Toxicology Talks with Toxijawn

She’s Got the Blues

Author: Nicholas Dulin, MD, Emergency Medicine Resident PGY1
Fellow: Alexis Cates, DO, Medical Toxicology Fellow PGY6
Faculty: Michael Kowalski, DO, Medical Toxicology / Emergency Medicine Attending

The case:

You just started your 12-hour day shift in the busiest Emergency Department in the city when your first patient is brought back immediately from the waiting room. She is a 29-year-old Caucasian female who presents with worsening shortness of breath and blue lips for two hours prior to arrival. She states she is usually fairly healthy; however, she is currently taking trimethoprim-sulfamethoxazole 160mg-800mg 1 tablet PO daily for the past 6 days for a urinary tract infection diagnosed earlier in the week by her primary care physician.  She was also prescribed an over-the-counter medication for dysuria.  She cannot remember the name of this particular medication. She states she has urinary tract infections a few times per year and this has never happened to her before.

Vitals: HR 98 bpm, BP 120/70, RR 22 bpm, SpO2 85% on room air, T 98.6F

Her physical exam is significant for mildly increased work of breathing and marked perioral and peripheral cyanosis.  She has an aphthous ulcer in her oral cavity.  She does not have an altered mental status, and her cardiopulmonary exam is unremarkable.  

She is initially placed on 2 L/min of oxygen via nasal cannula which was titrated to 15 L/min of oxygen via non-rebreather with no change in her pulse oximetry. There is no improvement of her dyspnea, although she can still communicate in full sentences. EKG revealed normal sinus rhythm and chest x-ray revealed no acute cardiopulmonary abnormalities. Urine pregnancy test is negative. You take a deep breath and start to consider what could cause sudden onset shortness of breath in an otherwise healthy female.

Learning Point 1: Initial Approach to Acute Shortness of Breath

• Horses are more common than zebras
• Differential diagnoses of acute shortness of breath with potential for hypoxia (not all-inclusive) ⁶
  • HEENT
    • angioedema
    • anaphylaxis
    • pharyngitis 
    • vocal cord dysfunction
    • foreign body
    • trauma
  • Chest wall/pulmonary
    • rib fracture
    • flail chest
    • pneumomediastinum
    • COPD exacerbation
    • asthma exacerbation
    • pulmonary embolism
    • pneumothorax
    • pleural effusion
    • pneumonia
    • acute respiratory failure
    • pulmonary contusion/trauma
    • pulmonary hemorrhage
    • exogenous allergic alveolitis
  • Cardiac
    • acute coronary syndrome/myocardial infarction
    • acutely decompensated congestive heart failure
    • pulmonary edema
    • high-output failure
    • cardiomyopathy
    • tachyarrhythmia
    • valvular heart disease
    • pericardial tamponade
    • Pulmonary hypertension
    • Eisenmenger’s syndrome
  • Toxic/metabolic
    • organophosphate poisoning
    • salicylate poisoning
    • carbon monoxide poisoning
    • methemoglobinemia
    • diabetic ketoacidosis
  • Other
    • sepsis
    • anemia
    • encephalitis
    • traumatic brain injury
    • anxiety
    • pregnancy
    • Hypoventilation obesity syndrome
• Narrowing it down
  • HEENT
    • Denies personal or family history of angioedema, anaphylaxis or vocal cord dysfunction, no pharyngeal erythema or edema, no evidence of trauma or foreign body sensation with patent airway
    • Decreased suspicion for HEENT etiology in this patient
  • Pulmonary
    • No history of asthma/COPD, or trauma with clear lung sounds & normal chest radiograph; no chest wall abnormalities (decreased suspicion for rib fracture, flail chest, pneumothorax, pleural effusion, pneumomediastinum, pneumonia, asthma/COPD exacerbation, pulmonary hemorrhage or contusion)
    • Denies inhalation of pulmonary irritants, recent travel, organic products (decreased suspicion for exogenous allergic alveolitis)
    • No history of blood clots however unable to use PERC rule in patient with SpO2 (pulmonary embolism remains on differential)
  • Cardiac
    • No history of cardiac abnormalities, family history of sudden cardiac death or early MI, normal cardiopulmonary exam with no JVD or peripheral edema, normal EKG & CXR (decreased suspicion for acute coronary syndrome, myocardial infarction, CHF exacerbation, pulmonary edema, cardiomyopathy, cardiac arrhythmia,  valvular heart disease, pericardial tamponade)
    • Patient presenting with dyspnea and central cyanosis with no additional cardiopulmonary physical exam findings (pulmonary hypertension & Eisenmenger’s syndrome remains on differential)
  • Toxic/metabolic
    • Denies recent exposure to pesticides, chemicals, excessive salicylate or peppermint oil usage, history of diabetes/polyuria/polydipsia,  prolonged exposure to combustible products, including space heater or engine fumes, sick contacts (decreased suspicion for organophosphate, salicylate, carbon monoxide poisoning, diabetic ketoacidosis)
    • Patient presenting with central cyanosis, dyspnea not improved with supplemental oxygen (methemoglobinemia remains on differential)
  • Other
    • Non- obese female with no history of anemia, hemorrhage, altered mental status, trauma presenting with peripheral edema, central cyanosis and negative pregnancy test. (decreased suspicion for traumatic brain injury, anxiety, pregnancy, hypoventilation syndrome)
    • Central cyanosis in SIRS criteria positive patient (anemia and sepsis remain on differential)
• Revised differential diagnosis
  • Methemoglobinemia
  • Pulmonary embolism
  • Pulmonary hypertension
  • Eisenmenger’s syndrome
  • Anemia
  • Sepsis
• Suspect methemoglobinemia in unexplained cyanosis or hypoxia that does not resolve with supplemental oxygen
  • Increased index of suspicion in patients with prior history or family history of methemoglobinemia or exposure to methemoglobinemia-inducing substance
  • Signs and symptoms are related to impaired oxygen carrying capacity and delivery to tissue
    • Usually manifest in correlation to % serum methemoglobinemia along with the rate of formation and elimination of methemoglobinemia (Figure 4)

