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Objective: To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU., Design: Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines' development. A general content review was completed face-to-face by all panel members in January 2017., Methods: Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as "strong," "conditional," or "good" practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified., Results: The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation., Conclusions: We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population.

Several lines of research show that cells of the immune response are sensitive to thermal variations in their microenvironment, such as that which occurs during inflammation and fever; these data have led to the hypothesis that strategic applications of heat could assist in controlling tumor growth in animal models. The innate immune response is known to play a critical role in the development of effective anti-tumor immunity and granulocytes such as polymorphonuclear neutrophils (PMNs), as key mediators of inflammation, have been suggested to have the potential to initiate immune response cascades against tumors. Thus, we hypothesized that PMNs may play a crucial role in mediating the anti-tumor effects of a mild, fever-range whole-body hyperthermia (FR-WBH) protocol, where core body temperatures are raised to 39.5-40 degrees C for 8 hrs. Indeed, in BALB/c mice bearing the colon tumor CT26, the anti-tumor effect of WBH correlates with increased granulocytic infiltrate at the tumor site as determined using immunohistochemical analysis for Gr-1+ cells. In both BALB/c mice bearing CT26 and SCID mice bearing human colon tumors, PMN depletion in vivo using anti-Gr-1 ascites ablated the anti-tumor effect of mild WBH. Because mild thermal stress is also found to enhance the respiratory burst of granulocytes, these data collectively suggest that the thermal stimulation of granulocytes may help to prevent tumor establishment. Overall, these results may have implications for the design of thermal therapy protocols in cancer immunotherapy.