I. What every physician needs to know.

Hyperthermia is an elevation in the body’s temperature due to excess generation of heat or the inability to dissipate heat. This process is not mediated by inflammatory cytokines like fever. Hyperthermia is frequently associated with medications that rapidly accelerate the body’s metabolism to generate heat or prevent the adequate elimination of excess heat.

Any patient with a core body temperature equal to 104°Fahrenheit (F) or greater should be evaluated for hyperthermia. It is unusual for infections in adults, with the exception of central nervous system infections, to cause a fever of 104°F or greater.

II. Diagnostic Confirmation: Are you sure your patient has hyperthermia?

Hyperthermia is confirmed through accurate core body temperature measurement. Core body temperature is most easily measured orally, rectally, or via tympanic membrane measurements. However, the most accurate measurements are via intravascular, esophageal, or bladder thermistors, although these are often not practical or available. Axillary temperature measurement is not recommended to confirm hyperthermia. Neuroleptic malignant syndrome and serotonin syndrome have clinical criteria for diagnosis.

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A. History Part I: Pattern Recognition:

Nearly all etiologies of hyperthermia are associated with mental status changes. The following additional features are associated with specific causes:

I. Neuroleptic malignant syndrome (NMS)

  • Rigidity in a patient taking antipsychotics or dopamine antagonists

II. Serotonin Syndrome

  • Hyperhidrosis

  • Agitation

  • Severe autonomic or neurologic derangement

III. Sympathomimetic poisoning/overdose

  • Severe adrenergic symptoms, such as hypertension and tachycardia

IV. Anticholinergic poisoning/exposure

  • Dry mouth

  • Lack of perspiration

  • Hypertension

V. Heat stroke (exposure hyperthermia)

  • Dry Skin

  • Delirium

  • Exposure to elevated ambient temperatures and/or severe exercise

VI. Central nervous system damage

  • May have sustained head trauma

  • May have meningeal signs (e.g. nuchal rigidity) associated with meningitis

VII. Endocrine (hyperthyroidism, pheochromocytoma)

  • Features of hyperthyroidism, such as tremulousness, irritability, tachycardia, hypertension, and evidence of recent weight loss may be present.

  • Severe hypertension and mood irritability may be present in a patient with pheochromocytoma.

B. History Part 2: Prevalence:

Deaths from hyperthermia are rare. The most common etiology is exposure to excessive heat, which results in approximately 500 deaths per year in the United States. Malignant hyperthermia associated with anesthesia causes approximately 400-500 deaths per year. All other causes of non-exposure hyperthermia results in approximately 200 deaths per year.

Patients older than age 65 are at greatest risk of dying from hyperthermia.

Men have twice the risk of dying from exposure hyperthermia compared to women.

C. History Part 3: Competing diagnoses that can mimic hyperthermia.

Fever must be considered. However, fevers caused by infections, with the exception of central nervous system (CNS) infections, rarely cause temperatures greater than 104° F. Drug fevers and some autoimmune diseases (Adult Still’s Disease) may present with temperatures greater than 104° F.

D. Physical Examination Findings.

  • Altered mental status including confusion and delirium is a key component of most presentations.

  • The lack of perspiration (heat stroke, anticholinergic toxicity) or the presence of excessive perspiration (serotonin syndrome) may point to a specific etiology.

  • Severe hypertension may be seen in a number of cases of hyperthermia, but is clearly associated with sympathomimetic toxicity and anticholinergic toxicity.

  • Hypotension may be seen with heat stroke.

  • Tachycardia is a feature of most causes of hyperthermia.

  • Muscle rigidity is key to making the diagnosis of neuroleptic malignant syndrome.

  • Nuchal rigidity may be seen with CNS infections (meningitis).

E. What diagnostic tests should be performed?

  • Core body temperature and vital signs must be measured. A detailed history is extremely important if it can be obtained, especially for potential drug-induced etiologies.

  • Blood cultures and a lumbar puncture should be performed if meningoencephalitis is being considered.

  • A creatine kinase or aldolase, although non-specific, is usually elevated in most etiologies of hyperthermia.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

  • Blood cultures and a lumbar puncture should be performed if meningoencephalitis is being considered.

  • A creatine kinase or aldolase should be ordered, although non-specific, these tests are usually elevated in most etiologies of hyperthermia.

  • If hyperthyroidism is being considered, a thyroid stimulating hormone (TSH) should be ordered.

  • If pheochromocytoma is being considered, a 24 hour urine collection for vanillylmandelic acid (VMA) can be ordered.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Imaging studies are not particularly helpful in diagnosing hyperthermia.

III. Default Management.

  • Any potential offending drugs should be stopped.

  • Active volume resuscitation with intravenous fluids should be started as soon as possible.

  • Active measures to lower body temperature below 101.4°F (38.5°Celsius):

    Application of ice packs to groin, axilla, and neck

    Evaporative cooling – spray naked patient with water or alcohol and then blow fans across patient

    Cooling blankets

    Immersion in cool water is an option, but may interfere with resuscitation

    Iced peritoneal or gastric lavage are options, but frequently associated with complications such as aspiration

    Extracorporeal bypass is an option of last resort

A. Immediate management.

The following measures may be taken if the etiology of the hyperthermia is determined:

Neuroleptic Malignant Syndrome (NMS)
  • Benzodiazepines (e.g. diazepam, lorazepam) for agitation

  • Dantrolene (IV) and bromocriptine (PO) used together may shorten the course

  • Electroconvulsive therapy (ECT) may be used for NMS from with malignant catatonia or Parkinsonism

Serotonin Syndrome
  • Benzodiazepines (e.g. diazepam, lorazepam) for agitation

  • Cyproheptadine to decrease serotonin production

  • If the temperature exceeds 105.8°F (41°C), intubation and neuromuscular paralysis should be considered

Sympathomimetic poisoning/overdose
  • Benzodiazepines for agitation

  • Nitroglycerin for chest pain

Anticholinergic poisoning/exposure
  • Treatment is generally supportive, but physostigmine may be used for severe cases.

  • Hyperthyroidism

  • Non-specific beta-blockers (propranolol)

  • Administer high-dose propylthiouracil (PTU)

  • Administer iodine compounds (Lugol’s solution, potassium iodide) at least one hour after initiating PTU

  • Administer high dose glucorticoids

Heat stroke (exposure hyperthermia)
  • Benzodiazepines for agitation

CNS damage
  • Begin antibiotics immediately if bacterial meningitis is suspected

B. Physical Examination Tips to Guide Management.

Patients with hyperthermia should be monitored closely for cardiac arrhythmias.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Patients with hyperthermia should be monitored for rhabdomyolysis and potential sequelae. The creatinine should be followed and fluids should be adjusted to maintain euvolemia and prevent the precipitation of myoglobin in the renal tubules.

D. Long-term management.

Drug-induced causes of hyperthermia require careful monitoring with re-initiation of any medications. An alternative should be used if appropriate. Otherwise, the lowest appropriate dose should be started and titrated under close supervision.

Heat stroke can be managed by avoidance of the circumstances that led to the prolonged exposure to heat (e.g. prolonged work or exercise). Ensuring adequate hydration is essential.

E. Common Pitfalls and Side-Effects of Management

  • Rapid correction of the temperature using a cool bath may result in severe peripheral vasoconstriction. Also, immersion in cool baths makes resuscitation difficult and should be a consideration if the patient is not hemodynamically stable.

  • Be sure to stop all cooling measures once the temperature is below 101.4o F (38.5o C) to prevent hypothermia.

  • Physostigmine is often associated with gastrointestinal side effects such as nausea, vomiting, and diarrhea. Dizzines and headache are also common.

