EM@3AM – Hemolytic Uremic Syndrome

Author: Brit Long, MD (@long_brit, EM Attending Physician, San Antonio) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

Welcome to EM@3AM, an emDocs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.

A 2-year-old female is brought to the ED for 3 days of diarrhea and recurrent fevers (Tmax 103.1). The patient’s mother reports the child as having “no appetite.” She is appropriately concerned that her daughter “has made only two wet diapers” in the previous 12 hours. Review of systems is positive for a brother with a recent diarrheal illness. The patient’s immunizations are up to date.

Triage vital signs (VS): BP 70/55, HR 122, T 102.0 Rectal, RR 14, SpO2 99% on room air.

The child is lethargic with dry mucous membranes, a capillary refill of 3 seconds, and decreased skin turgor. As you remove her diaper, you note bloody diarrhea (per the mother, a symptom that was not present prior to arrival).

What’s the next step in your evaluation and treatment?

Answer: Hemolytic Uremic Syndrome (HUS)^1-4

• Definition: A microangiopathic hemolytic anemia +/- thrombocytopenia and renal insufficiency/failure.
  • Renal insufficiency/failure => damage to renal vascular endothelium => deposition of platelets, complement, and fibrin => thrombocytopenia and reduced glomerular filtration rate.
• Etiology/Pathophysiology:
  • Primary (atypical) HUS: occurring secondary to complement dysregulation (50-60% of children have an identifiable genetic mutation).²
    • Pathophysiology: Complement dysregulation => injury to renal endothelial cells => fibrin microthrombus formation.²
  • Secondary HUS: caused by infections (Shiga-toxin producing coli (O157:H7) (most common in the U.S.), S. pneumoniae, Aeromonas, or HIV), drugs (chemotherapeutic agents), or idiopathic etiologies (pregnancy, systemic lupus erythematosus).
    • Pathophysiology: Shiga toxin injures renal endothelial cells => fibrin microthrombus formation.²
      • Note: infectious etiologies = HUS may be transmitted by person-to-person contact, or by contaminated food (unpasteurized dairy products or beef).
      • 80% of individuals infected by Shiga-toxin producing E. coli strains experience spontaneous resolution.²
•  Epidemiology: HUS is rare in persons > age 5.
•  Risk factors:
  • Family history of HUS => suggests a genetic or complement-mediated etiology.
  • Concurrent HUS in family member.²
•  Clinical Presentation: Secondary HUS (infectious): diarrhea (becomes bloody in 50-85% of cases within days of onset), crampy abdominal pain, +/- fever, seizures, and hypertension.¹ Patients may develop toxic megacolon, intussuception, or ischemic colitis. Infection due to S. pneumoniae => concomitant otitis media, sinusitis, pneumonia, or systemic bacteremia possible.¹
• Evaluation:
  • Assess ABCs and obtain VS.
  • Perform a thorough history: Question parents of pediatric patients regarding shared meals, sick contacts, diarrhea frequency/appearance, and urine output.
  • Perform a complete physical exam.
    • Signs of dehydration on presentation (dry mucous membranes, increased capillary refill, decreased skin turgor, etc.) => increased risk of renal failure in the setting of HUS.³
  • Laboratory evaluation:^1,2
    • CBC (anemia, thrombocytopenia), peripheral smear (schistocytes, helmet cells, burr cells, teardrop cells), aPTT, PT/INR, haptoglobin (decreased), LDH, reticulocyte count, D-dimer, CMP (hyperkalemia), serum phosphorus (hyperphosphatemia), ESR & CRP (commonly elevated in patients with Shiga-toxin producing E. coli O157:H7), UA with microscopy (ketonemia, hematuria, proteinuria), Shiga toxin stool assay, stool culture. Arterial or venous blood gas (evaluate severity of metabolic acidosis).
•  Treatment & Disposition:
  • Fluid resuscitation.
  • If hyperkalemia => obtain EKG, treat as appropriate.
  • Pancreatic insufficiency is a rare complication: hyperglycemia + ketonemia => insulin therapy.
  • Severe hyperkalemia, hyperphosphatemia, or severe metabolic acidosis => consult pediatric nephrologist for dialysis.
  • Patients with neurologic symptoms (e.g. seizure/stroke) – discuss plasmapheresis with specialist (research has yet to demonstrate mortality benefit in secondary HUS, more commonly utilized in primary HUS).^1,2
  • Blood products:¹
    • RBC transfusion recommended for Hgb < 6g/dL.
    • Perform a platelet transfusion prior to a procedure in the setting of a life-threatening bleed.
  • Anti-hypertensives:¹
    • Nifedipine ER (0.25-0.5 mg/kg/day oral)
    • Labetolol 1-3 mg/kg/day, divided into twice daily dosing (12 mg/kg/day up to 1200 mg/day)
    • Nitroprusside 0.3-0.5 ug/kg/min IV (max 10 ug/kg/min)
  • Seizures: administer benzodiazepines.
  • Do not administer anti-motility agents (risk of toxic megacolon) or antibiotics if etiology is believed to be E.coli O157:H7 (enhances release of toxin).
    • Pneumococcal associated HUS + pneumonia => ceftriaxone (50 mg/kg IV (max 2 g/dose) every 24 hours) + vancomycin (15 mg/kg IV four times daily (max 2 g/dose)).¹
  • Primary HUS => treated with eculizumab: monoclonal anti-C5 antibody that targets a downstream mediator in the complement cascade.²
• Pearls:
  • Early dialysis and supportive therapy = 90% patients with acute renal failure experience return to baseline renal function.¹
  • In severe cases, renal transplant may be required. HUS may recur in the transplanted kidney.
  • Recurrent HUS is associated with a 30% mortality rate.^1,4
  • The differential diagnosis of HUS should include: vasculitis, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, and non-microangiopathic etiologies of hemolytic anemia.¹

 References:

1. McCollough M, Rose E. Genitourinary and Renal Tract Disorders. In Rosen’s Emergency Medicine: Concepts and Clinical Practice. 9^thed.Philadelphia, Elsevier. 2018; 173:2163-2181.e3.
2. Joyce E, Ellis D, Miyashita Y. Nephrology. In Zitelli and Davis’ Atlas of Pediatric Physical Diagnosis. 7^thed.Philadelphia, Elsevier. 2018; 14:510-539.
3. Balestracci A, Martin S, Toledo I, et al. Dehydration at admission increased the need for dialysis in hemolytic uremic syndrome children. Pediatr Nephrol 2012; 27:1407-1410.
4. Grisaru S. Management of hemolytic-uremic syndrome in children. Int J Nephrol Renovas Dis. 2014; 7: 231-239.

For Additional Reading:

Hemolytic Uremic Syndrome (HUS): Pearls and Pitfalls