A Phase 2 interventional study of Ketamine (0.5 mg/kg) and Normal Saline (0.9% NaCl) in Critical Illness and Depressive Symptoms, sponsored by Hospital Italiano de Buenos Aires. Recruiting at 2 sites in 2 countries. Open to participants aged 18 Years to 99 Years. Per ClinicalTrials.gov, last updated 2026-09-02.
Sponsored by Hospital Italiano de Buenos Aires · Phase 2, Interventional, and Treatment
Depressive symptoms are common among patients admitted to the intensive care unit (ICU) and may adversely affect recovery, participation in care, treatment adherence, quality of life, and outcomes after critical illness. Conventional antidepressants have limited utility for rapidly treating depressive symptoms during an ICU admission because of their delayed onset of action and potential drug interactions in medically complex patients.
Ketamine is an N-methyl-D-aspartate receptor antagonist with rapid antidepressant effects when administered intravenously at subanesthetic doses. However, evidence regarding its efficacy and safety for depressive symptoms developing during critical illness remains limited.
The KID-ICU trial is a Phase II randomized, double-blind, placebo-controlled, multicenter trial evaluating subanesthetic intravenous ketamine for moderate-to-severe depressive symptoms in adult ICU patients. Eligible participants are adults who have been admitted to an ICU for 6 or more days and have a Patient Health Questionnaire-9 (PHQ-9) score of 10 or greater.
Participants will be randomized in a 1:1 ratio to receive either intravenous ketamine at 0.5 mg/kg, with a maximum dose of 60 mg per infusion, administered over 60 minutes once daily for 2 consecutive days, or normal saline placebo with an identical volume, appearance, and infusion duration.
The primary efficacy outcome is the change in PHQ-9 total score from baseline to Day 14 after the second scheduled infusion. Secondary outcomes include the longitudinal trajectory of PHQ-9 scores through Day 30, clinically meaningful PHQ-9 response at Day 14, anxiety and depressive symptoms assessed with the Hospital Anxiety and Depression Scale, Clinical Global Impression scores, prespecified safety events, time to ICU and hospital discharge alive, and 30-day all-cause mortality.
A total of 50 participants will be enrolled across participating ICUs in Argentina. Psychiatric and clinical follow-up will be provided to all participants regardless of treatment assignment.
Depressive symptoms are clinically relevant among patients with critical illness and may be exacerbated by acute illness, pain, immobility, sleep disruption, loss of autonomy, and prolonged hospitalization. These symptoms may negatively affect recovery, participation in care, treatment adherence, quality of life, and outcomes after critical illness.
Ketamine is an N-methyl-D-aspartate receptor antagonist with rapid antidepressant effects when administered at subanesthetic doses. In non-ICU populations, intravenous ketamine has been associated with early improvement in depressive symptoms. However, its efficacy and safety for depressive symptoms developing during critical illness remain uncertain.
KID-ICU is a Phase II randomized, double-blind, placebo-controlled, multicenter clinical trial with two parallel groups and 1:1 allocation. Eligible participants will be adult ICU patients with moderate-to-severe depressive symptoms, defined as a Patient Health Questionnaire-9 (PHQ-9) score of 10 or greater after 6 or more days of ICU admission. The PHQ-9 will be used to measure depressive symptom severity and not as a standalone diagnostic instrument for major depressive disorder.
Participants assigned to the ketamine group will receive intravenous ketamine at 0.5 mg/kg, with a maximum dose of 60 mg per infusion, administered over 60 minutes once daily for 2 consecutive days. Participants assigned to the placebo group will receive intravenous normal saline in an identical volume, appearance, and infusion duration. Study medication will be prepared by the research pharmacy in indistinguishable infusion bags.
Participants, care providers, investigators, and outcome assessors will remain blinded to treatment assignment. Only authorized unblinded research pharmacy personnel and the trial statistician responsible for generating or maintaining the allocation sequence will have access to treatment assignments. Emergency unblinding will be available through a predefined institutional procedure when knowledge of the assigned treatment is required for the clinical management of a serious or life-threatening event.
Randomization will be stratified by participating ICU site and implemented through the Research Electronic Data Capture randomization module. Treatment allocation will remain concealed until the database is locked, except when emergency unblinding is required.