  • Cyproheptadine is often associated with gastrointestinal side effects such as nausea, vomiting, abdominal pain, and diarrhea. Dry mouth and urinary retention are common. Agranulocytosis or thrombocytopenia may be seen with prolonged use.

  • Dantrolene may be hepatotoxic. It is often associated with an injection site reaction and often causes drowsiness and fatigue.

  • Bromocriptine often causes gastrointestinal side effects such as nausea, vomiting, diarrhea, constipation, and abdominal pain. Vasospasm, drowsiness, and fatigue are common. Bromocriptine may induce seizures and cardiac arrhythmias.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

Renal insufficiency may be caused by myoglobin from rhabdomyolysis in patients with hyperthermia. Intravenous fluids should be aggressively administered regardless.

B. Liver Insufficiency.

Caution with use of dantrolene because it can be hepatotoxic.

C. Systolic and Diastolic Heart Failure

Severe variation in core body temperature may precipitate arrhythmias. Vital signs and telemetry (when possible) should be monitored.

D. Coronary Artery Disease or Peripheral Vascular Disease

Severe variation in core body temperature may precipitate arrhythmias. Vital signs and telemetry (when possible) should be monitored.

E. Diabetes or other Endocrine issues

No change in standard therapy.

F. Malignancy

No change in standard therapy.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard therapy.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard therapy.

I. Gastrointestinal or Nutrition Issues

No change in standard therapy.

J. Hematologic or Coagulation Issues

Aggressive cooling may result in hypothermia and coagulation issues.

K. Dementia or Psychiatric Illness/Treatment

ECT may be used in Parkinson’s disease or malignant catatonia.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

  • Follow creatinine closely for evidence of myoglobin precipitation from rhabdoymyolysis

  • Will need close monitoring of mental status

  • Avoid all potential exacerbating agents

  • Maintain body temperature below 101.4° F

B. Anticipated Length of Stay.

The typical stay can vary between three days to two weeks. It may be longer if there is severe organ damage associated with the hyperthermia.

C. When is the Patient Ready for Discharge.

  • The patient has maintained his or her normal core body temperature without intervention for at least 24 hours.

  • Mental status changes have fully resolved.

  • Rhabdomyolysis is no longer an active issue and further intravenous fluids are no longer necessary.

  • There are no other acute organ injuries from the hyperthermia that have not been addressed (e.g. stroke, cardiac arrhythmias).

D. Arranging for Clinic Follow-up

If the patient needs to be restarted on an offending agent or a similar agent requiring titration, follow-up should be within two weeks.

1. When should clinic follow up be arranged and with whom.

  • Psychiatrist for those whose hyperthermia was caused by antipsychotics.

  • Neurologist for those with NMS.

  • Psychiatrist may be appropriate if serotonin syndrome involved selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors (MAOIs).

  • Endocrinologist for hyperthyroidism or pheochromocytoma.

  • Otherwise, primary care follow-up is appropriate. If the offending agents can be avoided and the patient has had a full recovery, follow-up can be within six months.

VI. Patient Safety and Quality Measures

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

The best way to avoid readmission is to avoid the medication and medication class that resulted in the hyperthermia. For those admitted for heat exposure, ensure appropriate hydration and avoidance of prolonged work or exercise in the heat.

What's the evidence?

O’Grady, N. “Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from American College of Critical Care Medicine and the Infectious Disease Society of America”. Crit Care Med. vol. 36. 2008. pp. 1330-1349.

Gruber, M. “Diagnosing neuroleptic malignant syndrome”. Chest. vol. 125. 2004. pp. 1960-1961.

Martinez, M. “Drug-associated heat stroke”. South Med J. vol. 95. 2002. pp. 799-802.

Marik, P. “Fever in the ICU”. Chest. vol. 117. 2000. pp. 855-869.

O’Neill, P. “Aging Homeostasis”. Rev Clin Geron. vol. 7. 1997. pp. 199-211.

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