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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.54 no.6 Campinas Nov./Dec. 2004
Methylene blue to treat anaphylaxis during anesthesia. Case report*
Uso del azul de metileno en el tratamiento de choque anafiláctico durante anestesia. Relato de caso
Renato Mestriner Stocche, TSA, M.D.I; Luís Vicente Garcia, TSA, M.D.II; Marlene Paulino dos Reis, TSA, M.D.III; Jyrson Guilherme Klamt, TSA, M.D. IV; Paulo Roberto B. Évora, M.D.V
Assistente do Serviço de Anestesiologia do HC da FMRP-USP
IIProfessor Assistente Doutor da Disciplina de Anestesiologia da FMRP-USP
IIIProfessora Associada da Disciplina de Anestesiologia da FMRP-USP
IVProfessor Assistente Doutor da Disciplina de Anestesiologia da FMRP-USP
VMédico Assistente do Departamento de Cirurgia do HC da FMRP-USP; Chefe do Laboratório Experimental de Óxido Nítrico da FMRP-USP
OBJECTIVES: The risk of perioperative anaphylaxis should always be considered.
The incidence of anesthetic allergic reactions is controversial, varying from
1/3,000 to 1/20,000, with mortality range between 3 and 9%. This report describes
the use of methylene blue as coadjuvant drug to treat anaphylaxis refractory
to conventional therapy.
CASE REPORT: A 53-year-old male patient was submitted to inguinal hernia correction under spinal anesthesia. After receiving 1.5 g intravenous dipirone at surgery completion, he immediately developed bronchospasm, cyanosis, decreased SpO2 and SBP, culminating with cardiac arrest. Resuscitation was started with external cardiac massage followed by tracheal intubation, as well as 1 mg epinephrine and 1 mg atropine injections. Heart rate returned (150 bpm) with no palpable pulse though. Additional 1 mg epinephrine and 1 g hydrocortisone were administered with central pulse recovery (8 minutes). Although receiving dopamine (20 µg.kg-1.min-1), patient remained hypotensive (60 mmHg) until 80 minutes. Intravenous 100 mg methylene blue was then administered with increased SBP to 85 and 105 mmHg after the second dose. Dopamine dose was tapered from 10 to 7, 5 and finally 2 µg.kg-1.min-1.
CONCLUSIONS: Histamine is the major anaphylaxis mediator. Inducing nitric oxide (NO) production, it consequently increases guanylate cyclase, which promotes arteriolar vasodilation by increasing cyclic GMP. Methylene blue may be helpful in such situations because it inhibits guanylate cyclase and consequently vasodilation, resulting in hemodynamic improvement.
Key Words: ANALGESICS dipirone; COMPLICATIONS, shock; DRUGS, methylene blue
Y OBJETIVOS: En el período peri-operatorio, el riesgo de anafilaxis
siempre debe ser considerado. La incidencia de reacciones alérgicas en
anestesia es polémica, variando entre 1/3000 a 1/20.000, con mortalidad
entre 3% y 9%. En este caso, se relata el uso del azul de metileno como coadyuvante
al tratamiento del choque anafiláctico refractario a la terapéutica
RELATO DEL CASO: Paciente del sexo masculino, 53 años, sometido a herniorrafia inguinal bajo raquianestesia. Al final del procedimiento, al recibir dipirona (1,5 g), por vía venosa, el paciente inmediatamente presentó broncoespasmo, cianosis, disminución de la SpO2 y de la PS, culminando con parada cardiorrespiratoria. Fue iniciada la reanimación cardiorrespiratoria con masaje cardíaco externo, seguida de IOT e inyección de adrenalina (1 mg), atropina (1 mg), restableciéndose FC de 150 lpm, sin embargo sin pulso palpable. Se administró más 1 mg de adrenalina además de 1 g de hidrocortisona, con restablecimiento de pulso central (8 minutos). A pesar de recibir dopamina (20 µg.kg-1.min-1), el paciente se mantuvo hipotenso (60 mmHg) hasta 80 minutos. Se administraron 100 mg de azul de metileno por vía venosa, cuando hubo aumento de la PS para 85 y 105 mmHg, después de la segunda dosis. Se siguió a la disminución de la dosis de dopamina de 20 para 10, 7, 5 y, finalmente, 2 µg.kg-1.min-1.
