Methylene blue and refractory hypotension

My name is Will Pendergraft, and I just completed the clinical portion of the joint nephrology fellowship between Brigham and Women’s Hospital and Massachusetts General Hospital. I was inspired for the first time by Nate Hellman during my residency at UCSF when I started to peruse this blog. If you have any free time, it’s worth looking back at his very first post from 2008. I am astonished by how he wrote these posts on a daily basis! As a contributor to the blog, my goal will be to provide short and useful, or at least interesting, nephrocentric snippets for first-year fellows.

With that said, I was walking through the cardiac surgery ICU at MGH a few months ago on my way to provide moral support for one of my co-fellows who was placing a difficult dialysis catheter in someone with almost no access, and upon entering the patient’s room, I noticed that the urine in the collection bag was of a Mediterranean shade (see image)! Given that we are differentialists by trade, www.urinecolors.com has a pretty good list of what can cause different urine colors.

The surgical team said they were intravenously infusing methylene blue “to improve the patient’s refractory hypotension,” an idea with which I was unfamiliar, so I sprinted to the nearest computer to look into this more deeply.

Methylene blue was created in 1876 and was first used in humans in 1881 by nobel laureate Paul Ehrlich to treat mild cases of malaria. It now has multiple indications, most notably including reduction of methemoglobin to hemoglobin in methemoglobinemia. Intravenous and oral formulations are easily excreted into the urine turning it blue to bluish-green. Interestingly, methylene blue also inhibits guanylate cyclase, a second messenger involved in nitric oxide-mediated vasodilation; thus, it prevents smooth muscle relaxation. In cases of shock where fluids, standard pressors du jour and steroids are ineffective, methylene blue may be another medication in the anti-hypotensive toolkit. Surprisingly, there are over ten clinical trials with positive results using methylene blue in refractory septic shock, and it is even used by anesthetists and surgeons to treat vasoplegia after cardiopulmonary bypass. The dosing regimen is 2 mg/kg IV once as a bolus followed by continuous infusion. Remember methylene blue the next time you see this shade of urine and be on the lookout for it in the cardiac surgery ICUs.

Posted by Will Pendergraft

Sepsis & AKI - an insoluble problem?

I expect very few medical users of this website went into nephrology to manage acute kidney injury (AKI) in the context of sepsis. It is hard to avoid pessimism when considering the state of play in this condition: 65% of patients with septic shock develop AKI; this AKI is an independent risk factor for death and up to 75% of patients with AKI and severe sepsis die.

It is, therefore, not surprising that research into this area continues. Much of which has focussed on the use of extra-corporeal blood purification techniques (EBP) to improve outcomes via immune modulation by removal of circulating inflammatory mediators (summarised in this recent review by Ricci et al.).

The most familiar EBP technique is standard CVVH delivered at high doses. Indeed, when I was training in ICU in 2008 we would regularly use high volume CVVH (often seeking treatments of up to 6 L/hr) in patients with co-existent severe sepsis and AKI. Although both the ATN and RENAL trials failed to demonstrate any benefit of this tactic in the management of severe AKI, many feel that the ‘high intensity’ groups in these trials were simply not high intensity enough to demonstrate a treatment effect in septic patients. This feeling largely stems from a favourable body of evidence (summarised in this review) from animal studies and small trials with soft end-points using CVVH doses of 45-115ml/kg/hr (in contrast to the ATN and RENAL CVVH doses of 35-40ml/kg/hr). The completed but unpublished IVOIRE trial prospectively randomised 139 patients with septic shock and AKI to 70ml/kg/hr or 35ml/kg/hr with a primary outcome of all-cause mortality and may help to settle this argument.

The counter view is that dose approaches are bound to fail because whilst inflammatory mediators are water-soluble, their molecular weight means that they are unlikely to be maximally cleared by standard haemofilters. This can be attacked in two ways: high-cut off membranes or haemadsorption.

High-cut off membranes have been evaluated in small studies and demonstrated reduction in vasopressor requirements in septic patients. However, when used in continuous treatments these filters are associated with a very large obligate loss of albumin, leading some to suggest such filters should only be used in intermittent treatments (i.e. dialysis; similar to strategies used in myeloma).

Haemadsorption passes blood across broadly interacting sorbents to attract larger molecules, which exceed the cut off of standard membranes, thus making this an attractive technique for EBP in sepsis. Use of this technology had previously been limited by poor biocompatibility and resultant haematological abnormalities but recent advances have eliminated this problem. The commonest sorbent is polymyxin B, a systemically toxic antibiotic which can bind lipopolysaccharide and damage gram-negative bacteria. Although a number of studies have evaluated polymyxin B haemadsorption significant further work is required to make a compelling case for this treatment (excellently summarised by Ricci et al.)

Furthermore, coupled plasma filtration and adsorption has been trialled. This allows initial separation of plasma from blood, followed by selective passage of the plasma across the sorbent and has demonstrated some efficacy in small initial studies.

I find it hard to see where this field is going to end up; only high volume haemofiltration strategies seem to have a consensus behind them and these will always now be open to the charge that randomised controlled trials have shown them to be ineffective. Adsorptive techniques are currently relatively heterogeneous and therefore, the large multicentre trials required to demonstrate their applicability seem a long way off. It appears that septic AKI may continue to be a feared condition for some time yet.