Repetitive neonatal procedural pain affects stress-induced plasma corticosterone increase in young adult females but not in male rats

Exposure to repetitive painful procedures in the neonatal intensive care unit results in long-lasting effects, especially visible after a “second hit” in adulthood. As the nociceptive system and the hypothalamic–pituitary–adrenal (HPA) axis interact and are vulnerable in early life, repetitive painful procedures in neonates may affect later-life HPA axis reactivity. The first aim of the present study was to investigate the effects of repetitive neonatal procedural pain on plasma corticosterone levels after mild acute stress (MAS) in young adult rats. Second, the study examined if MAS acts as a “second hit” and affects mechanical sensitivity. Fifty-two rats were either needle pricked four times a day, disturbed, or left undisturbed during the first neonatal week. At 8 weeks, the animals were subjected to MAS, and plasma was collected before (t0), after MAS (t20), and at recovery (t60). Corticosterone levels were analyzed using an enzyme-linked immunosorbent assay, and mechanical sensitivity was assessed with von Frey filaments. Results demonstrate that repetitive neonatal procedural pain reduces stress-induced plasma corticosterone increase after MAS only in young adult females and not in males. Furthermore, MAS does not affect mechanical sensitivity in young adult rats. Altogether, the results suggest an age- and sex-dependent effect of repetitive neonatal procedural pain on HPA axis reprogramming.</p

Repetitive neonatal procedural pain affects stress-induced plasma corticosterone increase in young adult females but not in male rats

Exposure to repetitive painful procedures in the neonatal intensive care unit results in long-lasting effects, especially visible after a “second hit” in adulthood. As the nociceptive system and the hypothalamic–pituitary–adrenal (HPA) axis interact and are vulnerable in early life, repetitive painful procedures in neonates may affect later-life HPA axis reactivity. The first aim of the present study was to investigate the effects of repetitive neonatal procedural pain on plasma corticosterone levels after mild acute stress (MAS) in young adult rats. Second, the study examined if MAS acts as a “second hit” and affects mechanical sensitivity. Fifty-two rats were either needle pricked four times a day, disturbed, or left undisturbed during the first neonatal week. At 8 weeks, the animals were subjected to MAS, and plasma was collected before (t0), after MAS (t20), and at recovery (t60). Corticosterone levels were analyzed using an enzyme-linked immunosorbent assay, and mechanical sensitivity was assessed with von Frey filaments. Results demonstrate that repetitive neonatal procedural pain reduces stress-induced plasma corticosterone increase after MAS only in young adult females and not in males. Furthermore, MAS does not affect mechanical sensitivity in young adult rats. Altogether, the results suggest an age- and sex-dependent effect of repetitive neonatal procedural pain on HPA axis reprogramming.</p

Pre- and Postnatal Maturation are Important for Fentanyl Exposure in Preterm and Term Newborns : A Pooled Population Pharmacokinetic Study

Publisher Copyright: © 2021, The Author(s).Background and Objective Fentanyl is an opioid commonly used to prevent and treat severe pain in neonates; however, its use is off label and mostly based on bodyweight. Given the limited pharmacokinetic information across the entire neonatal age range, we characterized the pharmacokinetics of fentanyl across preterm and term neonates to individualize dosing. Methods We pooled data from two previous studies on 164 newborns with a median gestational age of 29.0 weeks (range 23.9-42.3), birthweight of 1055 g (range 390-4245), and postnatal age (PNA) of 1 day (range 0-68). In total, 673 plasma samples upon bolus dosing (69 patients; median dose 2.1 mu g/kg, median 2 boluses per patient) or continuous infusions (95 patients; median dose 1.1 mu g/kg/h for 30 h) with and without boluses were used for population pharmacokinetic modeling in NONMEM(R) 7.4. Results Clearance in neonates with birthweight of 2000 and 3000 g was 2.8- and 5.0-fold the clearance in a neonate with birthweight of 1000 g, respectively. Fentanyl clearance at PNA of 7, 14, and 21 days was 2.7-fold, 3.8-fold, and 4.6-fold the clearance at 1 day, respectively. Bodyweight-based dosing resulted in large differences in fentanyl concentrations. Depending on PNA and birthweight, fentanyl concentrations increased slowly after the start of therapy for both intermittent boluses and continuous infusion and reached a maximum concentration at 12-48 h. Conclusions As both prenatal and postnatal maturation are important for fentanyl exposure, we propose a birthweight- and PNA-based dosage regimen. To provide rapid analgesia in the first 24 h of treatment, additional loading doses need to be considered.Peer reviewe

