Methylene Blue in Sepsis: A Randomized Controlled Trial (SMURF)
|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|
- 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 ]
- 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 ]
|Study Start Date:||June 2007|
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
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00486174
|Principal Investigator:||Daniel W Howes, MD||Queen's University|