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Basics ⬇

Outline

BASICS

Definition!!navigator!!

Methemoglobin is an abnormal form of hemoglobin where iron is in the ferric (Fe3+) rather than the normal ferrous (Fe2+) state. Methemoglobin reduces the oxygen-carrying capacity of blood, plus its presence shifts the oxyhemoglobin dissociation curve to the left (increases affinity of remaining hemoglobin for oxygen but releases oxygen to tissues less readily).

Pathophysiology!!navigator!!

  • Small quantities of methemoglobin are normally formed during binding of oxygen to the RBC iron–hemoglobin molecule. Normal concentration is 1.77%
  • Methemoglobin is usually continuously reduced back to hemoglobin by protective enzyme systems (major pathway via NADH-dependent methemoglobin reductase (cytochrome b5 reductase); minor pathway via NADPH–methemoglobin reductase; ascorbic acid and glutathione enzyme systems also play a role)
  • Methemoglobinemia is the presence of higher than normal concentrations of methemoglobin in the blood. It may be acquired or congenital and normally results when there is excessive production of methemoglobin and the body's regulatory mechanisms are overwhelmed
  • Methemoglobinemia results in systemic hypoxia and can be fatal
  • Many of the methemoglobin-producing oxidant toxins can also cause hemolysis by simultaneously oxidizing the sulfhydryl groups of the globin moiety in methemoglobin, resulting in denaturation and precipitation, Heinz body formation, and intravascular hemolysis

Systems Affected!!navigator!!

  • Hemic/lymphatic/immune—decreased RBC oxygen-carrying capacity, cyanosis, and muddy brown mucous membranes
  • Cardiovascular and respiratory—attempt to compensate for the decreased oxygen-carrying capacity, resulting in tachycardia and tachypnea
  • Renal/urologic—pigment nephropathy (in cases with concurrent hemolysis) and renal hypoxic insult may result in dysfunction
  • Hepatobiliary—hypoxia-induced centrilobular degeneration may occur
  • Gastrointestinal—hypoxic damage to intestines may result in motility disorders, impaction, and colic
  • Nervous—hypoxia may result in signs of lethargy and weakness
  • Musculoskeletal—laminar hypoxia may result in laminitis

Genetics!!navigator!!

There is a report of familial methemoglobinemia caused by decreased erythrocyte glutathione reductase and glutathione.

Incidence/Prevalence!!navigator!!

No incidence/prevalence data available.

Signalment!!navigator!!

  • Any age, breed, or sex
  • Familial methemoglobinemia and hemolytic anemia reported in 2 Trotter mares

Signs!!navigator!!

Historical Findings

  • Sudden onset of lethargy, inappetence, and signs of depression
  • Exercise intolerance, tachycardia, and tachypnea may also be noted
  • Cases with concurrent hemolysis may also have pigmenturia and icterus
  • Exposure to wilted or dried leaves or bark of red maple (Acer rubrum) (fall), Pistacia leaves or seeds, or nitrate-containing plants. Absence of this information should not rule out this differential

Physical Examination Findings

  • Findings depend on the severity of disease and organ systems involved
  • Muddy brown cyanotic mucous membranes with brownish discoloration of the blood
  • Clinical signs usually evident when methemoglobin concentrations are 30–40%, including weakness, lethargy, ataxia, tachycardia, tachypnea, exercise intolerance, colic, and laminitis
  • Low-grade fevers, icterus, and pigmenturia associated with hemolysis
  • Sudden death may occur

Causes!!navigator!!

  • Red maple (A. rubrum) toxicity
  • Pistacia leaf/seed ingestion
  • Other oxidant toxins, e.g. phenothiazine and onions (less severe)
  • Nitrite/nitrate poisoning (rare)
  • Deficiencies in protective RBC enzymes (glutathione reductase and flavin adenine dinucleotide deficiencies)

Risk Factors!!navigator!!

  • Access to dry/wilted red maple leaves/bark, or Pistacia leaves/seeds, often during fall
  • Exposure to nitrate/nitrite sources (e.g. plants, forages, silages, fertilizer spills)
  • Familial history of methemoglobinemia

Diagnosis ⬆ ⬇

Outline

DIAGNOSIS

Differential Diagnosis!!navigator!!

  • Immune-mediated hemolytic anemia can be differentiated by flow cytometry, RBC autoagglutination, hyperbilirubinemia, and bilirubinuria
  • Infectious causes of anemia include equine infectious anemia (positive Coggins test or C-ELISA test), piroplasmosis (organisms observed in Giemsa-stained smears or positive serology), and anaplasmosis (Anaplasma phagocytophilum) (granular inclusions in neutrophils in Giemsa-stained smears or positive PCR)
  • Hemolysis following administration of hypertonic or hypotonic solutions
  • Other toxicities, including IV DMSO, heavy metal toxicosis, and snake envenomation
  • Signs of depression and coma associated with endstage liver disease can be differentiated by increase in bile acids, liver enzymes, and chronic weight loss

CBC/Biochemistry/Urinalysis!!navigator!!

  • Horses may have concurrent Heinz body hemolytic anemia, hemoglobinemia, and neutrophilia
  • There may be evidence of hypoxic injury to various organ systems with increases in blood urea nitrogen, creatinine, and bilirubin concentrations and/or liver enzymes
  • Urinalysis may reveal hemoglobinuria, bilirubinuria, and proteinuria

Other Laboratory Tests!!navigator!!

  • Post-collection hemolysis of samples may falsely increase the methemoglobin value
  • Co-oximeter analysis of blood samples should be performed quickly to determine methemoglobin concentration (concentrations decrease rapidly in vitro)
  • The methemoglobin spot test consists of comparing a drop of patient blood, on absorbent paper, with that of a normal control horse. Methemoglobin content >10% results in a brown discoloration of patient blood compared with the red color of control blood
  • Pulse oximetry reveals low saturations (does not correlate with methemoglobin concentration)
  • Arterial PO2 is normal, as this is a measure of oxygen dissolved in the plasma and not the carrying capacity of the hemoglobin; aids in differentiation from hypoxemia

Imaging!!navigator!!

N/A

Other Diagnostic Procedures!!navigator!!

  • Blood smears stained with new methylene blue should be examined for Heinz bodies and Wright–Giemsa-stained smears for eccentrocytes and pyknocytosis
  • Testing for RBC enzyme deficiencies can be performed at specialist laboratories

Pathologic Findings!!navigator!!

May include centrilobular hepatic degeneration, hemoglobinemic renal tubular nephrosis, icteric tissues, and erythrophagocytosis by splenic, adrenal, and hepatic phagocytes.

Treatment ⬆ ⬇

Outline

TREATMENT

Appropriate Health Care!!navigator!!

  • In-hospital medical management may be necessary
  • Fluid therapy (IV) with isotonic crystalloids should be initiated for increased tissue perfusion, dilution of red cell fragments that might trigger DIC, prevention of hemoglobin-induced nephropathy, and to promote diuresis
  • Cross-matched blood or packed RBC transfusion may be considered if PCV falls to <11% over several days or to <18% in 1 day or less. Indication for blood transfusion can also include persistent tachycardia, tachypnea, weak pulse pressure, and poor response to isotonic fluids
  • If renal function is adequate, judicious NSAID use may decrease inflammation and provide analgesia
  • Administration of intranasal oxygen is of little benefit; low oxygen-carrying capacity of blood

Nursing Care!!navigator!!

Close monitoring of vital signs, fluid rates, urine output, and CBC/biochemistry is vital; and for signs of laminitis or colic.

Activity!!navigator!!

Exercise or stress, which may increase oxygen demand, is contraindicated.

Diet!!navigator!!

