Amikacin Pharmacokinetics To Optimize Dosing in Neonates with Perinatal Asphyxia Treated with Hypothermia.
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SUBMITTER: Cristea S
PROVIDER: S-EPMC5700363 | biostudies-literature | 2017 Dec
REPOSITORIES: biostudies-literature
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Amikacin Pharmacokinetics To Optimize Dosing in Neonates with Perinatal Asphyxia Treated with Hypothermia.
Cristea Sinziana S Smits Anne A Kulo Aida A Knibbe Catherijne A J CAJ van Weissenbruch Mirjam M Krekels Elke H J EHJ Allegaert Karel K
Antimicrobial agents and chemotherapy 20171122 12
Aminoglycoside pharmacokinetics (PK) is expected to change in neonates with perinatal asphyxia treated with therapeutic hypothermia (PATH). Several amikacin dosing guidelines have been proposed for treating neonates with (suspected) septicemia; however, none provide adjustments for cases of PATH. Therefore, we aimed to quantify the differences in amikacin PK between neonates with and without PATH to propose suitable dosing recommendations. Based on amikacin therapeutic drug monitoring data colle ...[more]
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Project description:UnlabelledWHAT IS KNOWN ABOUT THIS SUBJECT?: Diffusion-weighted MRI has demonstrated changes in the corpus callosum of term neonates with perinatal asphyxia. The severity of cerebral changes demonstrated using diffusion-weighted MRI is difficult to assess without measuring values of the Apparent Diffusion Coefficient (ADC). WHAT IS NEW?: ADC values of the anterior part of the corpus callosum are slightly higher than of the posterior part in full term infants with perinatal asphyxia. Low ADC values of the corpus callosum were associated with an adverse outcome in infants with perinatal asphyxia. In infants treated with hypothermia lower ADC values than with normothermia were associated with a poor outcome, supporting neuroprotective effects of hypothermia.BackgroundUsing MRI, changes can be detected in the corpus callosum (CC) following perinatal asphyxia which are associated with later neurodevelopmental outcome.AimTo study the association between the apparent diffusion coefficient of water (ADC) in the CC on MRI in neonates with perinatal asphyxia and neurodevelopmental outcome at 18 months of age.Subjects, methodsOf 121 infants 32 (26%) died and 13 (11%) survived with an adverse neurological outcome. Sixty-five (54%) received therapeutic hypothermia. MRI was performed within 7 days after birth using a 1.5 T or 3.0 T system, and ADC values were measured in the anterior and posterior CC. The association between ADC and composite outcome (death or abnormal neurodevelopment) was analyzed for both normothermia and hypothermia cases using receiver operating characteristics.ResultsADC values of the posterior CC were lower than of the anterior part (mean difference 0.050 x 10-3 mm2/s, p<0.001). Field strength did not affect ADC values. ADC values of the posterior part of the CC were significantly lower in infants with basal ganglia/thalamus or near total brain injury (p<0.001). Lower ADC values were associated with an adverse outcome, but cut-off levels were lower after hypothermia (1.024 x 10-3 mm2/s vs 0.969 x 10-3 mm2/s).ConclusionLow ADC values of the posterior part of the corpus callosum are associated with an adverse outcome in term or near term neonates with perinatal asphyxia. Therapeutic hypothermia slightly modifies this association, showing that lower values were needed for an adverse outcome.
