Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 35
Filtrar
1.
Antimicrob Agents Chemother ; 67(1): e0131222, 2023 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-36622154

RESUMO

In the present study, population pharmacokinetic (PK) analysis was performed based on meropenem data from a prospective study conducted in 114 critically ill patients with a wide range of renal functions and various disease conditions. The final model was a one-compartment model with linear elimination, with creatinine clearance and continuous renal replacement therapy affecting clearance, and total bodyweight impacting the volume of distribution. Our model is a valuable addition to the existing meropenem population PK models, and it could be particularly useful during implementation of a therapeutic drug monitoring program combined with Bayesian forecasting. Based on the final model developed, comprehensive Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) of 16 different dosing regimens. Simulation results showed that 2 g administered every 8 h with 3-h prolonged infusion (PI) and 4 g/day by continuous infusion (CI) appear to be two empirical dosing regimens that are superior to many other regimens when both target attainment and potential toxicity are considered and renal function information is not available. Following a daily CI dose of 6 g or higher, more than 30% of the population with a creatinine clearance of <60 mL/min is predicted to have neurotoxicity. With the availability of institution- and/or unit-specific meropenem susceptibility patterns, as well as an individual patient's renal function, our PTA results may represent useful references for physicians to make dosing decisions.


Assuntos
Antibacterianos , Unidades de Terapia Intensiva , Humanos , Meropeném/farmacocinética , Antibacterianos/farmacocinética , Estudos Prospectivos , Creatinina , Teorema de Bayes , Estado Terminal/terapia , Método de Monte Carlo , Testes de Sensibilidade Microbiana
2.
J Antimicrob Chemother ; 78(6): 1460-1470, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37071586

RESUMO

OBJECTIVES: We aimed to identify rational empirical dosing strategies for cefepime treatment in critically ill patients by utilizing population pharmacokinetics and target attainment analysis. PATIENTS AND METHODS: A prospective and opportunistic pharmacokinetic (PK) study was conducted in 130 critically ill patients in two ICU sites. The plasma concentrations of cefepime were determined using a validated LC-MS/MS method. All cefepime PK data were analysed simultaneously using the non-linear mixed-effects modelling approach. Monte Carlo simulations were performed to evaluate the PTA of cefepime at different MIC values following different dose regimens in subjects with different renal functions. RESULTS: The PK of cefepime in critically ill patients was best characterized by a two-compartment model with zero-order input and first-order elimination. Creatinine clearance and body weight were identified to be significant covariates. Our simulation results showed that prolonged 3 h infusion does not provide significant improvement on target attainment compared with the traditional intermittent 0.5 h infusion. In contrast, for a given daily dose continuous infusion provided much higher breakpoint coverage than either 0.5 h or 3 h intermittent infusions. To balance the target attainment and potential neurotoxicity, cefepime 3 g/day continuous infusion appears to be a better dosing regimen than 6 g/day continuous infusion. CONCLUSIONS: Continuous infusion may represent a promising strategy for cefepime treatment in critically ill patients. With the availability of institution- and/or unit-specific cefepime susceptibility patterns as well as individual patients' renal function, our PTA results may represent useful references for physicians to make dosing decisions.


Assuntos
Antibacterianos , Estado Terminal , Humanos , Cefepima , Antibacterianos/uso terapêutico , Cromatografia Líquida , Estudos Prospectivos , Espectrometria de Massas em Tandem , Método de Monte Carlo , Testes de Sensibilidade Microbiana
3.
Transfusion ; 62(4): 770-782, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35274303

RESUMO

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.


Assuntos
Biotina , Eritrócitos , Adulto , Anticorpos/metabolismo , Biotina/química , Sobrevivência Celular , Contagem de Eritrócitos , Eritrócitos/metabolismo , Humanos
4.
Pediatr Res ; 91(4): 947-954, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-33911194

