Thermoregulation Pathology

Quick Answer

Thermoregulation is the homeostatic process maintaining core body temperature within the narrow range of 36.5-37.5°C (97.7-99.5°F), controlled by the anterior hypothalamus (preoptic area). Temperature disorders in the ICU fall into two fundamental categories with distinct pathophysiology and management:

Key Pathological Concepts:

• Fever is a regulated increase in hypothalamic set-point mediated by pyrogens (IL-1, IL-6, TNF-α) acting via PGE2 on the organum vasculosum laminae terminalis (OVLT) and preoptic area (PMID: 10431336)
• Hyperthermia is a failure of thermoregulatory mechanisms with a NORMAL set-point - the body cannot dissipate heat faster than it is generated
• Hypothermia (core temp <35°C) causes progressive CNS depression, cardiac dysrhythmias (Osborn waves), and coagulopathy
• Targeted Temperature Management (TTM) uses induced hypothermia/normothermia for neuroprotection post-cardiac arrest

ICU Relevance:

• Fever increases metabolic demand by 10-12% per °C, worsening O₂ supply/demand mismatch
• Heat stroke requires aggressive cooling to <39°C within 30 minutes
• Hypothermic cardiac arrest: "No one is dead until warm and dead"
• TTM2 trial (PMID: 34133859) showed no benefit of 33°C vs normothermia in shockable arrest

Exam Focus:

• Draw thermoregulatory control loop with hypothalamic integration
• Explain PGE2-mediated fever pathophysiology
• Distinguish fever from hyperthermia
• Describe heat stroke, MH, NMS, serotonin syndrome pathophysiology
• Outline TTM evidence (HACA, Bernard, TTM, TTM2, HYPERION)

---

CICM First Part Exam Focus

What Examiners Expect

Written SAQ:

Common question stems:

• "Describe the physiology of thermoregulation" (appears in ~35% of First Part exams)
• "Explain the pathophysiology of fever"
• "Compare and contrast fever and hyperthermia"
• "Describe the pathophysiology of heat stroke"
• "Outline the physiological effects of hypothermia on body systems"
• "Describe the mechanisms by which malignant hyperthermia causes hyperthermia"
• "Explain the rationale for targeted temperature management post-cardiac arrest"

Expected depth:

• Detailed molecular mechanisms (pyrogens, PGE2, EP3 receptors)
• Quantitative values (set-point, temperature thresholds, metabolic effects)
• Clear diagrams of thermoregulatory control loops
• Comparison tables for hyperthermia syndromes
• Evidence base for TTM (key trials with PMIDs)

Written MCQ:

Common topics tested:

• Normal thermoregulatory mechanisms
• Fever pathophysiology (pyrogens, COX-2, PGE2)
• Heat stroke classification and pathophysiology
• Hypothermia staging and physiological effects
• Osborn waves and cardiac effects of hypothermia
• Malignant hyperthermia pharmacogenetics
• NMS vs serotonin syndrome differentiation
• TTM evidence base

Difficulty level:

• Application of pathophysiological principles
• Recognition of ECG changes
• Drug-induced hyperthermia differentiation

Oral Viva:

Expected discussion flow:

1. Define/Describe - Normal thermoregulation, hypothalamic control
2. Explain Mechanism - Fever vs hyperthermia at molecular level
3. Quantify - Temperature thresholds, metabolic costs, mortality rates
4. Compare/Contrast - MH vs NMS vs serotonin syndrome
5. Apply to ICU - TTM evidence, cooling strategies, rewarming protocols
6. Integrate - Australian context (heat waves, drowning)

Common viva scenarios:

• "Tell me about the physiology of temperature control"
• "A patient develops a temperature of 42°C intra-operatively - discuss"
• "Describe the physiological effects of accidental hypothermia"
• "What is the evidence for targeted temperature management?"

Pass vs Fail Performance

Pass Standard:

• Accurate description of hypothalamic thermoregulation
• Clear distinction between fever and hyperthermia
• Correct identification of PGE2 as fever mediator
• Understanding of heat stroke pathophysiology
• Knowledge of TTM evidence (at least TTM, TTM2, HYPERION)
• Draws clear control loop diagram when asked

Common Reasons for Failure:

• Confusing fever with hyperthermia
• Not knowing PGE2/COX-2 pathway
• Inability to differentiate MH, NMS, serotonin syndrome
• No knowledge of TTM trial results
• Cannot explain Osborn wave genesis
• Poor integration of pathology with clinical management

---

Key Points

Must-Know Facts

1. Hypothalamic Thermostat: The preoptic area of the anterior hypothalamus contains warm-sensitive and cold-sensitive neurons that integrate peripheral (skin) and central (blood, visceral) temperature signals to maintain set-point of 37°C (range 36.5-37.5°C) (PMID: 10431336)

2. Fever Mechanism: Exogenous pyrogens (LPS, bacteria) → Endogenous pyrogens (IL-1β, IL-6, TNF-α) → Act on OVLT (circumventricular organ with fenestrated BBB) → COX-2 activation → PGE2 synthesis → EP3 receptor activation → Raised set-point → Heat conservation/production (PMID: 10431335)

3. Hyperthermia vs Fever: Fever = elevated set-point (responds to antipyretics); Hyperthermia = failure of heat dissipation with normal set-point (antipyretics INEFFECTIVE). Critical distinction for management (PMID: 35115545)

4. Heat Stroke Classification: Classical (environmental, elderly, passive) vs Exertional (exercise-induced, young, athletes). Both cause core temp >40°C with CNS dysfunction and multi-organ failure (PMID: 35115545)

5. Hypothermia Stages: Mild (32-35°C) - shivering, tachycardia; Moderate (28-32°C) - shivering stops, bradycardia, Osborn waves; Severe (<28°C) - VF risk, areflexia, coma; Profound (<24°C) - asystole, apparent death (PMID: 23150943)

6. Osborn Waves (J-waves): Positive deflection at J-point (QRS-ST junction), appear <32°C, proportional to hypothermia severity. Caused by temperature-dependent transmural voltage gradient in ventricular myocardium (PMID: 25841022)

7. Malignant Hyperthermia: Pharmacogenetic disorder caused by RYR1 mutations (90%) leading to uncontrolled calcium release from sarcoplasmic reticulum when triggered by volatile anaesthetics or succinylcholine. Mortality >70% without dantrolene (PMID: 25431601)

8. TTM2 Trial (2021): 1,900 OHCA patients (mostly shockable rhythms) - 33°C vs normothermia (≤37.5°C) showed NO significant difference in 6-month mortality or neurological outcome. Changed practice from active cooling to fever prevention (PMID: 34133859)

9. HYPERION Trial (2019): Patients with non-shockable rhythms (asystole/PEA) - 33°C for 24h vs 37°C showed IMPROVED neurological outcomes at 90 days with hypothermia (CPC 1-2: 10.2% vs 5.7%, RR 1.83). Suggests benefit may persist in non-shockable rhythms (PMID: 31573909)

10. Drug-Induced Hyperthermia Triad: Malignant hyperthermia (RYR1, volatile agents/succinylcholine), Neuroleptic malignant syndrome (D2 blockade, antipsychotics), Serotonin syndrome (5-HT excess, serotonergics). Key differentiators: NMS = lead-pipe rigidity + bradyreflexia; SS = hyperreflexia + clonus (PMID: 15784664)

Essential Equations

Metabolic Rate Increase with Fever:

VO₂ increase = 10-12% per 1°C above normal

• At 40°C: metabolic rate increased ~40%
• Clinical significance: Increased O₂ demand, CO₂ production, cardiac output

Heat Balance Equation:

Heat Storage = Heat Production - Heat Loss
M + W = E ± R ± C ± K

• M = Metabolic heat production
• W = Work performed
• E = Evaporative heat loss
• R = Radiant heat exchange
• C = Convective heat exchange
• K = Conductive heat exchange

Temperature Conversion:

°C = (°F - 32) × 5/9
°F = (°C × 9/5) + 32

Normal Values Table

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Normal Thermoregulation

Hypothalamic Control Centre

The preoptic area of the anterior hypothalamus (POA) serves as the body's central thermostat, integrating thermal information and coordinating effector responses (PMID: 10431336).

