Methylene Blue as a Third-line Vasopressor in Septic Shock

Study Overview
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Brief Summary
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A randomized, prospective study comparing ProvayBlue® to standard care with multiple sympathomimetic vasopressors.

Detailed Description
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The study will be an un-blinded, Phase 2, randomized, 1:1, prospective trial comparing patients in septic shock receiving norepinephrine and vasopressin followed by phenylephrine versus ProvayBlue® as the third-line vasopressor. The third line vasopressor will be compared at 1 hour to see if it affects the patient's mean arterial blood pressure (MAP).

Official Title
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Methylene Blue as a Third-line Vasopressor in Septic Shock to Maintain Hemodynamics

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: Methylene Blue
* Drug: Phenylephrine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Meets Sepsis-3 Criteria (Suspected source of infection plus any 2 criteria of the qSOFA) 2 .Septic Shock (any patient requiring vasopressor therapy to maintain MAP >65 mmHg or any patient with serum lactate >2 mmol/dL even in the absence of hypovolemia ). 3) Greater than 18 years old 4 ) ICU Admission Exclusion Criteria: Inability to obtain informed consent from an appropriate surrogate decision maker. Also: Children less than 18 years old Pregnant women or positive urinary pregnancy test in reproductive-aged women Prisoners Evolving myocardial infarction or known cardiomyopathy with documented EF<35% Known grade 3 diastolic dysfunction document by echocardiogram Known hypersensitivity to thiazine dyes Pulmonary hypertension that is currently requiring vasodilator therapy Concurrent form of shock present or suspected: Obstructive, Neurogenic, Hemorrhagic Known documented history of G6PD deficiency or favism Active prior to admission medication prescription for a SSRI or SNRI , systemic heparin anticoagulation or other medications listed above (under Study Agent). These medications will be listed in the printed enrollment form. Severe renal failure is a contraindication to use of ProvayBlue®.

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Control group<br>Patients in the control group will have phenylephrine infusion starting at 50 mcg/min and titrated to maintain a MAP >65 mmHg as a third line vasopressor. Maximum dose of Phenylephrine is 300 mcg/min. | Drug: Phenylephrine<br>* Prior to the initiation of the randomized treatment, the subject will have received 2 vasopressors ( norepinephrine and vasopressin) already , they will be initiated on IV hydrocortisone . Once the patient is unable to maintain a mean arterial pressure of >65mmHg and the hydrocortisone has been administered there will be an addition of a third-line vasopressor. Patients enrolled in the intervention group will receive ProvayBlue® and Patients enrolled in the control group will receive Phenylephrine infusion as a third line vasopressor in the treatment of septic shock.<br>|
| Experimental: Intervention group<br>Patients enrolled in the intervention group will receive 2 mg/kg IBW (Ideal Body Weight) bolus, given over 15 mins, of ProvayBlue® followed by a concomitant infusion at 2 mg/kg/hr (IBW) mixed in D5W, which will continue for 24 hours. ProvayBlue® ( Methylene Blue) will be used as the third-line vasopressor. | Drug: Methylene Blue<br>* Prior to the initiation of the randomized treatment, the subject will have received 2 vasopressors ( norepinephrine and vasopressin), they will be initiated on IV hydrocortisone . Once the patient is unable to maintain a mean arterial pressure of >65mmHg and the hydrocortisone has been administered there will be an addition of a third-line vasopressor. Patients enrolled in the intervention group will receive ProvayBlue® and Patients enrolled in the control group will receive Phenylephrine infusion as a third line vasopressor in the treatment of septic shock.<br>* Other names: ProvayBlue®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mean arterial pressure | The primary objective is to determine if the administration of ProvayBlue® is non-inferior to the use of phenylephrine as a third-line vasopressor to keep a mean arterial pressure (MAP)>65 mmhg after one hour and at 24 hours after the initiation of the drugs. | One hour and 24 hours after dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of acute kidney injury requiring dialysis | The secondary objectives are to see if the total vasopressor dosing and renal replacement needs are different in those patients receiving ProvayBlue® rather than standard care with escalating number of vasopressors. | through time of patient discharge, an average of 8 days after admission | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Septic Shock, Methylene Blue, Vasopressors, Provay Blue®