Establishing reference ranges of cord blood: point-of-care hemostatic function assessment in preterm and term neonates.

BACKGROUND: Thrombelastometry, allowing timely assessment of global hemostatic function, is increasingly used to guide hemostatic interventions in bleeding patients. Reference values are available for adults and children, including infants but not neonates immediately after birth. METHODS: Neonates were grouped as preterm (30 + 0 to 36 + 6 weeks/days) and term (37 + 0 to 39 + 6 weeks/days). Blood samples were drawn from the umbilical cord immediately after cesarean section and analyzed by thrombelastometry. Reference ranges were determined for the extrinsic and intrinsic coagulation pathways, fibrin polymerization, and hyperfibrinolysis detection. RESULTS: All extrinsically activated test parameters, but maximum lysis (P = 0.139) differed significantly between both groups (P ≤ 0.001). Maximum clot firmness in the fibrin polymerization test was comparable (P = 0.141). All intrinsically activated test parameters other than coagulation time (P = 0.537) and maximum lysis (P = 0.888) differed significantly (P < 0.001), and so did all aprotinin-related test parameters (P ≤ 0.001) but maximum lysis (P = 0.851). CONCLUSIONS: This is the first study to identify reference ranges for thrombelastometry in preterm and term neonates immediately after birth. We also report differences in clot initiation and clot strength in neonates born <37 versus ≤40 weeks of gestation, mirroring developmental hemostasis. IMPACT: Impact: This prospective observational study is the first to present reference ranges in preterm and term infants for all types of commercially available tests of thrombelastometry, notably also including the fibrin polymerization test. IMPORTANCE: Viscoelastic coagulation assays such as thrombelastometry have become integral to the management of perioperative bleeding by present-day standards. Reference values are available for adults, children, and infants but not for neonates. Key message: Clot initiation and formation was faster and clot strength higher in the term than in the preterm group. Parameters of thrombelastometry obtained from cord blood do not apply interchangeably to preterm and term neonates.

Assessment of Vancomycin Pharmacokinetics and Dose Regimen Optimisation in Preterm Neonates.

BACKGROUND: The pharmacokinetics of vancomycin, a drug used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA), varies between paediatric and adult patients. OBJECTIVE: The objective of this study was to assess the pharmacokinetics of vancomycin in preterm neonates and determine the optimum dose regimen. METHODS: This was a randomised double-blind study of preterm neonates admitted to neonatal intensive care units. They all received vancomycin 15 mg/kg every 12 h. Blood was sampled just before administration of the third, sixth and ninth vancomycin dose. Pharmacokinetic parameters were estimated using a Bayesian approach implemented in Monolix 2018R2 software. Covariates assessed included postmenstrual age, current weight, creatinine clearance, albumin, gestational age, body surface area and current age. We used Monte Carlo simulations for dose regimen optimisation targeting area under the concentration-time curve up to 24 h (AUC0-24h) of ≥ 400 mg × h/L. RESULTS: In total, 19 preterm neonates were enrolled in the study with a median age of 14 (3-58) days. A one-compartment model with linear elimination best described the pharmacokinetics of vancomycin. Volume of distribution and clearance was 0.88 L and 0.1 L/h, respectively, for a typical neonate weighing 1.48 kg. Simulation of the current dose regimen showed that 27.5% of the neonates would achieve the target AUC0-24h of ≥ 400 mg × h/L, and 70.7% of the neonates would achieve it with 12 mg/kg every 8 h. CONCLUSION: The majority of the neonates were under dosed. Vancomycin 12 mg/kg should be administered every 8 h over 1 h infusion to improve the likelihood of achieving the AUC0-24h target of ≥ 400 mg × h/L. This target is considered optimal for MRSA infections, where the vancomycin minimum inhibitory concentration is ≤ 1 µg/mL.

Nutritional Assessment in Preterm Infants: A Practical Approach in the NICU.