RESUMO

BACKGROUND: The objective of this study was to determine sex-specific differences in inflammatory cytokine responses to red blood cell (RBC) transfusion in preterm infants in the neonatal period and their relationship to later neurocognitive status. METHODS: Infants with a birth weight <1000 g and gestational age 22-29 weeks were enrolled in the Transfusion of Prematures (TOP) trial. The total number of transfusions was used as a marker of transfusion status. Nineteen cytokines and biomarkers were analyzed from 71 infants longitudinally during the neonatal period. Twenty-six infants completed the Bayley Scales of Infant & Toddler Development, 3rd Edition (Bayley-III) at 12 months' corrected age. RESULTS: Nine cytokine levels were significantly elevated in proportion to the number of transfusions received. Of those, one cytokine showed a sex-specific finding (p = 0.004): monocyte chemoattractant protein-1, MCP-1, rose substantially in females (8.9% change per additional transfusion), but not in males (-0.8% change). Higher concentrations of MCP-1 exclusively were associated with worse Bayley-III scores: decreased cognitive raw scores (p = 0.0005) and motor scaled scores (p < 0.0001). CONCLUSIONS: This study provides evidence of a sex-specific difference in the inflammatory response to RBC transfusions during neonatal life, with MCP-1 levels rising only in females and inversely correlating with neurocognitive status at 12 months old. IMPACT: It is important to understand the risk factors for abnormal neurodevelopment in preterm infants, including anemia and RBC transfusion, in order to improve outcomes and provide potential targets for therapy. Our study investigates and provides the first evidence of sex-specific differences in inflammatory cytokine responses to RBC transfusions in preterm infants in the neonatal period, and their relationship to later cognitive outcomes. This study critically suggests that different transfusion thresholds may have a sex-specific effect on neurodevelopment: females have worse cognitive outcomes with increased number of transfusions, while males have worse outcomes with lower number of transfusions.


Assuntos
Citocinas , Transfusão de Eritrócitos , Recém-Nascido Prematuro , Transtornos Neurocognitivos , Citocinas/metabolismo , Transfusão de Eritrócitos/efeitos adversos , Feminino , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino , Transtornos Neurocognitivos/epidemiologia , Distribuição por Sexo , Resultado do Tratamento
5.
Transfusion ; 59(4): 1233-1245, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30897226

RESUMO

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.


Assuntos
Anemia , Enterocolite Necrosante , Doenças do Prematuro , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Mucosa Intestinal , Anemia/complicações , Anemia/metabolismo , Anemia/patologia , Animais , Modelos Animais de Doenças , Enterocolite Necrosante/etiologia , Enterocolite Necrosante/metabolismo , Enterocolite Necrosante/patologia , Feminino , Humanos , Recém-Nascido , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Interferon gama/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Proteína da Zônula de Oclusão-1/metabolismo
6.
Artigo em Inglês | MEDLINE | ID: mdl-29941653

RESUMO

Although the stability of ß-lactam antibiotics is a known issue, none of the previously reported bioanalytical methods had an adequate evaluation of the stability of these drugs. In the current study, the stability of cefepime, meropenem, piperacillin, and tazobactam under various conditions was comprehensively evaluated. The evaluated parameters included stock solution stability, short-term stability, long-term stability, freeze-thaw stability, processed sample stability, and whole-blood stability. When stored at -20°C, the stock solution of meropenem in methanol was stable for up to 3 weeks, and the stock solutions of cefepime, piperacillin, and tazobactam were stable for up to 6 weeks. All four antibiotics were stable in human plasma for up to 3 months when stored at -80°C and were stable in whole blood for up to 4 h at room temperature. Short-term stability results indicated that all four ß-lactams were stable at room temperature for 2 h, but substantial degradation was observed when the plasma samples were stored at room temperature for 24 h, with the degradation rates for cefepime, meropenem, piperacillin, and tazobactam being 30.1%, 75.6%, 49.0%, and 37.7%, respectively. Because the stability information is method independent, our stability results can be used as a reference by other research groups that work with these antibiotics.


Assuntos
Antibacterianos/metabolismo , Cefepima/metabolismo , Meropeném/metabolismo , Piperacilina/metabolismo , Tazobactam/metabolismo , Cromatografia Líquida , Estabilidade de Medicamentos , Humanos , Espectrometria de Massas em Tandem , Temperatura
7.
Artigo em Inglês | MEDLINE | ID: mdl-29941654

RESUMO

The highly variable pharmacokinetics of ß-lactam antibiotics and ß-lactamase inhibitors poses a significant challenge to clinicians in ensuring appropriate antibiotic doses in critically ill patients. Therefore, routine monitoring of plasma concentrations is important for individualization of antimicrobial therapy. Accordingly, a simple and robust analytical method for the simultaneous measurement of multiple ß-lactam antibiotics and ß-lactamase inhibitors is highly desirable to ensure quick decisions on dose adjustments. In this study, a sensitive, simple, and robust method for the simultaneous quantification of cefepime, meropenem, piperacillin, and tazobactam in human plasma was developed and rigorously validated according to FDA guidance. Sample extraction was accomplished by simple protein precipitation. Chromatographic separation of analytes was achieved using stepwise gradient elution. Analytes were monitored using tandem mass spectrometry (MS/MS) with a turbo ion spray source in positive multiple-reaction-monitoring mode. The calibration curve ranged from 0.5 to 150 µg/ml for cefepime, 0.1 to 150 µg/ml for meropenem and piperacillin, and 0.25 to 150 µg/ml for tazobactam. Inter- and intraday precision and accuracy, sensitivity, selectivity, dilution integrity, matrix effect, extraction recovery, and hemolysis effect were investigated for all four analytes, and the results met the acceptance criteria. Compared to other reported methods, our method is more robust because of the combination of the following features: (i) a simple sample extraction procedure, (ii) a short sample run time, (iii) a wide dynamic range, and (iv) the small plasma sample volume needed. Since our method already covers ß-lactams and a ß-lactamase inhibitor with highly heterogeneous physicochemical properties, further antibiotic candidates may easily be incorporated into this multianalyte method.


Assuntos
Antibacterianos/sangue , Cefepima/sangue , Cromatografia Líquida/métodos , Meropeném/sangue , Piperacilina/sangue , Espectrometria de Massas em Tandem/métodos , Tazobactam/sangue , beta-Lactamas/farmacocinética , Humanos , Sensibilidade e Especificidade
8.
Transfusion ; 58(2): 352-358, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29193118

RESUMO

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.


Assuntos
Preservação de Sangue , Transfusão de Sangue Autóloga , Transfusão de Eritrócitos , Eritrócitos , Recém-Nascido de Baixo Peso , Recém-Nascido Prematuro , Adulto , Feminino , Humanos , Recém-Nascido , Masculino , Fatores de Tempo
9.
Transfusion ; 58(8): 2068-2081, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29770455

RESUMO

The current reference method in the United States for measuring in vivo population red blood cell (RBC) kinetics utilizes chromium-51 (51 Cr) RBC labeling for determining RBC volume, 24-hour posttransfusion RBC recovery, and long-term RBC survival. Here we provide evidence supporting adoption of a method for kinetics that uses the biotin-labeled RBCs (BioRBCs) as a superior, versatile method for both regulatory and investigational purposes. RBC kinetic analysis using BioRBCs has important methodologic, analytical, and safety advantages over 51 Cr-labeled RBCs. We critically review recent advances in labeling human RBCs at multiple and progressively lower biotin label densities for concurrent, accurate, and sensitive determination of both autologous and allogeneic RBC population kinetics. BioRBC methods valid for RBC kinetic studies, including successful variations used by the authors, are presented along with pharmacokinetic modeling approaches for the accurate determination of RBC pharmacokinetic variables in health and disease. The advantages and limitations of the BioRBC method-including its capability of determining multiple BioRBC densities simultaneously in the same individual throughout the entire RBC life span-are presented and compared with the 51 Cr method. Finally, potential applications and limitations of kinetic BioRBC determinations are discussed.


Assuntos
Biotinilação/métodos , Eritrócitos/metabolismo , Cinética , Prática Clínica Baseada em Evidências , Humanos
10.
Transfusion ; 57(6): 1488-1496, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28261808

