ABSTRACT Opioids are the most commonly-used and effective drugs in the management of moderate to severe postoperative pain, but they have numerous adverse effects, the most serious being opioid-induced respiratory depression. An important and consistent finding in studies of opioid-induced respiratory depression is the highly variable risk across patient age, gender and co-morbidity profile. Identifying patients at highest risk of opioid-induced respiratory depression in the perioperative setting may help target enhanced monitoring (including hospital admission) and preventative strategies aimed at reducing adverse outcomes including respiratory complications and death. Changes in the central drive to respiratory muscles including the diaphragm are expected to impact the full range of ventilatory behaviors accomplished. It is essential to recognize that respiratory muscles are important in both sustaining ventilation and performing higher-force behaviors necessary for maintaining airway patency. Respiratory muscles accomplish a range of motor behaviors with forces generated for ventilatory behaviors comprising only a small fraction of their maximal force generating capacity. Thus, impairments in respiratory muscle function may not become clinically manifest despite substantial loss of functional reserve until ventilation is impaired. Monitoring for opioid effects on higher force behaviors may reveal patients with greater susceptibility to opioid-induced respiratory depression. Our working hypotheses are that opioid-induced respiratory depression limits the generation of higher forces by the diaphragm muscle, and that the early recognition of an individual patient’s response to opioids will help identify those at greatest risk for respiratory complications. Exciting recent studies support the utility of ultrasound-based shear wave elastography for measurements of diaphragm muscle function, but there is limited information available about their utility in healthy (not critically-ill) patient populations, or opioid effects. Two specific aims are proposed: 1) To test the hypothesis that shear wave elastography (SWE) reliably measures the range of forces generated by the diaphragm muscle, in relation to state-of-the-art respiratory function testing; and 2) To test the hypothesis that opioid-induced respiratory depression limits the range of forces generated by the diaphragm muscle, identifying a sub-population of patients potentially at greater risk for respiratory complications. We expect that the proposed studies in this novel application will determine the dose-dependent effect of opioids across a range of ventilatory and higher-force behaviors and the utility of SWE-based measurements of diaphragm muscle activity in the early recognition of patients displaying opioid- induced respiratory depression. Ultimately, the proposed work will help predict patients at greater risk for opioid-induced respiratory depression and permit assessment of the impact of individualized interventions in preventing postoperative respiratory complications.

PROJECT NARRATIVE Opioids are the most commonly-used and effective drugs in the management of moderate to severe postoperative pain, but they have numerous adverse effects, the most serious being opioid-induced respiratory depression. The proposed studies in this novel application will test the hypothesis that opioid-induced respiratory depression limits the generation of higher forces by the diaphragm muscle, and that the early recognition of an individual patient’s response to opioids will help identify those at greatest risk for respiratory complications. The proposed studies in this application are expected to advance the field by helping predict patients at greater risk for opioid-induced respiratory depression and permitting assessment of the impact of individualized interventions in preventing postoperative respiratory complications.