A practical approach for nutritional assessment in preterm infants under intensive care, based on anthropometric measurements and commonly used biochemical markers, is suggested. The choice of anthropometric charts depends on the purpose: Fenton 2013 charts to assess intrauterine growth, an online growth calculator to monitor intra-hospital weight gain, and Intergrowth-21st standards to monitor growth after discharge. Body weight, though largely used, does not inform on body compartment sizes. Mid-upper arm circumference estimates body adiposity and is easy to measure. Body length reflects skeletal growth and fat-free mass, provided it is accurately measured. Head circumference indicates brain growth. Skinfolds estimate reasonably body fat. Weight-to-length ratio, body mass index, and ponderal index can assess body proportionality at birth. These and other derived indices, such as the mid-upper arm circumference to head circumference ratio, could be proxies of body composition but need validation. Low blood urea nitrogen may indicate insufficient protein intake. Prealbumin and retinol binding protein are good markers of current protein status, but they may be affected by non-nutritional factors. The combination of a high serum alkaline phosphatase level and a low serum phosphate level is the best biochemical marker for the early detection of metabolic bone disease.

Assessment of Adequacy of Supplementation of Vitamin D in Very Low Birth Weight Preterm Neonates: A Randomized Controlled Trial.

OBJECTIVES: To compare the effect of 400 IU and 1000 IU vitamin D for 6 weeks in very low birth weight preterm neonates. DESIGN: Randomized, double-blinded controlled trial in a teaching hospital. PARTICIPANTS: Fifty very low birth weight preterm neonates. INTERVENTION: Vitamin D 400 IU/day (Group 1) or 1000 IU/day (Group 2). OUTCOME MEASURES: Change in serum calcium, phosphate, alkaline phosphatase (ALP), 25-hydroxy vitamin D (25-OHD), parathormone, incidence of skeletal hypomineralization and growth. RESULTS: After 6 weeks of supplementation, the mean serum calcium and 25-OHD levels were significantly higher (p < 0.001 each), while ALP and parathormone levels significantly lower (p < 0.001 each) in group 2. Skeletal hypomineralization was lesser and growth better in group 2. CONCLUSION: Vitamin D supplementation in a dose of 1000 IU/day is more effective in maintaining serum calcium, phosphate, ALP, 25-OHD and parathormone levels with lower incidence of skeletal hypomineralization and better growth.

Cerebral blood flow assessment of preterm infants during respiratory therapy with the expiratory flow increase technique / Avaliação do fluxo sanguíneo cerebral de recém-nascidos prematuros durante a fisioterapia respiratória com a técnica do aumento do fluxo expiratório

Objective: To assess the impact of respiratory therapy with the expiratory flow increase technique on cerebral hemodynamics of premature newborns. Methods: This is an intervention study, which included 40 preterm infants (≤34 weeks) aged 8-15 days of life, clinically stable in ambient air or oxygen catheter use. Children with heart defects, diagnosis of brain lesion and/or those using vasoactive drugs were excluded. Ultrasonographic assessments with transcranial Doppler flowmetry were performed before, during and after the increase in expiratory flow session, which lasted 5min. Cerebral blood flow velocity and resistance and pulsatility indices in the pericallosal artery were assessed. Results: Respiratory physical therapy did not significantly alter flow velocity at the systolic peak (p=0.50), the end diastolic flow velocity (p=0.17), the mean flow velocity (p=0.07), the resistance index (p=0.41) and the pulsatility index (p=0.67) over time. Conclusions: The expiratory flow increase technique did not affect cerebral blood flow in clinically-stable preterm infants.

Objetivo: Avaliar a repercussão da fisioterapia respiratória com a técnica de aumento do fluxo expiratório sobre a hemodinâmica cerebral de recém-nascidos prematuros. Métodos: Estudo de intervenção no qual foram incluídos 40 neonatos prematuros (≤34 semanas) com 8-15 dias de vida, clinicamente estáveis em ar ambiente ou em uso de cateter de oxigênio. Foram excluídas crianças com malformações cardíacas, diagnóstico de lesão cerebral e/ou em uso de drogas vasoativas. Exames de ultrassonografia com avaliação por dopplerfluxometria cerebral foram feitos antes, durante e depois da sessão de aumento do fluxo expiratório, que durou cinco minutos. Foram avaliadas as velocidades de fluxo sanguíneo cerebral e os índices de resistência e pulsatilidade na artéria pericalosa. Resultados: A fisioterapia respiratória não alterou significativamente a velocidade de fluxo no pico sistólico (p=0,50), a velocidade de fluxo diastólico final (p=0,17), a velocidade média de fluxo (p=0,07), o índice de resistência (p=0,41) e o índice de pulsatilidade (p=0,67) ao longo do tempo. Conclusões: A manobra de aumento do fluxo expiratório não afetou o fluxo sanguíneo cerebral em recém-nascidos prematuros clinicamente estáveis.

