Myoglobinuria

Definition

Pathophysiology

Causes

• Crush injury, compartment syndrome
• Electrical injury
• Vigorous exertion (e.g., marathon running, military training)
• Status epilepticus
• Hyperthermia / heat stroke
• Myonecrosis from prolonged coma or immobilization

• Glycogenoses (e.g., McArdle disease - phosphorylase deficiency)
• Lipid disorders (e.g., Carnitine palmitoyl transferase-2 / CPT-2 deficiency - precipitated by exercise, cold, or fever)
• Mitochondrial myopathies (cytochrome B deficiency)
• Hypokalemia, hypophosphatemia
• Malignant hyperthermia (RYR1 mutations)

• Dermatomyositis / polymyositis
• Viral / bacterial myositis
• Drugs and toxins (statins, alcohol)

Clinical Features

• Dark red to brown ("coca-cola" or "tea-colored") urine appearing within 1-2 days after the precipitating event
• Muscle tenderness, weakness, and cramps
• Oliguria or anuria if AKI develops
• Systemic features: fever, nausea, malaise

Laboratory Diagnosis

• Urine dipstick tests positive for heme in only up to 50% of rhabdomyolysis cases (myoglobin is rapidly cleared), so a negative dipstick does not rule out the diagnosis. Serum CK is the more reliable test.
• Accurate quantification can be done by urine myoglobin immunoassay.

• Hematuria: many RBCs on microscopy, normal serum
• Hemoglobinuria: pink serum, low haptoglobin, occasional RBCs
• Myoglobinuria: normal serum color, normal haptoglobin, markedly elevated CK, few RBCs on microscopy

Complications

• Acute Kidney Injury (AKI) - the most serious complication; myoglobin precipitates in tubules (especially in acidic urine), causes direct oxidative tubular injury and vasoconstriction
• Electrolyte abnormalities: hyperkalemia, hyperphosphatemia, hypocalcemia
• Disseminated intravascular coagulation (DIC) in severe cases
• Compartment syndrome (may be both a cause and a consequence)

Management

1. Aggressive IV fluid resuscitation - maintain urine output of 1-2 mL/kg/h to flush myoglobin from tubules; continue until serum CK is less than 5 times normal or urine myoglobin returns to normal
2. Urinary alkalinization - sodium bicarbonate may be added to increase urine pH > 6.5, reducing myoglobin precipitation (used in some centers)
3. Correct electrolyte abnormalities - especially hyperkalemia
4. Monitor for and treat AKI - may require dialysis in severe cases
5. Treat the underlying cause (e.g., immobilization, stop offending drugs)
6. Patients with myoglobinuria from electrical injury should be considered for fasciotomy if compartment syndrome is suspected

TRALI - Transfusion-Related Acute Lung Injury

Definition

Blood Products Implicated

• Fresh Frozen Plasma (FFP) - highest plasma volume
• Apheresis platelets - high plasma content
• Whole blood
• Packed Red Blood Cells (pRBCs)
• Cryoprecipitate (less common)

Epidemiology

• Historically, TRALI occurred in approximately 1 in 5,000-10,000 plasma-containing product transfusions
• True incidence is likely underestimated due to under-reporting and difficulty distinguishing TRALI from other causes of respiratory distress in critically ill patients
• After implementation of male-donor plasma policies, the incidence decreased from ~2.57 per 10,000 units to ~0.81 per 10,000 units
• Occurs equally in both sexes and all age groups
• Multiparous female donors are the most commonly implicated donors, due to HLA antibody formation from exposure to fetal leukocyte antigens during pregnancy

Pathogenesis - The Two-Hit Model

Hit 1: Neutrophil Priming

Hit 2: Neutrophil Activation by Transfused Products

• Donor plasma contains anti-HLA class I or class II antibodies or anti-Human Neutrophil Antigen (HNA) antibodies (especially anti-HNA3a)
• These antibodies react with recipient leukocytes (neutrophils, monocytes) and pulmonary endothelium
• Neutrophil degranulation and reactive oxygen species release damage the alveolar-capillary membrane
• Most commonly from multiparous female donors who develop HLA antibodies during pregnancy

• Stored blood products accumulate bioactive lipids (e.g., lysophosphatidylcholine) and CD40 ligand - both capable of activating primed neutrophils
• Older stored units contain more of these substances
• This mechanism explains TRALI in the absence of donor antibodies

Clinical Features

• Chest X-ray shows bilateral alveolar opacities with a normal cardiac silhouette and no pleural effusions
• Approximately 70% of patients require mechanical ventilation at presentation
• The illness tends to resolve within 48 hours in most cases
• Chest radiograph typically returns to normal within 4 days

Diagnostic Criteria (2019 International Consensus - TRALI Type I & II)

1. No evidence of acute lung injury before transfusion
2. Acute onset hypoxemia: PaO2/FiO2 ≤ 300 mmHg or SpO2 < 90% on room air
3. Bilateral infiltrates on chest imaging
4. No evidence of left atrial hypertension (or if present, not judged to be the primary cause)
5. Onset within 6 hours of blood product transfusion

• Respiratory status was stable in the 12 hours before transfusion
• Transfusion judged to have caused the acute deterioration

The 2019 consensus panel removed the older term "possible TRALI" and replaced it with this Type I/Type II classification.

Differentiation: TRALI vs TACO vs ARDS

Management

Immediate Steps:

1. Stop the transfusion immediately if TRALI is suspected
2. Keep the IV line open; do NOT discard the blood bag (send for investigation)
3. Notify the blood bank - quarantine all products from the implicated donor

Respiratory Support:

1. Supplemental oxygen - high-flow O2 via facemask as first step
2. Mechanical ventilation in ~70% of patients - use lung-protective strategy (same as ARDS: low tidal volumes 6 mL/kg, PEEP titration, plateau pressure < 30 cmH2O)
3. ECMO may be used in severe refractory cases (limited evidence)

Hemodynamic Support:

1. Avoid aggressive diuresis (unlike TACO) - TRALI involves capillary leak, and diuresis may worsen hypotension
2. IV fluid resuscitation may be needed to maintain end-organ perfusion

Pharmacological:

1. Corticosteroids: No convincing evidence of benefit; most providers avoid if lung injury is >14 days old (risk of worsening as in late-phase ARDS)
2. Vasopressors if hypotension is refractory

Laboratory Investigation:

• Test donor for anti-HLA (class I and II) and anti-HNA antibodies (especially anti-HNA3a)
• If donor has antibodies against recipient's leukocyte antigens: defer donor from future high-plasma donations
• Note: TRALI is a clinical diagnosis - absence of antibodies does not exclude it

Prognosis

• Estimated mortality: ~5% (Murray & Nadel's)
• Most patients recover within 48-96 hours with supportive care
• Patients who recover from TRALI are not at increased risk for recurrence if future transfusions avoid products from the implicated donor

Prevention