Highly Variable Paracetamol Pharmacokinetics After Multiple Oral Dosing in Frail Older People: A Population Pharmacokinetic Analysis.

INTRODUCTION: Paracetamol pharmacokinetics (PK) is highly variable in older fit adults after intravenous administration. Frailty and oral administration likely result in additional variability. The aim was to determine oral paracetamol PK and variability in geriatric inpatients. METHODS: A population PK analysis, using NONMEM 7.2, was performed on 245 paracetamol samples in 40 geriatric inpatients (median age 87 [range 80-95] years, bodyweight 66.4 [49.3-110] kg, 92.5% frail [Edmonton Frail Scale]). All subjects received paracetamol 1000 mg as tablet (72.5%) or granulate (27.5%) three times daily. Simulations of dosing regimens (1000 mg every 6 hours [q6h] or q8h) were performed to determine target attainment, using mean steady-state concentration (Css-mean) of 10 mg/L as target. RESULTS: A one-compartment model with first order absorption and lag time best described the data. The inter-individual variability was high, with absorption rate constant containing the highest variability. The inter-individual variability could not be explained by covariates. Simulations of 1000 mg q6h and q8h resulted in a Css-mean of 10.8 [25-75th percentiles 8.2-12.7] and 8.13 [6.3-9.6] mg/L, respectively, for the average geriatric inpatient. The majority of the population remained off-target (22.2% [q6h] and 52.2% [q8h] <8 mg/L; 31.3 [q6h] and 7.6% [q8h] >12 mg/L). CONCLUSION: A population of average geriatric inpatients achieved target Css-mean with paracetamol 1000 mg q6h, while q8h resulted in underexposure for the majority of them. Due to high unexplained variability, a relevant proportion remained either above or below the target concentration of 10 mg/L. Research focusing on PK, efficacy and safety is needed to recommend dosing regimens.

Prediction of postnatal outcome in fetuses with congenital lung malformation: 2-year follow-up study.

OBJECTIVES: To identify, in fetuses with a congenital lung malformation (CLM), prenatal predictors of the need for postnatal respiratory support and the need for surgery by calculating the CLM volume ratio (CVR), and to evaluate the concordance between the prenatal appearance and the postnatal type of CLM. METHODS: This was an analysis of prenatal, perinatal and postnatal data from fetuses diagnosed with a CLM at the Erasmus University Medical Center - Sophia Children's Hospital in Rotterdam, The Netherlands, between January 2007 and December 2016. For all included fetuses, CVR was measured retrospectively on stored ultrasound images obtained at 18 + 1 to 24 + 6 weeks (US1), 25 + 0 to 29 + 6 weeks (US2) and/or 30 + 0 to 35 + 6 weeks' gestation (US3). Postnatal diagnosis of CLM was based on computed tomography or histology. Primary outcomes were the need for respiratory support within 24 h and surgery within 2 years after birth. RESULTS: Of the 80 fetuses with a CLM included in this study, 14 (18%) required respiratory support on the first postnatal day, and 17 (21%) required surgery within 2 years. Only the CVR at US2 was predictive of the need for respiratory support, with a cut-off value of 0.39. Four of 16 (25%) fetuses which showed full regression of the CLM prenatally required respiratory support within 24 h after birth. The CVR at US1, US2 and US3 was predictive of surgery within 2 years. Overall, the prenatal appearance of the CLM showed low concordance with the postnatal type. Prenatally suspected microcystic congenital pulmonary airway malformation (CPAM) was shown on computed tomography after birth to be congenital lobar overinflation in 15/35 (43%) cases. Respiratory support within 24 h after birth and surgical resection within 28 days after birth were needed in all cases of macrocystic CPAM. CONCLUSIONS: CVR can predict the need for respiratory support within 24 h after birth and for surgery within 2 years. Regression of a CLM prenatally does not rule out respiratory problems after birth. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. - Legal Statement: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Repetitive noxious stimuli during early development affect acute and long-term mechanical sensitivity in rats.