Assessment of G6PD screening program in premature infants in a NICU.

OBJECTIVE: Targeted screening for glucose-6-phosphate dehydrogenase deficiency (G6PDdef) using fluorescent spot test (FST) is done in our newborn nursery (NN) and now in our NICU. Premature infants have higher G6PD levels than term infants. FST may result in under diagnosis of G6PDdef in preterms. We sought to determine if FST is appropriate for diagnosis of G6PDdef at<35 weeks and assess screening in NICU. STUDY DESIGN: Retrospective chart review of male, inborn infants<35 weeks in NICU from 2008 to 2011. Difference in G6PDdef incidence<5% between NN and NICU was acceptable for equivalence. RESULTS: Out of 679 subjects, 442 were screened for G6PDdef and 11.3% had abnormal results. Binomial testing comparing 11.3% (95% confidence interval (CI) 8.5 to 14.6) incidence of G6PDdef in NICU and reported incidence in NN (11%) demonstrated no difference. 12.2% of Black/African American males were not screened. CONCLUSION: FST is appropriate for screening all at-risk newborns. A number of at-risk premature males were not screened.

Serum caffeine concentrations and short-term outcomes in premature infants of ⩽29 weeks of gestation.

OBJECTIVE: Caffeine is effective in the treatment of apnea of prematurity but it is not well known if the therapeutic concentration of the drug has an impact on other neonatal outcomes such as chronic lung disease (CLD). The aim of this study was to determine if there is an association between caffeine concentrations and the incidence of CLD in premature infants of ⩽29 weeks of gestation. STUDY DESIGN: A retrospective chart review of all the infants born ⩽29 weeks of gestation from 2007 to 2011, who survived until discharge or 36 weeks postmenstrual age, was conducted. Caffeine concentrations were obtained weekly on infants getting the drug. Average caffeine concentrations (ACCs) were determined for the duration of caffeine therapy and correlated with CLD, length of stay (LOS), oxygen at discharge (OD), duration of ventilation (DV) and total charges for hospitalization for each patient. RESULTS: Of the 222 eligible infants, 198 met the inclusion criteria. ACC for infants without CLD was 17.0±3.8 µg ml(-1) compared with infants with CLD 14.3±6.1 µg ml(-1) (P<0.001). Infants receiving high ACC (>14.5 µg ml(-1)) had lower incidence of patent ductus arteriosus, lesser number of days on ventilator and oxygen, lesser need for diuretics, lower incidence of CLD, were more likely to go home without supplemental OD and had lower LOS and lower total hospital charges (all differences were significant P<0.05) Multiple logistic regression modeling after adjusting for confounding variables indicated that higher caffeine concentrations were significantly associated with decrease in CLD. Receiver operating curve analysis confirmed a significant predictive ability of caffeine concentration for CLD with a cutoff concentration of 14.5 µg ml(-1) (sensitivity of 42.6 and specificity of 86.8). The AUC (area under the curve) for the prediction of CLD was 0.632 (95% confidence interval 0.56-0.69, P=0.009). CONCLUSIONS: Caffeine concentrations >14.5 µg ml(-1) were strongly correlated with reduced CLD in infants born at ⩽29 weeks of gestation. Higher caffeine concentrations were associated with decreased total hospital charges, DV, OD and LOS. Additional randomized trials are needed to confirm these findings, to identify ideal serum concentrations and determine possible long-term neurologic benefits.

Assessment of bone health in preterm infants through quantitative ultrasound and biochemical markers.

OBJECTIVE: To assess bone status in preterm infants with quantitative ultrasound and to search for biochemical markers of bone health. METHODS: Metacarpus bone transmission time (mcBTT) was prospectively performed during hospitalization, together with biochemical and clinical outcomes analysis. RESULTS: 154 patients were studied. At 3rd week of life mcBTT positively correlated with serum phosphate. Urinary excretion of calcium and phosphate were assessed in a subgroup of 55 patients: on day 21 mcBTT positively correlated with phosphaturia, negatively with calciuria. Gestational age (GA), weight and length at 3rd week and at 36 weeks of GA correlated positively with mcBTT. We found negative correlation between mcBTT at 3rd week and days of parenteral nutrition, mechanical ventilation period and days to reach 1800 g. CONCLUSIONS: Serum phosphate, phosphaturia and calciuria correlate most with mcBTT. Further studies are necessary to verify the possible influence of early bone status on future bone health.

