Immunomodulatory Properties of Ketamine in Sepsis

NCT ID: NCT01089361

Last Updated: 2017-08-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 19 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-12-31
• Study Completion Date: 2011-06-30

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.

Conditions

Sepsis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: PLACEBO_COMPARATOR

Normal Saline placebo

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Ketamine

Intervention Type: DRUG

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.

Interventions

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 Type: 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.

Intervention Type: DRUG

Other Intervention Names

Ketamine Hydrochloride; Ketalar; 0.9% Sodium Chloride Solution

Eligibility Criteria

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

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Beth Israel Deaconess Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Daniel Talmor

Professor of Anaesthesia

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Daniel Talmor, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

Beth Israel Deaconess Medical Center

Locations

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Countries

United States

References

Calandra T, Bochud PY, Heumann D. Cytokines in septic shock. Curr Clin Top Infect Dis. 2002;22:1-23. No abstract available.

Reference Type: BACKGROUND

PMID: 12520644 (View on PubMed)

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. doi: 10.1073/pnas.0607028103. Epub 2006 Oct 10.

Reference Type: BACKGROUND

PMID: 17032758 (View on PubMed)

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. doi: 10.1097/00000539-199909000-00024.

Reference Type: BACKGROUND

PMID: 10475301 (View on PubMed)

Other Identifiers

2009P000259

Identifier Type: -

Identifier Source: org_study_id