Karen J. Johnson

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.

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.

AS‐1 red cells for neonatal transfusions: a randomized trial assessing donor exposure and safety

Background: Despite recent optimism about the use of erythropoietin therapy to treat the anemia of prematurity, very‐low‐birth‐weight infants who are severely ill receive multiple red cell (RBC) transfusions. Many physicians transfuse relatively fresh RBCs to newborn infants, exposing them to multiple donors and possibly increasing their risk of acquiring transfusion‐transmitted infections.

A randomized clinical trial comparing immediate versus delayed clamping of the umbilical cord in preterm infants: short-term clinical and laboratory endpoints

BACKGROUND: Most neonates less than 1.0 kg birth weight need red blood cell (RBC) transfusions. Delayed clamping of the umbilical cord 1 minute after delivery transfuses the neonate with autologous placental blood to expand blood volume and provide 60 percent more RBCs than after immediate clamping. This study compared hematologic and clinical effects of delayed versus immediate cord clamping.

The effect of inhaled nitric oxide therapy on bleeding time and platelet aggregation in neonates

The effect of inhaled nitric oxide (iNO) on bleeding time and platelet aggregation was studied in nine newborn infants with resolving pulmonary hypertension. Infants treated with iNO at 40 ppm for 30 minutes had bleeding times that were nearly twofold longer than those obtained 24 hours after iNO was discontinued. iNO had no effect on in vitro platelet aggregation studies.

Evaluation of fetal and maternal genetic variation in the progesterone receptor gene for contributions to preterm birth

Progesterone plays a critical role in the maintenance of pregnancy and has been effectively used to prevent recurrences of preterm labor. We investigated the role of genetic variation in the progesterone receptor (PGR) gene in modulating risks for preterm labor by examining both maternal and fetal effects. Cases were infants delivered prematurely at the University of Iowa. DNA was collected from the mother, infant, and father. Seventeen single nucleotide polymorphisms (SNP) and an insertion deletion variant in PGR were studied in 415 families. Results were then analyzed using transmission disequilibrium tests and log-linear-model–based analysis. DNA sequencing of the PGR gene was also carried out in 92 mothers of preterm infants. We identified significant associations between SNP in the PGR for both mother and preterm infant. No etiologic sequence variants were found in the coding sequence of the PGR gene. This study suggests that genetic variation in the PGR gene of either the mother or the fetus may trigger preterm labor.

Circulating RBC volume, measured with biotinylated RBCs, is superior to the Hct to document the hematologic effects of delayed versus immediate umbilical cord clamping in preterm neonates

BACKGROUND: One problem assessing the hematologic physiology of preterm infants after delivery and/or the efficacy and toxicity of therapeutic interventions affecting RBC measurements is the inability of blood Hct values to accurately reflect circulating RBC volume—owing to changes in plasma volume that influence Hct (i.e., a fall in plasma volume concentrates RBCs to increase Hct; a rise in plasma volume dilutes RBCs to decrease Hct).

Feasibility and safety of AS-3 red blood cells for neonatal transfusions☆☆☆★

OBJECTIVES Most extremely low birth weight (<1 kg) infants receive red blood cell (RBC) transfusions. RBCs stored up to 42 days can be transfused safely in small volumes to preterm infants; however, because the formulation of RBC anticoagulant/preservative solutions differs, clinical studies are required to document the safety of each solution before widespread use. Our goal was to study the feasibility and safety of AS-3 anticoagulant/preservative solution to preterm infants. STUDY DESIGN Two clinical studies were conducted in sequence: (1) a randomized trial to compare RBC transfusions given as stored (< or =42 days) AS-3 RBCs (11 infants) versus fresh (< or = 7 days) citrate, phosphate, dextrose, and adenine RBCs (10 infants) and (2) a subsequent evaluation of the safety of stored AS-3 RBCs in 33 additional preterm infants given 120 AS-3 RBC transfusions. RESULTS Results of both the randomized study and the subsequent evaluation documented that AS-3 RBCs stored < or =42 days and transfused in small volumes (15 mL/kg) were safe for RBC transfusions of preterm infants. Donor exposure was significantly reduced, clinical transfusion reactions were rare, and post-transfusion blood hematocrit, pH, and plasma Na, K, Ca, lactate, and glucose measurements were similar when AS-3 and citrate, phosphate, dextrose, and adenine RBC transfusions were compared. CONCLUSIONS AS-3 RBCs can be used safely for small-volume RBC transfusions for preterm infants.

