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Dexmedetomidine in Critically Ill Adults Requiring Noninvasive Ventilation

Possibly reduces intubation, delirium, ICU length of stay, and pneumonia; increases risk of bradycardia and hypotension

Benefits in NNT

6
1 in 6 were helped (lower risk of intubation)
6
1 in 6 were helped (lower risk of delirium)
6
1 in 6 were helped (lower risk of pneumonia)
6
17% lower risk of intubation requirement
6
19% lower risk of delirium
6
2.4 fewer ICU days
17% lower risk of pneumonia

Harms in NNT

4
1 in 4 were harmed (bradycardia)
5
1 in 5 were harmed (hypotension)
4
23% higher risk of bradycardia
5
18% higher risk of hypotension
View As:

Efficacy Endpoints

Need for intubation, delirium, intensive care unit length of stay, pneumonia, mortality

Harm Endpoints

Bradycardia, hypotension

Narrative

Noninvasive ventilation (NIV) is an effective therapy for hypercapnic and hypoxemic respiratory failure and can reduce the need for intubation and mechanical ventilation.1 It may also reduce intensive care unit (ICU) length of stay, pneumonia, and mortality.2, 3, 4, 5, 6 However, NIV can be uncomfortable for patients due to the mask interface and respiratory pressures delivered, and over one-third of patients placed on NIV will experience agitation.7, 8 Intolerance to NIV typically requires intubation. A variety of interventions can be utilized to improve compliance with NIV, including medications such as dexmedetomidine, an α-2 agonist with sedative and analgesic effects.9 Current guidelines recommend the use of a non-benzodiazepine sedative such as propofol or dexmedetomidine in critically ill, mechanically ventilated adults, as these medications may improve delirium, ICU length of stay, and duration of mechanical ventilation.10

The systematic review summarized here included randomized trials (RCTs) of adults > 18 years admitted to the ICU with acute respiratory failure treated with NIV.11 Authors included studies in which the intervention group received dexmedetomidine in the ICU (any dose, initiation day, route, frequency, formulation, administration, and duration) and the control group received a different form of pharmacologic sedation or placebo. Studies of patients treated chronically at home with NIV who were admitted to the ICU, patients supported with NIV for post-extubation respiratory failure, and patients with alcohol withdrawal were excluded. Outcomes included need for intubation and mechanical ventilation, delirium, ICU length of stay, mortality, duration of NIV, pneumonia, bradycardia, and hypotension.

The authors of the meta-analysis identified 12 RCTs comprising 738 ICU patients.11 The mean age was 61.5 years and 36% of patients were women. Four trials included 200 patients with baseline agitation or delirium. Four trials provided an intravenous (IV) loading dose of dexmedetomidine, 2 trials did not report a loading dose, and 6 trials used IV infusion only. Most studies used a dosing range of 0.2-0.7 micrograms/kilogram/hour IV, though 3 trials used a wider range of dosing (0.2-2 micrograms/kilogram/hour). Six RCTs used placebo as the comparator, while 2 used haloperidol, 3 used midazolam, 1 used propofol, and 1 utilized sedation according to the ICU team.

Dexmedetomidine reduced the need for intubation and mechanical ventilation (Relative risk [RR]: 0.54; 95% confidence interval [CI]: 0.41-0.71; absolute risk difference [ARD]: 17%; number needed to treat [NNT]: 6; moderate certainty), delirium (RR: 0.34; 95% CI: 0.22-0.54; ARD: 19%; NNT: 6; moderate certainty), ICU length of stay (mean difference [MD]: 2.40 days fewer ICU days; 95% CI: 3.51-1.29, low certainty), and pneumonia (RR: 0.30; 95% CI: 0.17- 0.52; ARR: 16.7%; NNT: 6; moderate certainty). Dexmedetomidine did not impact survival (low certainty). However, it increased the risk of bradycardia (RR: 2.80; 95% CI: 1.92-4.07; ARD: 23%; number needed to harm [NNH]: 4; moderate certainty) and hypotension (RR: 1.98; 95% CI: 1.32-2.98; ARD: 18%; NNH: 5; moderate certainty).11

