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Fever: physiology and pathophysiology

Fever (pyrexia) is a regulated elevation of core body temperature caused by an upward reset of the hypothalamic temperature set point. The body is not failing to control temperature. Instead, it is actively conserving and producing heat until the new, higher set point is reached.

This is the central distinction:

Fever: hypothalamic set point is raised, usually through cytokine-driven prostaglandin E2 (PGE2). The patient may shiver and have cold skin during the rising phase.
Hyperthermia: set point remains normal, but heat production or heat gain overwhelms heat dissipation. Examples include heat stroke, malignant hyperthermia, serotonin syndrome, and anticholinergic toxicity. Antipyretics do not reliably work in hyperthermia.

1. Normal thermoregulation: the physiology you need first

Normal core temperature

Core temperature is normally maintained within a narrow range, approximately 37°C, but it varies with:

Circadian rhythm: lowest in early morning, highest in late afternoon or evening, often by about 0.5°C.
Ovulatory cycle: progesterone raises basal temperature after ovulation.
Exercise, age, environment, food intake, and measurement site.

Temperature is a balance between:

[ \text{Heat storage} = \text{heat production} - \text{heat loss} ]

Heat production

Major sources:

Basal metabolic activity, especially in liver, brain, heart, and skeletal muscle
Skeletal-muscle activity and exercise
Shivering thermogenesis
Sympathetic stimulation of metabolism
Non-shivering thermogenesis, particularly brown adipose tissue in neonates

Heat loss

Radiation: infrared heat loss to cooler surroundings
Convection: transfer to moving air or water
Conduction: direct transfer to objects in contact with skin
Evaporation: sweat evaporation and respiratory water loss

At high ambient temperature, evaporation becomes the dominant means of heat loss.

2. Thermoregulatory control system

Think of thermoregulation as a negative-feedback system:

Component	Function
Sensors	Detect skin and core temperature
Integrator/comparator	Preoptic-anterior hypothalamus compares actual temperature with set point
Effectors	Alter heat production, conservation, loss, and behavior

A. Thermoreceptors

Peripheral thermoreceptors

Located in skin. They detect environmental temperature, particularly cold. Signals reach the hypothalamus through ascending spinal pathways.

Central thermoreceptors

Located in the:

Preoptic area and anterior hypothalamus
Spinal cord
Deep abdominal and thoracic tissues
Great veins and some viscera

The preoptic area of the anterior hypothalamus is the dominant integrator. It contains temperature-sensitive neurons, especially warm-sensitive neurons.

B. Hypothalamic response to temperature error

The hypothalamus compares:

[ \text{Actual core temperature} \quad \text{vs} \quad \text{set point} ]

If actual temperature is below the set point

The body activates heat-conserving and heat-producing responses:

Cutaneous vasoconstriction
Reduced sweating
Shivering
Increased sympathetic activity and metabolism
Behavioral responses: seeking warmth, adding clothes, curling up

If actual temperature is above the set point

The body activates heat-loss mechanisms:

Cutaneous vasodilation
Sweating through sympathetic cholinergic fibers
Reduced muscle tone and thermogenesis
Behavioral cooling: removing clothing, seeking shade, drinking fluids

This is why fever causes chills initially, but sweating during defervescence. The body’s response depends not simply on the thermometer reading, but on whether current temperature is below or above the hypothalamic set point.

Costanzo Physiology, 7th ed., regulation of body temperature and fever section.
Guyton and Hall Textbook of Medical Physiology, 14th ed., pp. 900-901.

3. What raises the set point? Pyrogens

A pyrogen is any substance capable of causing fever.

A. Exogenous pyrogens

These originate outside the host, most often from microorganisms or their products.

Examples:

Gram-negative bacterial lipopolysaccharide, LPS or endotoxin
Peptidoglycan and lipoteichoic acid from Gram-positive organisms
Bacterial exotoxins and superantigens
Viral nucleic acids and proteins
Fungal cell-wall products
Parasitic products

LPS is the classic exogenous pyrogen. It activates innate immune cells through pattern-recognition receptors, especially Toll-like receptor 4, TLR4.

B. Endogenous pyrogens, now called pyrogenic cytokines

These are host mediators released after innate immune activation.

Principal pyrogenic cytokines:

Interleukin-1 beta, IL-1β
Interleukin-6, IL-6
Tumor necrosis factor-alpha, TNF-α
Interferons, especially during viral infection
Ciliary neurotrophic factor, less clinically emphasized

These cytokines are produced mainly by:

Monocytes and macrophages
Dendritic cells
Neutrophils
Endothelial cells
Kupffer cells
Microglia, especially in CNS inflammation/injury

Importantly, fever is not restricted to infection. Sterile inflammation can induce the same cytokines. Therefore, fever can occur with:

Trauma and surgery
Myocardial infarction
Stroke or intracranial hemorrhage
Autoimmune and autoinflammatory disease
Malignancy
Transfusion reactions
Vaccination
Drug reactions

Harrison describes IL-1, IL-6, TNF, and ciliary neurotrophic factor as key pyrogenic cytokines, and notes that trauma, stroke, pericarditis, and immunization can all generate fever through these mediators. Harrison’s Principles of Internal Medicine, 22nd ed., p. 178.

4. The molecular pathway: infection to fever

High-yield sequence

[ \text{PAMP or tissue injury} \rightarrow \text{PRR/TLR activation} \rightarrow \text{IL-1β, IL-6, TNF-α} \rightarrow \text{COX-2 induction and PGE2 synthesis} \rightarrow \text{EP3 signaling in preoptic hypothalamus} \rightarrow \text{higher hypothalamic set point} \rightarrow \text{heat conservation + heat production} \rightarrow \text{fever} ]

Step 1: pathogen recognition and innate immune signaling

Microbial pathogen-associated molecular patterns, PAMPs, bind pattern-recognition receptors on macrophages, dendritic cells, and endothelial cells.

For example:

[ \text{LPS} \rightarrow \text{TLR4} \rightarrow \text{NF-κB activation} ]

NF-κB and related transcriptional pathways induce production of:

IL-1β
TNF-α
IL-6
COX-2
Other inflammatory mediators

IL-1β maturation specifically depends on inflammasome activation in many contexts:

[ \text{pro-IL-1β} \xrightarrow{\text{caspase-1}} \text{active IL-1β} ]

Step 2: communication between blood and brain

A question often asked is: How can cytokines in blood cause a hypothalamic response if the blood-brain barrier limits their entry?

The major answer is that circulating pyrogens act predominantly at circumventricular organs, especially the:

Organum vasculosum of the lamina terminalis, OVLT
Median preoptic area
Other vascular structures near the anterior hypothalamus

These regions have fenestrated capillaries and a relatively incomplete blood-brain barrier. Circulating cytokines and microbial products can act on the local brain endothelial cells.