BACKGROUND: Prematurely born infants are frequently exposed to painful procedures in the neonatal intensive care unit, causing changes to the development of the nervous system lasting into adulthood. The current study aims to study acute and long-term consequences of neonatal repetitive noxious stimulation. METHODS: Rat pups received either 4 or 10 unilateral needle pricks per day, while control littermates received 4 or 10 tactile stimuli in the first postnatal week. Behavioural sensitivity was assessed in the neonatal phase, in adulthood, and after re-injury of the same dermatome in adulthood. RESULTS: An increase in the number of repetitive painful stimuli, from 4 to 10 needle pricks per day, resulted in increased mechanical hypersensitivity during the neonatal period. In adulthood, repetitive painful stimuli resulted in hyposensitivity to mechanical stimuli, while thermal sensitivity was unaffected. After re-injury of the same dermatome in adulthood, the number of repetitive noxious stimuli did not affect mechanical hypersensitivity. Both needle prick groups showed an increased duration of postoperative hypersensitivity compared to control. CONCLUSION: This study shows that repetitive noxious stimulation during the early postnatal period affects acute and long-term mechanical sensitivity. Therefore, the amount of nociceptive stimuli should be minimized or adequately treated in a clinical setting.

Ultrasound markers for prediction of complex gastroschisis and adverse outcome: longitudinal prospective nationwide cohort study.

OBJECTIVES: To identify antenatal ultrasound markers that can differentiate between simple and complex gastroschisis and assess their predictive value. METHODS: This was a prospective nationwide study of pregnancies with isolated fetal gastroschisis that underwent serial longitudinal ultrasound examination at regular specified intervals between 20 and 37 weeks' gestation. The primary outcome was simple or complex (i.e. involving bowel atresia, volvulus, perforation or necrosis) gastroschisis at birth. Fetal biometry (abdominal circumference and estimated fetal weight), the occurrence of polyhydramnios, intra- and extra-abdominal bowel diameters and the pulsatility index (PI) of the superior mesenteric artery (SMA) were assessed. Linear mixed modeling was used to compare the individual trajectories of cases with simple and those with complex gastroschisis, and logistic regression analysis was used to estimate the strength of association between the ultrasound parameters and outcome. RESULTS: Of 104 pregnancies with isolated fetal gastroschisis included, four ended in intrauterine death. Eighty-one (81%) liveborn infants with simple and 19 (19%) with complex gastroschisis were included in the analysis. We found no relationship between fetal biometric variables and complex gastroschisis. The SMA-PI was significantly lower in fetuses with gastroschisis than in healthy controls, but did not differentiate between simple and complex gastroschisis. Both intra- and extra-abdominal bowel diameters were larger in cases with complex, compared to those with simple, gastroschisis (P < 0.001 and P < 0.005, respectively). The presence of intra-abdominal bowel diameter ≥ 97.7th percentile on at least three occasions, not necessarily on successive examinations, was associated with an increased risk of the fetus having complex gastroschisis (relative risk, 1.56 (95% CI, 1.02-2.10); P = 0.006; positive predictive value, 50.0%; negative predictive value, 81.4%). CONCLUSIONS: This large prospective longitudinal study found that intra-abdominal bowel dilatation when present repeatedly during fetal development can differentiate between simple and complex gastroschisis; however, the positive predictive value is low, and therefore the clinical usefulness of this marker is limited. © 2019 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Scaling Drug Clearance from Adults to the Young Children for Drugs Undergoing Hepatic Metabolism: A Simulation Study to Search for the Simplest Scaling Method.

Previous research showed that scaling drug clearance from adults to children based on body weight alone is not accurate for all hepatically cleared drugs in very young children. This study systematically assesses the accuracy of scaling methods that, in addition to body weight, also take age-based variables into account for drugs undergoing hepatic metabolism in children younger than five years, namely scaling with (1) a body weight-based function using an age-dependent exponent (ADE) and (2) a body weight-based function with fixed exponent of 0.75 (AS0.75) combined with isoenzyme maturation functions (MFPBPK) similar to those implemented in physiologically based pharmacokinetic (PBPK) models (AS0.75 + MFPBPK). A PBPK-based simulation workflow was used, including hypothetical drugs with a wide range of properties and metabolized by different isoenzymes. Adult clearance values were scaled to seven typical children between one day and four years. Prediction errors of ± 50% were considered reasonably accurate. Isoenzyme maturation was found to be an important driver of changes in hepatic metabolic clearance in children younger than five years, which prevents the systematic accuracy of ADE scaling. AS0.75 + MFPBPK, when accounting for maturation of isoenzymes and microsomal protein per gram of liver (MPPGL), can reasonably accurately scale hepatic metabolic clearance for all low and intermediate extraction ratio drugs except for drugs binding to alpha-1-acid glycoprotein in neonates. As differences in the impact of changes in system-specific parameters on drugs with different properties yield differences in clearance ontogeny, it is unlikely that for the remaining drugs, scaling methods that do not take drug properties into account will be systematically accurate.

