Clinical trial NCT03120637: Evaluating in Cirrhotics With Refractory Vasoplegia the Effect of Methylene Blue
Official title: Evaluating in Cirrhotics With Refractory Vasoplegia the Effect of Methylene Blue in Sepsis: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Septic Shock
Vasoplegia
Cirrhosis, Liver
Refractory Shock
Keywords: Methylene Blue
Septic Shock
Vasoplegia
Cirrhosis
Lead sponsor: Institute of Liver and Biliary Sciences, India
Sponsor class: OTHER
First posted: 2017-04-19
Enrollment: 111
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: SUPPORTIVE_CARE

Brief summary: Mortality rates associated septic shock remains unacceptably high, around 20-50%, with refractory hypotension in half of these patients. Widespread vasodilatation involves the activation of the soluble intracellular enzyme guanylate cyclase (GC) by nitric oxide (NO), resulting in the production of cyclic guanosine monophosphate (cGMP). Initially discovered as an endothelium-derived relaxing factor in blood vessels, NO is made by the enzyme nitric oxide synthase (NOS). It has been suggested that the inhibition of NO generation might be a treatment option for sepsis and septic shock. Methylene blue (MB) is a dye that easily crosses cell membranes, inhibits iNOS, and is capable of inhibiting the GC enzyme in vascular smooth muscle cells.Early use of MB can block the progressive decrease in systemic vascular resistance of patients unresponsive to noradrenaline and mitigate the need for prolonged vasoconstrictor use. The investigators propose to study the effect of methylene blue on cirrhotic adults with sepsis, with refractory vasoplegia unresponsive to maximum doses of noradrenaline and vasopressin.


Eligibility criteria: Inclusion Criteria:

1. Adult patients (\>18 years )
2. Refractory septic shock (Noradrenaline \>0.5mcg/kg/mt )

Exclusion Criteria:

1. Declined consent
2. Pregnancy
3. Less than 18 years old
4. Immunosuppressant patients (e.g. on steroid medication, active anti-cancer chemotherapeutic agent, etc.)
5. Glucose-6-phosphate dehydrogenase deficiency
6. Medication of Serotonin modulator/SSRI
7. Pre-existing Pulmonary Hypertension
8. CKD-Stage IV/V
9. Patients with GI bleed
10. Patients on DNR
11. Patients declared Brain dead

Primary outcomes:
measure: Survival in both groups
timeFrame: 2 days
Secondary outcomes:
measure: Systemic Vascular Resistance
timeFrame: 6 hours
measure: Mean Arterial Pressure
timeFrame: 6 hours
measure: Decrease of vasopressor dose of 20 percent from time of start of test drug.
timeFrame: 6 hours
Other outcomes:
Locations:
city: New Delhi
country: India
facility: Liver Coma ICU, Institute of Liver and Biliary Sciences
state: Delhi
Study officials:
affiliation: Institute of Liver and Biliary Sciences
name: Karthik Ponnappan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bassi E, Park M, Azevedo LC. Therapeutic strategies for high-dose vasopressor-dependent shock. Crit Care Res Pract. 2013;2013:654708. doi: 10.1155/2013/654708. Epub 2013 Sep 15.
citation: Park BK, Shim TS, Lim CM, Lee SD, Kim WS, Kim DS, Kim WD, Koh Y. The effects of methylene blue on hemodynamic parameters and cytokine levels in refractory septic shock. Korean J Intern Med. 2005 Jun;20(2):123-8. doi: 10.3904/kjim.2005.20.2.123.
citation: Kirov MY, Evgenov OV, Evgenov NV, Egorina EM, Sovershaev MA, Sveinbjornsson B, Nedashkovsky EV, Bjertnaes LJ. Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med. 2001 Oct;29(10):1860-7. doi: 10.1097/00003246-200110000-00002.
citation: Memis D, Karamanlioglu B, Yuksel M, Gemlik I, Pamukcu Z. The influence of methylene blue infusion on cytokine levels during severe sepsis. Anaesth Intensive Care. 2002 Dec;30(6):755-62. doi: 10.1177/0310057X0203000606.
citation: Juffermans NP, Vervloet MG, Daemen-Gubbels CR, Binnekade JM, de Jong M, Groeneveld AB. A dose-finding study of methylene blue to inhibit nitric oxide actions in the hemodynamics of human septic shock. Nitric Oxide. 2010 May 15;22(4):275-80. doi: 10.1016/j.niox.2010.01.006. Epub 2010 Jan 28.