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Many pediatric intensive care units use the COMFORT-Behavior scale (COMFORT-B) to assess pain in 0- to 3-year-old children. The objective of this study was to determine whether this scale is also valid for the assessment of pain in 0- to 3-year-old children with Down syndrome. These children often undergo cardiac or intestinal surgery early in life and therefore admission to a pediatric intensive care unit. Seventy-six patients with Down syndrome were included and 466 without Down syndrome. Pain was regularly assessed with the COMFORT-B scale and the pain Numeric Rating Scale (NRS). For either group, confirmatory factor analyses revealed a 1-factor model. Internal consistency between COMFORT-B items was good (Cronbach's α=0.84-0.87). Cutoff values for the COMFORT-B set at 17 or higher discriminated between pain (NRS pain of 4 or higher) and no pain (NRS pain below 4) in both groups. We concluded that the COMFORT-B scale is also valid for 0- to 3-year-old children with Down syndrome. This makes it even more useful in the pediatric intensive care unit setting, doing away with the need to apply another instrument for those children younger than 3. [ABSTRACT FROM AUTHOR]

Introduction: Midazolam-based continuous intravenous sedation in patients admitted to the intensive care unit (ICU) was a necessity during the COVID-19 pandemic. However, benzodiazepine-based sedation is associated with a high incidence of benzodiazepine-related delirium and additional days on mechanical ventilation. Due to the requirement of high midazolam doses in combination with the impaired renal clearance (CL) of the pharmacological active metabolite 1-OH-midazolam-glucuronide (10% compared to midazolam), ICU patients with COVID-19 and continuous renal replacement therapy (CRRT) were at risk of unintended prolonged sedation. Several CRRT-related factors may have influenced the delivered CL of midazolam and its metabolites. Therefore, the aim of the study was to identify and describe these CRRT-related factors., Methods: Pre-filter blood samples and ultrafiltrate samples were collected simultaneously. Midazolam, 1-OH-midazolam, and 1-OH-midazolam-glucuronide plasma samples were analyzed using an UPLC-MS/MS method. The prescribed CRRT dose was corrected for downtime and filter integrity using the urea ratio (urea concentration in effluent/urea concentration plasma). CL of midazolam and its metabolites were calculated with the delivered CRRT dose (corrected for downtime and saturation coefficient [SD])., Results: Three patients on continuous venovenous hemodialysis (CVVHD) and 2 patients on continuous venovenous hemodiafiltration (CVVHDF) were included. Midazolam, 1-OH-midazolam, and 1-OH-midazolam-glucuronide concentrations were 2,849 (0-6,700) μg/L, 153 (0-295) μg/L, and 27,297 (1,727-39,000) μg/L, respectively. The SD was 0.03 (0.02-0.03) for midazolam, 0.05 (0.05-0.06) for 1-OH-midazolam, and 0.33 (0.23-0.43) for 1-OH-midazolam-glucuronide. The delivered CRRT CL was 1.4 (0-1.7) mL/min for midazolam, 2.7 (0-3.5) mL/min for 1-OH-midazolam, and 15.7 (4.0-27.7) mL/min for 1-OH-midazolam-glucuronide., Conclusions: Midazolam and 1-OH-midazolam were not removed during CVVHD and CVVHDF. However, 1-OH-midazolam-glucuronide was removed reasonably, approximately up to 43%. CRRT modality, filter integrity, and downtime affect this removal. These data imply a personalized titration of midazolam in critically ill patients with renal failure and awareness for the additional sedative effects of its active metabolites., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: In hospitalized patients with COVID-19, the dosing and timing of corticosteroids vary widely. Low-dose dexamethasone therapy reduces mortality in patients requiring respiratory support, but it remains unclear how to treat patients when this therapy fails. In critically ill patients, high-dose corticosteroids are often administered as salvage late in the disease course, whereas earlier administration may be more beneficial in preventing disease progression. Previous research has revealed that increased levels of various biomarkers are associated with mortality, and whole blood transcriptome sequencing has the ability to identify host factors predisposing to critical illness in patients with COVID-19., Objective: Our goal is to determine the most optimal dosing and timing of corticosteroid therapy and to provide a basis for personalized corticosteroid treatment regimens to reduce morbidity and mortality in hospitalized patients with COVID-19., Methods: This is a retrospective, observational, multicenter study that includes adult patients who were hospitalized due to COVID-19 in the Netherlands. We will use the differences in therapeutic strategies between hospitals (per protocol high-dose corticosteroids or not) over time to determine whether high-dose corticosteroids have an effect on the following outcome measures: mechanical ventilation or high-flow nasal cannula therapy, in-hospital mortality, and 28-day survival. We will also explore biomarker profiles in serum and bronchoalveolar lavage fluid and use whole blood transcriptome analysis to determine factors that influence the relationship between high-dose corticosteroids and outcome. Existing databases that contain routinely collected electronic data during ward and intensive care admissions, as well as existing biobanks, will be used. We will apply longitudinal modeling appropriate for each data structure to answer the research questions at hand., Results: As of April 2023, data have been collected for a total of 1500 patients, with data collection anticipated to be completed by December 2023. We expect the first results to be available in early 2024., Conclusions: This study protocol presents a strategy to investigate the effect of high-dose corticosteroids throughout the entire clinical course of hospitalized patients with COVID-19, from hospital admission to the ward or intensive care unit until hospital discharge. Moreover, our exploration of biomarker and gene expression profiles for targeted corticosteroid therapy represents a first step towards personalized COVID-19 corticosteroid treatment., Trial Registration: ClinicalTrials.gov NCT05403359; https://clinicaltrials.gov/ct2/show/NCT05403359., International Registered Report Identifier (irrid): DERR1-10.2196/48183., (©Katrijn Daenen, Jilske A Huijben, Anders Boyd, Lieuwe D J Bos, Sara C M Stoof, Hugo van Willigen, Diederik A M P J Gommers, Hazra S Moeniralam, Corstiaan A den Uil, Nicole P Juffermans, Merijn Kant, Abraham J Valkenburg, Janesh Pillay, David M P van Meenen, Frederique Paulus, Marcus J Schultz, Virgil A S H Dalm, Eric C M van Gorp, Janke Schinkel, Henrik Endeman, PRoVENT- and PRoAcT-COVID Collaborative Group. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 02.06.2023.)

Background and Objective: Many patients treated for COVID-19 related acute respiratory distress syndrome in the intensive care unit are sedated with the benzodiazepine midazolam. Midazolam undergoes extensive metabolism by CYP3A enzymes, which may be inhibited by hyperinflammation. Therefore, an exaggerated proinflammatory response, as often observed in COVID-19, may decrease midazolam clearance. To develop a population pharmacokinetic model for midazolam in adult intensive care unit patients infected with COVID-19 and to assess the effect of inflammation, reflected by IL-6, on the pharmacokinetics of midazolam., Methods: Midazolam blood samples were collected once a week between March 31 and April 30 2020. Patients were excluded if they concomitantly received CYP3A4 inhibitors, CYP3A4 inducers and/or continuous renal replacement therapy. Midazolam and metabolites were analyzed with an ultra-performance liquid chromatography-tandem mass spectrometry method. A population pharmacokinetic model was developed, using nonlinear mixed effects modelling. IL-6 and CRP, markers of inflammation, were analyzed as covariates., Results: The data were described by a one-compartment model for midazolam and the metabolites 1-OH-midazolam and 1-OH-midazolam-glucuronide. The population mean estimate for midazolam clearance was 6.7 L/h (4.8-8.5 L/h). Midazolam clearance was reduced by increased IL-6 and IL-6 explained more of the variability within our patients than CRP. The midazolam clearance was reduced by 24% (6.7-5.1 L/h) when IL-6 increases from population median 116 to 300 pg/mL., Conclusions: Inflammation, reflected by high IL-6, reduces midazolam clearance in critically ill patients with COVID-19. This knowledge may help avoid oversedation, but further research is warranted., (© 2022. The Author(s).)