Population Pharmacokinetic Modeling of Acetaminophen and Metabolites in Children After Cardiac Surgery With Cardiopulmonary Bypass.

Children undergoing cardiac surgery often receive acetaminophen (paracetamol) as part of their postoperative pain treatment. To date, there is no information on the pharmacokinetics (PK) of acetaminophen in this special population, even though differences, as a result of altered hemodynamics and/or use of cardiopulmonary bypass, may be anticipated. Therefore, the aim of this study was to investigate the PK of intravenous acetaminophen in children after cardiac surgery with cardiopulmonary bypass. In the study, both children with and without Down syndrome were included. A population PK analysis, using NONMEM 7.2, was performed based on 161 concentrations of acetaminophen, acetaminophen sulfate, acetaminophen glucuronide, and oxidative metabolites from 17 children with Down syndrome and 13 children without Down syndrome of a previously published study (median age, 177 days [range, 92-944], body weight, 6.1 kg [4.0-12.9]). All children received 3 intravenous acetaminophen doses of 7.5 mg/kg (<10 kg) or 15 mg/kg (≥10 kg) at 8-hour intervals after cardiac surgery. For acetaminophen and its metabolites, 1-compartment models were identified. Clearance of acetaminophen and metabolites increased linearly with body weight. Acetaminophen clearance in a typical child of 6.1 kg is 0.96 L/h and volume of distribution 7.96 L. Down syndrome did not statistically significantly impact any of the PK parameters for acetaminophen, nor did any other remaining covariate. When comparing the PK parameters of acetaminophen in children after cardiac surgery with cardiopulmonary bypass with those from children of the same age following noncardiac surgery reported in the literature, clearance of acetaminophen was lower and volume of distribution higher.

Population pharmacokinetic modelling of intravenous paracetamol in fit older people displays extensive unexplained variability.

AIMS: Paracetamol is the analgesic most used by older people. The physiological changes occurring with ageing influence the pharmacokinetics (PK) of paracetamol and its variability. We performed a population PK-analysis to describe the PK of intravenous (IV) paracetamol in fit older people. Simulations were performed to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg every 6 h, every 8 h) using steady-state concentration (Css-mean ) of 10 mg l-1 as target for effective analgesia. METHODS: A population PK-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit older people (median age 77.3 years, range [61.8-88.5], body weight 79 kg [60-107]). All had received an IV paracetamol dose of 1000 mg (over 15 min) after elective knee surgery. RESULTS: A two-compartment PK-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a Css of 9.2 mg l-1 and 7.2 mg l-1 , for every 6 h and every 8 h respectively. Variability in paracetamol PK resulted in Css above 5.4 and 4.1 mg l-1 , respectively, in 90% of the population and above 15.5 and 11.7, respectively, in 10% at these dosing regimens. CONCLUSIONS: The target concentration was achieved in the average patient with 1000 mg every 6 h, while every 8 h resulted in underdosing for the majority of the population. Furthermore, due to a large (unexplained) interindividual variability in paracetamol PK a relevant proportion of the fit older people remained either under- or over exposed.

Analgesics and Sedatives in Critically Ill Newborns and Infants: The Impact on Long-Term Neurodevelopment.

Inadequate pain and/or stress management in preterm- and term-born infants has been associated with increased morbidity and even mortality. However, exposure to analgosedatives during early infancy may also be one of the risk factors for subsequent neurodevelopmental impairment, at least in animal studies. Because infants admitted to neonatal or pediatric intensive care units may receive high amounts of these drugs for prolonged periods of time and the majority of these infants nowadays survive to discharge, this is of major concern. A balanced approach that incorporates the assessment and quantification of both wanted effects as well as unwanted side effects is therefore needed. In this article, the optimal dose determination of commonly used analgosedative drugs as well as their potential long-term effects on the developing human brain and neuropsychological functioning are reviewed.

Cerebellar Growth Impairment Characterizes School-Aged Children Born Preterm without Perinatal Brain Lesions.

