Hyperthermia

by Puneet Sharma

 

Introduction

Hyperthermia is elevated body temperature. It generally due to failed thermoregulation which occurs when a body produces or absorbs more heat than it disseminates. Extreme temperature elevation then becomes a medical emergency requiring immediate treatment to prevent disability or death.

Temperature greater than 37.5–38.3 °C (99.5–100.9 °F) depending on the reference used is, hyperthermia, with severe hyperthermia being greater than 40°C(104°F). Different sources have different cut-offs.

Hyperthermia differs from fever in that the body’s temperature set point remains unchanged. When the core temperature is set higher, fever occurs. The action of the pre-optic region of the anterior hypothalamus in response to infection sets the core temperature. Hyperthermia, however, occurs when the body temperature rises without a change in the heat control centers.

 

Causes of Hyperthermia

Failure of hhermal homeostasis and increased heat production

  • Exercise-associated hyperthermia:- a continuum of heat-related conditions due to environmental heat and exercise.
    • Heat stress/cramps
    • Heat exhaustion
    • Heatstroke
  • Seizures
  • Agitation
  • Uncoupling of oxidative phosphorylation- e.g., Salicylate overdose.
  • Hepatic Metabolism stimulation-e.g -sympathomimetic drugs

Hyperthermia secondary to other processes

  • Neuroleptic Malignant Syndrome(NMS) – link
  • Serotonin Toxicity/syndrome(SS) – Serotonin TOXICITY – link
  • Malignant Hyperthermia (MH) – link

Differential Diagnoses

There are multiple differentials to the cause of hyperthermia. A good history from the patient (if possible), carers or relatives is crucial to the diagnosis. Few important differentials to consider in ED are:

  • Central nervous system infections,
  • Status epilepticus,
  • Stroke,
  • Brain trauma,
  • Neoplasms,
  • Acute intermittent porphyria,
  • Tetanus,
  • Thyroid Storm
  • Heat stroke,
  • Sepsis.
  • SSRI toxicity and other drug toxicities,
  • pheochromocytoma.

Malignant Hyperthermia (MH)

Incidence is about 1:10000-15000. All races are affected.
Mortality rates have fallen from 70-80 % to 2-3 % due to increase awareness, monitoring standards, and Dantrolene.

Genetically inherited disorder (autosomal dominant). About 70% of families are linked to the RYR1 gene located on chromosome 19q. Triggering drugs cause a release of sarcoplasmic reticulum Ca2+. Resulting ca2+ stimulated glycolysis, muscle contraction, uncoupling of oxidative phosphorylation leading to hyperthermia. Drugs causing MH are volatile inhalation halogenated anesthetics and muscle relaxant suxamethonium.

Pathophysiology

The usual body temperature of humans is between 36° C and 37.5°C.
When Core Body temperature (Rectal temperature/esophageal temperature) is greater than about 41.5°C it results in:

  • Progressive denaturing of number of vital cellular proteins.
  • Failure of vital energy-producing process in the cells like oxidative phosphorylation and failure of enzyme function.
  • Loss of cell membrane function with increasing permeability.

Tissues most at risk are:

  • Vascular endothelium
  • Nervous tissue
  • Hepatocytes

At organ level hyperthermia manifests as :

  • Rhabdomyolysis
  • Electrolyte disturbance
  • Renal and Liver failure
  • Cardiovascular dysfunction
  • Acute Pulmonary edema with ARDS (acute respiratory distress syndrome)
  • Disseminated intravascular coagulation ( DIC)
  • Neurological damage

Clinical Features

  • Failure to achieve muscle relaxation following succinylcholine, e.g., master spasm impeding intubation and persisting for 2 minutes.
  • Signs of increased metabolism: Tachycardia, Tachypnoea, dysrhythmia, increased CO2 production noted on the end-tidal CO2 monitor
  • Metabolic acidosis, rhabdomyolysis and hyperthermia and DIC.
  • Signs and symptoms may be delayed or may reappear after successful treatment.

