Metric evaluation of the anterior nasal spine to estimate sex and population group in South African individuals.

INTRODUCTION: The anterior nasal spine is a pointed, midline projection of the maxilla. This bony structure dictates the overlying soft tissues providing the phenotypic features of the nose and upper lip and determines the differences in the mid-face morphology. Little data is available on the metric features of the Anterior nasal spine (ANS). This study aimed to perform metric evaluations of the ANS of white and black South African males and females to ascertain if morphological variations exist and if the differences are viable for the use in sex and population identification. MATERIALS AND METHODS: The sample included 100 CBCT images for each population and sex group. Linear and angular measurements of the ANS were recorded in both the sagittal and axial planes. RESULTS: Classification decision trees (pruned) were fitted to ascertain the relationship between population group, sex and the ANS measurements including and excluding age. For population group, all the ANS measurements were statistically significant for females but in males, all the ANS measurements were significant when performed individually. However, when fitted to the classification tree, Sagittal 2 did not show any statistical significance. When considering sex, only 2 of the ANS measurements (Sagittal 2 and Axial 1) were found to be significant. The results did not differ significantly when comparing the decision trees including and excluding age. CONCLUSIONS: White South African individuals presented with a longer ANS that produced a more acute angle whereas black South African individuals presented with a shorter ANS and a more obtuse angle. Additionally, males presented with a longer ANS compared to females. ANS measurements were found to be more relevant for population discernment than for sex.

The Effect of Ibuprofen Exposure and Patient Characteristics on the Closure of the Patent Ductus Arteriosus in Preterm Infants.

Spontaneous closure of the ductus arteriosus depends on gestational age (GA) and might be delayed in preterm infants, resulting in patent ductus arteriosus (PDA). Ibuprofen can be administered to enhance closure, but the exposure-response relationship between ibuprofen and the closure of PDA remains uncertain. We investigated the influence of patient characteristics and ibuprofen exposure on ductus closure. A cohort of preterm infants with PDA and treated with ibuprofen was analyzed. Ibuprofen exposure was based on a previously developed population pharmacokinetic study that was in part based on the same study population. Logistic regression analyses were performed with ductus closure (yes/no) as outcome, to analyze the contribution of ibuprofen exposure and patient characteristics. In our cohort of 263 preterm infants (median GA 26.1 (range: 23.7-30.0) weeks, birthweight 840 (365-1,470) g) receiving ibuprofen treatment consisting of 3 doses that was initiated at a median postnatal age (PNAstart ) of 5 (1-32) days, PDA was closed in 55 (21%) patients. Exposure to ibuprofen strongly decreased with PNAstart . Overall, the probability of ductus closure decreased with PNAstart (odds ratio (OR): 0.7, 95% CI: 0.6-0.8) and Z-score for birthweight (ZBirthweight-for-GA ; OR: 0.8, 95% CI: 0.6-1.0), and increased with GA (OR: 1.5, 95% CI: 1.1-1.9). For patients with PNAstart  < 1 week, concentrations of ibuprofen, GA, and ZBirthweight-for-GA predicted probability of ductus closure. During a window of opportunity for ductus closure within the first days of life, probability of closure depends on GA, ZBirthweight-for-GA , and ibuprofen exposure. Increased, yet unstudied dosages might increase the effectivity of ibuprofen beyond the first week of life.

Ibuprofen treatment after the first days of life in preterm neonates with patent ductus arteriosus.

AIM: Patent ductus arteriosus (PDA) is treated with ibuprofen and it is known that the clearance of ibuprofen increases with postnatal age. We aimed to study whether postnatal age-adjusted ibuprofen dosages improve the effectiveness of treatment compared to standard ibuprofen dosages after the first days of life. METHODS: A historical cohort of 207 preterm neonates treated with standard ibuprofen dosages (Group A; 2011-2015) was compared to a prospective cohort of 66 preterm neonates treated with postnatal age-adjusted ibuprofen dosages (Group B; 2015-2016). RESULTS: Both groups had comparable background characteristics. Treatment was started after median 6 (25-75th percentile: 4-11) and 5 (25-75th percentile: 4-11) days and effectiveness was 33.2 and 44.7% (p = .17) in groups A and B, respectively. No hemodynamically significant PDA was found in 23/49 (46.9%) of the patients born before 28 weeks after adjusted ibuprofen dosages compared to 48/162 (29.6%) after standard ibuprofen dosages (p = .04). There were significantly more reversible side effects with the postnatal age-adjusted ibuprofen dosages (p = .04). CONCLUSIONS: There seems to be a trend to higher effectiveness with the adjusted ibuprofen dosages in preterm neonates before 28 weeks, but it is associated with more reversible side effects.