Thermoregulatory Control Loop

┌─────────────────────────────────────────────────────────────────────┐
│                    THERMOREGULATORY CONTROL LOOP                     │
├─────────────────────────────────────────────────────────────────────┤
│                                                                      │
│    SENSORS                    INTEGRATOR              EFFECTORS      │
│    ────────                   ──────────              ─────────      │
│                                                                      │
│    Peripheral                 ┌─────────────┐         Heat Loss      │
│    (Skin)                     │  ANTERIOR   │         ─────────      │
│    - Warm receptors ─────────►│ HYPOTHALAMUS│────────►Vasodilation   │
│      (TRPV1, TRPV3)           │  (Preoptic  │         Sweating       │
│    - Cold receptors           │    Area)    │         Behavioural    │
│      (TRPM8, TRPA1)           │             │                        │
│         │                     │  Set-point  │         Heat Gain      │
│         │                     │   37°C      │         ─────────      │
│    Central                    │             │────────►Vasoconstriction│
│    (Core)                     └─────────────┘         Shivering      │
│    - Blood temperature ─────────────┘                 Non-shivering  │
│    - Deep tissue                                      thermogenesis  │
│    - Spinal cord                                      Behavioural    │
│                                                                      │
└─────────────────────────────────────────────────────────────────────┘

Temperature-Sensitive Neurons

Warm-Sensitive Neurons (WSN):

• Constitute ~30% of POA neurons
• Increase firing rate with rising temperature
• Inhibited during fever (PGE2-mediated)
• Activate heat loss mechanisms when stimulated

Cold-Sensitive Neurons (CSN):

• Constitute ~5% of POA neurons
• Increase firing rate with falling temperature
• Activated during fever
• Drive heat conservation and production

Temperature-Insensitive Neurons:

• Majority (~65%) of POA neurons
• Provide tonic input for thermoregulatory balance
• Modulated by non-thermal inputs (circadian, behavioural)

Peripheral Thermoreceptors

Signal Integration:

• Peripheral signals via spinothalamic tract to lateral parabrachial nucleus → POA
• Core temperature signals via direct blood warming of hypothalamus
• Final integrated output determines effector activation

Heat Production Mechanisms

Obligatory (Basal) Heat Production

Metabolic Heat Generation:

• Basal metabolic rate (BMR): ~70-80 W at rest
• ATP hydrolysis efficiency: ~40% (60% released as heat)
• Major sources: liver (25%), brain (20%), skeletal muscle (25%), heart (10%)

Facultative Heat Production

Shivering Thermogenesis:

• Involuntary rhythmic muscle contractions (10-20 Hz)
• Increases metabolic rate 2-5 fold
• Maximum heat production: ~300-400 W
• Exhausts after 4-6 hours (glycogen depletion)
• Abolished below ~30-32°C core temperature

Non-Shivering Thermogenesis (NST):

• Brown adipose tissue (BAT) in neonates and adults
• Uncoupling protein-1 (UCP1) dissipates proton gradient as heat
• β3-adrenergic receptor activation
• Limited contribution in adults (~5-10% of cold-induced thermogenesis)
• More significant in neonates (who cannot shiver effectively)

Diet-Induced Thermogenesis:

• Heat generated from food metabolism
• ~10% of caloric intake
• Protein > carbohydrate > fat

Heat Loss Mechanisms

Dry Heat Exchange

Radiation (40-60% of heat loss at rest):

• Infrared electromagnetic radiation from body surface
• Proportional to temperature difference (body - environment)
• Stefan-Boltzmann law: Q = εσA(T₁⁴ - T₂⁴)
• Minimal when ambient temperature equals skin temperature

Convection (15-20%):

• Heat transfer to moving air/water
• Forced convection (wind, fans) increases heat loss dramatically
• Water convection 25× more effective than air

Conduction (<3% in air):

• Direct heat transfer between contacting surfaces
• Significant in water immersion (water thermal conductivity 25× air)
• Important for conductive cooling/warming devices

Evaporative Heat Loss

Sweating (Major mechanism at high ambient temperature):

• Eccrine sweat glands (2-4 million)
• Maximum sweat rate: 2-3 L/hour (short-term)
• Heat dissipation: 580 kcal/L evaporated (2,430 kJ/L)
• Controlled by sympathetic cholinergic fibres
• Ineffective at high humidity (>75%)

Insensible Water Loss:

• Respiratory evaporation: ~300 mL/day
• Transepidermal water loss: ~300-500 mL/day
• Contribution to heat loss: ~25% at rest

Circadian Temperature Variation

• Minimum: 04:00-06:00 (36.0-36.5°C)
• Maximum: 16:00-18:00 (37.0-37.5°C)
• Amplitude: 0.5-1.0°C
• Regulated by suprachiasmatic nucleus (SCN)
• Clinical significance: Fever definition must account for time of day

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Fever Pathophysiology

Definition and Classification

Fever: Elevation of core body temperature above the normal daily variation, due to an INCREASE in the hypothalamic set-point. The body actively generates and conserves heat to achieve the new, higher set-point (PMID: 10431336).

Temperature Thresholds:

The Pyrogenic Cascade

Exogenous Pyrogens

Pathogen-Associated Molecular Patterns (PAMPs):

Damage-Associated Molecular Patterns (DAMPs):

• HMGB1 (High Mobility Group Box 1)
• Uric acid crystals
• Heat shock proteins
• S100 proteins
• Mitochondrial DNA

Endogenous Pyrogens (Cytokines)

┌─────────────────────────────────────────────────────────────────────┐
│                    PYROGENIC CASCADE                                 │
├─────────────────────────────────────────────────────────────────────┤
│                                                                      │
│    EXOGENOUS PYROGENS          ENDOGENOUS PYROGENS                   │
│    (LPS, bacteria, etc.)       (Cytokines)                           │
│           │                           │                              │
│           ▼                           ▼                              │
│    ┌──────────────┐            ┌──────────────┐                      │
│    │  Macrophages │──────────► │   IL-1β      │                      │
│    │  Monocytes   │            │   IL-6       │                      │
│    │  Dendritic   │            │   TNF-α      │                      │
│    │    cells     │            │   IFN-α/β/γ  │                      │
│    └──────────────┘            └──────────────┘                      │
│                                       │                              │
│                                       ▼                              │
│                        ┌──────────────────────────┐                  │
│                        │  OVLT (Circumventricular │                  │
│                        │  organ - fenestrated BBB)│                  │
│                        └──────────────────────────┘                  │
│                                       │                              │
│                                       ▼                              │
│                        ┌──────────────────────────┐                  │
│                        │  Endothelial COX-2       │                  │
│                        │  Arachidonic acid → PGE2 │                  │
│                        └──────────────────────────┘                  │
│                                       │                              │
│                                       ▼                              │
│                        ┌──────────────────────────┐                  │
│                        │  EP3 receptors on POA    │                  │
│                        │  neurons                 │                  │
│                        └──────────────────────────┘                  │
│                                       │                              │
│                                       ▼                              │
│                        ┌──────────────────────────┐                  │
│                        │  SET-POINT ELEVATION     │                  │
│                        │  → Heat conservation     │                  │
│                        │  → Heat production       │                  │
│                        │  → Behavioural changes   │                  │
│                        └──────────────────────────┘                  │
│                                                                      │
└─────────────────────────────────────────────────────────────────────┘

