic (hemoglobin range, 65 to 78 gm/L) infants without symptoms (gestational age, (mean +/- SD) 28 +/- 2 weeks; birth weight, 1178 +/- 326 gm) were studied at a postconceptional age of 35 +/- 1.6 weeks. All measurements were done before and 36 to 48 hours after a transfusion of packed erythrocytes. Cardiac output, heart rate, and myocardial function were assessed. Oxygen consumption, carbon dioxide production, resting energy expenditure, arterial oxygen pressure for 50% hemoglobin saturation, and the concentrations of erythropoietin and 2,3-diphosphoglycerate were also determined. After transfusion, increased hemoglobin level (75 +/- 4 to 150 +/- 16 gm/L) and decreased oxyhemoglobin affinity (20.8 +/- 1.7 to 23.6 +/- 2.1 gm/L; p < 0.05) caused a decrease in plasma erythropoietin concentration (from 21.1 +/- 6.2 to 5.8 +/- 1.5 mU/ml; p < 0.01). There was a decrease in heart rate (from 155 +/- 10 beats/min to 146 +/- 7 beats/min) and cardiac output (from 281 +/- 73 ml/kg per minute to 199 +/- 62 ml/kg per minute; p < 0.05). Myocardial function indexes, weight gain, and metabolic demands were normal before and after transfusion. These results suggest that oxygenation is adequately maintained in symptom-free infants with anemia of prematurity.

Anemia, Neonatal↗
PubMed1994

Elevated erythropoietin levels in cord blood of newborns with Down's syndrome.

Plasma erythropoietin (Ep) was determined in umbilical cord blood in 18 infants with Down's syndrome. The 16 infants with Down's syndrome who were delivered after labor had significantly elevated plasma Ep levels compared to 36 control infants born after labor (p < 0.001). Six of the ten infants with Down's syndrome who had their packed cell volume (PCV) measured in the first 24 h of life were polycythemic based on a PCV of > or = 0.65. The presence of congenital heart disease in 9 of the 18 infants with Down's syndrome was not associated with a higher plasma Ep or PCV levels. Plasma Ep was correlated with neonatal PCV in the combined group of control and Down's syndrome infants (p = 0.003). Increased plasma Ep levels observed in infants with Down's syndrome suggested chronic fetal hypoxemia as a likely explanation for the high incidence of neonatal polycythemia observed in this group.

Down Syndrome↗