Methylene Blue and Microcirculation in Septic Shock

Study Overview
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Brief Summary
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This trial aims to identify the effects of methylene blue infusion on the the micro-circulation in patients with septic shock. The investigators will evaluate various indices of micro-circulation such as: microvascular ﬂow index, the flow heterogeneity index, the total vessel density, the perfused vessel density, and the proportion of perfused vessels.

Detailed Description
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The mortality rate of patients with septic shock remains very high. Arterial hypotension, related to arteriolar vasodilation and myocardial depression are the mainstays of septic shock pathology. At the level of the micro-circulation, there is insufficient delivery of oxygen to organs and tissues which results in organ dysfunction and potential organ necrosis.One key factor leading to vascular dysfunction is the inappropriately increased production of nitric oxide within the blood vessel endothelium. Elevated levels of nitric oxide results in the blood vessel endothelium receiving direct vasodilator input, as well as the inability to respond to norepinephrine-mediated vasoconstriction. Nitric oxide activates the soluble isoform of the enzyme guanylatecyclase, which in turn increases production of cyclic guanosine monophosphate. Nitric oxide has other beneficial effects which are mediated via other pathways than guanylatecyclase; therefore, administration of a guanylate cyclase inhibitor such as methylene blue could be a safer therapeutic option than the inhibition of nitric oxide production. These effects of methylene blue could be related to vasoconstriction and positive inotropic effects as well to an increase in blood volume, itself related to a decrease in vascular permeability. The use of methylene blue has been recently advocated as a potential adjunct in the treatment of shock states. However, the effect of MB at the level of the capillary bed, where vital exchange of oxygen and nutrients occurs, is unknown. Thus in this study, the investigators will investigate the effect of methylene blue in combination with NE at the microvascular level in septic shock.

Official Title
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The Effect of Methylene Blue on Microcirculation in Patients With Septic Shock: a Randomized Controlled Trial

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: Methylene Blue
* Drug: Norepinephrine infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Septic shock The patient is on norepinephrine infusion Exclusion Criteria: Elevated serum creatinine (above 1.4 mg/dL) Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: methylene blue group<br>The patients in this group will receive methylene blue bolus in addition to the norepinephrine infusion. | Drug: Methylene Blue<br>* The patient will receive Methylene Blue bolus with a dose of 2 mg/kg over 10 minutes.<br>Drug: Norepinephrine infusion<br>* The patient will receive norepinephrine infusion to maintain mean arterial pressure above 65 mmHg<br>* Other names: Levophed;|
| Active Comparator: Norepinephrine group<br>The patients in this group will receive norepinephrine infusion. | Drug: Norepinephrine infusion<br>* The patient will receive norepinephrine infusion to maintain mean arterial pressure above 65 mmHg<br>* Other names: Levophed;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microvascular flow index | The image will be divided into four quadrants and the vessels <20 μ m diameter will be assigned a score based on the predominant flow characteristics of the vessels in that quadrant (0 = absent flow; 1 = intermittent; 2 = sluggish; 3 = normal). The values in each quadrant will be averaged to give an microvascular flow index for each sublingual site at each time point. To determine heterogeneity of perfusion, the flow heterogeneity index will be calculated as the highest microvascular flow index minus the lowest microvascular flow index divided by the mean microvascular flow index. | 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total vessel density | The number of vessels per millimeters squared. | 6 hours | 
| Perfused vessel density | The number of vessels multiplied by the fraction of perfused vessels | 6 hours | 
| Proportion of perfused vessel | The number of vessels with flows 2 and 3 divided by the total number of vessels and multiplied by 100. | 6 hours | 
| mean arterial pressure | the mean arterial blood pressure measured in mmHg | 24 hours | 
| serum lactate | the value of lactate in the serum measured in milligrams per liter | 6 hours | 
| length of stay in the intensive care unit | the duration of stay in the intensive care unit measured in days | 28 days | 
| cardiac output | The amount of blood ejected by the heart in one minute measured in liters | 24 hours | 
| total consumption of norepinephrine | the total consumption of norepinephrine in 6 hours measured in micrograms. | 6 hours | 
| incidence of mortality | The number of dead patients divided by the total number of patients | 28 days |