Methylene Blue in Sepsis: A Randomized Controlled Trial (SMURF)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00486174
Recruitment Status : Withdrawn (primary site withdrew due to competing study: never enrolled any subjects.)
First Posted : June 14, 2007
Last Update Posted : May 29, 2008
The Physicians' Services Incorporated Foundation
Information provided by:
Queen's University

Brief Summary:
The purpose of this study is to investigate whether the addition of Methylene Blue to the standard treatment of septic shock will reduce vasopressor requirements

Condition or disease Intervention/treatment Phase
Sepsis Drug: methylene blue Not Applicable

Detailed Description:

The management of severe infections, sepsis and septic shock is a serious problem facing physicians. Septic shock kills 10,000 Canadians every year. It is the most common cause of death in intensive units and the rates of sepsis and septic shock continue to increase annually.

Septic shock is a complex interaction between pathologic vasodilation, relative and absolute hypovolemia, myocardial depression, and altered microvascular function resulting from a systemic inflammatory response to infection. After restoration of the circulating volume, many patients continue to suffer from a maldistribution of blood flow. Current hypotheses suggest that global indicators of hypoperfusion (serum lactate, hypotension, decreased oxygen delivery) represent an averaging of areas of normal or increased blood flow with areas where blood flow is decreased. These under-perfused areas become more hypoxic. The resulting tissue damage leads to more inflammation and more maldistribution, perpetuating a vicious cycle progressing on to death.

Vasopressive agents are used in an attempt to maintain mean arterial blood pressure and restore perfusion, but these agents work globally, potentially worsening blood flow to the under-perfused areas. As well, many vasopressors have deleterious side effects such as metabolic and endocrine functions, and changes to regional blood flow.

The microvascular changes are mediated by primarily nitric oxide (NO). Baseline levels of nitric oxide are produced by constitutive Nitric Oxide Synthase (cNOS), with NO levels measured in the nano-molar range. Inflammatory mediators cause increased production of inducible Nitric Oxide Synthase (iNOS) leading to NO levels measured in the micro-molar range.

Suppression of nitric oxide production using non-specific NOS inhibitors has had discouraging results. Methylene Blue is a selective iNOS inhibitor. The purpose of this pilot study is to confirm safety and demonstrate signs of benefit in the use of methylene blue in sepsis. In particular, this study will examine whether the addition of methylene blue to standard early goal directed therapy in sepsis will reduce vasopressor requirements.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Intermittent Bolus Infusion of Methylene Blue to Reduce Norepinephrine Requirements in Sepsis: A Randomized Controlled Trial
Study Start Date : June 2007

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sepsis
U.S. FDA Resources

Arm Intervention/treatment
Active Comparator: 1
standard sepsis therapy plus Methylene Blue
Drug: methylene blue
2.0 mg/kg of Methylene Blue administered every 6 hours (as required) for up to 48 hours.
No Intervention: 2
standard sepsis therapy

Primary Outcome Measures :
  1. The primary outcome of interest is to assess the norepinephrine requirements in the methylene blue groups to maintain a mean arterial blood pressure greater or equal to 65 mmHg in comparison to the control group. [ Time Frame: hourly for 96 hours ]

Secondary Outcome Measures :
  1. safety of methylene blue [ Time Frame: 96 hours ]
  2. survival to ICU discharge [ Time Frame: 30 days ]
  3. survival to hospital discharge [ Time Frame: 30 days ]
  4. total norepinephrine administered [ Time Frame: 96 hours ]
  5. number of whole hours norepinephrine free [ Time Frame: hourly for 96 hours ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • First presentation of sepsis syndrome: clinical evidence of infection with Systemic Inflammatory Response Syndrome (SIRS)as defined by two or more of:

    • Temperature > 38°C or < 36°C,
    • Heart rate > 90 beats per minute,
    • One or more of respiratory rate > 20, hyperventilation with PaCO2 < 32 mm Hg, requiring mechanical ventilation,
    • One or more of white blood cells > 12,000 X 109 /L or white blood cells < 4000 X 109 /L or immature neutrophils > 10%.
  • Undergoing early goal directed therapy with a mean arterial blood pressure (MAP) < 65 mmHg despite fluid resuscitation to CVP > 10mmHg.
  • Able to provide informed consent as per our institutional standard.
  • To receive first dose of study drug within six hours of first recorded hypotension (MAP < 65mmHg).

Exclusion Criteria:

  • Age < 18 years.
  • Undergoing palliation.
  • Not expected to survive 48 hours.
  • Resuscitated from a vital sign absent arrest.
  • Ongoing dialysis.
  • Anuric or creatinine > 300 μmol/L.
  • Pregnant.
  • Patient or family history of glucose-6-phosphate dehydrogenase deficiency.
  • Allergic to methylene blue, phenothiazines, thiazide diuretics, or food dyes.
  • Patient mass > 150 kg.
  • Demonstrated Pulmonary Hypertension (Mean Pulmonary Artery Pressure > 25 mmHg by Swan Ganz Catheter or Echo demonstrated Right Ventricular Systolic Pressure > 40 mmHg).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00486174

Sponsors and Collaborators
Queen's University
The Physicians' Services Incorporated Foundation
Principal Investigator: Daniel W Howes, MD Queen's University

Responsible Party: Dr. Daniel W Howes, Queen's University Identifier: NCT00486174     History of Changes
Other Study ID Numbers: EMED-090-07
PSI Grant application #2006-36
First Posted: June 14, 2007    Key Record Dates
Last Update Posted: May 29, 2008
Last Verified: May 2008

Keywords provided by Queen's University:
Methylene Blue

Additional relevant MeSH terms:
Systemic Inflammatory Response Syndrome
Pathologic Processes
Methylene Blue
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Autonomic Agents
Peripheral Nervous System Agents
Vasoconstrictor Agents
Enzyme Inhibitors