John A. Widness

Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants.

Objective. Although many centers have introduced more restrictive transfusion policies for preterm infants in recent years, the benefits and adverse consequences of allowing lower hematocrit levels have not been systematically evaluated. The objective of this study was to determine if restrictive guidelines for red blood cell (RBC) transfusions for preterm infants can reduce the number of transfusions without adverse consequences. Design, Setting, and Patients. We enrolled 100 hospitalized preterm infants with birth weights of 500 to 1300 g into a randomized clinical trial comparing 2 levels of hematocrit threshold for RBC transfusion. Intervention. The infants were assigned randomly to either the liberal- or the restrictive-transfusion group. For each group, transfusions were given only when the hematocrit level fell below the assigned value. In each group, the transfusion threshold levels decreased with improving clinical status. Main Outcome Measures. We recorded the number of transfusions, the number of donor exposures, and various clinical and physiologic outcomes. Results. Infants in the liberal-transfusion group received more RBC transfusions (5.2 ± 4.5 [mean ± SD] vs 3.3 ± 2.9 in the restrictive-transfusion group). However, the number of donors to whom the infants were exposed was not significantly different (2.8 ± 2.5 vs 2.2 ± 2.0). There was no difference between the groups in the percentage of infants who avoided transfusions altogether (12% in the liberal-transfusion group versus 10% in the restrictive-transfusion group). Infants in the restrictive-transfusion group were more likely to have intraparenchymal brain hemorrhage or periventricular leukomalacia, and they had more frequent episodes of apnea, including both mild and severe episodes. Conclusions. Although both transfusion programs were well tolerated, our finding of more frequent major adverse neurologic events in the restrictive RBC-transfusion group suggests that the practice of restrictive transfusions may be harmful to preterm infants.

Increased erythropoiesis and elevated erythropoietin in infants born to diabetic mothers and in hyperinsulinemic rhesus fetuses.

The pathogenesis of the increased erythrocytosis and extramedullary erythropoiesis observed in infants of diabetic mothers (IDM) has been obscure. In the present studies, IDM were found to have elevated umbilical plasma erythropoietin (Ep) concentrations by radioimmunoassay. 22 of 61 IDM (36%) had levels above the range of 28 nonasphyxiated, appropriately grown normal infants. In 16 controls and 20 IDM, plasma Ep correlated directly with plasma insulin (P less than 0.001, r = 0.73). To investigate this relationship further, a chronic rhesus model was studied with continuous fetal hyperinsulinemia for 21 d in utero in the last third of pregnancy. In five experimental fetuses, plasma insulin levels averaged 4,210 microU/ml at delivery, whereas plasma Ep was above the range of six controls. In addition, the experimental fetuses had elevated reticulocyte counts in umbilical cord blood. The mechanism for the increased plasma Ep associated with hyperinsulinemia in the fetus is unexplained but may be mediated by fetal hypoxia.

Chronic Hyperinsulinemia in the Fetal Rhesus Monkey: Effects on Fetal Growth and Composition

The delivery of 19 U of insulin a day for 21 days to the rhesus monkey fetus, coupled with the permeability properties of the placenta, has made it possible to produce fetal hyperinsulinemia in the presence of euglycemia. Fetal plasma insulin concentrations of 3525 μU/ml were attained with no apparent effects on the mother. In fetal macrosomia, a 34% increase in body weight was observed above the expected weight for gestational age (466 vs. 348 g). Relative organomegaly, matched for gestational age of fetal weight, was seen in the hyperinsulinemic fetuses with enlarged livers, placentas, hearts, and spleens. Liver composition in the fetuses was only slightly affected by hyperinsulinemia. Glycogen concentration was elevated, but not sufficiently, to explain the relative hepatomegaly produced. The lipid, protein, DNA, and RNA concentrations were not affected by hyperinsulinemia. Based on the similar DNA concentrations and protein/DNA ratios observed in hyperinsulinemic and control groups, the hepatomegaly appears to be the result of insulin-stimulated hyperplasia and not of hypertrophy. In the presence of normal plasma concentrations of growth substrates, insulin in the subhuman fetus has been shown to be a growth-promoting hormone that has specific growth-stimulating effects.

The Assessment of Newborn Iron Stores at Birth: A Review of the Literature and Standards for Ferritin Concentrations

Background: Serum ferritin measurements are used in clinical populations to estimate total body iron stores and the risk of subsequent iron deficiency or overload. The lack of normative newborn serum ferritin concentration data between 23 and 41 weeks has led to difficulty in establishing the incidence and degree of abnormal iron status in the neonatal period. Objectives: The primary objective of this review was to summarize the maternal and gestational factors that determine ferritin concentrations in full-term and pre-term newborn infants and to generate comprehensive reference values. The secondary objective was to assess serum ferritin concentrations in newborn infants at risk for abnormal fetal iron metabolism, including maternal diabetes mellitus, intrauterine growth restriction and maternal smoking during pregnancy. Methods: Serum ferritin and gestational age data at birth from 457 low-risk pre-term and term infants of 23–41 weeks gestation obtained from 35 published studies reviewed from a period of 25 years and from recently collected data from our centers were assessed by regression analysis. Slopes and intercepts of the high-risk groups were compared with the standard curve. Results: Umbilical cord serum ferritin concentrations increased with advancing gestational age, from a mean of 63 µg/l at 23 weeks to 171 µg/l at 41 weeks gestation (p < 0.001). The infants of diabetic mothers had a lower intercept than the control infants (p < 0.001). Conclusions: Iron deficiency and overload have been implicated in neurodevelopmental impairments. Normative cord serum ferritin data may permit a more precise assessment of infants who are at risk for abnormal iron status at birth.