Cytokines generally do not need to diffuse throughout the brain to cause fever. Instead, they induce local endothelial production of PGE2 near hypothalamic thermoregulatory circuits.

A second, faster route may involve neural signaling:

Peripheral inflammation and LPS can stimulate visceral afferents, particularly the vagus nerve.
Hepatic Kupffer-cell activation may contribute to early fever signaling.
This pathway may help explain rapid fever onset before large systemic cytokine elevations.

The established core pathway remains cytokine-induced PGE2 production in hypothalamic/circumventricular endothelial tissue.

5. PGE2: the final mediator of fever

A. Synthesis

Cytokines, particularly IL-1β and IL-6, induce:

Phospholipase A2, which releases arachidonic acid from membrane phospholipids
Cyclooxygenase-2, COX-2, which converts arachidonic acid into prostaglandin intermediates
Prostaglandin E synthase, especially microsomal PGE synthase-1
Formation of PGE2

[ \text{Membrane phospholipid} \rightarrow \text{arachidonic acid} \overset{\text{COX-2}}{\rightarrow} \text{PGH}_2 \rightarrow \text{PGE}_2 ]

B. Action in the preoptic area

PGE2 acts predominantly via the EP3 receptor in the preoptic-anterior hypothalamic area. EP3 receptor signaling changes activity of thermoregulatory neural circuits, reducing warm-sensitive neuronal signaling and causing the central system to interpret the present core temperature as too low.

The result is an upward shift in the defended temperature:

[ 37^\circ C \rightarrow 39^\circ C ]

If the actual temperature is still 37°C but the new set point is 39°C, the body behaves as though it is cold.

Experimental loss of EP3 receptors markedly impairs fever responses to endotoxin, IL-1β, and PGE2. Harrison’s Principles of Internal Medicine, 22nd ed., p. 178.

6. Phases of fever and their mechanisms

Phase 1: onset or chill phase

What happens?

Pyrogenic cytokines raise PGE2 concentration and rapidly increase the hypothalamic set point.

Example:

[ \text{Actual core temperature} = 37^\circ C ]

[ \text{New set point} = 39^\circ C ]

The hypothalamus now judges 37°C as too cold.

Physiological responses

Sympathetic cutaneous vasoconstriction
Cool, pale skin
Reduced heat loss
Shivering
Piloerection, minor in humans
Increased skeletal muscle tone
Behavioral heat seeking: blanket, warm room, curled posture

Symptoms

Feeling cold despite an elevated measured temperature
Chills and rigors
Cold extremities
Teeth chattering
“Goosebumps”

A rigor is a pronounced episode of involuntary shivering due to a rapidly rising set point. It is common in abrupt cytokine release, such as bacteremia, malaria, transfusion reactions, or severe infection.

The patient feels cold because their current temperature is below the new set point, not because their core temperature is actually low.

Phase 2: plateau or fastigium

Once core temperature reaches the new set point, the temperature error becomes small.

[ \text{Core temperature} \approx \text{new set point} ]

Heat production and heat loss again come into approximate balance, but at a higher temperature.

Typical findings:

Chills stop
Patient may feel neither hot nor cold, or feel warm
Skin often becomes warmer
Fever remains relatively stable while cytokine/PGE2 drive persists

Phase 3: defervescence or fever break

When inflammation resolves or antipyretic treatment lowers PGE2 production, the hypothalamic set point falls toward normal.

Example:

[ \text{Actual core temperature} = 39^\circ C ]

[ \text{set point falls to} = 37^\circ C ]

Now the body interprets 39°C as too hot.

Physiological responses

Cutaneous vasodilation
Sweating
Increased evaporative heat loss
Warm, flushed skin
Increased respiratory heat loss
Behavioral cooling

Symptoms

Sweating
Flushing
Feeling hot
Fall in temperature

Defervescence may be:

Lysis: gradual temperature reduction over days
Crisis: rapid fall in temperature over hours, often with marked sweating and vasodilation

The classic “fever breaking” sweat is a response to a decreased set point, not an uncontrolled collapse of thermoregulation. Guyton and Hall Textbook of Medical Physiology, 14th ed., p. 901.

7. Diagram: set point change explains chills and sweating

Hypothalamic set point rises during fever, producing chills until actual temperature reaches the set point; when the set point falls, sweating and vasodilation produce defervescence.

Guyton and Hall Textbook of Medical Physiology, 14th ed., p. 900.

8. Why fever causes systemic symptoms

Fever is part of the acute-phase response, not just a temperature abnormality.

Cytokines such as IL-1, IL-6, and TNF produce:

Manifestation	Main mechanism
Fever	Hypothalamic PGE2 and raised set point
Malaise, fatigue, somnolence	Cytokine effects on CNS circuits
Myalgia and arthralgia	Peripheral PGE2, cytokines, nociceptor sensitization
Anorexia	Hypothalamic and cytokine-mediated sickness behavior
Tachycardia	Increased metabolic demand and sympathetic activation
Tachypnea	Increased metabolism, CO2 production, and heat dissipation
Leukocytosis	IL-1, IL-6, colony-stimulating effects
Increased CRP, fibrinogen, hepcidin	Predominantly IL-6-induced hepatic acute-phase response

Cardiovascular and metabolic effects

For each 1°C increase in body temperature, heart rate commonly rises by roughly 10 beats/minute in adults, though there are important exceptions.

Fever increases:

Basal metabolic rate
Oxygen consumption
Carbon dioxide production
Insensible water loss
Catabolism
Cardiac workload

This explains why fever may be poorly tolerated in patients with:

Heart failure or ischemic heart disease
Severe lung disease
Sepsis
Limited physiological reserve
Neurologic injury
Infants and frail older adults

9. Is fever beneficial or harmful?

Potential host benefits

Moderate fever can:

Reduce replication or growth of some pathogens
Enhance neutrophil migration and phagocytic activity
Improve some lymphocyte and T-cell responses
Increase acute-phase and innate immune activity
Induce heat-shock proteins that can protect cells from stress

Thus, a moderate fever is often an adaptive host response, not automatically harmful.

Potential harms

Fever becomes more consequential when severe, prolonged, or occurring in vulnerable patients:

Increased metabolic and oxygen demand
Dehydration and electrolyte loss
Delirium or worsened encephalopathy
Increased myocardial workload
Increased cerebral metabolic demand, which is particularly problematic after stroke, traumatic brain injury, or cardiac arrest
Febrile seizures in susceptible children, though these are not caused by direct neuronal “damage” from routine fever

Very high temperatures can produce direct cellular injury. Temperatures over approximately 41-41.5°C are termed hyperpyrexia and demand urgent evaluation for severe infection, CNS pathology, drug toxicity, or hyperthermic syndromes.