RESUMO

BACKGROUND: Biotin-labeled red blood cells (BioRBCs) are used for in vivo kinetic studies. Because BioRBC dosing occasionally induces antibodies, a sensitive and specific anti-BioRBC detection assay is needed. STUDY DESIGN AND METHODS: Aims were to 1) develop a gel card assay to evaluate existing, naturally occurring and BioRBC-induced plasma antibodies, 2) compare gel card and tube agglutination detection results, and 3) test for a relationship of antibody induction and BioRBC dose. Reagent BioRBCs were prepared using sulfo-NHS biotin ranging from densities 18 (BioRBC-18) to 1458 (BioRBC-1458) µg/mL RBCs. RESULTS: Among BioRBC-exposed subjects, gel card and tube agglutination results were concordant in 21 of 22 adults and all 19 infant plasma samples. Gel card antibody detection sensitivity was more than 10-fold greater than tube agglutination. Twelve to 16 weeks after BioRBC exposure, induced anti-antibodies were detected by gel card in three of 26 adults (12%) at reagent densities BioRBC-256 or less, but in none of 41 infants. Importantly, induced anti-BioRBC antibodies were associated with higher BioRBC dose (p = 0.008); no antibodies were detected in 18 subjects who received BioRBC doses less than or equal to BioRBC-18. For noninduced BioRBC antibodies, six of 1125 naïve adults (0.3%) and none of 46 naïve infants demonstrated existing anti-BioRBC antibodies using reagent BioRBC-140 or -162. Existing anti-BioRBCs were all neutralized by biotin compounds, while induced antibodies were not. CONCLUSIONS: The gel card assay is more sensitive than the tube agglutination assay. We recommend reagent BioRBC-256 for identifying anti-BioRBCs. Use of a low total RBC biotin label dose (≤ BioRBC-18) may minimize antibody induction.


Assuntos
Anticorpos/imunologia , Biotina/química , Eritrócitos/imunologia , Adulto , Testes de Aglutinação , Bioensaio/métodos , Biotinilação , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Succinimidas/química
11.
Pediatr Res ; 81(6): 905-910, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28099421

RESUMO

BACKGROUND: Prior conclusions that autologous neonatal red blood cells (RBC) have substantially shorter lifespans than allogeneic adult RBCs were not based on direct comparison of autologous neonatal vs. allogeneic adult RBCs performed concurrently in the same infant. Biotin labeling of autologous neonatal RBCs and allogeneic adult donor RBCs permits concurrent direct comparison of autologous vs. allogeneic RBC lifespan. METHODS: RBCs from 15 allogeneic adult donors and from 15 very-low-birth-weight (VLBW) neonates were labeled at separate biotin densities and transfused simultaneously into the 15 neonates. Two mathematical models that account for the RBC differences were employed to estimate lifespans for the two RBC populations. RESULTS: Mean ± SD lifespan for adult allogeneic RBC was 70.1 ± 19.1 d, which is substantially shorter than the 120 d lifespan of both autologous and adult allogeneic RBC in healthy adults. Mean ± SD lifespan for neonatal RBC was 54.2 ± 11.3 d, which is only about 30% shorter than that of the adult allogeneic RBCs. CONCLUSION: This study provides evidence that extrinsic environmental factors primarily determine RBC survival (e.g., small bore of the capillaries of neonates, rate of oxygenation/deoxygenation cycles) rather than factors intrinsic to RBC.


Assuntos
Anemia/sangue , Biotina/metabolismo , Envelhecimento Eritrocítico , Adulto , Feminino , Humanos , Recém-Nascido , Masculino
12.
Mol Cell ; 29(5): 577-87, 2008 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-18342605

RESUMO

Glc7, the yeast protein phosphatase 1, is a component of the cleavage and polyadenylation factor (CPF). Here we show that downregulation of Glc7, or its dissociation from CPF in the absence of CPF subunits Ref2 or Swd2, results in similar snoRNA termination defects. Overexpressing a C-terminal fragment of Sen1, a superfamily I helicase required for snoRNA termination, suppresses the growth and termination defects associated with loss of Swd2 or Ref2, but not Glc7. Suppression by Sen1 requires nuclear localization and direct interaction with Glc7, which can dephosphorylate Sen1 in vitro. The suppressing fragment, and in a similar manner full-length Sen1, copurifies with the snoRNA termination factors Nrd1 and Nab3, suggesting loss of Glc7 from CPF can be compensated by recruiting Glc7 to Nrd1-Nab3 through Sen1. Swd2 is also a subunit of the Set1c histone H3K4 methyltransferase complex and is required for its stability and optimal methyltransferase activity.


Assuntos
Fosfoproteínas Fosfatases/metabolismo , Subunidades Proteicas/metabolismo , RNA Nucleolar Pequeno/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Transcrição Gênica , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Morte Celular/fisiologia , DNA Helicases , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas Fosfatases/genética , Proteína Fosfatase 1 , Subunidades Proteicas/genética , RNA Helicases , Splicing de RNA , RNA Nucleolar Pequeno/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/química , Fatores de Poliadenilação e Clivagem de mRNA/genética
13.
J Clin Lab Anal ; 30(4): 326-34, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25968472

RESUMO

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.


