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.

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.

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.

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.

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.

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.

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.

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.

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.

Pain management for necrotizing enterocolitis: getting the balance right.

BACKGROUND: Adequate pain management for preterm born neonates suffering from the extremely painful disease necrotizing enterocolitis (NEC) is essential, since neonatal exposure to pain is related to negative short-term and long-term consequences. The aim of this study was to describe the current pain management and its effectiveness in NEC patients. METHODS: In this single-center, retrospective study, neonates (gestational age < 32 weeks and/or birth weight < 1500 g) with NEC Bell's stage II or III were included. Information on pain (based on COMFORTneo and NRS scores) and analgesic therapy was collected and analyzed for the acute disease period. RESULTS: Of 79 patients included, 74 (94%) received intravenous analgesic therapy: most commonly morphine, fentanyl, and acetaminophen. The median COMFORTneo score was 11 (IQR 10-11), however, 49 patients had at least one COMFORTneo score ≥ 14 indicating pain. Nineteen patients had persistent high pain scores ≥ 14 with a median duration of 7.2 h (IQR 2.8-14.0). CONCLUSIONS: This study showed that despite analgesic therapy, most NEC patients showed signs of pain, and in some, pain persisted for several hours. It suggests that current analgesic therapy frequently failed to prevent pain and existing pain was often insufficiently treated. This supports the urgent need for individualized pain management guidelines for NEC patients. IMPACT: This study is unique in reporting on pain management in neonates suffering from necrotizing enterocolitis (NEC) during the full acute disease period. Despite analgesic therapy, the majority of NEC patients experience pain, and in some patients, pain persists for several hours. These findings highlight the need for improvement of neonatal pain management in NEC patients, including better pain monitoring and guidelines for individualized analgesic therapy. Improved pain management guidelines may help to prevent short-term and long-term consequences of neonatal exposure to pain, as well as excessive exposure to opioids.

Knowledge gaps in late-onset neonatal sepsis in preterm neonates: a roadmap for future research.

Late-onset neonatal sepsis (LONS) remains an important threat to the health of preterm neonates in the neonatal intensive care unit. Strategies to optimize care for preterm neonates with LONS are likely to improve survival and long-term neurocognitive outcomes. However, many important questions on how to improve the prevention, early detection, and therapy for LONS in preterm neonates remain unanswered. This review identifies important knowledge gaps in the management of LONS and describe possible methods and technologies that can be used to resolve these knowledge gaps. The availability of computational medicine and hypothesis-free-omics approaches give way to building bedside feedback tools to guide clinicians in personalized management of LONS. Despite advances in technology, implementation in clinical practice is largely lacking although such tools would help clinicians to optimize many aspects of the management of LONS. We outline which steps are needed to get possible research findings implemented on the neonatal intensive care unit and provide a roadmap for future research initiatives. IMPACT: This review identifies knowledge gaps in prevention, early detection, antibiotic, and additional therapy of late-onset neonatal sepsis in preterm neonates and provides a roadmap for future research efforts. Research opportunities are addressed, which could provide the means to fill knowledge gaps and the steps that need to be made before possible clinical use. Methods to personalize medicine and technologies feasible for bedside clinical use are described.

Introducing heart rate variability monitoring combined with biomarker screening into a level IV NICU: a prospective implementation study.

The aim of this study was to investigate the association between the implementation of a local heart rate variability (HRV) monitoring guideline combined with determination of inflammatory biomarkers and mortality, measures of sepsis severity, frequency of sepsis testing, and antibiotic usage, among very preterm neonates. In January 2018, a guideline was implemented for early detection of late-onset neonatal sepsis using HRV monitoring combined with determination of inflammatory biomarkers. Data on all patients admitted with a gestational age at birth of < 32 weeks were reviewed in the period January 2016-June 2020 (n = 1,135; n = 515 pre-implementation, n = 620 post-implementation). Outcomes of interest were (sepsis-related) mortality, sepsis severity (neonatal sequential organ failure assessment (nSOFA)), sepsis testing, and antibiotic usage. Differences before and after implementation of the guideline were assessed using logistic and linear regression analysis for binary and continuous outcomes respectively. All analyses were adjusted for gestational age and sex. Mortality within 10 days of a sepsis episode occurred in 39 (10.3%) and 34 (7.6%) episodes in the pre- and post-implementation period respectively (P = 0.13). The nSOFA course during a sepsis episode was significantly lower in the post-implementation group (P = 0.01). We observed significantly more blood tests for determination of inflammatory biomarkers, but no statistically significant difference in number of blood cultures drawn and in antibiotic usage between the two periods.Conclusion: Implementing HRV monitoring with determination of inflammatory biomarkers might help identify patients with sepsis sooner, resulting in reduced sepsis severity, without an increased use of antibiotics or number of blood cultures.

Cardiorespiratory monitoring of red blood cell transfusions in preterm infants.

Clinical improvement after red blood cell (RBC) transfusions in preterm infants remains debated. This study aims to investigate the effect of RBC transfusion on the occurrence of desaturations and hypoxia, and other cardiorespiratory outcomes in preterm infants. In this longitudinal observational study, prospectively stored cardiorespiratory parameters of preterm infants who received at least one RBC transfusion between July 2016 and June 2017 were retrospectively analyzed. Sixty infants with 112 RBC transfusions, median GA of 26.7 weeks, were included. The number of desaturations and area < 80% SpO2 limit, as a measure of the hypoxic burden, were calculated in 24 h before and after RBC transfusion. A mixed effects model was used to account for repeated measurements. Overall, the mean (SE) number of desaturations per hour decreased from 3.28 (0.55) to 2.25 (0.38; p < 0.001), and area < 80% SpO2 limit decreased from 0.14 (0.04) to 0.08 (0.02) %/s (p = 0.02). These outcomes were stratified for the number of desaturations in 24 h prior to RBC transfusion. The largest effect was observed in the group with the highest mean number of desaturations (≥ 6) prior to RBC transfusion, with a decrease from 7.50 (0.66) to 4.26 (0.38) (p < 0.001) in the number of desaturations and 0.46 (0.13) to 0.20 (0.06) in the area < 80% SpO2. Perfusion index increased significantly after RBC transfusion (p < 0.001). No other significant effects of RBC transfusion on cardiorespiratory data were observed.Conclusions: RBC transfusions in preterm newborns could help decrease the incidence of desaturations and the area < 80% SpO2 as a measure of the hypoxic burden. The higher the number of desaturations prior to the RBC transfusion, the larger the effect observed. What is Known: •Red blood cell transfusions potentially prevent hypoxia in anemic preterm infants by increasing the circulatory hemoglobin concentration and improving tissue oxygenation. •There is not a predefined hemoglobin concentration cut-off for the occurrence of symptomatic anemia in preterm infants. What is New: •Oxygen desaturations and hypoxia in anemic preterm infants can be improved by RBC transfusions, especially if more desaturations have occurred before transfusion. •Cardiorespiratory monitor data may help identify infants who will benefit most from red blood cell transfusions.

COVID-19 lockdown impacts the wellbeing of parents with infants on a Dutch neonatal intensive care unit.

PURPOSE: Parents of infants admitted to a neonatal intensive care unit (NICU) experience additional stress due to restrictions on their presence and visits by other family members during the COVID-19 pandemic. Our study aims to describe how this impacted parents and how NICU staff could support them. DESIGN AND METHODS: This was a cross-sectional study in which 25 parents (16 mothers, 9 fathers) of infants admitted to our NICU during the first COVID-19 lockdown completed online questionnaires with socio-demographic questions, the Parental Stressor Scale:NICU (PSS:NICU) and questions related to COVID-19. RESULTS: Being separated from, and not being able to hold their infant at all times were among the most important PSS:NICU stressors. Parents experienced additional stress because other family members were not allowed to visit. They indicated that NICU staff could support them by clearly explaining the reasons for visitor restrictions and by ensuring that they felt heard. Most parents supported the restrictions, but also mentioned that less strict measures would really help them. CONCLUSIONS: Parents who participated in this study found it very stressful that they could not be with their infant together with their partner and other family members. Furthermore, parents recommended the hospital management to continuously reconsider whether particular restrictions could be lifted in case of a new lockdown. Together with clear communication, this would result in less parenteral stress. PRACTICE IMPLICATIONS: Hospital management should be cautious on restricting the presence of parents and other family members and scale restrictions back whenever possible.

