SepsisPhase 1/2NCT01089361
Immunomodulatory Properties of Ketamine in Sepsis
A Phase 1/2 study testing Ketamine in people with Sepsis, run by Beth Israel Deaconess Medical Center at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 21 to 100 years
- Conditions the study is for
- Sepsis
- What is being tested?
- Ketamine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 19 participants
- Where
- 1 siteUnited States
- Study dates
- Dec 2009to Jun 2011
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- pregnant
- increased intracranial pressure or closed head injury
- history of psychotic mental disease
- receiving Continuous Veno - Venous Hemofiltration
Trial locations and contacts
1 site in 1 country.
United States1 site
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
About this study
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.
Read the detailed description
- Basic design A randomized placebo controlled trial of low dose ketamine in patients with severe sepsis in the ICU.
- 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.
- 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).
- 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.
- 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.
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
KetamineDrug
Also called Ketamine Hydrochloride, Ketalar
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.
Normal Saline placeboDrug
Also called 0.9% Sodium Chloride Solution
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.
| Study group | Role | What they receive |
|---|---|---|
| Normal saline placebo | Placebo comparator | 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. Receives: Drug: Normal Saline placebo |
| Ketamine | Experimental | 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. Receives: Drug: Ketamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Serum Levels of IL-6, IL-10 and TNFα
Measured: first 7 days of admission, Baseline and Day 7 reported
Secondary outcomes (5)
Adverse Effects Attributable to Ketamine
Measured: 7 days
Organ Failures
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
Measured: 7 days
Acute Physiology and Chronic Health Evaluation (APACHE) Scores
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.
Measured: First 24 hours after ICU admission
Length of Intensive Care Unit (ICU) Stay
Measured: 28 days
28 Day Mortality
Measured: 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Mar 2010 (estimated)
- Study startDec 2009
- Primary completionJun 2010
- Study completionJun 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for SepsisStudies of the same condition, open and under way.
- More trials run by Beth Israel Deaconess Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- Beth Israel Deaconess Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Daniel Talmor, Beth Israel Deaconess Medical Center
- Investigators
- Daniel Talmor, MD, MPH, Principal investigator, Beth Israel Deaconess Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01089361
- Sponsor's protocol ID
- 2009P000259
- Status last verified
- Jul 2017
- First submitted
- 12 Mar 2010
- Last updated
- 21 Aug 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Calandra T, Bochud PY, Heumann D. Cytokines in septic shock. Curr Clin Top Infect Dis. 2002;22:1-23. No abstract available.
PubMed 12520644Laudanski 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.
PubMed 17032758Kawasaki 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.
PubMed 10475301
Study at a glance
From the registry record, last updated by the sponsor on 21 Aug 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Immunomodulatory Properties of Ketamine in Sepsis
- ClinicalTrials.gov ID
- NCT01089361
- Acronym / sponsor ID
- 2009P000259
- Conditions
- Sepsis
- Keywords
- systemic inflammatory syndrome, sepsis syndrome, septic shock, Cytokine, Ketamine
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 19 participants (actual)
- Lead sponsor
- Beth Israel Deaconess Medical CenterUniversity, hospital or other
- Study start
- Dec 2009
- Primary completion
- Jun 2010 (actual)
- Study completion
- Jun 2011 (actual)
- First posted
- 18 Mar 2010 (estimated)
- Results
- Posted 21 Aug 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
- Basic design A randomized placebo controlled trial of low dose ketamine in patients with severe sepsis in the ICU.
- 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.
- 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).
- 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.
- 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Normal saline placebo | Placebo comparator | Drug: Normal Saline placeboThe 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 | Experimental | Drug: KetamineThe 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. |
Who may qualify
- Ages
- 21 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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:
Key exclusion criteria (4 listed)
- pregnant
- increased intracranial pressure or closed head injury
- history of psychotic mental disease
- receiving Continuous Veno - Venous Hemofiltration
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| KetamineAlso: Ketamine Hydrochloride, KetalarThe 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 | Ketamine |
| Normal Saline placeboAlso: 0.9% Sodium Chloride SolutionThe 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. | Drug | Normal saline placebo |
Primary outcome
Serum Levels of IL-6, IL-10 and TNFα
Time frame: first 7 days of admission, Baseline and Day 7 reported
5 secondary outcomes
Adverse Effects Attributable to Ketamine
Time frame: 7 days
Organ Failures
Time frame: 7 days
Acute Physiology and Chronic Health Evaluation (APACHE) Scores
Time frame: First 24 hours after ICU admission
Length of Intensive Care Unit (ICU) Stay
Time frame: 28 days
28 Day Mortality
Time frame: 28 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Aug 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 12520644Calandra T, Bochud PY, Heumann D. Cytokines in septic shock. Curr Clin Top Infect Dis. 2002;22:1-23. No abstract available.
- Background: PubMed 17032758Laudanski 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.
- Background: PubMed 10475301Kawasaki 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Daniel Talmor, MD, MPH principal investigator
Beth Israel Deaconess Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Ketamine in people with Sepsis, run by Beth Israel Deaconess Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Aug 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 21 Aug 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Serum Levels of IL-6, IL-10 and TNFα (time frame: first 7 days of admission, Baseline and Day 7 reported). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01089361, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Aug 2017.