Caveats

While 12 RCTs were included, not all trials reported all the outcomes. In particular, the data pertaining to mortality were limited. The low number of patients who died in the ICU resulted in imprecision in reporting this outcome. Second, due to the relatively small population of 738 patients, results may be associated with a type I or type II error due to overestimation or underestimation of the statistical significance of the results, respectively. Third, authors were unable to complete analysis of several prespecified outcomes such as hypertension and subgroup analyses by age and dose of dexmedetomidine due to limited patient-level data. This also limited subgroup analyses including patients with and without agitation or delirium at the time of enrollment. Fourth, the systematic review was not able to generate a funnel plot for publication bias due to the small number of trials. Of note, dexmedetomidine was associated with an increased risk of bradycardia and hypotension. Overall, bradycardia occurred in 78 of 236 patients and hypotension in 75 of 232 patients receiving dexmedetomidine. However, treatment for bradycardia and hypotension varied significantly in the included studies, including decreased dexmedetomidine infusion, vasopressor or inotrope infusion, or no intervention, with not all studies reporting treatment for bradycardia and hypotension. Finally, there was significant statistical heterogeneity concerning ICU length of stay, as well as clinical heterogeneity concerning the other outcomes. While the other outcomes demonstrated little to no statistical heterogeneity, the underlying etiology requiring the use of NIV differed in the included studies, raising concerns of significant clinical heterogeneity and threatening the validity of the results.

Based on the presented evidence, we have assigned a color recommendation of Yellow (Data Inadequate) for use of dexmedetomidine in critically ill patients undergoing NIV. Further data from larger trials are needed to provide a more accurate effect size and to evaluate the ideal dosing, as well as studies comparing dexmedetomidine with other agents. Additional research is also needed to assess the effects on important subgroups such as patients with pre-existing delirium or agitation, elderly patients, and those separated by etiology of acute respiratory failure (e.g., hypoxemic, hypercarbic).

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.

Author

Brit Long, MD; Michael Gottlieb, MD
Supervising Editors: Shahriar Zehtabchi, MD

Published/Updated

June 23, 2021

References:

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Girou E, Brun-Buisson C, Taillé S, Lemaire F, Brochard L. Secular trends in nosocomial infections and mortality associated with noninvasive ventilation in patients with exacerbation of COPD and pulmonary edema. JAMA. 2003 Dec 10;290(22):2985-91.
Girou E, Schortgen F, Delclaux C, Brun-Buisson C, Blot F, Lefort Y, et al. Association of noninvasive ventilation with nosocomial infections and survival in critically ill patients. JAMA. 2000 Nov 8;284(18):2361-7.
Plant PK, Owen JL, Parrott S, Elliott MW. Cost effectiveness of ward based non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease: economic analysis of randomised controlled trial. BMJ. 2003 May 3;326(7396):956.
Antonelli M, Conti G, Moro ML, Esquinas A, Gonzalez-Diaz G, Confalonieri M, et al. Predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study. Intensive Care Med. 2001 Nov;27(11):1718-28.
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L'Her E, Deye N, Lellouche F, Taille S, Demoule A, Fraticelli A, et al. Physiologic effects of noninvasive ventilation during acute lung injury. Am J Respir Crit Care Med. 2005 Nov 1;172(9):1112-8.
Charlesworth M, Elliott MW, Holmes JD. Noninvasive positive pressure ventilation for acute respiratory failure in delirious patients: understudied, underreported, or underappreciated? A systematic review and meta-analysis. Lung. 2012 Dec;190(6):597-603.
Weerink MAS, Struys MMRF, Hannivoort LN, Barends CRM, Absalom AR, Colin P. Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine. Clin Pharmacokinet. 2017 Aug;56(8):893-913.
Devlin JW, Skrobik Y, Gélinas C, Needham DM, Slooter AJC, Pandharipande PP, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018 Sep;46(9):e825-e873.
Lewis K, Piticaru J, Chaudhuri D, Basmaji J, Fan E, Møller MH, et al. Safety and Efficacy of Dexmedetomidine in Acutely Ill Adults Requiring Noninvasive Ventilation: A Systematic Review and Meta-analysis of Randomized Trials. Chest. 2021 Jun;159(6):2274-2288.

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