Guidelines:

Devlin JW, Skrobik Y, Gélinas C et al. Clinical practice guidelines for the prevention and management of pain/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med 2018; 46:e825-e873
PMID: 30113379

Comparison Between Administration Methods:

Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342:1471-7. RCT found daily interruption of sedation in a MICU population resulted in shorter duration of mechanical ventilation and ICU stay, less total dose of sedation, and less use of diagnostic tests to work-up impaired mental status compared to the control group. No increase in short term adverse outcomes in the intervention group identified but patients were not evaluated for subtle or long-term adverse outcomes.
PMID: 10816184
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Mehta S, Burry L, Cook D, et al. SLEAP Investigators. Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized controlled trial. JAMA 2012; 308:1985-92. Multicenter trial randomized 430 critically ill, mechanically ventilated adults to protocolized sedation vs protocolized sedation plus daily sedation interruption. There was no difference in time to successful extubation, length of ICU stay, length of hospital stay, or incidence of delirium. The daily sedation interruption group received higher doses of sedatives and opiates, and required greater nursing care based on a visual analog scale.
PMID: 23180503

Comparison Between Agents:

Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; 301:489-99. This study is noteworthy for finding use of dexmedetomidine reduced the prevalence of delirium (54% vs 77% with midazolam) and for providing further evidence of the safety of using dexmedetomidine at higher doses and longer duration. There was no difference in the primary outcome, time spent at target level of sedation. Duration of mechanical ventilation was shorter with dexmedetomidine but length of ICU stay was similar.
PMID: 19188334
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Hughes CG, Mailloux PT, Devlin JW, et al. Dexmedetomidine or propofol for sedation in mechanically ventilated adults with sepsis.  N Engl J Med. 2021; 384:1424-1436. Multicenter RCT of 422 patients found no difference in delirium, ventilator-free days, survival, or cognitive function at 6 months with use of the 2 agents.
PMID: 33528922
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Shehabi Y, Howe BD, Bellomo R, et al. Early sedation with dexmedetomidine in critically ill patients. N Engl J Med. 2019; 380:2506-17. RCT of 4000 patients undergoing ventilation in the ICU for less than 12 hours to receive dexmedetomidine as sole or primary agent vs usual care with target RASS score of -2 to +1. There was no difference in all cause mortality at 90 days but bradycardia and hypotension were more common in the dexmedetomidine group. Nearly ⅔ of the dexmedetomidine group received supplemental propofol to reach target sedation.
PMID: 31112380
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Delirium in the ICU:

Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004;291:1753-62. This study confirmed a high prevalence of ICU delirium (over 80% as identified by I-CAM) and was the first to show delirium is an independent risk factor for mortality. Specifically, ICU delirium was associated with 3-fold higher 6-month mortality. After adjusting for co-morbidities, illness severity, coma, and use of sedatives and analgesics, delirium was also associated with prolonged ICU and hospital stays, as well as cognitive impairment at hospital discharge.
PMID: 15082703
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Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369:1306-16. A prospective two center study of patients with respiratory failure or shock found that at 3 months 40% of patients had deficits in cognition similar to those seen in moderate traumatic brain injury, and 26% had deficits similar to mild Alzheimer’s disease. A similar pattern was evident at 12 months. Duration of delirium was associated with worse cognitive and executive function at both time points. Type of sedative and analgesic medications was not associated with degree of subsequent cognitive deficit.
PMID: 24088092
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Girard TD, Exline MC, Carson SS et al. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018; 379:2506-2516. This study randomized 566 patients with acute respiratory failure or shock and hypoactive (89%) or hyperactive delirium (11%) to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The primary endpoint was the number of days alive without delirium or coma during the 14-day intervention period. Compared to placebo, neither haloperidol or ziprasidone increased the number of days alive without delirium or coma during the 14-day intervention period. Outcomes did not differ in the smaller subset of patients with agitated delirium.
PMID: 30346242
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Andersen-Ranberg NC, Poulsen LM, Perner A, et al; AID-ICU Trial Group. Haloperidol for the treatment of delirium in ICU patients. N Engl J Med. 2022; 387:2425-2435.This RCT of 1,000 patients found haloperidol had no effect on the primary endpoint of days alive and out of the hospital at 90 days. This study is noteworthy for including a greater proportion of patients with hyperactive delirium (45%) than the previous study by Girard et al. Days alive without mechanical ventilation and days alive without delirium favored the haloperidol group but differences were not statistically significant. There was an unexpected 6.9% absolute lower 90-day mortality in the haloperidol group, but the study authors note that this finding is inconclusive.
PMID: 36286254