Dexmedetomidine is an alpha-2 receptor agonist with sedative and analgesic properties. Additional benefits include anti-inflammatory and anti-microbial properties superior to GABA agonists such as benzodiazepines and propofol. It also reduces neuronal apoptosis and promotes biomimetic sleep. Therefore, dexmedetomidine may lead to better clinical outcomes in septic patients compared to GABAergic agents.
In the general adult critical care population, dexmedetomidine is associated with improvement in delirium, coma rate, and duration on mechanical ventilation compared with lorazepam in the MENDS trial [1], and with midazolam in the Riker et al. trial [2]. A priori-determined subgroup analysis of septic vs non-septic patients from the MENDS revealed that patients treated with dexmedetomidine had better cognitive functioning and lower mortality rates compared to those that received a lorazepam-based sedation regimen. These results were more pronounced in septic patients than in non-septic patients [3].
Another trial with more patients compared dexmedetomidine to propofol or midazolam. Dexmedetomidine was non-inferior to comparators in maintaining light to moderate levels of sedation and was superior regarding the duration overall of mechanical ventilation. In addition, dexmedetomidine improved the patient's communication abilities while on the ventilator [4]. Around 50% of patients in this study had an infectious episode during their ICU stay; however, the trial did not stratify for sepsis. However, in the DESIRE trial, including the septic population, dexmedetomidine was not better than the non-dexmedetomidine regimen in improving mortality or ventilator-free days [5].
The SPICE III trial published in 2019 was the largest trial, including 4000 patients, and it evaluated dexmedetomidine versus its competitors (midazolam and propofol) on mortality rate [6]. 64% of the trial subjects were diagnosed with suspected or proven sepsis. The trial reported no overall difference in the primary outcome of mortality rate for patients using dexmedetomidine versus its competitors. Furthermore, there was no difference between the subgroup with suspected or proven sepsis and those without sepsis [6]. When the data was stratified based on the age, there was a higher mortality rate using dexmedetomidine below the age of 63.7 and a lower mortality above this age. Therefore, a secondary Bayesian analysis of the SPICE III trial population was conducted to quantify this finding. Two clusters were identified; the first included post-operative patients and the second included patients of no-operative status. Overall, dexmedetomidine exhibited a high probability of reduced 90-day mortality in older patients regardless of operative or non-operative cluster status. Conversely, a high probability of increased 90-day mortality was observed in younger patients of non-operative status [7].
The MENDS2 trial solely included patients who were diagnosed with sepsis (432 patients) and randomized them to receive either dexmedetomidine or propofol. The primary outcome of number of days alive without delirium or coma did not differ between the two groups. The secondary outcomes of ventilator-free days, death at 90 days, and global cognition score at 6 months were also the same. Despite some limitations of this study including relatively low trial doses of medications, a 14% rate of unmasking and a relatively high rate of rescue sedatives, this trial did not show that there is any benefit of dexmedetomidine in septic patients over propofol. The trial supports an equipoise position of dexmedetomidine compared to propofol in septic patients [8].
The MENDS2 trial solely included patients diagnosed with sepsis (432 patients) and randomized them to receive either dexmedetomidine or propofol. The primary outcome of number of days alive without delirium or coma did not differ between the two groups. The secondary outcomes of ventilator-free days, death at 90 days, and global cognition score at 6-months were also the same. Despite some limitations of this study, including relatively low trial doses of medications, a 14% rate of unmasking and a relatively high rate of rescue sedatives, this trial did not show any benefit of dexmedetomidine in septic patients over propofol. The study supports an equipoise position of dexmedetomidine compared to propofol in septic patients [8].
Therefore, for patients with sepsis requiring mechanical ventilation, dexmedetomidine is as equally efficacious as propofol as a sedative. The two main benefits of dexmedetomidine are the ability of the patient to interact on the ventilator and the anti-sympathomimetic effects of the medication. These anti-sympathomimetic effects decrease tachycardia and hypertension in post-operative patients, patients with alcohol withdrawal and patients with cocaine or amphetamine intoxication. Despite transitional research showing anti-inflammatory and bacterial clearance properties of dexmedetomidine, clinical research did not indicate its preference over propofol. The possible increased mortality in non-operative patients less than 64 years requires further investigation.
REFERENCES
1. Pandharipande PP, Pun BT, Herr DL, et al. Effect of Sedation With Dexmedetomidine vs Lorazepam on Acute Brain Dysfunction in Mechanically Ventilated Patients: The MENDS Randomized Controlled Trial. JAMA. 2007;298(22):2644–2653
2. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients: A Randomized Trial. JAMA. 2009;301(5):489–499.
3. Pandharipande PP, Sanders RD, Girard TD, et al. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial [published correction appears in Crit Care. 2011;15(1):402]. Crit Care. 2010;14(2):R38. doi:10.1186/cc8916
4. Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs Midazolam or Propofol for Sedation During Prolonged Mechanical Ventilation: Two Randomized Controlled Trials. JAMA. 2012;307(11):1151–1160
5. Kawazoe Y, Miyamoto K, Morimoto T, et al. Effect of Dexmedetomidine on Mortality and Ventilator-Free Days in Patients Requiring Mechanical Ventilation With Sepsis: A Randomized Clinical Trial. JAMA. 2017;317(13):1321–1328.
6. Shehabi Y, Howe BD, Bellomo R, Arabi YM, Bailey M, Bass FE, Bin Kadiman S, McArthur CJ, Murray L, Reade MC, Seppelt IM, Takala J, Wise MP, Webb SA; ANZICS Clinical Trials Group and the SPICE III Investigators. Early Sedation with Dexmedetomidine in Critically Ill Patients. N Engl J Med. 2019 Jun 27;380(26):2506-2517. doi: 10.1056/NEJMoa1904710. Epub 2019 May 19. PMID: 31112380.
7. Shehabi Y, Serpa Neto A, Howe BD, Bellomo R, Arabi YM, Bailey M, Bass FE, Kadiman SB, McArthur CJ, Reade MC, Seppelt IM, Takala J, Wise MP, Webb SA; SPICE III Study Investigators. Early sedation with dexmedetomidine in ventilated critically ill patients and heterogeneity of treatment effect in the SPICE III randomised controlled trial. Intensive Care Med. 2021 Apr;47(4):455-466. doi: 10.1007/s00134-021-06356-8. Epub 2021 Mar 8. PMID: 33686482; PMCID: PMC7939103.
8. Hughes CG, Mailloux PT, Devlin JW, Swan JT, Sanders RD, Anzueto A, Jackson JC, Hoskins AS, Pun BT, Orun OM, Raman R, Stollings JL, Kiehl AL, Duprey MS, Bui LN, O'Neal HR Jr, Snyder A, Gropper MA, Guntupalli KK, Stashenko GJ, Patel MB, Brummel NE, Girard TD, Dittus RS, Bernard GR, Ely EW, Pandharipande PP; MENDS2 Study Investigators. Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis. N Engl J Med. 2021 Apr 15;384(15):1424-1436. doi: 10.1056/NEJMoa2024922. Epub 2021 Feb 2. PMID: 33528922; PMCID: PMC8162695.
9. Devlin J 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; 46 (9): e825-e873.
Comentarios