| S-EPMC4414268 | biostudies-literature
Project description:ObjectiveMorphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population.Study designTerm and near-term encephalopathic neonates treated with therapeutic hypothermia and receiving morphine were included in two multicenter cohort studies between 2008-2010 (SHIVER) and 2010-2014 (PharmaCool). Data were collected during hypothermia and rewarming, including blood samples for quantification of morphine and its metabolites. Parental informed consent was obtained for all participants.Results244 patients (GA mean (sd) 39.8 (1.6) weeks, BW mean (sd) 3,428 (613) g, male 61.5%) were included. Morphine clearance was reduced under hypothermia (33.5°C) by 6.89%/°C (95% CI 5.37%/°C- 8.41%/°C, p<0.001) and metabolite clearance by 4.91%/°C (95% CI 3.53%/°C- 6.22%/°C, p<0.001) compared to normothermia (36.5°C). Simulations showed that a loading dose of 50 μg/kg followed by continuous infusion of 5 μg/kg/h resulted in morphine plasma concentrations in the desired range (between 10 and 40 μg/L) during hypothermia.ConclusionsClearance of morphine and its metabolites in neonates is affected by therapeutic hypothermia. The regimen suggested by the simulations will be sufficient in the majority of patients. However, due to the large interpatient variability a higher dose might be necessary in individual patients to achieve the desired effect.Trial registrationwww.trialregister.nl NTR2529.
| S-EPMC6375702 | biostudies-literature
Project description:Perinatal asphyxia (PA) still occurs in about three to five per 1,000 deliveries in developed countries; 20% of these infants show hypoxic-ischemic encephalopathy (HIE) on brain magnetic resonance imaging (MRI). The aim of our study was to apply metabolomic analysis to newborns undergoing therapeutic hypothermia (TH) after PA to identify a distinct metabotype associated with the development of HIE on brain MRI. We enrolled 53 infants born at >35 weeks of gestation with PA: 21 of them showed HIE on brain MRI (the "HIE" group), and 32 did not (the "no HIE" group). Urine samples were collected at 24, 48 and 72 hours of TH. Metabolomic data were acquired using high-resolution mass spectrometry and analyzed with univariate and multivariate methods. Considering the first urines collected during TH, untargeted analysis found 111 relevant predictors capable of discriminating between the two groups. Of 35 metabolites showing independent discriminatory power, four have been well characterized: L-alanine, Creatine, L-3-methylhistidine, and L-lysine. The first three relate to cellular energy metabolism; their involvement suggests a multimodal derangement of cellular energy metabolism during PA/HIE. In addition, seven other metabolites with a lower annotation level (proline betaine, L-prolyl-L-phenylalanine, 2-methyl-dodecanedioic acid, S-(2-methylpropionyl)-dihydrolipoamide-E, 2,6 dimethylheptanoyl carnitine, Octanoylglucuronide, 19-hydroxyandrost-4-ene-3,17-dione) showed biological consistency with the clinical picture of PA. Moreover, 4 annotated metabolites (L-lysine, L-3-methylhistidine, 2-methyl-dodecanedioic acid, S-(2-methylpropionyl)-dihydrolipoamide-E) retained a significant difference between the "HIE" and "no HIE" groups during all the TH treatment. Our analysis identified a distinct urinary metabotype associated with pathological findings on MRI, and discovered 2 putative markers (L-lysine, L-3-methylhistidine) which may be useful for identifying neonates at risk of developing HIE after PA.
| S-EPMC9380923 | biostudies-literature
Project description:BackgroundTheophylline, a non-selective adenosine receptor antagonist, improves renal perfusion in the setting of hypoxia-ischemia and may offer therapeutic benefit in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of theophylline in this population to guide dosing strategies.MethodsA population pharmacokinetic analysis was performed in 22 neonates with HIE undergoing hypothermia who were part of a prospective study or retrospective chart review. Aminophylline (intravenous salt form of theophylline) was given per institutional standard of care for low urine output and/or rising serum creatinine (5 mg/kg intravenous (i.v.) load then 1.8 mg/kg i.v. q6h). The ability of different dosing regimens to achieve target concentrations (4-10 mg/L) associated with clinical response was examined.ResultsBirth weight was a significant predictor of theophylline clearance and volume of distribution (p < 0.05). The median half-life was 39.5 h (range 27.2-50.4). An aminophylline loading dose of 7 mg/kg followed by 1.6 mg/kg q12h was predicted to achieve target concentrations in 84% of simulated neonates.ConclusionsIn neonates with HIE undergoing hypothermia, theophylline clearance was low with a 50% longer half-life compared to full-term normothermic neonates without HIE. Dosing strategies need to consider the unique pharmacokinetic needs of this population.ImpactTheophylline is a potential renal-protective therapy in neonates with HIE undergoing therapeutic hypothermia; however, the pharmacokinetics and dose needs in this population are not known. Theophylline clearance was low in neonates with HIE undergoing therapeutic hypothermia with a 50% longer half-life compared to full-term normothermic neonates without HIE. As theophylline is advanced in clinical development, dosing strategies will need to consider the unique pharmacokinetic needs of neonates with HIE undergoing therapeutic hypothermia.
