Immunomodulatory Properties of Ketamine in Sepsis

• Adverse effects attributable to ketamine [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
• Organ failures [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
  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 Thrmobocytopenia: platelet < 50k, platelet transfusion Liver: biopsy, ALT>200, AST>200, t.bil>2.0, ALP>300 Coaugulation failure: INR>2 if no anticoagulation therapy
• Daily Acute Physiology and Chronic Health Evaluation (APACHE) scores [ Time Frame: 7 days ] [ Designated as safety issue: No ]
  Difference in average APACHE-II score between the intervention and placebo groups. The point score is calculated from 12 routine physiological measurements (such as blood pressure, body temperature, heart rate etc.) during the first 24 hours after admission, information about previous health status and some information obtained at admission (such as age).
• Length of intensive care unit (ICU) stay [ Time Frame: 28 days ] [ Designated as safety issue: No ]
• 28 day mortality [ Time Frame: 28 days ] [ Designated as safety issue: No ]

• Adverse effects attributable to ketamine [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
• Organ failures [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
  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 ] [ Designated as safety issue: No ]
  Difference in average APACHE-II score between the intervention and placebo groups.
• Length of intensive care unit (ICU) stay [ Time Frame: 28 days ] [ Designated as safety issue: No ]
• 28 day mortality [ Time Frame: 28 days ] [ Designated as safety issue: No ]

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.

• 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.
• 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.

• Placebo Comparator: Normal saline
  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

• Calandra T, Bochud PY, Heumann D. Cytokines in septic shock. Curr Clin Top Infect Dis. 2002;22:1-23. Review. No abstract available.
• Laudanski K, Miller-Graziano C, Xiao W, Mindrinos MN, Richards DR, De A, Moldawer LL, Maier RV, Bankey P, Baker HV, Brownstein BH, Cobb JP, Calvano SE, Davis RW, Tompkins RG. Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways. Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15564-9. Epub 2006 Oct 10.
• Kawasaki T, Ogata M, Kawasaki C, Ogata J, Inoue Y, Shigematsu A. Ketamine suppresses proinflammatory cytokine production in human whole blood in vitro. Anesth Analg. 1999 Sep;89(3):665-9.

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