KetAmine and Recovery After Mechanical VentilAtion ( KARMA )

NCT07590687 | Not Yet Recruiting Phase 3

• 1 other identifier: APHP240938
• Study Type: interventional
• Target: 640
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Critical Illness

Keywords

Ketamine; Critical illness; Intensive care unit (ICU); Mechanical ventilation; Sedation; Delirium

Outcome Measures

Primary Outcomes (1)

• Number of days patients are alive and spent at home

  This endpoint will be collected by an independent research assistant, blinded to randomization groups, , and not involved in data monitoring onsite.

  At 60 days after ketamine initiation

Secondary Outcomes (10)

• Number of days alive free of encephalopathy

  During 14 days after randomization

• number of days spent alive without invasive mechanical ventilation

  At day 60

• Number of days spent alive without infusion norepinephrine infusion during ICU stay

  At day 60

• Mortality

  At Day 60 et Day 90

• Renal toxicity,

  At Day 60

Other Outcomes (2)

• Presence of anxiety and depression, defined by a score ≥11 on the anxiety and depression components of the Hospital Anxiety and Depression scale, respectively at 90 days;

  At Day 90

• Acute posttraumatic stressdisorder (PTSD)-related

  . At Day 90

Study Arms (2)

Intervention group

ACTIVE COMPARATOR

Ketamine will be started at a dose of 0.2 mg/kg/hour for 4 hours and then adjusted as necessary (+/-0.1 mg/kg/hour every 4 hours) from 0 to 0.6 mg/kg/hour to maintain a targeted RASS of -1 to 0, in addition to standard per local sedation and pain protocols. Duration of treatment: 14 days in maximum

Drug: Intervention Group

Control group

PLACEBO COMPARATOR

Intravenous placebo will be started at a dose of 0.2 mg/kg/hour for 4 hours and adjusted as necessary (+/-0.1 mg/kg/hour every 4 hours) from 0 to 0.6 mg/kg/hour to maintain a targeted RASS of -1 to 0, in addition to standard sedation per local protocol. Duration of treatment : 14 days in maximum

Drug: Placebo

Interventions

Intervention Group DRUG

Ketamine ® is supplied in 250 mg/5 ml vials containing sterile solution for dilution in sodium chlorure 0.9% for infusions.

Intervention group

Placebo DRUG

Placebo : NaCl 0.9% (vials)

Control group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients over 18 years of age
• 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" \[AME\])

You may not qualify if:

• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

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

Paris, 75018, France

Location

Related Publications (4)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 Critical Care Society and the Scandinavian Society of Anesthesiology and Intensive Care Medicine. Anesth Analg. 2025 Aug 1;141(2):309-326. doi: 10.1213/ANE.0000000000007173. Epub 2025 Jul 14.

  PMID: 39207913 BACKGROUND

• 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, Centofanti JE, Price C, Nikayin S, Misak CJ, Flood PD, Kiedrowski K, Alhazzani W. 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. doi: 10.1097/CCM.0000000000003299.

  PMID: 30113379 BACKGROUND

MeSH Terms

Conditions

Critical Illness; Delirium

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Neurocognitive Disorders; Mental Disorders

Study Officials

• Romain Prof SONNEVILLE, MD-PHD

  APHP

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Romain Prof SONNEVILLE, MD-PHD

CONTACT

1 40 25 61 39; romain.sonneville@aphp.fr

Matthieu Prof LEGRAND, M.D., Ph.D.

CONTACT

Matthieu.Legrand@ucsf.edu

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Treatments will be conditioned and labelled by AGEPS according to a list provided by an independent person and assigning a treatment arm to each treatment number. Patients, investigation site staff, persons performing the assessments, and data managers will remain blinded to the treatment codes from the time of randomization until database lock, using the following methods: * Randomization and treatment numbers lists are kept strictly confidential until the time of unblinding, and will not be accessible by anyone involved in the study, with the exception of the independent, unblinded statistician approving the randomization scheme; * The study will be kept blinded to patients, investigators and study personnel also during the entire study period; * The identification of treatment will be concealed by the use of a matching placebo to the study product that will be provided in boxes identical in packaging, labelling and appearance.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Two study groups will be formed: one will receive intravenous ketamine, while the other will receive an intravenous placebo

Study Record Dates

• First Submitted: May 5, 2026
• First Posted: May 15, 2026
• Study Start (Estimated): October 19, 2026
• Primary Completion (Estimated): December 19, 2029
• Study Completion (Estimated): January 19, 2030
• Last Updated: May 15, 2026

Record last verified: 2026-05

Locations

FR (1)