When will the Glomerular Filtration Rate in Former Preterm Neonates Catch up with Their Term Peers?

AIMS: Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs. METHODS: We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR. We developed a GFR function consisting of GFRbirth (GFR at birth), and an Emax model dependent on PNA (with GFRmax, PNA50 (PNA at which half of GFR max is reached) and Hill coefficient). The final GFR model was applied to predict gentamicin, tobramycin and vancomycin concentrations. RESULT: In the GFR model, GFRbirth varied with birthweight linearly while in the PNA-based Emax equation, GA was the best covariate for PNA50, and current weight for GFRmax. The final model showed that for a child born at 26 weeks GA, absolute GFR is 18%, 63%, 80%, 92% and 96% of the GFR of a child born at 40 weeks GA at 1 month, 6 months, 1 year, 3 years and 12 years, respectively. PopPK models with the GFR maturation equations predicted concentrations of renally cleared antibiotics across (pre)term-born neonates until 18 years well. CONCLUSIONS: GFR of preterm individuals catches up with term peers at around three years of age, implying reduced dosages of renally cleared drugs should be considered below this age.

Biomarkers for assessing pain and pain relief in the neonatal intensive care unit.

Newborns admitted to the neonatal intensive care unit (NICU) regularly undergo painful procedures and may face various painful conditions such as postoperative pain. Optimal management of pain in these vulnerable preterm and term born neonates is crucial to ensure their comfort and prevent negative consequences of neonatal pain. This entails accurate and timely identification of pain, non-pharmacological pain treatment and if needed administration of analgesic therapy, evaluation of treatment effectiveness, and monitoring of adverse effects. Despite the widely recognized importance of pain management, pain assessment in neonates has thus far proven to be a challenge. As self-report, the gold standard for pain assessment, is not possible in neonates, other methods are needed. Several observational pain scales have been developed, but these often rely on snapshot and largely subjective observations and may fail to capture pain in certain conditions. Incorporation of biomarkers alongside observational pain scores holds promise in enhancing pain assessment and, by extension, optimizing pain treatment and neonatal outcomes. This review explores the possibilities of integrating biomarkers in pain assessment in the NICU.

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.

Global cross-sectional survey on neonatal pharmacologic sedation and analgesia practices and pain assessment tools: impact of the sociodemographic index (SDI).

BACKGROUND: There is variability in the use of sedatives and analgesics in neonatal intensive care units (NICUs). We aimed to investigate the use of analgesics and sedatives and the management of neonatal pain and distress. METHODS: This was a global, prospective, cross-sectional study. A survey was distributed May-November 2022. The primary outcome of this research was to compare results between countries depending on their socio-sanitary level using the sociodemographic index (SDI). We organized results based on geographical location. RESULTS: The survey collected 1304 responses, but we analyzed 924 responses after database cleaning. Responses from 98 different countries were analyzed. More than 60% of NICUs reported having an analgosedation guideline, and one-third of respondents used neonatal pain scales in more than 80% of neonates. We found differences in the management of sedation and analgesia between NICUs on different continents, but especially between countries with different SDIs. Countries with a higher SDI had greater availability of and adherence to analgosedation guidelines, as well as higher rates of analgosedation for painful or distressing procedures. Countries with different SDIs reported differences in analgosedation for neonatal intubation, invasive ventilation, and therapeutic hypothermia, among others. CONCLUSIONS: Socio-economic status of countries impacts on neonatal analgosedation management. IMPACT: There is significant variability in the pain management practices in neonates. There is a lack of knowledge related to how neonatal pain management practices differ between regions. Sociodemographic index is a key factor associated with differences in neonatal pain management practices across global regions.

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 < 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.

Grading the level of evidence of neonatal pharmacotherapy: midazolam and phenobarbital as examples.

