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METHYLENE BLUE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Methylene blue is a thiazine dye with antiseptic and dose-dependent oxidation or reduction properties.

Specific Substances

    1) Methylthionine chloride
    2) Methylthionium chloride
    3) Tetramethylthionine chloride
    4) CAS 61-73-4 (anhydrous methylene blue)
    5) CAS 7220-79-3 (methylene blue trihydrate)
    6) Molecular Formula C1(6)-H(18)-ClN(3)-S,3H(2)O
    7) AIZEN METHYLENE BLUE FZ
    8) BASIC BLUE 9
    9) C.I. BASIC BLUE 9
    10) CALCOZINE BLUE ZF
    11) CHROMOSMON
    12) D & C BLUE NUMBER 1
    13) D AND C BLUE NUMBER 1
    14) EXT D & C BLUE NO. 1
    15) EXT D AND C BLUE NO. 1
    16) EXTERNAL BLUE 1
    17) LEATHER PURE BLUE HB
    18) METHYLENE BLUE CHLORIDE
    19) METHYLENE BLUE POLYCHROME
    20) METHYLENIUM CERULEUM
    21) METHYLTHIONINE
    22) MITSUI METHYLENE BLUE
    23) MODR METHYLENOVA (CZECH)
    24) SCHULTZ NO. 1038
    25) SWISS BLUE
    26) TETRAMETHYLENE BLUE
    27) YAMAMOTO METHYLENE BLUE
    1.2.1) MOLECULAR FORMULA
    1) C16H18ClN3S

Available Forms Sources

    A) FORMS
    1) Methylene blue is available in the United States as 10 mg/mL intravenous solution (Prod Info methylene blue 1% IV injection, 2011) and 2% topical solution.
    B) USES
    1) Methylene blue is indicated for the treatment of drug-induced methemoglobinemia (Prod Info methylene blue 1% IV injection, 2011). It is also used to treat patients with ifosfamide-induced encephalopathy (Pelgrims et al, 2000; Kupfer et al, 1996; Demandt & Wandt, 1996; Zulian et al, 1995; Kupfer et al, 1994; Donegan, 2001; Turner et al, 2003; Alonso et al, 1996), as an antiseptic agent, a diagnostic agent, and an indicator dye (Prod Info UROLENE BLUE(R) oral tablets, 2006).
    2) Methylene blue is a selective nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway inhibitor. This pathway (increased nitric oxide and cGMP production) is involved in the pathophysiology of distributive shock, caused by conditions such as sepsis and anaphylaxis. Methylene blue has been studied for the use in patients with refractory distributive shock, when conventional treatment fails (Jang et al, 2013).
    a) The use of methylene blue in patients with septic shock has been associated with a transient increase in vascular tone and myocardial function. Intravenous administration of methylene blue (1 to 2 mg/kg as a single bolus) in patients with severe septic shock increased arterial blood pressure, systemic vascular resistance, and left ventricular stroke work and decreased arterial blood lactate concentrations. Administration of methylene blue did not have a significant affect on cardiac filling pressures, heart rate, cardiac output, blood gases, oxygen delivery, or oxygen consumption. Use of methylene blue has not resulted in sustained clinical improvement or reduced the mortality rate of patients. Methylene blue may counteract some of the negative hemodynamic effects of nitric oxide by inhibition of guanylate cyclase, the target enzyme of nitric oxide (Andresen et al, 1998; Brown et al, 1996; Driscoll et al, 1996; Preiser et al, 1995; Daemen-Gubbels et al, 1995; Schneider et al, 1992). In contrast, other research indicates that the use of methylene blue in patients with septic shock may be detrimental and increase mortality (Schneider, 1995).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Methylene blue is used to treat drug-induced methemoglobinemia and ifosfamide-induced encephalopathy. It has also been used as a mild urinary antiseptic agent, a diagnostic agent, and indicator dye.
    B) PHARMACOLOGY: Methylene blue, in low concentrations, acts as a cofactor to accelerate the conversion of methemoglobin to hemoglobin in erythrocytes. In high concentrations, methylene blue oxidizes the ferrous iron of hemoglobin to the ferric state, facilitating the conversion of hemoglobin to methemoglobin.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Nausea, abdominal and precordial pain, diarrhea, dizziness, headache, profuse sweating, mental confusion, hypertension, dysrhythmias, and methemoglobin formation may occur following large intravenous methylene blue doses. Skin discoloration, burning sensation of the mouth and oropharynx, painful micturition, blue discoloration of the conjunctiva, persistent upper and lower lid swelling, amblyopia, nystagmus, dysrhythmias, hypotension, and hypertension have also been reported following the use of methylene blue.
    2) Methemoglobinemia has been reported following oral, intravenous, cervical administration, intraamniotic injection, and intraperitoneal administration in adults and neonates. Signs and symptoms of methemoglobinemia include cyanosis, headache, lethargy, dizziness, fatigue, syncope, dyspnea, CNS depression, seizures, dysrhythmia, and shock.
    3) HIGH RISK GROUPS: Patients with underlying conditions such as COPD, anemia, or coronary artery disease are more susceptible to the development of symptoms. Delayed hemolysis may be noted in patients with G-6-PD deficiency.
    4) DRUG INTERACTION: Methylene blue has MAOI activity. Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome.
    5) PREGNANCY: Methylene blue is classified as pregnancy category X.
    E) WITH POISONING/EXPOSURE
    1) Large doses of methylene blue may result in nausea, vomiting, abdominal pain, chest pain, headache, dizziness, confusion, profuse sweating, and methemoglobinemia. Necrosis, ulceration, and abscess formation may develop if injected subcutaneously. Hypotension, tachycardia, and cyanosis occurred in a 4-year-old boy following a 1 g IV dose of methylene blue during surgery. A woman who inadvertently received anterior capsule staining with methylene blue 1% instead of trypan blue 0.025% during a cataract surgery, developed iris discoloration and stromal corneal edema with severe visual loss on the first postoperative day.
    2) INTRATHECAL INJECTION: Initial vomiting, shock, and collapse followed by paraplegia, radiculopathy, cauda equine syndrome, cranial nerve dysfunction, encephalopathy, optic neuritis and meningeal irritation have been reported after intrathecal injection of methylene blue.
    0.2.20) REPRODUCTIVE
    A) Hemolytic anemia, hyperbilirubinemia, methemoglobinemia, intestinal obstruction and a blue discoloration of the mucous membranes, urine and bronchial secretions have been seen in neonates after intra-amniotic injection of methylene blue. Do not administer this drug to a pregnant woman. If pregnancy occurs, apprise patient of potential for fetal harm. It is unknown whether methylene blue is present in human milk, affects milk production, or impacts the breastfed infant. Advise women to discontinue nursing during and for up to 8 days after treatment with methylene blue.

