Methylene Blue and Microcirculation in Septic Shock

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

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.

Study Overview

• Status: Unknown
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Methylene Blue; Drug: Norepinephrine infusion

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 32
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: ahmed hasanin, Professor; Phone Number: +201095076954; Email: ahmedmohamedhasanin@gmail.com
• Study Contact Backup: Name: kareman abdelghaffar, Demonstrator; Phone Number: +201223931469; Email: kareman_86@hotmail.com

Study Locations

• Egypt
  • Cairo, Egypt
    • Cairo University
    • Contact: Ashraf Rady, Professor; Email: ashrafrady83@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Septic shock
• The patient is on norepinephrine infusion

Exclusion Criteria:

• Elevated serum creatinine (above 1.4 mg/dL)
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Cairo University
• Investigators: Principal Investigator: Ahmed Mukhtar, Professor, Professor of Anesthesia

Study record dates

Study Major Dates

• Study Start (Anticipated): March 10, 2020
• Primary Completion (Anticipated): September 10, 2020
• Study Completion (Anticipated): September 20, 2020

Study Registration Dates

• First Submitted: March 3, 2020
• First Submitted That Met QC Criteria: March 3, 2020
• First Posted (Actual): March 5, 2020

Study Record Updates

• Last Update Posted (Actual): March 5, 2020
• Last Update Submitted That Met QC Criteria: March 3, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Adrenergic alpha-Agonists; Adrenergic Agonists; Sympathomimetics; Vasoconstrictor Agents; Norepinephrine; Methylene Blue
• Other Study ID Numbers: N-13-2019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No