BACKGROUND AND PURPOSE: Infants born preterm are commonly diagnosed with structural brain lesions known to affect long-term neurodevelopment negatively. Yet, the effects of preterm birth on brain development in the absence of intracranial lesions remain to be studied in detail. In this study, we aim to quantify long term consequences of preterm birth on brain development in this specific group. MATERIALS AND METHODS: Neonatal cranial sonography and follow-up T1-weighted MR imaging and DTI were performed to evaluate whether the anatomic characteristics of the cerebrum and cerebellum in a cohort of school-aged children (6-12 years of age) were related to gestational age at birth in children free of brain lesions in the perinatal period. RESULTS: In the cohort consisting of 36 preterm (28-37 weeks' gestational age) and 66 term-born infants, T1-weighted MR imaging and DTI at 6-12 years revealed a reduction of cerebellar white matter volume (ß = 0.387, P < .001), altered fractional anisotropy of cerebellar white matter (ß = -0.236, P = .02), and a reduction of cerebellar gray and white matter surface area (ß = 0.337, P < .001; ß = 0.375, P < .001, respectively) in relation to birth age. Such relations were not observed for the cerebral cortex or white matter volume, surface area, or diffusion quantities. CONCLUSIONS: The results of our study show that perinatal influences that are not primarily neurologic are still able to disturb long-term neurodevelopment, particularly of the developing cerebellum. Including the cerebellum in future neuroprotective strategies seems therefore essential.

Analgosedation in paediatric severe traumatic brain injury (TBI): practice, pitfalls and possibilities.

Analgosedation is a fundamental part of traumatic brain injury (TBI) treatment guidelines, encompassing both first and second tier supportive strategies. Worldwide analgosedation practices continue to be heterogeneous due to the low level of evidence in treatment guidelines (level III) and the choice of analgosedative drugs is made by the treating clinician. Current practice is thus empirical and may result in unfavourable (often hemodynamic) side effects. This article presents an overview of current analgosedation practices in the paediatric intensive care unit (PICU) and addresses pitfalls both in the short and long term. We discuss innovative (pre-)clinical research that can provide the framework for initiatives to improve our pharmacological understanding of analgesic and sedative drugs used in paediatric severe TBI and ultimately facilitate steps towards evidence-based and precision pharmacotherapy in this vulnerable patient group.

Intravenous Paracetamol Dosing Guidelines for Pain Management in (pre)term Neonates Using the Paediatric Study Decision Tree.

BACKGROUND: Intravenous paracetamol (acetaminophen) has not been licensed for analgesia in preterm neonates or infants < 2 years, respectively, in Europe and the United States. A variety of dosing regimens is therefore used off-label. Because evidence supports the use of the same target mean steady state paracetamol concentration (Cssmean, 9-11 mg/L) for pain relief in neonates compared to older children and adults, dosing regimens based on this Cssmean were evaluated in a two-step approach. METHODS: First, a systematic search was performed to provide pharmacokinetic (PK)-based dosing guidelines for pain in neonates (with subsequent searches on safety in these papers). Second, concentration-time profiles based on these dosing guidelines were generated to provide a dosing advice for paracetamol to treat neonatal pain. RESULTS: Of 2334 potentially relevant articles, 9 studies were included. For typical term neonates, dosages specified in packaging (labels) resulted in Cssmean below target (7.65 mg/L), while dosages from investigator-initiated studies resulted in either a Cssmean above (15.31), or around the target (11.78 and 10.21) for (pre)term neonates >32 weeks. Only one study suggested a dosing resulting in a tailored concentration (8.7) in preterm neonates <32 weeks. CONCLUSION: A loading dose 20 mg/kg, followed by 10 mg/kg/6h is recommended for 32-44 weeks' neonates, which is supported by short-term safety. For neonates < 32 weeks, a loading dose of 12 mg/kg and a maintenance dose of 6mg/kg/6h seems to lead to the target Cssmean, though additional clinical studies are needed to support its safety.

Neonatal Plasticity of the Nociceptive System: Mechanisms, Effects, and Treatment of Repetitive Painful Procedures During NICU Admittance.

INTRODUCTION: In the Neonatal Intensive Care Unit (NICU), prematurely born infants undergo a range of skin breaking and painful procedures. At the same time, the spinal nociceptive system is in a sensitive developmental stage. Both neonatal repetitive painful procedures and their treatment can induce plasticity of the neonatal spinal nociceptive system, causing long-lasting alterations to pain processing and pain reactivity. METHODS: This review focuses on developmental processes related to the nociceptive network in the spinal dorsal horn and more specifically at mechanisms related to 1. Modulation of afferent systems; 2. The role of interneurons; 3. Descending inhibitory pathways; and 4. The central neuro-immune responses and microglial cell responses. The effects and possible mechanisms underlying the long-term effects of repetitive painful procedures on the developing nociceptive system as well as subsequent pharmacological treatment (acetaminophen, morphine) in early life are discussed. RESULTS: Repetitive stimulation of the nociceptive system in a rat model with use of needle pricks in the hind-paw closely mimics the clinical situation for infants in the NICU. CONCLUSION: Activity dependent plasticity in early postnatal life induces long-lasting alterations that then may cause altered pain perception in adulthood. For a future choice of optimal analgesic drugs these considerations have to be taken into account beyond the classical classes of drugs used nowadays.

