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Fever: Evidence Based Practice

3 Contact Hours including 3 Advanced Pharmacology Hours
This peer reviewed course is applicable for the following professions:
Advanced Registered Nurse Practitioner (ARNP), Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Midwife (MW), Nursing Student, Registered Nurse (RN)
This course will be updated or discontinued on or before Saturday, February 18, 2023
Outcomes

≥92% of participants will know current evidence-based fever treatment.

Objectives

After completing this module the learner will be able to:

  1. Explain the process of temperature regulation.
  2. Explain how and why fever is initiated.
  3. Explain limitations, advantages of methods of measuring body temperature.
  4. Identify methods of fever reduction.
  5. Explain evaluation and treatment of fever, focusing on two specific age groups.
CEUFast Inc. did not endorse any product, or receive any commercial support or sponsorship for this course. The Planning Committee and Authors do not have any conflict of interest.

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To earn of certificate of completion you have one of two options:
  1. Take test and pass with a score of at least 80%
  2. Reflect on practice impact by completing self-reflection, self-assessment and course evaluation.
    (NOTE: Some approval agencies and organizations require you to take a test and self reflection is NOT an option.)
Author:    Dana Bartlett (RN, BSN, MA, MA, CSPI)

Introduction

Fever is a common alteration of the vital signs, and fever is a very common complication of infectious diseases. Fever can also be caused by non-infectious diseases, inflammation, injury, and by drugs. Many hospitalized patients will present with a fever; many patients develop a fever at some point during their hospital stay (Chiumello et al., 2016; Doyle et al., 2016; Nakajima, 2016; Dai et al., 2012). Fever is also one of the most common signs of illness in children (Peetom et al., 2016), and the care and treatment of patients with fever occupy a considerable amount of time for many nurses.

But despite this extensive experience, there are important questions about fever that are unanswered, and even healthcare professionals have misconceptions about the adverse effects of a fever and disagree about when and how a fever should be treated (Brick et al., 2017; Lava et al., 2016; Schortgen et al., 2012). In most cases, a fever will not cause harm, and it may be helpful. In addition, fever reduction is often not needed and may be harmful. In certain clinical situations, fever reduction can be beneficial, and nurses need to know when and how fever reduction should be done. For very young children who are febrile and the elderly patient who has a fever, the evaluation process must consider specific information about the risks of fever and signs and symptoms that are specific to those groups.

Learning Break:
Fever and hyperthermia are not interchangeable terms: they are different and distinct processes. Hyperthermia and other clinical conditions characterized by an elevated body temperature will be briefly discussed later in the module.

Case Studies

Case Study 1

A 56-year-old male comes to the emergency room, and he reports that he has had abdominal pain, anorexia, diaphoresis, fever, and vomiting for five days before arrival. He has a past medical history of alcohol abuse and hypertension. The patient's temperature is 39.8°C (measured rectally), his pulse is 116, his blood pressure is 78/40 mm Hg, and his respiratory rate is 28. He is pale, diaphoretic, and his extremities are cool to the touch. The laboratory test results are normal except for a white blood cell count of 19,000/μL.

Because of the fever, hypotension, tachypnea, and leukocytosis, septic shock is diagnosed. Blood and urine cultures are obtained, an IV infusion of Ringer's lactate is started, therapy with several broad-spectrum antibiotics is started, and the patient is assigned a bed in the intensive care unit (ICU). Three hours after arrival at the hospital, the infection source is unknown; the physician suspects necrotizing pancreatitis, but more diagnostic tests need to be done. The physician asks the nurse to give the patient an acetaminophen suppository, 650 mg. She also orders a cooling blanket to be applied, and a rectal probe monitors the patient's temperature.

The physician makes a point of telling the nurse that the acetaminophen should be given before external cooling is started. The physician also informs the nurse that the current research does not provide strong evidence of a beneficial or a detrimental effect of fever control in all critical patients. However, there is a lot of strong evidence suggesting that lowering body temperature in septic shock cases may decrease the mortality rate, decrease the need for vasopressors, and improve outcomes. The physician advises the nurse to watch the patient closely for signs that cooling is proceeding too fast. Cooling techniques can lower body temperature quickly, but temperature probes "lag" behind in the reading.

Case Study 2

A three-year-old boy is brought to the emergency room by his parents. The parents report that for the past two days, the child has had a fever as high as 102°F, he has been listless, and his oral intake has been well below normal. The child has no prior medical history and does not take any prescription medications. The parents have been giving the child acetaminophen whenever his temperature was above 99°F because they had read on the internet that a high fever can cause permanent brain damage and seizures, and that "the normal temperature should not be higher than 98.6°F". Neither parent can remember how much acetaminophen they give the child with each dose or how often they have given it. The mother says, "you can buy acetaminophen at any drug store, and they wouldn't sell it over-the-counter if it weren't safe." They have also been giving the child ibuprofen "every once in a while" because again, they had read on the internet that using acetaminophen and ibuprofen was a better way to lower fever than using either one alone.

After reviewing the history of the current illness and examining the child, the physician diagnoses otitis media and prescribes an antibiotic. The physician informs the parents that a temperature of 102°F is not unusual in otitis media cases. She also tells the parents:

  • A high fever in a child who has a simple infectious process will not cause brain damage
  • Treating a fever will not prevent febrile seizures
  • Lowering a fever caused by a simple, self-limiting infectious process will not decrease the time it takes for the illness to resolve
  • Fever is a defense mechanism, and fever may decrease an infectious illness's length
  • A fever can be treated if it is > 100.4°, but this is an arbitrary number and lowering the fever is not the goal

The goal is to lower the fever to make the child comfortable and help increase oral intake. The physician advises the parents that there is no evidence that alternating antipyretics is more effective than using one alone. Overusing over-the-counter antipyretics, especially acetaminophen given to a child with a fever, can be dangerous and cause liver damage.

Definition of Fever

Fever is an elevation of body temperature at or above a specific point. The definition of a fever varies depending on the source, the patient's age, time of day, and how temperature is measured. Several definitions of fever are provided in Table 1 (Smitherman et al., 2017; Ward, 2016; Kasper et al., 2016).

Table 1: Definitions of Fever
Neonates to three months of ageRectal temperature ≥38.0ºC (100.4ºF)
Three months to 36 monthsRectal temperature from ≥38.0 to 39.0ºC (100.4 to 102.2ºF)
Older children and adultsOral temperature ≥37.8 to 39.4ºC (100.0 to 103.0ºF)

Fever is an elevated body temperature with a specific cause distinct from other mechanisms that increase body temperature. Also, in certain clinical situations, a body temperature of < 38°C should be considered a fever. This point will be discussed later in the course.

Celsius and Fahrenheit Scales

The letter C indicates that the temperature was measured using the Celsius scale; the letter F indicates that the temperature was measured using the Fahrenheit scale. Either scale can be used, but the Celsius scale is more commonly used by medical personnel than the Fahrenheit. Celsius will be used in this course when referring to body temperature. Conversion tables or calculations are available by internet search.

To convert Fahrenheit to Celsius:

  • Subtract 32 from the temperature in degrees Fahrenheit
  • Multiply the result from step 1 by 5
  • Divide the result from step 2 by 9

Example:

  • 100°F – 32 = 68
  • 68 x 5 = 340
  • 340 ÷ 9 = 37.7°C

To convert Celsius to Fahrenheit:

  • Multiply the temperature in degrees Celsius by 9
  • Divide the result from step 1 by 5
  • Add 32 to the result from step 2

Example:

  • 36°C x 9 = 324
  • 324/5 = 64.8
  • 64.8 + 32 = 96.8°F

Normal Temperature Variations and Measurement

Normal body temperature ranges from >37.2°C/98.9°F in the morning and >37.7°C/99.9°F in the evening. This variation is due to variation in the hypothalamic set point. Children normally have a higher body temperature than adults. Menstruating women have a greater variation in the range of body temperature than other adults, especially in the two weeks before and during ovulation. Older adults typically have a lower body temperature than adults and children. During strenuous exercise, the body temperature can be as high as 40°C, and strenuous exercise can increase heat production to 20 times the normal level.

Measurement of body temperature is an attempt to determine the core temperature. Core temperature is the temperature of the organs and structures deep within the body. Normal temperature is where the body functions best. Body temperature can be measured invasively or non-invasively. Body temperature methods are all accurate and consistent if done correctly, but they are all subject to operator error.

  • Oral measurement is usually an accurate and reliable method of determining body temperature, and it is convenient. Oral temperature readings are lower than the core temperature, and many variables can affect the reliability and accuracy. Oral temperatures are usually lower than rectal temperatures.
  • Rectal measurement is the commonly used method that most accurately and consistently reflects core temperature.
  • Tympanic temperature measures the heat of the tympanic membrane and the ear canal, and they are typically lower than the rectal temperature. A tympanic thermometer is less accurate in children less than three months old if it is not placed properly in the ear canal or if excessive cerumen is present (Treitz et al., 2016).
  • Axillary measurement is typically lower than an oral or rectal temperature.
  • Temperature strips (Tempa•Dot™) are small plastic strips placed in the mouth, on the forehead, or under the axilla.
  • Skin temperature sensors placed over the carotid artery accurately measure core temperature. This method provides accurate and consistent readings, albeit slightly lower than rectal measurement (Imani et al., 2016).
  • Temporal artery thermometers measure heat emitted from the temporal artery. The temporal artery is highly perfused. This method of obtaining a temperature is an accurate way of estimating core temperature. It compares well with other methods.
  • Bladder temperature sensors provide an accurate measurement of body temperature. A small study found that a urinary bladder sensor was more accurate than rectal or axillary body temperature measurements.
  • Esophageal temperature probes provide an accurate measurement of core temperature, but the accuracy is very dependent on the proper positioning of the probe (Snoek et al., 2016).
  • An invasive cardiovascular catheter sensor is done via a pulmonary artery catheter. The temperature measured by a sensor in a pulmonary artery catheter is considered to reflect core temperature most closely.