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 (CLFORMATION KETO-DOXAPRAM) and clearance of doxapram via other routes (CLDOXAPRAM OTHER ROUTES). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CLFORMATION KETO-DOXAPRAM was 0.115 L/h (relative standard error (RSE) 12%) and CLDOXAPRAM 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.

Association of inflammatory biomarkers with subsequent clinical course in suspected late onset sepsis in preterm neonates.

BACKGROUND: Sepsis is a major health issue in preterm infants. Biomarkers are used to diagnose and monitor patients with sepsis, but C-reactive protein (CRP) is proven not predictive at onset of late onset neonatal sepsis (LONS) diagnosis. The aim of this study was to evaluate the association of interleukin-6(IL-6), procalcitonin (PCT) and CRP with subsequent sepsis severity and mortality in preterm infants suspected of late onset neonatal sepsis. METHODS: The study was conducted at the Erasmus University Medical Center-Sophia Children's Hospital Rotterdam. Patient data from January 2018 until October 2019 were reviewed for all preterm neonates born with a gestational age below 32 weeks with signs and symptoms suggestive of systemic infection, in whom blood was taken for blood culture and for inflammatory biomarkers determinations. Plasma IL-6 and PCT were assessed next to CRP at the moment of suspicion. We assessed the association with 7-day mortality and sepsis severity (neonatal sequential organ failure assessment (nSOFA) score, need for inotropic support, invasive ventilation and thrombocytopenia). RESULTS: A total of 480 suspected late onset neonatal sepsis episodes in 208 preterm neonates (gestational age < 32 weeks) were retrospectively analyzed, of which 143 episodes were classified as sepsis (29.8%), with 56 (11.7%) cases of culture negative, 63 (13.1%) cases of gram-positive and 24(5.0%) cases of gram-negative sepsis. A total of 24 (5.0%) sepsis episodes resulted in death within 7 days after suspicion of LONS. Both IL-6 (adjusted hazard ratio (aHR): 2.28; 95% CI 1.64-3.16; p < 0.001) and PCT (aHR: 2.91; 95% CI 1.70-5.00; p < 0.001) levels were associated with 7-day mortality; however, CRP levels were not significantly correlated with 7-day mortality (aHR: 1.16; 95% CI (0.68-2.00; p = 0.56). Log IL-6, log PCT and log CRP levels were all significantly correlated with the need for inotropic support. CONCLUSIONS: Our findings show that serum IL-6 and PCT levels at moment of suspected late onset neonatal sepsis offer valuable information about sepsis severity and mortality risk in infants born below 32 weeks of gestation. The discriminative value was superior to that of CRP. Determining these biomarkers in suspected sepsis may help identify patients with imminent severe sepsis, who may require more intensive monitoring and therapy.

Protocol: Pentoxifylline optimal dose finding trial in preterm neonates with suspected late onset sepsis (PTX-trial).

BACKGROUND: Late onset sepsis is a leading cause of death and morbidity in preterm infants. Despite optimal antibiotic treatment, sepsis related mortality and morbidity is still high. Pentoxifylline (PTX) is a methylxanthine with promising immunomodulatory properties, which can be used as an additional therapy next to antibiotics in preterm infants. PTX is increasingly used off-label in neonatal intensive care units, however up till now no dose finding study has been done for PTX in this specific population. The aim of this study (PTX-trial) is to determine the optimal dose of PTX in preterm infants (gestational age < 30 weeks) with (suspected) late onset sepsis. Dose finding in this particular population is unique, since for most drugs used in neonates the optimal dosage has not been investigated in phase II dose-seeking studies. METHODS: The PTX-trial is a prospective open label sequential dose-optimization study with an adapted continual reassessment method. An up-and-down dose-response design will be used, with dose step-up and step-down titration after every 3 patients. The PTX starting dosage will be 30 mg/kg/day in 6 hours as described in most previous neonatal studies. Efficacy is defined by means of biochemical and clinical parameters. Toxicity in these vulnerable patients is unwarranted. The optimal dose is defined as the ED75 (i.e., clinically and chemically effective dose for 75% of patients) in preterm neonates with late onset sepsis. We plan to include 30 neonates to determine the optimal dose using this study design. Subsequently, the optimal dose will be validated in 10 additional preterm neonates. In parallel, pharmacokinetics of PTX and its metabolites will be described as well as longitudinal evaluation of metabolomics and proteomics. DISCUSSION: The study has been approved by the Regional Medical Ethics Board of Erasmus Medical Center University Rotterdam (MEC 2019-0477) and registered at Clinicaltrials.gov (NCT04152980). Results of the main trial and each of the secondary endpoints will be submitted for publications in peer-reviewed journals. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04152980 , Registered November 6th, 2019.