10. Fever versus hyperthermia: essential exam distinction

Feature	Fever	Hyperthermia
Hypothalamic set point	Raised	Normal
Main mediator	Cytokines and PGE2	Excess heat load or uncontrolled heat production
Chills in rising phase	Common	Usually absent
Sweating	Often appears when set point falls	Can be absent, especially in heat stroke or anticholinergic toxicity
Antipyretics	Usually reduce temperature	Usually ineffective
Examples	Infection, autoimmune disease, malignancy, drug fever	Heat stroke, malignant hyperthermia, NMS, serotonin syndrome, thyrotoxic crisis

Why antipyretics fail in hyperthermia

Antipyretics lower temperature by reducing hypothalamic PGE2-mediated set-point elevation. In heat stroke, malignant hyperthermia, or NMS, the set point is not primarily elevated by PGE2. The problem is excessive heat production, impaired heat loss, or both.

Harrison emphasizes that hyperthermia is an uncontrolled temperature rise with an unchanged hypothalamic setting, and that it characteristically does not respond to antipyretics. Harrison’s Principles of Internal Medicine, 22nd ed., p. 177.

11. Mechanism of antipyretics

NSAIDs and aspirin

Examples: ibuprofen, naproxen, aspirin.

Mechanism:

[ \text{COX inhibition} \rightarrow \downarrow \text{PGE2} \rightarrow \downarrow \text{hypothalamic set point} ]

Once the set point falls, the previously febrile body temperature is now above the set point. The body responds with:

Vasodilation
Sweating
Heat loss
Defervescence

Paracetamol/acetaminophen

Acetaminophen also lowers fever mainly through central reduction of prostaglandin-mediated thermoregulatory signaling, though its full molecular pharmacology differs from peripheral NSAID action and remains less completely defined.

Glucocorticoids

They can reduce fever by suppressing inflammatory cytokine transcription and inhibiting phospholipase A2-mediated arachidonic acid release, thereby decreasing prostaglandin formation. They are not used simply to suppress routine fever because treatment should target the underlying cause.

12. Important special forms of temperature elevation

Central or hypothalamic fever

This can occur after:

Intracerebral hemorrhage
Subarachnoid hemorrhage
Traumatic brain injury
Hypothalamic trauma, tumor, or inflammation

Mechanisms may include direct disruption of thermoregulatory pathways plus local CNS cytokine production. It is a diagnosis of exclusion after infection and other causes are assessed.

Drug fever

Can arise through several mechanisms:

Hypersensitivity reaction
Cytokine release
Direct central thermoregulatory effects
Drug-induced hyperthermic syndromes, which must be distinguished from true fever

Examples include some antimicrobials, anticonvulsants, allopurinol, and biologic therapies.

Neuroleptic malignant syndrome and serotonin syndrome

These are usually categorized as hyperthermic syndromes, not simple cytokine-mediated fever. They result from altered central neurotransmission with severe muscle activity or rigidity and autonomic dysregulation. They need cause-specific treatment and aggressive cooling, not merely antipyretics.

Malignant hyperthermia

A pharmacogenetic skeletal muscle disorder, usually triggered by volatile anesthetic agents or succinylcholine. Excess sarcoplasmic reticulum calcium release causes sustained muscle contraction, markedly increased CO2 generation, acidosis, and heat production. It is hyperthermia, not fever.

13. One-line mechanism for exams

Exogenous pyrogens activate innate immune cells, causing release of IL-1β, IL-6, and TNF-α. These act at hypothalamic circumventricular endothelial sites, particularly the OVLT, inducing COX-2-dependent PGE2 synthesis. PGE2 acts mainly via EP3 receptors in the preoptic-anterior hypothalamus, raises the thermoregulatory set point, and activates vasoconstriction, shivering, increased thermogenesis, and heat-seeking behavior until core temperature reaches the new set point.

14. Fast recall summary

Fever pathway

[ \boxed{ \text{Infection/tissue injury} \rightarrow \text{IL-1, IL-6, TNF} \rightarrow \text{COX-2} \rightarrow \text{PGE2} \rightarrow \text{EP3 receptor} \rightarrow \text{higher hypothalamic set point} \rightarrow \text{chills and shivering} \rightarrow \text{fever} } ]

Phases

Set point rises: patient feels cold, vasoconstricts, shivers.
Plateau: core temperature equals raised set point.
Set point falls: patient feels hot, vasodilates, sweats.

Key distinction

[ \boxed{\text{Fever = raised set point}} ]

[ \boxed{\text{Hyperthermia = normal set point + failed heat balance}} ]

Compare fever, hyperthermia, and heat stroke

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Fever vs hyperthermia vs heat stroke

Core relationship:

[ \boxed{\text{Heat stroke is a life-threatening subtype of hyperthermia}} ]

[ \boxed{\text{Fever is regulated temperature elevation due to a raised hypothalamic set point}} ]

Feature	Fever (pyrexia)	Hyperthermia	Heat stroke
Definition	Regulated rise in core temperature due to increased hypothalamic set point	Unregulated rise in core temperature because heat gain/production exceeds heat loss	Severe hyperthermia with CNS dysfunction after heat exposure or exertion
Hypothalamic set point	Raised	Normal	Normal, but thermoregulatory mechanisms have failed
Main mechanism	Cytokines, mainly IL-1β, IL-6, TNF-α, induce COX-2 and PGE2	Excess external heat, excess endogenous heat production, impaired heat loss, or drug toxicity	Extreme environmental/exertional heat load plus failed heat dissipation and systemic inflammatory injury
Typical causes	Infection, autoimmune disease, malignancy, tissue injury, vaccination, drug fever	Heat exposure, exercise, endocrine/drug syndromes, malignant hyperthermia, NMS, serotonin syndrome	Classic or exertional heat exposure
Chills/rigors	Common during rising phase	Usually absent	Usually absent
Skin during onset	Often cool or cold due to vasoconstriction	Often hot	Hot. May be dry or sweaty
Sweating	Reduced during chill phase; marked during defervescence	Variable	May be absent in classic heat stroke, but often present in exertional heat stroke
Antipyretic response	Usually responds to paracetamol/acetaminophen or NSAIDs	Usually does not respond	Does not respond adequately
Primary treatment	Treat cause; antipyretic for comfort/select indications	Remove cause, active cooling, syndrome-specific therapy	Immediate aggressive cooling and emergency supportive care
Organ injury	Usually limited in ordinary fever	Depends on severity/cause	Common: CNS, renal, hepatic, skeletal muscle, coagulation, cardiovascular system

1. Fever

Mechanism

Infection or sterile inflammation activates innate immune cells:

[ \text{PAMPs/tissue injury} \rightarrow \text{IL-1β, IL-6, TNF-α} \rightarrow \text{COX-2} \rightarrow \text{PGE2} \rightarrow \text{EP3 receptors in preoptic hypothalamus} \rightarrow \text{raised set point} ]

If the set point rises from 37°C to 39°C while actual core temperature is still 37°C, the hypothalamus perceives the body as cold. It therefore initiates:

Cutaneous vasoconstriction
Shivering
Increased muscle tone and thermogenesis
Heat-seeking behavior

This produces chills and rigors. Once the body reaches the new set point, the fever plateaus.