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.

Abnormal iron distribution in infants of diabetic mothers: Spectrum and maternal antecedents

Because chronic hypoxemia causes a redistribution of iron from serum and storage pools into an expanding erythrocyte mass, and because infants of diabetic mothers are often hypoxemic in utero and have a high prevalence of polycythemia at birth, we studied iron distribution in 43 term infants of diabetic mothers. Twenty-four infants were at an appropriate size for gestational age; 19 were large for gestational age. At birth, 28 infants (65%) had abnormal serum iron profiles; eight had decreased ferritin concentrations only (stage 1), nine had decreased ferritin and increased total iron-binding capacity values (stage 2), and 11 had these serum findings plus elevated free erythrocyte protoporphyrin concentrations (stage 3). The hypoglycemic infants who were large for gestational age (n = 14) had a higher prevalence of abnormal iron profiles than euglycemic infants who were appropriate in size for gestational age (n = 20; 93% vs 50%; p = 0.009). Progressively abnormal iron profiles were associated with higher glycosylated fetal hemoglobin values, greater degrees of macrosomia, increased hemoglobin and erythropoietin concentrations, and increased erythrocyte/storage iron ratios. Erythropoietin concentrations were inversely linearly correlated with serum iron values (n = 32, r = -0.54; p = 0.003). The combined erythrocyte and storage iron pools were significantly lower in infants with abnormal iron values whose mothers were diabetic, particularly in infants of women with confirmed diabetic vasculopathy. We speculate that these findings are likely due to (1) increased fetal iron utilization during compensatory hemoglobin synthesis in response to chronic hypoxemia and (2) reduced iron transfer during late gestation complicated by diabetes.

Phlebotomy overdraw in the neonatal intensive care nursery.

Objective. Because blood loss attributable to laboratory testing is the primary cause of anemia among preterm infants during the first weeks of life, we quantified blood lost attributable to phlebotomy overdraw, ie, excess that might be avoided. We hypothesized that phlebotomy overdraw in excess of that requested by the hospital laboratory was a common occurrence, that clinical factors associated with excessive phlebotomy loss would be identified, and that some of these factors are potentially correctable. Design, Outcome Measures, and Analysis. Blood samples drawn for clinical purposes from neonates cared for in our 2 neonatal special care units were weighed, and selected clinical data were recorded. The latter included the test performed; the blood collection container used; the infants location (ie, neonatal intensive care unit [NICU] and intermediate intensive care unit); the infants weight at sampling; and the phlebotomists level of experience, work shift, and clinical role. Data were analyzed by univariate and multivariate procedures. Phlebotomists included laboratory technicians stationed in the neonatal satellite laboratory, phlebotomists assigned to the hospitals central laboratory, and neonatal staff nurses. Phlebotomists were considered experienced if they had worked in the nursery setting for >1 year. Blood was sampled from a venous or arterial catheter or by capillary stick from a finger or heel. Blood collection containers were classified as tubes with marked fill-lines imprinted on the outside wall, tubes without fill-lines, and syringes. Infants were classified by weight into 3 groups: <1 kg, 1 to 2 kg, and >2 kg. The volume of blood removed was calculated by subtracting the weight of the empty collection container from that of the container filled with blood and dividing by the specific gravity of blood, ie, 1.050 g/mL. The volume of blood withdrawn for individual laboratory tests was expressed as a percentage of the volume requested by the hospital laboratory. Results. The mean (± standard error of the mean) volume of blood drawn for the 578 tests drawn exceeded that requested by the hospital laboratory by 19.0% ± 1.8% per test. The clinical factors identified as being significantly associated with greater phlebotomy overdraw in the multiple regression model included: 1) collection in blood containers without fill-lines; 2) lighter weight infants; and 3) critically ill infants being cared for in the NICU. Because the overall R 2 of the multiple regression for these 3 clinical factors was only .24, the random factor of individual phlebotomist was added to the model. This model showed that there was a significant variation in blood overdraw among individual phlebotomists, and as a result, the overallR 2 increased to .52. An additional subset analysis involving 2 of the 3 groups of blood drawers (ie, hospital and neonatal laboratory phlebotomists) examining the effect of work shift, demonstrated that there was significantly greater overdraw for blood samples obtained during the evening shift, compared with the day shift when drawn using unmarked tubes for the group of heavier infants cared for in the NICU. Conclusion. Significant volumes of blood loss are attributable to overdraw for laboratory testing. This occurrence likely exacerbates the anemia of prematurity and may increase the need for transfusions in some infants. Attempts should be made to correct the factors involved. Common sense suggests that blood samples drawn in tubes with fill-lines marked on the outside would more closely approximate the volumes requested than those without. Conversely, the use of unmarked tubes could lead to phlebotomy overdraw because phlebotomists may overcompensate to avoid having to redraw the sample because of an insufficient volume for analysis. We were surprised to observe that the lightest and most critically ill infants experienced the greatest blood overdraw. Because the volume indicators on the outside of syringe barrels are seemingly analogous to the blood collection tubes with fill-lines, it was also unexpected to observe that blood overdraw was greater with syringes than with either marked or unmarked tubes. It is likely that this is attributable in part to the unavoidable presence of the air bubble inevitably originating in the syringe tip. Educating individual phlebotomists, nurses, and other members of the care team on reducing unnecessary blood loss, eg, ordering only essential blood tests, exercising the greatest care in the smallest infants, practice in drawing blood samples into syringes, etc, may also help. Other promising means for reducing laboratory blood loss include technologic improvements to further reduce laboratory sample volume required, more reproducible and better capillary blood sampling containers, and use of point-of-care laboratory testing in which little to no blood loss results.

Temporal Response of Immunoreactive Erythropoietin to Acute Hypoxemia in Fetal Sheep

ABSTRACT. Acute hypoxemia was produced in chronically catheterized sheep fetuses to determine the response time necessary to increase plasma immunoreactive erythropoietin (Ep) concentration. Sodium nitrite (0.2 mM) was infused via a fetal vein to induce fetal hypoxemia. The resultant fetal methemoglobinemia was associated with a predictable, incremental decrease in arterial oxygen content. Twelve nitrite infusions were performed in eight fetal sheep preparations (gestational ages 115-146 days). Mean methemoglobin level increased to 33% of total Hb after 1- 2 h of NaNO2 infusion. These results were compared to those obtained in nine control studies in eight fetuses in which no change was observed for plasma Ep, arterial oxygen content, Pao2, pHa, or whole blood lactate. In the nitrite infused group, however, a significant and progressive increase in mean plasma Ep level over baseline levels was observed during the 4th and 5th h of hypoxemia (p<0.01). This change in Ep was significantly greater compared to the control group. These results, however, were confounded by the concomitant development of a lactic acidemia secondary to the fetal hypoxemia. To examine the theoretic possibility that lactic acidemia may primarily affect fetal Ep levels, an additional group of five fetuses was infused with L-lactic acid for the same time period. Although the decrements in pHa and whole blood lactate levels achieved in these fetuses were in excess of those observed during the nitrite infusions, this possibility was ruled out since no change in fetal plasma Ep levels occurred. We conclude that during the 4th h of acute fetal hypoxemia a predictable, progressive increase in plasma Ep level is observed. This response of plasma Ep to hypoxemia in late gestation fetal sheep is qualitatively similar to that observed in adult animals, thus demonstrating developmental maturity of the fetus.

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.

Reduction in Red Blood Cell Transfusions Among Preterm Infants: Results of a Randomized Trial With an In-Line Blood Gas and Chemistry Monitor

Background. Critically ill, extremely premature infants develop anemia because of intensive laboratory blood testing and undergo multiple red blood cell (RBC) transfusions in the early weeks of life. To date, researchers have had only limited success in finding ways to reduce transfusions significantly in this patient population. Objective. To reduce RBC transfusions for these infants by using a point-of-care bedside monitor that returns analyzed blood to the patient. Design, Setting, and Patients. This was a prospective, 2-center, randomized, open, controlled, clinical trial with a 1:1 assignment of extremely low birth weight infants (weighing 500–1000 g at birth) to control or monitor groups and analysis with the intention-to-treat approach. Predefined RBC transfusion criteria were applied uniformly in the 2 groups. Interventions. Clinical treatment of study subjects with an in-line, ex vivo, bedside monitor that withdraws blood through an umbilical artery catheter, analyzes blood gases and sodium, potassium, and hematocrit levels, and returns the sample to the patient. Main Outcome Measures. The total volume and number of RBC transfusions during the first 2 weeks of life and the total volume of blood removed for laboratory testing. Results. The trial was terminated prematurely when one centers NICU changed its standard method of laboratory testing. In the first 2 weeks of life, there was a nonsignificant 17% lower cumulative RBC transfusion volume in the monitor group (n = 46), compared with the control group (n = 47). However, data from the first week only (the period of greater catheter use) demonstrated a significant 33% lower cumulative RBC transfusion volume in the monitor group. Cumulative phlebotomy loss was ∼25% less in the monitor group throughout the 2-week study period. There was no difference between groups in neonatal mortality, morbidity, and neurodevelopmental outcome rates at 18 to 24 months. This is the first randomized trial documenting that RBC transfusions administered to neonates can by reduced by decreasing laboratory phlebotomy loss. Conclusions. As long as an umbilical artery catheter is available for blood sampling with an in-line blood gas and chemistry monitor, significant reductions in neonatal RBC transfusions can be achieved. The patients most likely to benefit from monitor use are the smallest, most critically ill newborns.