Challenges in developing a consensus definition of neonatal sepsis.

Sepsis remains a leading cause of morbidity and mortality in the neonatal population, and at present, there is no unified definition of neonatal sepsis. Existing consensus sepsis definitions within paediatrics are not suited for use in the NICU and do not address sepsis in the premature population. Many neonatal research and surveillance networks have criteria for the definition of sepsis within their publications though these vary greatly and there is typically a heavy emphasis on microbiological culture. The concept of organ dysfunction as a diagnostic criterion for sepsis is rarely considered in neonatal literature, and it remains unclear how to most accurately screen neonates for organ dysfunction. Accurately defining and screening for sepsis is important for clinical management, health service design and future research. The progress made by the Sepsis-3 group provides a roadmap of how definitions and screening criteria may be developed. Similar initiatives in neonatology are likely to be more challenging and would need to account for the unique presentation of sepsis in term and premature neonates. The outputs of similar consensus work within neonatology should be twofold: a validated definition of neonatal sepsis and screening criteria to identify at-risk patients earlier in their clinical course. IMPACT: There is currently no consensus definition of neonatal sepsis and the definitions that are currently in use are varied.A consensus definition of neonatal sepsis would benefit clinicians, patients and researchers.Recent progress in adults with publication of Sepsis-3 provides guidance on how a consensus definition and screening criteria for sepsis could be produced in neonatology.We discuss common themes and potential shortcomings in sepsis definitions within neonatology.We highlight the need for a consensus definition of neonatal sepsis and the challenges that this task poses.

Lidocaine as treatment for neonatal seizures: Evaluation of previously developed population pharmacokinetic models and dosing regimen.

AIMS: Lidocaine is used to treat neonatal seizures refractory to other anticonvulsants. It is effective, but also associated with cardiac toxicity. Previous studies have reported on the pharmacokinetics of lidocaine in preterm and term neonates and proposed a dosing regimen for effective and safe lidocaine use. The objective of this study was to evaluate the previously developed pharmacokinetic models and dosing regimen. As a secondary objective, lidocaine effectiveness and safety were assessed. METHODS: Data from preterm neonates and (near-)term neonates with and without therapeutic hypothermia receiving lidocaine were included. Pharmacokinetic analyses were performed using non-linear mixed effects modelling. Simulations were performed to evaluate the proposed dosing regimen. Lidocaine was considered effective if no additional anticonvulsant was required and safe if no cardiac adverse events occurred. RESULTS: Data were available for 159 neonates; 50 (31.4%) preterm and 109 term neonates, of whom 49 (30.8%) were treated with therapeutic hypothermia. Lidocaine clearance increased with postmenstrual age by 0.69%/day (95% confidence interval 0.54-0.84%). During therapeutic hypothermia (33.5°C), lidocaine clearance was reduced by 21.8% (7.26%/°C, 95% confidence interval 1.63-11.2%) compared to normothermia (36.5°C). Simulations demonstrated that the proposed dosing regimen leads to adequate average lidocaine plasma concentrations. Effectiveness and safety were assessed in 92 neonates. Overall effectiveness was 53.3% (49/92) and 56.5% (13/23) for neonates receiving the proposed dosing regimen. No cardiac toxicity was observed. CONCLUSION: Lidocaine pharmacokinetics was adequately described across the entire neonatal age range. With the proposed dosing regimen, lidocaine can provide effective and safe treatment for neonatal seizures.

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.