Comparison of hematologic indices and markers of infection in umbilical cord and neonatal blood.

OBJECTIVE: Evaluation of a neonate for suspected early neonatal sepsis routinely includes blood tests such as complete blood count, C-reactive protein (CRP) and culture. In order to obviate the need for venepuncture, we prospectively compared these tests in paired samples from umbilical cord and peripheral venous blood drawn during the first hours after birth in both preterm and term infants. METHODS: Paired blood samples were studied from asymptomatic neonates with risk factors for early sepsis. Data were collected on maternal and neonatal factors that may have influenced the correlation between the tests. RESULTS: Three hundred fifty pairs of samples were studied. Significant correlation between umbilical cord and peripheral venous samples was found for white blood cell (WBC; r = 0.683) and platelets (PLT) (r = 0.54). Correlation for hemoglobin was lower (r = 0.36). No cases of early neonatal sepsis were detected. However, contamination rates were 12% in umbilical cord blood and 2.5% in peripheral venous blood cultures. WBC rose after birth and the 90th percentile rose from 22 500 in umbilical cord blood to 29 700 in peripheral blood. CONCLUSIONS: Screening for sepsis with umbilical cord CBC may be useful provided normal ranges are adjusted accordingly.

Is additional oral phosphate supplementation for preterm infants necessary: an assessment of clinical audit.

UNLABELLED: Adequate phosphate intake is important for the prevention of metabolic bone disease in preterm infants. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition recommends a daily phosphate intake of 184-230 mg/kg/day, which should be met by standard feed volumes of either commercially fortified breast milk or preterm formulae. We sought to investigate whether our local practise of providing supplemental oral phosphate for all infants born before 32 weeks' gestation continues to be necessary. Details of parenteral and milk feeding and both oral and parenteral phosphate supplementation from birth until 8 weeks of age were collected retrospectively from the case notes of 31 preterm infants. Routinely collected biochemical markers of bone mineral status were also recorded. Mean (SD) plasma phosphate concentration was higher when oral phosphate supplementation was given [2.10 (0.38) versus 1.92(0.50) mM/L without supplement (p < 0.001)]. A minimum average phosphate intake of 184 mg/kg/day was achieved by 47 and 77 % of babies in weeks 1 and 2, respectively, and by 84-100 % of infants from week 3. The percentage of plasma phosphate measurements below the minimum target of 1.8 mM/L was greater amongst unsupplemented babies (45 versus 18 %). CONCLUSION: A majority of infants <32 weeks' gestation did not achieve the recommended phosphate intake during the first week of life. Despite achieving the recommended phosphate intake from week 3, many infants did not have plasma phosphate concentrations within the accepted normal range. Additional oral supplementation may help to achieve blood phosphate concentrations within this target range.

New insight into the pathogenesis of retinopathy of prematurity: assessment of whole-genome expression.

BACKGROUND: Retinopathy of prematurity (ROP) is one of the most common preventable causes of blindness and impaired vision among children in developed countries. The aim of the study was to compare whole-genome expression in the first month of life in groups of infants with and without ROP. METHODS: Blood samples were drawn from 111 newborns with a mean gestational age of 27.8 wk on the 5th, 14th, and 28th day of life (DOL). The mRNA samples were evaluated for gene expression with the use of human whole-genome microarrays. The infants were divided into two groups: no ROP (n = 61) and ROP (n = 50). RESULTS: Overall, 794 genes were differentially expressed on the 5th DOL, 1,077 on the 14th DOL, and 3,223 on the 28th DOL. In each of the three time points during the first month of life, more genes were underexpressed than overexpressed in the ROP group. Fold change (FC), which was used in analysis of gene expression data, ranged between 1.0 and 1.5 in the majority of genes differentially expressed. CONCLUSION: Pathway enrichment analysis revealed that genes in four pathways related to inflammatory response were consistently downregulated due to the following variables: ROP and gestational age.

