Ultrasonographic Estimation of Ventricular Volume in Infants Born Preterm with Posthemorrhagic Ventricular Dilatation: A Nested Substudy of the Randomized Controlled Early Versus Late Ventricular Intervention Study (ELVIS) Trial

Objective: To study the potential role of ventricular volume (VV) estimation in the management of posthemorrhagic ventricular dilatation related to the need for ventriculoperitoneal (VP)-shunt insertion and 2-year neurodevelopmental outcome in infants born preterm. Study design: We included 59 patients from the Early vs Late Ventricular Intervention Study from 4 participating centers. VV was manually segmented in 209 3-dimensional ultrasound scans and estimated from 2-dimensional ultrasound linear measurements in a total of 1226 ultrasounds. We studied the association of both linear measurements and VV to the need for VP shunt and 2-year neurodevelopmental outcome in the overall cohort and in the 29 infants who needed insertion of a reservoir. We used general estimating equations to account for repeated measures per individual. Results: Maximum pre-reservoir VV (β coefficient = 0.185, P = .0001) and gestational age at birth (β = −0.338; P = .0001) were related to the need for VP shunt. The estimated optimal single VV measurement cut point of 17 cm3 correctly classified 79.31% with an area under the curve of 0.76 (CI 95% 0.74-0.79). Maximum VV (β = 0.027; P = .012) together with VP shunt insertion (β = 3.773; P = .007) and gestational age (β = −0.273; P = .0001) were related to cognitive outcome at 2 years. Maximum ventricular index and anterior horn width before reservoir insertion were independently associated with the need of VP shunt and the proposed threshold groups in the Early vs Late Ventricular Intervention Study trial were associated with long-term outcome. Conclusions: Pre-reservoir VV measurements were associated with the need for VP-shunt insertion and 2-year cognitive outcome among infants born preterm with posthemorrhagic ventricular dilatation. Trial registration: ISRCTN43171322

Rapidly maturing fentanyl clearance in preterm neonates

BACKGROUND: Fentanyl is frequently used off-label in preterm newborns. Due to very limited pharmacokinetic and pharmacodynamic data, fentanyl dosing is mostly based on bodyweight. This study describes the maturation of the pharmacokinetics in preterm neonates born before 32 weeks of gestation. METHODS: 442 plasma samples from 98 preterm neonates (median gestational age: 26.9 (range 23.9-31.9) weeks, postnatal age: 3 (range 0-68) days, bodyweight 1.00 (range 0.39-2.37) kg) were collected in an opportunistic trial and fentanyl plasma levels were determined. NONMEM V.7.3 was used to develop a population pharmacokinetic model and to perform simulations. RESULTS: Fentanyl pharmacokinetics was best described by a two-compartment model. A pronounced non-linear influence of postnatal and gestational age on clearance was identified. Clearance (L/hour/kg) increased threefold, 1.3-fold and 1.01-fold in the first, second and third weeks of life, respectively. In addition, clearance (L/hour/kg) was 1.4-fold and 1.7-fold higher in case of a gestational age of 28 and 31 weeks, respectively, compared with 25 weeks. Volume of distribution changed linearly with bodyweight and was 8.7 L/kg. To achieve similar exposure across the entire population, a continuous infusion (µg/kg/hour) dose should be reduced by 50% and 25% in preterm neonates with a postnatal age of 0-4 days and 5-9 days in comparison to 10 days and older. CONCLUSION: Because of low clearance, bodyweight-based dosages may result in fentanyl accumulation in neonates with the lowest postnatal and gestational ages which may require dose reduction. Together with additional information on the pharmacodynamics, the results of this study can be used to guide dosing.status: publishe

Enantiomer specific pharmacokinetics of ibuprofen in preterm neonates with patent ductus arteriosus