Maturation of Paracetamol Elimination Routes in Preterm Neonates Born Below 32 Weeks of Gestation

Purpose: Despite being off-label, intravenous paracetamol (PCM) is increasingly used to control mild-to-moderate pain in preterm neonates. Here we aim to quantify the maturation of paracetamol elimination pathways in preterm neonates born below 32 weeks of gestation. Methods: Datasets after single dose (rich data) or multiple doses (sparse data) of intravenous PCM dose (median (range)) 9 (3–25) mg/kg were pooled, containing 534 plasma and 44 urine samples of PCM and metabolites (PCM–glucuronide, PCM–sulfate, PCM–cysteine, and PCM–mercapturate) from 143 preterm neonates (gestational age 27.7 (24.0–31.9) weeks, birthweight 985 (462–1,925) g, postnatal age (PNA) 5 (0–30) days, current weight 1,012 (462–1,959) g. Population pharmacokinetic analysis was performed using NONMEM® 7.4. Results: For a typical preterm neonate (birthweight 985 g; PNA 5 days), PCM clearance was 0.137 L/h, with glucuronidation, sulfation, oxidation and unchanged renal clearance accounting for 5.3%, 73.7%, 16.3% and 4.6%, respectively. Maturational changes in total PCM clearance and its elimination pathways were best described by birthweight and PNA. Between 500–1,500 g birthweight, total PCM clearance increases by 169%, with glucuronidation, sulfation and oxidation clearance increasing by 347%, 164% and 164%. From 1–30 days PNA for 985 g birthweight neonate, total PCM clearance increases by 167%, with clearance via glucuronidation and oxidation increasing by 551%, and sulfation by 69%. Conclusion: Birthweight and PNA are the most important predictors for maturational changes in paracetamol clearance and its glucuronidation, sulfation and oxidation. As a result, dosing based on bodyweight alone will not lead to consistent paracetamol concentrations among preterm neonates.</p

Agitation as adverse drug reaction of doxapram in preterm neonates:Prevalence and potential risk factors

Agitation as adverse drug reaction of doxapram in preterm neonates: prevalence and potential risk factors Background Apnea of prematurity (AOP) is a common complication in premature neonates. AOP can be treated with methylxanthines (e.g. caffeine) and maximal non-invasive ventilation. If this treatment does not suffice, doxapram can be added. Doxapram is used off-label in preterm neonates and evidence on efficacy and safety of its use is limited. Objective This research aimed to investigate the prevalence of agitation as possible adverse drug reaction (ADR) of doxapram treatment in preterm neonates. The secondary aim was to identify risk-factors for occurrence of this ADR. Design All patients born &lt; 32 weeks of gestation that were treated with doxapram between December 2013 and May 2017 on the neonatal intensive care unit (NICU) of the Erasmus University Medical Center in Rotterdam were eligible for inclusion. All relevant demographic data and the numeric rating scale (NRS) agitation of the included patients were collected retrospectively. An event of agitation was defined as an NRS agitation of ≥ 4. Causality was formally assessed by a pharmacist and clinician using an adjusted version of Kramer's algorithm. Prevalence was calculated by dividing all patients with a causally related event of agitation by the total number of patients. Associations of potential risk factors with agitation as an ADR of doxapram were investigated by performing univariable and multivariable logistic regression. Results 119 patients were included. Prevalence of agitation as ADR of doxapram was 17.6%. The male sex was significantly associated with agitation as ADR of doxapram (odds ratio [OR] = 4.5; 95% confidence interval [CI] = 1.2-16.3). None of the other potential risk factors was associated with agitation as an ADR of doxapram. Conclusion The prevalence of agitation as ADR of doxapram in premature neonates was 17.6% and the male sex was significantly associated with the occurrence of agitation. Extra attention towards agitation as possible ADR of doxapram treatment in preterm neonates is needed.</p

Agitation as adverse drug reaction of doxapram in preterm neonates:Prevalence and potential risk factors

Agitation as adverse drug reaction of doxapram in preterm neonates: prevalence and potential risk factors Background Apnea of prematurity (AOP) is a common complication in premature neonates. AOP can be treated with methylxanthines (e.g. caffeine) and maximal non-invasive ventilation. If this treatment does not suffice, doxapram can be added. Doxapram is used off-label in preterm neonates and evidence on efficacy and safety of its use is limited. Objective This research aimed to investigate the prevalence of agitation as possible adverse drug reaction (ADR) of doxapram treatment in preterm neonates. The secondary aim was to identify risk-factors for occurrence of this ADR. Design All patients born &lt; 32 weeks of gestation that were treated with doxapram between December 2013 and May 2017 on the neonatal intensive care unit (NICU) of the Erasmus University Medical Center in Rotterdam were eligible for inclusion. All relevant demographic data and the numeric rating scale (NRS) agitation of the included patients were collected retrospectively. An event of agitation was defined as an NRS agitation of ≥ 4. Causality was formally assessed by a pharmacist and clinician using an adjusted version of Kramer's algorithm. Prevalence was calculated by dividing all patients with a causally related event of agitation by the total number of patients. Associations of potential risk factors with agitation as an ADR of doxapram were investigated by performing univariable and multivariable logistic regression. Results 119 patients were included. Prevalence of agitation as ADR of doxapram was 17.6%. The male sex was significantly associated with agitation as ADR of doxapram (odds ratio [OR] = 4.5; 95% confidence interval [CI] = 1.2-16.3). None of the other potential risk factors was associated with agitation as an ADR of doxapram. Conclusion The prevalence of agitation as ADR of doxapram in premature neonates was 17.6% and the male sex was significantly associated with the occurrence of agitation. Extra attention towards agitation as possible ADR of doxapram treatment in preterm neonates is needed.</p

Vascular reactivity is altered in the placentas of fetuses with congenital diaphragmatic hernia

Introduction: Infants with congenital diaphragmatic hernia (CDH) often develop pulmonary hypertension but frequently fail to respond to vasodilator therapy, for instance because of an altered pulmonary vasoreactivity. Investigating such alterations in vivo is impossible. We hypothesised that these alterations are also present in fetoplacental vessels, since both vasculatures are exposed to the same circulating factors (e.g. endothelin-1) and respond similarly to certain stimuli (e.g. hypoxia). As proof-of-concept, we compared fetoplacental vasoreactivity between healthy and CDH-affected placentas. Methods: Fetoplacental vascular function of healthy and antenatally diagnosed left-sided CDH fetuses was assessed by wire myography. Placental expression of enzymes and receptors involved in the altered vasoreactive pathways was measured using quantitative PCR. Results: CDH arteries (n = 6) constricted more strongly to thromboxane A2 agonist U46619 (p &lt; 0.001) and dilated less to bradykinin (p = 0.01) and nitric oxide (NO)-donor sodium nitroprusside (p = 0.04) than healthy arteries (n = 8). Vasodilation to prostacyclin analogue iloprost and adenylate cyclase stimulator forskolin, and vasoconstriction to endothelin-1 were not different between both groups. Angiotensin II did not induce vasoconstriction. Phosphodiesterase inhibitors sildenafil and milrinone did not affect responses to sodium nitroprusside, forskolin, or U46619. The mRNA expression of guanylate cyclase 1 soluble subunit alpha 1 (p = 0.003) and protein kinase cyclic guanine monophosphate (cGMP)-dependent 1 (p = 0.02) were reduced in CDH versus healthy placentas. Discussion: The identified changes in the thromboxane and NO-cGMP pathways in the fetoplacental vasculature correspond with currently described alterations in the pulmonary vasculature in CDH. Therefore, fetoplacental arteries may provide an opportunity to predict pulmonary therapeutic responses in infants with CDH.</p