Spontaneous Closure of the Ductus Arteriosus in Preterm Infants: A Systematic Review.

The optimal management strategy for patent ductus arteriosus in preterm infants remains a topic of debate. Available evidence for a treatment strategy might be biased by the delayed spontaneous closure of the ductus arteriosus in preterm infants, which appears to depend on patient characteristics. We performed a systematic review of all literature on PDA studies to collect patient characteristics and reported numbers of patients with a ductus arteriosus and spontaneous closure. Spontaneous closure rates showed a high variability but were lowest in studies that only included preterm infants with gestational ages below 28 weeks or birth weights below 1,000 g (34% on day 4; 41% on day 7) compared to studies that also included infants with higher gestational ages or higher birth weights (up to 55% on day 3 and 78% on day 7). The probability of spontaneous closure of the ductus arteriosus keeps increasing until at least 1 week after birth which favors delayed treatment of only those infants that do not show spontaneous closure. Better prediction of the spontaneous closure of the ductus arteriosus in the individual newborn is a key factor to find the optimal management strategy for PDA in preterm infants.

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.

Simulation-based suggestions to improve ibuprofen dosing for patent ductus arteriosus in preterm newborns.

PURPOSE: Ibuprofen is the drug of choice for treatment of patent ductus arteriosus (PDA). There is accumulating evidence that current ibuprofen-dosing regimens for PDA treatment are inadequate. We aimed to propose an improved dosing regimen, based on all current knowledge. METHODS: We performed a literature search on the clinical pharmacology and effectiveness of ibuprofen. (R)- and (S)-ibuprofen plasma concentration-time profiles of different dosing regimens were simulated using a population pharmacokinetic model and evaluated to obtain a safe, yet likely more efficacious ibuprofen exposure. RESULTS: The most effective intravenous ibuprofen dosing in previous clinical trials included a first dose of 20 mg kg-1 followed by 10 mg kg-1 every 24 h. Simulations of this dosing regimen show an (S)-ibuprofen trough concentration of 43 mg L-1 is reached at 48 h, which we assumed the target through concentration. We show that this target can be reached with a first dose of 18 mg kg-1, followed by 4 mg kg-1 every 12 h. After 96 h postnatal age, the dose should be increased to 5 mg kg-1 every 12 h due to maturation of clearance. This twice-daily dosing has the advantage over once-daily dosing that an effective trough level may be maintained, while peak concentrations are substantially (22%) lower. CONCLUSIONS: We propose to improve intermittent ibuprofen-dosing regimens by starting with a high first dose followed by a twice-daily maintenance dosing regimen that requires increase over time and should be continued until sufficient effect has been achieved.

Limited effects of intravenous paracetamol on patent ductus arteriosus in very low birth weight infants with contraindications for ibuprofen or after ibuprofen failure.

UNLABELLED: Finding the optimal pharmacological treatment of a patent ductus arteriosus (PDA) in preterm neonates remains challenging. There is a growing interest in paracetamol as a new drug for PDA closure. In this prospective observational cohort study, we evaluated the effectiveness of intravenous paracetamol in closing a PDA in very low birth weight infants with a hemodynamically significant PDA who either did not respond to ibuprofen or had a contraindication for ibuprofen. They received high-dose paracetamol therapy (15 mg/kg/6 h intravenous) for 3-7 days. Cardiac ultrasounds were performed before and 3 and 7 days after treatment. Thirty-three patients were included with a median gestational age of 25(1/7) weeks (IQR 1.66), a median birth weight of 750 g (IQR 327), and a median postnatal age of 14 days (IQR 12). Paracetamol was ineffective in 27/33 patients (82 %). Even more, after previous exposure to ibuprofen, this was even 100 %. CONCLUSION: In this study, paracetamol after ibuprofen treatment failure was not effective for PDA closure in VLBW infants. From the findings of this study, paracetamol treatment for PDA closure cannot be recommended for infants with a postnatal age >2 weeks. Earlier treatment with paracetamol for PDA might be more effective.