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Immunomodulatory Properties of Ketamine in Sepsis

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ClinicalTrials.gov Identifier: NCT01089361
Recruitment Status : Completed
First Posted : March 18, 2010
Results First Posted : August 21, 2017
Last Update Posted : August 21, 2017
Sponsor:
Information provided by (Responsible Party):

March 12, 2010
March 18, 2010
December 22, 2015
August 21, 2017
August 21, 2017
December 2009
June 2010   (Final data collection date for primary outcome measure)
Serum Levels of IL-6, IL-10 and TNFα [ Time Frame: first 7 days of admission, Baseline and Day 7 reported ]
Serum levels of IL-6, IL-10 and TNFα and other cytokines [ Time Frame: first 7 days of admission ]
Complete list of historical versions of study NCT01089361 on ClinicalTrials.gov Archive Site
  • Adverse Effects Attributable to Ketamine [ Time Frame: 7 days ]
  • Organ Failures [ Time Frame: 7 days ]
    Incidence of new organ failure as detected by Sequential Organ Failure Assessment [SOFA] score. Definitions are as follows. Central nervous system: delirium, coma, uncontrollable seizures, ICP>20cm H2O Cardiac: MAP <60mmHg, blood pressure supported with pressors, 50 > HR > 120 Respiratory: vented, RR>30, PaO2<60, PaCO2 > 55, Sat<92% Kidney: RIFLE criteria Anemia: Hct<27, transfusion of PRBC Thrombocytopenia: platelet < 50k, platelet transfusion Liver: biopsy, ALT>200, AST>200, t.bil>2.0, ALP>300 Coagulation failure: INR>2 if no anticoagulation therapy
  • Acute Physiology and Chronic Health Evaluation (APACHE) Scores [ Time Frame: First 24 hours after ICU admission ]
    Difference in average APACHE-II score between the intervention and placebo groups. APACHE II (Acute Physiology and Chronic Health Evaluation II) is a severity of disease classification system for patients admitted to the Intensive Care Unit. It uses an integer score from 0 to 71 that is computed based on age, 12 routine physiological measurements (i.e. heart rate, temperature, laboratory values), and previous health status obtained during the first 24 hours after ICU admission. Higher scores correspond to more severe disease and a higher risk of death.
  • Length of Intensive Care Unit (ICU) Stay [ Time Frame: 28 days ]
  • 28 Day Mortality [ Time Frame: 28 days ]
  • Adverse Effects Attributable to Ketamine [ Time Frame: 7 days ]
  • Organ Failures [ Time Frame: 7 days ]
    Incidence of new organ failure as detected by Sequential Organ Failure Assessment [SOFA] score.
  • Daily Acute Physiology and Chronic Health Evaluation (APACHE) scores [ Time Frame: 7 days ]
    Difference in average APACHE-II score between the intervention and placebo groups.
  • Length of Intensive Care Unit (ICU) Stay [ Time Frame: 28 days ]
  • 28 Day Mortality [ Time Frame: 28 days ]
PCR Substudy [ Time Frame: Daily up to 7 days ]
PCR analysis on serum samples for presence of bacterial and mitochondrial DNA; This substudy was not done.
Not Provided
 
Immunomodulatory Properties of Ketamine in Sepsis
Immunomodulatory Properties of Ketamine in Sepsis
The aim of the study is to assess the effect of short-term infusion of ketamine at analgesic dosage on the immune response, morbidity and mortality among patients suffering from septic shock. We hypothesize that ketamine will modulate the cytokine response to sepsis and reduce morbidity and mortality.
  1. Basic design A randomized placebo controlled trial of low dose ketamine in patients with severe sepsis in the ICU.
  2. Assembly of Subjects Patients meeting the ACCP/ SCCM definition of severe sepsis will be enrolled in the study5. These patients should have a known or suspected source of infection based on the clinical data at the time of screening. They must exhibit 3 or more of the following signs of clinical inflammation

    • Core temperature < 36ºC or > 38ºC.
    • Heart rate of 90 or greater not explained by another medical condition.
    • A respiratory rate of > 20 min-1, a PaCO2 < 32min-1 or the need for mechanical ventilation.
    • A white cell count of < 4000 cell/ml or > 12000 cells/ml or a WBC showing greater then 10% immature neutrophils.

    In addition the patient will have to be within 12 hours of the development of one or more organ dysfunctions as outlined in Bone et al 5.

    Several exclusion criteria will be in place to safeguard patient's safety 11. Patients with closed head trauma or with increased intracranial pressure will be excluded. Patients with a history of psychotic mental disease will also be excluded as they may be at risk for relapse following administration of ketamine.

  3. Exposures Patients will be randomized into a treatment group and a control group. The treatment group will receive 0.25mg/kg of ketamine over a period of one hour followed by a continuous infusion of ketamine at 0.1 mg/kg/hr for a further 23 hours. To help insure protocol compliance and safeguard patient care, a member of the study team will be present at the time the study drug infusion is started, and will also contact the clinical team when the infusion is due to be terminated. The dose of the ketamine is considered analgesic not anesthetic in nature and follows general practice in pain management 11. The control group will receive a similar volume of normal saline as a placebo. Additionally all patients enrolled in the study will receive lorazepam 1mg every 6 hours to further lower the risk of side effect from ketamine. Patients, staff and investigators will all be blinded to the treatment groups. All other care, including the need for further sedation, will be according to unit protocols.

    Prior to administration of the study drug a 10cc sample of the patient's blood will be drawn and frozen for later analysis. 2 hours after starting infusion another 10ml of blood will be obtained. Following 24 hour infusion of ketamine, blood samples will be drawn each day, for the following 7 days, processed and frozen.

    Patient demographic and clinical data will be collected on admission to the study and daily follow-up. Particular attention will be paid to calculation of the patient's APACHE II/MODS score on the day of admission and on the following days22. This will allow us to compare severity of disease in a potentially heterogeneous ICU patient population. We will also monitor use of the vasopressors, additional pain and sedative medication and physiological parameters (BP, HR, Sat, ABG, LFT, lactic acid) in studied population before and after administration of the drug. The adverse effect of ketamine will assessed by using delirium questionnaire and special chart designed to capture the emergence of side effect (delirium, psychosis, others).

  4. Outcomes and their measurement The primary outcome of the study will be serum levels of IL-6, IL-10 and TNFα and other cytokines over the first 7 days of admission. Measurement of cytokine levels will be done using enzyme linked immunoassay, or with flow cytometry at the end of the study by at researcher who will be blinded to the study groups. We also plan to separate leukocytes for further studies of mRNA levels to corroborate serum cytokine levels with activity of mRNA.

    Secondary outcomes will include adverse effects attributable to ketamine, organ failures, daily APACHE scores, length of ICU stay and 28 day mortality. A clinical research associate will carry out a daily patient assessment. This investigator will be blinded to the treatment groups. Data will be collected on a patient study chart. In addition to the incidence of organ dysfunction, death and length of stay, specific information will be gathered to assess patient's level of conscience, possible dreams or hallucinations and other effects, which may be attributable to ketamine.

  5. Substudy of serum samples We plan to perform real-time quantitative PCR analyses on the existing serum samples for the presence of bacterial and mitochondrial DNA on the samples. We will use primers targeting bacterial 16S-rRNA consensus areas and primers targeting gram-positive (S. Aureus), gram-negative (e. coli) and anaerobic (B. Fragilis) species. These tests may be able to accurately discriminate between systemic inflammation ("SIRS") due to invasive bacterial infections from SIRS due to tissue injury than do conventional bacteriologic analyses.
Interventional
Phase 1
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Sepsis
  • Drug: Ketamine
    The treatment group will receive 0.25mg/kg of ketamine over a period of one hour followed by a continuous infusion of ketamine at 0.1 mg/kg/hr for a further 23 hours.
    Other Names:
    • Ketamine Hydrochloride
    • Ketalar
  • Drug: Normal Saline placebo
    The control group will receive 0.25mg/kg of normal saline over a period of one hour followed by a continuous infusion of normal saline at 0.1 mg/kg/hr for a further 23 hours.
    Other Name: 0.9% Sodium Chloride Solution
  • Placebo Comparator: Normal saline placebo
    The control group will receive 0.25mg/kg of normal saline over a period of one hour followed by a continuous infusion of normal saline at 0.1 mg/kg/hr for a further 23 hours.
    Intervention: Drug: Normal Saline placebo
  • Experimental: Ketamine
    The treatment group will receive 0.25mg/kg of ketamine over a period of one hour followed by a continuous infusion of ketamine at 0.1 mg/kg/hr for a further 23 hours.
    Intervention: Drug: Ketamine

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
19
June 2011
June 2010   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients meeting the ACCP/ SCCM definition of severe sepsis will be enrolled in the study. These patients should have a known or suspected source of infection.
  • Patients within 12 hours of the development of one or more organ dysfunctions
  • Patients must exhibit 3 or more of the following signs of clinical inflammation:

    • Core temperature < 36ºC or > 38ºC.
    • Heart rate of 90 or greater not explained by another medical condition.
    • A respiratory rate of > 20 min-1, a PaCO2 < 32min-1 or the need for mechanical ventilation.
    • A white blood cell count of < 4000 cell/ml or > 12000 cells/ml or a WBC showing greater then 10% immature neutrophils.

Exclusion Criteria:

  • pregnant
  • increased intracranial pressure or closed head injury
  • history of psychotic mental disease
  • receiving Continuous Veno - Venous Hemofiltration
Sexes Eligible for Study: All
21 Years to 100 Years   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01089361
2009P000259
No
Not Provided
Plan to Share IPD: No
Daniel Talmor, Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center
Not Provided
Principal Investigator: Daniel Talmor, MD, MPH Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center
July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP