Quantifying individual noxious-evoked baseline sensitivity to optimise analgesic trials in neonates
- University of Oxford, United Kingdom
Abstract
Despite the high burden of pain experienced by hospitalised neonates there are few analgesics with proven efficacy. Testing analgesics in neonates is experimentally and ethically challenging and minimising the number of neonates required to demonstrate efficacy is essential. EEG-derived measures of noxious-evoked brain activity can be used to assess analgesic efficacy, however, as variability exists in neonate's responses to painful procedures, large sample sizes are often required. Here we present a novel experimental paradigm to account for individual differences in noxious-evoked baseline sensitivity which can be used to improve the design of analgesic trials in neonates. The paradigm is developed and tested across four observational studies using clinical, experimental and simulated data (92 neonates). We provide evidence of the efficacy of gentle brushing and paracetamol, substantiating the need for randomised controlled trials of these interventions. This work provides an important step towards safe, cost-effective clinical trials of analgesics in neonates.
Data availability
Source data to produce figures 2-5 are provided with the paper. The data that support the findings of this study are available upon reasonable request from the corresponding author. Due to ethical restrictions, we consider appropriate to monitor the access and usage of the data as it includes highly sensitive information. Data sharing requests should be directed to rebeccah.slater@paediatrics.ox.ac.uk.Code availability: The magnitude of noxious-evoked brain activity in response to the experimental noxious stimuli and clinically-required procedures was calculated using the template of noxious evoked brain activity previously validated for experimental and clinical stimuli and available from (Hartley et al., 2017). The code to perform simulations to compare the sample size needed to assess an intervention effect with and without taking into account individual nociceptive sensitivity presented in study 2 are available from https://gitlab.com/paediatric_neuroimaging/simulating_power_nociceptive_sensitivity.git
Article and author information
Author details
Funding
Wellcome Trust (Senior Fellowship Award,207457/Z/17/Z)
- Rebeccah Slater
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Ethical approval was obtained from the National Research Ethics Service (reference 12/SC/0447) and informed written parental consent was obtained prior to each study.
Copyright
© 2021, Cobo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Quantifying individual noxious-evoked baseline sensitivity to optimise analgesic trials in neonates
eLife 10:e65266.
https://doi.org/10.7554/eLife.65266
Further reading
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- Medicine
- Neuroscience
It has been well documented that cold is an enhancer of lipid metabolism in peripheral tissues, yet its effect on central nervous system lipid dynamics is underexplored. It is well recognized that cold acclimations enhance adipocyte functions, including white adipose tissue lipid lipolysis and beiging, and brown adipose tissue thermogenesis in mammals. However, it remains unclear whether and how lipid metabolism in the brain is also under the control of ambient temperature. Here, we show that cold exposure predominantly increases the expressions of the lipid lipolysis genes and proteins within the paraventricular nucleus of the hypothalamus (PVH) in male mice. Mechanistically, by using innovatively combined brain-region selective pharmacology and in vivo time-lapse photometry monitoring of lipid metabolism, we find that cold activates cells within the PVH and pharmacological inactivation of cells blunts cold-induced effects on lipid peroxidation, accumulation of lipid droplets, and lipid lipolysis in the PVH. Together, these findings suggest that PVH lipid metabolism is cold sensitive and integral to cold-induced broader regulatory responses.
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- Medicine
Background:
Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is a severe and deadly adverse event following ERCP. The ideal method for predicting PEP risk before ERCP has yet to be identified. We aimed to establish a simple PEP risk score model (SuPER model: Support for PEP Reduction) that can be applied before ERCP.
Methods:
This multicenter study enrolled 2074 patients who underwent ERCP. Among them, 1037 patients each were randomly assigned to the development and validation cohorts. In the development cohort, the risk score model for predicting PEP was established via logistic regression analysis. In the validation cohort, the performance of the model was assessed.
Results:
In the development cohort, five PEP risk factors that could be identified before ERCP were extracted and assigned weights according to their respective regression coefficients: –2 points for pancreatic calcification, 1 point for female sex, and 2 points for intraductal papillary mucinous neoplasm, a native papilla of Vater, or the pancreatic duct procedures (treated as ‘planned pancreatic duct procedures’ for calculating the score before ERCP). The PEP occurrence rate was 0% among low-risk patients (≤0 points), 5.5% among moderate-risk patients (1–3 points), and 20.2% among high-risk patients (4–7 points). In the validation cohort, the C statistic of the risk score model was 0.71 (95% CI 0.64–0.78), which was considered acceptable. The PEP risk classification (low, moderate, and high) was a significant predictive factor for PEP that was independent of intraprocedural PEP risk factors (precut sphincterotomy and inadvertent pancreatic duct cannulation) (OR 4.2, 95% CI 2.8–6.3; p<0.01).
Conclusions:
The PEP risk score allows an estimation of the risk of PEP prior to ERCP, regardless of whether the patient has undergone pancreatic duct procedures. This simple risk model, consisting of only five items, may aid in predicting and explaining the risk of PEP before ERCP and in preventing PEP by allowing selection of the appropriate expert endoscopist and useful PEP prophylaxes.
Funding:
No external funding was received for this work.
