1. Respiratory Support

Dysfunctional hemoglobin severely limits the oxygen-carrying capacity of blood. Therefore, the primary goals of respiratory support are to maximize the amount of dissolved oxygen in the plasma and prevent respiratory muscle fatigue or failure.

A. Supplemental Oxygen: Indications & Limitations

• Indications: Administer high-concentration oxygen for any patient with MetHb levels of 20–30% or higher, or for any symptomatic patient (e.g., tachypnea, altered mental status, chest pain), regardless of the level. This also applies to other dyshemoglobinemias like carboxyhemoglobinemia (COHb) above 20%.
• Delivery Methods: Start with a non-rebreather mask at 15 L/min or a high-flow nasal cannula (HFNC) at 30–60 L/min. The goal is to maximize the fraction of inspired oxygen (FiO₂) to maintain an arterial partial pressure of oxygen (PaO₂) above 80 mm Hg.
• Limitations: Supplemental oxygen increases dissolved O₂ but does not directly convert ferric (Fe³⁺) iron back to its ferrous (Fe²⁺) state. Consequently, pulse oximetry (SpO₂) readings will remain falsely low, often plateauing around 85%, and should not be used to guide therapy.

B. Mechanical Ventilation: When to Escalate

• Indications for Intubation: Escalation to mechanical ventilation is necessary for refractory hypoxemia (e.g., PaO₂/FiO₂ ratio < 150 despite maximal non-invasive support), evidence of respiratory muscle fatigue (paradoxical breathing, tachypnea), or a declining mental status.
• Ventilator Strategy: Employ a lung-protective strategy with low tidal volumes (6 mL/kg of predicted body weight). Permissive hypercapnia is acceptable to avoid high airway pressures. Avoid excessive oxygenation (hyperoxia), as it can theoretically worsen hemoglobin oxidation. Titrate positive end-expiratory pressure (PEEP) to optimize alveolar recruitment without compromising cardiac preload.

C. Hyperbaric Oxygen (HBO): Role in Refractory Cases

HBO therapy dramatically increases the amount of oxygen dissolved in plasma, providing a temporary bypass to hemoglobin-based oxygen transport. It may also enhance the non-enzymatic reduction of methemoglobin.

• Consider When: HBO is a rescue therapy for patients with severe methemoglobinemia (MetHb > 50%) that persists despite adequate doses of methylene blue, or in patients with G6PD deficiency where methylene blue is contraindicated.
• Practical Issues: HBO chambers are not widely available, and transferring a critically ill patient poses significant risks. If considering HBO, coordinate with the nearest hyperbaric unit as early as possible.

2. Hemodynamic Support

Hypotension in methemoglobinemia can result from cellular hypoxia, direct effects of the causative agent, or a concurrent systemic inflammatory response. The goal is to maintain adequate mean arterial pressure (MAP) to ensure end-organ perfusion.

A. Fluid Management & Vasopressors

• Initial Resuscitation: Begin with a bolus of 20–30 mL/kg of an isotonic crystalloid (e.g., Lactated Ringer’s or Normal Saline) to address any relative hypovolemia.
• Vasopressors:
  • Norepinephrine: The first-line agent due to its potent alpha-1 adrenergic effects, which increase systemic vascular resistance (SVR). Start at 0.05 mcg/kg/min and titrate to a target MAP of ≥ 65 mm Hg.
  • Vasopressin: Can be added as a second agent (at a fixed dose of 0.03 units/min) to reduce the required dose of catecholamines.
  • Avoid Dopamine: High doses are associated with increased risk of arrhythmias and mortality in shock states.

B. Monitoring Cardiac Output & Perfusion Markers

Use a combination of invasive and non-invasive markers to assess the adequacy of resuscitation.

• Dynamic Indices: If the patient is intubated and has an arterial line, use dynamic parameters like stroke volume variation (SVV) or pulse pressure variation (PPV) to guide fluid administration.
• Perfusion Surrogates: Track lactate clearance (aim for >10% reduction every 2 hours), urine output (target ≥ 0.5 mL/kg/h), and capillary refill time as indicators of improving tissue perfusion.

3. Prevention of ICU-Related Complications

Critically ill patients are at high risk for complications such as venous thromboembolism (VTE) and stress-related mucosal bleeding. Standard ICU prophylaxis protocols should be implemented, tailored to the patient’s specific risk factors.

A. VTE Prophylaxis

B. Stress Ulcer Bleeding Prophylaxis

• Indications: Prophylaxis is recommended for patients on mechanical ventilation for more than 48 hours or those with a significant coagulopathy (e.g., INR > 1.5 or platelet count < 50,000/μL).
• Agents:
  • Proton Pump Inhibitors (PPIs): Pantoprazole 40 mg IV daily is highly effective but may be associated with a slightly increased risk of ventilator-associated pneumonia (VAP).
  • H₂-Receptor Blockers: Famotidine 20 mg IV twice daily is an alternative with potentially lower VAP risk, though it is less potent.
• De-escalation: Discontinue prophylaxis once the patient is extubated or tolerating an enteral diet.

C. Infection Prevention Bundles

Adherence to evidence-based bundles is crucial for preventing nosocomial infections.