Neuroleptic Malignant Syndrome(NMS) and Serotonin Toxicity/syndrome(SS)

Occurs due to increased motor activity and central resetting of hypothalamic thermostat

Neuroleptic Malignant Syndrome(NMS)

There is Dopamine depletion/dopamine receptor (D2) blockade in the hypothalamus, nigrostriatal pathways and spinal cord which leads to increased muscle rigidity and tremor via extrapyramidal pathways.
Hypothalamic D2 blockade leads to elevated temperature set point and impairment of heat dissipation. This is an idiosyncratic reaction to neuroleptic agents. All classes of antipsychotics have been associated with neuroleptic malignant syndrome, most frequently in patients taking haloperidol and chlorpromazine. It occurs in response to a single agent and may occur in therapeutic dosages. It maybe dose-related and more commonly seen in patients on higher dose, depot neuroleptics.

Clinical Features

Usually develops in patients who have recently started a neuroleptic treatment or have recently increased the dose. The onset of the symptoms is 4-14 days after the first day of therapy; most of the cases occur within 10 days. Usually associated with almost all antipsychotics and also in patients in whom dopaminergic agents have been withdrawn (e.g., in Parkinson ’s). Similar to Serotonin syndrome, there is a latent period of several hours to days.

Four Classic Signs

  1. Hyperthermia >38° C
  2. Severe Muscular rigidity (typically “lead pipe” rigidity)
  3. Altered mental state
  4. Autonomic instability

There is a broad spectrum of clinical illness; Diaphoresis,Pallor ,Dysphagia ,Dyspnea ,Tremor ,Incontinence ,shuffling gait, agitation ,delirium progressing to lethargy, stupor, coma

Examination findings showing autonomic dysregulation include:

  • Diaphoresis ,sialorrhea ,tachycardia ,tachypnea, respiratory distress ,hypertension / labile blood pressure ,hypoxia.

Good drug history may help to differentiate between the NMS and Serotonin syndrome.

Serotonin syndrome

There is excess CNS (Central Nervous System) Serotonin (5HT- 5Hydroxy Tryptamine) due to multiple mechanisms based on different 5HT receptors in the brain.

SS is most often caused by simultaneous ingestion of 2 or more serotonergic medications.There may be a recent history of dose increase. Excess serotonergic activity can be precipitated by any of the following mechanisms and drugs (ones in bold seen commonly in ED as overdose):

  • Direct 5HT-receptor stimulation — Buspirone, triptans, lithium, carbamazepine, lysergic acid diethylamide (LSD), mescaline-containing cacti (peyote and others).
  • Direct 5HT release from stored vesicles — Amphetamines, MDMA, cocaine, reserpine, levodopa, MAOIs(monoamine oxidase inhibitors), codeine, dextromethorphan, pentazocine.
  • Increased availability of 5HT precursors — L-tryptophan.
  • Decreased 5HT reuptake — SSRIs(slow serotonin reuptake inhibitors), trazodone, nefazodone, venlafaxine, TCAs(Tricyclic antidepressants), dextromethorphan, tramadol, meperidine, (, Hypericum species (St. John’s wort), amphetamines, carbamazepine, methadone, linezolid.
  • Decreased 5HT degradation — MAOIs, St. John’s wort.

Clinical Features

CNS, Autonomic and Motor Dysfunction related features

  • Agitation, anxiety, confusion, decreased level of consciousness, seizures
  • Clonus, Hyperreflexia, Hypertonia, Incoordination, Myoclonus, Tremor
  • Diaphoresis, Diarrhoea, Hypertension, Hyperthermia, Tachycardia
    mydriasis, piloerection, and muscular rigidity
  • CVS features include sinus tachycardia, flushing, hypertension, and hypotension (rare).
  • Citalopram causes dose-dependent QT prolongation.

Develops after a latent period, ranging from few hours to several days.
Most patients are mildly affected, but the disease spectrum is very broad.
Most cases resolve within 24-48 hours after withdrawal of the precipitating agent.

Workup

Diagnosis of hyperthermia disorders is based on a detailed history, clinical picture, and exclusion of alternative diagnoses. Drug history is very important and clinical suspicion is paramount. Investigations are directed towards the exclusion of other causes of pyrexia, e.g., sepsis and other disorders
Investigations are done to rule out complications and guide treatment.