BACKGROUND: Many drugs are used off-label or unlicensed in neonates. This does not mean they are used without evidence or knowledge. We aimed to apply and evaluate the Grading and Assessment of Pharmacokinetic-Pharmacodynamic Studies (GAPPS) scoring system for the level of evidence of two commonly used anti-epileptic drugs. METHODS: Midazolam and phenobarbital as anti-epileptics were evaluated with a systematic literature search on neonatal pharmacokinetic (PK) and/or pharmacodynamic [PD, (amplitude-integrated) electroencephalography effect] studies. With the GAPPS system, two evaluators graded the current level of evidence. Inter-rater agreement was assessed for dosing evidence score (DES), quality of evidence (QoE), and strength of recommendation (REC). RESULTS: Seventy-two studies were included. DES scores 4 and 9 were most frequently used for PK, and scores 0 and 1 for PD. Inter-rater agreements on DES, QoE, and REC ranged from moderate to very good. A final REC was provided for all PK studies, but only for 25% (midazolam) and 33% (phenobarbital) of PD studies. CONCLUSIONS: There is a reasonable level of evidence concerning midazolam and phenobarbital PK in neonates, although using a predefined target without integrated PK/PD evaluation. Further research is needed on midazolam use in term neonates with therapeutic hypothermia, and phenobarbital treatment in preterms. IMPACT: There is a reasonable level of evidence concerning pharmacotherapy of midazolam and phenobarbital in neonates. Most evidence is however based on PK studies, using a predefined target level or concentration range without integrated, combined PK/PD evaluation. Using the GAPPS system, final strength of recommendation could be provided for all PK studies, but only for 25% (midazolam) to 33% (phenobarbital) of PD studies. Due to the limited PK observations of midazolam in term neonates with therapeutic hypothermia, and of phenobarbital in preterm neonates these subgroups can be identified for further research.

Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial).

BACKGROUND: Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. METHODS: The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. DISCUSSION: Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.

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.

Diversity of Parent Emotions and Physician Responses During End-of-Life Conversations.

BACKGROUND AND OBJECTIVES: To provide support to parents of critically ill children, it is important that physicians adequately respond to parents' emotions. In this study, we investigated emotions expressed by parents, physicians' responses to these expressions, and parents' emotions after the physicians' responses in conversations in which crucial decisions regarding the child's life-sustaining treatment had to be made. METHODS: Forty-nine audio-recorded conversations between parents of 12 critically ill children and physicians working in the neonatal and pediatric intensive care units of 3 Dutch university medical centers were coded and analyzed by using a qualitative inductive approach. RESULTS: Forty-six physicians and 22 parents of 12 children participated. In all 49 conversations, parents expressed a broad range of emotions, often intertwining, including anxiety, anger, devotion, grief, relief, hope, and guilt. Both implicit and explicit expressions of anxiety were prevalent. Physicians predominantly responded to parental emotions with cognition-oriented approaches, thereby limiting opportunities for parents. This appeared to intensify parents' expressions of anger and protectiveness, although their anxiety remained under the surface. In response to more tangible emotional expressions, for instance, grief when the child's death was imminent, physicians provided parents helpful support in both affect- and cognition-oriented ways. CONCLUSIONS: Our findings illustrate the diversity of emotions expressed by parents during end-of-life conversations. Moreover, they offer insight into the more and less helpful ways in which physicians may respond to these emotions. More training is needed to help physicians in recognizing parents' emotions, particularly implicit expressions of anxiety, and to choose helpful combinations of responses.

Inflammation, sepsis severity and neurodevelopmental outcomes of late-onset sepsis in preterm neonates.

BACKGROUND: The aim of this study was to investigate the association between inflammatory biomarkers (C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6)) and sepsis severity (neonatal-Sequential-Organ-Failure-Assessment (nSOFA)) and neurodevelopmental outcomes at 2 years, among very preterm neonates. METHODS: Data on preterm neonates (gestational age <30 weeks) from 2016 until 2020 were reviewed. Outcomes of interest were NDI (no, mild, severe) and the motor and cognitive score on the Dutch-Bayley-Scales-of-Infant-and-Toddler-Development (Bayley-III-NL) assessed at the corrected age of 2 years. Logistic and linear regression analysis were used for categorical and continuous outcomes, respectively. All analyses were adjusted for gestational age, sex and birthweight-for-gestational-age SD-score. RESULTS: In total 410 patients were eligible for analysis. Maximum CRP concentrations were associated with lower motor and cognitive scores (effect estimate -0.03 points,(95% CI -0.07; -0.00) and -0.03 points,(95% CI -0.06; -0.004), respectively) and increased risk of severe NDI (odds ratio (OR) 1.01, (95% CI 1.00; 1.01)). High nSOFA scores (≥4) during sepsis episodes were associated with an increased risk of mild NDI (OR 2.01, (95% CI 1.34; 3.03)). There were no consistent associations between IL-6, PCT and the outcomes of interest. CONCLUSION: High CRP concentrations and sepsis severity in preterm neonates seem to be associated with neurodevelopmental outcomes in survivors at the age of 2 years. IMPACT STATEMENT: The level of inflammation and sepsis severity are associated with neurodevelopmental outcome in preterm neonates at 2 years of corrected age. Sepsis is a major health issue in preterm neonates and can lead to brain damage and impaired neurodevelopment. Biomarkers can be determined to assess the level of inflammation. However, the relation of inflammatory biomarkers with neurodevelopmental outcome is not known. The level of inflammation and sepsis severity are related to neurodevelopmental outcome in preterm neonates. Maximum CRP concentration and high nSOFA scores are associated with an increased risk of neurodevelopmental impairment in survivors at the corrected age of 2 years.

