Immunomodulatory Properties of Ketamine in Sepsis

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.