Pancreatic Enzyme Use Reduces Pancreatitis Frequency in Children With Acute Recurrent or Chronic Pancreatitis: A Report From INSPPIRE.

INTRODUCTION: Among children who suffer from acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), acute pancreatitis (AP) episodes are painful, often require hospitalization, and contribute to disease complications and progression. Despite this recognition, there are currently no interventions to prevent AP episodes. In this retrospective cohort study, we assessed the impact of pancreatic enzyme therapy (PERT) use on clinical outcomes among children with pancreatic-sufficient ARP or CP. METHODS: Children with pancreatic-sufficient ARP or CP in the INSPPIRE-2 cohort were included. Clinical outcomes were compared for those receiving vs not receiving PERT, as well as frequency of AP before and after PERT. Logistic regression was used to study the association between development of AP episodes after starting PERT and response predictors. RESULTS: Among 356 pancreatic-sufficient participants, 270 (76%) had ARP, and 60 (17%) received PERT. Among those on PERT, 42% did not have a subsequent AP episode, during a mean 2.1 years of follow-up. Children with a SPINK1 mutation ( P = 0.005) and those with ARP (compared with CP, P = 0.008) were less likely to have an AP episode after starting PERT. After initiation of PERT, the mean AP annual incidence rate decreased from 3.14 down to 0.71 ( P < 0.001). DISCUSSION: In a retrospective analysis, use of PERT was associated with a reduction in the incidence rate of AP among children with pancreatic-sufficient ARP or CP. These results support the need for a clinical trial to evaluate the efficacy of PERT to improve clinical outcomes among children with ARP or CP.

Pediatric Drug-Associated Pancreatitis Reveals Concomitant Risk Factors and Poor Reliability of Causality Scoring: Report From INSPPIRE.

OBJECTIVES: Drug-associated acute pancreatitis (DAP) studies typically focus on single acute pancreatitis (AP) cases. We aimed to analyze the (1) characteristics, (2) co-risk factors, and (3) reliability of the Naranjo scoring system for DAP using INSPPIRE-2 (the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2) cohort study of acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) in children. METHODS: Data were obtained from ARP group with ≥1 episode of DAP and CP group with medication exposure ± DAP. Physicians could report multiple risk factors. Pancreatitis associated with Medication (Med) (ARP+CP) was compared to Non-Medication cases, and ARP-Med vs CP-Med groups. Naranjo score was calculated for each DAP episode. RESULTS: Of 726 children, 392 had ARP and 334 had CP; 51 children (39 ARP and 12 CP) had ≥1 AP associated with a medication; 61% had ≥1 AP without concurrent medication exposure. The Med group had other risk factors present (where tested): 10 of 35 (28.6%) genetic, 1 of 48 (2.1%) autoimmune pancreatitis, 13 of 51 (25.5%) immune-mediated conditions, 11 of 50 (22.0%) obstructive/anatomic, and 28 of 51 (54.9%) systemic risk factors. In Med group, 24 of 51 (47%) had involvement of >1 medication, simultaneously or over different AP episodes. There were 20 ARP and 4 CP cases in "probable" category and 19 ARP and 7 CP in "possible" category by Naranjo scores. CONCLUSIONS: Medications were involved in 51 of 726 (7%) of ARP or CP patients in INSPPIRE-2 cohort; other pancreatitis risk factors were present in most, suggesting a potential additive role of different risks. The Naranjo scoring system failed to identify any cases as "definitive," raising questions about its reliability for DAP.

Analysis of INSPPIRE-2 Cohort: Risk Factors and Disease Burden in Children With Acute Recurrent or Chronic Pancreatitis.