  • Serum electrolytes- to check imbalance and supportive treatment
  • Creatinine Kinase – Guides treatment of Rhabdomyolysis.
  • Serum Glucose – Rule out hypo/ hyperglycemia as the cause of altered mental state.
  • ECG- arrhythmia, electrolyte abnormalities.
  • Urine- Toxins
  • Multiorgan dysfunction workup
    • Clotting screen- coagulopathy (DIC)LFT’s, Renal functions- detect complications such as AKI(Acute Kidney Injury) and rhabdomyolysis.
  • Cardiac enzymes.
  • Chest X-ray- To investigate complications and rule out the differential diagnosis.
  • Specialist investigation:
    • Muscle biopsy using in-vitro contracture test (IVCT) which is the gold standard for MH diagnosis. This is done in specialized MH centers. 8 to 10 muscle specimens are taken and considered positive if muscle contracts to halothane and/or caffeine

Treatment

Supportive and cooling measures for hyperthermia in general

  • Evaporative cooling- Remove all clothing, and spray the patient with tepid water while blowing air with a fan. Areas with increased vascular beds, e.g., neck, axillae, groins should be asked with ice packs.
  • Iced water immersion: – Can cause awkward patient access and difficulty in monitoring. Not very practical in the Emergency Department.
  • Invasive methods: Cold IV fluids, urinary bladder lavage, peritoneal/pleural lavage with cold fluid.

Serotonin Syndrome( SS)

  • Mild cases- May need observation in ED for a few hours and safely discharged if asymptomatic.
  • More serious cases would need supportive treatment and pharmacological therapy with observation and treatment for complications in ICU.
  • Pharmacological Therapy
    • Mild SS- No treatment is needed or small doses of benzodiazepines.
    • Severe SS: Neuromuscular paralysis should be considered early especially in cases with a low GCS.
    • Antiserotoninergic drugs:
      • Chlorpromazine- 12.5-50mg IM/IV
      • Cyproheptadine- 4-8mg orally 8 hourly.

Neuroleptic Malignant Syndrome

  • Benzodiazepines for anxiety and agitation.
  • Stop all neuroleptics
  • Correct volume depletion and hypotension with intravenous fluids
  • Reduce hyperthermia (see above)
  • Alkalinization of urine with sodium bicarbonate for prevention of renal failure following rhabdomyolysis.
  • Bromocriptine as dopamine agonist can be given orally/NG tube, 2.5-10mg TDS.

Malignant Hyperthermia

  • Avoiding the triggering agents prevents MH.
  • Using inhalation agent free machines during anesthesia.
  • Dantrolene Sodium- Inhibits the release of calcium from the sarcoplasmic reticulum.
    • 2.5mg /kg IV initially repeated every 15 minutes to maximum 30mg/ kg.
      AAGBI guidelines for treatment of MH poster link

Prognosis and Disposition

  • Early intensive care referral is indicated.
  • Prognosis is worse with complications and multi-system failure.
  • Mortality remains high in this group if untreated.
  • Malignant hyperthermia: Modification of anesthesia in the future with inhalation agent free machines and no use of suxamethonium. Family members should be tested for susceptibility.

References and Further Reading

  • Fever and hyperthermia difference
    https://medicine.ucsf.edu/education/resed/Chiefs_cover_sheets/april11_fever_hyperthermia.pdf
  • Emergency Medicine – Hyperthermia: By Anjali Hulbanni M.D. and Mudassir Khan M.D. – https://www.youtube.com/watch?v=u5LmpK3gS6E&feature=youtu.be
  • Hyperthermia – Chris Nickson, Last updated August 11, 2014 – https://lifeinthefastlane.com/ccc/hyperthermia/
  • Hyperthermia Syndromes – http://rebelem.com/hyperthermia-syndromes/
  • Malignant Hyperthermia – https://emedicine.medscape.com/article/2231150-overview
  • Cooling Techniques for Hyperthermia – https://emedicine.medscape.com/article/149546-overview
  • Malignant Hyperthermia Crisis
  • AAGBI Safety Guideline – https://www.aagbi.org/sites/default/files/MH%20guideline%20for%20web%20v2.pdf
  • Neuroleptic Malignant Syndrome – https://emedicine.medscape.com/article/816018-overview