Methemoglobinemia

Epidemiology

  • G6PD Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency, [[Glucose-6-Phosphate Dehydrogenase Deficiency]]): risk factor for acquired methemoglobinemia
    • Endemic in populations of Mediterranean and African descent

Etiology

Hereditary/Congenital Methemoglobinemia

Hemoglobin M Disease

  • General Comments: usually autosomal dominant
  • Hb Ms
  • Hb MIwate
  • Hb MBoston
  • Hb MHyde Park
  • Hb MSaskatoon

Hemoglobin E Disease

  • Hb E beta-thalassemia patients have been demonstrated to have increased methemoglobin levels

NADH Cytochrome b5 Reductase (cyb5R) Deficiency

  • General Comments
    • Autosomal recessive
    • Mechanism: decreased enzymatic reduction of methemoglobin back to normal hemoglobin
  • Type I Cytochrome b5 Reductase (cyb5R) Deficiency: most common type (represents 85-90% of cases)
    • Endemic in specific Native American tribes (Navajo, Athabaskan Alaskans) and Yakutsk people of Siberia
    • Cytochrome b5 reductase (cyb5R) deficiency is limited to red blood cells
  • Type II Cytochrome b5 Reductase (cyb5R) Deficiency: represents 10-15% of cases
    • Cytochrome b5 reductase (cyb5R) deficiency in multiple tissues (including red blood cells, liver, fibroblasts, and brain)
    • Clinical features
      • Severe central nervous symptoms (encephalopathy, microcephaly, hypertonia, athetosis, opisthotonos, strabismus, mental retardation, growth retardation)
      • Cyanosis: evident at an early age
  • Type III Cytochrome b5 Reductase (cyb5R) Deficiency
    • Cytochrome b5 reductase (cyb5R) deficiency in red blood cells, white bood cells, platelets
    • Clinical features: cyanosis is the only symptom
  • Type IV Cytochrome b5 Reductase (cyb5R) Deficiency
    • Cytochrome b5 reductase (cyb5R) deficiency is limited to red blood cells
    • Clinical features: cyanosis is the only symptom

NADPH-Flavin Reductase Deficiency

  • May also cause methemoglobinemia

Cytochrome b5 Deficiency

  • Rare

Anesthetics

  • General Comments: while skin/mucosal breaches may increase absorption of the anesthetic agents, methemoglobinemia may occur due to either a previously-undiagnosed methemoglobin reductase enzyme deficiency or idiosyncratic toxicity
  • Benzocaine (see Benzocaine, [[Benzocaine]])
    • Epidemiology: common etiology
      • Incidence of methemoglobinemia when using benzocaine during trans-esophageal echocardiogram (TEE) has been reported to be 1:1000 cases
      • In TEE-associated cases, active infection and anemia appear to increase the risk of methemoglobinemia
    • Physiology: unclear mechanism, as prior/subsequent benzocaine exposure may not elicit methemoglobinemia in affected patients
    • Clinical: severe methemoglobinemia may occur
  • Bupivicaine (see Bupivicaine, [[Bupivicaine]])
    • Epidemiology: common etiology
  • Cetacaine
    • Epidemiology: common etiology
  • Lidocaine (see Lidocaine, [[Lidocaine]])
    • Epidemiology: common etiology
  • Prilocaine
    • Epidemiology: common etiology

Nitrites and Nitrates (see Nitrites and Nitrates, [[Nitrites and Nitrates]])

  • Amyl Nitrite
  • Cerium Nitrate
  • Farryl Nitrite
  • Ingestion of High Nitrite/Nitrate Foods: beets, spinach, carrots, borage, chard
  • Ingestion of Nitrite-Contaminated Well Water: cases have been reported where well water has been contaminated by nitrite runoff from fertilized farm fields
  • Ingestion of Nitrites in Packaged Foods
  • Inhaled Nitric Oxide (iNO) (see Nitric Oxide, [[Nitric Oxide]]): however, in clinical trials of iNO in ARDS, clinically significant methemoglobinemia was not observed
  • Isobutyl Nitrite (Inhaled “Rush”, “Poppers”) (see Isobutyl Nitrite, [[Isobutyl Nitrite]])
  • Isosorbide Dinitrate (see Isosorbide, [[Isosorbide]])
  • Methyl Nitrite
  • Nitroglycerin (see Nitroglycerin, [[Nitroglycerin]])
  • Nitroprusside (Nipride) (see Nitroprusside, [[Nitroprusside]])
  • Silver Nitrate (see Silver Nitrate, [[Silver Nitrate]])
  • Sodium Nitrite (see Sodium Nitrite, [[Sodium Nitrite]])