| S-EPMC7704857 | biostudies-literature
Project description:Background and purposeCerebral venous oxygen saturation can be used as an indirect measure of brain health, yet it often requires either an invasive procedure or a noninvasive technique with poor sensitivity. We aimed to test whether cerebral venous oxygen saturation could be measured using quantitative susceptibility mapping, an MR imaging technique, in 3 distinct groups: healthy term neonates, injured term neonates, and preterm neonates.Materials and methodsWe acquired multiecho gradient-echo MR imaging data in 16 neonates with perinatal asphyxia and moderate or severe hypoxic-ischemic encephalopathy (8 term age: average, 40.0 [SD, 0.8] weeks' gestational age; 8 preterm, 33.5 [SD, 2.0] weeks' gestational age) and in 8 healthy term-age controls (39.3 [SD, 0.6] weeks, for a total of n = 24. Data were postprocessed as quantitative susceptibility mapping images, and magnetic susceptibility was measured in cerebral veins by thesholding out 99.95% of lower magnetic susceptibility values.ResultsThe mean magnetic susceptibility value of the cerebral veins was found to be 0.36 (SD, 0.04) ppm in healthy term neonates, 0.36 (SD, 0.06) ppm in term injured neonates, and 0.29 (SD, 0.04) ppm in preterm injured neonates. Correspondingly, the derived cerebral venous oxygen saturation values were 73.6% (SD, 2.8%), 71.5% (SD, 7.4%), and 72.2% (SD, 5.9%). There was no statistically significant difference in cerebral venous oxygen saturation among the 3 groups (P = .751).ConclusionsQuantitative susceptibility mapping-derived oxygen saturation values in preterm and term neonates agreed well with values in past literature. Cerebral venous oxygen saturation in preterm and term neonates with hypoxic-ischemic encephalopathy, however, was not found to be significantly different between neonates or healthy controls.
| S-EPMC8324259 | biostudies-literature
Project description:ObjectiveTo assess the impact of hypothermic neural rescue at birth on health-related quality of life (HRQL) in middle childhood.DesignSix-year to 7-year follow-up of surviving children from the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) Trial.SettingCommunity study including a single parental questionnaire to collect information on children's HRQL.Patients145 children (70 in the control group, 75 in the hypothermia group) whose parents consented and returned the questionnaire.InterventionsIntensive care with cooling of the body to 33.5°C for 72 hours or intensive care alone.Main outcome measuresHRQL attributes and utility scores using the Health Utilities Index (HUI).ResultsAt 6-7 years, speech appeared disproportionately affected when compared with other aspects of HRQL but levels of normal emotional functioning were similar in both groups. The mean (SE) HUI3 HRQL scores were 0.73 (0.05) in the hypothermia group and 0.62 (0.06) in the control group; mean difference (95% CI) 0.11 (-0.04 to 0.26).ConclusionsFindings of non-significant differences were not unexpected; the study used data from long-term survivors in a neonatal trial and was underpowered. However, results favoured moderate hypothermia and so complement the clinical results of the TOBY Children study. The work provides further insight into the long-term HRQL impact of perinatal asphyxial encephalopathy and provides previously unavailable utility data with which to contemplate the longer term cost-effectiveness of hypothermic neural rescue.Trial registration numberThis study reports on the follow-up of the TOBY clinical trial: ClinicalTrials.gov number NCT01092637.