Therapeutic Drug Monitoring in Neonates: What Makes them Unique?

INTRODUCTION: Therapeutic drug monitoring (TDM) refers to the interpretation of quantified drug concentrations in strategically timed samples of bodily fluids, with the aim to maximize therapeutic benefit, while minimizing toxicity. In essence, TDM criteria for neonates are similar to those for adults, but specific issues should be considered. This review focusses on the relevance of these specific issues: larger variability in pharmacokinetics (PK), and non-PK related factors, sampling opportunities, analytical techniques, therapeutic range. Specific issues: Larger variability in PK, and non-PK related factors in neonates compared to adults result in a less clear relation between the administered dose and the concentration measured. Sophisticated dosing regimens derived from population PK-models can partly overcome this variability, thereby reducing the need for TDM. Dosing can be further individualized using Bayesian forecasting as a tool for TDM. Besides PK related factors, concentrations of endogenous substances (e.g. immunoglobulin A, plasma protein) in neonates differ from those in adults, which may complicate interpretation of measured drug concentrations. Blood sampling opportunities in neonates are limited by the small blood volume and the need to minimize painful procedures. Dried blood spot sampling may be less invasive. This method has been facilitated by more sensitive analytical techniques, such as chromatography followed by mass spectrometry. For the same reason, saliva is gaining attention as an alternative non-invasive bodily fluid. Lastly, reference values for therapeutic ranges of drugs in neonates are mostly adapted from adult studies, although pharmacodynamics may be quite different in neonates. This review concludes with recommendations for future research on these specific issues.

Population pharmacokinetics of haloperidol in terminally ill adult patients.

PURPOSE: Over 80% of the terminally ill patients experience delirium in their final days. In the treatment of delirium, haloperidol is the drug of choice. Very little is known about the pharmacokinetics of haloperidol in this patient population. We therefore designed a population pharmacokinetic study to gain more insight into the pharmacokinetics of haloperidol in terminally ill patients and to find clinically relevant covariates that may be used in developing an individualised dosing regimen. METHODS: Using non-linear mixed effects modelling (NONMEM 7.2), a population pharmacokinetic analysis was conducted with 87 samples from 28 terminally ill patients who received haloperidol either orally or subcutaneously. The covariates analysed were patient and disease characteristics as well as co-medication. RESULTS: The data were accurately described by a one-compartment model. The population mean estimates for oral bioavailability, clearance and volume of distribution for an average patient were 0.86 (IIV 55%), 29.3 L/h (IIV 43%) and 1260 L (IIV 70%), respectively. This resulted in an average terminal half-life of haloperidol of around 30 h. CONCLUSION: Our study showed that the pharmacokinetics of haloperidol could be adequately described by a one-compartment model. The pharmacokinetics in terminally ill patients was comparable to other patients. We were not able to explain the wide variability using covariates.

Changes in thyroid hormone concentrations during neonatal extracorporeal membrane oxygenation.

OBJECTIVE: Thyroid hormone concentrations can be disturbed during critical illness. Our aim was to determine changes in thyroid hormone concentrations during neonatal extracorporeal membrane oxygenation (ECMO). STUDY DESIGN: We included 21 ECMO-treated neonates. Age-specific s.d. scores (SDS) of free and total thyroxine (FT4; TT4), reverse and total triiodothyronine (rT3; TT3), thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) were determined at six fixed time-points. Data were analyzed using general linear models. RESULTS: At baseline, mean SDS FT4 (-0.78, 95% CI: -1.37 to -0.19), TT4 (-1.97, 95% CI: -2.76 to -1.18), TT3 (-0.88, 95% CI: -1.13 to -0.63), TSH (-2.14, 95% CI: -2.93 to -1.35) and TBG (-3.52, 95% CI: -4.55 to -2.50) were low with high mean SDS rT3 (0.53, 95% CI: 0.28 to 0.78). One hour after start ECMO, TT4, TSH and TBG had further declined; 12 h after start ECMO TT3 had declined (all P<0.05). After this decline, mean SDS TSH increased to the baseline level 12 h after start ECMO (-2.50, 95% CI: -3.22 to -1.79), and was higher than baseline 48 h after start ECMO (-0.56, 95% CI: -1.29 to 0.17). This TSH increase was followed by increases in TT4 and TT3. FT4 remained constant within the normal range during ECMO. CONCLUSIONS: Thyroid hormone concentrations before ECMO were suggestive of non-thyroidal illness syndrome (NTIS). During ECMO, increases in TSH, TT4 and TT3 after an initial decline possibly reflect spontaneous restoration of the hypothalamic-pituitary-thyroid axis. FT4 remained constant within the normal range. This suggests that thyroxine therapy is not required during ECMO.

