Immunomodulatory Properties of Ketamine in Sepsis
Condition: Sepsis
MeSH terms: Sepsis; Toxemia
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

Intervention name(s): Ketamine; Normal Saline placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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 intervention name(s): Ketamine Hydrochloride; Ketalar; 0.9% Sodium Chloride Solution
Intervention MeSH terms: Ketamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: systemic inflammatory syndrome; sepsis syndrome; septic shock; Cytokine; Ketamine