| S-EPMC6047162 | biostudies-literature
Project description:OBJECTIVE:To assess the impact of hypothermic neural rescue for perinatal asphyxia at birth on healthcare costs of survivors aged 6-7 years, and to quantify the relationship between costs and overall disability levels. DESIGN:6-7?years follow-up of surviving children from the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial. SETTING:Community study including a single parental questionnaire to collect information on children's healthcare resource use. PATIENTS:130 UK children (63 in the control group, 67 in the hypothermia group) whose parents consented and returned the questionnaire. INTERVENTIONS:Intensive care with cooling of the body to 33.5°C for 72?hours or intensive care alone. MAIN OUTCOME MEASURES:Healthcare resource usage and costs over the preceding 6?months. RESULTS:At 6-7 years, mean (SE) healthcare costs per child were £1543 (£361) in the hypothermia group and £2549 (£812) in the control group, giving a saving of -£1005 (95% CI -£2734 to £724). Greater levels of overall disability were associated with progressively higher costs, and more parents in the hypothermia group were employed (64%?vs 47%). Results were sensitive to outlying observations. CONCLUSIONS:Cost results although not significant favoured moderate hypothermia and so complement the clinical results of the TOBY Children study. Estimates were however sensitive to the care requirements of two seriously ill children in the control group. A quantification of the relationship between costs and levels of disability experienced will be useful to healthcare professionals, policy makers and health economists contemplating the long-term economic consequences of perinatal asphyxia and hypothermic neural rescue. TRIAL REGISTRATION NUMBER:This study reports on the follow-up of the TOBY clinical trial: ClinicalTrials. gov number NCT01092637.
| S-EPMC6764253 | biostudies-literature
Project description:As therapeutic hypothermia is only partially protective for neonatal encephalopathy, safe and effective adjunct therapies are urgently needed. Melatonin and erythropoietin show promise as safe and effective neuroprotective therapies. We hypothesized that melatonin and erythropoietin individually augment 12-h hypothermia (double therapies) and hypothermia + melatonin + erythropoietin (triple therapy) leads to optimal brain protection. Following carotid artery occlusion and hypoxia, 49 male piglets (<48 h old) were randomized to: (i) hypothermia + vehicle (n = 12), (ii) hypothermia + melatonin (20 mg/kg over 2 h) (n = 12), (iii) hypothermia + erythropoietin (3000 U/kg bolus) (n = 13) or (iv) triple therapy (n = 12). Melatonin, erythropoietin or vehicle were given at 1, 24 and 48 h after hypoxia-ischaemia. Hypoxia-ischaemia severity was similar across groups. Therapeutic levels were achieved 3 hours after hypoxia-ischaemia for melatonin (15-30 mg/l) and within 30 min of erythropoietin administration (maximum concentration 10 000 mU/ml). Compared to hypothermia + vehicle, we observed faster amplitude-integrated EEG recovery from 25 to 30 h with hypothermia + melatonin (P = 0.02) and hypothermia + erythropoietin (P = 0.033) and from 55 to 60 h with triple therapy (P = 0.042). Magnetic resonance spectroscopy lactate/N-acetyl aspartate peak ratio was lower at 66 h in hypothermia + melatonin (P = 0.012) and triple therapy (P = 0.032). With hypothermia + melatonin, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells were reduced in sensorimotor cortex (P = 0.017) and oligodendrocyte transcription factor 2 labelled-positive counts increased in hippocampus (P = 0.014) and periventricular white matter (P = 0.039). There was no reduction in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells with hypothermia + erythropoietin, but increased oligodendrocyte transcription factor 2 labelled-positive cells in 5 of 8 brain regions (P < 0.05). Overall, melatonin and erythropoietin were safe and effective adjunct therapies to hypothermia. Hypothermia + melatonin double therapy led to faster amplitude-integrated EEG recovery, amelioration of lactate/N-acetyl aspartate rise and reduction in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells in the sensorimotor cortex. Hypothermia + erythropoietin double therapy was in association with EEG recovery and was most effective in promoting oligodendrocyte survival. Triple therapy provided no added benefit over the double therapies in this 72-h study. Melatonin and erythropoietin influenced cell death and oligodendrocyte survival differently, reflecting distinct neuroprotective mechanisms which may become more visible with longer-term studies. Staggering the administration of therapies with early melatonin and later erythropoietin (after hypothermia) may provide better protection; each therapy has complementary actions which may be time critical during the neurotoxic cascade after hypoxia-ischaemia.