Adherence to All Steps of a Pain Management Protocol in Intensive Care Patients after Cardiac Surgery Is Hard to Achieve.

Purpose. To investigate adherence to our pain protocol considering analgesics administration, number and timing of pain assessments, and adjustment of analgesics upon unacceptably high (NRS ≥ 4) and low (NRS ≤ 1) pain scores. Material and Methods. The pain protocol for patients in the intensive care unit (ICU) after cardiac surgery consisted of automated prescriptions for paracetamol and morphine, automated reminders for pain assessments, a flowchart to guide interventions upon high and low pain scores, and reassessments after unacceptable pain. Results. Paracetamol and morphine were prescribed in all 124 patients. Morphine infusion was stopped earlier than protocolized in 40 patients (32%). During the median stay of 47 hours [IQR 26 to 74 hours], 702/706 (99%) scheduled pain assessments and 218 extra pain scores were recorded. Unacceptably high pain scores accounted for 96/920 (10%) and low pain scores for 546/920 (59%) of all assessments. Upon unacceptable pain additional morphine was administered in 65% (62/96) and reassessment took place in 15% (14/96). Morphine was not tapered in 273 of 303 (90%) eligible cases of low pain scores. Conclusions. Adherence to automated prescribed analgesics and pain assessments was good. Adherence to nonscheduled, flowchart-guided interventions was poor. Improving adherence may refine pain management and reduce side effects.

Children's outcomes at 2-year follow-up after 4 years of structured multi-professional medical-ethical decision-making in a neonatal intensive care unit.

OBJECTIVE: We reviewed our decisions about continuation/withdrawal of life-sustaining treatments in a group of critically ill newborns who were discussed in structured medical ethical decision-making meetings, and provide the surviving children's outcomes at 2-year follow-up. STUDY DESIGN: In an explorative observational study, 61 cases were evaluated. The children involved had been discussed in such a structured way from 2009 to 2012 in a level III-D neonatal intensive care unit. RESULTS: Decisions made were: full treatment (n=6), earlier restriction cancelled (n=3), treatment restriction (n=30) and palliative care (n=22). Parents of six children disagreed with the decision proposed. Thirteen (54%) of the 24 children who survived (39%) had moderate to severe neurological problems; 8 (33%) had additional sequelae; only one 2-year-old child was healthy. CONCLUSIONS: Decisions made varied to a large extent. The poor outcomes should be disseminated among decision makers. Future studies must explore new ways to improve outcome prediction, extend follow-up periods and consider what living with severe handicaps really means for both child and family.

Morphine Pharmacodynamics in Mechanically Ventilated Preterm Neonates Undergoing Endotracheal Suctioning.

To date, morphine pharmacokinetics (PKs) are well quantified in neonates, but results about its efficacy are ambiguous. This work presents an analysis of a previously published study on pain measurements in mechanically ventilated preterm neonates who received either morphine or placebo to improve comfort during invasive ventilation. The research question was whether morphine reduces the pain associated with endotracheal or nasal suctioning before, during, and after suctioning. Because these neonates cannot verbalize their pain levels, pain was assessed on the basis of several validated pain measurement instruments (i.e., COMFORT-B, preterm infant pain profile [PIPP], Neonatal Infant Pain Scale (NIPS), and visual analogue scale (VAS)). The item response theory (IRT) was used to analyze the data in order for us to handle the data from multiple-item pain scores. The analysis showed an intra-individual relationship between morphine concentrations and pain reduction, as measured by COMFORT-B and VAS. However, the small magnitude of the morphine effect was not considered clinically relevant for this intervention in preterm neonates.