Short Reports Continuous Infusion of Methylene Blue for Septic

Postgrad Med J 1996; 72: 612 - 624 (© The Fellowship of Postgraduate Medicine, 1996 Short reports Postgrad Med J: first published as 10.1136/pgmj.72.852.612 on 1 October 1996. Downloaded from Continuous infusion of methylene blue for septic shock Glen Brown, David Frankl, Terry Phang Summary presented to a community hospital with a 10- Nitric oxide has been determined to be a day history of left-sided chest pain causing potential mediator of the haemodynamic shortness of breath. Chest X-ray on the day of changes associated with sepsis. The hae- presentation demonstrated a left lower lobe modynamic eects of nitric oxide can be consolidation and a left pleural effusion. The partially antagonised by methylene blue, provisional diagnosis was community-acquired through inhibition of the enzyme, guany- pneumonia, and cefuroxime and erythromcyin late cyclase. The case report presented were initiated. The hypoxaemia worsened, here demonstrates a beneficial haemody- necessitating intubation and mechanical venti- namic eect of continuous infusion of lation on the following day. Sputum and blood methylene blue during sepsis. These find- samples grew no pathogens, and a ventilation- ings could be extrapolated to other pa- perfusion scan indicated no pulmonary embo- tients or prompt additional research. lism. To attempt to improve ventilation, a chest tube was placed which evacuated ap- Keywords: methylene blue, nitric oxide, septic shock proximately 2.5 litres of a greenish-brown odourless liquid, which subsequently grew Candida albicans and an unidentified yeast. Nitric oxide has recently been implicated as a The patient was transferred to this institution potential mediator of both the peripheral after nine days of mechanical ventilation. vascular and the cardiac reponse to endotoxin On presentation here, the patient was febrile, which results in the syndrome of septic shock.' had a white cell count of 15.5 x 109/l and chest Nitric oxide produces these effects by stimulat- X-ray demonstrated left lower lobe consolida- ing the soluble guanylate cyclase of vascular tion. A sample ofpleural fluid was obtained the smooth muscle and cardiac cells, increasing next day which grew Candida parapsilosis. A cyclic GMP levels and producing vascular fiberoptic bronchoscopy performed on day 3 relaxation and impaired cardiac contraction.' was unremarkable and protected brush speci- Pharmacologic antagonism of nitric oxide mens from the bronchoscopy grew Candida. production or receptor interaction has been Despite anti-fungal therapy, the patient dete- http://pmj.bmj.com/ shown to have beneficial effects on both the riorated and developed adult respiratory dis- peripheral vascular and cardiac response to tress syndrome. On day 33, the patient endotoxin.' Methylene blue has been demon- developed septic haemodynamics requring strated to inhibit guanylate cyclase' and anec- vasopressors. Sputum and blood samples grew dotal experience with methylene blue no pathogens; urine culture yielded Enterococ- administration to patients with septic shock cusfaecium and vancomycin was begun. Over a refractory to catecholamines has demonstrated 24 hour period, increasing vasopressor require- on September 29, 2021 by guest. Protected copyright. short-term benefits of the drug.'4 Improve- ments resulted in treatment with dopamine at ments in mean arterial pressure and systemic 10 4ug/kg/min and norepinephrine at 15 jMg/min vascular resistance have been demonstrated, to maintain tissue perfusion and end-organ although corresponding decreases in cardiac function. A single dose of methylene blue output have been noted.34 In an unblinded 100 mg (approximately 1.5 mg/kg) was admi- clinical trial of methylene blue administered to nistered to antagonise the possible nitric oxide- patients with septic shock requiring inotropic mediated peripheral vasodilation of septic support, doses of 2 mg/kg over 15 minutes shock. This resulted in a transient improve- St Paul's Hospital, resulted in improved mean arterial pressure.5 ment in blood pressure after 24 hours (figure 1081 Burrard Street, However, in all of the above studies, the 1) allowing a slight reduction in vasopressor Vancouver, British beneficial effects of methylene blue were support. Since the beneficial haemodynamic Columbia, Canada transient, with return to pre-methylene blue effects ofmethylene blue were transient follow- V6Z 1Y6 haemodynamics within three hours.'