When inflammation resolves or an antipyretic reduces PGE2, the set point falls back toward normal. Now the patient’s temperature is above the set point, producing:

Vasodilation
Sweating
Flushing
Heat loss and defervescence

Harrison’s Principles of Internal Medicine, 22nd ed., p. 178.
Guyton and Hall Textbook of Medical Physiology, 14th ed., pp. 900-901.

2. Hyperthermia

Definition

Hyperthermia is a rise in body temperature despite an unchanged hypothalamic set point. The body is already trying to lose heat, but heat production or environmental heat gain exceeds the capacity for heat dissipation.

[ \text{Heat production + heat gain} > \text{heat loss} ]

Unlike fever, this is not chiefly a cytokine-PGE2-mediated resetting of the thermostat.

Major mechanisms

Excess environmental heat
- High ambient temperature
- High humidity, which prevents sweat evaporation
- Poor ventilation
- Excess clothing or protective equipment
Increased endogenous heat production
- Strenuous exercise
- Seizures
- Severe agitation
- Thyroid storm
- Sympathomimetic toxicity
Impaired heat loss
- Dehydration or hypovolemia
- Anticholinergic drugs impairing sweating
- Skin vasoconstriction or poor cardiovascular reserve
- High humidity preventing evaporation
Drug or toxin syndromes
- Neuroleptic malignant syndrome
- Serotonin syndrome
- Malignant hyperthermia
- Sympathomimetic toxicity
- Anticholinergic toxicity

Why antipyretics do not work

NSAIDs and acetaminophen lower a PGE2-mediated hypothalamic set point. In hyperthermia, the set point has not been raised. Therefore, the priority is physical cooling plus correction of the underlying mechanism.

3. Heat stroke

Definition

Heat stroke is the most severe form of heat-related illness:

[ \boxed{\text{Hyperthermia} + \text{central nervous system dysfunction}} ]

Classically, it is associated with core temperature around or above 40°C, but treatment should not wait for a numerical cutoff when the clinical picture indicates heat stroke.

CNS dysfunction includes:

Confusion
Delirium
Ataxia
Agitation
Seizures
Coma

The CDC heat illness guidance describes heat stroke as a medical emergency in which thermal homeostasis fails, risking injury to brain, kidneys, liver, and heart.

Types

A. Classic, nonexertional heat stroke

Usually occurs during heat waves in people with reduced capacity to dissipate heat:

Older adults
Infants
People with chronic heart, lung, renal, or neurologic disease
People without air conditioning
Those taking diuretics, anticholinergics, antipsychotics, antihistamines, or some cardiovascular drugs

Typical setting: prolonged heat exposure, often indoors or in poorly ventilated housing.

B. Exertional heat stroke

Occurs in otherwise young or fit people generating a very large heat load during exertion.

Examples:

Athletes
Military personnel
Manual workers
People exercising in heat and humidity

Sweating can be profuse in exertional heat stroke. Therefore, “hot dry skin” is a traditional clue but is not a required feature and should never exclude heat stroke.

4. Heat stroke pathophysiology

Heat stroke starts as failed heat balance but progresses to multisystem cellular injury.

Stepwise process

[ \text{Heat exposure/exercise} \rightarrow \text{increased core temperature} \rightarrow \text{dehydration + reduced skin blood flow} \rightarrow \text{failed cooling} \rightarrow \text{cellular thermal injury} \rightarrow \text{systemic inflammation + endothelial injury} \rightarrow \text{multiorgan dysfunction} ]

Important injury mechanisms

Direct protein denaturation and enzyme dysfunction
Mitochondrial failure and ATP depletion
Endothelial injury and capillary leak
Splanchnic hypoperfusion and increased gut permeability
Translocation of endotoxin or bacterial products from gut
Systemic inflammatory response resembling sepsis
Coagulation activation and possible DIC
Rhabdomyolysis, especially in exertional heat stroke
Acute kidney injury from dehydration, shock, myoglobin, and direct thermal injury
Hepatic injury or acute liver failure
Cerebral dysfunction due to direct heat injury, hypoperfusion, edema, and inflammation

Thus, heat stroke is not merely “a high temperature.” It is a time-critical multisystem emergency.

5. Key clinical differences

Finding	Fever	Hyperthermia	Heat stroke
Patient feels cold despite raised temperature	Common in onset phase	Uncommon	Uncommon
Rigors	Possible	Unusual	Unusual
Recent infection/inflammatory illness	Often present	Not necessary	Not necessary
Hot environment/exertion history	Not required	May be present	Usually present
Mental status change	Depends on underlying disease	Variable	Hallmark of severe disease
Core temperature	Often 38-40°C	Variable, may be very high	Often ≥40°C, but diagnosis is clinical
CK elevation/rhabdomyolysis	Not typical from uncomplicated fever	Depends on cause	Common in exertional heat stroke
Hepatic injury/DIC/AKI	Unusual in routine fever	Possible if severe	Suggests severe heat stroke
Antipyretic effect	Temperature falls	Little/no effect	Little/no effect
Definitive immediate action	Identify/treat cause	Active cooling/cause-specific treatment	Rapid cooling first, emergency care

6. Management contrast

Fever

Assess and treat the underlying cause.
Use fluids as appropriate.
Antipyretics can improve comfort and reduce metabolic demand in selected patients.
Do not assume every fever requires suppression.

Hyperthermia

Stop the heat source or causative drug.
Begin external cooling.
Give supportive care and address the specific syndrome.
Examples: dantrolene for malignant hyperthermia, sedation and supportive treatment in severe sympathomimetic toxicity, syndrome-specific treatment for serotonin syndrome or NMS.

Suspected heat stroke

This is an emergency:

Remove from heat and remove excess clothing.
Begin rapid cooling immediately, ideally cold-water immersion where feasible.
Call emergency services and arrange hospital care.
Monitor airway, circulation, glucose, electrolytes, renal function, CK, liver function, and coagulation.
Do not delay cooling to obtain labs or transfer.

The practical target is rapid reduction of core temperature to approximately 39°C, then reassessment to avoid overshoot. The recent emergency review emphasizes that prompt aggressive cooling is the main determinant of outcome.

Exam pearl

Fever is a thermostat problem: the hypothalamic set point is deliberately raised by PGE2.
Hyperthermia is a heat-balance problem: the set point is normal, but the body cannot get rid of heat.
Heat stroke is hyperthermia with CNS dysfunction and potential multiorgan failure.

