Hyperthermia( NMS HH etc)

What are the two main causes of hyperthermia?

Environment-induced hyperthermia

• Heat-related illnesses (heat exhaustion and heat stroke)

Drug-induced hyperthermia(s)

• Malignant Hyperthermia

• Neuroleptic malignant syndrome

• Serotonin syndrome

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What is the difference between hyperthermia and fever?

• Fever:

  • Normal thermoregulatory system operating at a higher setpoint

• Hyperthermia:

  • Abnormal thermoregulation where thermoregulatory system is no longer able to maintain constant body temperature in response to thermal stress.

What is the genetic component of malignant hyperthermia?

• Autosomal dominant pattern if inheritance

• Mutation in the ryanodine receptor RYR1

What is the pathophysiology of MH?

• Occurs in response to volatile anaesthesia agents (Halothane/ Sevoflurane/ Desflurane) and/or depolarizing neuromuscular blockers/muscle relaxants (Succinylcholine).

• Excessive release of Ca2+ from sarcoplasmic reticulum in skeletal muscle that cause uncoupling of oxidative phosphorylation resulting in sustained excitation-contraction coupling.

• Sustained contraction and increased Ca2+ -ATPase activity results in increased metabolic rate and increased glycolysis (at first aerobic but as blood flow to muscles decreases the metabolism becomes anaerobic with onset of metabolic acidosis).

How does MH present?

• Generalized muscle rigidity → rhabdomyolysis → myoglobinuria → renal failure

• Hyperthermia (often >40°C, generated from muscle rigidity)

• Depressed consciousness → agitation → coma

• Autonomic instability: hypotension, arrhythmias

• Onset Within 2 hours of exposure

• Earliest:

  • Clinical: Masseter spams (non-specific and non-sensitive)

  • Monitors: ↑ in CO2 (hypercarbia disproportional to minute ventilation), tachycardia and rapidly rising temperature

How is MH managed?

• Stop offending agent (if using anaesthetic circuit → flush circuit) and increase minute ventilation (to blow of residual agent present)

• Dantrolene Sodium

  • Blocks release of Ca2+ from SR and cause muscle relaxation

  • 2.5mg/kg IV bolus stat followed by repeat boluses every 5-10 minutes (until hypercarbia and temperature respond)

  • Maximal initial dose: 10mg/kg (median required 6mg/kg)

  • Should be continued at 1mg/kg 4-6hrly for 24-48 hrs

  • Side-effects:

    • Risk of hepatocellular injury

    • Muscle weakness (resolves 2-4 days after stopping)

  • Failure to respond to dantrolene should prompt a search for alternative diagnosis

• Treat hyperkalaemia/metabolic acidosis with bicarbonate

• Cool patient to 36-38°C

• Identify and treat complications

  • Cardiac arrythmias:

    • Usually responds to correction of hyperkalaemia and acidosis

    • Avoid calcium antagonists, which may cause severe hyperkalaemia and cardiac arrest with high dose dantrolene

  • Rhabdomyolysis

  • DIC

What is Neuroleptic malignant syndrome?

Similar to Malignant Hyperthermia

Idiosyncratic reaction

Pathophysiology:

• Result from central dopamine antagonism (predominantly D2)

• In hypothalamus – results in hyperthermia

• In meso-cortical and nigrostriatal blockade – mental state changes and extrapyramidal symptoms

• Loss of central integration – autonomic instability

What are the features of NMS?

• 1st

  • Muscle rigidity (“lead-pipe rigidity”

  • Altered mental state (delirium ⇔ agitation ⇔ coma)

• Then (8-10hrs after)

  • Hyperthermia (>41°C but <42°C)

  • Autonomic instability (labile BP/persistent ↓BP)

• Onset:

  • Occurs within 24-72hrs after onset of drug action in the 1st 2weeks of introduction/dose increments

  • Gradual onset

What causes NMS?