Assuntos
Estado Terminal , Hemoglobinas/análise , Recém-Nascido de muito Baixo Peso/sangue , Reticulócitos/metabolismo , Adulto , Criança , Eritropoese , Feminino , Ferritinas/sangue , Humanos , Recém-Nascido , Masculino
14.
J Pediatr ; 167(5): 1001-6, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26363547

RESUMO

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.


Assuntos
Biotina/química , Transfusão de Eritrócitos/métodos , Adulto , Biotinilação , Sobrevivência Celular , Eritropoese , Feminino , Citometria de Fluxo , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Sistema do Grupo Sanguíneo Kidd , Masculino , Modelos Teóricos , Estudos Prospectivos , Transplante Autólogo , Transplante Homólogo
15.
Transfusion ; 54(10 Pt 2): 2724-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24611672

RESUMO

BACKGROUND: The quality of transfused red blood cells (RBCs) to treat anemia depends on its potential for oxygen delivery, governed by two properties: 1) initial posttransfusion recovery and 2) life span of initially surviving RBCs. The latter property is poorly evaluated by the traditional mean potential life span (MPL) or mean cell age (MA), because these parameters do not evaluate how long transfused RBCs remain in circulation. Furthermore, evaluation of MPL is based on two problematic assumptions regarding transfused RBCs: 1) they were produced at a constant steady-state rate and 2) they have similar storage life spans. STUDY DESIGN AND METHODS: This work introduces a new parameter, the mean remaining life span (MRL) to quantify transfused RBC survival (TRCS) and presents a simple algorithm for its evaluation. The MRL was calculated for four adult subjects with sickle cell disease and four adult diabetic and nondiabetic subjects using RBC survival data sets with existing TRCS parameters. RESULTS: The RBC survival curves in the sickle cell subjects were nonlinear with rapid decline in survival within the first 5 days. The MRL was approximately 4.6 days. Thus, the MRL was indicative of the survival of all transfused RBCs. For the diabetic and nondiabetic subjects, the RBC disappearance curves did not deviate substantially from a linear decline. Thus, the estimates for MRL ranging from 39 to 51 days are similar to the MA previously computed. CONCLUSION: MRL overcomes limitations of previously proposed TRCS parameters, is simpler to calculate, and is physiologically and clinically more appropriate.


Assuntos
Bancos de Sangue/normas , Preservação de Sangue/normas , Transfusão de Sangue/normas , Eritrócitos/citologia , Modelos Teóricos , Garantia da Qualidade dos Cuidados de Saúde , Adulto , Algoritmos , Anemia Falciforme/terapia , Preservação de Sangue/métodos , Sobrevivência Celular , Diabetes Mellitus/terapia , Humanos , Armazenamento de Sangue/métodos
16.
Pediatr Res ; 75(2): 336-42, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24216541

RESUMO

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.


Assuntos
Transfusão de Eritrócitos/métodos , Eritropoetina/farmacologia , Recém-Nascido Prematuro , Flebotomia , Anemia/sangue , Anemia/prevenção & controle , Peso ao Nascer , Volume Sanguíneo , Simulação por Computador , Eritropoetina/sangue , Humanos , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Fatores de Tempo , Reação Transfusional
17.
Am J Physiol Regul Integr Comp Physiol ; 304(9): R772-81, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23485870

RESUMO

A population pharmacokinetics/pharmacodynamic (PK/PD) model was developed to describe changes in erythropoiesis as a function of plasma erythropoietin (EPO) concentration over the first 30 days of life in preterm infants who developed severe anemia requiring red blood cell (RBC) transfusion. Several covariates were tested as possible factors influencing the responsiveness to EPO. Discarded blood samples in 27 ventilated preterm infants born at 24-29 wk of gestation were used to construct plasma EPO, hemoglobin (Hb), and RBC concentration-time profiles. The amount of Hb removed for laboratory testing and that transfused throughout the study period were recorded. A population PK/PD model accounting for the dynamic Hb changes experienced by these infants was simultaneously fitted to plasma EPO, Hb, and RBC concentrations. A covariate analysis suggested that the erythropoietic efficacy of EPO is increased for preterm infants at later gestational ages. The PD analysis showed a sevenfold difference in maximum Hb production rate dependent on gestational age and indicated that preterm infants, when stimulated by EPO, have the capacity to produce additional Hb that may result in a decrease in RBC transfusions. The present model has utility in clinical trial simulations investigating the treatment potential of erythropoietic stimulating agents in the treatment of anemia of prematurity.