The method that should be used will depend on the clinical situation. When done correctly, all methods will consistently provide a measurement of the body temperature that accurately reflects the core temperature within their limits. The cardiovascular catheters, the bladder temperature sensors, and the esophageal temperature probes provide the closest approximation of core temperature. However, in almost all clinical situations in which a patient's temperature must be measured, or when a patient with a fever needs constant temperature monitoring, using the axillary, oral, or rectal methods is appropriate, accurate, and consistent.

Body Temperature Productions and Maintenance

Body temperature represents the balance between heat production and heat loss. Body heat is produced by the metabolic activity of organs such as the brain, heart, liver, and muscular activity, involuntary or voluntary. These processes generate heat as a byproduct of their functions. Body heat is lost by radiation, conduction, convection, and evaporation. Small amounts of body heat are also lost by defecation, respiration, and urination.

  • Radiation is the movement of heat from one object to another colder one; in this case, the body to the environment.
  • Conduction is the transfer of heat between objects with different temperatures in contact with each other.
  • Evaporation is heat loss caused by water vaporization: Evaporation happens by sweat and insensible water loss. Insensible water loss occurs from the lungs, skin, excretion, and respiratory tract.
  • Convection causes heat loss by cold air moving past and over the body. The surface temperature is lowered, blood vessels dilate to bring more heat to the skin, and heat is lost from the circulating blood.

Humans can maintain body temperature at an optimal point, increasing or decreasing heat production, and increasing or decreasing heat loss. This process is called thermoregulation. Thermoregulation is activated and maintained through a brain structure called the hypothalamus.

The hypothalamus contains a group of heat-sensitive neurons collectively called the temperature-regulating center. The hypothalamus's heat-sensitive neurons receive input from the blood's temperature as it passes through the hypothalamus. The heat-sensitive neurons also receive afferent messages from peripheral temperature receptors in the skin, deep tissues, and spinal cord.

The hypothalamus' thermoregulatory center can be usefully thought of as a thermostat. It has a "setpoint" of body temperature that it tries to maintain in response to internal and external environmental conditions. If the body temperature is too high, the hypothalamus heat-sensitive neurons initiate cooling mechanisms:

  • Vasodilation
  • Shunting blood from the core to the periphery
  • Increased heart rate and cardiac output
  • Decreasing the metabolic rate
  • Decreasing muscular activity and
  • Increased sweating

If the body temperature is too low, heat conservation mechanisms are initiated:;

  • Sweating is decreased
  • Blood vessels are constricted
  • Muscular activity is increased, causing shivering
  • The metabolic rate is increased
Table 2: Heat Loss and Heat Conservation
increased_body_temp
decreased_body_temp

These mechanisms for heat loss and heat conservation are usually coordinated and balanced, and despite changes in the internal and external environment, normal body temperature is maintained.

Pathogenesis of Fever due to Infection

Infection usually causes fever due to a micro-organism. The bacteria or the virus or other pathogens act as pyrogens and stimulate monocytes, macrophages, and Kupffer cells to produce and release cytokines (Doyle et al., 2016; Ward, 2016). Cytokines are small proteins produced by cells of the immune system. Cytokines perform many complex activities, but they typically are involved in generating an immune response to illness or infection. These cytokines interferon, interleukin-1, interleukin-6, and tumor necrosis factor act as endogenous pyrogens. They stimulate the hypothalamus to produce an elevated level of prostaglandin E2 (PGE2) (Doyle et al., 2016). An elevated level of PGE2 causes the "setpoint" of the temperature regulation center in the hypothalamus to be elevated, causing fever.

When this setpoint is changed upwards, the thermoregulatory center senses incorrectly that body temperature is too low. Heat production and heat conservation mechanisms are activated, and the patient develops a fever (Kasper et al., 2016). Elevated levels of PGE2 are also produced in the peripheral tissues that account for the arthralgias and myalgias, aka the aches and pains, which are often part of a febrile illness.

Effect of Fever

Is fever helpful or harmful? Should it be treated, and if so, when, how, and in whom? Fever is one of the most common signs of illness, but even with years of experience and research, the answers to these questions are not clear (Doyle et al., 2016). Fever has long been considered by lay people to be dangerous (Kelly et al., 2016). At times, healthcare professionals are apprehensive and misinformed about fever's consequences and implications (Ward, 2016; Rafaelli et al., 2016).

