Safe and effective pain relief is an unmet critical medical need in children. In the U.S., ~6 million children undergo painful surgery each year. Opioids are the preferred analgesics to reduce surgical pain. Because opioids have narrow therapeutic indices and huge inter-child variations in responses, more than 30% of children undergoing surgery suffer from serious adverse effects. Several deaths and anoxic brian injuries from respiratory depression (RD) have been attributed to opioid use in children. Children with obstructive sleep apnea (OSA) are more sensitive to, and have an increased incidence of opioid-induced RD. Current trial-and-error opioid dosing, based solely on weight, compromises safety and increases the economic burden of untreated pain and serious adverse events. This major public health problem is preventable. Currently, there is a lack of understanding of inter-child variability in opioid pharmacokinetics and pharmacodynamics. There is also an almost complete lack of reliable, real-time, bedside tools to assess the central nervous system (CNS) effects of opioids. Quantitative Pupillometry (QP) is a safe, effective tool to assess brainstem function and analgesic effects of opioids in children. QP is a real-time, non-invasive digital, and objective measure of pupil size and reaction to light. Several genetic markers associated with RD in children have already been identified. This innovative study uniquely uses known genetic risk factors and the novel biomarker QP to better predict postoperative RD in children. The long-term goal is to personalize pain management with the right dose of the right analgesic for each child, improving safety and efficacy while reducing the cost of perioperative care. The overall objective is is to proactively determine children?s individual risk of opioid-induced RD at the bedside using QP, a clinically adaptable, novel and non-invasive tool. This critical new knowledge will proactively identify children at risk of RD and improve outcomes. Encouraging preliminary data are supportive of the use of QP as a predictor of RD in children. The central hypothesis is that intraoperative QP, before and after an intraoperative morphine bolus dose, predicts postoperative morphine- induced RD (primary safety outcome), better predicts RD than corresponding blood morphine concentration, and improves genetics-based prediction of RD in children.
The specific aims are 1) Identify pupillary effects of intraoperative morphine that are predictive of postoperative RD, 2) Determine if intraoperative QP measures are better predictors of postoperative RD than blood morphine concentrations; and if children with OSA have higher pharmacodynamic sensitivity to opioids compared to children without OSA, and 3) Improve prediction of clinical RD by integrating QP measures and known genetic risk factors of postoperative RD. Ultimately, critical new QP and genetics-based predictive knowledge from this research will proactively identify children at risk for postoperative RD, and guide personalized use of the right analgesics at the right dose to maximize surgical pain relief while minimizing preventable serious adverse effects in millions of children undergoing surgery.
The proposed research is relevant to public health because it aims to develop a bedside tool to proactively predict life threatening respiratory depression in children undergoing painful surgery using objective pupillometry and genetic risk factors. Moreover, this research will provide novel insights into how genes, sleep apnea, race, and opioid metabolism influence serious adverse outcomes related to morphine, a standard opioid to treat surgical pain in children. This research is expected to improve our ability to preoperatively identify children at risk of respiratory depression with a bedside tool, and personalize pain management to maximize surgical pain relief and safety of pain medications.