Assuntos
Anemia/diagnóstico , Anemia/tratamento farmacológico , Eritropoese/fisiologia , Eritropoetina/farmacocinética , Eritropoetina/uso terapêutico , Recém-Nascido Prematuro/fisiologia , Adulto , Algoritmos , Volume Sanguíneo/fisiologia , Interpretação Estatística de Dados , Epoetina alfa , Envelhecimento Eritrocítico/fisiologia , Feminino , Idade Gestacional , Hemoglobinas/metabolismo , Humanos , Recém-Nascido , Modelos Estatísticos , Flebotomia , Substitutos do Plasma/farmacologia , População , Gravidez , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico
18.
Transfusion ; 53(6): 1353-60, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23033916

RESUMO

BACKGROUND: Very preterm infants commonly develop anemia requiring multiple red blood cell transfusions (RBCTx). This is in part attributable to heavy laboratory phlebotomy loss. Quantification of the extent to which laboratory blood loss contributes to anemia sufficient to prompt RBCTx has not been examined. STUDY DESIGN AND METHODS: Twenty-six preterm infants weighing less than 1500 g at birth requiring ventilator support who received one or more RBCTx were intensively studied during the first month of life. Hemoglobin (Hb) loss via laboratory blood loss and RBC senescence and Hb gain from RBCTx were precisely accounted for in a Hb mass balance mathematical model developed to assess the impact of phlebotomy on RBCTx when restrictive RBCTx criteria were applied. RESULTS: Study subjects had a birth weight of 880 ± 240 g (mean ± SD) and a Hb level of 14.4 ± 2.4 g/dL at birth and received 3.81 ± 2.15 RBCTx during the study period. Modeling indicated that even with the total elimination of laboratory phlebotomy loss, a reduction of 41% to 48% in RBCTx was achievable. CONCLUSION: The present modeling results indicate that while phlebotomy reduction can significantly decrease the number of RBCTx administered to preterm infants, total elimination of all RBCTx will likely require other approaches, for example, stimulation of erythropoiesis with erythropoiesis-stimulating agents.


Assuntos
Anemia Neonatal/fisiopatologia , Anemia Neonatal/terapia , Transfusão de Sangue , Modelos Cardiovasculares , Flebotomia/efeitos adversos , Anemia Neonatal/tratamento farmacológico , Peso ao Nascer , Volume Sanguíneo/fisiologia , Determinação do Volume Sanguíneo/métodos , Simulação por Computador , Eritropoetina/uso terapêutico , Feminino , Hematínicos/uso terapêutico , Hemoglobinas , Humanos , Recém-Nascido , Recém-Nascido Prematuro/sangue , Recém-Nascido de muito Baixo Peso/sangue , Masculino , Gravidez
19.
Pediatr Res ; 74(6): 689-97, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24108188

RESUMO

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.


Assuntos
Biotina/metabolismo , Sobrevivência Celular , Transfusão de Eritrócitos , Eritrócitos , Recém-Nascido Prematuro , Sistema do Grupo Sanguíneo Kidd/imunologia , Adulto , Eritrócitos/imunologia , Eritrócitos/metabolismo , Hemoglobina Fetal/metabolismo , Citometria de Fluxo , Humanos , Recém-Nascido
20.
Pediatr Res ; 74(5): 592-600, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24088873

RESUMO

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.


Assuntos
Anemia/terapia , Volume de Eritrócitos , Citometria de Fluxo/métodos , Recém-Nascido Prematuro/sangue , Recém-Nascido de muito Baixo Peso/sangue , Transfusão de Sangue/métodos , Cromatografia Líquida de Alta Pressão/métodos , Hemoglobina Fetal/metabolismo , Humanos , Recém-Nascido , Sistema do Grupo Sanguíneo Kidd/análise , Análise de Regressão
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA