Methylene Blue & CPB

Is Methylene blue an Effective Adjunct Therapy for Treating Refractory Hypotension in Septic Endocarditis?

This question was posed to me from a member of Perflist who submitted the question a few months ago.

I really wasn’t familiar with the topic, have never seen Methylene Blue used for anything but urology cases to inspect the patency of ureters (to make sure they weren’t accidentally nicked during surgery).

The use of Methylene Blue on Bypass is actually an interesting question and it seems that it has potential clinical merit specifically for patients presenting with infective endocarditis.

I will present the following and let you draw you own conclusions.  There is lots of room for discussion, especially when reviewing some theoretical potential side effects…

Any comments or suggestions are encouraged for our mutual benefit, and in particular this one perfusionist who brought up the topic.

Cheers !

Methylene blue is a monoamine oxidase inhibitor (MAOI).

Methylene blue is a component of a frequently prescribed urinary analgesic/anti-infective/anti-spasmodic known as “Prosed”.

In Terms of CPB … Methylene blue has been used to treat refractory vasoplegia after cardiopulmonary bypass (CPB), anaphylaxis, and septic shock.

The following is a case study of methylene blue used in the CPB prime and in the context of refractory hypotension in a patient undergoing valve replacement surgery for infective endocarditis.

Case Study: 

Clinical summary

A 72-year-old man weighing 80 kg was admitted for investigation of a 3-month history of worsening shortness of breath associated with malaise, rigors, and swollen ankles.

Abnormal results of routine blood tests included a C-reactive protein level of 69.2 mg/L and a white blood cell count of 16.4 x 109 cells/L. A transthoracic echocardiogram showed two large, highly mobile vegetations on the aortic valve, with resultant severe aortic regurgitation and a thickened anterior mitral valve leaflet with moderate mitral regurgitation.

The patient’s left ventricle was not dilated and was noted to have reasonable function. A diagnosis of infective endocarditis was made, and surgery was planned for the next day.

Upon induction, anesthesia was maintained with isoflurane up to 1.2%.

Persistent hypotension was treated with phenylephrine hydrochloride boluses to a total dose of 1.6 mg before CPB. A dopamine infusion was commenced at 5.2 µg/(kg x min), and a norepinephrine infusion was started, increasing to 0.02 µg/(kg x min).

Despite this, the blood pressure remained low at 100/22 mm Hg.  The measured  cardiac output was 6.0 L/min with a systemic vascular resistance (SVR) of 550 dynes x s/cm5.

On the basis of refractory hypotension and a low SVR, 160 mg methylene blue (2 mg/kg) was added to the pump prime before the start of CPB, and once CPB was established a central venous infusion was commenced at 1 mg/(kg x h).

Dopamine was continued at 4.2 µg/(kg x min) during CPB, but the norepinephrine was stopped.

Surgery was uncomplicated with the removal of both the mitral and aortic valves and replacement with prosthetic 29-mm CarboMedics and 25-mm CarboMedics Top Hat valves (Sulzer CarboMedics Inc, Austin, Tex), respectively.

During CPB no further phenylephrine or norepinephrine was used, and mean blood pressure was maintained at 50 mm Hg. Separation from CPB was achieved with dopamine at 4.2 µg/(kg x min) and methylene blue at 0.5 mg/(kg x h).

The CPB time was 155 minutes, and the crossclamp time was 124 minutes. Five minutes after CPB, the blood pressure was 118/54 mm Hg, the heart rate was 103 beats/min in sinus rhythm, the cardiac output was 3.3 L/min, and the SVR was 1600 dynes x s/cm5.

Methylene blue was continued until 30 minutes after CPB. There were no episodes of cardiac ischemia or arrhythmia after CPB. Before CPB the ratio of Pao2 to inspired oxygen fraction was 31 kPa, whereas after CPB it dropped to 14 kPa. The patient was admitted to the cardiothoracic intensive care unit and extubated 15 hours later. Subsequent blood and valve cultures isolated Streptococcus mitis.