Participants will undergo continuous clinical monitoring during and after each infusion, including heart rate, cardiac rhythm, blood pressure, peripheral oxygen saturation, respiratory status, and mental status. Adverse events will be assessed before, during, and after each infusion using clinical monitoring and the Ketamine Side Effect Tool. An infusion may be temporarily interrupted or permanently discontinued because of clinically significant hypertension, tachycardia, bradycardia, arrhythmia, respiratory deterioration, deterioration in consciousness, severe agitation, psychotic symptoms, or another serious adverse event according to prespecified criteria and investigator judgment.
Study assessments will be performed at baseline before the first infusion, before the second infusion, 24 hours after the second scheduled infusion, and at Days 7, 14, and 30 after the second scheduled infusion. Telephone follow-up will be permitted for participants discharged before completion of follow-up, using the same standardized outcome assessment procedures.
Depressive symptoms will be assessed with the PHQ-9. Anxiety and depressive symptoms will be assessed using the anxiety and depression subscales of the Hospital Anxiety and Depression Scale. Global clinical severity and improvement will be assessed using the Clinical Global Impression-Severity and Clinical Global Impression-Improvement scales.
The primary efficacy outcome is the change in PHQ-9 total score from baseline to Day 14 after the second scheduled infusion. Secondary outcomes include the longitudinal trajectory of PHQ-9 scores through Day 30, clinically meaningful PHQ-9 response at Day 14, longitudinal changes in Hospital Anxiety and Depression Scale subscale scores, Clinical Global Impression scores, prespecified treatment-emergent safety events, time to ICU discharge alive, time to hospital discharge alive, and all-cause mortality within 30 days after randomization.
The primary efficacy analysis will follow the intention-to-treat principle and compare PHQ-9 scores at Day 14 between treatment groups, adjusting for baseline PHQ-9 score and participating site. The treatment effect will be reported with a 95 percent confidence interval. Longitudinal PHQ-9 scores will be evaluated using a mixed-effects model including treatment group, categorical assessment time, and the treatment-by-time interaction. Time-to-discharge outcomes will account for death as a competing event. Secondary analyses will be considered exploratory.
All data will be collected prospectively using the Research Electronic Data Capture platform. Bedside assessments may initially be documented on paper source forms and subsequently transcribed into the electronic database. The planned sample size is 50 participants, with 25 participants assigned to each treatment group.
**Inclusion Criteria:**
**Exclusion Criteria:**
Participants receive intravenous subanesthetic ketamine at 0.5 mg/kg (maximum 60 mg/day regardless of body weight), administered over 40-60 minutes, once daily for 2 consecutive days. The drug is prepared by the research pharmacy in bags visually identical to placebo. Administration via peripheral or central venous access with continuous hemodynamic monitoring.
Drug: Ketamine (0.5 mg/kg)
Participants receive intravenous normal saline (0.9% NaCl) prepared by the research pharmacy in bags visually identical to the ketamine preparation (same volume, color, and infusion duration of 40-60 minutes), once daily for 2 consecutive days. Identical hemodynamic monitoring and psychiatric assessment schedule as the experimental arm.
Other: Normal Saline (0.9% NaCl)
Ketamine hydrochloride for injection, diluted in 100 mL normal saline. Dose: 0.5 mg/kg (maximum 60 mg per infusion). Route: intravenous. Rate: infused over 40-60 minutes. Frequency: once daily. Duration: 2 consecutive days. Total maximum cumulative dose: 120 mg. Administered via peripheral or central venous catheter under continuous monitoring in the ICU.
Also known as: Ketalar, Ketamine hydrochloride
Normal saline (0.9% NaCl) in 100 mL bag, identical in appearance to the ketamine preparation. Infused over 40-60 minutes, once daily for 2 consecutive days. Administered via peripheral or central venous catheter.
Change in PHQ-9 Score from Baseline to Day 14 Post-Last Infusion
The Patient Health Questionnaire-9 (PHQ-9) is a validated 9-item self-report scale measuring the severity of depressive symptoms (score range 0-27; higher scores indicate greater severity). The primary efficacy endpoint is the change in PHQ-9 total score (ΔPHQ-9 = baseline score minus Day-14 score), where positive values indicate improvement.
