Methylene Blue in Sepsis: A Randomized Controlled Trial

NCT ID: NCT00486174

Last Updated: 2008-05-29

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: NA
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-06-30

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

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.

Conditions

Sepsis

Keywords

Sepsis; Methylene Blue; Norepinephrine

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

standard sepsis therapy plus Methylene Blue

Group Type: ACTIVE_COMPARATOR

methylene blue

Intervention Type: DRUG

2.0 mg/kg of Methylene Blue administered every 6 hours (as required) for up to 48 hours.

2

standard sepsis therapy

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

methylene blue

2.0 mg/kg of Methylene Blue administered every 6 hours (as required) for up to 48 hours.

Intervention Type: DRUG

Eligibility 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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Physicians' Services Incorporated Foundation

OTHER

Sponsor Role: collaborator

Queen's University

OTHER

Sponsor Role: lead

Responsible Party

Queen's University

Principal Investigators

Daniel W Howes, MD

Role: PRINCIPAL_INVESTIGATOR

Queen's University

Countries

Canada

Other Identifiers

PSI Grant application #2006-36

Identifier Type: -

Identifier Source: secondary_id

EMED-090-07

Identifier Type: -

Identifier Source: org_study_id