CONCLUSIONES: La anafilaxis tiene como principal mediador la liberación de histamina, que induce la producción de óxido nítrico (NO), con consecuente aumento de guanilato ciclase que promueve vasodilatación arteriolar por aumento del GMP cíclico. El azul de metileno puede ser útil en estas situaciones, pues inhibe la guanilato ciclase y consecuentemente la vasodilatación, lo que resulta en una mejoría hemodinámica.
Anaphylaxis risk is increased during the perioperative period due to exposure to a high number of drugs. The first perioperative anaphylaxis report dates from 1936, when a patient presented unexpected reaction after the administration of d-tubocurarine 1. The incidence of anesthetic allergic reactions is controversial, varying from 1/3,000 to 1/20,000 and, even with immediate conventional treatment (epinephrine, volume expansion, steroids, ventilatory support and anti-histaminic drugs), mortality rate may be as high as 3% and 9% 2-4.
Anaphylaxis is a complex and partially understood reaction. Several chemical mediators are released, which account for cardiovascular and respiratory collapse. Histamine and bradykinin are among major mediators 5. Massive release of these substances induces nitric oxide production 5-8, which increases vascular endothelium cGMP that promotes its typical arteriolar vasodilatation 9.
This report describes the use of methylene blue, a cGMP-synthase inhibitor, as coadjuvant to treat anaphylaxis refractory to conventional therapy.
A 53-year-old male patient was submitted to right inguinal hernia correction under spinal anesthesia with hyperbaric 15 mg bupivacaine. He was given 3 mg intravenous midazolam and monitored with cardioscopy in DII and V5 leads, automatic blood pressure (oscillometry) and pulse oximetry.
At surgery completion, patient was awakened and hemodynamically stable for more than one hour (BP 125/80 mmHg), when 1.5 g intravenous dipirone were given for postoperative analgesia. He immediately referred tongue tingling, evolving to bronchospasm and decreased systolic blood pressure (70 mmHg). Oxygen 100% was administered under mask followed by 10 mg IV ephedrine. Respiratory symptoms however have rapidly worsened with cyanosis, glottis edema, skin erythema, decreased hemoglobin saturation, blood pressure undetected by oscillometry, absence of peripheral pulses and HR decrease to 37 bpm.
Resuscitation maneuvers were started with intravenous 1 mg epinephrine, 1 mg atropine and 100 mg succinylcholine, followed by tracheal intubation, manual ventilation with 100% oxygen and external cardiac massage. Cardiac electric activity was reestablished with no pulse though, when additional 1 mg epinephrine and 1 g hydrocortisone were administered, still with no hemodynamic improvement.
At 8 minutes, 1 mg additional epinephrine was administered when patient presented sustained ventricular tachycardia, corrected with 2 mg.kg-1 lidocaine. Ten minutes after VT recovery, there was hemodynamic improvement (140 bpm and SBP = 60 mmHg). Aminophylline and dopamine (20 µg.kg-1.min-1) were then administered.
Twenty-five minutes later, cardiac rhythm changed to atrial fibrillation with high ventricular response and SBP decreased to 50 mmHg. Arrhythmia reverted after the third cardioversion attempt (100, 150 and 200 J). In the meantime, vesical and nasogastric probes were inserted, central venous puncture was performed and arterial blood gases analysis and blood electrolytes dosage were required. At 80 minutes, with volume corrected with 2500 crystalloids and 500 mL of 4% polyamide (14 cmH2O PVC) and with no electrolytic changes, patient maintained sinusoidal tachycardia (145 bpm) and severe hypotension (SBP between 60 and 75 mmHg), even after high dopamine doses (20 µg.kg-1.min-1).
We then decided to administer 100 mg IV methylene blue in slow injection (5 minutes). Immediately after administration, SBP has increased to 85 mmHg. This mild improvement was maintained for 5 minutes, when additional 100 mg methylene blue was given, with subsequent SBP increase to 105 mmHg. Right after, dopamine infusion was rapidly tapered (20 minutes) from 20 to 10, 7, 5 and finally 2 µg.kg-1.min-1, which was maintained to stimulate diuresis.
