Potential Neurodevelopmental Effects of Pediatric Intensive Care Sedation and Analgesia: Repetitive Benzodiazepine and Opioid Exposure Alters Expression of Glial and Synaptic Proteins in Juvenile Rats

O'Meara, A M Iqbal; Ferguson, Nikki Miller; Zven, Sidney; Karam, Oliver; Meyer, Logan C.; Bigbee, John W.; Sato‐Bigbee, Carmen

doi:10.1097/cce.0000000000000105

Cited by 16 publications

(14 citation statements)

References 73 publications

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“…Interestingly, astrocytes also express TLR-4, and are important participants in, and modulators of, neuroinflammation through their expression of S100 calciumbinding protein (S100B) (Bowman et al, 2003;Van Eldik and Wainwright, 2003;Li et al, 2020). While opioids are typically associated with neuroinflammation through TLR4, Iqbal O'Meara et al (2020) found a significant increase in cerebral S100B levels in childhood-approximate rats treated with benzodiazepine. Exacerbated neuroinflammation may be a key mechanism by which sedatives contribute to intensive care neurologic morbidity, and because cholinergic signaling is antiinflammatory, the anticholinergic activity of some opioids and sedatives needs to be considered as well.…”

Section: Common Analgesics and Sedatives Induce Neuropathologic Changes In The Mammalian Brainmentioning

confidence: 99%

Cognitive Dysfunction After Analgesia and Sedation: Out of the Operating Room and Into the Pediatric Intensive Care Unit

Turner

Sullivan

Drury

et al. 2021

Front. Behav. Neurosci.

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In the midst of concerns for potential neurodevelopmental effects after surgical anesthesia, there is a growing awareness that children who require sedation during critical illness are susceptible to neurologic dysfunctions collectively termed pediatric post-intensive care syndrome, or PICS-p. In contrast to healthy children undergoing elective surgery, critically ill children are subject to inordinate neurologic stress or injury and need to be considered separately. Despite recognition of PICS-p, inconsistency in techniques and timing of post-discharge assessments continues to be a significant barrier to understanding the specific role of sedation in later cognitive dysfunction. Nonetheless, available pediatric studies that account for analgesia and sedation consistently identify sedative and opioid analgesic exposures as risk factors for both in-hospital delirium and post-discharge neurologic sequelae. Clinical observations are supported by animal models showing neuroinflammation, increased neuronal death, dysmyelination, and altered synaptic plasticity and neurotransmission. Additionally, intensive care sedation also contributes to sleep disruption, an important and overlooked variable during acute illness and post-discharge recovery. Because analgesia and sedation are potentially modifiable, understanding the underlying mechanisms could transform sedation strategies to improve outcomes. To move the needle on this, prospective clinical studies would benefit from cohesion with regard to datasets and core outcome assessments, including sleep quality. Analyses should also account for the wide range of diagnoses, heterogeneity of this population, and the dynamic nature of neurodevelopment in age cohorts. Much of the related preclinical evidence has been studied in comparatively brief anesthetic exposures in healthy animals during infancy and is not generalizable to critically ill children. Thus, complementary animal models that more accurately “reverse translate” critical illness paradigms and the effect of analgesia and sedation on neuropathology and functional outcomes are needed. This review explores the interactive role of sedatives and the neurologic vulnerability of critically ill children as it pertains to survivorship and functional outcomes, which is the next frontier in pediatric intensive care.

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Section: Common Analgesics and Sedatives Induce Neuropathologic Changes In The Mammalian Brainmentioning

confidence: 99%

Cognitive Dysfunction After Analgesia and Sedation: Out of the Operating Room and Into the Pediatric Intensive Care Unit

Turner

Sullivan

Drury

et al. 2021

Front. Behav. Neurosci.

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“…Starting at postnatal day 3 (P3), pups are given a single subcutaneous (s.c.) injection of 1 mg/kg midazolam (mixed with sterilized saline and administered at a uniform volume of 100 µL/10 g of birth weight of pup) and ramped up using a dose-escalation method until day 21 to closely mimic increments as performed in a NICU (Figure 6). Due to faster drug metabolism in rodents than in humans, a higher relative dose is required to induce an equivalent of 60 min sedation, which is similar to the NICU setting [6] This dosage was adapted based on previously published studies [5,6,26,48,49]. Immediately after injection, pups are monitored for any distresses, including placing them under a heating lamp to prevent thermal loss.…”

Section: Midazolam Treatmentmentioning

confidence: 99%

“…Previous studies have described MDZ sedation as contributing to spatial learning and memory impairments in vivo and disrupting synaptogenesis in vitro [5]. Importantly, it has been shown that a single exposure to MDZ with other anesthetic agents causes synaptic alterations and later causes learning disturbances in both clinical and preclinical models [4][5][6]. However, to date, there are no studies that have characterized how long-term exposure to MDZ during very early stages of development induces changes at the synaptic level.…”

Section: Introductionmentioning

confidence: 99%

Decoding the Synaptic Proteome with Long-Term Exposure to Midazolam during Early Development

Nguyen

Vellichirammal

Guda

et al. 2022

IJMS

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The intensive use of anesthetic and sedative agents in the neonatal intensive care unit (NICU) has raised controversial concerns about the potential neurodevelopmental risks. This study focused on midazolam (MDZ), a common benzodiazepine regularly used as a sedative on neonates in the NICU. Mounting evidence suggests a single exposure to MDZ during the neonatal period leads to learning disturbances. However, a knowledge gap that remains is how long-term exposure to MDZ during very early stages of life impacts synaptic alterations. Using a preclinical rodent model system, we mimicked a dose-escalation regimen on postnatal day 3 (P3) pups until day 21. Next, purified synaptosomes from P21 control and MDZ animals were subjected to quantitative mass-spectrometry-based proteomics, to identify potential proteomic signatures. Further analysis by ClueGO identified enrichment of proteins associated with actin-binding and protein depolymerization process. One potential hit identified was alpha adducin (ADD1), belonging to the family of cytoskeleton proteins, which was upregulated in the MDZ group and whose expression was further validated by Western blot. In summary, this study sheds new information on the long-term exposure of MDZ during the early stages of development impacts synaptic function, which could subsequently perturb neurobehavioral outcomes at later stages of life.

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“…Previous animal studies have included midazolam and revealed changes in neuronal structure [ 14 , 39 ]. However, benzodiazepines were included along with volatile anesthetics, opioids, and nitrous oxide in these studies, and any individual effects cannot be determined.…”

Section: Anesthetic Agentsmentioning

confidence: 99%

Neurotoxic Impact of Individual Anesthetic Agents on the Developing Brain

Karlik

2022

Children

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Concerns about the safety of anesthetic agents in children arose after animal studies revealed disruptions in neurodevelopment after exposure to commonly used anesthetic drugs. These animal studies revealed that volatile inhalational agents, propofol, ketamine, and thiopental may have detrimental effects on neurodevelopment and cognitive function, but dexmedetomidine and xenon have been shown to have neuroprotective properties. The neurocognitive effects of benzodiazepines have not been extensively studied, so their effects on neurodevelopment are undetermined. However, experimental animal models may not truly represent the pathophysiological processes in children. Multiple landmark studies, including the MASK, PANDA, and GAS studies have provided reassurance that brief exposure to anesthesia is not associated with adverse neurocognitive outcomes in infants and children, regardless of the type of anesthetic agent used.

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Potential Neurodevelopmental Effects of Pediatric Intensive Care Sedation and Analgesia: Repetitive Benzodiazepine and Opioid Exposure Alters Expression of Glial and Synaptic Proteins in Juvenile Rats

Cited by 16 publications

References 73 publications

Cognitive Dysfunction After Analgesia and Sedation: Out of the Operating Room and Into the Pediatric Intensive Care Unit

Cognitive Dysfunction After Analgesia and Sedation: Out of the Operating Room and Into the Pediatric Intensive Care Unit

Decoding the Synaptic Proteome with Long-Term Exposure to Midazolam during Early Development

Neurotoxic Impact of Individual Anesthetic Agents on the Developing Brain

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