The influence of intensive care treatment in infancy on cortisol levels in childhood and adolescence.

BACKGROUND: Infants admitted to the intensive care unit experience numerous early-life stressors, which may have long-term effects on hypothalamic-pituitary-adrenal axis functioning. AIMS: To determine the effects of intensive care treatment and related exposure to stress, pain, and opioids in infancy on cortisol levels in childhood and adolescence. STUDY DESIGN: Cross-sectional study. SUBJECTS: Children and adolescents aged 8 to 18 years with a history of intensive care treatment in infancy and healthy controls. The intensive care treatment cohort consisted of four subgroups with varying levels of exposure to stress, pain, and opioids in infancy. They received either mechanical ventilation, extracorporeal membrane oxygenation, major surgery, or excochleation of a giant congenital melanocytic nevus. OUTCOME MEASURES: Between-group differences in stress reactivity to a study visit consisting of pain threshold testing and an MRI examination and diurnal cortisol levels, as measured in saliva. RESULTS: After adjustment for age, sex, and gestational age, the diurnal cortisol output (AUCg) in the overall intensive care group (N = 76) was 18 % (approximately 1000 nmol/L) (95 % CI [-31 %, -3 %], P = 0.022) lower than that in the control group (N = 67). Cortisol awakening response, diurnal decline, and stress reactivity neither differed significantly between the overall intensive care group and control group, nor between the intensive care subgroups and control group. CONCLUSION: Children and adolescents with a history of intensive care treatment in infancy have similar cortisol profiles to those of healthy controls, except for an 18 % lower diurnal cortisol output. The clinical relevance of this reduction is yet to be determined.

Sedation Prior to Intubation at Birth in Infants with Congenital Diaphragmatic Hernia: An International Survey on Current Practices.

INTRODUCTION: Infants with congenital diaphragmatic hernia (CDH) are commonly intubated immediately after birth. Consensus on whether to provide sedation prior to intubation in the delivery room is lacking, although avoidance of stress is especially important in this population with high risk of pulmonary hypertension. We aimed at obtaining an overview of local pharmacological interventions and at providing guidance on delivery room management. METHODS: An electronic survey was sent to international clinicians in referral centres for prenatal and postnatally diagnosed infants with CDH. This survey addressed demographic information, use of sedation and/or muscle relaxant prior to intubation, and use of pain scales in the delivery room. RESULTS: We received 93 relevant responses from 59 centres. Most centres were from Europe (n = 33, 56%), followed by North America (n = 16, 27%), Asia (n = 6, 10%), Australia (n = 2, 3%), and South America (n = 2, 3%). A total of 19% (11/59) of the centres routinely provided sedation prior to intubation in the delivery room, with midazolam and fentanyl being most often used. Methods of administration varied for all medications provided. Only 5 of 11 centres using sedation reported an adequate sedative effect prior to intubation. Muscle relaxants prior to intubation were used in 12% (7/59) of the centres, although not always in combination with sedation. CONCLUSION: This international survey shows a substantial variation in sedation practices in the delivery room and scarce use of both sedative agents and muscle relaxants prior to intubation of CDH infants. We provide guidance on developing protocols for pre-intubation medication in this population.

Early prediction of severe retinopathy of prematurity requiring laser treatment using physiological data.