Assessment of oxidant/antioxidant system in newborns and their breast milks.

AIM: In this study, it is aimed to investigate total oxidant and antioxidant status of newborns and their breast milks. METHODS: Totally, 184 infants who were born in our hospital were included in the study. Study group was divided into two main study groups, including term and preterm groups; main study groups were also divided into two sub-groups, AGA and SGA. TOS and TAC levels were measured in cord blood of all newborns and in mother milks. Groups were statistically compared with each other in terms of TOS, TAC and OSI levels. RESULTS: The study included 92 preterm newborns (Group I) and 92 term newborns (Group II). TOS, TAC and OSI levels were found significantly higher in Group I than Group II (p < 0.0001, p = 0.17, p < 0.0001, respectively). When sub-groups of Group I and Group II, namely TAGA, TSGA and PAGA and PSGA, were compared with each other. TOS and OSI levels were significantly higher and TAC levels were significantly lower in TSGA group relative to TAGA group (p < 0.0001; p = 0.001; p < 0.0001, respectively). No statistically significant difference was found between Group I and Group II and between sub-groups of Group I and II with regards the TOC, TAC and OSI levels of mother milk. CONCLUSION: In preterm newborns and term SGA infants, total oxidant stress is increased and antioxidant capacity is low. No significant difference was found between mother milks of preterm and term AGA and SGA infants.

Evaluation of vancomycin dosing regimens in preterm and term neonates using Monte Carlo simulations.

STUDY OBJECTIVE: To compare four common dosing regimens for vancomycin in preterm and term neonates by assessing the probability that each regimen would achieve the widely used therapeutic target serum trough concentrations of 5-15 mg/L and the newly suggested target of 15-20 mg/L. DESIGN: Retrospective population pharmacokinetic analysis using therapeutic drug monitoring data obtained from 1990-2007, with a subsequent simulation study performed on the pharmacokinetic model. SETTING: Tertiary-care children's hospital. PATIENTS: One hundred thirty-four preterm (66%) and term (34%) neonates, with a postnatal age of 1-121 days and postmenstrual age of 24.6-44 weeks. MEASUREMENTS AND MAIN RESULTS: Therapeutic drug monitoring data for vancomycin were used to develop a population pharmacokinetic model in the target population. Parameter estimates for the derived pharmacostatistical model were used to perform Monte Carlo simulations for four recommended dosing regimens: a standard dose for all neonates, postmenstrual age-based dosing, postmenstrual and postnatal age-based dosing, and serum creatinine-based dosing. Multivariate age-weight distributions were established for term and preterm neonates using Centers for Disease Control and Prevention growth charts and intrauterine and postnatal growth charts from the literature, respectively. Each dosing regimen was treated as a separate scenario in which 200 replicates with 100 patients/replicate were simulated. The 5-15-mg/L target trough serum concentration was achieved in 34% (90% confidence interval [CI] 20-53%), 42% (90% CI 31-55%), 52% (90% CI 43-60%), and 63% (90% CI 54-72%) of patients receiving the standard dose, postmenstrual age-based dose, postmenstrual and postnatal age-based dose, and serum creatinine-based dose, respectively. Serum creatinine-based dosing produced trough concentrations predominantly in the 5-15-mg/L target range, with the smallest variability in both term and preterm neonates. As expected, when the target range was narrow and higher (15-20 mg/L), only 13-21% of patients were within the range across the four dosing regimens. CONCLUSION: Monte Carlo simulations based on our population pharmacokinetic model suggest that vancomycin dosing guidelines based on serum creatinine concentration have a greater likelihood of achieving trough concentrations in the 5-15-mg/L range compared with other evaluated dosing regimens. None of the four dosing regimens is suitable to produce target trough concentration of 15-20 mg/L in an acceptable number of patients.

Near-infrared spectroscopy assessment of cerebral oxygen metabolism in the developing premature brain.