Laboratory Monitoring

    A) Monitor vital signs in symptomatic patients.
    B) Monitor serum electrolytes in patients with significant diarrhea and/or vomiting.
    C) Determine baseline CBC and serum hemoglobin in patients suspected of G-6-P D deficiency.
    D) In a cyanotic patient, a methemoglobin level should be obtained to confirm the diagnosis. Methemoglobin levels will be artificially low if blood is not analyzed within a few hours.
    E) Pulse oximetry may give a false reading in the 80% to low 90% range. An arterial blood gas test will reveal a falsely normal calculated oxygen saturation despite low measured pulse oximetry. If oxygen saturation is measured, it will be low relative to the pO2. This saturation gap suggests methemoglobinemia.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat hypotension with IV fluids, dopamine, or norepinephrine. Treat seizures with IV benzodiazepines or barbiturates.
    C) INTRATHECAL OVERDOSE
    1) Inadvertent intrathecal injection has been reported with methylene blue. Monitor neurologic exam. Keep the patient upright and begin aggressive attempts to remove as much as drug possible. Immediately drain AT LEAST 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon immediately for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline (NS) or lactated ringers (LR) through ventricular catheter, drain fluid from lumbar catheter; typical volumes are 80 to 150 mL/hr for at least 24 hours). Fresh frozen plasma (FFP) (25 mL FFP/liter NS or LR) or albumin 5% should be added to the fluid used for perfusion to increase protein binding and replace CSF protein. Administer dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) PREHOSPITAL: Prehospital decontamination is generally not recommended.
    2) HOSPITAL: Consider activated charcoal in a patient with a recent, substantial overdose who is alert or in whom airway is protected.
    E) AIRWAY MANAGEMENT
    1) Patients with methemoglobinemia and severe dyspnea, tachypnea, seizure, or evidence of end-organ ischemia may require intubation for airway protection or to minimize excessive work of breathing.
    F) ANTIDOTE
    1) None
    G) METHEMOGLOBINEMIA
    1) Obtain a methemoglobin level in cyanotic patients. Methemoglobin levels of less than 30% will usually correct themselves in 3 days without treatment being necessary. Profound cyanosis may occur in individuals with methemoglobinemia who appear to be in no respiratory distress. Treat symptomatic patients (generally with methemoglobin concentrations of more than 30% but patients with anemia or underlying cardiopulmonary disease may be symptomatic at lower concentrations) with oxygen. Hyperbaric oxygen, and exchange transfusion may be necessary in severe cases.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with any degree of cyanosis should be referred to a health care facility. Patients with mild headache or nausea may be managed at home.
    2) OBSERVATION CRITERIA: Patients with symptoms of methemoglobinemia should be monitored for several hours. Patients that are asymptomatic can be discharged.
    3) ADMISSION CRITERIA: All patients demonstrating cyanosis with symptoms, or methemoglobin levels greater than 20%, should be admitted. In less severe cases of methemoglobinemia, the possibility of continued absorption of methylene blue must be ruled out before the patient may be safely discharged. When doubt exists, it is probably best to admit the patient.
    4) CONSULT CRITERIA: A medical toxicologist or poison control center should be consulted for patients with methemoglobin concentrations above 30% or for symptomatic patients with lower concentrations. Consultation is recommended for patients with familial methemoglobinemia or G-6-PD deficiency.
    I) PITFALLS
    1) When managing a suspected methylene blue overdose, the possibility of multi-drug involvement should be considered. The arterial pO2 is usually normal despite significant methemoglobinemia. Pulse oximetry may overestimate oxygen saturation in patients with significant methemoglobinemia and should not be used to reflect arterial oxygen content or tissue oxygen delivery.
    J) PHARMACOKINETICS
    1) Methylene blue is not highly tissue bound. Vd: 70.6 L (range 13.7 to 192.6). Metabolism: Methylene blue is rapidly reduced to leucomethylene blue by red blood cells. Excretion: 74% of an ingested dose was recovered in urine (range 53% to 97%). Elimination half-life: In healthy adults, terminal half-life was an estimated 5.25 hours following intravenous administration of methylene blue.
    K) DIFFERENTIAL DIAGNOSIS
    1) Toxic and nontoxic causes of methemoglobinemia (ie, dapsone, benzocaine, chloroquine, sulfonamide, aniline dyes, naphthalene, phenazopyridine, NADH methemoglobin reductase deficiency).
    0.4.6) PARENTERAL EXPOSURE
    A) INTRATHECAL OVERDOSE: Inadvertent intrathecal injection has been reported with methylene blue. Monitor neurologic exam. Keep the patient upright and begin aggressive attempts to remove as much as drug possible. Immediately drain AT LEAST 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon immediately for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline (NS) or lactated ringers (LR) through ventricular catheter, drain fluid from lumbar catheter; typical volumes are 80 to 150 mL/hr for at least 24 hours). Fresh frozen plasma (FFP) (25 mL FFP/liter NS or LR) or albumin 5% should be added to the fluid used for perfusion to increase protein binding and replace CSF protein. Administer dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.

Range Of Toxicity

    A) TOXICITY: There are insufficient data in the literature to accurately assess the minimum toxic or lethal dose of methylene blue. Doses exceeding 4 mg/kg may result in signs and symptoms of toxicity. Toxicity may occur in children at lower doses. ADULTS: Oral doses of 300 mg daily have been used in the treatment of idiopathic methemoglobinemia, in conjunction with ascorbic acid. Nystagmus, expressive aphasia, and confusion occurred in a woman who received 7.5 mg/kg (total dose of 650 mg) of methylene blue as an intravenous infusion during a parathyroidectomy. The patient's symptoms spontaneously resolved within 48 hours post-infusion. CHILDREN: Doses of 2 to 4 mg/kg, given to neonates, caused Heinz body formation and hemolytic anemia.
    B) THERAPEUTIC DOSES: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is either available as 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules or 10 mg/1 mL (1% solution) vials.

Clinical Effects

Summary Of Exposure

    A) USES: Methylene blue is used to treat drug-induced methemoglobinemia and ifosfamide-induced encephalopathy. It has also been used as a mild urinary antiseptic agent, a diagnostic agent, and indicator dye.
    B) PHARMACOLOGY: Methylene blue, in low concentrations, acts as a cofactor to accelerate the conversion of methemoglobin to hemoglobin in erythrocytes. In high concentrations, methylene blue oxidizes the ferrous iron of hemoglobin to the ferric state, facilitating the conversion of hemoglobin to methemoglobin.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Nausea, abdominal and precordial pain, diarrhea, dizziness, headache, profuse sweating, mental confusion, hypertension, dysrhythmias, and methemoglobin formation may occur following large intravenous methylene blue doses. Skin discoloration, burning sensation of the mouth and oropharynx, painful micturition, blue discoloration of the conjunctiva, persistent upper and lower lid swelling, amblyopia, nystagmus, dysrhythmias, hypotension, and hypertension have also been reported following the use of methylene blue.
    2) Methemoglobinemia has been reported following oral, intravenous, cervical administration, intraamniotic injection, and intraperitoneal administration in adults and neonates. Signs and symptoms of methemoglobinemia include cyanosis, headache, lethargy, dizziness, fatigue, syncope, dyspnea, CNS depression, seizures, dysrhythmia, and shock.
    3) HIGH RISK GROUPS: Patients with underlying conditions such as COPD, anemia, or coronary artery disease are more susceptible to the development of symptoms. Delayed hemolysis may be noted in patients with G-6-PD deficiency.
    4) DRUG INTERACTION: Methylene blue has MAOI activity. Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome.
    5) PREGNANCY: Methylene blue is classified as pregnancy category X.
    E) WITH POISONING/EXPOSURE
    1) Large doses of methylene blue may result in nausea, vomiting, abdominal pain, chest pain, headache, dizziness, confusion, profuse sweating, and methemoglobinemia. Necrosis, ulceration, and abscess formation may develop if injected subcutaneously. Hypotension, tachycardia, and cyanosis occurred in a 4-year-old boy following a 1 g IV dose of methylene blue during surgery. A woman who inadvertently received anterior capsule staining with methylene blue 1% instead of trypan blue 0.025% during a cataract surgery, developed iris discoloration and stromal corneal edema with severe visual loss on the first postoperative day.
    2) INTRATHECAL INJECTION: Initial vomiting, shock, and collapse followed by paraplegia, radiculopathy, cauda equine syndrome, cranial nerve dysfunction, encephalopathy, optic neuritis and meningeal irritation have been reported after intrathecal injection of methylene blue.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Topical ocular therapeutic use of methylene blue has resulted in blue discoloration of the conjunctiva, resolving 7 to 18 months after discontinuation of the product (Brownstein et al, 1989).
    2) Persistent upper and lower lid swelling and amblyopia were reported in a 2-year-old following nasolacrimal duct probing, which was performed at 10 months of age, with methylene blue (Kushner, 1993).
    3) NYSTAGMUS: Nystagmus, expressive aphasia, and confusion occurred in a 52-year-old woman who received 7.5 mg/kg (total dose of 650 mg) of methylene blue as an intravenous infusion during a parathyroidectomy. The patient's symptoms spontaneously resolved within 48 hours post-infusion (Majithia & Stearns, 2006).
    B) WITH POISONING/EXPOSURE
    1) A 60-year-old woman who inadvertently received anterior capsule staining with methylene blue 1% instead of trypan blue 0.025% during a phacoemulsification cataract surgery, developed iris discoloration and stromal corneal edema with severe visual loss (visual acuity declined to 20/150 right eye with an intraocular pressure of 16 mm Hg) on the first postoperative day. Although she was started on dexamethasone 0.1% and chloramphenicol 1% eyedrops 4 time daily, her visual acuity deteriorated over the next 12 months (visual acuity declined to 20/200). She developed bullous keratopathy and underwent penetrating keratoplasty 16 months after the cataract surgery. Her symptoms gradually resolved over the next 9 months (Brouzas et al, 2006).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Normal adult volunteers had significant reduction in T and R wave height when given 500 mg of methylene blue. The dose was given over 5 to 30 minutes, usually over about 10 minutes (Nadler et al, 1934).
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Hypotension, tachycardia, and cyanosis occurred in a 4-year-old boy following a 1 g IV dose of methylene blue during surgery (Blass & Fung, 1976).
    C) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Transient, but severe, hypertension occurred in all of 12 patients given a 20 mL dose of 1% methylene blue IV over 15 seconds (200 mg). Hypertension persisted for approximately 3 minutes (Birch & Boyce, 1976).
    D) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Cardiac dysrhythmias were observed during peak episodes of hypertension in 5 patients. In these patients, renal vascular resistance increased significantly at 30 seconds and 60 seconds following injection (Birch & Boyce, 1976).
    E) VASCULAR DISORDER
    1) WITH THERAPEUTIC USE
    a) Methylene blue inhibits the vasoconstrictor and vasodilator response of saphenous veins harvested for coronary artery bypass grafting (Barber et al, 1995).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In the normal dosage range one may see slight increases in respiratory rate and dyspnea. This was also seen in adults given 500 mg IV (Nadler et al, 1934).
    B) CYANOSIS
    1) WITH THERAPEUTIC USE
    a) Cyanosis may occur at higher doses as a result of methemoglobinemia.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ANXIETY
    1) WITH POISONING/EXPOSURE
    a) Apprehension and restlessness have been reported in doses of 500 mg IV in adults (Nadler et al, 1934).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache may occur following large intravenous methylene blue doses (Prod Info methylene blue 1% IV injection, 2011).
    2) WITH POISONING/EXPOSURE
    a) Headache may occur at higher doses or when administered intrathecally (Evans & Keegan, 1960) and IV (Nadler et al, 1934).
    C) APHASIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 59-year-old male was given an IV infusion 700 mg of methylene blue during a parathyroidectomy. During his postoperative recovery, he demonstrated a marked aphasia. The aphasia improved over the next hours, but his speech remained slow and he was not orientated to time or place. His mentation gradually improved and had returned to preoperative levels on the second postoperative day (Bach et al, 2004).
    b) CASE REPORT: A 52-year-old woman received 7.5 mg/kg (total dose of 650 mg) of methylene blue as an intravenous infusion prior to a parathyroidectomy. Post-operatively, following the methylene blue infusion, the patient developed nystagmus, expressive aphasia, and confusion. The patient spontaneously improved, making a complete recovery 48 hours later. The authors suggest that the patient's neurological symptoms are due to a direct effect of methylene blue (Majithia & Stearns, 2006).
    D) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) Confusion and dizziness may occur following large intravenous methylene blue doses (Prod Info methylene blue 1% IV injection, 2011).
    2) WITH POISONING/EXPOSURE
    a) Confusion, dizziness, and excitement have occurred after IV injection of 500 milligrams in adult volunteers. The mental confusion lasted 12 hours (Nadler et al, 1934).
    E) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH POISONING/EXPOSURE
    a) INTRATHECAL INJECTION: Paraplegia and quadriparesis have been seen when methylene blue has been injected intrathecally into the lumbar region (Evans & Keegan, 1960).
    b) CASE REPORT: Schultz & Schwarz (1970) described radiculomyelopathy following intrathecal administration of methylene blue in a 32-year-old male to determine the origin of a CSF leak (Schultz & Schwarz, 1970).
    c) Severe back pain and numbness have followed intrathecal injection of methylene blue into the lumbar region (Evans & Keegan, 1960).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) HYPERESTHESIA
    1) WITH THERAPEUTIC USE
    a) Intravenous doses may cause a burning sensation of the mouth and warmth in the stomach (Nadler et al, 1934; Boyce et al, 1967; Narsapur & Naylor, 1983).