OBJECTIVES: The objective of this study is to investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). METHODS: Data were obtained from INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2), the largest multi-center prospective cohort study in pediatric patients with ARP or CP. RESULTS: Of 689 children, 365 had ARP (53%), 324 had CP (47%). CP was more commonly associated with female sex, younger age at first acute pancreatitis (AP) attack, Asian race, family history of CP, lower BMI%, genetic and obstructive factors, PRSS1 mutations and pancreas divisum. CFTR mutations, toxic-metabolic factors, medication use, hypertriglyceridemia, Crohn disease were more common in children with ARP. Constant or frequent abdominal pain, emergency room (ER) visits, hospitalizations, medical, endoscopic or surgical therapies were significantly more common in CP, episodic pain in ARP. A total of 33.1% of children with CP had exocrine pancreatic insufficiency (EPI), 8.7% had diabetes mellitus. Compared to boys, girls were more likely to report pain impacting socialization and school, medical therapies, cholecystectomy, but no increased opioid use. There was no difference in race, ethnicity, age at first AP episode, age at CP diagnosis, duration of disease, risk factors, prevalence of EPI or diabetes between boys and girls. Multivariate analysis revealed that family history of CP, constant pain, obstructive risk factors were predictors of CP. CONCLUSIONS: Children with family history of CP, constant pain, or obstructive risk factors should raise suspicion for CP.

Antibodies against biotin-labeled red blood cells can shorten posttransfusion survival.

BACKGROUND: In hematologic and transfusion medicine research, measurement of red blood cell (RBC) in vivo kinetics must be safe and accurate. Recent reports indicate use of biotin-labeled RBC (BioRBC) to determine red cell survival (RCS) offers substantial advantages over 51 Cr and other labeling methods. Occasional induction of BioRBC antibodies has been reported. STUDY DESIGN AND METHODS: To investigate the causes and consequences of BioRBC immunization, we reexposed three previously immunized adults to BioRBC and evaluated the safety, antibody emergence, and RCS of BioRBC. RESULTS: BioRBC re-exposure caused an anamnestic increase of plasma BioRBC antibodies at 5-7 days; all were subclass IgG1 and neutralized by biotinylated albumin, thus indicating structural specificity for the biotin epitope. Concurrently, specific antibody binding to BioRBC was observed in each subject. As biotin label density increased, the proportion of BioRBC that bound increased antibody also increased; the latter was associated with proportional accelerated removal of BioRBC labeled at density 6 µg/mL. In contrast, only one of three subjects exhibited accelerated removal of BioRBC density 2 µg/mL. No adverse clinical or laboratory events were observed. Among three control subjects who did not develop BioRBC antibodies following initial BioRBC exposure, re-exposure induced neither antibody emergence nor accelerated BioRBC removal. DISCUSSION: We conclude re-exposure of immunized subjects to BioRBC can induce anamnestic antibody response that can cause an underestimation of RCS. To minimize chances of antibody induction and underestimation of RCS, we recommend an initial BioRBC exposure volume of ≤10 mL and label densities of ≤18 µg/mL.

Health-Related Quality of Life in Pediatric Acute Recurrent or Chronic Pancreatitis: Association With Biopsychosocial Risk Factors.

OBJECTIVES: Abdominal pain, emergency department visits, and hospitalizations impact lives of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Data on health-related quality of life (HRQOL) in this population, however, remains limited. We aimed to evaluate HRQOL in children with ARP or CP; and test biopsychosocial risk factors associated with low HRQOL. METHODS: Data were acquired from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE registry. Baseline demographic and clinical questionnaires, the Child Health Questionnaire (measures HRQOL) and Child Behavior Checklist (measures emotional and behavioral functioning) were completed at enrollment. RESULTS: The sample included 368 children (54.3% girls, mean age = 12.7years, standard deviation [SD] = 3.3); 65.2% had ARP and 34.8% with CP. Low physical HRQOL (M = 38.5, SD = 16.0) was demonstrated while psychosocial HRQOL (M = 49.5, SD = 10.2) was in the normative range. Multivariate regression analysis revealed that clinical levels of emotional and behavioral problems (B = -10.28, P  < 0.001), episodic and constant abdominal pain (B = 04.66, P = 0.03; B = -13.25, P < 0.001) were associated with low physical HRQOL, after accounting for ARP/CP status, age, sex, exocrine, and endocrine disease (F [9, 271] = 8.34, P < 0.001). Borderline and clinical levels of emotional and behavioral problems (B = -10.18, P < 0.001; B = -15.98, P < 0.001), and constant pain (B = -4.46, P < 0.001) were associated with low psychosocial HRQOL (F [9, 271] = 17.18, P < 0.001). CONCLUSIONS: Findings highlight the importance of assessing HRQOL and treating pain and psychosocial problems in this vulnerable group of children.

Vascular Complications in Pediatric Pancreatitis: A Case Series.