Background: Morphine is commonly used for postoperative analgesia in children. Here we studied the pharmacodynamics of morphine in children after cardiac surgery receiving protocolized morphine., Methods: Data on morphine rescue requirements guided by validated pain scores in children (n = 35, 3-36 months) after cardiac surgery receiving morphine as loading dose (100 μg kg -1 ) with continuous infusion (40 μg kg -1  h -1 ) from a previous study on morphine pharmacokinetics were analysed using repeated time-to-event (RTTE) modelling., Results: During the postoperative period (38 h (IQR 23-46)), 130 morphine rescue events (4 (IQR 1-5) per patient) mainly occurred in the first 24 h (107/130) at a median morphine concentration of 29.5 ng ml -1 (range 7-180 ng ml -1 ). In the RTTE model, the hazard of rescue morphine decreased over time (half-life 18 h; P < 0.001), while the hazard for rescue morphine (21.9% at 29.5 ng ml -1 ) increased at higher morphine concentrations (P < 0.001)., Conclusions: In this study on protocolized morphine analgesia in children, rescue morphine was required at a wide range of morphine concentrations and further increase of the morphine concentration did not lead to a decrease in hazard. Future studies should focus on a multimodal approach using other opioids or other analgesics to treat breakthrough pain in children., Impact: In children receiving continuous morphine infusion, administration of rescue morphine is an indicator for insufficient effect or an event. Morphine rescue events were identified at a wide range of morphine concentrations upon a standardized pain protocol consisting of continuous morphine infusion and morphine as rescue boluses. The expected number of rescue morphine events was found to increase at higher morphine concentrations. Instead of exploring more aggressive morphine dosing, future research should focus on a multimodal approach to treat breakthrough pain in children., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objectives: To compare the pharmacokinetics and pharmacodynamics of IV midazolam after cardiac surgery between children with and without Down syndrome., Design: Prospective, single-center observational trial., Setting: PICU in a university-affiliated pediatric teaching hospital., Patients: Twenty-one children with Down syndrome and 17 without, 3-36 months, scheduled for cardiac surgery with cardiopulmonary bypass., Interventions: Postoperatively, nurses regularly assessed the children's pain and discomfort with the validated COMFORT-Behavioral scale and Numeric Rating Scale for pain. A loading dose of morphine (100 µg/kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 µg/kg/hr. Midazolam was started if COMFORT-Behavioral scale score of greater than 16 and Numeric Rating Scale score of less than 4 (suggestive of undersedation). Plasma midazolam and metabolite concentrations were measured for population pharmacokinetic- and pharmacodynamic analysis using nonlinear mixed effects modeling (NONMEM) (Version VI; GloboMax LLC, Hanover, MD) software., Measurements and Main Results: Twenty-six children (72%) required midazolam postoperatively (15 with Down syndrome and 11 without; p = 1.00). Neither the cumulative midazolam dose (p = 0.61) nor the time elapsed before additional sedation was initiated (p = 0.71), statistically significantly differed between children with and without Down syndrome. Population pharmacokinetic and pharmacodynamics analysis revealed no statistically significant differences between the children with and without Down syndrome. Bodyweight was a significant covariate for the clearance of 1-OH-midazolam to 1-OH-glucuronide (p = 0.003). Pharmacodynamic analysis revealed a marginal effect of the midazolam concentration on the COMFORT-Behavioral score., Conclusions: The majority of children with and without Down syndrome required additional sedation after cardiac surgery. This pharmacokinetic and pharmacodynamic analysis does not provide evidence for different dosing of midazolam in children with Down syndrome after cardiac surgery., Competing Interests: Drs. Valkenburg’s and Peeters’s institutions received funding from National Children’s Research Centre, Dublin, Ireland. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Introduction: Enhanced clinical outcomes in the Paediatric Intensive Care Unit following standardisation of analgesia and sedation practice are reported. Little is known about the impact of standardisation of analgesia and sedation practice including incorporation of a validated distress assessment instrument on infants post cardiac surgery, a subset of whom have Trisomy 21. This study investigated whether the parallel introduction of nurse-led analgesia and sedation guidelines including regular distress assessment would impact on morphine administered to infants post cardiac surgery, and whether any differences observed would be amplified within the Trisomy 21 population., Methodology: A retrospective single centre before/after study design was used. Patients aged between 44 weeks postconceptual age and one year old who had open cardiothoracic surgery were included., Results: 61 patients before and 64 patients after the intervention were included. After the intervention, a reduction in the amount of morphine administered was not evident, while greater use of adjuvant sedatives and analgesics was observed. Patients with Trisomy 21 had a shorter duration of mechanical ventilation after the change in practice., Conclusion: The findings from this study affirm the importance of the nurses' role in managing prescribed analgesia and sedation supported by best available evidence. A continued education and awareness focus on analgesia and sedation management in the pursuit of best patient care is imperative., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Titrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study is to explore the concentration-effect relationship for morphine-associated oversedation after cardiac surgery in children aged 3 months to 3 years. Data on morphine dosing, as well as morphine plasma concentrations, were available from a previous study on the pharmacokinetics of morphine after cardiac surgery in children. Oversedation was defined as scores below 11 on the validated COMFORT-behavioral scale. Population pharmacokinetic-pharmacodynamic modeling was performed in NONMEM 7.3. The probability of oversedation as a function of morphine concentration was best described using a step function in which the EC 50 was 46.3 ng/mL. At morphine concentrations below the EC 50 , the probability of oversedation was 2.9% (0.4& to 18%), whereas above the EC 50 percentages were 13% (1.9% to 52%) (median value [95% prediction interval from interindividual variability]). Additionally, the risk of oversedation was found to be increased during the first hours after surgery (P < .001) and was significantly lower during mechanical ventilation (P < .005). We conclude that morphine concentrations above approximately 45 ng/mL may increase the probability of oversedation in children after cardiac surgery. The clinician must evaluate, on a case-by-case basis, whether the analgesic benefits arising from dosing regimen associated with such concentrations outweigh the risks., (© 2020, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

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., (© 2019, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Background: The clinical relevance of the suggested hyperalgesic effects of remifentanil is still unclear, especially in the long term., Objective: The current study evaluated the impact of remifentanil on thermal thresholds 3 days and 12 months after surgery, measured with Quantitative Sensory Testing., Design: A single-blind, randomised controlled trial., Setting: A tertiary care teaching hospital in The Netherlands, from 2014 to 2016., Patients: A total of 126 patients aged between 18 and 85 years, undergoing cardiothoracic surgery via sternotomy (coronary artery bypass grafts and/or valve replacement) were included. Exclusion criteria were BMI above 35 kg m, history of cardiac surgery, chronic pain conditions, neurological conditions, allergy to opioids or paracetamol, language barrier and pregnancy., Interventions: Patients were allocated randomly to receive intra-operatively either a continuous remifentanil infusion or intermittent intra-operative fentanyl as needed in addition to standardised anaesthesia with propofol and intermittent intravenous fentanyl at predetermined time points., Main Outcome Measures: Warm and cold detection and pain thresholds 3 days and 12 months after surgery. In addition the use of remifentanil, presence of postoperative chronic pain, age, opioid consumption and pre-operative quality of life were tested as a predictor for altered pain sensitivity 12 months after surgery., Results: Both warm and cold detection, and pain thresholds, were not significantly different between the remifentanil and fentanyl groups 3 days and 12 months after surgery (P > 0.05). No significant predictors for altered pain sensitivity were identified., Conclusion: Earlier reports of increased pain sensitivity 1 year after the use of remifentanil could not be confirmed in this randomised study using Quantitative Sensory Testing. This indicates that remifentanil plays a minor role in the development of chronic thoracic pain. Still, the relatively high incidence of chronic thoracic pain and its accompanying impact on quality of life remain challenging problems., Trial Registration: The study was registered at EudraCT (ref: 2013-000201-23) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02031016).