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea may occur following large intravenous methylene blue doses (Prod Info methylene blue 1% IV injection, 2011).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may occur following intrathecally administered methylene blue (Evans & Keegan, 1960) and oral doses (Nadler et al, 1934; Smith, 1972).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal and precordial pain may occur following large intravenous methylene blue doses (Prod Info methylene blue 1% IV injection, 2011).
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea may be occasionally noted after oral doses (Boyce et al, 1967; Narsapur & Naylor, 1983).
    E) PERITONITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 56-year-old woman with diabetes and end stage renal disease requiring continuous ambulatory peritoneal dialysis, complicated by E. coli peritonitis, received intraperitoneal methylene blue for evaluation of a suspected entero-peritoneal fistula. Two hours later she developed severe abdominal pain with rebound tenderness, hypotension and diaphoresis which responded to 500 mL of intravenous normal saline and peritoneal flushes repeated until the blue color disappeared (Macia et al, 1995).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HYPERBILIRUBINEMIA
    1) WITH POISONING/EXPOSURE
    a) Hyperbilirubinemia has been reported in newborns exposed to methylene blue in-utero (Crooks, 1982; Plunkett, 1973).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) DYSURIA
    1) WITH THERAPEUTIC USE
    a) Painful micturition as well as burning sensation of the scrotum and groin may be noted with large oral doses (Nadler et al, 1934; Narsapur & Naylor, 1983).
    B) URINE COLOR ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Green discoloration of the urine has been reported in patients treated with methylene blue (Wiersinga et al, 2009; Rowley et al, 2009).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT\ADULT: Hemolytic anemia was reported in a 46-year-old man with normal G-6-PD levels and in the presence of renal failure, following injection of methylene blue 1 milligram/kilogram for the treatment of phenazopyridine- induced methemoglobinemia (26%) (Sharon et al, 1986).
    2) WITH POISONING/EXPOSURE
    a) NEONATE: Hemolytic anemia with Heinz body formation has been noted in infants receiving 2 to 4 mg/kg and those receiving doses in amniotic fluid (Kirsh & Cohen, 1980; Plunkett, 1973; Vincer et al, 1987a; Sills & Zinkham, 1994).
    b) CASE SERIES\NEONATE: Hemolytic anemia, with Heinz body formation, and hyperbilirubinemia secondary to hemolysis have been described in several newborn infants following injection of methylene blue and intraamniotic administration (Crooks, 1982; Cowett et al, 1976a) Kirsch & Cohen, 1980; (Breault et al, 1997). Similar symptoms were reported in a 32-week (1.7 kg) infant that received intraperitoneal administration of methylene blue to check the patency of a gastrostomy tube placement secondary to esophageal atresia. The infant was G-6-PD negative. The patient recovered and no long-term effects were reported (Albert et al, 2003)
    B) METHEMOGLOBINEMIA
    1) WITH THERAPEUTIC USE
    a) Methemoglobin formation may occur following large intravenous methylene blue doses (Prod Info methylene blue 1% IV injection, 2011).
    2) WITH POISONING/EXPOSURE
    a) SUMMARY: Methemoglobinemia has been described in adults and neonates following intravenous and intraamniotic injections, as well as administration of methylene blue through the cervix to determine tubal patency during laparoscopic exam (Bilgin et al, 1998). It has also occurred following intraperitoneal administration in a neonate (Albert et al, 2003).
    b) CASE SERIES\NEONATE: Methemoglobinemia has been seen in neonates after intraamniotic injection. One infant developed methemoglobinemia, hemolytic anemia, and hyperbilirubinemia after an intraamniotic injection of 2 mL of a 1% solution (Spahr et al, 1980; McEnerney & McEnerney, 1983a).
    c) CASE REPORT\NEONATE: Methemoglobinemia occurred in a 10-day-old female with RSV pneumonia after receiving a total oral dose of methylene blue (used as a diagnostic aid to rule out aspiration) of 30 to 40 mg over a 40 hour period (Breault et al, 1997). The patient was transfused with 20 mL/kg of packed red blood cells; hemoglobin increased to 11.9 g/dL from 6.3 g/dL. The infant recovered completely.
    d) CASE REPORT/NEONATE: Methemoglobinemia occurred in a 32-week, 1.7 kg infant with esophageal atresia that received intraperitoneal methylene blue to check the patency of a gastrostomy tube. The infant recovered and no long-term effects were reported (Albert et al, 2003).
    e) CASE SERIES\ADULT: An intravenous dose of approximately 5 mg/kg has resulted in a mean peak methemoglobin concentration of 10% in several adult patients. Most of the patients had no clinical sequelae (Lamont et al, 1986) Whitwam et al, 1979).
    f) CASE REPORT\ADULT: A 26-year-old female with a previously unknown history of G-6-PD deficiency developed methemoglobinemia following cervical administration of methylene blue to determine fallopian tube patency. Symptoms resolved with ascorbic acid administration (a total of 2 g) (Bilgin et al, 1998).
    C) HEMOLYSIS
    1) WITH THERAPEUTIC USE
    a) RARE EFFECTS: Delayed hemolysis may occur in persons with G-6-PD deficiency.
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: An 18-year-old man developed an unsteady gait, drowsiness, vomiting, methemoglobinemia, and coma following exposure to a cleaning solvent. For treatment of his methemoglobinemia, methylene blue 1% solution was infused at a dose of 1 mg/kg body weight. Seventy-two hours later, following administration of a total of 4 doses of methylene blue, the patient's hemoglobin level decreased. Peripheral blood smears showed evidence of severe hemolysis with nucleated red cells, polychromasia, toxic neutrophilia and left shift. The red cells also appeared to be microspherocytic with a single polarized hemoglobin, believed to be a Heinz body. Despite transfusion of two units of packed cells, the patient developed acute renal failure and a series of cardiac arrests resulting in death (Khanduri et al, 2004).
    b) CASE REPORT: A 38-year-old woman, with a previously unknown history of G6PD deficiency, developed hemolysis (hemoglobin level of 8.1 g/dL) and methemoglobinemia (methemoglobin level of 8.8% [normal range, 0.4% to 1.5%]) believed to be a result of ingestion of foods containing high amounts of nitrates and nitrites. Administration of methylene blue resulted in exacerbation of her hemolysis (hemoglobin level of 6.5 g/dL). The G6PD activity, subsequently measured in a blood sample from the patient, was 3.9 units per gram of hemoglobin (normal range, 4.6 to 13.5). The patient recovered following supportive care. A follow-up hemoglobin measurement, obtained several months later, was 12.6 g/dL (Janssenh et al, 2004).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DISCOLORATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) CASE SERIES\ADULT: The skin and mucous membranes of adult volunteers have discolored after a 500 mg IV injection (Nadler et al, 1934).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES\INFANT: Several infants developed a blue staining of the skin which persisted for 4 to 6 days following doses of about 15 milligrams/kilogram and 1 gram IV (Goluboff & Wheaton, 1961; Blass & Fung, 1976).
    B) SKIN NECROSIS
    1) WITH POISONING/EXPOSURE
    a) In higher doses, ulceration, necrosis, and necrotic abscesses may occur after subcutaneous injection (Perry & Meinhard, 1974; Ruhlen, 1982).
    C) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Sweating has been noted in higher doses (Narsapur & Naylor, 1983).
    b) Profuse sweating may occur following large intravenous methylene blue doses (Prod Info methylene blue 1% IV injection, 2011).
    D) PHOTOSENSITIVITY
    1) WITH POISONING/EXPOSURE
    a) Photosensitivity reactions, presenting as edema and erythema of the skin with subsequent bullae formation and desquamation, developed in preterm infants exposed to high doses of intraamniotic methylene blue (Porat et al, 1996).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) KNEE JOINT EFFUSION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Instillation of methylene blue into the knee joint (to evaluate joint integrity) following a patella laceration resulted in the development of a knee effusion in a 13-year-old male. Arthrocentesis was required twice for swelling, then the patient was lost to follow-up (Lee & Valente, 1999).

Reproductive

    3.20.1) SUMMARY
    A) Hemolytic anemia, hyperbilirubinemia, methemoglobinemia, intestinal obstruction and a blue discoloration of the mucous membranes, urine and bronchial secretions have been seen in neonates after intra-amniotic injection of methylene blue. Do not administer this drug to a pregnant woman. If pregnancy occurs, apprise patient of potential for fetal harm. It is unknown whether methylene blue is present in human milk, affects milk production, or impacts the breastfed infant. Advise women to discontinue nursing during and for up to 8 days after treatment with methylene blue.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In pregnant animals, administration of oral methylene blue at doses up to 350 mg/kg/day during organogenesis resulted in maternal and embryofetal toxicities including increased spleen weight, reduced fetal weight, post-implantation loss, edema, and enlarged lateral ventricles. Maternal death was observed with doses of 100 mg/kg/day and embryofetal toxicities including spontaneous abortion, and umbilical hernia were reported with 100 and 150 mg/kg/day doses (Prod Info PROVAYBLUE(TM) intravenous injection, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) Do not administer this drug to a pregnant woman. If pregnancy occurs, apprise patient of potential for fetal harm (Prod Info PROVAYBLUE(TM) intravenous injection, 2016).
    B) FETAL/NEONATAL ADVERSE EFFECTS
    1) Intraamniotic injection with a methylene blue class product during the second trimester of pregnancy resulted in neonatal intestinal atresia and death. Administration in days and hours leading to birth may result in hyperbilirubinemia, hemolytic anemia, skin staining, methemoglobinemia, respiratory distress, and/or photosensitivity in the newborn infant and supportive care may be required (Prod Info PROVAYBLUE(TM) intravenous injection, 2016).
    2) Fetal exposure to intra-amniotic methylene blue dye during mid-trimester amniocentesis in twin pregnancy is associated with a high risk of small intestinal atresia and fetal death. A retrospective cohort study conducted from 1980 to 1991 compared women who were exposed to methylene blue dye during amniocentesis to women who had the procedure without dye exposure. Fetal death occurred in 31.8% of pregnancies that had exposure to a high concentration (1% solution in normal saline) of methylene blue, compared with 14.5% of pregnancies exposed to a low concentration (0.125% to 0.25% solution of methylene blue in normal saline), and 4.3% of pregnancies with no exposure to methylene blue dye. It is unknown whether fetal death was more likely in the twin whose amniotic sac had been injected with methylene blue (Kidd et al, 1996; Van Der Pol et al, 1992; Nicolini & Monni, 1990).
    3) Intra-amniotic injection of methylene blue has resulted in hemolytic anemia, hyperbilirubinemia, methemoglobinemia, and a blue discoloration of the mucous membranes, urine, and bronchial secretions in neonates delivered less than 5 weeks after injection (Troche, 1989; Poinsot et al, 1988; Vincer et al, 1987; Fish & Chazen, 1992). Intra-amniotic injection of methylene blue in doses ranging from 3.2 to 58.8 mg/kg at between weeks 34 and 38 of gestation resulted in newborns with blue tracheal secretions, skin stained blue, methemoglobinemia, hyperbilirubinemia, jaundice, and Heinz body hemolytic anemia. Between 23 to 58 hours after birth, serum bilirubin rose to levels ranging from 16.1 to 22.5 mg/dL. Jaundice developed and peaked between 1 and 4 days after birth. Most infants required phototherapy and up to 2 exchange transfusions to correct the hyperbilirubinemia and anemia. In some infants hemolysis continued for up to 10 days after injection of methylene blue. On the average the infants remained hospitalized for 26 days (McEnerney & McEnerney, 1983; Crooks, 1982a; Cowett et al, 1976; Spahr et al, 1980a; Vincer et al, 1987).
    C) LACK OF EFFECT
    1) Injection of a 0.2% aqueous solution of methylene blue into the fallopian tubes of a pregnant woman during the first trimester resulted in no adverse effects on the infant (Katz & Lancet, 1981).
    D) ANIMAL STUDIES
    1) In pregnant animals, administration of oral methylene blue at doses up to 350 mg/kg/day during organogenesis resulted in maternal and embryofetal toxicities including increased spleen weight, reduced fetal weight, post-implantation loss, edema, and enlarged lateral ventricles. Maternal death was observed with doses of 100 mg/kg/day and embryofetal toxicities including spontaneous abortion, and umbilical hernia were reported with 100 and 150 mg/kg/day doses (Prod Info PROVAYBLUE(TM) intravenous injection, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether methylene blue is present in human milk, affects milk production, or impacts the breastfed infant (Prod Info PROVAYBLUE(TM) intravenous injection, 2016). According to the World Health Organization, methylene blue should be avoided during breastfeeding, especially if the infant is premature. If used while breastfeeding, the infant should be monitored for any signs of side effects, such as hemolysis or jaundice (Anon, 2002). Advise women to discontinue nursing during and for up to 8 days after treatment with methylene blue (Prod Info PROVAYBLUE(TM) intravenous injection, 2016).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) PANCREATIC ISLET ADENOMAS OR CARCINOMAS
    1) In a 2-year study, methylene blue induced pancreatic islet adenomas or carcinomas in rats administered oral doses up to 50 mg/kg, much higher than the clinical dose of 1 mg/kg based on body surface area (Prod Info PROVAYBLUE(TM) intravenous injection, 2016).
    2) In a 2-year study, methylene blue induced no drug-related neoplastic effects in mice administered oral doses up to 25 mg/kg, much higher than the clinical dose of 1 mg/kg based on body surface area (Prod Info PROVAYBLUE(TM) intravenous injection, 2016).