Figure 4. Goldfrank’s Toxicologic Emergencies, 11e. Lewis S. Nelson, Mary Ann Howland, Neal A. Lewin, Silas W. Smith, Lewis R. Goldfrank, Robert S. Hoffman.

• SpO2 reading in the mid 80s percentile which is non-responsive to supplemental oxygen in the setting of recent oxidative stress exposure is classic for methemoglobinemia
  • May present with <<< 85% in severe cases 
  • Pulse oximeters work by detecting the ratio of the absorption of light in deoxygenated (infrared or 660nm) blood to oxygenated (red or 940nm) blood
    • Methemoglobin absorbs light at both wavelengths and high methemoglobin concentrations tricks the pulse oximeter reading the ratio of oxygenated to deoxygenated blood as 1.0 or 85% (Ludlow JT et al.)
    • Methemoglobin has a higher affinity to oxygen than its surrounding tissues and therefore supplemental oxygen will have little to no effect on standard pulse oximetry
• “Chocolate brown blood” or ruddy cyanosis
  • Another classic finding and is a consequence to how our wavelength detectors (eyes) perceive light absorption at different wavelengths
• Fatigue, dyspnea, weakness, syncope, tachypnea, CNS depression
  • Non-specific findings related to end-organ hypoxia

 Learning Point 2: Introduction to Methemoglobinemia

• Methemoglobin is produced when the iron atom of a hemoglobin molecule loses an electron from its ferrous (Fe²⁺) state and becomes oxidized to its ferric (Fe³⁺) state (Figure 1).

Figure 1: https://coreem.net/core/methemoglobinemia/

• Methemoglobinemia is defined as an methemoglobin level of >1% which may result in an asymptomatic presentation all the way to respiratory distress and death
• The remaining binding sites on a methemoglobin molecule will have a greater affinity for oxygen and inhibit oxygen atoms from diffusing into peripheral tissue secondary to a leftward shift in the oxyhemoglobin dissociation curve (Figure 2).

