HYPERTHERMIA

    DEFINITION

    Hyperthermia is a body core temperature in excess of 40.0°C.

    TOXIC CAUSES

    Anticholinergic Agents
         Antihistamines
         Atropine and related alkaloids

    Antidepressants
         Monoamine oxidase inhibitors (overdose and interactions with
           serotonin reuptake inhibitors)
         Tricyclic antidepressants

    Antipsychotics
         Butyrophenones
         Lithium
         Loxapine
         Phenothiazines (mainly flufenazine)

    Drugs of abuse
         Amphetamines and related compounds
         Cocaine
         Phencyclidine

    Drug withdrawal
         Barbiturates
         Benzodiazepines
         Ethanol

    Natural toxins
         Lactrodectus species

    Strychnine

    Sympathomimetic and anorectic agents

    Thyroid Hormones
         Thyroxine (T4)
         Tri-iodo-thyronine (T3)

    Uncouplers of oxidative phosphorylation
         Ioxynil
         Nitrophenols and pentachlorophenol
         Salicylates

    NONTOXIC CAUSES

    Brain tumors
    Heat stroke
    Hypoxic brain damage may result in thermodysregulation
    Infections (viral, bacterial, rickettsial, malaria, etc)
    Status epilepticus
    Thyroid storm

    CLINICAL FEATURES

    The key investigation is the core temperature (usually the rectal
    temperature; oral and axillary temperatures are not reliable).
    Clinically, the patient may be sweating profusely due to
    thermoregulation or the skin may be dry, due to anticholinergic agents
    or dehydration.

    Sustained hyperthermia leads to several serious acute complications. 
    Hypovolaemia from sweating and vasodilation reduces cardiac output and
    hinders thermoregulation. Muscle breakdown leads to hyperkalaemia,
    myoglobinuria, and acute renal failure. Endothelial damage results in
    disseminated intravascular coagulopathy.  Most importantly, sustained
    hyperthermia causes acute brain damage and convulsions.
    Non-cardiogenic pulmonary oedema (adult respiratory distress syndrome)
    also may occur.  Death is often sudden and probably the result of a
    cardiac arrhythmia. 

    Initially, signs and symptoms may differ according to the drugs
    involved. For example. anticholinergic agents are usually associated
    with warm, dry skin, while sympathomimetic agents (e.g., amphetamines,
    cocaine) are more likely to present with pale, moist skin, tremors,
    and convulsions.  Several heat illness syndromes have been
    well-described:

     Malignant Hyperthermia (MH)

    An inherited syndrome in which certain anaesthetic agents cause
    widespread muscle cell contraction leading to massive heat production
    and acute lactic acidosis. Common causes include: Enflurane,
    Halothane, Isoflurane, and Succinylcholine.

     Neuroleptic Malignant Syndrome (NMS)

    A syndrome characterized by mental confusion, muscle rigidity,
    diaphoresis, and hyperthermia in patients taking potent antipsychotic
    drugs. May occur after first dose or during regular treatment.
    Mechanism is thought to be related to CNS dopamine blockade.

     Serotonin Syndrome

    Occurs when serotonin reuptake inhibitors (eg, fluoxetine, paroxetine,
    venlafaxine, sertraline, tryptophan, dextromethorphan, meperidine) are
    given to a patient taking a monoamine oxidase inhibitor. 
    Characterized by agitation, muscle hyperactivity, and hyperthermia.

    RELEVANT INVESTIGATIONS

    Arterial blood gases
    Plasma biochemical parameters
         urea nitrogen
         creatinine
         electrolytes
         creatine phosphokinase activity (CPK)
         platelet count
         fibrinogen level
         partial thromboplastin and prothrombin times

    Drug screening may be indicated depending on the suspected causes.
    Investigations to exclude other causes of pyrexia and hypermetabolism
    (e.g., thyroid crisis, severe bacterial or viral infection, malaria).

    TREATMENT

    Stop exposure to any triggering factors 

     Control of Muscle Hyperactivity

    It is essential to control muscle hyperactivity as quickly as possible
    to prevent further heat production.

    1.   Treat convulsions aggressively.
    2.   In some cases the agitated patient may respond to  diazepam, 5
         to 20 mg IV or another benzodiazepine.  Older literature
         suggested use of chlorpromazine, which provides sedation as well
         as promoting vasodilation, but this drug may lower the seizures
         threshold and can cause hypotension, especially if the patient is
         hypovolaemic.
    3.   Patients with suspected  malignant hyperthermia should be
         treated with  dantrolene, 1 to 5 mg/kg IV, repeated up to a
         total of 10 mg/kg IV. Dantrolene has also been reported
         successful in the management of other causes of hyperthermia
         associated with muscle rigidity, such as neuroleptic malignant
         syndrome and exertional heatstroke associated with amphetamine
         intoxication.
    4.    Neuroleptic malignant syndrome has been treated effectively
         with  bromocriptine, 2.5 to 10 mg orally or by gastric tube 2 to
         6 times per day (5 to 30 mg per day). 
    5.   In patients with persistent muscle rigidity or hyperactivity
         despite these measures, institute neuromuscular paralysis with a
         non-depolarizing agent (e.g.,  pancuronium, 5 to 10 mg IV) and
         controlled ventilation.

     Cooling Methods

    1.   Sponging and spraying with medium temperature water, along with
         fanning promotes heat loss through evaporative cooling.
    2.   Cooling blankets (hypothermic blankets) or iced saline gastric
         lavage may be appropriate.
    3.   Care for patient in relatively cool environment.
    4.   Antipyretic medications (e.g. salicylate, paracetamol) are
         ineffective in most cases.
    5.   Extracorporeal circulation cooling may be considered.

     Other general measures

    Give supplemental high-flow oxygen.
    Correct hypoglycaemia, and provide supplemental glucose intravenously.
    Most patients are hypovolaemic: give 1 to 2 liters of IV fluids (e.g.,
    saline) and monitor volume status and urine output.
    Correct electrolyte and metabolic imbalance.

    CLINICAL COURSE AND MONITORING

    Core temperature and response to cooling measures.
    State of hydration and central venous pressure.
    Electrolytes, urea nitrogen, creatinine, potassium, calcium, CPK.
    Platelet count, fibrinogen level and  prothrombin times
    ECG

    LONG-TERM COMPLICATIONS

    Brain injury
    Renal failure

    AUTHORS/REVIEWERS

    Author:        Based on information provided by J. Henry (UK)

    Peer review:   Cardiff 3/95.
                   Berlin 10/95: A. Wong, T. Meredith, V. Danel
                   Cardiff  9/96: V. Afanasiev, M. Burger, T. Della Puppa,
                   L. Fruchtengarten, K. Olsen, J. Szajewski.