Anti-Malarials

Anti-Neoplastic Agents

  • 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (Triapine): ribonucleotide reductase inhibitor
  • Cyclophosphamide (Cytoxan) (see Cyclophosphamide, [[Cyclophosphamide]])
  • Flutamide (Eulexin) (see Flutamide, [[Flutamide]])
  • Ifosfamide (Ifex) (see Ifosfamide, [[Ifosfamide]]): due to interaction between 4-thiofosfamide metabolite and glutathione -> resulting in oxidative stress

Other Drugs/Toxins

  • 2,4-Dinitrophenol: weight loss agent
  • Acetaminophen (Tylenol) (see Acetaminophen, [[Acetaminophen]])
  • Acetanilid (see Acetanilid, [[Acetanilid]])
  • Ammonium Carbonate: smelling salts
  • Benzene Derivatives
    • Aniline/Aniline Dyes/Aniline Derivatives (Aminophenol, Phenylhydroxylamine)
    • Naphthalene
    • Nitrobenzene: precursor to aniline
    • Resorcinol
  • Bromates: municipal water contaminants
  • Chrlorates: oxidizers which are found in matches, explosives, and fungicides
  • Clofazimine (see Clofazimine, [[Clofazimine]])
  • Cocaine (see Cocaine, [[Cocaine]])
  • Copper Sulfate
  • Curcumin: the main curcuminoid in turmeric has been demonstrated to cause methemoglobinemia in rats treated with dapsone
  • Dapsone (see Dapsone, [[Dapsone]])
    • Epidemiology: common etiology
      • Significant methemoglobinemia may be seen with Dapsone use to treat dermatitis herpetiformis or pneumocystis jirovecii
      • Risk is probably dose-related
    • Induction of Dapsone Tolerance: cimetidine (see Cimetidine, [[Cimetidine]]) may be used to chronically enhance Dapsone tolerance, as it is a selective inhibitor of N-hydroxylation and chronically lowers methemoglobin levels by >25%
  • Ingestion of Fava Beans in a Patient with G6PD Deficiency (see Favism, [[Favism]])
  • Herbicides/Pesticides
    • Aluminum Phosphide
    • Indoxacarb
    • Paraquat (Dipyridylium) (see Paraquat, [[Paraquat]])
  • Indigo Carmine: intravenous dye used during urologic surgery (it is rapidly filtered by the kidneys and turns the urine blue)
  • Menadione (“Vitamin K3”): nutritional supplement (it is an analog of 1,4-naphthoquinone)
  • Methylene Blue (see Methylene Blue, [[Methylene Blue]])
    • At high doses, methylene blue functions as an oxidant: it can cause acute hemolysis in patients with G6PD deficiency -> further decreasing oxygen delivery
    • At high doses, methylene blue can also paradoxically cause methemoglobinemia
  • Metoclopramide (Reglan) (see Metoclopramide, [[Metoclopramide]])
  • Naphthalene (see Naphthalene, [[Naphthalene]]): moth balls
  • Naphthoquinone: plants with compounds derived from naphthoquinone are used in China and South America for their medicinal properties
  • Nitroethane: nail polish remover
  • Nitrofurans: anti-microbials
    • Furazolidone
    • Furylfuramide
    • Nifuratel
    • Nifuroxazide
    • Nifurquinazol
    • Nifurtimox
    • Nifurtoinol
    • Nifurzide
    • Nitrofurantoin (Macrodantin) (see Nitrofurantoin, [[Nitrofurantoin]])
    • Nitrofurazone
    • Ranbezolid
  • P-Aminosalicylic Acid
  • Phenacetin (see Phenacetin, [[Phenacetin]])
  • Phenazopyridine (Pyridium) (see Phenazopyridine, [[Phenazopyridine]])
  • Phenylamine: psychoactive stimulant used as a recreational drug
  • Rasburicase (Elitek) (see Rasburicase, [[Rasburicase]])
    • Patients with low inherited or acquired catalase activity may be at risk for methemoglobinemia after rasburicase administration: due to the formation of hydrogen peroxide
    • Some authors recommend the measurement of catalase activity before administering rasburicase
  • Smoke Inhalation (see Smoke Inhalation, [[Smoke Inhalation]]): due to inhalational exposure to oxidants
  • Sodium Chlorite (see Sodium Chlorite, [[Sodium Chlorite]])
  • Sulfonamides (see Sulfonamides, [[Sulfonamides]])
  • Toxic Mushrooms (see Toxic Mushrooms, [[Toxic Mushrooms]]): for gyromitrin-containing mushrooms
  • Zopiclone (Imovane, Zimovane) (see Zopiclone, [[Zopiclone]])

Miscellaneous Other Conditions

  • Cirrhosis (see End-Stage Liver Disease, [[End-Stage Liver Disease]]): red blood cells in cirrhotic patients undergo severe oxidative stress, especially in the setting of bleeding complications: levels of methemoglobin are significantly higher in the red blood cells of bleeding cirrhotics than in non-bleeding cirrhotics [MEDLINE]
  • Post-Splenectomy: increased methemoglobin levels have been observed in patients following splenectomy
  • Sepsis (see Sepsis, [[Sepsis]]): methemoglobin levels may increase in sepsis [MEDLINE]
    • May be related to synthesis of nitric oxide that occurs in sepsis: nitric oxide is converted to methemoglobin and nitrate

Physiology

Normal Methemoglobin Physiology

  • Auto-Oxidation of Hemoglobin to Methemoglobin: in normal individuals, hemoglobin is auto-oxidized to methemoglobin at the rate of 0.5-3% per day
    • Methemoglobin levels of <1-3% are considered normal
  • Potential Chemical Mechanisms to Reduce Methemoglobin Back to Hemoglobin
    • NADH-Dependent Reaction Catalyzed by Cytochrome b5 Reductase (b5R): this is the only physiologically important mechanism under normal conditions (accounting for clearance of 95-99% of the methemoglobin that is produced under normal circumstances)
    • Generation of NADPH by Glucose-6-Phosphate Dehydrogenase (G6PD) in the Hexose Monophosphate Shunt within the Red Blood Cell: this mechanism is not natively physiologically active, as it requires an extrinsically-administered electron acceptor (such as methylene blue and riboflavin)
      • This mechanism becomes important in the treatment of methemoglobinemia: methylene blue accelerates the NADPH-dependent methemoglobin reduction pathway
      • Note: G6PD deficiency is a risk factor for acquired methemoglobinemia

Pathophysiology in Patient with Methemoglobinemia

  • Oxidation of Iron in Hemoglobin from the Ferrous (Fe2+) to the Ferric (Fe3+) State: results in a “functional anemia” and consequent decreased oxygen delivery to tissues
    • Ferric Hemes of Methemoglobin are Unable to Bind Oxygen
    • Left-Shifting of Hemoglobin Dissociation Curve: due to increased oxygen affinity by the remaining ferrous hemes in the hemoglobin tetramer
      • Left shifting results in impaired oxygen unloading at the tissues

Predisposition of Premature Neonates and Infants to Methemoglobinemia

  • Factors Increasing Risk of Methemoglobinemia in Premature Neonates/Infants <4 mo of Age
    • Propensity of fetal hemoglobin to more easily oxidize than adult hemoglobin
    • Low levels of NADH reductase at birth: NADH reducase levels increase to adult levels by 4 mo of age
    • Higher gastric pH with increased basterial conversion of dietary nitrates to nitrites
    • Association of methemoglobinemia with gastroenteritis illnesses in infants: this may be related to increased stool loss of bicarbonate

Diagnosis

Pulse Oximetry

  • Decreased SpO2
    • When Methemoglobin is <30%: pulse oximetry will overestimate the percentage of oxyhemoglobin in presence of methemoglobin by an amount roughly equal to 50% of the amount of methemoglobin present
      • In presence of 20% methemoglobin and a SpO2 of 90%: percentage of oxyhemoglobin will be 80%
    • When Methemoglobin is >30%: pulse oximetry will plateau at about 85%
    • Note that severity of the cyanosis does not correspond to the pulse oximetry reading
  • Principle of Pulse Oximetry: pulse oximeter only measures the relative absorbance of 2 light wavelengths (660 nm and 940 nm) to differentiate oxyhemoglobin from deoxyhemoglobin
    • Methemoglobin increases absorption of both light wavelengths (although moreso at 940 nm): therefore, it optically interferes with the pulse oximetry
    • Newer Generation Multi-Wavelength Pulse Oximeters: while these are being developed, their accuracy is still being investigated

Arterial Blood Gas (ABG)