| S-EPMC7876304 | biostudies-literature
Project description:ObjectivesThe primary objective was to compare the volume of distribution (Vd), clearance (CL), elimination rate (Ke), and half-life (t½) of amikacin in neonates with cyanotic defects, acyanotic defects, and controls, adjusted for gestational and postnatal age. Secondary objectives were to compare the incidence of acute kidney injury (AKI) between controls and the congenital heart disease (CHD) group and to identify potential risk factors.MethodsThis retrospective cohort study included neonates receiving amikacin from January 1, 2013 to August 31, 2016. Patients were excluded if concentrations were not appropriately obtained or if AKI or renal anomalies were identified prior to amikacin initiation. Congenital heart disease was classified as acyanotic or cyanotic. Patients with CHD were matched 1:1 with non-CHD controls according to postmenstrual age. Bivariate analyses were performed using Wilcoxon-Mann-Whitney test, Pearson χ2 tests, or Fisher exact as appropriate with a p value <0.05. Regression analyses included logistic and analysis of covariance.ResultsFifty-four patients with CHD were matched with 54 controls. Median (IQR) postnatal age (days) at amikacin initiation significantly differed between CHD and controls, 3.0 (1.0-16.0) versus 1.0 (1.0-3.0), p = 0.016. After adjusting for gestational and postnatal age, there was no difference in the mean (95% CI) Vd (L/kg) and CL (L/kg/hr) between CHD and controls, 0.47 (0.44-0.50) versus 0.46 (0.43-0.49), p = 0.548 and 0.05 (0.05-0.05) versus 0.05 (0.05-0.05), p = 0.481, respectively. There was no difference in Ke or t½ between groups. There was no difference in AKI between the CHD and controls, 18.5% versus 9.3%, p = 0.16.ConclusionsClinicians should consider using standard amikacin dosing for neonates with CHD and monitor renal function, since they may have greater AKI risk factors.
| S-EPMC8139570 | biostudies-literature
Project description:Dexmedetomidine is a promising sedative and analgesic for newborns with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Pharmacokinetics and safety of dexmedetomidine were evaluated in a phase I, single-center, open-label study to inform future trial strategies. We recruited 7 neonates ?36 weeks' gestational age diagnosed with moderate-to-severe HIE, who received a continuous dexmedetomidine infusion during TH and the 6?h rewarming period. Time course of plasma dexmedetomidine concentration was characterized by serial blood sampling during and after the 64.8?±?6.9 hours of infusion. Noncompartmental analysis yielded descriptive pharmacokinetic estimates: plasma clearance of 0.760?±?0.155?L/h/kg, steady-state distribution volume of 5.22?±?2.62?L/kg, and mean residence time of 6.84?±?3.20?h. Naive pooled and population analyses according to a one-compartment model provided similar estimates of clearance and distribution volume. Overall, clearance was either comparable or lower, distribution volume was larger, and mean residence time or elimination half-life was longer in cooled newborns with HIE compared to corresponding estimates previously reported for uncooled (normothermic) newborns without HIE at comparable gestational and postmenstrual ages. As a result, plasma concentrations in cooled newborns with HIE rose more slowly in the initial hours of infusion compared to predicted concentration-time profiles based on reported pharmacokinetic parameters in normothermic newborns without HIE, while similar steady-state levels were achieved. No acute adverse events were associated with dexmedetomidine treatment. While dexmedetomidine appeared safe for neonates with HIE during TH at infusion doses up to 0.4??g/kg/h, a loading dose strategy may be needed to overcome the initial lag in rise of plasma dexmedetomidine concentration.
| S-EPMC7060842 | biostudies-literature