Interleukin-1β (IL-1β): (PMID: 10431335)

• Most potent endogenous pyrogen
• Produced by macrophages, monocytes, dendritic cells
• Acts on OVLT endothelial cells to induce COX-2
• Also has direct hypothalamic effects

Interleukin-6 (IL-6):

• Major circulating pyrogen
• Crosses BBB at circumventricular organs
• Induces acute phase response in liver
• Levels correlate with fever magnitude

Tumour Necrosis Factor-α (TNF-α):

• Rapid, short-acting pyrogen
• Induces IL-1 and IL-6 production
• Also causes anorexia, catabolism

Interferons (IFN-α, IFN-β, IFN-γ):

• Antiviral cytokines with pyrogenic activity
• Contribute to viral illness fever pattern

Prostaglandin E2 (PGE2) - The Central Mediator

Synthesis Pathway: (PMID: 10585013)

Membrane phospholipids
        │
        ▼ (Phospholipase A2)
Arachidonic acid
        │
        ▼ (Cyclooxygenase-2) ◄── Inhibited by NSAIDs
Prostaglandin H2
        │
        ▼ (Prostaglandin E synthase)
Prostaglandin E2 (PGE2)
        │
        ▼
EP3 receptors (POA neurons)

PGE2 Mechanism of Action:

• Lipid-soluble: crosses fenestrated OVLT BBB
• Binds EP3 receptors (Gi-coupled) on POA warm-sensitive neurons
• Inhibits warm-sensitive neurons (decreased firing)
• Disinhibits cold-sensitive neurons
• Net effect: body perceives temperature as "too low"
• Triggers heat conservation and production

EP Receptor Subtypes:

Fever Response - Physiological Changes

Heat Conservation Phase ("Chill"):

• Peripheral vasoconstriction (cold, pale skin)
• Piloerection ("goosebumps")
• Curling posture (reduces surface area)
• Subjective sensation of cold

Heat Production Phase:

• Shivering
• Increased metabolic rate (10-12% per °C)
• Increased heart rate (~10 bpm per °C)
• Increased respiratory rate
• Non-shivering thermogenesis

New Equilibrium (Plateau):

• Core temperature at new set-point
• Subjective sensation of comfort at higher temperature
• Stable metabolic state

Defervescence (Set-Point Returns to Normal):

• Vasodilation (warm, flushed skin)
• Sweating
• Subjective sensation of warmth
• Occurs when pyrogens cleared or antipyretics given

Beneficial Effects of Fever

Moderate fever (38-39°C) enhances immune function: (PMID: 25907458)

Harmful Effects of Fever

Metabolic Costs:

• VO₂ increases 10-12% per °C
• Increased cardiac output (20% per °C)
• Increased minute ventilation
• Risk of decompensation in cardiac/respiratory disease

Neurological Effects:

• Febrile seizures (6 months - 5 years): 2-5% of children
• Delirium in elderly
• Worsens outcome in brain injury (increased ICP, metabolic demand)

Other Effects:

• Protein catabolism
• Dehydration (increased insensible losses)
• Electrolyte disturbances

---

Hyperthermia Pathophysiology

Definition and Distinction from Fever

Hyperthermia: Elevation of core body temperature above 38.5°C due to FAILURE of thermoregulatory mechanisms to dissipate heat, with a NORMAL hypothalamic set-point (PMID: 35115545).

Critical Distinction: Fever vs Hyperthermia

Clinical Significance: Antipyretics (paracetamol, NSAIDs) are INEFFECTIVE in true hyperthermia because the hypothalamic set-point is already normal. Active cooling is required.

Heat Stroke

Classification (PMID: 35115545)

Classical (Non-Exertional) Heat Stroke:

• Environmental heat exposure
• Passive heat gain exceeds dissipation capacity
• Risk factors: Elderly, chronic illness, medications, poverty, social isolation
• Often develops over days
• Sweating may be absent (anhidrosis in 50%)
• Associated with heat waves

Exertional Heat Stroke:

• Strenuous physical activity in hot/humid conditions
• Endogenous heat production exceeds dissipation
• Young, healthy individuals (athletes, military, laborers)
• Rapid onset (minutes to hours)
• Sweating usually present
• Higher peak temperatures, more severe rhabdomyolysis

Pathophysiology of Heat Stroke

Phase 1: Heat Stress Response (Compensated)

↑ Core temperature
      │
      ▼
Hypothalamic activation
      │
      ├──► Cutaneous vasodilation (up to 8 L/min skin blood flow)
      │
      ├──► Sweating (up to 2 L/hour)
      │
      └──► Cardiovascular compensation (↑ HR, ↑ CO, splanchnic vasoconstriction)

Phase 2: Decompensation and Organ Injury

When heat stress exceeds compensatory capacity, a catastrophic inflammatory cascade ensues:

┌─────────────────────────────────────────────────────────────────────┐
│              HEAT STROKE PATHOPHYSIOLOGY                             │
├─────────────────────────────────────────────────────────────────────┤
│                                                                      │
│    DIRECT HEAT INJURY                   SYSTEMIC INFLAMMATION        │
│    ──────────────────                   ─────────────────────        │
│                                                                      │
│    ┌────────────────┐                   ┌────────────────────┐       │
│    │ Cellular damage│                   │ Gut barrier failure│       │
│    │ >40°C = protein│                   │ Ischaemia from     │       │
│    │ denaturation   │                   │ splanchnic shunt   │       │
│    └───────┬────────┘                   └─────────┬──────────┘       │
│            │                                      │                  │
│            ▼                                      ▼                  │
│    Heat shock proteins                   LPS translocation           │
│    (HSP70, HSP90)                        (Endotoxaemia)              │
│            │                                      │                  │
│            └──────────────┬───────────────────────┘                  │
│                           │                                          │
│                           ▼                                          │
│              ┌────────────────────────┐                              │
│              │  SYSTEMIC INFLAMMATORY │                              │
│              │  RESPONSE SYNDROME     │                              │
│              │  (SIRS)                │                              │
│              └───────────┬────────────┘                              │
│                          │                                           │
│            ┌─────────────┼─────────────┐                             │
│            ▼             ▼             ▼                             │
│    ┌───────────┐  ┌───────────┐  ┌───────────┐                       │
│    │ Endothelial│  │   DIC     │  │  MODS     │                       │
│    │ activation │  │           │  │           │                       │
│    └───────────┘  └───────────┘  └───────────┘                       │
│                                                                      │
└─────────────────────────────────────────────────────────────────────┘

Key Pathophysiological Mechanisms:

1. Direct Cellular Heat Injury:

   • Protein denaturation begins at 40-41°C
   • Membrane instability, ion pump failure
   • Mitochondrial dysfunction
   • Heat shock protein (HSP) expression (protective but overwhelmed)
   • Cellular necrosis and apoptosis

2. Intestinal Barrier Failure: (PMID: 35115545)

   • Splanchnic vasoconstriction (blood shunted to skin)
   • Gut ischaemia → increased intestinal permeability
   • Bacterial translocation → endotoxaemia (LPS in circulation)
   • "Leaky gut" drives systemic inflammation

3. Systemic Inflammatory Response:

   • LPS activates monocytes/macrophages
   • Cytokine storm (IL-1, IL-6, TNF-α)
   • Endothelial activation
   • Paradoxically, same cytokines that cause fever drive further inflammation

4. Coagulopathy and DIC:

   • Endothelial injury → tissue factor exposure
   • Activated coagulation cascade
   • Microvascular thrombosis
   • Consumption coagulopathy
   • Bleeding complications

5. Multi-Organ Dysfunction Syndrome (MODS):

   • CNS: Cerebral oedema, seizures, coma
   • Cardiovascular: Hypotension, arrhythmias, high-output failure
   • Respiratory: ARDS, aspiration
   • Renal: ATN from rhabdomyolysis, hypoperfusion
   • Hepatic: Centrilobular necrosis, coagulopathy
   • Haematological: DIC, thrombocytopenia

Heat Stroke - Organ System Effects

Australian Context - Heat Waves

Epidemiology:

• Australia experiences significant heat wave mortality
• 2009 Victorian heat wave: 374 excess deaths, ED presentations increased 12%
• Elderly, socially isolated, chronic illness at highest risk
• Urban heat island effect in major cities

Vulnerable Populations:

• Aboriginal and Torres Strait Islander communities
• Remote communities with limited access to cooling
• Elderly in non-air-conditioned housing
• Homeless populations
• Outdoor workers

Drug-Induced Hyperthermia Syndromes

Malignant Hyperthermia (MH)

Pharmacogenetics: (PMID: 25431601)

• Autosomal dominant inheritance
• RYR1 mutations (~70% of cases): Ryanodine receptor Type 1 (skeletal muscle SR calcium channel)
• CACNA1S mutations (~1%): Dihydropyridine receptor (L-type Ca²⁺ channel)
• Incidence: 1:10,000-15,000 anaesthetics

Triggering Agents:

Pathophysiology: (PMID: 20147492)

┌─────────────────────────────────────────────────────────────────────┐
│              MALIGNANT HYPERTHERMIA PATHOPHYSIOLOGY                  │
├─────────────────────────────────────────────────────────────────────┤
│                                                                      │
│    Normal Excitation-Contraction Coupling:                           │
│    ─────────────────────────────────────                             │
│    Action potential → T-tubule → DHPR → RYR1 opens briefly →        │
│    Ca²⁺ release → Contraction → SERCA pumps Ca²⁺ back → Relaxation  │
│                                                                      │
│    In MH-Susceptible Individual + Trigger:                           │
│    ─────────────────────────────────────                             │
│    Trigger agent → Mutant RYR1 remains OPEN → Uncontrolled Ca²⁺     │
│                                                     │                │
│                                                     ▼                │
│                              ┌─────────────────────────────┐         │
│                              │  CALCIUM STORM IN MYOPLASM  │         │
│                              └─────────────────────────────┘         │
│                                          │                           │
│              ┌───────────────────────────┼───────────────────────┐   │
│              ▼                           ▼                       ▼   │
│    ┌─────────────────┐      ┌─────────────────┐      ┌───────────────┐
│    │ Sustained muscle│      │  ATP depletion  │      │ SERCA/Na-K    │
│    │ contraction     │      │  (futile Ca²⁺   │      │ ATPase        │
│    │ (rigidity)      │      │   cycling)      │      │ overactivity  │
│    └────────┬────────┘      └────────┬────────┘      └───────┬───────┘
│             │                        │                       │       │
│             ▼                        ▼                       ▼       │
│    ┌─────────────────────────────────────────────────────────────┐   │
│    │                    HYPERMETABOLIC STATE                      │   │
│    │  • Heat production (hyperthermia)                            │   │
│    │  • ↑ O₂ consumption, ↑ CO₂ production                        │   │
│    │  • Lactate → Metabolic acidosis                              │   │
│    │  • ATP depletion → Cell membrane failure                     │   │
│    │  • K⁺, myoglobin, CK leak → Hyperkalaemia, rhabdomyolysis    │   │
│    └─────────────────────────────────────────────────────────────┘   │
│                                                                      │
└─────────────────────────────────────────────────────────────────────┘

Clinical Features:

Dantrolene Mechanism: (PMID: 15302720)

• Hydantoin derivative
• Binds RYR1 at N-terminal region
• Inhibits Ca²⁺ release from sarcoplasmic reticulum
• Does NOT affect Ca²⁺ reuptake (SERCA function preserved)
• Dose: 2.5 mg/kg IV, repeat every 5-10 min until response
• Maximum: No ceiling dose (may require >10 mg/kg)
• Reduces mortality from >70% to <5%

Neuroleptic Malignant Syndrome (NMS)

Pathophysiology: (PMID: 21199511)

• Central D2 dopamine receptor blockade
• Primarily in hypothalamus and nigrostriatal pathway
• Leads to impaired heat dissipation and muscle rigidity

Causative Agents:

Clinical Features: (PMID: 17272118)

• Onset: 1-3 days to weeks after drug initiation or dose increase
• "Lead-pipe" rigidity (extrapyramidal)
• Bradyreflexia or normal reflexes
• Hyperthermia (typically 38-40°C)
• Altered mental status
• Autonomic instability (diaphoresis, tachycardia, labile BP)
• CK markedly elevated (often >1,000 IU/L)
• Leukocytosis

Treatment:

• Discontinue offending agent
• Supportive care (cooling, fluids, airway protection)
• Bromocriptine (D2 agonist): 2.5-10 mg TDS
• Dantrolene: 1-2.5 mg/kg IV (for severe cases)
• Consider ECT for refractory cases

Serotonin Syndrome (SS)

Pathophysiology: (PMID: 15784664)

• Excess synaptic serotonin (5-HT)
• Overstimulation of 5-HT1A and 5-HT2A receptors
• Central and peripheral effects

Causative Agents:

Hunter Criteria (Diagnosis requires serotonergic agent + ONE of):

1. Spontaneous clonus
2. Inducible clonus + agitation OR diaphoresis
3. Ocular clonus + agitation OR diaphoresis
4. Tremor + hyperreflexia
5. Hypertonia + temperature >38°C + (ocular OR inducible clonus)

Clinical Features:

• Onset: Rapid (minutes to hours after dose change)
• Hyperreflexia, CLONUS (lower limbs, ocular)
• Tremor
• Agitation
• Diaphoresis
• Mydriasis
• Diarrhoea
• Hyperthermia (usually <40°C unless severe)
• CK mildly elevated (usually <1,000 IU/L)

Treatment:

• Discontinue serotonergic agents
• Supportive care
• Benzodiazepines for agitation
• Cyproheptadine (5-HT2A antagonist): 12 mg initial, then 2-4 mg Q1-4h
• Active cooling if temperature >40°C

Comparison of Drug-Induced Hyperthermia Syndromes

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Hypothermia Pathophysiology

Definition and Classification

Hypothermia: Core body temperature <35°C (95°F) (PMID: 23150943)

