Gerbrich E. van den Bosch

Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery: A randomized controlled trial

IMPORTANCE Continuous morphine infusion as standard postoperative analgesic therapy in young infants is associated with unwanted adverse effects such as respiratory depression. OBJECTIVE To determine whether intravenous paracetamol (acetaminophen) would significantly (>30%) reduce morphine requirements in neonates and infants after major surgery. DESIGN, SETTING, AND PATIENTS Single-center, randomized, double-blind study conducted in a level 3 pediatric intensive care unit in Rotterdam, The Netherlands. Patients were 71 neonates or infants younger than 1 year undergoing major thoracic (noncardiac) or abdominal surgery between March 2008 and July 2010, with follow-up of 48 hours. INTERVENTIONS All patients received a loading dose of morphine 30 minutes before the end of surgery, followed by continuous morphine or intermittent intravenous paracetamol up to 48 hours postsurgery. Infants in both study groups received morphine (boluses and/or continuous infusion) as rescue medication on the guidance of the validated pain assessment instruments. MAIN OUTCOME MEASURES Primary outcome was cumulative morphine dose (study and rescue dose). Secondary outcomes were pain scores and morphine-related adverse effects. RESULTS The cumulative median morphine dose in the first 48 hours postoperatively was 121 (interquartile range, 99-264) μg/kg in the paracetamol group (n = 33) and 357 (interquartile range, 220-605) μg/kg in the morphine group (n = 38), P < .001, with a between-group difference that was 66% (95% CI, 34%-109%) lower in the paracetamol group. Pain scores and adverse effects were not significantly different between groups. CONCLUSION AND RELEVANCE Among infants undergoing major surgery, postoperative use of intermittent intravenous paracetamol compared with continuous morphine resulted in a lower cumulative morphine dose over 48 hours. TRIAL REGISTRATION trialregister.nl Identifier: NTR1438.

Brain connectivity during verbal working memory in children and adolescents

Working memory (WkM) is a fundamental cognitive process that serves as a building block for higher order cognitive functions. While studies have shown that children and adolescents utilize similar brain regions during verbal WkM, there have been few studies that evaluate the developmental differences in brain connectivity. Our goal was to study the development of brain connectivity related to verbal WkM in typically developing children and adolescents. Thirty‐five healthy children and adolescents, divided into three groups: 9–12 (children), 13–16 (young adolescents), and 17–19 (older adolescents) years, were included in this functional magnetic resonance imaging (fMRI) study. The verbal WkM task involved a modified Sternberg item recognition paradigm using three different loads. Brain connectivity analysis was performed using independent component analyses and regressing the components with the design matrix to determine task‐related networks. Connectivity analyses resulted in four components associated solely with encoding, four solely with recognition and two with both. Two networks demonstrated age‐related differences with respect to load, (1) the left motor area and right cerebellum, and 2) the left prefrontal cortex, left parietal lobe, and right cerebellum. Post hoc analyses revealed that the first network showed significant effects of age between children and the two older groups. There was increasing connectivity with increasing load for adolescents. The second network demonstrated age‐related differences between children and older adolescents. Children have higher task‐related connectivity at lower loads, but they tend to equalize with the adolescents with higher loads. Finally, a non‐load related network involving the orbital frontal and anterior cingulate cortices showed less connectivity in children. Hum Brain Mapp 35:698–711, 2014.

Pain insensitivity syndrome misinterpreted as inflicted burns

We present a case study of a 10-year-old child with severe burns that were misinterpreted as inflicted burns. Because of multiple injuries since early life, the family was under suspicion of child abuse and therefore under supervision of the Child Care Board for 2 years before the boy was burned. Because the boy incurred the burns without feeling pain, we conducted a thorough medical examination and laboratory testing, evaluated detection and pain thresholds, and used MRI to study brain morphology and brain activation patterns during pain between this patient and 3 healthy age- and gender-matched controls. We found elevated detection and pain thresholds and lower brain activation during pain in the patient compared with the healthy controls and reference values. The patient received the diagnosis of hereditary sensory and autonomic neuropathy type IV on the basis of clinical findings and the laboratory testing, complemented with the altered pain and detection thresholds and MRI findings. Hereditary sensory and autonomic neuropathy IV is a very rare congenital pain insensitivity syndrome characterized by the absence of pain and temperature sensation combined with oral mutilation due to unawareness, fractures, and anhidrosis caused by abnormalities in the peripheral nerves. Health care workers should be aware of the potential presence of this disease to prevent false accusations of child abuse.

Long-Term Effects of Neonatal Morphine Infusion on Pain Sensitivity: Follow-Up of a Randomized Controlled Trial

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.

Neuroimaging, Pain Sensitivity, and Neuropsychological Functioning in School-Age Neonatal Extracorporeal Membrane Oxygenation Survivors Exposed to Opioids and Sedatives.

Objectives: Animal studies found negative long-term effects of exposure to sedatives and opioids in early life, especially when administered in the absence of pain. Around the world, children who require extracorporeal membrane oxygenation receive opioids and sedatives for extended periods, generally in the absence of major pain as extracorporeal membrane oxygenation cannulation is considered minor surgery. Therefore, our objective was to determine the long-term effects of extracorporeal membrane oxygenation treatment with respect to pain sensitivity, brain functioning during pain, brain morphology, and neuropsychological functioning in humans. Design: Prospective follow-up study. Setting: Level III university hospital. Subjects: Thirty-six extracorporeal membrane oxygenation survivors (8.1–15.5 yr) and 64 healthy controls (8.2–15.3 yr). Measurements and Main Results: We measured detection and pain thresholds, brain activity during pain (functional MRI), brain morphology (high-resolution structural MRI), and neuropsychological functioning and collected information regarding the subject’s experience of chronic pain. We found a significant difference in the detection threshold for cold measured in a reaction time–dependent fashion (extracorporeal membrane oxygenation group, 29.9°C [SD, 1.4]; control group, 30.6°C [SD, 0.8]; p < 0.01), but no differences in other modalities or in pain sensitivity between groups. Furthermore, no differences in brain activation during pain, brain morphology, or in the occurrence of chronic pain were observed. However, extracorporeal membrane oxygenation survivors performed significantly worse on a verbal memory test compared with controls (p = 0.001). Conclusions: While the most critically ill newborns receive extracorporeal membrane oxygenation and, relatedly, large doses of opioids and sedatives for extended periods, global measures of pain sensitivity and neurobiological and neuropsychological development appear to have minor long-term consequences. Possible memory deficits in extracorporeal membrane oxygenation survivors require additional study, but neonatal extracorporeal membrane oxygenation treatment and associated exposure to opioids and sedatives seem less harmful to humans than expected from animal studies.

Long-term Effects of Early Exposure to Stress, Pain, Opioids and Anaesthetics on Pain Sensitivity and Neurocognition

Background Experimental studies have shown that neonatal exposure to stress, pain, opioids and anaesthetics may cause histologic and morphologic changes in the central nervous system with associated functional and behavioural changes in the long term. An important question is whether this holds true for humans also - and in particular for sick neonates who often are exposed to pain and receive anaesthetics and sedatives. Methods In this narrative review, we evaluate the effects of neonatal exposure to stress, pain, opioids and anaesthetics in infancy and childhood in animals and in preterm born and term born humans on pain sensitivity, brain morphology, cognition and behaviour later in life. Results In animals, neonatal exposure to stress, pain, opioids and early exposure to anaesthetics are associated with neurodegeneration and cognitive problems later in life. Human studies mainly focus on pain sensitivity, cognition and behaviour and find contradictory outcomes. Dramatic long-term effects found in animal studies could not be confirmed in human. Conclusion While studies in animals suggest neurotoxic effects of early exposure to stress, pain, opioids and anaesthetics, these effects seem clinically less relevant in humans. A possible reason is that the latter often receive opioids in the presence of pain and opioids and anaesthetics in balanced therapeutic dosages and with adequate monitoring of physiological parameters, in contrast to animal studies.