Aims: Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice., Methods: The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77-90 kg, C-reactive protein level 0.1-341 mg l -1 and 0-4 failing organs) using graphical and numerical diagnostics., Results: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) <30%]. Using the model for extrapolation resulted in well-predicted clearance values in critically ill and healthy adults (MPE <30%), while clearance in preterm neonates was over predicted (MPE >180%)., Conclusion: The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates., (© 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Quantitative sensory testing (QST) is often used to measure children's and adults' detection- and pain thresholds in a quantitative manner. In children especially the Thermal Sensory Analyzer (TSA-II) is often applied to determine thermal detection and pain thresholds. As comparisons between studies are hampered by the different testing protocols used, we aimed to present a standard protocol and reference values for thermal detection- and pain thresholds in children., Methods: Our standard testing protocol includes reaction time dependent and independent tests and takes about 14-18 min to complete. Reference values were obtained from a sample of 69 healthy term born children and adolescents with a median age of 11.2 years (range 8.2 to 17.9 years old). Seventy-one children were recruited and data of 28 males and 41 females was obtained correctly. We studied possible age and sex differences., Results: This study provides Dutch reference values and presents a standard quantitative sensory testing protocol for children with an age from 8 years onwards. This protocol appeared to be feasible, since only two out of 71 participants were not able to correctly complete the protocol due to attention deficits and were therefore excluded. We found some significant age and sex differences: females were statistically significantly more sensitive for both cold and heat pain compared to males, and the youngest children (8-9 years old) were less sensitive to detect a warm stimulus. The youngest children tend to be more sensitive to heat pain in comparison to older participants, although the difference was not statistically significant., Conclusions: We present a feasible thermal quantitative sensory testing protocol for children and reference values that are easy to interpret and may serve as normative values for future studies.

Objective: To compare the pharmacodynamics and pharmacokinetics of IV morphine after cardiac surgery in two groups of children-those with and without Down syndrome., Design: Prospective, single-center observational trial., Setting: PICU in a university-affiliated pediatric teaching hospital., Patients: Twenty-one children with Down syndrome and 17 without, 3-36 months old, scheduled for cardiac surgery with cardiopulmonary bypass., Interventions: A loading dose of morphine (100 μg/kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 μg/kg/hr. During intensive care, nurses regularly assessed pain and discomfort with validated observational instruments (COMFORT-Behavior scale and Numeric Rating Scale-for pain). These scores guided analgesic and sedative treatment. Plasma samples were obtained for pharmacokinetic analysis., Measurements and Main Results: Median COMFORT-Behavior and Numeric Rating Scale scores were not statistically significantly different between the two groups. The median morphine infusion rate during the first 24 hours after surgery was 31.3 μg/kg/hr (interquartile range, 23.4-36.4) in the Down syndrome group versus 31.7 μg/kg/hr (interquartile range, 25.1-36.1) in the control group (p = 1.00). Population pharmacokinetic analysis revealed no statistically significant differences in any of the pharmacokinetic variables of morphine between the children with and without Down syndrome., Conclusions: This prospective trial showed that there are no differences in pharmacokinetics or pharmacodynamics between children with and without Down syndrome if pain and distress management is titrated to effect based on outcomes of validated assessment instruments. We have no evidence to adjust morphine dosing after cardiac surgery in children with Down syndrome.

Aim: The aim of this study was to compare thermal detection and pain thresholds in children with Down syndrome with those of their siblings., Method: Sensory detection and pain thresholds were assessed in children with Down syndrome and their siblings using quantitative testing methods. Parental questionnaires addressing developmental age, pain coping, pain behaviour, and chronic pain were also utilized., Results: Forty-two children with Down syndrome (mean age 12y 10mo) and 24 siblings (mean age 15y) participated in this observational study. The different sensory tests proved feasible in 13 to 29 (33-88%) of the children with Down syndrome. These children were less sensitive to cold and warmth than their siblings, but only when measured with a reaction time-dependent method, and not with a reaction time-independent method. Children with Down syndrome were more sensitive to heat pain, and only 6 (14%) of them were able to adequately self-report pain, compared with 22 (92%) of siblings (p<0.001)., Interpretation: Children with Down syndrome will remain dependent on pain assessment by proxy, since self-reporting is not adequate. Parents believe that their children with Down syndrome are less sensitive to pain than their siblings, but this was not confirmed by quantitative sensory testing., (© 2015 Mac Keith Press.)

This critical opinion article deals with the challenges of finding the most effective pharmacotherapeutic options for the management of pain in intellectually disabled children and provides recommendations for clinical practice and research. Intellectual disability can be caused by a wide variety of underlying diseases and may be associated with congenital anomalies such as cardiac defects, small-bowel obstructions or limb abnormalities as well as with comorbidities such as scoliosis, gastro-esophageal reflux disease, spasticity, and epilepsy. These conditions themselves or any necessary surgical interventions are sources of pain. Epilepsy often requires chronic pharmacological treatment with antiepileptic drugs. These antiepileptic drugs can potentially cause drug-drug interactions with analgesic drugs. It is unfortunate that children with intellectual disabilities often cannot communicate pain to caregivers. Although these children are at high risk of experiencing pain, researchers nevertheless often have to exclude them from trials on pain management because of ethical considerations. We therefore make a plea for prescribers, researchers, patient organizations, pharmaceutical companies, and policy makers to study evidence-based, safe and effective pharmacotherapy in these children through properly designed studies. In the meantime, parents and clinicians must resort to validated pain assessment tools such as the revised FLACC scale.

Short-term and long-term effects of neonatal pain and its analgesic treatment have been topics of translational research over the years. This study aimed to identify the long-term effects of continuous morphine infusion in the neonatal period on thermal pain sensitivity, the incidence of chronic pain, and neurological functioning. Eighty-nine of the 150 participants of a neonatal randomized controlled trial on continuous morphine infusion versus placebo during mechanical ventilation underwent quantitative sensory testing and neurological examination at the age of 8 or 9 years. Forty-three children from the morphine group and 46 children from the placebo group participated in this follow-up study. Thermal detection and pain thresholds were compared with data from 28 healthy controls. Multivariate analyses revealed no statistically significant differences in thermal detection thresholds and pain thresholds between the morphine and placebo groups. The incidence of chronic pain was comparable between both groups. The neurological examination was normal in 29 (76%) of the children in the morphine group and 25 (61%) of the children in the control group (P = .14). We found that neonatal continuous morphine infusion (10 μg/kg/h) has no adverse effects on thermal detection and pain thresholds, the incidence of chronic pain, or overall neurological functioning 8 to 9 years later. Perspective: This unique long-term follow-up study shows that neonatal continuous morphine infusion (10 μg/kg/h) has no long-term adverse effects on thermal detection and pain thresholds or overall neurological functioning. These findings will help clinicians to find the most adequate and safe analgesic dosing regimens for neonates and infants., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Information about pain prevalence in institutionalized individuals with intellectual disabilities is scarce, most likely because communication problems impede pain assessment. We aimed to inventory pain prevalence and actual pain management in intellectually disabled individuals living in a representative special care facility in the Netherlands. Caregivers rated the residents' present pain and overall pain during the preceding week on an 11-point numerical rating scale (NRS-11). In addition, behavioral pain assessment was performed with validated pain scales; the Rotterdam Elderly Pain Observation Scale (REPOS) or Checklist Pain Behavior (CPG). Ratings suggested that 47 of the 255 included residents (18%) suffered from pain either at present or during the preceding week, 14 of whom (30%) experienced pain on both occasions. Most of these 47 (85%) residents with pain had no analgesic prescription, not even in the case of severe pain (NRS 7 or higher). Ratings for nearly one out of every five residents suggested they suffered pain. This proportion is lower than in other studies and could imply that caregivers probably underestimate residents' prevalence of pain. Pain treatment might be inadequate in light of the low percentage of analgesic prescriptions. To prevent unnecessary suffering in institutes for residents with an intellectual disability (ID) we recommend use of a pain protocol including a validated pain measurement instrument., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Morphine is widely used to treat severe pain in neonatal intensive care unit patients. Animal studies suggest adverse long-term side effects of neonatal morphine, but a follow-up study of 5-year-old children who participated in a morphine-placebo controlled trial as newborns found no such effects on the child's general functioning. This study indicated that morphine may negatively affect response inhibition, a domain of executive functions. Therefore, we performed a second follow-up study in the same population at the age of 8 to 9 years, focused on the child's general functioning in terms of intelligence, visual motor integration, and behavior and on executive functions. Children in the morphine group showed significantly less externalizing problems according to the parents but more internalizing behavior according to the teachers, but only after adjustment for intelligence quotient (IQ), potential confounders using a propensity score, and additional open-label morphine. Morphine-treated children showed significantly fewer problems with executive functions in daily life as rated by parents for the subscales inhibition and organization of materials and for planning/organizing as rated by the teachers. After adjustment for IQ and the propensity score, executive functioning as rated by the parents remained statistically significantly better in the morphine-treated group. The influence of the additional morphine given was not of a significant influence for any of the outcome variables. Overall, the present study demonstrates that continuous morphine infusion of 10 μg/kg/h during the neonatal period does not harm general functioning and may even have a positive influence on executive functions at 8 to 9 years., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Background:   Intellectually disabled children are more likely to undergo surgical interventions and almost all have comorbidities that need to be managed. Compared with controls, intellectually disabled children tend to receive less intraoperative analgesia and fewer of them are assessed for postoperative pain., Aim:   To evaluate perceptions and practices of anesthesiologists in the Netherlands concerning pain management in intellectually disabled children., Methods/materials:   We surveyed members of the Section on Pediatric Anesthesiology of the Netherlands Society of Anesthesiology in 2005 and 2009, using a self-designed questionnaire., Results:   The response rate was 47% in both years. In 2005, 32% of the anesthesiologists rated intellectually disabled children as 'more sensitive to pain' than nonintellectually disabled children--vs 25% in 2009. But no more than 7% in 2005 vs 6% in 2009 agreed with the statement 'children with intellectually disabled children need more analgesia'. Most anesthesiologists gave similar doses of intraoperative opioids for intellectually disabled and nonintellectually disabled children, 92% in 2005 vs 89% in 2009. In 2005, only 3% applied a pain assessment tool validated for intellectually disabled children, vs 4% in 2009., Conclusions: Anesthesiologists in the Netherlands take a different approach when caring for intellectually disabled children and they were not aware of pain observation scales for these children. However, the majority think that intellectually disabled children are not more sensitive to pain or require more analgesia. These opinions did not change over the 4-year period. One way to proceed is to implement validated pain assessment tools and to invest in education., (© 2012 Blackwell Publishing Ltd.)

Introduction: Pain is usually assessed by the interpretation of behavior, which can be subjective. Therefore, there is an ongoing search for more objective methods. Performance of skin conductance measurement as a pain assessment tool is variable, as some studies report low specificity and a low predictive value of the method. The aim of this pilot study was to test whether autoregulation of the skin temperature influences the skin conductance of pain-free infants., Results: Skin conductance was highly correlated with skin temperature in all subjects. Moreover, a significant change in all other vital parameters was observed on comparing before- and after-peak data., Discussion: These results indicate that sympathetic neural activity to maintain homeostasis (such as autoregulation of skin temperature) results in skin conductance peaks. Real-time evaluation of the sympathetic nervous system would be valuable for pain assessment. However, the technique should be better defined to increase both sensitivity and specificity for the measurement of pain before use in daily practice can be advocated., Methods: We included 11 infants, median (interquartile range (IQR)) age of 34 (13-76) d, who were admitted to the surgical high-care unit for monitoring after surgery. None was treated with opioids or sedatives, and observational pain scores were low.

Background: Reports conflict on optimal postoperative analgesic treatment in children with intellectual disability. We retrospectively compared postoperative analgesics consumption between neonates with and without Down's syndrome in relation to anaesthesia requirements and pain scores., Methods: We analysed hypnotic and analgesic drug administration, pain scores [COMFORT-Behaviour (COMFORT-B) scale], and duration of mechanical ventilation during the first 48 h after surgical repair of congenital duodenal obstruction in neonates, between 1999 and 2011. Data of 15 children with Down's syndrome were compared with data of 30 children without Down's syndrome., Results: General anaesthesia requirements did not differ. The median (inter-quartile range) maintenance dose of morphine during the first 24 h after operation was 9.5 (7.8-10.1) µg kg(-1) h(-1) in the Down's syndrome group vs 7.7 (5.0-10.0) µg kg(-1) h(-1) in the control group (P=0.46). Morphine doses at postoperative day 2 and COMFORT-B scores at day 1 did not significantly differ between the two groups. COMFORT-B scores at day two were lower in children with Down's syndrome (P=0.04). The duration of postoperative mechanical ventilation did not statistically differ between the two groups (P=0.89)., Conclusions: In this study, neonates with and without Down's syndrome received adequate postoperative analgesia, as judged from comparable analgesic consumption and pain scores. We recommend prospective studies in children of different age groups with Down's syndrome and in other groups of intellectually disabled children to provide further investigation of the hypothesis that intellectual disability predisposes to different analgesic requirements.

The primary focus of pain research in intellectually disabled individuals is still on pain assessment. Several observational pain assessment scales are available, each with its own characteristics, its own target group and its own validated use. Observational studies report differences in the treatment of intra- and postoperative pain of intellectually disabled children and almost all children with intellectual disability have comorbidities that need to be addressed. The scope of research has started to broaden. In this review we aim to answer the question: Can we integrate validated ways of pain assessment and postoperative pain treatment in intellectually disabled children to develop specific analgesic algorithms? Regrettably there is little knowledge on possible interaction effects and other relevant pharmacological issues. Possible genotype-phenotype associations related to pain in children with Down syndrome have several promises as six possible candidate genes are located on chromosome 21. In conclusion, the pain assessment tools for intellectually disabled children are there. We should now focus on tailoring the pain treatment. To this aim we need to perform pharmacokinetic and pharmacodynamic studies of analgesics and obtain information about the genotype-phenotype relationships for pain. This can lead to the development of specific analgesic algorithms.

Background: Very few data are available on the use of bispectral index (BIS) monitoring in children who are intellectually disabled. Epileptiform electroencephalogram activity, underlying cerebral pathology, or anticonvulsant/spasmolytic therapy might influence BIS monitoring. Our aim in this exploratory study was to first compare BIS values at 4 different stages of anesthesia between intellectually disabled children and controls. Our second aim was to investigate the discriminative properties of BIS between consciousness and unconsciousness for intellectually disabled children and for controls., Methods: Eighteen intellectually disabled children and 35 control children, aged 2-13 yr, were included. BIS values, landmark events, and standard monitoring values of vital functions were recorded throughout the whole procedure. The performance of BIS in distinguishing between a conscious and unconscious state was assessed from receiver operating characteristic curves., Results: Median (interquartile range) BIS values for the intellectually disabled group were significantly lower than those for controls in the awake state (72 [48-77] vs 97 [84-98], P < 0.001), during stable intraoperative anesthesia (34 [21-45] vs 43 [33-52], P = 0.02), and during return of consciousness (59 [36-68] vs 73 [64-78], P = 0.009). The discriminative properties of the BIS monitor for the state of consciousness were comparable between the 2 groups according to the receiver operating characteristic curves. Nevertheless, the optimal cutoff BIS value for discrimination between conscious and unconscious state was 28 points lower for the intellectually disabled group., Conclusions: We advise anesthesiologists to be alert to possible lower BIS values in intellectually disabled children. There is a risk that they will inadvertently misinterpret the state of consciousness in intellectually disabled children. New multicenter studies must find the optimal manner of evaluating (un)consciousness in intellectually disabled patients with documented and confirmed specific etiologies of their intellectual disability.