Classification by Severity

Swiss Staging System (Clinical)

Physiological Effects by Organ System

Cardiovascular Effects

┌─────────────────────────────────────────────────────────────────────┐
│                    CARDIOVASCULAR EFFECTS OF HYPOTHERMIA             │
├─────────────────────────────────────────────────────────────────────┤
│                                                                      │
│    Temperature    Cardiac Response    ECG Changes                    │
│    ───────────    ────────────────    ───────────                    │
│                                                                      │
│    35°C ─────── ► Tachycardia ─────► Sinus tachycardia               │
│    │              ↑ CO, ↑ BP                                         │
│    │                                                                 │
│    32°C ─────── ► Bradycardia ────► PR prolongation                  │
│    │              ↓ CO               QT prolongation                 │
│    │                                 Osborn waves appear             │
│    │                                                                 │
│    28°C ─────── ► Atrial           ► Atrial fibrillation            │
│    │              fibrillation        (50% of patients)              │
│    │              ↓↓ CO                                              │
│    │                                                                 │
│    24°C ─────── ► VF threshold     ► Ventricular fibrillation        │
│    │              reached            (very difficult to defibrillate)│
│    │                                                                 │
│    <20°C ────── ► Asystole ───────► Isoelectric                      │
│                                                                      │
└─────────────────────────────────────────────────────────────────────┘

Osborn Waves (J-waves): (PMID: 25841022)

• Positive deflection at J-point (junction of QRS and ST segment)
• Appear at temperatures <32°C
• Height proportional to degree of hypothermia
• Mechanism: Temperature-dependent transmural voltage gradient in ventricular myocardium (Ito current)
• Present in ~80% of patients with core temp <30°C
• NOT pathognomonic - also seen in hypercalcaemia, subarachnoid haemorrhage, early repolarisation

Arrhythmia Progression:

1. Sinus tachycardia → Sinus bradycardia
2. Atrial fibrillation (very common at 28-32°C)
3. Ventricular fibrillation (below 28°C)
4. Asystole (below 20°C)

Critical Point: Below 28°C, the heart is:

• Highly irritable (VF with minimal stimulation)
• Resistant to defibrillation
• Resistant to pharmacological therapy

Respiratory Effects

Oxyhemoglobin Dissociation Curve:

• Left shift with hypothermia
• ↑ Hb-O₂ affinity, ↓ O₂ delivery to tissues
• Effect: ~7% decrease in O₂ offloading per °C drop

ABG Interpretation in Hypothermia:

• pH-stat: Corrects to patient's temperature
• Alpha-stat: Reports at 37°C (most commonly used)
• In hypothermia: Temperature-corrected pH is higher, PaCO₂ is lower

Neurological Effects

Neuroprotective Effects:

• Reduced cerebral metabolic rate (CMRO₂): ~7% per °C
• Decreased excitotoxic neurotransmitter release
• Reduced free radical formation
• Decreased inflammatory response
• Basis for therapeutic hypothermia

Coagulation Effects

Cold-Induced Coagulopathy: (PMID: 15082496)

Laboratory Paradox:

• Standard coagulation tests (PT, aPTT) are warmed to 37°C
• May appear NORMAL in laboratory
• In the PATIENT, these enzymes are not functioning
• Clinical coagulopathy present despite "normal" labs

Massive transfusion + Hypothermia = Lethal Triad:

• Hypothermia
• Coagulopathy
• Acidosis
• Each worsens the others in positive feedback loop

Metabolic and Endocrine Effects

• impaired ADH response, renal tubular dysfunction | | Thyroid | Decreased T3/T4 conversion | | Adrenal | Impaired cortisol response |

Renal Effects

• Cold Diuresis: Impaired ADH response, decreased renal tubular reabsorption
• Initial polyuria (can worsen hypovolaemia)
• GFR decreases with progressive hypothermia
• Oliguria in severe hypothermia

Special Considerations

Hypothermia in Drowning (Australian Context)

Submersion vs Immersion:

• Immersion: Head above water, hypothermia from water exposure
• Submersion: Head below water, hypoxia + hypothermia

Protective Effect of Cold Water:

• Cold water submersion may provide neuroprotection IF hypothermia develops BEFORE hypoxia
• Rapid cooling (cold water <5°C) can lower brain temperature before cardiac arrest
• Explains remarkable survival after prolonged submersion in very cold water
• Anna Bågenholm case: 80 min submersion, core temp 13.7°C, survived with CPR + ECMO

"No one is dead until they are warm and dead": (PMID: 26772244)

• In hypothermic cardiac arrest, resuscitation efforts should continue
• ECMO/CPB rewarming is the gold standard for cardiac arrest with core temp <28°C
• Neurological recovery possible after prolonged CPR if hypothermia was present before arrest

Australian Drowning Epidemiology:

• ~290 drowning deaths per year in Australia
• Aboriginal and Torres Strait Islander communities: 2.5-3× higher drowning rates
• Remote community river/waterhole drowning common
• Cold water immersion in southern states (Victoria, Tasmania, SA)

Trauma and Hypothermia

Lethal Triad (Trauma Triad of Death):

1. Hypothermia
2. Acidosis
3. Coagulopathy

Prevention in Trauma:

• Aggressive warming in ED and OR
• Warmed IV fluids (38-40°C)
• Forced air warming blankets
• Minimise exposure time
• Target core temp >35°C

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Targeted Temperature Management (TTM)

Historical Context and Evolution

Early Trials:

• 2002: Two landmark RCTs established therapeutic hypothermia post-cardiac arrest

HACA Trial (2002) (PMID: 11856793):

• 273 OHCA patients, VF/VT
• 32-34°C for 24 hours vs standard care
• Good neurological outcome: 55% vs 39% (NNT=6)
• Mortality: 41% vs 55% (NNT=7)

Bernard et al. (2002) (PMID: 11856794):

• 77 OHCA patients, VF
• 33°C for 12 hours vs normothermia
• Good neurological outcome: 49% vs 26%

These trials established TTM as standard of care for 15+ years.

TTM Trial (2013) (PMID: 24237006)

Design:

• 950 OHCA patients (presumed cardiac cause)
• 33°C vs 36°C for 24 hours
• Followed by rewarming and fever prevention

Results:

• No significant difference in mortality at end of trial (50% vs 48%)
• No significant difference in neurological outcome
• Fewer adverse events in 36°C group

Impact: Raised questions about optimal target temperature

TTM2 Trial (2021) (PMID: 34133859)

Design:

• 1,900 OHCA patients (presumed cardiac or unknown cause)
• Predominantly shockable rhythms (72%)
• Targeted hypothermia (33°C) for 28 hours vs targeted normothermia (≤37.5°C with early treatment of fever)
• Both groups avoided fever (<37.8°C) for 72 hours

Primary Outcome:

• Death from any cause at 6 months
• 33°C: 50% mortality
• Normothermia: 48% mortality
• HR 1.04 (95% CI 0.94-1.14), p=0.37

Secondary Outcomes:

• No difference in neurological outcome at 6 months
• No difference in any pre-specified subgroup

Impact:

• For shockable rhythm OHCA: Fever prevention (normothermia) is as effective as 33°C
• Shifted practice from active cooling to aggressive fever prevention
• Simpler, fewer complications (less shivering management, arrhythmias)

HYPERION Trial (2019) (PMID: 31573909)

Design:

• 584 OHCA patients with NON-SHOCKABLE rhythms (asystole or PEA)
• 33°C for 24 hours vs 37°C
• Primary outcome: Survival with favorable neurological outcome (CPC 1-2) at 90 days

Results:

• Favorable neurological outcome: 10.2% (33°C) vs 5.7% (37°C)
• RR 1.83 (95% CI 1.04-3.21), p=0.03
• NNT = 22

Impact:

• Suggests benefit of 33°C may persist for NON-shockable rhythms
• These patients have worse prognosis overall
• May still benefit from active hypothermia
• More recent guidelines retain option for 33°C in non-shockable rhythms

Current Evidence Summary

Current Recommendations (Post-TTM2)

Shockable Rhythms (VF/VT):

• Target normothermia (≤37.5°C)
• Aggressive fever prevention for 72 hours
• Active cooling to 33°C is NOT superior

Non-Shockable Rhythms (Asystole/PEA):

• 33°C for 24 hours may provide benefit (HYPERION)
• OR normothermia with fever prevention
• Clinical judgment based on patient factors

All Patients:

• Avoid hyperthermia (>37.5°C) for at least 72 hours
• Fever is independently associated with worse outcome
• Targeted temperature management should be part of post-resuscitation care bundle

Mechanisms of Neuroprotection

Proposed Mechanisms of Hypothermic Neuroprotection:

Complications of TTM

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Clinical Management Summary

Fever Management in ICU

When to Treat:

• Increased metabolic demand in cardiac/respiratory failure
• Traumatic brain injury, stroke (fever worsens outcome)
• Patient discomfort
• Very high fever (>40°C)

When NOT to Treat (Consider Benefits):

• Immunocompetent patient with infection
• Fever may enhance immune function at 38-39°C
• No evidence that antipyretics improve survival in sepsis

Treatment:

• Antipyretics: Paracetamol 1g QDS, NSAIDs (if not contraindicated)
• Surface cooling (if needed)
• Treat underlying cause

Hyperthermia Management in ICU

Heat Stroke:

• IMMEDIATE aggressive cooling
• Goal: Core temp <39°C within 30 minutes
• Methods:
  • "Evaporative: Spray water + fan"
  • Ice water immersion (most effective)
  • Cold IV fluids
  • Invasive cooling catheters
• Antipyretics are INEFFECTIVE (set-point is normal)
• Supportive care: Fluids, monitoring for MODS

Malignant Hyperthermia:

• STOP trigger agents immediately
• 100% O₂ at high flow
• Dantrolene 2.5 mg/kg IV, repeat Q5-10min
• Active cooling (stop at 38°C to avoid overshoot)
• Treat hyperkalaemia
• ICU monitoring for 24+ hours (recrudescence risk)

NMS:

• Discontinue dopamine antagonists
• Bromocriptine 2.5-10 mg TDS
• Dantrolene for severe cases
• Supportive care, hydration

Serotonin Syndrome:

• Discontinue serotonergic agents
• Cyproheptadine 12 mg initial, then 2-4 mg Q1-4h
• Benzodiazepines for agitation
• Active cooling if severe

Hypothermia Management in ICU

Mild (32-35°C):

• Passive rewarming (blankets, warm room)
• Forced air warming
• Warm IV fluids

Moderate (28-32°C):

• Active external rewarming (forced air, heating blankets)
• Warmed IV fluids (38-40°C)
• Warmed humidified oxygen
• Monitor for arrhythmias

Severe (<28°C) or Cardiac Arrest:

• ECMO/CPB for cardiac arrest (gold standard)
• Active internal rewarming (thoracic lavage, peritoneal lavage if ECMO not available)
• Continuous CPR until rewarmed
• Withhold defibrillation until core temp >30°C (unlikely to be effective)
• Space medications (metabolism impaired)

Australian Context:

• ECMO/CPB available at major centres
• Retrieval services (NETS, CareFlight, RFDS) for transport
• Remote/rural areas may require prolonged CPR during transport

---

Indigenous Health Considerations

Aboriginal and Torres Strait Islander Populations

Heat-Related Illness:

• Remote communities with limited access to air conditioning
• Overcrowded housing reducing heat dissipation
• Outdoor work exposure (agriculture, mining, construction)
• Cultural activities in heat (hunting, ceremony)
• Chronic disease burden (diabetes, CKD) increases vulnerability

Drowning and Hypothermia:

• 2.5-3× higher drowning rates than non-Indigenous Australians
• River/waterhole drowning common in remote areas
• Limited swimming and water safety education
• Delays in retrieval from remote locations

Cultural Considerations:

• Aboriginal Health Workers/Liaison Officers involvement essential
• Extended family involvement in decision-making
• Elder authority in healthcare decisions
• Sorry business protocols may affect timing of care discussions
• Language barriers - use interpreters
• Distrust of healthcare system - build rapport

Māori Populations (New Zealand)

Similar Vulnerabilities:

• 2-2.5× higher drowning rates
• Socioeconomic factors affecting housing, cooling access
• Outdoor occupation exposure

Cultural Protocols:

• Whānau (extended family) involvement
• Kaumātua (elder) consultation
• Tikanga (cultural protocols) considerations
• Manaakitanga (hospitality/respect) in care delivery

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SAQ Practice

SAQ 1: Thermoregulation and Fever (15 marks)

Question: A 68-year-old man is admitted to ICU with community-acquired pneumonia. His core temperature is 39.8°C.

a) Describe the normal physiological mechanisms of thermoregulation (5 marks) b) Explain the pathophysiology of fever at the molecular level (6 marks) c) Discuss the metabolic consequences of fever in the critically ill (4 marks)

Model Answer:

a) Normal Thermoregulation (5 marks)

The hypothalamus, specifically the preoptic area of the anterior hypothalamus, acts as the central thermostat. (1 mark)

Afferent Inputs:

• Peripheral thermoreceptors in skin (TRPV1, TRPM8 channels) via spinothalamic tract
• Central thermoreceptors sensing blood and core temperature
• Integration of warm-sensitive (~30%) and cold-sensitive (~5%) neurons (1 mark)

Heat Production Mechanisms:

• Basal metabolic heat (70-80W)
• Shivering thermogenesis (involuntary muscle contraction, increases metabolism 2-5 fold)
• Non-shivering thermogenesis (brown adipose tissue, UCP1) (1 mark)

Heat Loss Mechanisms:

• Radiation (40-60%): Infrared emission proportional to temperature gradient
• Convection (15-20%): Heat transfer to moving air/water
• Evaporation: Sweating (2-3 L/hr maximum), respiratory losses
• Conduction (<3%): Direct contact (1 mark)

Control:

• Set-point of 37°C (range 36.5-37.5°C)
• Circadian variation of 0.5-1.0°C
• Negative feedback loop maintains temperature within narrow range (1 mark)

b) Fever Pathophysiology (6 marks)

Exogenous Pyrogens:

• PAMPs (LPS, lipoteichoic acid) and DAMPs from pathogens and tissue damage
• Activate immune cells via pattern recognition receptors (TLRs) (1 mark)

Endogenous Pyrogens:

• Monocytes, macrophages, dendritic cells release cytokines
• IL-1β (most potent), IL-6, TNF-α, interferons
• Circulate to brain (1 mark)

Hypothalamic Action:

• Cytokines act on OVLT (organum vasculosum laminae terminalis)
• OVLT has fenestrated blood-brain barrier (circumventricular organ)
• Cytokines activate endothelial COX-2 (1 mark)