• VAP Prevention: Maintain head-of-bed elevation at 30–45 degrees, perform daily sedation interruptions (“sedation vacations”) and spontaneous breathing trials, use oral hygiene with chlorhexidine, and utilize subglottic suctioning endotracheal tubes where available.
• Catheter-Related Infection Prevention: Ensure aseptic technique during insertion and meticulous daily maintenance of all central venous and urinary catheters.
• Nutrition: Initiate enteral nutrition within 24–48 hours of ICU admission to maintain gut integrity and reduce infection risk.

4. Monitoring Strategies

Effective management requires a multi-faceted monitoring approach, combining continuous physiological data with serial laboratory assessments to track disease progression and response to therapy.

A. Continuous Cardiorespiratory Monitoring

All patients with significant dyshemoglobinemia require continuous monitoring in an ICU setting, including:

• Electrocardiogram (ECG): To detect arrhythmias or signs of ischemia.
• Invasive Arterial Pressure: For real-time blood pressure monitoring and access for frequent blood sampling.
• End-Tidal CO₂ (Capnography): To monitor ventilation status in intubated patients.
• Central Venous Oxygen Saturation (ScvO₂): If a central line is in place, ScvO₂ can provide an additional marker of the balance between oxygen delivery and consumption, though it must be interpreted with caution.

B. Pulse Oximetry vs. Co-oximetry

Understanding the limitations of standard pulse oximetry is critical.

• Frequency of Co-oximetry: Measure MetHb levels every 1–2 hours during active treatment with an antidote, then space to every 6–12 hours once the patient is clinically stable and levels are trending down.

C. Laboratory Surveillance

• Methemoglobin Level: The primary target is a MetHb level < 5% in adults.
• Hemolysis Panel: If there is a risk of G6PD deficiency or if hemolysis is suspected after methylene blue administration, check a hemolysis panel (hemoglobin, haptoglobin, LDH, indirect bilirubin).
• Lactate: Monitor serum lactate every 2–4 hours until a clear downward trend is established, indicating improved tissue perfusion.

5. Management of Iatrogenic Complications

Antidotal therapy, while life-saving, is not without risk. Clinicians must anticipate and be prepared to manage complications such as drug-induced hemolysis and serotonin syndrome.

A. Hemolysis in G6PD-Deficient Patients

Methylene blue can induce severe hemolysis in patients with G6PD deficiency. Prompt recognition and management are key.

B. Serotonin Syndrome Risk

• Risk Factors: Methylene blue is a monoamine oxidase inhibitor (MAOI). The risk of serotonin syndrome is high in patients concurrently taking other serotonergic agents like SSRIs, SNRIs, or other MAOIs.
• Signs & Symptoms: Onset is typically within hours of IV methylene blue administration. Look for the clinical triad of altered mental status (agitation, confusion), autonomic instability (hyperthermia, tachycardia, labile blood pressure), and neuromuscular hyperactivity (clonus, hyperreflexia, tremor).
• Management: Immediately discontinue all serotonergic agents. Administer cyproheptadine (a serotonin antagonist), starting with a 12 mg oral loading dose, followed by 2 mg every 2 hours until symptoms improve. Provide aggressive supportive care, including external cooling for hyperthermia.

6. Multidisciplinary Goals-of-Care

The use of high-risk, resource-intensive therapies warrants early and frequent communication among the clinical team, the patient, and their family to ensure that the plan of care aligns with the patient’s values and goals.

A. Ethical Framework for High-Risk Interventions

Before proceeding with therapies like exchange transfusion, hyperbaric oxygen, or extracorporeal membrane oxygenation (ECMO), engage in a shared decision-making process. This should include a frank discussion of the potential benefits versus the burdens, the likely prognosis, and the impact on quality of life.

B. Communication with Patients, Families & Teams

• Early Family Meeting: A structured family meeting should be held within 48 hours of ICU admission to establish rapport, explain the clinical situation, and understand the patient’s wishes.
• Structured Communication: Utilize frameworks like the VALUE mnemonic (Value family statements, Acknowledge emotions, Listen, Understand the patient as a person, Elicit questions) to guide these difficult conversations.
• Documentation: All goals-of-care discussions and decisions, including code status, must be clearly and accessibly documented in the electronic medical record.

7. Special Settings

Management must be adapted for specific patient populations where the risks of both the disease and its treatments are altered.

A. Pregnancy: Maternal vs. Fetal Risks

Methemoglobinemia in pregnancy is a delicate balance. Maternal hypoxia poses a significant risk to the fetus. However, methylene blue (a Category C drug) can cross the placenta and has been associated with teratogenicity in the first trimester and neonatal hemolysis later in pregnancy.

• Risk-Benefit Analysis: For maternal MetHb levels > 20% or in symptomatic patients, the risk of untreated hypoxia to the fetus generally outweighs the risks of methylene blue.
• Consultation: Management should always be undertaken in close consultation with obstetrics and maternal-fetal medicine specialists.

B. Perioperative Management

The operating room is a high-risk environment for the development of methemoglobinemia due to the common use of oxidizing agents like topical anesthetics (benzocaine, lidocaine) and inhaled nitric oxide.

• Preoperative Screening: Inquire about personal or family history of dyshemoglobinemias and consider G6PD screening in high-risk populations before elective procedures involving known oxidizing agents.
• Intraoperative Preparedness: Ensure that methylene blue, co-oximetry capabilities, and blood products are immediately available in the operating suite.