A 3-day-old female newborn is brought to the emergency department because of fever, poor feeding, and irritability for 6 hours. She was delivered at home at 39 weeks' gestation and delivery was uncomplicated. The mother had no prenatal care. Her temperature is 39.8°C (103.6°F), pulse is 172/min, respirations are 58/min, and blood pressure is 74/45 mm Hg. She appears lethargic. Physical examination shows expiratory grunting and nasal flaring. Serum studies show elevated levels of interleukin-6. Which of the following is the most likely effect of this laboratory finding?

Increased release of fibrinogen

Decreased synthesis of hepcidin

Decreased expression of MHC class II

Increased classical activation of macrophages

A 38-year-old man comes to the physician because of severe muscle pain and swelling of his eyelids for 3 days. He has also had fever and chills during this period. For the last 2 days, he has had severe pain in his mouth while chewing. He had an episode of diarrhea a month ago for which he did not seek medical care. He has no history of serious illness. His sister has dermatomyositis. He returned from a hunting trip to eastern Europe 45 days ago. His temperature is 38.1°C (100.6°F), pulse is 80/min, and blood pressure is 130/70 mm Hg. Examination shows periorbital edema and severe generalized muscle tenderness. There are splinter hemorrhages on both hands. Laboratory studies show: Hemoglobin 14.2 g/dL Leukocyte count 12,500/mm3 Segmented neutrophils 60% Eosinophils 18% Lymphocytes 20% Monocytes 2% Serum Glucose 117 mg/dL Creatinine 1.1 mg/dL Alkaline phosphatase 72 U/L Creatine kinase 765 U/L Urinalysis is within normal limits. Which of the following is most likely to have prevented this patient's condition?

Consume pasteurized dairy products

Metronidazole at the onset of diarrhea

A 42-year-old man undergoes therapeutic hypothermia (target temperature 33°C/91.4°F) following cardiac arrest with return of spontaneous circulation. During the cooling phase, he develops shivering, which increases oxygen consumption and interferes with target temperature achievement. He is already on sedation and neuromuscular blockade is being considered. Evaluate the most appropriate management strategy considering both efficacy and safety.

Increase sedation and add surface counter-warming of extremities before neuromuscular blockade

Administer meperidine alone to reduce shivering threshold

Abandon therapeutic hypothermia due to complications

Use only mechanical restraints to prevent movement

Immediate neuromuscular blockade without additional measures

Fever pathophysiology for USMLE Step 3: High-Yield Physiology Lessons

Fever vs. Hyperthermia - Not The Same Heat

	Fever	Hyperthermia
Set-Point	↑ Elevated	Normal
Cause	Pyrogens (IL-1, PGE₂) → ↑ Set-point	Failed heat dissipation / External source
Antipyretics	Effective (resets set-point)	Ineffective

Fever pathophysiology: Pyrogens and hypothalamic set-point

The Pyrogen Cascade - How Fever Ignites

Triggers: Exogenous pyrogens (e.g., Lipopolysaccharide [LPS]) from pathogens stimulate immune cells.
Mediators: Immune cells release endogenous pyrogens, primarily cytokines:
- Interleukin-1 (IL-1)
- Interleukin-6 (IL-6)
- Tumor Necrosis Factor-alpha (TNF-α)
Central Mechanism: These cytokines induce Cyclooxygenase-2 (COX-2) in the perivascular cells of the hypothalamus, leading to increased production of Prostaglandin E2 ($PGE_2$).
Set Point Reset: $PGE_2$ acts on the preoptic nucleus of the hypothalamus, raising the thermoregulatory set point.

⭐ NSAIDs (e.g., ibuprofen, aspirin) reduce fever by inhibiting COX-2, thereby blocking the production of $PGE_2$ and preventing the rise in the hypothalamic set point.

Fever's Purpose - A Double-Edged Sword

Fever enhances immune responses but at a significant metabolic cost.

Benefits (Immunologic)
- ↑ Leukocyte mobility & phagocytosis
- ↑ T-cell & B-cell proliferation
- ↑ Interferon activity
- ↓ Growth of some bacteria/viruses
Detriments (Metabolic & Systemic)
- ↑ Basal metabolic rate & oxygen consumption
- ↑ Heart rate & cardiac output
- Can induce delirium, especially in the elderly
- Risk of febrile seizures in children (<5 years)
- At temperatures >41°C (105.8°F), risk of protein denaturation & irreversible cell injury.

⭐ For every 1°C rise in core body temperature, the basal metabolic rate (BMR) increases by 10-15%, significantly raising oxygen and caloric demands.

Breaking the Fever - The Cooldown Crew

Endogenous Cryogens: The body releases its own "coolants" (e.g., IL-10, glucocorticoids) to counteract pyrogens.
Hypothalamic Reset: The anterior hypothalamus lowers the thermoregulatory set-point back to ~37°C.
Heat Dissipation Activated:
- Vasodilation: Blood vessels in the skin widen, releasing heat.
- Sweating (Diaphoresis): Evaporation of sweat cools the body.
Antipyretics (The Meds Crew):
- NSAIDs/Aspirin: Inhibit COX enzymes → ↓ Prostaglandin E₂ ($PGE_2$) synthesis in the hypothalamus.
- Acetaminophen: Primarily a central COX inhibitor.

⭐ Unlike NSAIDs, acetaminophen has poor peripheral anti-inflammatory activity because it's inactivated by peroxidases in inflammatory cells.

Antipyretic mechanism: COX inhibition & PGE2 synthesis

High‑Yield Points - ⚡ Biggest Takeaways

Exogenous pyrogens (e.g., LPS) trigger immune cells to release endogenous pyrogens like IL-1, IL-6, and TNF-α.

These cytokines act on the organum vasculosum of the lamina terminalis (OVLT), increasing COX-2 activity.

Increased COX-2 drives prostaglandin E₂ (PGE₂) synthesis.

PGE₂ elevates the thermoregulatory set-point in the anterior hypothalamus.

The body initiates shivering and vasoconstriction to raise core temperature to the new set-point.

NSAIDs reduce fever by inhibiting COX enzymes, thus blocking PGE₂ production.

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