BACKGROUND: Early risk stratification for developing retinopathy of prematurity (ROP) is essential for tailoring screening strategies and preventing abnormal retinal development. This study aims to examine the ability of physiological data during the first postnatal month to distinguish preterm infants with and without ROP requiring laser treatment. METHODS: In this cohort study, preterm infants with a gestational age <32 weeks and/or birth weight <1500 g, who were screened for ROP were included. Differences in the physiological data between the laser and non-laser group were identified, and tree-based classification models were trained and independently tested to predict ROP requiring laser treatment. RESULTS: In total, 208 preterm infants were included in the analysis of whom 30 infants (14%) required laser treatment. Significant differences were identified in the level of hypoxia and hyperoxia, oxygen requirement, and skewness of heart rate. The best model had a balanced accuracy of 0.81 (0.72-0.87), a sensitivity of 0.73 (0.64-0.81), and a specificity of 0.88 (0.80-0.93) and included the SpO2/FiO2 ratio and baseline demographics (including gestational age and birth weight). CONCLUSIONS: Routinely monitored physiological data from preterm infants in the first postnatal month are already predictive of later development of ROP requiring laser treatment, although validation is required in larger cohorts. IMPACT: Routinely monitored physiological data from the first postnatal month are predictive of later development of ROP requiring laser treatment, although model performance was not significantly better than baseline characteristics (gestational age, birth weight, sex, multiple birth, prenatal glucocorticosteroids, route of delivery, and Apgar scores) alone. A balanced accuracy of 0.81 (0.72-0.87), a sensitivity of 0.73 (0.64-0.81), and a specificity of 0.88 (0.80-0.93) was achieved with a model including the SpO2/FiO2 ratio and baseline characteristics. Physiological data have potential to play a significant role for future ROP prediction and provide opportunities for early interventions to protect infants from abnormal retinal development.

COMFORTneo scale: a reliable and valid instrument to measure prolonged pain in neonates?

OBJECTIVE: We studied the reliability and validity of the COMFORTneo scale, designed to measure neonatal prolonged pain. STUDY DESIGN: This prospective observational study evaluated four clinimetric properties of the COMFORTneo scale from NICU nurses' assessments of neonates' pain. Intra-rater reliability was determined from three video fragments at two time points. Inter-rater reliability and construct validity were determined in five neonates per nurse with the COMFORTneo and numeric rating scales (NRS) for pain and distress. Pain scores using N-PASS were correlated with COMFORTneo scores to further evaluate construct validity. RESULT: Intra-rater reliability: Twenty-two nurses assessed pain twice with an intraclass correlation coefficient (ICC) of 0.70. Inter-rater reliability: The ICC for 310 COMFORTneo scores together with 62 nurses was 0.93. Construct validity: Correlation between COMFORTneo and NRS pain, distress, and N-PASS was 0.34, 0.72, and 0.70, respectively. CONCLUSION: The COMFORTneo can be used to reliably and validly assess pain in NICU patients.

Current pain management practices for preterm infants with necrotizing enterocolitis: a European survey.

BACKGROUND: Necrotizing enterocolitis (NEC) is a highly painful intestinal complication in preterm infants that requires adequate pain management to prevent short- and long-term effects of neonatal pain. There is a lack of international guidelines for pain management in NEC patients. Therefore, this study aims to describe current pain management for NEC patients in European neonatal intensive care units (NICUs). METHODS: An online survey was designed and conducted to assess current practices in pain management for NEC patients in European NICUs. The survey was distributed via neonatal societies, digital platforms, and professional contacts. RESULTS: Out of the 259 responding unique European NICUs from 36 countries, 61% had a standard protocol for analgesic therapy, 73% assessed pain during NEC, and 92% treated NEC patients with intravenous analgosedatives. There was strong heterogeneity in the used pain scales and initial analgesic therapy, which mainly included acetaminophen (70%), fentanyl (56%), and/or morphine (49%). A third of NICU representatives considered their pain assessment adequate, and half considered their analgesic therapy adequate for NEC patients. CONCLUSIONS: Various pain scales and analgesics are used to treat NEC patients in European NICUs. Our results provide the first step towards an international guideline to improve pain management for NEC patients. IMPACT: This study provides an overview of current pain management practices for infants with necrotizing enterocolitis (NEC) in European neonatal intensive care units. Choice of pain assessment tools, analgosedatives, and dosages vary considerably among NICUs and countries. A third of NICU representatives were satisfied with their current pain assessment practices and half of NICU representatives with their analgesic therapy practices in NEC patients in their NICU. The results of this survey may provide a first step towards developing a European pain management consensus guideline for patients with NEC.

Development of Best Evidence Dosing Recommendations for Term and Preterm Neonates (NeoDose Project).