Palatable and nutritious diet should be provided to encourage voluntary feed intake.

Client Education!!navigator!!

Clients should be warned of the hazards of exposure to wilted red maple leaves (including hybrids), Pistacia leaves/seeds, and nitrate/nitrite-containing plants or fertilizer spills.

Surgical Considerations!!navigator!!

  • General anesthesia should be avoided due to hypoxia and associated risk
  • Surgical hemorrhage also likely to exacerbate hypoxia

Medications ⬆ ⬇

Outline

MEDICATIONS

Drug(s) of Choice!!navigator!!

  • If nitrate/nitrite poisoning is suspected, methylene blue (4.4 mg/kg) may be administered slowly IV as a 1–2% solution in isotonic saline (repeat if necessary after 30 min) (see Precautions)
  • If toxin ingestion is suspected, access should be eliminated and mineral oil and activated charcoal administered to reduce further absorption

Contraindications!!navigator!!

  • Methylene blue treatment is contraindicated with diagnosed glucose-6-phosphate dehydrogenase deficiency because this enzyme is required for NADPH synthesis, which in turn is required for methemoglobin reductase to function. Furthermore, as methylene blue is not reduced, it can cause RBC oxidative stress, resulting in hemolysis
  • Corticosteroids have been associated with decreased survival

Precautions!!navigator!!

Methylene blue is now rarely used in horses as it is considered ineffective and may exacerbate concurrent Heinz body hemolytic anemia. Use has been associated with decreased survival.

Possible Interactions!!navigator!!

N/A

Alternative Drugs!!navigator!!

  • High doses of vitamin C (50–100 g IV daily) (not proven)
  • Acetylcysteine at 50–140 mg/kg IV or PO for antioxidant support (not proven)

Follow-up ⬆ ⬇

Outline

FOLLOW-UP

Patient Monitoring!!navigator!!

  • If methylene blue is administered, PCV should be monitored closely
  • Clinical signs should be monitored for improvement/deterioration
  • Renal function and urine output should be monitored

Prevention/Avoidance!!navigator!!

Limiting access to oxidant-containing plants and nitrate/nitrite sources.

Possible Complications!!navigator!!

  • Include colic, diarrhea, and laminitis; and cases with concurrent hemolysis are at risk of pigment nephropathy and acute anuric renal failure
  • Coma and death if methemoglobin content of blood >80%

Expected Course and Prognosis!!navigator!!

  • Cyanosis and the brown discoloration of blood should resolve if methemoglobin content falls below 10%
  • Prognosis is generally guarded
  • Mortality rates for cases of red maple toxicity can be around 60%

Miscellaneous ⬆ ⬇

Outline

MISCELLANEOUS

Associated Conditions!!navigator!!

Heinz body hemolytic anemia.

Age-Related Factors!!navigator!!

Diagnosis is more likely at a younger age with familial methemoglobinemia.

Zoonotic Potential!!navigator!!

N/A

Pregnancy/Fertility/Breeding!!navigator!!

N/A

Synonyms!!navigator!!

N/A

Abbreviations!!navigator!!

  • DMSO = dimethylsulfoxide
  • ELISA = enzyme-linked immunosorbent assay
  • NSAID = nonsteroidal anti-inflammatory drug
  • PCR = polymerase chain reaction
  • PCV = packed cell volume
  • PO2 = partial pressure of oxygen
  • RBC = red blood cell

Suggested Reading ⬆ ⬇

Bozorgmanesh R, Magdesian KG, Rhodes DM, et al. Hemolytic anemia in horses associated with ingestion of Pistacia leaves. J Vet Intern Med 2015;29:410–413.

Author(s) ⬆

Author: Rana Bozorgmanesh

Consulting Editors: David Hodgson, Harold C. McKenzie, and Jennifer L. Hodgson

Acknowledgment: The author and editors acknowledge the prior contribution of Nicholas Malikides.