Time frame: From baseline (before first infusion, Day 0) to Day 14 after the last infusion
Incidence of Safety Events During and After Ketamine Infusion
Safety is assessed by the incidence of: (1) clinically significant hemodynamic instability requiring intervention (severe hypertension SBP ≥180 mmHg or DBP ≥110 mmHg requiring antihypertensives; sustained tachycardia ≥160 bpm; bradycardia \<50 bpm; vasopressor initiation); (2) acute neuropsychiatric events (confusion, agitation, disorientation, dissociation, hallucinations, psychotic symptoms); (3) treatment discontinuation due to adverse events. Assessed using the Ketamine Side Effect Tool (KSET) and continuous monitoring.
Time frame: During infusion and up to 240 minutes after each infusion (Days 1 and 2), and at follow-up visits (Days 1, 7, 14, and 30 post-last infusion)
Longitudinal Change in PHQ-9 Total Score Through Day 30 Post-Last Infusion
The PHQ-9 total score ranges from 0 to 27, with higher scores indicating greater depressive symptom severity. PHQ-9 scores will be assessed repeatedly at baseline, 24 hours, Day 7, Day 14, and Day 30 post-last infusion. Longitudinal trajectories will be compared between treatment groups. The analysis will estimate between-group differences in change from baseline at each follow-up time point and the overall treatment-by-time interaction.
Time frame: Baseline, 24 hours, Day 7, Day 14, and Day 30 post-last infusion
PHQ-9 Response Rate (Sensitivity Analysis): Proportion Achieving ≥5-Point Reduction
Proportion of patients with a clinically significant improvement defined as a reduction of ≥5 points in PHQ-9 total score from baseline to Day 14
Time frame: Baseline to Day 14 post-last infusion
Change From Baseline in Hospital Anxiety and Depression Scale Total Score at Day 14
The Hospital Anxiety and Depression Scale (HADS) is a 14-item participant-reported questionnaire assessing anxiety and depressive symptoms. Total scores range from 0 to 42, with higher scores indicating greater symptom severity. For each participant, change will be calculated as the baseline HADS total score minus the Day-14 score; therefore, positive values indicate improvement. The change in HADS total score will be compared between treatment groups, adjusting for baseline HADS score and participating site.
Time frame: Time Frame: Baseline before the first infusion to Day 14 after the second scheduled infusion
Longitudinal Change in Hospital Anxiety and Depression Scale Total Score Through Day 30
The Hospital Anxiety and Depression Scale (HADS) is a 14-item participant-reported questionnaire assessing anxiety and depressive symptoms. Total scores range from 0 to 42, with higher scores indicating greater symptom severity. HADS total scores will be assessed repeatedly at baseline, 24 hours, Day 7, Day 14, and Day 30 after the second scheduled infusion. The analysis will estimate between-group differences in change from baseline at each follow-up assessment and the overall treatment-by-time interaction.
Time frame: Baseline (Day 0, before first infusion), 24 hours, Day 7, Day 14, and Day 30 post-last infusion
Clinical Global Impression - Improvement Score
The Clinical Global Impression - Improvement scale is a clinician-rated instrument used to assess overall clinical improvement compared with baseline. The score ranges from 1 to 7, where 1 indicates "very much improved" and 7 indicates "very much worse." Scores will be compared between groups at each assessment point.
Time frame: Infusion Day 2, 24 hours post-last infusion, Day 7, Day 14, and Day 30 post-last infusion.
Clinical Global Impression - Severity Score
The Clinical Global Impression - Severity scale is a clinician-rated instrument used to assess overall psychiatric illness severity. The score ranges from 1 to 7, where 1 indicates "normal, not at all ill" and 7 indicates "among the most extremely ill patients." Scores will be compared between groups at each assessment point.
Time frame: Baseline, Infusion Day 1, Infusion Day 2, 24 hours post-last infusion, Day 7, Day 14, and Day 30 post-last infusion.
Intensive Care Unit Length of Stay
Number of days from randomization to Intensive Care Unit discharge
Time frame: From the date of randomization to the date of Intensive Care Unit discharge, for up to 100 days
30-Day Mortality
Proportion of patients who die within 30 days of the last infusion
Time frame: From randomization to hospital discharge or Day 30 post-last infusion, whichever comes first
Hospital length of stay
Number of days from randomization to hospital discharge, with death treated as a competing event
Time frame: From the date of randomization to the date of hospital discharge, for up to 100 days
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Hospital Italiano de Buenos Aires