Thursday, March 21, 2013

Methylene Blue: A Wash in Septic Shock?

Even with all the therapies available for the management of septic shock, there still remains a great incidence of morbidity and mortality associated with this condition. One therapeutic agent that has been advocated for refractory septic shock is methylene blue (MB). Yes, you read that right...the same agent used as an antidote for the treatment of methemoglobinemia.

Here is the low down. Nitric oxide (NO) is thought to be one of the major culprits for the manifestation of the vasodilatory effects seen in septic shock, as it activates guanylate cyclase to produce cyclic guanosine monophosphate (cGMP). Nitric oxide is produced through the activate of nitric oxide synthase (NOS), of which there are two types that exist: (1) constitutive NOS (cNOS) and (2) inducible NOS (iNOS), the latter being activated in the presence of cytokines and endotoxins. The downstream effects of accumulated cGMP include decreased sensitivity to vasopressor therapy, increased permeability within the vasculature, decreased systemic vascular resistance, and depressed contractility of the myocardium. On the flip side, NO may have potential benefits in septic shock with its actions as a free radical scavenger and may help enhance oxygen delivery to ischemic tissue as well as increase the activity of macrophages. Because of this, non-selective suppression of NOS can have harmful effects in the patient with refractory septic shock.

Enter MB, which acts on iNOS to competitively inhibit the activation of guanylate cyclase in the vascular smooth muscle. With this specific inhibition of guanylate cyclase, the theoretical benefits of this process include increased mean arterial pressure and improved vascular resistance, which has been demonstrated in animal studies.

So what about the effects of MB in refractory septic shock in humans? There have only been a couple of controlled clinical trials that have been published regarding this, which are reviewed in the table below:



Other small observational studies have been conducted, and have been reviewed here and here. Based on the results of the studies, MB seems to improve hemodynamic parameters (i.e. "make the numbers look good") but had no real impact in improving clinical outcomes (i.e. mortality). Varying dosing and administration strategies (bolus versus continuous infusion) of MB have been employed in these small studies as well, and with lack of a homogenous patient population across these studies, it may be difficult to determine which patients with refractory septic shock can receive the greatest short-term and long-term benefits from treatment with MB.

In addition, there are some considerations that we need to keep in mind as well. MB may be ineffective in patients with G6PD deficiency, and because these patients are at greater risk of experiencing hemolytic anemia, use of MB is generally not recommended. In addition, discoloration of the skin, bodily fluids, and mucous membranes is a potential adverse effect associated with treatment.


Moreover, in critically patients with refractory septic shock, it is not uncommon to find that continuous renal replacement therapy (CRRT) is used to help manage and prevent further progression of acute renal failure. In fact, an estimated 5% of all critically ill patient will receive CRRT during the course of their hospital stay. What are the implications of CRRT on the efficacy of MB should it be used in such patients with refractory septic shock? Only one case report has been published that has evaluated this, which found that MB is not significantly removed in CVVHDF, and the authors concluded that caution should be used when administering MB for refractory septic shock in patients concomitantly receiving CVVHDF.

The jury for MB in the management of refractory septic shock is still out. Careful consideration of the patient being selected for treatment with MB as well as the dosing strategy and place of MB in the course of the treatment of the patient are important factors to determine whether or not the patient will truly benefit from MB. Bear in mind that although the hemodynamic status may improve in patients being treated with MB for refractory septic shock, the mortality benefits have not been demonstrated.

References:
Kirov MY, Evgenov OV, Evgenov NV, et al. Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med 2001; 29:1860-1867.
Memis D, Karamanlioglu B, Yuksel M, et al. The influence of methylene blue infusion on cytokine levels during severe sepsis. Anaesth Intensive Care 2002; 30:755-762.