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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):
Daniel Talmor, Beth Israel Deaconess Medical Center

Tracking Information
First Submitted Date  ICMJE March 12, 2010
First Posted Date  ICMJE March 18, 2010
Results First Submitted Date  ICMJE December 22, 2015
Results First Posted Date  ICMJE August 21, 2017
Last Update Posted Date August 21, 2017
Study Start Date  ICMJE December 2009
Actual Primary Completion Date June 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 21, 2017)
Serum Levels of IL-6, IL-10 and TNFα [ Time Frame: first 7 days of admission, Baseline and Day 7 reported ]
Original Primary Outcome Measures  ICMJE
 (submitted: March 17, 2010)
Serum levels of IL-6, IL-10 and TNFα and other cytokines [ Time Frame: first 7 days of admission ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 21, 2017)
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 17, 2010)
  • 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 ]
Current Other Pre-specified Outcome Measures
 (submitted: July 21, 2017)
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.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Immunomodulatory Properties of Ketamine in Sepsis
Official Title  ICMJE Immunomodulatory Properties of Ketamine in Sepsis
Brief Summary 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.
Detailed Description
  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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Sepsis
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 21, 2017)
19
Original Estimated Enrollment  ICMJE
 (submitted: March 17, 2010)
32
Actual Study Completion Date  ICMJE June 2011
Actual Primary Completion Date June 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01089361
Other Study ID Numbers  ICMJE 2009P000259
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Daniel Talmor, Beth Israel Deaconess Medical Center
Original Responsible Party Daniel Talmor, MD, MPH, Beth Israel Deaconess Medical Center
Current Study Sponsor  ICMJE Beth Israel Deaconess Medical Center
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Daniel Talmor, MD, MPH Beth Israel Deaconess Medical Center
PRS Account Beth Israel Deaconess Medical Center
Verification Date July 2017

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