ABSTRACT: We reviewed INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) database for splanchnic venous thrombosis or arterial pseudoaneurysms to determine the incidence, risk factors and outcomes of peripancreatic vascular complications in children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). Of 410 children with diagnostic imaging studies, vascular complications were reported in five (1.2%); two had ARP, three CP. The vascular events were reported during moderately severe or severe acute pancreatitis (AP) in four, mild AP in one. Venous thrombosis occurred in four, arterial pseudoaneurysm (left gastric artery) in one. Two patients with venous thrombosis were treated with anticoagulant, one achieved recanalization (splenic vein). In two patients who did not receive anticoagulants, one re-canalized. No adverse effects were observed with anticoagulants. The child with pseudoaneurysm underwent aneurysmal coiling. Anti-coagulants appear to be safe in children with acute pancreatitis, their long-term benefit needs to be further investigated.

Neonatal Umbilical Arterial Catheter Removal Is Accompanied by a Marked Decline in Phlebotomy Blood Loss.

BACKGROUND: Umbilical arterial catheters (UACs) are frequently used in critically ill neonates. UAC are convenient, reliable, and allow for caregiver convenience in performing painless arterial blood sampling. We hypothesized that UAC removal in extremely low birth weight (ELBW) neonates will result in significantly less phlebotomy blood loss (PBL) after correcting for severity of illness. STUDY DESIGN AND METHODS: PBL was measured at a single center in 99 ELBW infants who survived to day 28. Individual infant's paired daily PBL for the two 24-h periods before and after UAC removal were compared using the paired t test. Daily PBL up to 7 days before and 7 days after UAC removal were compared using a logistic regression with mixed model analysis for repeated measures. Cumulative 28-day phlebotomy loss was evaluated by multiple linear regression analysis. RESULTS: PBL 24 h before and after UAC removal were 1.7 mL (95% CI 1.5-1.9) and 0.9 mL (95% CI 0.8-1.0; p < 0.0001), respectively. Cumulative 28-day PBL increased by 2.2 mL (±0.7) per day that a UAC was present with or without correction for severity of illness (p < 0.001). CONCLUSION: UAC removal is independently associated with a marked decline in PBL. We speculate the ease and convenience of UAC blood sampling lead to more frequent blood testing and greater PBL.

Target-mediated disposition population pharmacokinetics model of erythropoietin in premature neonates following multiple intravenous and subcutaneous dosing regimens.

Routine erythropoietin (Epo) therapy for neonatal anemia is presently controversial due to its modest response. We speculate that an important contributor to this modest response is that previous clinical study designs were not driven by rigorous mechanistic and kinetic insights into the complex pharmacokinetics (PK) and pharmacodynamics (PD) of Epo in this population. To address this therapeutic opportunity, we conducted a prospective clinical study to investigate the PK of Epo in very-low-birth-weight (VLBW) premature neonates using a unique Epo dosing algorithm that accounts for complex neonatal erythropoietic physiology. Twenty-seven subjects received up to 10 intravenous or subcutaneous exogenous doses of Epo (600 or 1200 U/kg) during the first 4 weeks of life. Subjects were administered two doses of Epo 1200 U/kg on days 2 and 16, and eight doses of Epo 600 U/kg on days 4, 5, 6, 7, 9, 14, 15, and 28 following birth. We have developed for the first time a mechanistic, target-mediated disposition model that provides novel insights into the mechanisms driving Epo PK in VLBW neonates. Epo association rate, kon, was estimated to be 0.00610 pM-1h-1, and the dissociation rate koff was 0.112 h-1. Internalization of the Epo-target complex (kint) and the total receptor concentration (Rmax) were estimated to be 0.118 h-1 and 133 pM, respectively. Following s.c. administration, the absorption rate (ka) of Epo was 0.0738h-1 and bioavailability was 78.0%. Our mechanism-based population pharmacokinetic analysis provided quantitative insight into Epo kinetics in VLBW neonates; the information gained will assist in deriving dosing strategies for neonatal anemia and for neuroprotection efficacy studies.

Anemia induces gut inflammation and injury in an animal model of preterm infants.

BACKGROUND: While very low birth weight (VLBW) infants often require multiple red blood cell transfusions, efforts to minimize transfusion-associated risks have resulted in more restrictive neonatal transfusion practices. However, whether restrictive transfusion strategies limit transfusions without increasing morbidity and mortality in this population remains unclear. Recent epidemiologic studies suggest that severe anemia may be an important risk factor for the development of necrotizing enterocolitis (NEC). However, the mechanism whereby anemia may lead to NEC remains unknown. STUDY DESIGN AND METHODS: The potential impact of anemia on neonatal inflammation and intestinal barrier disruption, two well-characterized predisposing features of NEC, was defined by correlation of hemoglobin values to cytokine levels in premature infants and by direct evaluation of intestinal hypoxia, inflammation and gut barrier disruption using a pre-clinical neonatal murine model of phlebotomy-induced anemia (PIA). RESULTS: Increasing severity of anemia in the preterm infant correlated with the level of IFN-gamma, a key pro-inflammatory cytokine that may predispose an infant to NEC. Gradual induction of PIA in a pre-clinical model resulted in significant hypoxia throughout the intestinal mucosa, including areas where intestinal macrophages reside. PIA-induced hypoxia significantly increased macrophage pro-inflammatory cytokine levels, while reducing tight junction protein ZO-1 expression and increasing intestinal barrier permeability. Macrophage depletion reversed the impact of anemia on intestinal ZO-1 expression and barrier function. CONCLUSIONS: Taken together, these results suggest that anemia can increase intestinal inflammation and barrier disruption likely through altered macrophage function, leading to the type of predisposing intestinal injury that may increase the risk for NEC.

Body temperatures of very low birth weight infants on admission to a neonatal intensive care unit.

OBJECTIVE: Hypothermia occurs frequently in the first minutes after birth in preterm infants. Hyperthermia also occurs, often as a consequence of efforts to provide thermal support. Both hypothermia and hyperthermia are potentially harmful. Our objective was to examine the distribution of admission temperatures of very low birth weight (VLBW) infants, the effect of gestational age on admission temperatures, and the time required for correction of low temperatures. METHODS: Admission axillary temperatures were retrieved from the medical records for all VLBW infants born in our hospital during a 5-year period. The temperatures were classified as severe (<35.0 °C), moderate (35.0-35.9 °C), or mild (36.0-36.4 °C) hypothermia, normothermia (36.5-37.4 °C), or hyperthermia (≥37.5 °C). The relationship between gestational age and admission temperature was examined. In addition, we analyzed the time required for normalization of low temperatures. RESULTS: Overall, 12% of infants were severely hypothermic, 40% moderately hypothermic, 27% mildly hypothermic, 19% normothermic, and 2% hyperthermic. Gestational age was inversely related to hypothermia risk and to the time required for recovery to normothermia. CONCLUSION: Admission hypothermia is common among VLBW infants and is affected by gestational age.

In premature infants there is no decrease in 24-hour posttransfusion allogeneic red blood cell recovery after 42 days of storage.

BACKGROUND: Critically ill preterm very-low-birthweight (VLBW) neonates (birthweight ≤ 1.5 kg) frequently develop anemia that is treated with red blood cell (RBC) transfusions. Although RBCs transfused to adults demonstrate progressive decreases in posttransfusion 24-hour RBC recovery (PTR24 ) during storage-to a mean of approximately 85% of the Food and Drug Administration-allowed 42-day storage-limited data in infants indicate no decrease in PTR24 with storage. STUDY DESIGN AND METHODS: We hypothesized that PTR24 of allogeneic RBCs transfused to anemic VLBW newborns: 1) will be greater than PTR24 of autologous RBCs transfused into healthy adults and 2) will not decrease with increasing storage duration. RBCs were stored at 4°C for not more than 42 days in AS-3 or AS-5. PTR24 was determined in 46 VLBW neonates using biotin-labeled RBCs and in 76 healthy adults using 51 Cr-labeled RBCs. Linear mixed-model analysis was used to estimate slopes and intercepts of PTR24 versus duration of RBC storage. RESULTS: For VLBW newborns, the estimated slope of PTR24 versus storage did not decrease with the duration of storage (p = 0.18) while for adults it did (p < 0.0001). These estimated slopes differed significantly in adults compared to newborns (p = 0.04). At the allowed 42-day storage limit, projected mean neonatal PTR24 was 95.9%; for adults, it was 83.8% (p = 0.0002). CONCLUSIONS: These data provide evidence that storage duration of allogeneic RBCs intended for neonates can be increased without affecting PTR24 . This conclusion supports the practice of transfusing RBCs stored up to 42 days for small-volume neonatal transfusions to limit donor exposure.

