Methylene Blue: the drug you’ve never used
“Major Major had been born too late and too mediocre. Some men are born mediocre, some men achieve mediocrity, and some men have mediocrity thrust upon them. With Major Major it had been all three …”
In my younger days, parked on a bench overlooking Stanley Park, I sought truth in the absurdist novels of the mid-20th century; Catch-22 by Joseph Heller is perhaps one of my absolute favourites. As I moved through medical school, residency and fellowship, I clung to science and medicine like flotsam in the shifting chaos of human sickness and health. During these objective pursuits, however, a creeping realization twisted itself over me like a winding sheet – dogma and bias also deck these hallowed halls. So I look to the cosmos – our place in the universe. With this I am enthralled, mystified and piqued with anxiety; yet the definite appears increasingly illusory. Alas, it seems, I am left with these three anecdotal truths to guide me:
No one loves you like your mother
No one is more excited to see you than your dog
When faced with completely recalcitrant distributive shock, try a dose of methylene blue
A 30 year old woman is admitted from the ED to the medical intensive care unit following intentional ingestion of multiple bottles of her father’s blood pressure medication. Her father had recently refilled his nifedipine 90 mg XL prescription which included 3 month’s supply; all 90 pills appeared to have been ingested. The patient was last seen well-appearing 10 hours prior to being found unresponsive in her bedroom. She is intubated for altered mental status and aspiration pneumonia. She has acute kidney injury, a lactate level of 9.8 mmol/L and an initial blood pressure of 55/20 with a heart rate of 93 beats per minute. The remainder of a toxicology screen is negative and she is given 4 litres of lactated ringers, started on antibiotics, as well as: epinephrine, vasopressin, phenylephrine, noradrenaline and a glucagon infusion. Further, she receives 10 mg of dexamethasone. A bedside TTE reveals a preserved LV ejection fraction, but her blood pressure remains 80/30 with no urine output. The partial pressure of carbon dioxide from a peripherally-obtained venous blood gas is 92 mmHg with a simultaneously-obtained arterial partial pressure of carbon dioxide of 36 mmHg.
While there certainly can be a mismatch between macrovascular hemodynamic parameters and microvascular physiology, recalcitrant precapillary arteriolar dilation can impair the pressure head for organ perfusion. In the face of systemic smooth muscle dilation secondary to calcium channel blocker toxicity, therapy can be challenging.
The vasoconstrictive properties of methylene blue [MB] are only pronounced when the patient’s pathophysiology is marked by an upregulation of nitric oxide [NO]. Recall that cyclic GMP promotes smooth muscle vasodilation by reducing the amount of calcium there is within the cytosol. When there is diminished calcium within the cytosol, actin and myosin cannot interact and contraction cannot occur. Calcium channel blockade also reduces the amount of calcium in the cytosol. By contrast, stimulation of adrenergic receptors increases intracellular calcium concentration, and therefore smooth muscle contraction. Nitric oxide stimulates the production of cGMP; therefore vasodilation is enhanced by nitric oxide. Methylene blue, by contrast, lowers cGMP by two mechanisms. Firstly, MB directly inhibits the production of nitric oxide via nitric oxide synthase [NOS]. Secondly, MB blocks the generation of cGMP from GTP by inhibiting the iron heme moiety of soluble guanylate cyclase [sGC], the enzyme which turns GTP into cGMP [see figure 1].
Figure 1: The right side of the diagram represents the ‘relaxation pathway’ where cytokines and reactive oxygen species [ROS] upregulate nitric oxide synthase [NOS] and stimulate soluble guanylate cyclase [sGC], both of which augment the generation of cyclic GMP [cGMP]. cGMP lowers intracellular calcium concentration by shifting calcium into the sarcoplasmic reticulum [SR]. By contrast, adrenergic agents, which stimulate adrenergic receptors increase intracellular calcium [Ca++] which facilitates actin-myosin interaction and therefore contraction on the left side of the diagram. Methylene blue [MB] inhibits both NO synthesis and cGMP synthesis. This inhibition of the ‘relaxation pathway’ favours contraction.From Figure 1, it can be seen that MB tends to inhibit the right-sided vasodilatory pathway, especially in states when NO is upregulated. Therefore, the left-sided vasoconstrictive pathway is favoured. Importantly, the pathways in figure 1 also affect cardiac myocytes, which means that increasing cGMP within the heart will alter cardiac contractility as well.
The Use of Methylene Blue
Cardiopulmonary bypass [CPB] is a common precipitating event for refractory vasodilation. Notably, there is literature which has systematically surveyed the use of several vasopressor agents following CPB – no evidence of organ dysfunction was found nor was one agent discovered to be superior to the others. While MB is typically used only in recalcitrant vasodilation following CPB, one study suggested benefit when MB was given pre-operatively in those at high risk for loss of vascular tone post-CPB.
Small studies have looked at the use of MB in both liver transplantation and septic shock. There are case reports of MB use in severe calcium channel blocker overdose. In totality, however, there is little good data to help direct when this potentially-underutilized drug can and should be administered. In one meta-analysis of a heterogeneous and small population of patients including severe sepsis, post-CPB and liver transplantation, MB was found to improve mean arterial pressure without significant adverse reactions. In general, MB tends to be a drug of 'last resort.'
For more information, please see this excellent and recent review by Hosseinian and colleagues.
Firstly, MB is likely a partial inhibitor of monoamine oxidase A, so its use with concomitant serotonergic agents is cautioned. Secondly, as mentioned above, focusing on macrovascular hemodynamics without consideration for microvascular abnormalities may lead us astray. One potential illustration of this is the decade-old study which investigated the inhibition of NOS in patients with sepsis – that is, a life-threatening organ dysfunction as a consequence of a dysregulated response to infection. There was an increase in mortality. Perhaps NOS has pleiotropic effects regulating microvascular perfusion? One potential, though imperfect, method to assess global microcirculatory perfusion is tissue carbon dioxide tension – specifically, the ratio of VCO2 to VO2. In the studies of MB in sepsis listed above, none recorded venous changes in the partial pressure of carbon dioxide relative to changes in oxygen kinetics.
Return to the Case
The patient receives a single dose of MB at 2 mg/kg. Within two hours, her MAP rises; epinephrine, and phenylephrine are titrated off. There is a blue discolouration of her skin and urine and the reading of her pulse oximeter is ignored. Repeat ABG-VBG analysis of her right brachial artery and vein demonstrate partial pressures of carbon dioxide of 50 mmHg – 40 mmHg, respectively. Three days later she is liberated from both vasoactive medications and mechanical ventilation. She concludes her treatment of aspiration pneumonia and is transferred to the inpatient psychiatry service for further care.
While I am left with the aforementioned anecdotes as my guiding-principles, I now find myself returning to my younger self; I look to the absurd and consider one final aphorism given to us by Camus.
4. The struggle itself toward the heights is enough to fill a (wo)man's heart. One must imagine Sisyphus happy.