Little is known about cerebral blood flow, cerebral blood volume (CBV), oxygenation, and oxygen consumption in the premature newborn brain. We combined quantitative frequency-domain near-infrared spectroscopy measures of cerebral hemoglobin oxygenation (SO(2)) and CBV with diffusion correlation spectroscopy measures of cerebral blood flow index (BF(ix)) to determine the relationship between these measures, gestational age at birth (GA), and chronological age. We followed 56 neonates of various GA once a week during their hospital stay. We provide absolute values of SO(2) and CBV, relative values of BF(ix), and relative cerebral metabolic rate of oxygen (rCMRO(2)) as a function of postmenstrual age (PMA) and chronological age for four GA groups. SO(2) correlates with chronological age (r=-0.54, P value ≤0.001) but not with PMA (r=-0.07), whereas BF(ix) and rCMRO(2) correlate better with PMA (r=0.37 and 0.43, respectively, P value ≤0.001). Relative CMRO2 during the first month of life is lower when GA is lower. Blood flow index and rCMRO(2) are more accurate biomarkers of the brain development than SO(2) in the premature newborns.

Red blood cell transfusion in preterm infants: restrictive versus liberal policy.

Preterm neonates represent a category of patients with high transfusion needs. Ideally, red blood cells (RBC) transfusion should be tailored to the individual requirements of the single infant. However, despite the progress in neonatal transfusion medicine, many controversies still remain, and the decision on whether to transfuse or not is often made on empirical basis, with large variation in transfusion practices among neonatologists. Recently, a few clinical trials have been performed with the aim to compare the risk/benefit ratio of restrictive versus liberal transfusion criteria. Most of the studies failed to demonstrate significant differences in short-term outcomes, suggesting that the restrictive criteria may reduce the need for transfusion and the related side effects. Neurodevelopmental long-term outcome seemed more favorable in the liberal group at a first evaluation, especially for boys, and significantly better in the restrictive group at a later clinical investigation. Magnetic resonance imaging scans, performed at an average age of 12 years, showed that intracranial volume was substantially smaller in the liberal group compared with controls. When sex effects were evaluated, the girls in the liberal group had the most significant abnormalities. In conclusion, when preventive measures, as favoring cord clamping delay or cord milking, ensuring optimal nutrition, and minimizing phlebotomy losses, fail to avoid the need for transfusion, it is preferable to adopt restrictive criteria.

High plasma cytokine levels, white matter injury and neurodevelopment of high risk preterm infants: assessment at two years.

BACKGROUND: Controversy exists regarding association of high levels of proinflammatory cytokines, neonatal morbidities and poor neurodevelopment outcome in very low birth weight infants. OBJECTIVE: To determine association between severity of early inflammatory response and neurodevelopment outcome in high risk very low birth weight infants. METHODS: Sixty-two very preterm infants with high risk for early-onset sepsis were followed up to 24 months corrected age. Blood sample was collected for IL-6, IL-8, IL-10, IL-1ß, and TNF-α analysis. Neurodevelopment outcome by Bayley Scales of Infant Development II was assessed at 22 to 24 months. Magnetic Resonance Image was performed at least once during the first 12 months. RESULTS: In 24 (38.7%) MDI was <85, and 16 (25.8%) had PDI<85. Low birth weight was significantly associated with low MDI, and birth weight and periventricular leukomalacia were significantly associated with low PDI by multiple regression analysis. After controlling for birth weight and gestational age, none of the studied variables was associated with low MDI, and only periventricular leukomalacia with low PDI. Each additional 100g in the birth weight reduced the probability of low MDI and PDI scores in 14%. CONCLUSIONS: There was no association of high cytokines plasma levels with poor neurodevelopment outcome at 22 to 24 months' corrected age, suggesting that elevations of plasma proinflammatory cytokines early in life do not play an important role in pathophysiology of brain injury in high risk preterm infants.

Population pharmacokinetics of vancomycin in premature Malaysian neonates: identification of predictors for dosing determination.