Safety and Immunogenicity of Sequential Rotavirus Vaccine Schedules.

BACKGROUND AND OBJECTIVES: Although both licensed rotavirus vaccines are safe and effective, it is often not possible to complete the schedule by using the same vaccine formulation. The goal of this study was to investigate the noninferiority of the immune responses to the 2 licensed rotavirus vaccines when administered as a mixed schedule compared with administering a single vaccine formulation alone. METHODS: Randomized, multicenter, open-label study. Healthy infants (6-14 weeks of age) were randomized to receive rotavirus vaccines in 1 of 5 different schedules (2 using a single vaccine for all doses, and 3 using mixed schedules). The group receiving only the monovalent rotavirus vaccine received 2 doses of vaccine and the other 4 groups received 3 doses of vaccine. Serum for immunogenicity testing was obtained 1 month after the last vaccine dose and the proportion of seropositive children (rotavirus immunoglobulin A ≥20 U/mL) were compared in all the vaccine groups. RESULTS: Between March 2011 and September 2013, 1393 children were enrolled and randomized. Immune responses to all the sequential mixed vaccine schedules were shown to be noninferior when compared with the 2 single vaccine reference groups. The proportion of children seropositive to at least 1 vaccine antigen at 1 month after vaccination ranged from 77% to 96%, and was not significantly different among all the study groups. All schedules were well tolerated. CONCLUSIONS: Mixed schedules are safe and induced comparable immune responses when compared with the licensed rotavirus vaccines given alone.

Reticulocyte Hemoglobin Content During the First Month of Life in Critically Ill Very Low Birth Weight Neonates Differs From Term Infants, Children, and Adults.

BACKGROUND: Reticulocyte hemoglobin content (RET-He)-an established indicator of iron status in children and adults-was determined in very low birth weight (VLBW) infants. METHODS: Longitudinal retrospective RET-He data in 26 VLBW neonates during the first month of age were compared with: (a) concurrent complete blood counts (CBCs), including hemoglobin (Hb) concentration, reticulocyte count, and immature reticulocyte fraction (IRF), and erythropoietin (EPO) levels; (b) clinical variables; and (c) RET-He data from the literature for term infants, children, and adults. RESULTS: RET-He within 24 hr following birth was 31.8 ± 1.1 pg (mean ± SEM). This was followed by an abrupt, significant decline to 28.3 ± 1.1 pg at 2-4 days, and to steady state levels of 28.4 ± 0.5 pg thereafter. The changes in RET-He were mirrored by changes in plasma EPO, reticulocyte count, and IRF, but not Hb. Steady state RET-He values after 4 days were significantly lower than RET-He values for term infants, children, and adults (31.6 ± 0.11, 32.0 ± 0.12, and 33.0 ± 0.13 pg, respectively). CONCLUSION: Although RET-He values in VLBW infant were lower than term infants, children, and adults, the significance and mechanism(s) responsible are unknown. The present VLBW infant data are relevant to investigations assessing hemoglobinization following treatment with recombinant human EPO (r-HuEPO) and/or iron.

Autologous Infant and Allogeneic Adult Red Cells Demonstrate Similar Concurrent Post-Transfusion Survival in Very Low Birth Weight Neonates.