Aims: Racemic ibuprofen is widely used for the treatment of preterm neonates with patent ductus arteriosus. Currently used bodyweight-based dosing guidelines are based on total ibuprofen, while only the S-enantiomer of ibuprofen is pharmacologically active. We aimed to optimize ibuprofen dosing for preterm neonates of different ages based on an enantiomer-specific population pharmacokinetic model. Methods: We prospectively collected 210 plasma samples of 67 preterm neonates treated with ibuprofen for patent ductus arteriosus (median gestational age [GA] 26 [range 24–30] weeks, median body weight 0.83 [0.45–1.59] kg, median postnatal age [PNA] 3 [1–12] days), and developed a population pharmacokinetic model for S- and R-ibuprofen. Results: We found that S-ibuprofen clearance (CL S, 3.98 mL/h [relative standard error {RSE} 8%]) increases with PNA and GA, with exponents of 2.25 (RSE 6%) and 5.81 (RSE 15%), respectively. Additionally, a 3.11-fold higher CL S was estimated for preterm neonates born small for GA (RSE 34%). Clearance of R-ibuprofen was found to be high compared to CL S (18 mL/h [RSE 24%]), resulting in a low contribution of R-ibuprofen to total ibuprofen exposure. Current body weight was identified as covariate on both volume of distribution of S-ibuprofen and R-ibuprofen. Conclusion: S-ibuprofen clearance shows important maturation, especially with PNA, resulting in an up to 3-fold increase in CL S during a 3-day treatment regimen. This rapid increase in clearance needs to be incorporated in dosing guidelines by adjusting the dose for every day after birth to achieve equal ibuprofen exposure. </p

Enantiomer specific pharmacokinetics of ibuprofen in preterm neonates with patent ductus arteriosus

AIMS: Racemic ibuprofen is widely used for the treatment of preterm neonates with patent ductus arteriosus. Currently used bodyweight-based dosing guidelines are based on total ibuprofen, while only the S-enantiomer of ibuprofen is pharmacologically active. We aimed to optimize ibuprofen dosing for preterm neonates of different ages based on an enantiomer-specific population pharmacokinetic model. METHODS: We prospectively collected 210 plasma samples of 67 preterm neonates treated with ibuprofen for patent ductus arteriosus (median gestational age [GA] 26 [range 24-30] weeks, median body weight 0.83 [0.45-1.59] kg, median postnatal age [PNA] 3 [1-12] days), and developed a population pharmacokinetic model for S- and R-ibuprofen. RESULTS: We found that S-ibuprofen clearance (CLS , 3.98 mL/h [relative standard error {RSE} 8%]) increases with PNA and GA, with exponents of 2.25 (RSE 6%) and 5.81 (RSE 15%), respectively. Additionally, a 3.11-fold higher CLS was estimated for preterm neonates born small for GA (RSE 34%). Clearance of R-ibuprofen was found to be high compared to CLS (18 mL/h [RSE 24%]), resulting in a low contribution of R-ibuprofen to total ibuprofen exposure. Current body weight was identified as covariate on both volume of distribution of S-ibuprofen and R-ibuprofen. CONCLUSION: S-ibuprofen clearance shows important maturation, especially with PNA, resulting in an up to 3-fold increase in CLS during a 3-day treatment regimen. This rapid increase in clearance needs to be incorporated in dosing guidelines by adjusting the dose for every day after birth to achieve equal ibuprofen exposure.status: publishe

Recently Registered Midazolam Doses for Preterm Neonates Do Not Lead to Equal Exposure:A Population Pharmacokinetic Model

Contains fulltext : 208056.pdf (publisher's version ) (Open Access

Recently Registered Midazolam Doses for Preterm Neonates Do Not Lead to Equal Exposure: A Population Pharmacokinetic Model.

Contains fulltext : 208056.pdf (publisher's version ) (Open Access

The bioavailability and maturing clearance of doxapram in preterm infants

Background: Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of doxapram and keto-doxapram in preterm infants. Methods: Data (302 samples) from 75 neonates were included with a median (range) gestational age (GA) 25.9 (23.9–29.4) weeks, bodyweight 0.95 (0.48–1.61) kg, and postnatal age (PNA) 17 (1–52) days at the start of continuous treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling (NONMEM®). Results: A two-compartment model best described the pharmacokinetics of doxapram and keto-doxapram. PNA and GA affected the formation clearance of keto-doxapram (CL FORMATION KETO-DOXAPRAM) and clearance of doxapram via other routes (CL DOXAPRAM OTHER ROUTES). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CL FORMATION KETO-DOXAPRAM was 0.115 L/h (relative standard error (RSE) 12%) and CL DOXAPRAM OTHER ROUTES was 0.645 L/h (RSE 9%). Oral bioavailability was estimated at 74% (RSE 10%). Conclusions: Dosing of doxapram only based on bodyweight results in the highest exposure in preterm infants with the lowest PNA and GA. Therefore, dosing may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. For switching to oral therapy, a 33% dose increase is required to maintain exposure. Impact: Current dosing regimens of doxapram in preterm infants only based on bodyweight result in the highest exposure in infants with the lowest PNA and GA.Dosing of doxapram may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events.Describing the pharmacokinetics of doxapram and its active metabolite keto-doxapram following intravenous and gastroenteral administration enables to include drug exposure to the evaluation of treatment of AOP.The oral bioavailability of doxapram in preterm neonates is 74%, requiring a 33% higher dose via oral than intravenous administration to maintain exposure

