KetAmine and Recovery After Mechanical VentilAtion ( KARMA )

Официальное название

Intensive Care Treatment With Adjuvant KetAmine and Recovery After Mechanical ventilAtion: a Multicenter Doubleblind Randomized Controlled Trial.

Обзор

Invasive mechanical ventilation of critically ill patients in the intensive care unit (ICU) is associated with significant morbidity and mortality, as well as a severe prognosis in survivors, in terms of functional, psychological, and cognitive sequelae. During the initial phase, invasive mechanical ventilation aims to promote oxygenation and reduce respiratory effort, with most patients receiving continuous intravenous sedation comprising gamma-aminobutyric acid (GABA) agonists (propofol, midazolam), and opioids. This continuous intravenous sedation is associated with complications, particularly hemodynamic issues (e.g., hypotension, vasopressor dependency), and neurological concerns (e.g., coma, delayed awakening, withdrawal syndrome upon discontinuation of sedation) during the acute phase and is linked to prolonged mechanical ventilation and long-term neurocognitive sequelae. The use of ketamine as an alternative sedative agent in ICU has garnered considerable attention in recent years. Ketamine has a rapid onset of action and a short duration of effect, potentially beneficial bronchodilatory effects, and minimal impact on hemodynamics or respiratory drive. It also provides effective analgesia. Due to its action on N-methyl-D-aspartate (NMDA) glutamatergic receptors, its mechanism of action differs from other commonly used agents such as propofol and benzodiazepines. Furthermore, emerging research suggests that ketamine may have anti-inflammatory/immunomodulatory and neuroprotective properties that could be advantageous in critically ill patients. Recent observational studies utilizing low-dose ketamine have suggested an improvement in neurological complications in ICU (e.g., coma, delirium) while other authors have raised concerns about potential renal and hepatic toxicity associated with high doses of ketamine used for sedation. Despite its increasing use, there is currently a lack of high-quality data on the efficacy and safety of ketamine use for sedation in critically ill patients. In this trial, we hypothesise that, critically ill patients requiring unplanned invasive mechanical ventilation, adjunctive treatment with low dose of ketamine will translate into better outcomes, with higher numbers of days alive outside of the hospital. The study is a multicenter, randomised, double-blinded placebo-controlled superiority trial involving adult patients requiring unplanned mechanical ventilation, and sedation for more than 6 hours in the ICU. Patients will be randomised within 48 hours following initiation of mechanical ventilation adhering to a 1:1 allocation of ketamine or placebo. Patients will be randomized to receive either intravenous ketamine or placebo as an adjunctive sedative agent during ICU stay for a maximum duration of 14 days. Follow-up visits will be performed at day 3, day 14, ICU discharge, day 60, and day 90 after randomization. The primary endpoint, "days alive and at home," will be assessed at day 60. The end of the research visit is the day 90 follow-up visit. If the patient has been discharged from the hospital, the day-90 visit will consist of telephone contact with the patient by a centralized research assistant and he also will complete the scales at D90. Data collected by phone consist in Vital status, scales's results and Retrieval of Adverse Events if the patient has been discharged home or with the medical team of the healthcare structure if the patient has been discharged to another structure.

Подробное описание

Phase III study Prospective, multicenter, superiority, double-blind, randomized controlled study with two arms (1:1).

The study includes a screening/baseline visit (V0), followed by daily assessments during the intervention period (V1 to V4), and post-discharge (V5) follow-up visits at Day 60 (V6) and Day 90 (V7).

At screening and baseline (within 48 hours prior to Day 1), eligibility is confirmed, and informed consent is obtained when possible. In cases where prior consent cannot be obtained, deferred consent procedures are applied in accordance with French legislation. Baseline data include medical history, comorbidities, concomitant treatments, clinical examination, and pregnancy testing when applicable.

Randomization is performed at Day 1 (V1). From Day 1 to Day 14 (V4), patients will be receive either intravenous ketamine or placebo as an adjunctive sedative agent during ICU stay for a maximum duration of 14 days.

Until ICU discharge (V5), patients undergo daily assessments including clinical examination, vital status, organ dysfunction (Sequential Organ Failure Assessment \[SOFA\] score), At Day 14 (V4), opioid and sedative consumption during the treatment period will be quantified.

At Day 60 (V6), ventilator-free days and vasopressor-free days will be assessed.

Duration of delirium and coma are assessed using the RASS/CAM-ICU, at V 4, during the first 14 days following randomization.

Biological monitoring includes daily measurement of serum creatinine and liver function parameters (ASAT, ALAT, gamma-GT, and bilirubin) to evaluate potential renal and hepatic toxicity. Adverse events are collected throughout the ICU stay, and assessed at Day 60 (V6) At ICU discharge (V5), a clinical evaluation and morbidity/mortality assessment are performed if the patient is still hospitalized.

The primary endpoint-the number of days alive and at home-is assessed at Day 60. Secondary outcomes, including mortality (all-cause deaths), are assessed at both Day 60 (V6) and Day 90(V7).