  • Appearance of Blood in ABG Syringe: chocolate or brown-blue color
  • pO2: normal
    • Note that the pO2 reflects the plasma oxygen content and does not reflect the oxygen-carrying capacity of hemoglobin
  • Co-Oximetry SaO2: normal
    • “Saturation Gap” (occurs in methemoglobinemia): difference between SpO2 measured from pulse oximetry and the SaO2 calculated from co-oximetry
  • Co-Oximetry
    • Principle: co-oximeter is a simplified spectrophotometer that can measure the relative absorbance of 4 different wavelengths of light
      • It quantifies the percentages of methemoglobin (absorbs at 631 nm), carboxyhemoglobin, oxyhemoglobin, and deoxyhemoglobin
      • Newer co-oximeters can also measure sulfhemoglobin, which may be confused with methemoglobin on older devices
    • Normal Range of Methemoglobin: <1-3%
    • Relationship of Percentage of Methemoglobin to Clinical Symptoms: clinical symptoms are correlated with the precentage of methemoglobin
    • False-Positive Results
      • May occur in presence of sulhemoglobinemia
      • May occur in the presence of methylene blue
      • May occur in the presence of lipemia
    • Inaccuracy: may occur with the use of blood substitutes

Evelyn-Malloy Assay of Methemoglobin

  • Technique
    • Addition of cyanide, which binds to positively charged methemoglobin -> eliminates the peak at 630-635 nm
    • Subsequent addition of ferricyanide -> converts entire specimen to cyanomethemoglobin, which allows measurement of total hemoglobin concentration
  • Specificity: more specific than co-oximetry for detection of methemoglobin
  • Clinical Utility: this assay is a good confirmatory test and is especially useful after methylene blue administration

Potassium Cyanide Test

  • Distinguishes between methemoglobin and sulfhemoglobin
    • Methemoglobin reacts with cyanide to form cyanomethemoglobin: bright red color change
    • Sulfhemoglobin does not react with cyanide: lack of bright red color change

Drop Test

  • Technique: place 1-2 drops of blood onto white filter paper -> in the presence of significant methemoglobinemia, blood will remain dark (ie: will not oxygenate as normal blood would)
    • May accelerate process by gently blowing 100% onto the blood drop on the filter paper

Aeration of Tube of Blood with 100% Oxygen

  • Technique: bubble 100% oxygen through blood -> in the presence of significant methemoglobinemia, blood will remain dark (ie: will not oxygenate as normal blood would)

Hemoglobin Electrophoresis

  • May be used to identify hemoglobin M

Clinical Manifestations

Congenital Methemoglobinemia

Type I Cytochrome b5 Reductase Deficiency-Related Methemoglobinemia

  • General Comments: functional deficiency of cytochrome b5 reductase is limited to red blood cells
    • Methemoglobin Level: usually 10-35%
  • Asymptomatic Cyanosis (see Cyanosis, [[Cyanosis]]): usually the only clinical manifestation and is often present from birth
    • Cyanosis is clinically apparent when methemoglobin levels exceed 8-12% (at a normal hemoglobin concentration): equivalent to >1.5 g/dL
  • Polycythemia (see Polycythemia, [[Polycythemia]]): rarely observed

Type II Cytochrome b5 Reductase Deficiency-Related Methemoglobinemia

  • General Comments: cytochrome b5 reductase is deficient in all cells
  • Cyanosis (see Cyanosis, [[Cyanosis]]): often present from birth
  • Developmental Abnormalities
  • Mental Retardation
  • Death Within First Year of Life

Acquired Methemoglobinemia

General Comments

  • Relationship of Clinical Symptoms to Methemoglobin Level
    • Methemoglobin <1-3%: normal
    • Methemoglobin Level 3-15%: slight cyanosis (pale, gray-blue)
    • Methemoglobin Level 15-20%: cyanosis (although patients may be relatively asymptomatic)
    • Methemoglobin Level 25-50%: headache, dyspnea, dizziness, syncope, weakness, confusion/delirium, palpitations, chest pain
    • Methemoglobin Level 50-70%: arrhythmia, delirium, seizures, coma, metabolic acidosis
    • Methemoglobin Level >70%: usually fatal
  • Influence of Heterozygous State for Cytochrome b5R Deficiency: although patients heterozygous for cytochrome b5R deficiency may develop methemoglobinemia more readily than normals, most acquired methemoglobinemia cases occur in patients who are not heterozygous for cytochrome b5R deficiency
  • Influence of Anemia: the clinical symptoms of methemoglobinemia are exacerbated in the presence of anemia

Cardiovascular Manifestations

Neurologic Manifestations

Pulmonary Manifestations

  • Appearance of Chocolate-Brown Blood in the Bronchoscopic Field of View: may be observed in cases that occur during bronchoscopy (or during other videoscopic procedures)
  • Cyanosis (see Cyanosis, [[Cyanosis]])
    • Bluish-brown coloration of skin and mucous membranes
    • Cyanosis is clinically apparent when methemoglobin levels exceed 8-12% (at a normal hemoglobin concentration): equivalent to >1.5 g/dL
      • Note: in contrast, a deoxyhemoglobin level of 5 g/dL is required to produce clinical cyanosis
      • In patients with severe anemia, a higher percentage of methemoglobin is required for cyanosis to be clinically apparent
        • These patients are more likely to exhibit signs of hypoxemia and have less degrees of cyanosis, as compared to non-anemic patients
        • The clinical symptoms of methemoglobinemia are exacerbated in the presence of anemia
    • Lack of Response of Cyanosis to Supplemental Oxygen (in Absence of Cardiopulmonary Disease): hallmark of methemoglobinemia
      • While cyanosis in most pulmonary diseases will respond to supplemental oxygen, cyanosis in cardiac disease with a right-to-left intra-cardiac shunt usually do not respond to oxygen administration
  • Dyspnea/Respiratory Distress (see Dyspnea, [[Dyspnea]])

Renal Manifestations


Treatment

Treatment of Congenital Methemoglobinemia

  • Ascorbic Acid (Vitamin C) (see Vitamin C, [[Vitamin C]]): may cosmetically decrease cyanosis
  • Riboflavin (Vitamin B2) (see Vitamin B2, [[Vitamin B2]]): may cosmetically decrease cyanosis
  • Methylene Blue (see Methylene Blue, [[Methylene Blue]]): may cosmetically decrease cyanosis

Treatment of Hemoglobin M Disease-Associated Methemoglobinemia

  • No effective treatment

Treatment of Acquired Methemoglobinemia

Withdraw or Avoid the Drug or Offending Agent

  • Recommended
    • Dietary avoidance of orally ingested precipitant agents
    • Removal of clothing that may contain the agent
  • Withdrawal/avoidance alone may be adequate in an asymptomatic patient with methemoglobin <20%

Supplemental Oxygen

  • Recommended

Dextrose-Containing Intravenous (IV) Fluid

  • The NADPH-dependent methemoglobin reductase enzyme system requires glucose for the clearance of methemoglobin

Correction of Metabolic Acidosis

  • Bicarbonate therapy may be necessary (especially in cases in infants)

Methylene Blue (see Methylene Blue, [[Methylene Blue]])

  • Pharmacology: reduces methemoglobin (by serving as an artificial electron transporter) via a NADPH-dependent pathway
    • Results in rapid clinical improvement
  • Indications: methylene blue is considered the preferred treatment for patients with the appropriate indications
    • Hypoxic Symptoms
    • Methemoglobin >20-30%: these levels are considered life-threatening
    • Methemoglobin 10% In Setting of Significant Co-Morbid Disease or End-Organ Dysfunction (Cardiac Ischemia, etc): treatment of this group should be considered
  • Contraindications
    • Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency, [[Glucose-6-Phosphate Dehydrogenase Deficiency]]): methylene blue is ineffective in this group (since it requires NADPH generated by G6PD) and these patients are at high risk for hemolysis after administration
      • G6PD Deficiency is found in African-Americans, Mediterranean Descent, Southeast Asians
    • Use of Other Serotonergic Agents (see Serotonin Syndrome, [[Serotonin Syndrome]]): since methylene blue functions as a reversible monoamine oxidase (MAO) inhibitor (see Monoamine Oxidase Inhibitors, [[Monoamine Oxidase Inhibitors]]), it may preceipitate the serotonin syndrome
    • Hemoglobin M Disease
    • NADPH Methemoglobin Reductase (Diaphorase II) Deficiency
    • Sulfhemoglobinemia
  • Administration: 1-2 mL/kg (of 1% solution) IV over 5 min
    • Latency: resolution typically occurs within 1 hr (often within 20 min)
    • Re-Treatment: treatment can be repeated in 1 hr if methemoglobin level remains elevated
    • Serial Monitoring of Methemoglobin Level (by Evans-Malloy Method)
      • Co-oximetry cannot be used to follow serial methemoglobin levels after methylene blue dosing, since methylene blue is erroneously “read” as methemoglobin
      • Serial monitoring of methemoglobin levels is recommended, due to prolonged absorption of the offending drug from topical sites/GI tract
      • Some cases may manifest significant rebound methemoglobinemia up to 18 hrs later
      • Dapsone undergoes enterohepatic recirculation: re-treatment may be necessary
  • Adverse Effects/Cautions
    • Blue Discoloration of Skin After Administration: methylene blue can impart a blue discoloration to the skin after administration -> note that this does not imply treatment failure
    • Excessive Dosing: cumulative doses >7 mg/kg can cause hemolysis, dyspnea, and chest pain
    • Interference with Pulse Oximetry: since methylene blue interferes with subsequent pulse oximetry, must not rely on improving SpO2 as a marker for successful treatment
    • Serotonin Syndrome (see Serotonin Syndrome, [[Serotonin Syndrome]])