Many drugs are used off-label in neonates which leads to large variation in prescribed drugs and dosages in neonatal intensive care units (NICUs). The NeoDose project aimed to develop best evidence dosing recommendations (DRs) for term and preterm neonates using a three-step approach: 1) drug selection, 2) establishing consensus-based DRs, and 3) establishing best evidence DRs. METHODS: The selection of drugs was based on frequency of prescribing, availability of a neonatal DR in the Dutch Pediatric Formulary, and the labeling status. Clinical need, pharmacological diversity, and Working Group Neonatal Pharmacology (WGNP) preferences were also taken into account, using a consensus-based approach. For the second step, we requested local dosing protocols from all ten Dutch NICUs and established consensus-based DRs within the WGNP, consisting of neonatologists, clinical pharmacologists, hospital pharmacists, and researchers. In the third step, the consensus-based DRs were compared with the available literature, using standardized PubMed searches. RESULTS: Fourteen drugs were selected for which the local dosing protocols were collected. These protocols differed mostly in total daily dose, dosing frequency, and/or route of administration. Strikingly, almost none of the dosing protocols of these 14 drugs distinguished between preterm and term neonates. The working group established consensus-based DRs, which after literature review needed modification in 56%, mainly in terms of a dose increase. Finally, we established 37 best evidence DRs, 22 for preterm and 15 for term neonates, representing 19 indications. CONCLUSION: This project showed the successful three-step approach for the development of DRs for term and preterm neonates.

Oxygen saturation histogram classification system to evaluate response to doxapram treatment in preterm infants.

BACKGROUND: An oxygen saturation (SpO2) histogram classification system has been shown to enable quantification of SpO2 instability into five types, based on histogram distribution and time spent at SpO2 ≤ 80%. We aimed to investigate this classification system as a tool to describe response to doxapram treatment in infants with severe apnea of prematurity. METHODS: This retrospective study included 61 very-low-birth-weight infants who received doxapram. SpO2 histograms were generated over the 24-h before and after doxapram start. Therapy response was defined as a decrease of ≥1 histogram types after therapy start. RESULTS: The median (IQR) histogram type decreased from 4 (3-4) before to 3 (2-3) after therapy start (p < 0.001). The median (IQR) FiO2 remained constant before (27% [24-35%]) and after (26% [22-35%]) therapy. Thirty-six infants (59%) responded to therapy within 24 h. In 34/36 (94%) of the responders, invasive mechanical ventilation (IMV) was not required during the first 72 h of therapy, compared to 15/25 (60%) of non-responders (p = 0.002). Positive and negative predictive values of the 24-h response for no IMV requirement within 72 h were 0.46 and 0.94, respectively. CONCLUSIONS: Classification of SpO2 histograms provides an objective bedside measure to assess response to doxapram therapy and can serve as a tool to detect changes in oxygenation status around respiratory interventions. IMPACT: The SpO2 histogram classification system provides a tool for quantifying response to doxapram therapy. The classification system allowed estimation of the probability of invasive mechanical ventilation requirement, already within a few hours of treatment. The SpO2 histogram classification system allows an objective bedside assessment of the oxygenation status of the preterm infant, making it possible to assess the changes in oxygenation status in response to respiratory interventions.

Oral Ibuprofen Is More Effective than Intravenous Ibuprofen for Closure of a Patent Ductus Arteriosus: Can Pharmacokinetic Modeling Help Us to Understand Why?

INTRODUCTION: Oral ibuprofen is more effective than intravenous (IV) ibuprofen for closure of a patent ductus arteriosus (PDA). This study explored whether higher concentrations of the biologically active S-enantiomer or increased R- to S-conversion following oral dosing could explain this finding. METHODS: Two datasets containing 370 S- and R-ibuprofen concentrations from 95 neonates with PDA treated with oral (n = 27, 28%) or IV ibuprofen were analyzed using nonlinear mixed effects modeling. Concentration-time profiles in typical neonates were explored and compared in different dosing or R- to S-conversion scenarios. RESULTS: Postnatal age (PNA), gestational age (GA), and being small for GA impacted S- and R-ibuprofen clearance. Upon oral dosing, S-ibuprofen concentrations were lower compared to IV ibuprofen for a large part of the dosing interval. We could show that R- to S-conversion will not exceed 45%. Exploration of a 30% presystemic R- to S-conversion resulted in a 25-32% increase in S-ibuprofen exposure following oral administration with AUC72h values varying between 700-2,213 mg*h/L (oral) and 531-1,762 (IV) for the standard or 1,704-2,893 (oral) and 1,295-2,271 mg*h/L (IV) for PNA-based dosing. DISCUSSION: The absence of higher S-ibuprofen concentrations does not support a beneficial concentration-time profile after oral dosing. While a fraction of up to 45% presystemic R- to S-conversion could not be ruled out, the impact of such a low conversion might be only relevant for the standard but not high dosing regimens, considering reported exposure-response targets. Perhaps, the lack of high peak concentrations observed following IV dosing may play a role in the observed effects upon oral dosing.