The present study determined the pharmacokinetic profile of vancomycin in premature Malaysian infants. A one-compartment infusion model with first-order elimination was fitted to serum vancomycin concentration data (n = 835 points) obtained retrospectively from the drug monitoring records of 116 premature newborn infants. Vancomycin concentrations were estimated by a fluorescence polarization immunoassay. Population and individual estimates of clearance and distribution volume and the factors which affected the variability observed for the values of these parameters were obtained using a population pharmacokinetic modeling approach. The predictive performance of the population model was evaluated by visual inspections of diagnostic plots and nonparametric bootstrapping with replacement. Dosing guidelines targeting a value of > or =400 for the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC(24)/MIC ratio) were explored using Monte Carlo simulation. Body size (weight), postmenstrual age, and small-for-gestational-age status are important factors explaining the between-subject variability of vancomycin pharmacokinetic parameter values for premature neonates. The typical population parameter estimates of clearance and distribution volume for a 1-kg premature appropriate-for-gestational-age neonate with a postmenstrual age of 30 weeks were 0.0426 liters/h and 0.523 liters, respectively. There was a 20% reduction in clearance for small-for-gestational-age infants compared to the level for the appropriate-for-gestational-age control. Dosage regimens based on a priori target response values were formulated. In conclusion, the pharmacokinetic parameter values for vancomycin in premature Malaysian neonates were estimated. Improved dosage regimens based on a priori target response values were formulated by incorporating body size, postmenstrual age, and small-for-gestational-age status, using Monte Carlo simulations with the model-estimated pharmacokinetic parameter values.

Disparity in circulating adiponectin multimers between term and preterm infants.

AIMS: To study circulating levels and distribution of adiponectin multimers [low molecular weight (LMW)-, medium molecular weight (MMW)- and high molecular weight (HMW)-adiponectin] in preterm and full-term infants. METHODS: Total serum adiponectin and its multimers were measured in 40 healthy infants at the age of one month and associations with anthropometric parameters [body weight and length, body mass index (BMI)], weight gain and metabolic indices (glucose, insulin) were examined. Twenty of the infants were born preterm (gestational age 33.2+/-1.6 weeks). RESULTS: LMW-adiponectin level and its fractional ratio to total adiponectin were significantly higher in full-term than in preterm infants (P<0.001 and P<0.01, respectively), whereas, MMW-adiponectin level and its ratio were significantly lower (P=0.03 and P=0.01, respectively). HMW-adiponectin did not differ significantly between full-term and preterm infants and accounted for almost 60% of total adiponectin levels in both groups. HMW-adiponectin, but not MMW adiponectin or LMW adiponectin, correlated significantly with anthropometric measurements, similarly to total adiponectin; in addition, HMW adiponectin correlated significantly with weight gain. CONCLUSIONS: HMW adiponectin is the most prevalent form in infants. Circulating levels and distribution of MMW- and LMW-adiponectin differ between full-term and preterm infants, but the role of these adiponectin multimers needs to be studied further.

Therapeutic drug monitoring for caffeine in preterm neonates: an unnecessary exercise?

OBJECTIVE: Our goal was to determine the value of measuring plasma caffeine levels in preterm neonates treated with caffeine for apnea. We evaluated plasma concentrations of caffeine attained in preterm neonates at standard doses, at varying postconceptual ages, with renal or hepatic dysfunction and when there was clinical lack of efficacy. We hypothesized that measurement of plasma caffeine concentrations during apnea therapy is not clinically helpful. PATIENTS/METHODS: An observational study was conducted at Hutzel Women's Hospital between January 2000 and September 2005. Preterm neonates who were being treated with caffeine and who had a plasma caffeine level measured on at least 1 occasion were included. RESULTS: A total of 231 caffeine blood levels were obtained from 101 preterm neonates with a median gestation of 28 weeks (range: 23-32 weeks) and birth weight of 1030 g (range: 540-2150 g). The caffeine citrate dose used ranged form 2.5 to 10.9 mg/kg (median: 5 mg/kg), and the levels ranged from 3.0 to 23.8 mg/L. Levels were between 5.1 and 20 mg/L in 94.8%, <5 mg/L in 2.1%, and >20 mg/L in 3.1%. Levels in the 5.1 to 20 mg/L range were attained on 91.3% of occasions when there was concomitant renal dysfunction (n = 23) and in all cases of hepatic dysfunction (n = 13). The median (25th, 75th quartiles) levels drawn for lack of efficacy (14.1 [10.2, 8.3] mg/L; n = 94) were comparable to those obtained for routine monitoring (13.7 [11, 9] mg/L; n = 107). CONCLUSIONS: A majority of preterm neonates attain plasma caffeine levels between 5 and 20 mg/L, independent of gestation. This observation held even for the small number of subjects with elevated blood urea nitrogen, serum creatinine, or liver enzyme levels. Therapeutic drug monitoring is not necessary when caffeine is used for the treatment of apnea of prematurity in neonates.