Patient was transferred to the ICU 155 minutes after beginning of symptoms receiving dopamine (2 µg.kg-1.min-1), presenting satisfactory diuresis (2 mL.kg-1.h-1), SBP = 105 mmHg, HR = 150 bpm, cold extremities, mechanical ventilation, mild bronchospasm and with no electrolytic changes. Patient started reacting 2 hours later, when continuous IV midazolam was started. He was extubated 16 hours after surgery completion, hemodynamically stable with no vasoactive drug support, being then discharged from the ICU.
Anaphylaxis is a feared complication due to its fast onset and unexpected nature, with a high morbidity and mortality rates. This report has described a typical clinical situation, according to most frequent symptoms described in the literature: cardiovascular collapse (90%) 10, supraventricular tachycardia (80%) 11, cardiac arrest (11%) 12, bronchospasm (50%) 13, skin erythema and edema (eyelid and glottis), among others. In spite of the prompt institution of conventional treatment (epinephrine, steroids, anti-histaminic drugs and rapid fluid replacement), there has been partial clinical improvement with hemodynamic instability for more than one hour after beginning of reaction.
The role of nitric oxide (NO) in anaphylaxis is still controversial and partially explained. It may be responsible for both typical vasodilatation and contraposition to released coronary vasoconstrictor mediators 14. NO-synthase inhibitors in dogs submitted to induced anaphylaxis has promoted hypotension improvement but has also decreased cardiac output and increased mortality 15,16. These divergent actions may be explained by NO synthesis inhibition, both in its induced and constitutive form. Constitutive mechanism inhibition is undesirable and may result in bronchospasm and more cardiac depression, since constitutive NO is involved in several systems responsible for homeostasis 16.
In vessels' smooth muscle cells, NO stimulates cGMP synthesis which ultimately produces relaxation and vasodilation9. Methylene blue inhibits guanylyl-synthase, thus reducing cGMP formation and blocking NO vasodilating action, not acting though in other tissues and organs, like other NO-synthase inhibitors do.
Intravenous methylene blue is safe; it is a drug used for many years to treat metahemoblobinemia and malaria, and as an urinary antiseptic. Lethal dose determined by in vivo pharmacological studies in ewes was higher than 40 mg.kg-1 17. This stain has also been used to treat vasoplegic states associated to sepsis 18-20 or post cardiopulmonary bypass vasoplegy 21,22. The use of NO-inhibitor during sepsis leads to decreased cardiac output 20 while methylene blue does not change or even increases cardiac output 23, evidencing the different action mechanisms of each drug. In our case, there was a significant SBP improvement immediately after methylene blue administration.
This report on methylene blue as coadjuvant to treat anaphylaxis during anesthesia confirms its already reported efficacy in anaphylaxis to contrasts or antibiotics 24-26.
In this case, methylene blue was used after obtaining only partial anaphylaxis improvement with conventional therapy. It is not possible to definitely establish the cause/effect relationship between methylene blue and hemodynamic improvement, which could have been a consequence of late effects of drugs initially used or simply spontaneous improvement with time. However, some facts suggest that methylene blue has been beneficial. First of all, hemodynamic improvement was observed without any change in the therapy already in course. Secondly, there has been a 15 mmHg SBP increase immediately after the first methylene blue dose and an approximately 20 mmHg increase right after the second dose. Lastly, dopamine infusion rate could be tapered from 20 to 2 µg.kg-1.h-1 still maintaining hemodynamic parameters.
We consider that there are not enough evidences in the literature to support the use of methylene blue as single therapeutic drug for anaphylaxis. So, conventional treatment should be started as soon as possible, and methylene blue should be kept for refractory cases or as coadjuvant drug. Our experience, reported in this case, and other published cases, suggest that in the future, methylene blue may play a critical role in the treatment of anaphylaxis.
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Dr. Renato Mestriner Stocche
Address: Rua Adolfo Serra, 237 Alto da Boa Vista
ZIP: 14025-520 City: Ribeirão Preto, Brazil
Submitted for publication
March 8, 2003
Accepted for publication July 1, 2004
* Received from Serviço de Anestesiologia do Hospital das Clínicas de Ribeirão Preto, SP (HC FMRP USP)