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This study has been withdrawn prior to enrollment.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

June 12, 2007
May 26, 2008
June 2007
Not Provided
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 ]
  • 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 ]
  • total norepinephrine administered [ Time Frame: 96 hours ]
  • number of whole hours norepinephrine free [ Time Frame: hourly for 96 hours ]
Complete list of historical versions of study NCT00486174 on ClinicalTrials.gov Archive Site
  • 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 ]
  • safety of methylene blue [ Time Frame: 96 hours ]
  • survival to ICU discharge [ Time Frame: 30 days ]
  • survival to hospital discharge [ Time Frame: 30 days ]
Not Provided
Not Provided
 
Methylene Blue in Sepsis: A Randomized Controlled Trial
Intermittent Bolus Infusion of Methylene Blue to Reduce Norepinephrine Requirements in Sepsis: A Randomized Controlled Trial

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

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.

Interventional
Not Provided
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Sepsis
Drug: methylene blue
2.0 mg/kg of Methylene Blue administered every 6 hours (as required) for up to 48 hours.
  • Active Comparator: 1
    standard sepsis therapy plus Methylene Blue
    Intervention: Drug: methylene blue
  • No Intervention: 2
    standard sepsis therapy
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Withdrawn
0
Not Provided
Not Provided

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).
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Not Provided
 
NCT00486174
EMED-090-07, PSI Grant application #2006-36
Yes
Dr. Daniel W Howes, Queen's University
Queen's University
The Physicians' Services Incorporated Foundation
Principal Investigator: Daniel W Howes, MD Queen's University
Queen's University
May 2008

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP