Indo cyanine green retention test to study the effect of methylene blue on splanchnic circulation in patients with refractory septic shock proof of concept study.

Vasopressors are vital in the treatment of fluid-unresponsive septic shock. Current evidence suggests the use of noradrenaline as the first line vasopressor, followed by other drugs such as vasopressin, adrenaline, angiotensin-II, and terlipressin. There is an interest in the use of methylene blue infusion as a vasoconstrictor. One of the theoretical adverse effects of vasopressor therapy is their vasoconstrictive effect on the splanchnic circulation. This may impair already compromised gut circulation, leading to translocation of bacteria across the ischemic gut endothelium, worsening the septic shock. It was believed previously that noradrenaline worsens the gut and renal perfusion due to splanchnic vasoconstriction.However, noradrenaline actually increases the renal and gut perfusion by increasing the cardiac output as well as mean arterial pressure.

The inflammatory mediators such as endotoxins, cytokines,tumor necrosis factor alpha and interleukin-2 can induce a calcium-independent induced nitric oxide synthase (iNOS), leading to a sustained production of nitric oxide that does not respond tonegativefeedback mechanisms.  Nitric oxide causes significant vasodilatation leading to hypotension in patients with septic shock. Increased levels of NO are associated with diminished response to vasopressor therapy leading to need for high dose of vasopressors, altered regional blood flow distribution, increased capillary leakage and multiple organ dysfunction.

Methylene blue (MB) is an inhibitor of the inducible nitric oxide synthase (iNOS) and its downstream enzyme soluble guanylate cyclase (sGC), leading to vasoconstriction. Through its indirect pressor effects, it has been shown to restore vasoregulation in conditions of NO upregulation and inturn reduces the vasopressors dose.

Indocyanine green (ICG) is a fluorescent dye with high protein binding capacity which is exclusively metabolized in the liver and excreted in the bile. ICG retention test is often used to determinesplanchnic perfusion. Splanchnic blood flow can be estimated from the extraction of ICG from the plasma by the liver, this indirectly gives an idea about splanchnic circulation. In our hospital, ICG retention test is routinely used to assess the function of liver in patients planned for hepatic resection using peripheral blood sampling (without canulation of the hepatic vein) and has been standardized for this purpose. We intend to use this test for assessing the effect of MB on the splanchnic circulation.

From some recent studies, methylene blue (MB) seems to be effective as an adjunct for patients on dual vasopressor therapy (refractory septic shock). We are currently evaluating use of MB as an adjunct to Noradrenaline and Vasopressin in such patients in our ICU. (IEC Project no. 4216). Since we are using MB in these patients, we aim to evaluate the splanchnic perfusion in patients receiving methylene blue using ICG retention. This is a proof of concept study and we will recruit 10 patients, who are randomised in our other study to receive MB.