A recent review of thermoregulatory limits and a meta-analysis of cardiovascular heat responses support the importance of heat strain and duration of exposure, but they do not change these clinical distinctions (PMIDs: 41177350, 40087302).

clinical review

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Clinical review: fever, hyperthermia, and heat stroke

1. First clinical question

In any patient with high temperature, ask:

Is this fever with a raised hypothalamic set point, or hyperthermia with failed heat dissipation?

This distinction determines treatment.

Fever: treat the underlying inflammatory cause. Antipyretics can help.
Hyperthermia/heat stroke: start active cooling immediately. Antipyretics are ineffective.

2. Bedside definitions

Condition	Clinical definition
Fever	Regulated elevation of temperature caused by a raised hypothalamic set point, usually cytokine and PGE2 mediated
Hyperthermia	Uncontrolled temperature elevation with an unchanged set point, caused by excess heat generation/gain or inadequate heat loss
Heat stroke	Severe hyperthermia, usually core temperature ≥40°C, plus CNS dysfunction in the setting of heat exposure or exertion

Do not rely entirely on an arbitrary temperature cutoff. A person with heat exposure, confusion, and a temperature that has fallen before assessment may still have heat stroke.

3. Clinical assessment of a hot patient

A. Immediate priorities: ABCDE

A and B

Airway protection if reduced consciousness, recurrent seizures, or vomiting.
Oxygen only if hypoxemic or critically ill.
Assess respiratory rate, work of breathing, and aspiration risk.

C

Heart rate, BP, peripheral perfusion, capillary refill.
Establish IV access in suspected heat stroke or severe systemic illness.
ECG for significant hyperthermia, electrolyte abnormalities, chest symptoms, or instability.

D

Measure GCS/mental status.
Check bedside glucose early.
Look for agitation, delirium, ataxia, confusion, seizures, rigidity, clonus, or focal deficits.

E

Remove excess clothing.
Inspect skin for sweating, rash, trauma, injection marks, cellulitis, meningism, or signs of infection.
Assess hydration and environmental exposure.

B. Measure the right temperature

For suspected heat stroke, rectal core temperature is preferred. Oral, tympanic, forehead, and axillary temperatures can substantially underestimate core temperature after exertion or environmental heat exposure.

The CDC Yellow Book recommends rectal temperature as the most reliable method in suspected heat stroke.

4. Focused history

History suggesting fever

Ask about:

Cough, dysuria, abdominal pain, diarrhea, headache, neck stiffness
Rash, joint pain, sore throat, focal pain
Recent infection, travel, animal or insect exposure
Immunosuppression, malignancy, indwelling devices
Recent surgery, trauma, infarction, thrombosis
New medications, antibiotics, anticonvulsants, biologics, illicit drugs

Clues favoring fever:

Infective or inflammatory symptoms
Chills/rigors
Cold extremities in the rising phase
No clear heat exposure or exertional trigger
Temperature falls after antipyretic treatment

History suggesting hyperthermia or heat stroke

Ask specifically about:

Hot or humid environment
Exercise, military training, manual labor, sport
Duration of heat exposure
Fluid intake, vomiting, diarrhea, alcohol use
Clothing or personal protective equipment
Lack of air conditioning or inability to leave a hot environment
Drug use: amphetamines, cocaine, MDMA, anticholinergics, antipsychotics, serotonergic drugs
Anaesthetic exposure, particularly volatile agents or succinylcholine
Thyroid disease and symptoms of thyrotoxicosis

Clues favoring heat stroke:

Collapse during exertion or after sustained environmental heat exposure
Altered behavior, confusion, seizures, or coma
Marked tachycardia, hypotension, and hyperventilation
Very high core temperature
No chill phase
Poor response to antipyretics

5. Examination patterns

Feature	Fever	Hyperthermia	Heat stroke
Set point	Raised	Normal	Normal
Chills/rigors	Common, especially during onset	Unusual	Unusual
Skin	May be cool early due to vasoconstriction	Warm/hot	Hot; dry in some classic cases, but sweaty in exertional cases
Sweating	Common when fever breaks	Variable	May be absent or present
CNS dysfunction	Not typical from ordinary fever itself	Depends on cause	Defining feature
Trigger	Infection/inflammation commonly	Heat, drugs, endocrine or metabolic causes	Heat exposure or exertion
Antipyretic response	Often present	No meaningful effect	No meaningful effect
Main treatment	Treat cause ± antipyretic	Cooling + treat cause	Immediate rapid cooling + resuscitation

Exam pearl: sweating does not rule out heat stroke. Exertional heat stroke often presents with profuse sweating.

6. Recognizing heat stroke

Suspect heat stroke when there is:

[ \boxed{\text{Heat exposure or exertion} + \text{hyperthermia} + \text{CNS dysfunction}} ]

CNS findings include:

Irritability or behavioral change
Confusion and delirium
Ataxia
Collapse or syncope
Seizures
Coma

Additional findings:

Tachycardia and hypotension
Tachypnea
Nausea/vomiting
Muscle cramps or weakness
Rhabdomyolysis, especially exertional cases
Acute kidney injury
Transaminitis or acute hepatic failure
Coagulopathy or DIC

Heat stroke can be exertional in young healthy people or classic/nonexertional in older patients with chronic illness during heat waves. Both require the same immediate priority: rapid cooling.

7. Differentials for hyperthermia plus altered mental status

Diagnosis	Helpful clues
Sepsis/meningitis/encephalitis	Infective focus, hypotension, rash, meningism, immunosuppression
Heat stroke	Heat/exertion exposure, high core temperature, CNS dysfunction
Serotonin syndrome	Serotonergic medication, clonus, hyperreflexia, agitation, diarrhea
Neuroleptic malignant syndrome	Dopamine antagonist or dopamine withdrawal, lead-pipe rigidity, hyporeflexia, elevated CK
Malignant hyperthermia	During/soon after anaesthesia, hypercapnia, rigidity, acidosis, rapidly rising temperature
Sympathomimetic toxicity	Cocaine/amphetamine/MDMA, agitation, mydriasis, diaphoresis, hypertension
Anticholinergic toxicity	Dry hot skin, mydriasis, urinary retention, ileus, delirium
Thyroid storm	Thyrotoxic symptoms, goiter, tremor, atrial fibrillation, GI symptoms
Exercise-associated hyponatremia	Prolonged exercise, excessive hypotonic fluid intake, confusion/seizures, often lower temperature than heat stroke
Status epilepticus	Witnessed seizures or prolonged postictal state, elevated CK/lactate

A key clinical danger is labeling a patient “septic” or “febrile” and delaying cooling in actual heat stroke.

8. Investigations

In uncomplicated fever

Investigations should be directed by history and examination. Avoid indiscriminate testing in a well patient with an obvious self-limited viral syndrome.