Вмешательства

• Препарат Intervention Group
  Ketamine ® is supplied in 250 mg/5 ml vials containing sterile solution for dilution in sodium chlorure 0.9% for infusions.
• Препарат Placebo
  Placebo : NaCl 0.9% (vials)

Первичные конечные точки

• Number of days patients are alive and spent at home [Срок оценки: At 60 days after ketamine initiation]

Вторичные конечные точки (10)

• Number of days alive free of encephalopathy [Срок оценки: During 14 days after randomization]
• number of days spent alive without invasive mechanical ventilation [Срок оценки: At day 60]
• Number of days spent alive without infusion norepinephrine infusion during ICU stay [Срок оценки: At day 60]
• Mortality [Срок оценки: At Day 60 et Day 90]
• Renal toxicity, [Срок оценки: At Day 60]
• Liver toxicity [Срок оценки: At Day 60]
• Quantification of opioid and sedative consumption [Срок оценки: Within the 14 days after randomization]
• Mean daily pain (BPS) [Срок оценки: During the first 14 days after randomisation]
• Cumulative incidence of hallucination events [Срок оценки: During 14 days after randomization]
• Mean daily sedation score (RASS) [Срок оценки: During the first 14 days after randomisation]

Критерии участия

Критерии включения

• Patients over 18 years of age
• Signed informed consent or inclusion under the emergency provisions of the law (ArticleL1122 -1-3 of the PHC / modified by Order n°2016-800 of June 16 2016 - art. 2)
• Need for unplanned invasive mechanical ventilation
• Need for continuous intravenous sedative agents (propofol, midazolam or dexmedetomidine) for more than 6 hours.
• Affiliation to a social security system (excluding "Aide Médicale d'Etat" \[AME\])

Критерии исключения

• Refusal to participate in the study
• Acute brain injuries (i.e. acute stroke, traumatic brain injury, cardiac arrest, brain infections) or conditions (status epilepticus or coma with suspected/confirmed intracranial hypertension at admission requiring deep sedation)
• Psychosis
• Status asthmaticus
• Current liver failure with Model for End-Stage Liver Disease (MELD) > 30
• Initiation of mechanical ventilation > 48 hours
• Expected lifespan < 24 hours
• Patients already receiving a continuous infusion of ketamine
• Currently participating in another interventional clinical trial investigating sedation or protocols using Ketamine or another drug which may interact with Ketamine or which may have an impact on the evaluation of the trial's judgement criteria.
• Positive highly sensitive pregnancy test
• Persons deprived of liberty
• Persons on a protective judicial measure
• Breastfeeding
• Severe arterial hypertension (mean arterial pressure>130 mmHg) despite treatment
• Hypersensitivity to the active substances or any of the excipients
• Known contraindications to ketamine according to the SmPC (Severe heart failure, history of stroke, severe uncontrolled hypertension, severe aneurysmal disease, pheochromocytoma)

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

Двойное слепое

Основная цель

Лечение

Центры проведения

Франция · 1 центр

• Department of Intensive Care Medicine, APHP.Nord, hôpital Bichat Claude Bernard, — Paris

Публикации

• de Tymowski C, Depret F, Dudoignon E, Legrand M, Mallet V; Keta-Cov Research Group. Ketamine-induced cholangiopathy in ARDS patients. Intensive Care Med. 2021 Oct;47(10):1173-1174. doi: 10.1007/s00134-021-06482-3. Epub 2021 Jul 27. No abstract available. PMID 34313797
• Legrand M, Constantin JM, Burry L, Sonneville R. Ketamine and Traumatic Memory After Intensive Care Unit Discharge: Patient Population and Sedation Concerns. Anesth Analg. 2025 Oct 1;141(4):e48-e49. doi: 10.1213/ANE.0000000000007643. Epub 2025 Jul 17. No abstract available. PMID 40675617
• Amer M, Hylander Moller M, Alshahrani M, Shehabi Y, Arabi YM, Alshamsi F, Ingi Sigurethsson M, Rehn M, Chew MS, Kalliomaki ML, Lewis K, Al-Suwaidan FA, Al-Dorzi HM, Al-Fares A, Alsadoon N, Bell CM, Groth CM, Parke R, Mehta S, Wischmeyer PE, Al-Omari A, Olkkola KT, Alhazzani W. Ketamine Analgo-sedation for Mechanically Ventilated Critically Ill Adults: A Rapid Practice Guideline from the Saudi Crit PMID 39207913
• Devlin JW, Skrobik Y, Gelinas C, Needham DM, Slooter AJC, Pandharipande PP, Watson PL, Weinhouse GL, Nunnally ME, Rochwerg B, Balas MC, van den Boogaard M, Bosma KJ, Brummel NE, Chanques G, Denehy L, Drouot X, Fraser GL, Harris JE, Joffe AM, Kho ME, Kress JP, Lanphere JA, McKinley S, Neufeld KJ, Pisani MA, Payen JF, Pun BT, Puntillo KA, Riker RR, Robinson BRH, Shehabi Y, Szumita PM, Winkelman C, C PMID 30113379

Идентификаторы

NCT: NCT07590687 · APHP240938

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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