Figure 2: David SR, Sawal NS, Bin Hamzah MN, Rajabalaya R. The blood blues: A review on methemoglobinemia. J Pharmacol Pharmacother [serial online] 2018 [cited 2021 Mar 13];9:1-5. Available from: http://www.jpharmacol.com/text.asp?2018/9/1/1/236322

• Methemoglobin is usually cleared by a reducing enzyme creatively named NADH hemoglobin reductase
• This enzyme could be overwhelmed by oxidant stressors
• A short list of xenobiotics that are most commonly implicated in methemoglobinemia:
  • Local anesthetics
    • Benzocaine (most common, especially 20% spray form)
  • Dapsone
  • Nitroglycerin/nitroprusside/nitric oxide
  • Phenazopyridine 
  • Sulfonamides (trimethoprim and sulfamethoxazole aka Bactrim)
  • House fires (inhalation from nitrogen combustion products cause oxidative stress)
• The biochemical pathway shown in Figure 3 shows that accumulation of Hb(Fe³⁺) or methemoglobin is the underlying problem in symptomatic methemoglobinemia and the cornerstone of management is removal of oxidant stress (if applicable) and reduction back to hemoglobin using methylene blue

Figure 3: Goldfrank’s Toxicologic Emergencies, 11e. Lewis S. Nelson, Mary Ann Howland, Neal A. Lewin, Silas W. Smith, Lewis R. Goldfrank, Robert S. Hoffman.

Learning Point 3: Management and Special Considerations

• High index of suspicion in the right clinical context
  • If you don’t think about it, you may not find it
  • Methylene blue is reported to be used approximately 100 times per year in the United States; however, this may be severely underreported
• Pulse oximetry is unreliable in cases of methemoglobinemia
  • Consider obtaining an arterial blood gas
  • Co-oximeter blood panel will give you a MetHb % level along with a hemoglobin oxygen saturation, carboxyhemoglobin, oxyhemoglobin, and deoxyhemoglobin %
• Call Toxicology! (1-800-222-1222 is the universal number for the Poison Control Centers)
• Give 100% FiO2 as the patient is functionally hypoxic
  • Remember if the patient is anemic at baseline a 20% reduction of functional hgb may be more clinically devastating
    • 80% of a normal hemoglobin may still be functionally within normal limits (80% of 15.5g/dL = 12.4g/dL)
    • 80% functional hemoglobin in an anemic patient at baseline may present with more profound hypoxia (80% of 8.0g/dL = 6.4g/dL) 
• Consider using this algorithm mentioned in Figure 5
  • Consider holding methylene blue and observing asymptomatic patients with MetHb <25%
  • Consider administering methylene blue if symptomatic with MetHb <25% or in all patients with MetHb >25
  • TLDR: if your patient has cyanosis, a history consistent with methemoglobinemia, and is refractory to supplemental O2 (especially with a detectable level of MetHb), consider methylene blue
    
    

Figure 5: Goldfrank’s Toxicologic Emergencies, 11e. Lewis S. Nelson, Mary Ann Howland, Neal A. Lewin, Silas W. Smith, Lewis R. Goldfrank, Robert S. Hoffman.