Discussion

Infective endocarditis is a life-threatening condition that occasionally necessitates emergency valve replacement. It has a spectrum of clinical presentation and is associated with a systemic inflammatory response and the release of endothelial nitric oxide.

Many of the drugs used in cardiac anesthesia and the process of CPB itself may exacerbate the reduction in SVR through both similar and unknown mechanisms.

In this case there was a clear temporal relationship with the administration of methylene blue and the reduced quantities of vasopressors required to maintain normotension through an increase in the SVR.

Sepsis is characterized by arterial vasodilatation, a high cardiac output despite myocardial depression, and a decreased sensitivity of the heart and peripheral vessels to sympathomimetic agents.

The myocardial depression and relative insensitivity to sympathomimetic agents may be mediated in part by nitric oxide. This has been demonstrated in vitro by the inhibition of vascular smooth muscle and cardiomyocyte contraction by serum from patients with sepsis.

Methylene blue inhibits this process by decreasing intracellular cGMP concentrations through guanylate cyclase inhibition, and it increases myocardial function, arterial pressure, and oxygen delivery after a single dose.

Adverse Reactions

Detrimental effects of methylene blue on gas exchange may occur through a process of pulmonary vasoconstriction and disruption of cGMP-dependent ventilation-perfusion matching.

Other uncommon side effects described with the use of methylene blue include cardiac ischemia and arrhythmias.

Although neither occurred in this case, side effects may become a problem in patients with critical coronary perfusion or an irritable myocardium. Heparin neutralization by methylene blue has been described; however, there were no difficulties with anticoagulation while the patient was on CPB.

Hypertension is listed as an adverse reaction, and from reading further seems to be the desired effect secondary to postoperative hypotension demonstrated in patients with infective endocarditis.

Conclusion

Patients with an ongoing systemic inflammatory response as a result of infective endocarditis and those who require CPB for emergency valve replacement may demonstrate resistant hypotension related to vasoplegia.

Methylene blue should be added to the CPB prime (2 mg/kg) and continued as an infusion (0.25-2 mg/[kg x h]) to ameliorate this hypotension.

Such a regimen may be extended to other clinical circumstances in which resistant hypotension is contributed to by activation of the nitric oxide pathway, such as anaphylaxis and CPB.

References

  • Methylene blue during cardiopulmonary bypass to treat refractory hypotension in septic endocarditis  Link

M. Grayling, MB, BS, FRCAa, C. D. Deakin, MA, MD, MRCP, FRCAb Southampton, United Kingdom

From Shackleton Department of Anaesthesia, Southampton General Hospital, Southampton, United Kingdom.

Cited from Above Article…

  • Evora PR. Should methylene blue be the drug of choice to treat vasoplegias caused by cardiopulmonary bypass and anaphylactic shock? J Thorac Cardiovasc Surg. 2000;119:632-4.[Free Full Text]
  • Kirov MY, Evgenov OV, Evgenov NV, Egorina EM, Sovershaev MA, Sveinbjornsson B, et al. Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med. 2001;29:1860-7.[Medline]
  • Hollenberg SM, Cunnion RE, Parrillo JE. Effect of septic serum on vascular smooth muscle: in vitro studies using rat aortic rings. Crit Care Med. 1992;20:993-8.[Medline]
  • Daemen-Gubbels CR, Groeneveld PH, Groeneveld AB, van Kamp GJ, Bronsveld W, Thijs LG. Methylene blue increases myocardial function in septic shock. Crit Care Med. 1995;23:1363-70.[Medline]
  • Hyhan AL, Lippton HL, Kadowitz PJ. Methylene blue prevents hypoxic pulmonary vasoconstriction in cats. Am J Physiol. 1991;260(2 Pt 2):H586-92.[Abstract/Free Full Text]
  • Kikura M, Lee MK, Levy JH. Heparin neutralization with methylene blue, hexadimethrine, or vancomycin after cardiopulmonary bypass. Anesth Analg. 1996;83:223-7.[Abstract/Free Full Text]