PGE2 Production:

• COX-2 converts arachidonic acid to PGH2
• PGE synthase converts to PGE2
• PGE2 is lipid-soluble, crosses into hypothalamus (1 mark)

Set-Point Elevation:

• PGE2 binds EP3 receptors on preoptic area neurons
• Inhibits warm-sensitive neurons
• Disinhibits cold-sensitive neurons
• Body perceives temperature as "too low" (1 mark)

Effector Response:

• Heat conservation: Vasoconstriction, piloerection, behavioural changes
• Heat production: Shivering, increased metabolism
• Body temperature rises to new set-point (explains "chills" during fever onset) (1 mark)

c) Metabolic Consequences (4 marks)

Increased Metabolic Demand:

• VO₂ increases 10-12% per 1°C above normal
• At 40°C: ~40% increase in metabolic rate
• Increased cardiac output (20% per °C) to meet demand (1 mark)

Oxygen Supply-Demand Mismatch:

• Increased O₂ consumption may exceed delivery capacity
• Particularly problematic in cardiac/respiratory disease
• May precipitate organ dysfunction (1 mark)

Protein Catabolism:

• Increased nitrogen losses
• Negative nitrogen balance
• May worsen sarcopenia and weakness (0.5 marks)

Fluid and Electrolyte:

• Increased insensible losses (sweating, tachypnoea)
• Risk of dehydration
• Electrolyte disturbances (0.5 marks)

Neurological:

• Delirium more common
• Febrile seizures in children
• Worsens outcome in brain injury (increased ICP, metabolic demand) (1 mark)

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SAQ 2: Heat Stroke and Drug-Induced Hyperthermia (15 marks)

Question: A 25-year-old male marathon runner is brought to the Emergency Department with altered consciousness and a core temperature of 42°C.

a) Explain the pathophysiology of exertional heat stroke (5 marks) b) Describe the key differences between heat stroke, malignant hyperthermia, and neuroleptic malignant syndrome (6 marks) c) Outline the emergency management of severe hyperthermia (4 marks)

Model Answer:

a) Exertional Heat Stroke Pathophysiology (5 marks)

Definition: Core temperature >40°C with CNS dysfunction due to exercise-induced heat production exceeding heat dissipation. (0.5 marks)

Heat Balance Failure:

• Strenuous exercise generates 15-20× resting metabolic heat
• Overwhelms thermoregulatory capacity despite normal set-point
• Exacerbated by hot/humid environment limiting evaporative cooling (1 mark)

Compensatory Responses (Initial):

• Cutaneous vasodilation (up to 8 L/min to skin)
• Profuse sweating (2-3 L/hour)
• Splanchnic vasoconstriction (blood shunted to skin)
• Cardiovascular stress (high-output state) (1 mark)

Decompensation:

• Direct cellular injury: Protein denaturation at >40°C, membrane instability
• Gut barrier failure: Splanchnic ischaemia → increased intestinal permeability → bacterial/LPS translocation
• Systemic inflammation: LPS triggers cytokine storm (IL-1, IL-6, TNF-α) (1 mark)

Multi-Organ Dysfunction:

• CNS: Cerebral oedema, neuronal injury
• Cardiovascular: Myocardial injury, hypotension
• Renal: ATN from rhabdomyolysis, hypoperfusion
• Hepatic: Centrilobular necrosis (delayed 24-72h)
• Haematological: DIC from endothelial activation (1 mark)

Paradox: Same cytokines that mediate fever in infection drive further inflammation in heat stroke, creating positive feedback. (0.5 marks)

b) Differentiation of Hyperthermia Syndromes (6 marks)

(2 marks for table structure with correct comparisons for at least 4 features)

Key Distinguishing Features:

• History and setting are critical (operating room vs psychiatric ward vs sports event) (1 mark)
• MH: ↑ETCO₂ is often first sign; masseter spasm with succinylcholine (1 mark)
• NMS: Extrapyramidal features, slow onset, psychiatric medication history (1 mark)
• Serotonin syndrome (additional differential): HYPERREFLEXIA and CLONUS distinguish from NMS (1 mark)

c) Emergency Management of Severe Hyperthermia (4 marks)

Immediate Priorities:

• Airway protection (if GCS reduced)
• IV access, monitoring
• Core temperature measurement (oesophageal, rectal) (1 mark)

Aggressive Cooling (Goal: <39°C within 30 minutes):

• Ice water immersion (most effective for exertional)
• Evaporative cooling: Spray water + fans
• Cold IV fluids (4°C crystalloid)
• Ice packs to axillae, groin, neck
• Invasive cooling catheters if available
• STOP cooling at 38°C (avoid overshoot) (1 mark)

Specific Treatments:

• Heat stroke: Cooling + supportive care; antipyretics INEFFECTIVE
• Malignant hyperthermia: STOP triggers + Dantrolene 2.5 mg/kg IV Q5min
• NMS: Bromocriptine 2.5-10 mg TDS ± dantrolene
• Serotonin syndrome: Cyproheptadine 12 mg then 2-4 mg Q1-4h (1 mark)

Supportive Care:

• Fluid resuscitation (correct hypovolaemia)
• Correct electrolytes (especially K⁺)
• Monitor for rhabdomyolysis (CK, myoglobinuria)
• Monitor for DIC
• ICU admission for monitoring and organ support (1 mark)

---

Viva Scenarios

Viva 1: Normal Thermoregulation and Fever

Examiner: "Tell me about the physiology of temperature regulation."

Candidate: "The hypothalamus, specifically the preoptic area of the anterior hypothalamus, acts as the body's central thermostat. It integrates temperature information from two sources:

• Peripheral thermoreceptors in the skin via the spinothalamic tract
• Central thermoreceptors sensing blood and core temperature

The hypothalamus contains warm-sensitive neurons (about 30%) and cold-sensitive neurons (about 5%) that compare current temperature against the set-point of approximately 37°C."

Examiner: "What are the mechanisms for heat production?"

Candidate: "Heat production occurs through:

1. Obligatory thermogenesis: Basal metabolic rate generates about 70-80 watts at rest
2. Shivering thermogenesis: Involuntary rhythmic muscle contractions at 10-20 Hz can increase metabolic rate 2-5 fold
3. Non-shivering thermogenesis: Brown adipose tissue using uncoupling protein-1 (UCP1) to dissipate the proton gradient as heat - more significant in neonates

The major heat-producing organs are liver (25%), brain (20%), skeletal muscle (25%), and heart (10%)."

Examiner: "And heat loss?"

Candidate: "Heat loss occurs through four mechanisms:

1. Radiation (40-60% at rest): Infrared emission proportional to the temperature gradient
2. Convection (15-20%): Heat transfer to moving air or water
3. Evaporation: Sweating can dissipate up to 580 kcal per litre evaporated, becoming the dominant mechanism at high ambient temperatures
4. Conduction (<3% in air): Direct contact heat transfer, but significant in water immersion due to water's thermal conductivity being 25 times that of air"

Examiner: "A patient in ICU develops a temperature of 39.5°C. Explain the pathophysiology."

Candidate: "Fever represents an elevation of the hypothalamic set-point, distinct from hyperthermia which is failure of heat dissipation with a normal set-point.

