PROJECT SUMMARY/ABSTRACT More than 24,000 children develop acute respiratory failure (ARF) and require invasive mechanical ventilation (MV) – an intrusive, painful, yet lifesaving procedure – in the US each year. There is a critical knowledge gap regarding the optimal approach for analgosedation (analgesia-based sedation) in these children. As a result, the current standard-of-care is to provide opioids for the duration of MV. Despite high-dose opioid exposure, more than 90% of these children have suboptimal pain control. Studies show that repeated episodes of acute pain and prolonged opioid exposure put children at risk for chronic pain, opioid tolerance, withdrawal, delirium, and other negative effects. Yet, few randomized controlled trials (RCTs) target optimizing acute pain management in this high-risk population. In our study, Optimizing Pain Treatment In Children On Mechanical ventilation (OPTICOM), the central hypothesis is that a protocolized strategy of administering non-opioid adjuvant therapies to children with ARF will reduce pain and decrease opioid exposure. The primary objective of OPTICOM is to define the effectiveness of supplementing opioids with acetaminophen and/or ketorolac at decreasing episodes of acute pain in children with ARF on MV. This large-scale multi-site double- blind placebo controlled RCT will enroll 644 children across 14 pediatric intensive care units (PICUs) and randomize to one of 4 arms: Acetaminophen + Placebo; Ketorolac + Placebo; Acetaminophen + Ketorolac; or Placebo + Placebo. We will systematically monitor all children for acute pain for the first 5 days of IMV and quantify total opioid exposure in morphine milligram equivalents per kg as defined by the HEAL common data elements. Effects of acetaminophen and ketorolac will be determined using a 2x2 factorial design. This innovative proposal will leverage the extensive resources and experience of the Collaborative Pediatric Critical Care Research Network (CPCCRN) at executing clinical trials in the complicated PICU environment to achieve results within the 5-year study period. CPCCRN will ensure enrollment of a geographically, racially, and socioeconomically diverse patient population to allow for wide generalizability of study findings. By expanding HEAL-KIDS research into a unique and unstudied population, this project will lead to a paradigm shift in the care provided to critically ill children. Consistent with the goals of the Acute Pain Clinical Trials Program, the OPTICOM study will advance the treatment of acute pain in a diverse population of children across the age- spectrum and advance our ultimate goal of developing comprehensive evidence-based clinical guidelines for management of pain in children with ARF.