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

This study has been withdrawn prior to enrollment.
(primary site withdrew due to competing study: never enrolled any subjects.)
Sponsor:
Collaborator:
The Physicians' Services Incorporated Foundation
Information provided by:
Queen's University
ClinicalTrials.gov Identifier:
NCT00486174
First received: June 12, 2007
Last updated: May 26, 2008
Last verified: May 2008
  Purpose

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 Intervention
Sepsis
Drug: methylene blue

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Intermittent Bolus Infusion of Methylene Blue to Reduce Norepinephrine Requirements in Sepsis: A Randomized Controlled Trial

Resource links provided by NLM:


Further study details as provided by Queen's University:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • safety of methylene blue [ Time Frame: 96 hours ] [ Designated as safety issue: Yes ]
  • survival to ICU discharge [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
  • survival to hospital discharge [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
  • total norepinephrine administered [ Time Frame: 96 hours ] [ Designated as safety issue: Yes ]
  • number of whole hours norepinephrine free [ Time Frame: hourly for 96 hours ] [ Designated as safety issue: Yes ]

Enrollment: 0
Study Start Date: June 2007
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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).
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00486174

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

No publications provided

Responsible Party: Dr. Daniel W Howes, Queen's University
ClinicalTrials.gov Identifier: NCT00486174     History of Changes
Other Study ID Numbers: EMED-090-07, PSI Grant application #2006-36
Study First Received: June 12, 2007
Last Updated: May 26, 2008
Health Authority: Canada: Health Canada

Keywords provided by Queen's University:
Sepsis
Methylene Blue
Norepinephrine

Additional relevant MeSH terms:
Sepsis
Toxemia
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Methylene Blue
Norepinephrine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Vasoconstrictor Agents
Cardiovascular Agents
Therapeutic Uses
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents

ClinicalTrials.gov processed this record on April 17, 2014