Possible tests if clinically indicated:

CBC with differential
CRP/ESR
Urea, creatinine, electrolytes
LFTs
Urinalysis and urine culture
Blood cultures before antibiotics when bacteremia/sepsis is suspected
Chest radiograph, viral testing, malaria testing, lumbar puncture, imaging, etc., based on the syndrome

In suspected heat stroke or severe hyperthermia

Obtain tests without delaying cooling:

Rectal core temperature
Bedside glucose
CBC
Electrolytes, urea, creatinine
Calcium, phosphate, magnesium
LFTs and bilirubin
CK and urinalysis for myoglobinuria
Venous or arterial blood gas and lactate
Coagulation profile, fibrinogen, D-dimer if severe illness
ECG and cardiac biomarkers if indicated
Blood cultures and infection evaluation if sepsis remains possible
Toxicology testing when history or signs suggest poisoning

Expected serious abnormalities include:

AKI
Hyperkalemia or other electrolyte abnormalities
Metabolic acidosis
High CK and myoglobinuria
Elevated aminotransferases, sometimes delayed
Thrombocytopenia, prolonged PT/INR, DIC

9. Management

A. Fever

Identify and treat the cause.
Give oral or IV fluids when clinically needed.
Use paracetamol/acetaminophen or an NSAID mainly for discomfort or high metabolic burden, if not contraindicated.
Treat sepsis, meningitis, malaria, inflammatory disease, drug reaction, etc., according to the working diagnosis.

Antipyretics lower hypothalamic PGE2 signaling, reset the set point downward, then produce sweating and vasodilation.

B. Hyperthermia

Stop exposure and remove the triggering drug if possible.
Undress patient and begin active external cooling.
Give supportive care, including fluids when hypovolemia is present.
Treat the specific cause.

Do not expect paracetamol or NSAIDs to fix hyperthermia.

C. Suspected heat stroke: emergency sequence

1. Cool first

Remove from heat and remove clothing.
Start rapid cooling at once.
Cold-water immersion is preferred for exertional heat stroke when feasible.
If immersion is unavailable: spray/mist with tepid water and use high-flow fans, applying ice packs to neck, axillae, and groin as adjuncts.
Continue cooling until core temperature is around 39°C.

The CDC guidance and emergency medicine review both emphasize that cooling should start immediately and should not be delayed for transport, investigations, or diagnostic certainty.

2. Support physiology

Airway protection if coma/severe agitation.
IV isotonic crystalloid guided by perfusion, volume status, urine output, and cardiac/renal risk.
Correct hypoglycemia and clinically important electrolytes.
Treat seizures with benzodiazepines.
Consider benzodiazepines for severe agitation or shivering that impairs cooling.
Monitor cardiac rhythm, urine output, CK, renal function, LFTs, and coagulation.

3. Avoid

Delaying cooling to complete diagnostic workup
Routine antipyretics
Using shivering-inducing cooling methods without managing shivering
Assuming dry skin is required for the diagnosis
Giving large volumes of hypotonic fluids in a patient who may have exercise-associated hyponatremia

10. Heat exhaustion versus heat stroke

Feature	Heat exhaustion	Heat stroke
Core temperature	Normal to moderately raised	Usually markedly raised
CNS function	May have headache, fatigue, dizziness; severe persistent CNS signs absent	Delirium, ataxia, seizures, coma, or significant altered behavior
Organ injury	Usually absent	May include AKI, rhabdomyolysis, liver injury, DIC
Management	Rest, cooling, oral/IV rehydration, reassess	Emergency rapid cooling, hospital-level resuscitation and monitoring

If a patient presumed to have heat exhaustion has persistent confusion, seizure, coma, or a rising temperature, manage as heat stroke until proven otherwise.

11. High-yield viva answers

Why does a febrile patient shiver?
Because PGE2 raises the hypothalamic set point. The current core temperature becomes lower than the new target, so the body activates heat production and conservation.

Why do patients sweat when the fever breaks?
The set point falls to normal, often after inflammation resolves or PGE2 is inhibited. The current body temperature is then above the set point, causing vasodilation and sweating.

Why do antipyretics not work in heat stroke?
Heat stroke is hyperthermia with an unchanged set point, not PGE2-mediated set-point elevation.

What is the defining clinical feature of heat stroke?
Hyperthermia with central nervous system dysfunction in an appropriate heat or exertion context.

What is the most important initial treatment of heat stroke?
Immediate rapid active cooling.

clinical review on fever and pyrexia and hyperthermia

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Merck Manual fever evaluation adults clinical approach hyperthermia antipyretics

Clinical review: fever (pyrexia) and hyperthermia

1. Definitions

Fever / pyrexia

Fever and pyrexia are synonymous. They mean a regulated elevation of core body temperature due to an upward reset of the hypothalamic set point.

Usually caused by infection or sterile inflammation.
Mediated by cytokines, especially IL-1β, IL-6, and TNF-α, which induce hypothalamic PGE2.
The patient may experience chills and shivering because, after the set point rises, the existing core temperature is perceived as too low.

Hyperthermia

Hyperthermia is an unregulated elevation of body temperature caused by excessive heat production, environmental heat gain, impaired heat loss, or a combination.

Hypothalamic set point is not raised.
The body may already be attempting to lose heat, but cannot keep up.
It can progress rapidly to cellular injury and multiorgan failure.
Antipyretics do not treat the primary mechanism.

[ \boxed{\text{Fever = raised set point}} ]

[ \boxed{\text{Hyperthermia = normal set point + excess heat load/failed heat loss}} ]

2. Normal temperature and definitions of abnormal temperature

Core temperature has a circadian variation, typically lowest early in the morning and highest in the late afternoon or evening. Measurement site matters.

Common clinical cutoffs:

Fever: oral temperature approximately ≥38.0°C, or rectal/core temperature ≥38.0°C.
Hyperpyrexia: very high fever, usually >41°C or >41.5°C depending on the definition used.
Hyperthermia: elevated temperature without hypothalamic set-point elevation.
Heat stroke: severe hyperthermia with CNS dysfunction, typically with core temperature around or above 40°C.

A single temperature reading should never be interpreted without clinical context, measurement site, exposure history, medications, age, and mental status.

3. Clinical physiology of fever

Pyrogenic pathway

[ \text{Microbe/tissue injury} \rightarrow \text{innate immune activation} \rightarrow \text{IL-1β, IL-6, TNF-α} \rightarrow \text{COX-2 activation} \rightarrow \text{PGE2 synthesis} \rightarrow \text{hypothalamic EP3 signaling} \rightarrow \text{raised temperature set point} ]

PGE2 acts mainly in the preoptic-anterior hypothalamic region, including areas close to the organum vasculosum of the lamina terminalis, OVLT, a circumventricular organ where circulating inflammatory signals can influence central temperature regulation.

