Dexmedetomidine-Esketamine Combination for Sedation and Analgesia in ICU Patients

Официальное название

Effect of Dexmedetomidine-Esketamine Combination for Sedation and Analgesia on Delirium in ICU Patients With Mechanical Ventilation: A Multicenter Randomized Trial

Обзор

Patients with mechanical ventilation in the intensive care unit (ICU) often develop anxiety and agitation, sleep distuebances, and delirium. Delirium occurrence is associated with worse early and long-term outcomes. Dexmedetomidine and ketamine are recommended for sedation and analgesia in ICU patients, but each may induce side effects. The sedative effects of dexmedetomidine can help mitigate the psychiatric side effects of esketamine. Recent studies showed that dexmedetomidine-esketamine combination improved analgesia and sleep quality without increasing psychiatric side effects. This trial is designed to test the hypothesis that dexmedetomidine-esketamine combination for sedation and analgesia in ICU patients with mechanical ventilation may reduce delirium and improve respiratory recovery.

Подробное описание

Patients with respiratory failure or other severe conditions often require non-invasive or invasive mechanical ventilation in the Intensive Care Unit (ICU). The uncomfortable stimulation produced by mechanical ventilation may lead to anxiety and agitation of patients and adverse consequences such as ventilator asynchrony, increased oxygen consumption, stress responses, self-extubation, and potentially prolonged mechanical ventilation. The above factors, together with the ICU environment, underlying illnesses, treatment measures, and painful procedures, often result in sleep disturbances in ICU patients.

Mechanical ventilation, painful stimulation, and sleep disturbances are important risk factors of delirium in ICU patients. Delirium is an acutely occurred brain dysfunction symdrome characteristized with fluctuating disturbances in attention, cognition, and consciousness, and is reported to occur in up to 80% of ICU patients with mechanical ventilation. Delirium occurrence is associated with worse outcomes, including prolonged mechanical ventilation duration, extended ICU and hospital stays, increased healthcare burden and costs, and elevated mortality risk, as well as long-term sequelae including cognitive decline, reduced quality of life, and decreased survival.

Dexmedetomidine is a highly selective α2-adrenergic receptor agonist with sedative, analgesic, and anxiolytic effects. It exerts effects by activating the endogenous sleep-promoting pathways, inducing a state like non-rapid eye movement sleep. Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Esketamine, the more potent enantiomer of ketamine, has a higher affinity for the NMDA receptor and is approximately twice as potent as ketamine, with a lower incidence of adverse effects. Both dexmedetomidine and ketamine are recommended for sedation and analgesia in ICU patients. However, sedative dose dexmedetomidine is associated with bradycardia and hypotension. Even low-dose esketamine can induce psychotropic side effects such as dissociation, hallucinations, and nightmares.

The sedative effects of dexmedetomidine can help mitigate the psychiatric side effects of esketamine. Recent studies showed that dexmedetomidine-esketamine combination improved analgesia and sleep quality without increasing psychiatric side effects. It is hypothesized that dexmedetomidine-esketamine combination for sedation and analgesia in ICU patients with mechanical ventilation may reduce delirium and improve respiratory recovery.

Вмешательства

• Препарат Dexmedetomidine-Esketamine Combination
  For patients with invasive ventilation, nighttime sedation (20:00-06:00) is provided with an initial infusion rate of \[0.05×kg\] ml/h which is increased by \[0.025×kg\] ml/h every 10 min, until the Richmond Agitation-Sedation Scale (RASS) reaches -2 to -1, maximal infusion rate reaches \[0.175×kg\] ml/h, or adverse reactions occur. Daytime sedation (06:00-20:00) is provided as above when considered necessary by the ICU physicians, with a target RASS score of -2 to +1. For patients with non-inv
• Препарат Dexmedetomidine
  For patients with invasive ventilation, nighttime sedation (20:00-06:00) is provided with an initial infusion rate of \[0.05×kg\] ml/h which is increased by \[0.025×kg\] ml/h every 10 min, until the Richmond Agitation-Sedation Scale (RASS) reaches -2 to -1, maximal infusion rate reaches \[0.175×kg\] ml/h, or adverse reactions occur. Daytime sedation (06:00-20:00) is provided as above when considered necessary by the ICU physicians, with a target RASS score of -2 to +1. For patients with non-inv

Первичные конечные точки

• Incidence of delirium within 7 days [Срок оценки: Up to 7 days after enrollment]