• Drugs that inhibit dopaminergic transmission (in basal ganglia and hypothalamic-pituitary axis)

  • Anti-psychotic agents:

    • Haloperidol

    • Clozapine

    • Risperidone

• Anti-emetic agents:

  • Metoclopramide

  • Droperidol

• CNS stimulants:

  • Amphetamines

  • Cocaine

• Other:

  • Lithium/TCA overdose

• Discontinuation of drugs that facilitate dopaminergic transmission

  • Bromocriptine

  • Levodopa

What lab tests support NMS dx?

• ↑CK (>100IU/L)

• Leukocytosis >40000 (thus can be confused with sepsis)

• DIC

• AKI

• Neuroimaging and CSF normal

• EEG shows generalized slowing

How is NMS managed?

• Resuscitation – volume, sedation and neuromuscular blockade (may reduce severity of hyperthermia, rhabdomyolysis and other complications)

• Cessation of causative agent or re-introduction of withdrawn dopamine agonist

• Cooling to maintain <39°C

• Supportive care and management of complications:

  • Respiratory failure (hypoventilation or aspiration)

  • Rhabdomyolysis

  • AKI

  • DIC

  • Arrhythmias

• Potential adjunctive therapies:

  • Benzodiazepines/central alpha agonist for agitation

  • Benzodiazepines for seizures or catatonia

  • Bromocriptine 2.5-5mg po 8-hrly for up to 10 days after clinical resolution (reduces extrapyramidal symptoms and mortality BUT may worsen hypotension/psychosis)

  • Dantrolene in severe cases

  • Heparin prophylaxis (very high risk for VTE)

What causes serotonin syndrome?

• Due to overstimulation of serotonin receptors in the central nervous system (via 5HT2A receptors)

What are features of SS?

• Mental status changes

• Hyperthermia

• Autonomic hyperactivity (tachycardia, hypertension, mydriasis)

• Neuromuscular abnormalities (hyperkinesis, hyperreflexia, clonus and muscle rigidity)

Discuss pathophysiology of SS?

• ↑ serotonin synthesis:

  • Tryptans

• ↓ serotonin breakdown

  • MAOIs (incl. linezolid and methylene blue)

  • Ritonvir

• ↑ serotonin release:

  • Amphetamines

  • MDMA

  • Cocaine

• ↓ serotonin reuptake:

  • SSRIs and SNRIs

  • TCA

  • Fentanyl

  • Tramadol

• Serotonin receptor agonists:

  • Lithium

  • Buspirone

  • Sumitriptan

  • LSD

When is onset of SS?

• Abrupt

• Within 6 hours of drug intake

What is criteria used for dx of SS?

• Hunter Serotonin toxicity criteria to diagnose serotonin syndrome:

  • Patient has taken serotonergic agent AND

  • Meets one of the following criteria:

    • Spontaneous clonus

    • Inducible clonus + [agitation or diaphoresis]

    • Ocular clonus + [agitation or diaphoresis]

    • Tremor + hyperreflexia

    • Hypertonia + temperature >38°C + [ocular clonus or inducible clonus]

What are features of SS?

• Hyperreflexia

• Lower limb or ocular clonus

• Myoclonus

• Rigidity mainly in lower limbs

How is SS managed?

• Stop and remove offending drug

• Resuscitation

• Cooling

• Supportive care:

  • Control agitation

    • Benzodiazepines

    • Avoid restraints (it encourages muscle contraction and aggravates the muscle injury that worsens rhabdomyolysis and promotes lactic acidosis)

• Serotonin antagonists

  • Cyproheptadine (5HT2A agonist) 4-8mg po 6-hrly– use in severe cases

• Neuromuscular paralysis

  • May be required to control muscle rigidity and ↑ temp >41°C

  • NB:

    • Dantrolene does NOT work for muscle rigidity/hyperthermia in serotonin syndrome

  • Do NOT use succinyl choline – it aggravates hyperkalemia associated with rhabdomyolysis

  • Use non-depolarizing agents i.e. vecuronium