Genotoxicity

    A) Methylene blue was genotoxic in the Ames test of mutagenicity, an in vitro sister chromatid exchange test, and an in vitro chromosomal aberration test in Chinese hamster ovary cells. However, micronucleus induction was negative in peripheral blood or bone marrow taken from mice administered methylene blue (Prod Info PROVAYBLUE(TM) intravenous injection, 2016).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs in symptomatic patients.
    B) Monitor serum electrolytes in patients with significant diarrhea and/or vomiting.
    C) Determine baseline CBC and serum hemoglobin in patients suspected of G-6-P D deficiency.
    D) In a cyanotic patient, a methemoglobin level should be obtained to confirm the diagnosis. Methemoglobin levels will be artificially low if blood is not analyzed within a few hours.
    E) Pulse oximetry may give a false reading in the 80% to low 90% range. An arterial blood gas test will reveal a falsely normal calculated oxygen saturation despite low measured pulse oximetry. If oxygen saturation is measured, it will be low relative to the pO2. This saturation gap suggests methemoglobinemia.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Perform a methemoglobin determination.
    2) Check for hemolysis by following hemoglobin, hematocrit, reticulocytes, haptoglobin, plasma free hemoglobin, and peripheral blood smear.
    3) Newborns exposed in utero to methylene blue should be checked for both hemolysis and hyperbilirubinemia (Crooks, 1982).
    B) ACID/BASE
    1) INDICATIONS: Arterial blood gases should be drawn in all cyanotic patients, and %O2 saturation measured if possible. A significant disparity between the calculated and measured %O2 saturation may be due to methemoglobin. The pO2 is usually relatively normal, even in the presence of severe methemoglobinemia.
    2) Methylene blue may cause a false positive methemoglobin level when measuring arterial blood gases using a co-oximeter (Kirlangitis et al, 1990).
    C) BLOOD/SERUM CHEMISTRY
    1) Newborns exposed in utero to methylene blue should be checked for both hemolysis and hyperbilirubinemia (Crooks, 1982).
    4.1.4) OTHER
    A) OTHER
    1) OTHER
    a) Methylene blue may color the urine, feces, saliva, skin and mucous membranes a bluish color.
    2) OXYGEN SATURATION
    a) The administration of methylene blue may produce spuriously low saturation values by pulse oximetry (Reider et al, 1989; Watcha et al, 1989; Scott & Cooper, 1991).
    b) Methylene blue injection caused the reading on a pulse oximeter to drop from 99% to 65% within 30 seconds. No actual hypoxia developed, other such cases have been reported (Kessler, 1986; (Sidi et al, 1987).
    c) In patients with true saturation values greater than 85%, the presence of high levels of methemoglobin will produce a false decrease in the saturation.
    1) In patients with true saturation values less than 85%, the presence of methemoglobin will result in a false increase in the saturation (Anderson et al, 1988; Barker et al, 1989).
    d) Methylene blue may produce a false positive on phenolsulfophthalein excretion test, causing urine diagnex blue excretion to be increased with a false positive or high reading.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) NOTE - METHEMOGLOBIN LEVELS WILL BE REDUCED if blood is not analyzed rapidly (few hours) by endogenous methemoglobin reductase.
    2) BEDSIDE METHOD - Initial bedside determination can be made by placing a drop of blood on filter paper with a control drop of blood nearby.
    a) If there is greater than 15% methemoglobinemia, the affected blood will have a chocolate brown color in comparison with the control blood.
    b) This test is most reliable for concentrations greater than 25% and less reliable in the range of 12 to 14%.
    3) RELIABILITY - In a double-blind study, house officers were asked to make observations about methemoglobin blood alone, and then in comparison with control blood, first in vacutainer and then on filter paper (Henretig et al, 1988).
    a) LEVEL INTERPRETATION > 25% - All house officers interpreted the chocolate color when compared with control either in vacutainers or on filter paper when methemoglobin concentration was greater than 25% (Henretig et al, 1988).
    b) LEVEL INTERPRETATION < 15% - Only 50% of house officers could detect the chocolate color when compared with control blood at methemoglobin concentrations of 12 to 14% (Henretig et al, 1988). There was no control group to detect false positives.
    c) CONCLUSION - Bedside test is not reliable, particularly for methemoglobin concentrations in the range of 12 to 14%.
    4) BUBBLING OXYGEN - Another test involves bubbling 100% oxygen through a sample of venous blood. While normal hemoglobin will turn bright red, methemoglobin will not.
    5) POTASSIUM CYANIDE - Venous blood containing significant methemoglobin concentrations diluted by 1:100 with deionized water will turn bright pink with the addition of a crystal of potassium cyanide, secondary to production of cyanohemoglobin (Done, 1976).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) All patients demonstrating cyanosis with symptoms, or methemoglobin levels greater than 20%, should be admitted. In less severe cases of methemoglobinemia, the possibility of continued absorption of methylene blue must be ruled out before the patient may be safely discharged. When doubt exists, it is probably best to admit the patient.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with any degree of cyanosis should be referred to a health care facility. Patients with mild headache or nausea may be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) A medical toxicologist or poison control center should be consulted for patients with methemoglobin concentrations above 30% or for symptomatic patients with lower concentrations. Consultation is recommended for patients with familial methemoglobinemia or G-6-PD deficiency.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with symptoms of methemoglobinemia should be monitored for several hours. Patients that are asymptomatic can be discharged.