OBJECTIVE: Based on the hypothesis that neonatal autologous red blood cell (RBC) survival (RCS) is substantially shorter than adult RBC, we concurrently tracked the survival of transfused biotin-labeled autologous neonatal and allogeneic adult RBC into ventilated, very low birth weight infants. STUDY DESIGN: RBC aliquots from the first clinically ordered, allogeneic adult RBC transfusion and from autologous infant blood were labeled at separate biotin densities (biotin-labeled RBC [BioRBC]) and transfused. Survival of these BioRBCs populations were concurrently followed over weeks by flow cytometric enumeration using leftover blood. Relative tracking of infant autologous and adult allogeneic BioRBC was analyzed by linear mixed modeling of batched weekly data. When possible, Kidd antigen (Jka and Jkb) mismatches between infant and donor RBCs were also used to track these 2 populations. RESULTS: Contrary to our hypothesis, concurrent tracking curves of RCS of neonatal and adult BioRBC in 15 study infants did not differ until week 7, after which neonatal RCS became shortened to 59%-79% of adult enumeration values for uncertain reasons. Analysis of mismatched Kidd antigen RBC showed similar results, thus, confirming that BioRBC tracking is not perturbed by biotin RBC labeling. CONCLUSIONS: This study illustrates the utility of multidensity BioRBC labeling for concurrent measurement of RCS of multiple RBC populations in vivo. The similar RCS results observed for neonatal and adult BioRBCs transfused into very low birth weight infants provides strong evidence that the circulatory environment of the newborn infant, not intrinsic infant-adult RBC differences, is the primary determinant of erythrocyte survival. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00731588.

Pharmacodynamically optimized erythropoietin treatment combined with phlebotomy reduction predicted to eliminate blood transfusions in selected preterm infants.

BACKGROUND: Preterm very-low-birth-weight (VLBW) infants weighing <1.5 kg at birth develop anemia, often requiring multiple red blood cell transfusions (RBCTx). Because laboratory blood loss is a primary cause of anemia leading to RBCTx in VLBW infants, our purpose was to simulate the extent to which RBCTx can be reduced or eliminated by reducing laboratory blood loss in combination with pharmacodynamically optimized erythropoietin (Epo) treatment. METHODS: Twenty-six VLBW ventilated infants receiving RBCTx were studied during the first month of life. RBCTx simulations were based on previously published RBCTx criteria and data-driven Epo pharmacodynamic optimization of literature-derived RBC life span and blood volume data corrected for phlebotomy loss. RESULTS: Simulated pharmacodynamic optimization of Epo administration and reduction in phlebotomy by ≥ 55% predicted a complete elimination of RBCTx in 1.0-1.5 kg infants. In infants <1.0 kg with 100% reduction in simulated phlebotomy and optimized Epo administration, a 45% reduction in RBCTx was predicted. The mean blood volume drawn from all infants was 63 ml/kg: 33% required for analysis and 67% discarded. CONCLUSION: When reduced laboratory blood loss and optimized Epo treatment are combined, marked reductions in RBCTx in ventilated VLBW infants were predicted, particularly among those with birth weights >1.0 kg.

Tracking donor RBC survival in premature infants: agreement of multiple populations of biotin-labeled RBCs with Kidd antigen-mismatched RBCs.

BACKGROUND: Anemia, a common condition among critically ill premature infants, is affected by red blood cell (RBC) survival (RCS). We hypothesized that transfused allogeneic Kidd antigen-mismatched RBCs would demonstrate the same concurrent RCS tracking as RBCs multilabeled at separate, discrete low densities with biotin (BioRBCs). METHODS: Allogeneic RBCs from adult donors were labeled at four biotin densities, mixed, and transfused into 17 anemic premature infants. Nine of the donors and neonates were Kidd antigen mismatched. Serial posttransfusion blood samples were assayed for up to 8 wk by flow cytometry to track the survival of the proportions of Kidd antigen-mismatched and Kidd antigen-biotinylated RBCs. RESULTS: Using linear mixed modeling to compare results, RCS of the three lowest BioRBC densities was similar to RCS by Kidd antigen mismatch and to one another. RCS of RBCs labeled at the highest BioRBC density was shortened. CONCLUSION: RCS of different populations of RBCs can be tracked concurrently and reliably using the three lowest BioRBC densities. Although comparable RCS results can be achieved using Kidd antigen mismatches, BioRBCs are preferred for investigating neonatal anemia because biotin labeling of both allogeneic and autologous RBCs is possible.

Comparison of multiple red cell volume methods performed concurrently in premature infants following allogeneic transfusion.