The pathophysiology involves a cascade:

1. Exogenous pyrogens such as LPS or bacterial components activate immune cells via pattern recognition receptors
2. Endogenous pyrogens - cytokines including IL-1β (most potent), IL-6, and TNF-α are released by monocytes and macrophages
3. These cytokines act on the OVLT, a circumventricular organ with a fenestrated blood-brain barrier
4. This activates endothelial COX-2 which converts arachidonic acid to prostaglandin E2
5. PGE2 binds to EP3 receptors on preoptic area neurons
6. This inhibits warm-sensitive neurons and disinhibits cold-sensitive neurons
7. The body perceives temperature as 'too low' and activates heat conservation and production mechanisms"

Examiner: "Why does the patient shiver and feel cold when the fever is rising?"

Candidate: "Because the set-point has been elevated. The actual body temperature is now below the new set-point, so the hypothalamus perceives the body as 'too cold'. This triggers heat conservation mechanisms - peripheral vasoconstriction giving cold, pale skin - and heat production mechanisms - shivering. The patient feels subjectively cold despite their core temperature already being elevated. This is why patients with rising fever feel 'chills' and want blankets."

Examiner: "Would you give antipyretics?"

Candidate: "The decision depends on clinical context. Antipyretics like paracetamol and NSAIDs work by inhibiting COX enzymes and blocking PGE2 synthesis.

Reasons to treat:

• Increased metabolic demand in patients with limited cardiac or respiratory reserve
• Traumatic brain injury or stroke where fever worsens outcome
• Patient discomfort
• Very high fever (>40°C) with risk of cellular damage

Reasons to consider withholding:

• Moderate fever (38-39°C) may enhance immune function
• There is no evidence that antipyretics improve survival in sepsis
• The HEAT trial showed no mortality difference with acetaminophen in ICU fever"

Examiner: "Excellent. What is the metabolic cost of fever?"

Candidate: "Oxygen consumption increases by approximately 10-12% for every degree Celsius above normal. At 40°C, metabolic rate is increased by about 40%. This also means increased CO₂ production, increased cardiac output (approximately 20% per degree), and increased minute ventilation. In patients with limited cardiorespiratory reserve, this can tip them into failure. Additionally, fever causes protein catabolism, increased insensible fluid losses, and in the brain-injured patient, worsens outcome through increased cerebral metabolic rate."

---

Viva 2: TTM and Hypothermia Management

Examiner: "A 55-year-old man is brought to the Emergency Department after out-of-hospital cardiac arrest with an initial rhythm of VF. He has ROSC after 25 minutes. Discuss temperature management."

Candidate: "This patient requires targeted temperature management as part of post-resuscitation care. The approach has evolved significantly based on recent evidence.

For patients with shockable rhythms like VF, the TTM2 trial published in 2021 compared targeted hypothermia at 33°C with targeted normothermia, maintaining temperature at or below 37.5°C. In 1,900 patients, there was no significant difference in 6-month mortality or neurological outcome.

Based on this evidence, for shockable rhythm cardiac arrest, current practice has shifted to:

• Aggressive fever prevention - maintaining temperature ≤37.5°C
• Avoiding hyperthermia (>37.5°C) for at least 72 hours
• Active cooling to 33°C is no longer routinely recommended as it offers no benefit and has more complications"

Examiner: "What if the initial rhythm was asystole?"

Candidate: "For non-shockable rhythms like asystole or PEA, the evidence is different. The HYPERION trial in 2019 randomised 584 patients with non-shockable rhythm cardiac arrest to 33°C for 24 hours versus 37°C.

The results showed a significant improvement in favourable neurological outcome at 90 days - 10.2% in the hypothermia group versus 5.7% in the normothermia group, with a number needed to treat of 22.

So for non-shockable rhythms, there may still be benefit from active cooling to 33°C, though overall outcomes are worse than for shockable rhythms. Clinical guidelines retain the option for either approach, and the decision may be individualised based on patient factors."

Examiner: "What are the proposed mechanisms of neuroprotection with hypothermia?"

Candidate: "Hypothermia provides neuroprotection through multiple mechanisms:

1. Reduced cerebral metabolic rate - approximately 7% reduction per degree Celsius below 37°C
2. Decreased excitotoxic neurotransmitter release - less glutamate-mediated injury
3. Reduced free radical production - less oxidative stress
4. Attenuated inflammatory response - reduced microglial activation
5. Decreased apoptosis - reduced programmed cell death pathways
6. Reduced blood-brain barrier permeability - less cerebral oedema
7. Anticonvulsant effect - decreased seizure activity"

Examiner: "The patient's core temperature is found to be 26°C. He was found in a river. How does this change management?"

Candidate: "This is severe accidental hypothermia, likely from cold water immersion. This dramatically changes the prognosis and management approach.

The key principle is: 'No one is dead until they are warm and dead.'

At 26°C:

• The heart is highly irritable and resistant to defibrillation
• Standard ACLS medications have impaired metabolism
• The patient may appear dead with fixed dilated pupils and no vital signs
• BUT there is potential for neurological recovery because hypothermia is neuroprotective

Management:

• Continue CPR - resuscitation efforts should not be abandoned
• ECMO or cardiopulmonary bypass is the gold standard for rewarming in cardiac arrest with severe hypothermia
• If ECMO unavailable, continue CPR with active internal rewarming (warmed IV fluids, warm humidified oxygen, bladder/peritoneal lavage)
• Withhold or space defibrillation attempts until core temperature >30°C as they are unlikely to be effective
• Space medications (reduced metabolism)
• Transfer to ECMO-capable centre while continuing CPR

There are remarkable survival cases, including Anna Bågenholm who survived with full recovery after 80 minutes of submersion with a core temperature of 13.7°C."

Examiner: "What ECG changes would you expect at 26°C?"

Candidate: "At this temperature, I would expect to see:

• Osborn waves (J-waves): Positive deflections at the J-point, at the junction of QRS and ST segment. They appear below 32°C and their height is proportional to the degree of hypothermia.
• Bradycardia: Sinus or junctional rhythm
• Prolonged PR interval
• Widened QRS
• Prolonged QT interval
• Possibly atrial fibrillation, which is very common at 28-32°C

The Osborn waves are caused by a temperature-dependent transmural voltage gradient in the ventricular myocardium, related to the Ito potassium current. They're present in about 80% of patients with temperature below 30°C, but are NOT pathognomonic - they can also be seen in hypercalcaemia and subarachnoid haemorrhage."

Examiner: "What is the cold-induced coagulopathy?"

Candidate: "This is a critical complication of hypothermia. The coagulation cascade enzymes are temperature-dependent and function poorly below 37°C.

There's a laboratory paradox: Standard coagulation tests (PT, aPTT) are performed at 37°C in the laboratory, so they may appear NORMAL. However, in the patient's cold blood, these enzymes are not functioning, and clinical coagulopathy is present.

The mechanisms include:

• Enzyme inhibition: Coagulation cascade enzymes have exponentially decreasing activity below 37°C
• Platelet dysfunction: Sequestration in liver and spleen, impaired aggregation, decreased thromboxane synthesis
• DIC-like state: In severe cases

This is particularly important in trauma where hypothermia, coagulopathy, and acidosis form the 'lethal triad' - each worsening the others in a positive feedback loop. This is why aggressive warming is critical in trauma patients."

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Related Topics

• Temperature Regulation Physiology
• Cardiac Arrest Management
• Post-Cardiac Arrest Care
• Rhabdomyolysis
• DIC and Coagulopathy
• MODS Pathology
• Sedation and Anaesthesia