Ascorbic Acid (Vitamin C) (see Vitamin C, [[Vitamin C]])

  • Indication
    • G6PD Deficiency
  • Administration: moderate dose 300-1000 mg/day in divided doses
    • Avoid high dose as this may cause oxidant hemolysis in G6PD deficient patients

Hyperbaric Oxygen (see Hyperbaric Oxygen, [[Hyperbaric Oxygen]])

  • Technique: permits tissue oxygenation to occur through oxygen dissolved in plasma, rather than through hemoglobin-bound oxygen
  • Indications
    • Methemoglobinemia with Either Resistance to Methylene Blue or Contraindications to Its Use
      • G6PD Deficiency
      • Methemoglobinemia Associated with Aniline Derivatives: may be resistant

PRBC Transfusion/Exchange Transfusion (see Packed Red Blood Cells, [[Packed Red Blood Cells]])

  • Indications
    • Methemoglobinemia with Either Resistance to Methylene Blue or Contraindications to Its Use
      • G6PD Deficiency
      • Methemoglobinemia Associated with Aniline Derivatives: may be resistant

Other Agents

  • Cimetidine (Tagamet) (see Cimetidine, [[Cimetidine]]): may be used in the setting of dapsone to increase tolerance to this agent
  • N-Acetylcysteine (see N-Acetylcysteine, [[N-Acetylcysteine]]): although has been effective in some studies, not currently approved for the treatment of methemoglobinemia
  • Riboflavin (Vitamin B2) (see Vitamin B2, [[Vitamin B2]])

References

  • Failure of methylene blue treatment in toxic methemoglobinemia. Association with glucose-6-phosphate dehydrogenase deficiency. Ann Intern Med 1971;75:83-6
  • Toxic methemoglobinemia after topical anesthesia for transesophageal echocardiography. J Am Soc Echocardiogr. Nov-Dec 1996;9(6):874-6
  • Acute effects of inhaled nitric oxide in adult respiratory distress syndrome. Eur Respir J 1998; 12:1164-1171
  • Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Crit Care Med 1998; 26:15-23
  • Elevated methemoglobin in patients with sepsis. Acta Anaesthesiol Scand. Jul 1998;42(6):713-6 [MEDLINE]
  • Innovations in mechanical ventilation. Current Opin Crit Care 1999; 5:43-51
  • Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. Intensive Care Med 1999; 25:911-919
  • Inhaled nitric oxide in ARDS: modulator of lung injury? Intensive Care Med 1999; 25:1024-1026
  • Metoclopramide-induced methemoglobinemia in a patient with co-existing deficiency of glucose-6-phosphate dehydrogenase and NADH-cytochrome b5 reductase: failure of methylene blue treatment Haematologica 2001;86:659
  • Toxicol Review 2003: 22: 13-27
  • J Am Soc Echocardiograpy 2003: 16: 170-175
  • Recognition and management of methemoglobinemia and hemolysis in a G6PD-deficient patient on experimental anticancer drug Triapine. Am J Hematol 2006;81:210-1 [MEDLINE]
  • Methemoglobinemia and transesophageal echo. Proc West Pharmacol Soc. 2007;50:134-5
  • Level of oxidative stress in the red blood cells of patients with liver cirrhosis. Indian J Med Res. Sep 2007;126(3):204-10 [MEDLINE]
  • Infection and the Risk of Topical Anesthetic Induced Clinically Significant Methemoglobinemia after Transesophageal Echocardiography. Echocardiography. Aug 31 2009
  • Coma, metabolic acidosis, and methemoglobinemia in a patient with acetaminophen toxicity. J Popul Ther Clin Pharmacol. 2013;20(3):e207-11. Epub 2013 Sep 6 [MEDLINE]