Monitoring

    A) Monitor vital signs in symptomatic patients.
    B) Monitor serum electrolytes in patients with significant diarrhea and/or vomiting.
    C) Determine baseline CBC and serum hemoglobin in patients suspected of G-6-P D deficiency.
    D) In a cyanotic patient, a methemoglobin level should be obtained to confirm the diagnosis. Methemoglobin levels will be artificially low if blood is not analyzed within a few hours.
    E) Pulse oximetry may give a false reading in the 80% to low 90% range. An arterial blood gas test will reveal a falsely normal calculated oxygen saturation despite low measured pulse oximetry. If oxygen saturation is measured, it will be low relative to the pO2. This saturation gap suggests methemoglobinemia.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Prehospital decontamination is generally not recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Methylene blue has been demonstrated to be adsorbed to charcoal both in vitro and in animal models (Rohmann & Gericke, 1932; Dingemanse & Lacqueur, 1925).
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs in symptomatic patients.
    2) Monitor serum electrolytes in patients with significant diarrhea and/or vomiting.
    3) Determine baseline CBC and serum hemoglobin in patients suspected of G-6-PD deficiency.
    4) In a cyanotic patient, a methemoglobin level should be obtained to confirm the diagnosis. Methemoglobin levels will be artificially low if blood is not analyzed within a few hours.
    5) Pulse oximetry may give a false reading in the 80% to low 90% range. An arterial blood gas test will reveal a falsely normal calculated oxygen saturation despite low measured pulse oximetry. If oxygen saturation is measured, it will be low relative to the pO2. This saturation gap suggests methemoglobinemia.
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    C) METHEMOGLOBINEMIA
    1) Obtain a methemoglobin level in cyanotic patients. Methemoglobin levels of less than 30% will usually correct themselves in 3 days without treatment being necessary.
    2) Profound cyanosis may occur in individuals with methemoglobinemia who appear to be in no respiratory distress.
    3) Treat symptomatic patients (generally with methemoglobin concentrations of more than 30% but patients with anemia or underlying cardiopulmonary disease may be symptomatic at lower concentrations) with oxygen. Hyperbaric oxygen, and exchange transfusion may be necessary in severe cases.
    D) OXYGEN
    1) Oxygen should be administered to all cyanotic patients. Cyanosis secondary to methemoglobinemia will not respond to oxygen therapy.
    2) In symptomatic patients with methemoglobin levels of greater than 30%, hyperbaric oxygen has been recommended as adjunctive therapy (Donovan, 1983).
    3) Hyperbaric oxygen has been shown to decrease mortality from methemoglobinemia in animals (Sheehy & Way, 1974; Goldstein & Doull, 1971).
    E) EXCHANGE TRANSFUSION
    1) Exchange transfusion should be done if the methemoglobinemia is progressive in a symptomatic individual.
    2) The mortality rate from methemoglobin levels greater than 70% is high, and exchange transfusion should be considered if levels approach this figure.

Range Of Toxicity

Summary

    A) TOXICITY: There are insufficient data in the literature to accurately assess the minimum toxic or lethal dose of methylene blue. Doses exceeding 4 mg/kg may result in signs and symptoms of toxicity. Toxicity may occur in children at lower doses. ADULTS: Oral doses of 300 mg daily have been used in the treatment of idiopathic methemoglobinemia, in conjunction with ascorbic acid. Nystagmus, expressive aphasia, and confusion occurred in a woman who received 7.5 mg/kg (total dose of 650 mg) of methylene blue as an intravenous infusion during a parathyroidectomy. The patient's symptoms spontaneously resolved within 48 hours post-infusion. CHILDREN: Doses of 2 to 4 mg/kg, given to neonates, caused Heinz body formation and hemolytic anemia.
    B) THERAPEUTIC DOSES: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is either available as 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules or 10 mg/1 mL (1% solution) vials.

Therapeutic Dose

    7.2.1) ADULT
    A) 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is either available as 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules or 10 mg/1 mL (1% solution) vials (Prod Info PROVAYBLUE(TM) intravenous injection, 2016; Prod Info methylene blue 1% intravenous injection, 2011).
    7.2.2) PEDIATRIC
    A) 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is either available as 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules or 10 mg/1 mL (1% solution) vials (Prod Info PROVAYBLUE(TM) intravenous injection, 2016; Prod Info methylene blue 1% intravenous injection, 2011).

