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Sepsis: Your Zebras

The publication and enforcement of sepsis guidelines and bundles has decreased mortality in severe sepsis and septic shock, but we run the risk of defaulting to autopilot when treating our febrile patients and missing other potential fatal diagnoses. What else do you need to keep in mind when evaluating and treating the febrile patient, besides sepsis?

Hear hoofbeats, treat for horses, consider zebras.

Here's a basic back-pocket differential diagnosis for the non-infected febrile patient.

  1. Malignancy

  2. Leukemia, lymphoma, pheochromocytoma

  3. Autoimmune

  4. rheumatoid arthritis, systemic lupus erythematosus

  5. In patients with lupus and fever, fever is caused by infection 54%, and caused by a lupus flare 42%

  6. Drugs

  7. Allergic reactions

  8. Drug allergy: DRESS syndrome

  9. Drug rash with eosinophilia and systemic symptoms

  10. Fever present in 90% of patients

  11. Most common with antiepileptics, allopurinol, antipsychotics

  12. Rx: corticosteroids

  13. Anaphylaxis with fever

  14. Metabolic consequence

  15. Serotonin syndrome

  16. Excess serotonin -> AMS, tachycardia, hyperreflexia, muscle breakdown and rhabdo. Linezolid, fentanyl, SSRIs

  17. Hunter criteria: SSRI + one of following

  18. Hypertonia, temperature > 38, and ocular or induced clonus.

  19. Tremor and hyperreflexia

  20. Ocular clonus and agitation/diaphoresis

  21. inducible clonus and agitation/diaphoresis

  22. Spontaneous clonus

  23. Rx: benzodiazepines, stop the SSRI, cyproheptadine if severe.

  24. Neuroleptic malignant syndrome

  25. AMS, tachycardia, lead pipe rigidity. From dopaminergic antagonists or withdrawal from parkinson’s meds. Also antiemetics can precipitate. Most commonly Haloperidol and fluphenazine

  1. Can cause rhabdomyolysis

  2. Rx: Stop offending agent, supportive care, dantrolene, bromocriptine if severe.

  3. Sympathomimetic toxidrome (amphetamines/MDMA/EtOH withdrawal)

  4. Tachycardia, agitation, hyperthermia, hypertension. Sweating. Dilated reactive pupils.

  5. Rx: benzodiazepines.

  6. Anticholinergic toxidrome (tricyclics especially)

  7. Dilated nonreactive pupils, urinary retention, anhidrotic hyperthermia.

  8. Rx: benzodiazepines, physostigmine (but controversial)

  9. Salicylates

  10. Respiratory alkalosis, Non-anion gap metabolic acidosis, anion-gap metabolic acidosis (from lactic acid).

  11. Can cause tinnitus in mild toxicity

  12. Can present as sepsis, DKA in severe toxicity

  13. Rx: bicarbonate, dialysis

  14. Environmental fever from high external temps

  15. Neuro manifestations. Tachycardia.

  16. Death heat stroke (t > 40c) 3000 from 2006-201010

  17. Rx: evaporative + convective cooling, chilled IV fluids: fan over wet body spra


  1. Dantrolene not recommended

  2. Evaporative cooling

  3. Hyperthyroidism

  4. Can be set off by neck trauma (in some cases intubation), infection, iodinated contrast.

  5. Fever, diaphoresis, N/V/D, tachycardia > fever are common. Progresses to paranoia, psychosis, and in some cases, status or coma.

  6. Rx: beta blockade, steroids, thyroid hormone inhibition, IV iodide, fluids.

  7. Neurologic

  8. Subarachnoid/intracranial hemorrhage

  9. Embolic vs thrombosis vs infarction (much less likely)

  10. MI

  11. Renal infarct

  12. PE

  13. "low grade fever" is part of the classic pulmonary embolism triad, but in reality, on 6% of patients have a fever of greater than 38 degrees celsius.

  14. Iatrogenic

  15. Blood transfusion reaction

  16. Malignant hyperthermia

  17. Anesthetics (can happen after succinylcholine), hypercarbia, muscle rigidity

  18. Rx: Dantrolene


McGugan EA. Hyperpyrexia in the emergency department. Emergency Medicine 2001;13(1):116.

Stein PD, Afzal A, Henry JW, Villareal CG. Fever in acute pulmonary embolism. Chest 2000;117(1):39–42.

Boushra MN, Miller SN, Koyfman A, Long B. Consideration of Occult Infection and Sepsis Mimics in the Sick Patient Without an Infectious Source. J Emerg Med. 2018 Nov 2.

Bommersbach TJ et al. Management of Psychotropic Drug-Induced DRESS Syndrome: A systematic review. Mayo Clin Proc. 2016 Jun;91(6):787-801.

Dewitt S et al. Evaluation of fever in the emergency department. Am J Emerg Med 35(2017)1755-1758.

Reulbach U, Duetsch C, Biermann T, et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care 2007;11: R4.

Birch et al. 83-year-old Woman with a Fever and Emesis. Clin Pract Cases Emerg Med. 2018 Oct 16;2(4):276-282.

Gaudio FG, Grissom CK. Cooling Methods in Heat Stroke. J Emerg Med. 2016 Apr;50(4):607-16.

Zhou WJ et al. The Causes of and Clinical Significance of Fever in Systemic Lupus Erythematosus: A Retrospective Study of 487 Hospitalized Patients. Lupus 18(9):807, August 2009.

Klubo-Gwiezdzinska J, Wartofsky L. Thyroid emergencies. Med Clin North Am. 2012 Mar;96(2):385-403.

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