• Methylene blue
  • Used as a treatment in the late 1930s as a treatment for drug-induced methemoglobinemia (particularly sulfanilamides)
  • Sulfanilamide is also related to another toxicologic disaster but that’s a story for another post
    • Also used prophylactically during surgery in individuals with congenital methemoglobinemia
  • Mechanism of action (refer to Figure 3)
    • Accelerates the enzymatic reduction of methemoglobin by NADPH-methemoglobin reductase
    • Facilitates reduction of MetHb back to hemoglobin
  • Give methylene blue in 1-2 mg/kg IV bolus over 5 minutes, can use additional bolus if methemoglobinemia persists
    • Local pain at infusion site mitigated by flushing line after infusion
    • Cyanosis should disappear within 30-60 min after infusion
    • Consider alternative causes or additional methylene blue if initial bolus does not work
      • Congenital NADPH-methemoglobin reductase deficiency
      • Sulfhemoglobinemia
    • Though not solidified in the literature, there have been some reports of continuous infusions of methylene blue in refractory cases 
      • In simple cases of topical benzocaine induced methemoglobinemia one bolus of methylene blue at 2 mg/kg will likely result in normalization of methemoglobin fractions
      • Consider continuous methylene blue infusion in
        • unrecognized G6PD deficiency.
        • coexistent sulfhemoglobinemia (which commonly occurs with methemoglobinemia)
        • NADPH methemoglobin reductase deficiency
        • In cases where methemoglobinemia that improves but keeps bouncing back (methemoglobin-inducers with long half lives)
          • Think aniline, nitrobenzene, and dapsone!
      • Continuous methylene blue infusion typically runs at 0.1 mg/kg/hr for 3 to 5 days in cases of refractory methemoglobinemia with serial methemoglobin fractions
    • Serotonin syndrome may occur when combining serotonergic agents with methylene blue at a dose of 5 mg/kg⁷
  • Pulse oximetry will read scary low false SpO2% after administration 
    • Methylene blue & deoxygenated hemoglobin both absorb light at 660nm
    • Recommend discontinuing pulse oximetry use after administration 
    • Can follow perfusion and relative hypoxia based on clinical manifestations or via arterial blood gases
  • Controversial in G6PD deficiency patients
    • Theoretically could precipitate hemolytic anemia although evidence supporting this assumption clinically is scarce
    • When indicated for life-threatening and symptomatic methemoglobinemia, methylene blue can be life-saving
    • As of now, there is scant evidence for alternative or adjunctive therapies in patients who have relative contraindications to methylene blue
• Dapsone
  • Produces prolonged methemoglobinemia
    • Dapsone metabolites are oxidants with long half-lives
    • Metabolized by cytochrome P450 (CYP2C9 and CYP3A4)
  • Cimetidine (H2 receptor antagonist) 
    • Competitive inhibitor in the cytochrome P450 metabolic pathway
    • Dapsone metabolism will be inhibited by cimetidine
    • Cimetidine can be used with methylene blue as adjunctive treatment, though clinical evidence to support this is rare
• Disposition
  • No extended monitoring or admission required if 
    • Asymptomatic after methylene blue administration 
    • Short acting methemoglobin producing agent
    • Minimal concern for recurrence
  • Consider admission vs extended observation if
    • Long acting methemoglobin producing agent (e.g. dapsone)
    • Recurrence of methemoglobin suspected
    • Patient is hemodynamically unstable
    • Patient requires additional intervention (e.g. multiple MB doses)

Case conclusion:

You return to your cyanotic patient’s room to gather more history as the pharmacy dusts off the methylene blue. Her methemoglobin level turned out to be 32%!  She looked up the name of the medication she takes for dysuria and it turned out to be phenazopyridine. You also ask her if she uses any other medications including over-the-counter sprays and she reveals she has been using numbing gel (benzocaine) for a canker sore but forgot to mention that before. She doesn’t know what a G6PD deficiency is and doesn’t think she has that condition. You begin methylene blue 2 mg/kg IV over 5 minutes.  Although she experienced some pain at the infusion site which resolved after the line was flushed, her cyanosis resolved within the next 35 minutes. You recheck a methemoglobin level and it is within a normal fraction.  You caution her on the use of methemoglobin-inducers, explain what methemoglobinemia is and how some of her medications may have played a role. After a period of observation in the ED, her symptoms completely resolved and she was discharged from the ED in stable condition. 

References:

1. David SR, Sawal NS, Bin Hamzah MN, Rajabalaya R. The blood blues: A review on methemoglobinemia. J Pharmacol Pharmacother 2018;9:1-5 [Fig 2] 
2. Goldfrank’s Toxicologic Emergencies, 11e. Lewis S. Nelson, Mary Ann Howland, Neal A. Lewin, Silas W. Smith, Lewis R. Goldfrank, Robert S. Hoffman. [Fig 3, 4, 5]
3. Ludlow JT, Wilkerson RG, Nappe TM. Methemoglobinemia. [Updated 2020 Sep 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537317/
4. Swaminathan, Anand. “Methemoglobinemia.” Core EM, 15 Nov. 2017, coreem.net/core/methemoglobinemia/. https://coreem.net/core/methemoglobinemia/ [Fig 1]
5. Tox & Hound. Tox and Hound – Fellow Friday – Methylene Blue Infusions. EMCrit Blog. Published on June 22, 2018. Accessed on March 16th 2021. Available at [https://emcrit.org/toxhound/refractory-methemoglobinemia/ ].
6. Berliner D, Schneider N, Welte T, Bauersachs J. The Differential Diagnosis of Dyspnea. Dtsch Arztebl Int. 2016;113(49):834-845. doi:10.3238/arztebl.2016.0834
7. Gillman PK. Methylene blue implicated in potentially fatal serotonin toxicity. Anaesthesia. 2006 Oct;61(10):1013-4. doi: 10.1111/j.1365-2044.2006.04808.x. PMID: 16978328.