Maximum Tolerated Exposure

    A) Methylene blue doses 1 to 4 mg/kg body weight intravenously (0.1 to 0.4 mL/kg of 1% solution) have been used (Goluboff & Wheaton, 1961). Doses much in excess of this may produce hemolytic anemia or methemoglobinemia (Hanel, 1964; Goluboff & Wheaton, 1961; Tada et al, 1987).
    B) Serious toxic effects occur in high doses (7 mg/kg). Normal or small doses are serious if given by inadvisable routes of administration or in the presence of G-6-PD deficiency.
    C) ADULTS
    1) Oral doses of 300 mg daily have been used in the treatment of idiopathic methemoglobinemia, in conjunction with ascorbic acid (JEF Reynolds , 2000).
    2) IFOSFAMIDE-INDUCED ENCEPHALOPATHY: Use of methylene blue, 50 mg in a 2% aqueous solution given up to 6 times daily intravenously has resulted in reversal of ifosfamide neurotoxicity. In patients with a history of ifosfamide-induced encephalopathy requiring additional doses of ifosfamide, the prophylactic use of methylene blue (50 mg) 3 or 4 times daily orally or intravenously prevented further episodes of encephalopathy (Pelgrims et al, 2000a; Kupfer et al, 1996a; Demandt & Wandt, 1996a; Zulian et al, 1995a; Kupfer et al, 1994a).
    3) As much as 26 grams has been taken by mouth over several weeks without toxic symptoms (Marshall, 1920).
    4) Nystagmus, expressive aphasia, and confusion occurred in a 52-year-old woman who received 7.5 mg/kg (total dose of 650 mg) of methylene blue as an intravenous infusion during a parathyroidectomy. The patient's symptoms spontaneously resolved within 48 hours post-infusion (Majithia & Stearns, 2006).
    D) CHILDREN
    1) CASE REPORTS: Doses of 2 to 4 mg/kg, given to neonates, caused Heinz body formation and hemolytic anemia (Kirsh & Cohen, 1980). Adults seem to be able to tolerate much higher doses without sequelae (DiSanto & Wagner, 1971a).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 150 mg/kg ((RTECS, 2000))
    B) LD50- (ORAL)MOUSE:
    1) 3500 mg/kg ((RTECS, 2000))
    C) LD50- (INTRAPERITONEAL)RAT:
    1) 180 mg/kg ((RTECS, 2000))
    D) LD50- (ORAL)RAT:
    1) 1180 mg/kg ((RTECS, 2000))
    E) LD50- (SUBCUTANEOUS)RAT:
    1) 190 mg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Methylene blue forms an oxidation-reduction system. In low doses (1 to 2 mg/kg) it will aid in reduction of methemoglobin back to hemoglobin. In vivo, the drug is rapidly reduced to the leuko form by diphosphopyridine nucleotide (DPN). The reduced leuko form then reacts with the oxidized methemoglobin (Fe+3) to produce normal hemoglobin (Fe+2) and methylene blue (Kirsh & Cohen, 1980).

Toxicologic Mechanism

    A) Large doses cause or exacerbate HEINZ BODY HEMOLYTIC ANEMIA. Paradoxically, methylene blue in toxic amounts directly oxidizes hemoglobin to methemoglobin (Spahr et al, 1980).
    1) Following larger doses, enzymatically formed leukomethylene blue reduces O2 to hydrogen peroxide. Some of this H2O2 is detoxified through the hexose monophosphate shunt, but when this mechanism is overwhelmed, reduced glutathione is depleted.
    2) The remaining hydrogen peroxide then oxidizes both membrane lipid components and hemoglobin. The oxidized hemoglobin leads to the creation of sulfhemoglobin and consequently Heinz bodies.
    3) The hemolysis is thought to be a consequence of the damage to cell lipid membranes and the pitting of the Heinz bodies by reticuloendothelial cells (Kirsh & Cohen, 1980).
    B) It releases serotonin from neuronal and platelet sites (causing mental confusion), produces irritation of injection site, gastrointestinal tract, and genitourinary tract. Accidental subcutaneous injection will produce tissue necrosis.
    C) Contraindications: Glucose-6-phosphate dehydrogenase deficiency (may result in hemolytic anemia), carbon monoxide poisoning (may further decrease oxygen carrying capacity of blood).
    1) In chlorate or bromate poisoning it may enhance toxicity, and in cyanide poisoning methylene blue may release cyanide making it available to produce toxicity.

Physicochemical

Physical Characteristics

    A) METHYLENE BLUE: Odorless, or practically odorless, dark green crystals or crystalline powder with bronze-like luster; powder is soluble in water (1:25), alcohol (1:65), and chloroform (Sweetman, 2014); IV injection is a clear, dark blue solution with an osmolality of 10 to 15 milliosmoles/kg (Prod Info PROVAYBLUE(TM) intravenous injection, 2016).

Ph

    A) 3 to 4.5 (Prod Info PROVAYBLUE(TM) intravenous injection, 2016)

Molecular Weight

    A) 319.86 g/mol (Prod Info PROVAYBLUE(TM) intravenous injection, 2016)

Animal Toxicology

Clinical Effects

    11.1.6) FELINE/CAT
    A) Cats are very sensitive to the oxidizing effect of methylene blue on hemoglobin. Even small doses of methylene blue can cause severe, possibly fatal, Heinz body hemolytic anemia.

References

General Bibliography

    1) Addiego JE, Ridgway D, & Bleyer WA: The acute management of intrathecal methotrexate overdose: pharmacologic rationale and guidelines. J Pediatr 1981; 98(5):825-828.
    2) Albert M, Lessin MS, & Gilchrist BF: Methylene blue: Dangerous dye for neonates. J Ped Surg 2003; 38(8):1244-1245.
    3) Alonso JL, Nieto Y, Lopez JA, et al: Ifosfamide encephalopathy and methylene-blue: a case report. Ann Oncol 1996; 7(6):643-644.
    4) Anderson ST, Hajduczek J, & Barker SJ: Benzocain induced methemoglobinemia in an adult. accuracy of pulse oximetry with methemoglobinemia. Anesth Analg 1988; 67:1099-1101.
    5) Andresen M, Dougnac A, Diaz O, et al: Use of methylene blue in patients with refractory septic shock: impact on hemodynamics and gas exchange. J Crit Care 1998; 13(4):164-168.
    6) Anon: Breastfeeding and Maternal Medication. World Health Organization, Geneva, Switzerland, 2002.
    7) Bach KK, Lindsay FW, Berg LS, et al: Prolonged postoperative disorientation after methylene blue infusion during parathyroidectomy. Anes Analg 2004; 99:1573-1574.
    8) Barber DA, Rubin JW, & Zumbro GL: The use of methylene blue as an extravascular surgical marker impairs vascular responses of human saphenous veins. J Thorac Cardiovasc Surg 1995; 109:21-29.
    9) Barker SJ, Tremper KK, & Hyatt J: Effects of methemoglobinemia on pulse oximetry and mixed venous oximetry. Anesthesiology 1989; 70:112-117.
    10) Bilgin H, Ozcan B, & Bilgin T: Methemoglobinemia induced by methylene blue pertubation during laparoscopy. Acta Anaesthesiol Scand 1998; 42:594-595.
    11) Birch AA & Boyce WH: Hypertension and decreased renal blood flow following methylene blue injection. Anesth Analg 1976; 55:674-676.
    12) Blaney SM, Poplack DG, Godwin K, et al: Effect of body position on ventricular CSF methotrexate concentration following intralumbar administration. J Clin Oncol 1995; 13(1):177-179.
    13) Blass N & Fung D: Dyed but not dead - methylene blue overdose. Anesthesiology 1976; 45:458-459.
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