- We ing the initial five intermittent 100 mg doses Department of (hours 24, 42, 48, 54, 60), a continuous Pharmacy now report a patient in whom the continuous G Brown infusion of methylene blue over 44 hours was infusion of methylene blue 17 mg/h was Department of Critical associated with sustained haemodynamic ben- initiated. The infusion was administered con- Care efit and lack of toxicity. tinuously for 44 hours (hours 72-116), over D Frankl which time the norepinephrine was tapered to Department of Case report nil, and the dopamine to 3,g/kg/min (figure Surgery 1). Transient drops in the mean arterial blood T Phang The patient was a previously well, non- pressure (hours 84 and 100) during the Accepted 12 January 1996 immunocompromised, 61-year-old man who methylene blue infusion represent periods of Continuous infusion of methylene blue 613 100 _ Methylene blue Postgrad Med J: first published as 10.1136/pgmj.72.852.612 on 1 October 1996. Downloaded from * is a non-selective inhibitor of the enzyme E 80- guanylate cyclase, and thereby inhibits the E effects of endogenous and exogenous nitric oxide 60 * antagonises the nitric oxide-mediated vasodilation seen with sepsis 20 ' * reduces sepsis-induced negative inotropism of the heart * does not produce methaemoglobinaemia at nitric oxide- 5)~~ ~ ~~~~~~~~~~~~~~~~~~~~~= doses successful in antagonising c , , ; ,, \~~~~~~-10 induced haemodynamic changes * single intravenous doses have only a transient (< 4 hours) effect on haemodynamics Hours response, although this administration sche- Figure 1 The mean arterial pressure (upper solid line) and corresponding vasopressor dule would not be expected to offset pharmco- requirements (dopamine - dashed line, norepinephrine - dotted line) following dynamic mechanisms. This case report methylene blue 100mg doses (arrows) and infusion, 17 mg/h (thick solid line) demonstrates an ongoing beneficial response to methylene blue over 44 hours of continuous intravenous administration. The use of methy- aggressive diuresis (urine output> 1200 ml in lene blue may have restored vascular reactivity four hours). The patient demonstrated no to endogenous catecholamines suggesting that significant toxicity during or following the its use results in more than antagonism ofnitric infusion. The patient's urine turned a blue- oxide.3 Also, the methylene blue may have green colour which persisted for three days improved myocardial function6 which pro- after stopping the infusion, and he developed a duced sustained benefits after withdrawal. It noticeable blue - grey skin colouration that is possible that the patient's haemodynamics persisted for six days. No cardiac ischaemia could have improved regardless of the methy- or peripheral thrombosis were detected. The lene blue treatment. The underlying sepsis patient was sedated with continuous intrave- could have been resolving during the treatment nous narcotics and benzodiazepines, prevent- period since antibiotic therapy was ongoing ing the assessment of the effects of methylene (vancomycin for Enterococcus faecium in the blue on central nervous system function. No urine). We suspect that the underlying condi- assessment of methaemoglobinaemia was tion must have improved to some degree since made. discontinuation of the methylene blue did not Following recovery from the septic episode, result in a subsequent increase in vasopressor the patient's adult respiratory distress sydrome, requirements. It is also possible that methylene http://pmj.bmj.com/ debilitation and weakness necessitated a slow blue 'bought time' until the underlying sepsis wean from the ventilator. On day 87 of regressed. hospitalisation, the patient was transferred The potential toxicity of continuous admin- from the intensive care unit to the general istration of methylene blue must be consid- medical ward, breathing room air via a ered. In single doses of 1 -2 mg/kg, methylene tracheostomy. blue has been demonstrated to be safe in sepsis, and in the treatment of methhaemoglo- on September 29, 2021 by guest. Protected copyright. Discussion binaemia. Single doses of 2 mg/kg have not been associated with the development of The beneficial haemodynamic effects of methaemoglobinaemia,56 and the 50% lethal methylene blue on septic shock have until dose in sheep has been estimated at 40 mg/kg.7 now only been demonstrated to be transient.` Methylene blue has been reported to produce a The patient outcome of those individuals blue - grey skin colouration which may be treated in the initial reports was frequently confused with cyanosis.8 death, despite the apparent short-term haemo- The antagonism of nitric oxide-mediated dynamic benefits of the methylene blue. The peripheral vasodilation may counter the bene- mechanism for the attenuation of response to ficial effects of nitrates on myocardial blood the intermittent administration of methylene flow, resulting in cardiac ischaemia.9 Similarly, blue is unknown, but a variety of pharmaco- methylene blue may inhibit beneficial effects of dynamic and pharmacokinetic mechanisms are nitroglycerin on platelet disposition on ex-

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