Harrison’s Principles of Internal Medicine, 22nd ed., p. 178.
Costanzo Physiology, 7th ed., pp. 1090-1098.

Clinical phases

Phase	Set point compared with actual temperature	Clinical features
Onset/chill phase	Set point suddenly rises above actual core temperature	Feeling cold, chills, rigors, vasoconstriction, pale/cool skin, shivering
Plateau/fastigium	Actual temperature reaches raised set point	Chills stop; patient may feel hot or relatively comfortable; temperature remains high
Defervescence	Set point falls toward normal but core temperature remains high	Vasodilation, warm flushed skin, sweating, temperature falls

Important bedside implication

A patient with a temperature of 39°C can feel cold and shiver if their set point has just risen to 40°C. Conversely, the same patient can feel hot and sweat when the set point returns to 37°C.

4. Causes of fever

Fever is a sign, not a diagnosis. Organize the differential into four major groups.

A. Infection

Viral syndromes, influenza, COVID-19
Pneumonia
Urinary tract infection and pyelonephritis
Meningitis, encephalitis
Intra-abdominal infection
Tuberculosis
Malaria and other travel-associated infections
Infective endocarditis
Skin, soft tissue, bone, joint, and device-related infections
Sepsis

B. Noninfectious inflammatory disease

SLE and vasculitis
Adult-onset Still disease
Rheumatoid disease flare
Sarcoidosis
Inflammatory bowel disease
Gout or pseudogout
Pericarditis
Pancreatitis

C. Malignancy

Lymphoma
Leukemia
Renal-cell carcinoma
Hepatocellular carcinoma
Advanced solid malignancy

D. Other causes

Drug fever
Transfusion reaction
Pulmonary embolism or DVT
Myocardial infarction
Tissue injury, trauma, surgery, burns
Thyroiditis
CNS injury, for example hemorrhage or stroke
Vaccination

5. Clinical approach to a patient with fever

Step 1: Assess severity first

Look immediately for:

Hypotension, shock, poor perfusion
Hypoxia or respiratory distress
Altered mental state
Meningism, seizures, focal neurologic deficits
Non-blanching rash or purpura
Severe headache or photophobia
Severe abdominal pain
Neutropenia or immunocompromise
Pregnancy/postpartum status
Indwelling vascular catheter, prosthetic valve, joint, or device
Extremes of age
Recent surgery or invasive procedure

If these are present, consider sepsis, meningitis, encephalitis, severe malaria, toxic shock, necrotizing soft-tissue infection, or other time-critical diagnoses.

Step 2: Focused history

Ask:

Time course

Onset, duration, maximum recorded temperature
Continuous, intermittent, remittent, relapsing, or periodic pattern
Chills or true rigors
Response to antipyretics

Localizing symptoms

Respiratory: cough, sputum, dyspnea, pleuritic pain
Urinary: dysuria, frequency, flank pain
CNS: headache, photophobia, neck stiffness, confusion
GI: vomiting, diarrhea, abdominal pain
Skin: rash, wound discharge, cellulitis
Musculoskeletal: monoarthritis, back pain, myalgia
Constitutional: weight loss, night sweats, fatigue

Exposure history

Travel, freshwater exposure, insect or tick bite
Animal contact
Sick contacts
Food and sexual history
Injection drug use
Occupational exposure
Recent hospital admission or antimicrobial use

Host factors

Diabetes, CKD, cirrhosis, HIV
Chemotherapy, steroids, transplant drugs, biologics
Cancer and neutropenia
Prosthetic material or implanted devices
Pregnancy

Drug history

Ask specifically about recently introduced drugs. Drug fever may occur with antimicrobials, anticonvulsants, allopurinol, antiarrhythmics, and many other agents. A 2024 systematic review found that drug fever is a meaningful consideration in nosocomial fever, though prevalence varies markedly by setting and study design (PMID: 37690845).

Step 3: Examination

Perform a complete examination rather than examining only the presumed organ system:

Vital signs, including repeat temperature and oxygen saturation
Hydration, perfusion, mental state
Skin and mucosa: rash, petechiae, eschar, cellulitis, IV sites
Lymph nodes
Oral cavity and dentition
Heart: murmurs, peripheral endocarditis stigmata
Lungs
Abdomen, hepatosplenomegaly, costovertebral angle tenderness
Joints, spine, muscles
Neurologic examination and meningism
Rectal, pelvic, or prostate examination only when clinically indicated

6. Investigation strategy in fever

Investigations must be guided by the syndrome, stability, risk profile, and likely focus. Do not send broad panels without a clinical question.

Common initial tests in an unwell adult

CBC with differential
Urea, creatinine, electrolytes, glucose
Liver function tests
CRP, with or without procalcitonin depending on local use
Urinalysis and urine culture if urinary symptoms/risk
Blood cultures if sepsis, bacteremia, endocarditis, neutropenia, or unexplained significant fever is suspected
Chest radiograph if respiratory features or unclear systemic illness
Lactate and blood gas if sepsis/shock is possible
Respiratory viral testing when epidemiologically or clinically relevant

Targeted tests

Clinical clue	Potential next test
Meningism or altered sensorium	CT first if indicated, then lumbar puncture and CSF studies
Travel/tropical exposure	Malaria smear or rapid antigen test, dengue/enteric fever tests as appropriate
New murmur, embolic phenomena, IV drug use	Multiple blood cultures and echocardiography for endocarditis
Persistent back pain	MRI if vertebral osteomyelitis/epidural abscess suspected
Monoarthritis	Urgent arthrocentesis for Gram stain, culture, crystals
Immunocompromise	Broader microbiology and early imaging based on risk
Persistent/recurrent fever	CT, autoimmune evaluation, PET-CT or biopsy directed by clues

Fever of unknown origin, FUO

Classically, FUO is:

Temperature >38.3°C on several occasions
Illness lasting >3 weeks
No diagnosis after appropriate evaluation

The historical requirement for one week of inpatient investigation is less relevant now. The practical approach is repeated, careful history and examination, testing driven by diagnostic clues, and avoidance of empiric therapies that may mask a diagnosis unless the patient is unstable.

The main diagnostic categories are:

Infections
Malignancy
Noninfectious inflammatory disease
Miscellaneous causes, including drug fever and thromboembolism

7. Fever treatment

Treat the cause

This is the priority:

Antibiotics for a proven or strongly suspected bacterial infection
Antimalarial therapy when indicated
Source control for abscess or infected device
Immunomodulatory therapy only after appropriate exclusion of infection in inflammatory disease
Stop a likely culprit medication in drug fever

Antipyretics

Paracetamol/acetaminophen

Useful for discomfort and to lower fever-associated metabolic demand.