Treatment thresholds for intervention in posthaemorrhagic ventricular dilation : a randomised controlled trial

Objective To compare a low versus a higher threshold for intervention in preterm infants with posthaemorrhagic ventricular dilatation. Design Multicentre randomised controlled trial (ISRCTN43171322). Setting 14 neonatal intensive care units in six countries. Patients 126 preterm infants ≤34 weeks gestation with ventricular dilatation after grade III-IV haemorrhage were randomised to low threshold (LT) (ventricular index (VI) >p97 and anterior horn width (AHW) >6 mm) or higher threshold (HT) (VI>p97+4 mm and AHW >10 mm). Intervention Cerebrospinal fluid tapping by lumbar punctures (LPs) (max 3), followed by taps from a ventricular reservoir, to reduce VI, and eventually a ventriculoperitoneal (VP) shunt if stabilisation of the VI below the p97+4 mm did not occur. Composite main outcome measure VP shunt or death. Results 19 of 64 (30%) LT infants and 23 of 62 (37%) HT infants were shunted or died (P=0.45). A VP shunt was inserted in 12/64 (19%) in the LT and 14/62 (23%) infants in the HT group. 7/12 (58%) LT infants and 1/14 (7%) HT infants required shunt revision (P<0.01). 62 of 64 (97%) LT infants and 36 of 62 (58%) HT infants had LPs (P<0.001). Reservoirs were inserted in 40 of 64 (62%) LT infants and 27 of 62 (43%) HT infants (P<0.05). Conclusions There was no significant difference in the primary composite outcome of VP shunt placement or death in infants with posthaemorrhagic ventricular dilatation who were treated at a lower versus a higher threshold for intervention. Infants treated at the lower threshold received more invasive procedures. Assessment of neurodevelopmental outcomes will provide further important information in assessing the risks and benefits of the two treatment approaches

Treatment thresholds for intervention in posthaemorrhagic ventricular dilation:A randomised controlled trial

Objective To compare a low versus a higher threshold for intervention in preterm infants with posthaemorrhagic ventricular dilatation. Design Multicentre randomised controlled trial (ISRCTN43171322). Setting 14 neonatal intensive care units in six countries. Patients 126 preterm infants ≤34 weeks gestation with ventricular dilatation after grade III-IV haemorrhage were randomised to low threshold (LT) (ventricular index (VI) >p97 and anterior horn width (AHW) >6 mm) or higher threshold (HT) (VI>p97+4 mm and AHW >10 mm). Intervention Cerebrospinal fluid tapping by lumbar punctures (LPs) (max 3), followed by taps from a ventricular reservoir, to reduce VI, and eventually a ventriculoperitoneal (VP) shunt if stabilisation of the VI below the p97+4 mm did not occur. Composite main outcome measure VP shunt or death. Results 19 of 64 (30%) LT infants and 23 of 62 (37%) HT infants were shunted or died (P=0.45). A VP shunt was inserted in 12/64 (19%) in the LT and 14/62 (23%) infants in the HT group. 7/12 (58%) LT infants and 1/14 (7%) HT infants required shunt revision (P<0.01). 62 of 64 (97%) LT infants and 36 of 62 (58%) HT infants had LPs (P<0.001). Reservoirs were inserted in 40 of 64 (62%) LT infants and 27 of 62 (43%) HT infants (P<0.05). Conclusions There was no significant difference in the primary composite outcome of VP shunt placement or death in infants with posthaemorrhagic ventricular dilatation who were treated at a lower versus a higher threshold for intervention. Infants treated at the lower threshold received more invasive procedures. Assessment of neurodevelopmental outcomes will provide further important information in assessing the risks and benefits of the two treatment approaches