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Managing pain and delirium are crucial to patients, families, and caregivers in intensive care units. The Society of Critical Care Medicine 2018 Pain, Agitation/Sedation, Delirium, Immobility, and Sleep disruption (PADIS) guidelines reviewed literature until October 2015 and made its recommendations for critically-ill adults. This chapter addresses evidence gaps, identified during the guideline process, most relevant to clinicians, adds newer evidence published after the PADIS 2018 guidelines were produced, describes hindsight-driven PADIS process or content-related gaps, and reflects on how these considerations may help inform future research investigations and new guideline efforts.