Вторичные конечные точки (4)

• Days alive without delirium or come during the 7-day period [Срок оценки: Up to 7 days after enrollment]
• Ventilator-free days within 30 days [Срок оценки: Up to 30 days after enrollment]
• Length of stay in the ICU [Срок оценки: Up to 30 days after enrollment]
• 30-day all-cause mortality [Срок оценки: Up to 30 days after enrollment]

Критерии участия

Критерии включения

• Aged ≥18 years;
• Receiving invasive or non-invasive mechanical ventilation in the ICU, with an expected duration ≥24 hours;
• Require sedation as judged by ICU physicians.

Критерии исключения

• Pregnant or lactating women;
• History of schizophrenia, epilepsy, Parkinson's disease, or myasthenia gravis;
• Unable to communicate due to coma, severe dementia, or language barrier prior to invasive/non-invasive mechanical ventilation;
• After stroke, hypoxic encephalopathy, traumatic brain injury, or neurosurgery;
• Comorbid with hyperthyroidism or pheochromocytoma;
• Left ventricular ejection fraction <30%, sick sinus syndrome, severe sinus bradycardia (heart rate <50 bpm), second-degree or higher atrioventricular block without a pacemaker, or systolic blood pressure <90 mmHg despite use of vasopressors;
• Severe liver dysfunction (Child-Pugh Class C), severe renal dysfunction (requiring dialysis), or expected survival ≤24 hours;
• Allergy to dexmedetomidine and/or esketamine, or any other conditions that are considered unsuitable for study participation.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Профилактика

Центры проведения

Китай · 3 центра

• Peking University First Hospital — Пекин
• Peking University International Hospital — Пекин
• Tianjin Medical University General Hospital — Тяньцзинь

Публикации

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• Hempel G, Simon P, Salz P, Wrigge H. [Respiratory Failure: Innovations in Diagnostics and Therapy]. Anasthesiol Intensivmed Notfallmed Schmerzther. 2018 Feb;53(2):126-140. doi: 10.1055/s-0043-108216. Epub 2018 Feb 9. German. PMID 29426051
• May AD, Parker AM, Caldwell ES, Hough CL, Jutte JE, Gonzalez MS, Needham DM, Hosey MM. Provider-Documented Anxiety in the ICU: Prevalence, Risk Factors, and Associated Patient Outcomes. J Intensive Care Med. 2021 Dec;36(12):1424-1430. doi: 10.1177/0885066620956564. Epub 2020 Oct 9. PMID 33034254
• Tate JA, Devito Dabbs A, Hoffman LA, Milbrandt E, Happ MB. Anxiety and agitation in mechanically ventilated patients. Qual Health Res. 2012 Feb;22(2):157-73. doi: 10.1177/1049732311421616. Epub 2011 Sep 9. PMID 21908706
• Cooper AB, Thornley KS, Young GB, Slutsky AS, Stewart TE, Hanly PJ. Sleep in critically ill patients requiring mechanical ventilation. Chest. 2000 Mar;117(3):809-18. doi: 10.1378/chest.117.3.809. PMID 10713011
• Hardin KA, Seyal M, Stewart T, Bonekat HW. Sleep in critically ill chemically paralyzed patients requiring mechanical ventilation. Chest. 2006 Jun;129(6):1468-77. doi: 10.1378/chest.129.6.1468. PMID 16778263
• Honarmand K, Rafay H, Le J, Mohan S, Rochwerg B, Devlin JW, Skrobik Y, Weinhouse GL, Drouot X, Watson PL, McKinley S, Bosma KJ. A Systematic Review of Risk Factors for Sleep Disruption in Critically Ill Adults. Crit Care Med. 2020 Jul;48(7):1066-1074. doi: 10.1097/CCM.0000000000004405. PMID 32433122
• Gehlbach BK, Chapotot F, Leproult R, Whitmore H, Poston J, Pohlman M, Miller A, Pohlman AS, Nedeltcheva A, Jacobsen JH, Hall JB, Van Cauter E. Temporal disorganization of circadian rhythmicity and sleep-wake regulation in mechanically ventilated patients receiving continuous intravenous sedation. Sleep. 2012 Aug 1;35(8):1105-14. doi: 10.5665/sleep.1998. PMID 22851806

Идентификаторы

NCT: NCT06468436 · 2024-239

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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