Erythrocyte incorporation and absorption of 58Fe in premature infants treated with erythropoietin

We hypothesized that treatment of very low birth weight premature infants with r-HuEPO would increase erythrocyte incorporation and gastrointestinal absorption of iron. Infants with birth weights ≤1.25 kg and gestational ages <31 wk were randomized to receive 6 wk of 500 U of r-HuEPO/kg/wk (epo group, n = 7) or placebo (placebo group, n = 7). All infants received daily enteral supplementation with 6 mg of elemental iron per kg. An enteral test dose of a stable iron isotope, 58Fe, was administered after the 1st (“early dosing”) and 4th (“late dosing”) wk of treatment. Mean (±SD) erythrocyte incorporation of the dose of 58Fe administered determined 2 wk after early dosing was significantly greater in the epo group compared with the placebo group (4.4%± 1.6 versus 2.0 ± 1.4%, p = 0.013). In contrast, after late 58Fe dosing, there was no difference between groups in incorporation (3.8 ± 1.6% versus 5.5 ± 2.7%). Within the epo group, percentage erythrocyte incorporation of58 Fe did not differ between early and late dosing, whereas in the placebo group it increased 3-fold (p < 0.01). Percentage absorption of 58Fe was not different between the epo and placebo groups after both early dosing (30 ± 22% versus 34 ± 8%) and late dosing (32 ± 9% versus 31 ± 6%). Absorption of nonlabeled elemental iron and 58Fe were significantly correlated with one another. The percentage of the absorbed 58Fe dose incorporated into Hb was not different between groups. We conclude that, although erythropoietin treatment stimulates erythrocyte iron incorporation in premature infants, it has no effect on iron absorption at the r-HuEPO dose studied.

Acute physiological effects of packed red blood cell transfusion in preterm infants with different degrees of anaemia

Objective The safe lower limit of haematocrit or haemoglobin that should trigger a red blood cell (RBC) transfusion has not been defined. The objective of this study was to examine the physiological effects of anaemia and compare the acute responses to transfusion in preterm infants who were transfused at higher or lower haematocrit thresholds. Methods The authors studied 41 preterm infants with birth weights 500–1300 g, who were enrolled in a clinical trial comparing high (‘liberal’) and low (‘restrictive’) haematocrit thresholds for transfusion. Measurements were performed before and after a packed RBC transfusion of 15 ml/kg, which was administered because the infants haematocrit had fallen below the threshold defined by study protocol. Haemoglobin, haematocrit, RBC count, reticulocyte count, lactic acid and erythropoietin were measured before and after transfusion using standard methods. Cardiac output was measured by echocardiography. Oxygen consumption was determined using indirect calorimetry. Systemic oxygen transport and fractional oxygen extraction were calculated. Results Systemic oxygen transport rose in both groups following transfusion. Lactic acid was lower after transfusion in both groups. Oxygen consumption did not change significantly in either group. Cardiac output and fractional oxygen extraction fell after transfusion in the low haematocrit group only. Conclusions These studys results demonstrate no acute physiological benefit of transfusion in the high haematocrit group. The fall in cardiac output with transfusion in the low haematocrit group shows that these infants had increased their cardiac output to maintain adequate tissue oxygen delivery in response to anaemia and, therefore, may have benefitted from transfusion.