NSAIDs

Can reduce fever but require caution in:

AKI or CKD
Peptic ulcer disease or GI bleeding
Thrombocytopenia
Anticoagulation
Heart failure
Some viral illnesses and dehydration states

Antipyretics lower PGE2 production and return the hypothalamic set point toward normal. They are mainly for patient comfort and selected high-risk contexts, not a substitute for finding and treating the cause.

Routine fever suppression is not always necessary in an otherwise healthy adult. It is more reasonable to treat when there is substantial discomfort, very high temperature, dehydration risk, cardiorespiratory disease, or acute neurologic injury. A 2024 systematic review found that elevated temperature is particularly concerning in acute brain injury populations (PMID: 39538310).

8. Hyperthermia: clinical recognition

Causes

Environmental and exertional

Heat exposure
High humidity
Exercise in heat
Dehydration
Heavy protective clothing
Poor ventilation or no access to air conditioning

Drug and toxicologic

Anticholinergic toxicity
Sympathomimetics: cocaine, amphetamines, MDMA
Serotonin syndrome
Neuroleptic malignant syndrome, NMS
Malignant hyperthermia after anaesthesia

Endocrine/metabolic and neurologic

Thyroid storm
Pheochromocytoma crisis
Status epilepticus
Severe agitation
CNS injury affecting thermoregulation

Red flags for hyperthermia

Clear heat/exertion or toxicologic context
Temperature rising despite antipyretics
Lack of chills
Marked tachycardia, hypotension, dehydration
Altered mental status
Severe rigidity, clonus, hyperreflexia, or seizures
Very elevated CK, metabolic acidosis, hyperkalemia, AKI, or liver injury

9. Fever vs hyperthermia: practical comparison

Feature	Fever / pyrexia	Hyperthermia
Hypothalamic set point	Raised	Unchanged
Core mechanism	Cytokines → COX-2 → PGE2	Excess heat gain/production or impaired heat loss
Chills and rigors	Common, especially early	Usually absent
Skin	Cool/pale in chill phase; sweaty when defervescing	Often hot; sweat may be present or absent
Typical cause	Infection or inflammation	Heat, exertion, drugs, toxins, endocrine/metabolic disease
Antipyretics	Often effective	Usually ineffective
Cooling	Adjunct in selected severe fever	Essential, immediate in severe cases
Major danger	Usually underlying disease	Direct thermal injury and multiorgan failure

Harrison emphasizes that hyperthermia may be rapidly fatal, is not driven by pyrogenic molecules, and characteristically fails to respond to antipyretics. Harrison’s Principles of Internal Medicine, 22nd ed., p. 177.

10. Hyperthermic syndromes: distinguishing features

Syndrome	Typical trigger	Neuromuscular findings	Skin/GI findings	Initial priorities
Heat stroke	Exertion/environmental heat	CNS dysfunction; seizures possible	Hot skin, sweating may be absent or present	Rapid active cooling
Serotonin syndrome	Serotonergic drugs/interactions	Hyperreflexia and inducible/spontaneous clonus, often lower limbs	Diarrhea, hyperactive bowel sounds, diaphoresis	Stop drug, benzodiazepines, cooling, supportive care
NMS	Dopamine antagonist or dopamine withdrawal	Lead-pipe rigidity, hyporeflexia/bradyreflexia	Autonomic instability	Stop drug, cooling, supportive care, consider specific therapy
Malignant hyperthermia	Volatile anaesthetic/succinylcholine	Rigidity, rising CO2, acidosis	Usually intraoperative/perioperative	Stop trigger, dantrolene, active cooling
Anticholinergic toxicity	Atropine-like drugs	Delirium, no clonus	Hot, dry skin; mydriasis, urinary retention, ileus	Cooling, benzodiazepines, toxicology management
Sympathomimetic toxicity	Cocaine/amphetamine/MDMA	Agitation, tremor, seizures	Diaphoresis, mydriasis, hypertension	Benzodiazepines, cooling, supportive care
Thyroid storm	Severe thyrotoxicosis	Tremor/agitation	Goiter, AF, GI symptoms	Antithyroid therapy, beta-blockade when appropriate, steroids, cooling

11. Heat stroke: emergency clinical review

Heat stroke is a form of severe hyperthermia defined clinically by:

[ \boxed{\text{Heat exposure or exertion} + \text{CNS dysfunction} + \text{marked hyperthermia}} ]

CNS dysfunction may include confusion, ataxia, delirium, seizures, or coma.

Two patterns:

Exertional heat stroke: young, healthy, active individual; collapse during exertion; sweating is often profuse.
Classic/nonexertional heat stroke: older patient with comorbidity, chronic illness, medications, or prolonged heat-wave exposure; sweating may be absent.

Immediate management

Start cooling immediately. Do not wait for laboratory results, transport, or diagnostic certainty.
Remove clothing and relocate to a cool environment.
Use cold-water immersion if feasible, especially in exertional heat stroke.
If immersion is impractical, use evaporative cooling: mist with water plus fans, with ice packs as adjuncts.
Monitor rectal core temperature and stop aggressive cooling near 39°C.
Support airway, circulation, glucose, seizures, and agitation.
Monitor for AKI, rhabdomyolysis, hepatic injury, DIC, electrolyte disorders, and shock.

The CDC heat illness guidance identifies altered mental status with marked hyperthermia as a presumptive field diagnosis of heat stroke, and recommends rectal temperature when available. The Merck heat-stroke review similarly advises rapid cooling and stopping near 39°C to avoid overshoot.

Do not use antipyretics to treat heat stroke. They do not correct the pathophysiology and may add renal, hepatic, or coagulation risk in a critically ill patient.

12. When fever needs urgent escalation

Urgently assess or refer a febrile patient with:

Sepsis physiology: hypotension, tachypnea, hypoxia, high lactate, altered mentation
Suspected meningitis or encephalitis
Purpura, non-blanching rash, or rapidly progressive skin lesions
Severe headache, neck stiffness, seizures, or focal neurologic signs
Neutropenia or significant immunosuppression
Pregnancy/postpartum fever
Fever after surgery, invasive procedure, transplant, or central line
Persistent fever with weight loss, night sweats, lymphadenopathy, or hepatosplenomegaly
Fever plus acute monoarthritis
Fever with severe abdominal, back, or flank pain
Temperature >41°C or suspected hyperthermia
Any hyperthermia with altered mental status

13. Exam and ward-round summary

Fever or pyrexia is a regulated rise in body temperature due to cytokine-induced PGE2 elevation of the hypothalamic set point. It may present with chills during onset, plateau at the new set point, and sweating during defervescence.

Hyperthermia is an unregulated rise in temperature with an unchanged set point, due to excessive heat load or failed heat loss. It requires physical cooling and treatment of the cause, not antipyretics.

Heat stroke is hyperthermia with CNS dysfunction and possible multiorgan injury. Treat it as a time-critical emergency: cool first, investigate in parallel.

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