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- plausible. Decreased sensitivity of guanylate posed aortic media. 0 Methylene blue may cyclase to methylene blue over time, or non- inhibit platelet aggregation, which could affect guanylate-cyclase-mediated haemodynamic ef- haemostasis in thrombotic or haemorrhagic fects are potential mechanisms. Similarly, states."l Methylene blue has also been demon- metabolism, distribution through tissue bind- strated to antagonise the anticoagulant effects ing, or excretion of methylene blue may of heparin."2 The potential for methylene blue explain the attenuated response. Continuous to cause haemolytic anaemia should be appre- administration of methylene blue could poten- ciated. The administration of larger doses tially overcome the pharmacokinetic mechan- (500 mg over 10 minutes) has caused rest- isms accounting for the attenuation of lessness, anxiety and reversible paresthesias. 614 Brown, Franki, Phang
The larger doses also produced dyspepsia and Based on the short-term haemodynamic a sensation of burning in the mouth which benefits of methylene blue in septic shock, we persisted for 24 hours.'3 Despite methylene would encourage investigators to consider Postgrad Med J: first published as 10.1136/pgmj.72.852.612 on 1 October 1996. Downloaded from blue's potential to cause diverse anti-inflam- more prolonged administration of the drug. matory and physiologic effects,'4"15 we were Data on benefit and absence of toxicity can unable to detect any significant toxicity in our only be obtained through increased investiga- patient. tion.
1 Kilbourn RG, Jubran A, Gross SS, et al. Reversal of 9 Greutter CA, Kadowitz PH, Ignarro Q. Methylene blue endotoxin-mediated shock by NG-methyl-Larginine, an inhibits coronary arterial relaxation and guanylate cyclase inhibitor of nitric oxide synthesis. Biochem Biophys Res activation by nitroglycerin, sodium nitrite, and amyl nitrite. Commun 1990; 172: 1132-8. Can J Physiol Pharmacol 1981; 59: 150 - 6. 2 Kilbourn RG, Cromeens DM, Chelly FD, Griffith OW. 10 Johnstone MT, Lam JYT, Lacost L, Baribeau J, Theroux P, NG-Methyl-L-arginine, an inhibitor of nitric oxide forma- Waters D. Methylene blue inhibits the antithrombotic effect tion, acts synergistically with dobutamine to improve of nitroglycerin. JAm Coil Cardiol 1993; 20: 255-9. cardiovascular performance in endotoxemic dogs. Crit Care 11 Lusche W, Bosua A, Hekker R, Pescarmona GP, Arese P, Med 1994; 22: 1835-40. Till U. Methylene blue inhibits the arachidonic acid 3 Schneider F, Lutun PH, Hasselmann M, Stoclet JC, metabolism in human blood platelets. Biomed Biochim Acta Temple JD. Methylene blue increases systemic vascular 1988; 47 (suppl):S100-S103. resistance in human septic shock. Intensive Care Med 1992; 12 Sloand EM, Kessler CM, McIntosh CL, Klein HG. 18: 309-11. Methylene blue for neutralization of heparin. Thromb Res 4 Gachot B, Bedos JP, Veber B, Wolff M, Regnier B. Short- 1989; 54: 677-686. term haemodynamic effects of methylene blue in refractory 13 Nadler JE, Green H, Rosenbaum A. Intravenous injection septic shock. Intensive Care Med 1994; 20: (suppl 2)S10 of methylene blue in man with reference to its toxic (Abstract). symptoms and effect on the electrocardiogram. Am J Med 5 Preiser JC, Lejeune P, Roman A, et al. Methylene blue Sci 1934; 188: 15-21. administration in septic shock: a clinical trial. Crit Care Med 14 Culo F, Sabolovic D, Somogyi L, Marusic M, Berbiguier N, 1995; 23: 259-64. Galey L. Anti-tumoral and anti-inflammatory effects of 6 Daemen-Gubbels CRGH, Groeneveld PHP, Groenveld biological stains. Agents Actions 1991; 34: 424-8. ABJ, van Kamp GJ, Bronsveld W. Thijs LG. Methylene 15 Torres M, Ceballos G, Rubio R. Possible role ofnitric oxide blue increases myocardial function in septic shock. Crit Care in catecholamine secretion by chromaffin cells in the Med 1995; 23: 1363-70. presence and absence of cultured endothelial cells. J 7 Burrows GE. Methylene blue: effects and disposition in Neurochem 1994; 63: 988-96. sheep. J Vet Pharmacol Ther 1984; 7: 225 - 31. 8 Blass N, Fung D. Dyed but not dead - methylene blue overdose. Anesthesiology 1976; 45: 458-9.
Cushing's syndrome due to autonomous macronodular adrenal hyperplasia: long-term
follow-up after unilateral adrenalectomy http://pmj.bmj.com/
Mauro Boronat, Tomas Lucas, Balbino Barcelo, Carmen Alameda, Hassan Hotait, Javier Estrada
Summary Case report This report describes a case of Cushing's on September 29, 2021 by guest. Protected copyright. syndrome due to autonomous macronod- In 1984, a 53-year-old man presented with ular adrenocortical hyperplasia in which weakness, weight gain, easy bruising and unilateral resection of the right adrenal impotence, which had developed over a period resolved the Cushing's syndrome. of two years. He had a history of chronic obstructive pulmonary disease, heart failure Keywords: Cushing's sydrome, suprarrenal hyperpla- and mixed angina, and was known to have sia, adrenalectomy been hypertensive for 10 years. On physical examination, the patient was found to have cushingoid appearance, with centripetal obe- Clinica Puerta de Endogenous adrenocorticotropin (ACTH)- sity, atrophic skin and ecchymoses on fore- Hierro, C/San Martin independent Cushing's syndrome is caused arms. de Porres 4, 28035 by an autonomous adrenal production of Endocrine assessment is summarised in the Madrid, Spain cortisol. In most cases, it is due to a primary table. Computed tomography (CT) of the Department of Endocrinology adrenal neoplasm, adenoma or carcinoma, turcica sella was normal. Abdominal CT M Boronat usually unilateral. Rare nontumourous primary revealed a tumour mass occupying the entire T Lucas adrenal processess that can also cause Cush- right adrenal gland. The contralateral gland B Barcel6 ing's syndrome are bilateral. They include was also enlarged and contained a focal nodule C Alameda pigmented micronodular adrenal dysplasial localised in its central portion (figure 1). J Estrada and autonomous macronodular adrenocortical Scanning with 131I-labelled cholesterol demon- Pathology Services H Hotait hyperplasia (AMAH).`4 We describe a patient strated bilateral but asymmetrical uptake of the with AMAH who was treated successfully by tracer, indicating much greater activity on the Accepted 12 January 1996 unilateral adrenalectomy. right arm than on the left gland (figure 2).