Low Dose Dexmedetomidine and Delirium After Cardiac Surgery (LOWDEXDEL)

Does LOW Dose DEXmedetomidine After Cardiopulmonary Bypass Separation Decrease the Incidence of DELirium: A Double-blind Randomized Placebo-controlled Study (LOWDEXDEL Study)

Delirium after cardiac surgery can occur in up to 50% of the patients and has been shown to be significantly associated with increased morbidity and mortality. Advanced age is a significant risk factor of delirium. Numerous studies have shown that sedation with high doses of Dexmedetomidine in the ICU reduces the incidence of postoperative delirium. On the other hand animal studies have shown neuroprotective effects of Dexmedetomidine by means of stimulating alpha2A-adrenoceptors. It is not clear whether the administration of a low dose Dexmedetomidine in cardiac surgery would have any neuroprotective effects by stimulating the alpha 2A-receptors and as such would decrease the incidence of postoperative delirium.

Postoperative delirium (PD) is a common problem in cardiac surgical patients. Its incidence varies among studies and can reach up to 50% of the patients. PD is associated with increased morbidity and mortality. Its occurrence is the resultant between the predisposing factors and the precipitating factors. Age seems to be a significant predisposing factor. In this regard the pathophysiology of PD is not yet fully understood. There are several hypothetical mechanisms for the development of PD. The first hypothesis is cerebral ischemia and BBB breakdown. The second hypothesis is neuro-inflammation. Peripheral pro-inflammatory mediators especially released during surgery would interact with the brain. Otherwise there is the problem of sleep deprivation/fragmentation in patients admitted to the hospital. Dexmedetomidine is a potent and more selective alpha2-adrenergic receptor than clonidine. Studies have demonstrated that it has neuroprotective and anti-inflammatory actions. Numerous studies including trials in cardiac surgery have shown a decreased incidence of delirium when Dexmedetomidine was used as sedative in the ICU compared with other sedatives acting on the GABA receptors. However, in these studies high doses of Dexmedetomidine were used for periods up to 24h. Dexmedetomidine was started in the ICU and was not compared in a double-blind fashion with placebo. In a recent randomized double-blind placebo-controlled trial a very low dose of Dexmedetomidine decreased the occurrence of PD when compared to placebo. However this study was performed in non-cardiac patients. Moreover the patients were included after their arrival in the ICU, which means that those patients who were intubated at their arrival in the ICU were not included. And again the study medication was only started after arrival in the ICU. The aim of this study is to elucidate whether the administration of Dexmedetomidine at a low dose would decrease the incidence of PD in elderly patients undergoing cardiac surgery. The hypothesis is that Dexmedetomidine at low doses, by only stimulating the alpha2A adrenoceptors,would have neuroprotective affects ans as such decrease the incidence of PD. Dexmedetomidine would also have anti-inflammatory effects and effects on the quality of sleep. Both mechanisms would play a role in the pathophysiology of PD.

Dexmedetomidine will be administered at 0.4ug/kg/h (5mL/h) starting at the closure of the chest and continued during 10h.

NaCl 0.9% will be administered at 5mL/h starting at the closure of the chest and continued during 10h.

Dexmedetomidine will be started at 5mL/h while the patient is still in the operating room. The patient will be transferred to the intensive care unit with a sedative regimen based on propofol.

A continuous infusion of NaCL 0.9% will be started at 5mL/h while the patient is still in the operating room. The patient will be transferred to the intensive care unit with a sedative regimen based on propofol.

Inclusion Criteria: Patients undergoing cardiac surgery with cardiopulmonary bypass Exclusion Criteria: Hepatic dysfunction (hepatic function tests 3 times the normal value) Preoperative renal replacement therapy Preoperative delirium Emergency surgery not allowing neurologic evaluation by MMSE Mini invasive cardiac surgery Patients not speaking French

Paris A, Mantz J, Tonner PH, Hein L, Brede M, Gressens P. The effects of dexmedetomidine on perinatal excitotoxic brain injury are mediated by the alpha2A-adrenoceptor subtype. Anesth Analg. 2006 Feb;102(2):456-61. doi: 10.1213/01.ane.0000194301.79118.e9.

Maier C, Steinberg GK, Sun GH, Zhi GT, Maze M. Neuroprotection by the alpha 2-adrenoreceptor agonist dexmedetomidine in a focal model of cerebral ischemia. Anesthesiology. 1993 Aug;79(2):306-12. doi: 10.1097/00000542-199308000-00016.

Jiang L, Hu M, Lu Y, Cao Y, Chang Y, Dai Z. The protective effects of dexmedetomidine on ischemic brain injury: A meta-analysis. J Clin Anesth. 2017 Aug;40:25-32. doi: 10.1016/j.jclinane.2017.04.003. Epub 2017 Apr 17.

Tasdogan M, Memis D, Sut N, Yuksel M. Results of a pilot study on the effects of propofol and dexmedetomidine on inflammatory responses and intraabdominal pressure in severe sepsis. J Clin Anesth. 2009 Sep;21(6):394-400. doi: 10.1016/j.jclinane.2008.10.010.

Su X, Meng ZT, Wu XH, Cui F, Li HL, Wang DX, Zhu X, Zhu SN, Maze M, Ma D. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet. 2016 Oct 15;388(10054):1893-1902. doi: 10.1016/S0140-6736(16)30580-3. Epub 2016 Aug 16.

Shehabi Y, Grant P, Wolfenden H, Hammond N, Bass F, Campbell M, Chen J. Prevalence of delirium with dexmedetomidine compared with morphine based therapy after cardiac surgery: a randomized controlled trial (DEXmedetomidine COmpared to Morphine-DEXCOM Study). Anesthesiology. 2009 Nov;111(5):1075-84. doi: 10.1097/ALN.0b013e3181b6a783.

Djaiani G, Silverton N, Fedorko L, Carroll J, Styra R, Rao V, Katznelson R. Dexmedetomidine versus Propofol Sedation Reduces Delirium after Cardiac Surgery: A Randomized Controlled Trial. Anesthesiology. 2016 Feb;124(2):362-8. doi: 10.1097/ALN.0000000000000951.

Momeni M, Khalifa C, Lemaire G, Watremez C, Tircoveanu R, Van Dyck M, Kahn D, Rosal Martins M, Mastrobuoni S, De Kerchove L, Zango SH, Jacquet LM. Propofol plus low-dose dexmedetomidine infusion and postoperative delirium in older patients undergoing cardiac surgery. Br J Anaesth. 2021 Mar;126(3):665-673. doi: 10.1016/j.bja.2020.10.041. Epub 2020 Dec 24.