BACKGROUND: Study of the pathophysiology and treatment of anemia of prematurity is facilitated by direct measurement of red cell volume (RCV) utilizing microliter quantities of blood samples. Our objective was to compare concurrent measurements of multiple direct RCV methods in infants. METHODS: Eighteen preterm infants receiving clinically indicated transfusions had concurrent flow cytometric determinations of RCV and 24-h red blood cell (RBC) recovery based on donor-recipient differences of biotin-labeled RBCs (BioRBCs), Kidd antigen mismatched RBCs, and fetal hemoglobin-positive (HbF(+)) RBCs. High-performance liquid chromatography (HPLC) was also used for measuring HbF and adult hemoglobin protein concentrations for the determination of RCV. RESULTS: Concurrent RCV measurements using BioRBCs (18 and 54 µg/ml), Kidd antigen, and HbF flow cytometry were not statistically different compared with RCVs measured using the reference BioRBC density (6 µg/ml). By contrast, the HbF-HPLC method overestimated RCV by 45% compared with the reference method. All the methods demonstrated 100% 24-h posttransfusion RBC recovery (PTR24). CONCLUSION: Because BioRBC, Kidd antigen, and fetal hemoglobin (HbF) flow cytometry are safe and accurate methods requiring <10 µl of patient blood for determining RCV and PTR24 in preterm infants, they can be useful in clinical and research studies of anemia and other conditions.

Safety and immune responses in children after concurrent or sequential 2009 H1N1 and 2009-2010 seasonal trivalent influenza vaccinations.

BACKGROUND: Administering 2 separate vaccines for seasonal and pandemic influenza was necessary in 2009. Therefore, we conducted a randomized trial of monovalent 2009 H1N1 influenza vaccine (2009 H1N1 vaccine) and seasonal trivalent inactivated influenza vaccine (TIV; split virion) given sequentially or concurrently in previously vaccinated children. METHODS: Children randomized to 4 study groups and stratified by age received 1 dose of seasonal TIV and 2 doses of 2009 H1N1 vaccine in 1 of 4 combinations. Injections were given at 21-day intervals and serum samples for hemagglutination inhibition antibody responses were obtained prior to and 21 days after each vaccination. Reactogenicity and adverse events were monitored. RESULTS: All combinations of vaccines were safe in the 531 children enrolled. Generally, 1 dose of 2009 H1N1 vaccine and 1 dose of TIV, regardless of sequence or concurrency of administration, was immunogenic in children ≥ 10 years of age; children <10 years of age required 2 doses of 2009 H1N1 vaccine. CONCLUSIONS: Vaccines were generally well tolerated. The immune responses to 2009 H1N1 vaccine were adequate regardless of the sequence of vaccination in all age groups but the sequence affected titers to TIV antigens. Two doses of 2009 H1N1 vaccine were required to achieve a protective immune response in children <10 years of age. CLINICAL TRIALS REGISTRATION: NCT00943202.

Red blood cell (RBC) survival determined in humans using RBCs labeled at multiple biotin densities.

BACKGROUND: Safe, accurate methods permitting simultaneous and/or repeated measurement of red blood cell (RBC) survival (RCS) are important to investigate pathophysiology and therapy of anemia. Methods using chromium 51 ((51) Cr)-labeled RBCs are unacceptable for infants, children, and pregnant women. We report RCS measured in vivo using RBCs labeled with several densities of biotin (BioRBCs). STUDY DESIGN AND METHODS: Aliquots of autologous RBCs from eight healthy adult subjects were labeled separately at four discrete biotin densities, mixed, and infused. The proportion of each population of BioRBCs circulating was determined serially by flow cytometry over 20 weeks. For each population, RCS was assessed by the following: 1) posttransfusion BioRBC recovery at 24 hours (PTR(24) ); 2) time to decrease to 50% of the enrichment at 24 hours (T(50) ); and 3) mean potential lifespan (MPL). RESULTS: Among the four BioRBC densities, no significant differences in PTR(24) were observed. T(50) and MPL were similar for the two lowest BioRBC densities. In contrast, the two highest BioRBC densities demonstrated progressively decreased T(50) and MPL. CONCLUSIONS: RBCs labeled at four biotin densities can be used to independently and accurately measure PTR(24 ) and two lowest biotin densities can accurately quantitate long-term RCS. This method provides a tool for investigating anemia in infants, fetuses, and pregnant women with the following advantages over the standard (51) Cr method: 1) study subjects are not exposed to radiation; 2) small blood volumes (e.g., 20 µL) are required; and 3) multiple independent RCS measurements can be made simultaneously in the same individual.

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 infant's 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 study's 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.