Nevertheless, fever is a self-limiting phenomenon, and in many situations, it is not harmful and is probably helpful (Doyle et al., 2016). A fever can be directly toxic to the bacteria, viruses, and other pathogens that cause fever, and fever can also inhibit growth. Fever increases the expression and activity of heat shock proteins (HSPs), proteins that protect the host's cells and tissues against heat stress. Fever reduces the expression and activity of intracellular proteins produced in response to heat stress. These proteins can be damaging to the host. Unless hyperthermia feedback mechanisms cause elevated body temperature, prevent body temperature from rising to levels that cause systemic damage. Hyperthermia is discussed later in this course. Fever can also be used as a diagnostic and prognostic tool.

The cells and organs' basic enzymatic processes do not function optimally if the body temperature is abnormally elevated. Generating a fever requires the body to increase its metabolic rate six times beyond baseline. Increasing body temperature from 37°C to 39°C increases the metabolic rate by approximately 25%, increasing cardiac output, heart rate, and oxygen demand.

For most people who have a fever caused by a self-limiting infectious process, the body temperature will not be that high. The fever will be unpleasant, but of no consequence. However, a fever can be a significant stressor if a febrile patient has a chronic illness such as cardiovascular disease, diabetes, or pulmonary disease. In some clinical situations, cerebral hemorrhage, or septic shock, lowering a fever can decrease the mortality rate.

Non-infectious Causes of Fever

Infection is the most likely source of a fever, but auto-immune disorders, drugs, endocrine disorders, inflammatory reactions, malignancies, and vascular disorders can also cause fever (Bond, 2017). Examples of non-infectious causes of fever include:

  • Sarcoidosis
  • Thyrotoxic storm
  • Acute respiratory distress syndrome
  • Lymphomas
  • Cerebral infarction
  • Sympathomimetic drugs

Because of their basic pharmacologic effects, certain drugs can increase body temperature when taken in excess amounts. These medications increase body temperature by the following mechanisms or a combination of the following mechanisms:

  • Dramatically increasing the metabolic rate
  • Intensely increasing muscular activity
  • Depressing heat loss mechanisms
  • Stimulating an immune response.

Nonsteroidal anti-inflammatory drugs such as ibuprofen and corticosteroids such as prednisone can decrease the fever response to an infection. The following are examples of commonly used drugs that can increase body temperature in these ways (Hoffman et al., 2015).

Table 3: Drugs That Can Increase Body Temperature
  • Anticholinergics, e.g., antihistamines, benztropine, tricyclic anti-depressants
  • Hallucinogenic amphetamines, e.g., MDMA (a.k.a. ecstasy)
  • Monoamine oxidase inhibitors (MAOIs)
  • Salicylates
  • Selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine and paroxetine, can cause serotonin syndrome, increasing body temperature
  • Sympathomimetics, e.g., amphetamine, cocaine, phencyclidine (PCP)
  • Thyroid medications, e.g., levothyroxine
  • Vaccines

Drug Fever

Another non-infectious source of fever is drug fever. Drug fever is a febrile response caused by the administration of a therapeutic dose of a medication. The elevated temperature coincides with drug administration, and the body temperature returns to normal when the drug is discontinued. Antimicrobials, anticonvulsants, and antiarrhythmics are drugs that commonly cause drug fever. However, many medications can cause drug fever.

Drug fever can happen at any time. It is not uncommon for drug fever to begin weeks, months, or even years after a medication has been first prescribed (Bor, 2016), but 7-10 days after starting medication therapy is the median time of onset. At least five mechanisms can cause drug fever: a hypersensitivity reaction is the most common. Drugs that have been commonly associated with drug fever are listed in Table 4 (Bor, 2016).

Table 4: Drugs Commonly Associated with Drug Fever
  • Antiarrhythmic drugs (quinidine, procainamide)
  • Antiepileptic drugs (barbiturates and phenytoin)
  • Antihypertensive drugs
  • Antimicrobials (sulfonamides, penicillin, nitrofurantoin, vancomycin, anti-malarial drugs)
  • Anti-Thyroid drugs
  • Contaminants such as quinine that accompany injected cocaine or heroin
  • H1- and H2-blocking antihistamines
  • Iodides
  • Nonsteroidal anti-inflammatory drugs (including salicylates)

Metal or Polymer Fume Fever

Metal fume fever is a febrile illness caused by the inhalation of fumes containing metal particles. Metal fume fever can happen when galvanized metal is being burned or welded, and the person or persons doing the work is not wearing a respirator.

Persons with metal fume fever typically have a fever, and they complain of a headache, malaise, and muscle aches. Metal fume fever is self-limiting; there should be no sequelae, and the illness resolves with time and supportive care, although severe cases may take several weeks to resolve (Greenberg et al., 2015). The pathogenesis of metal fume fever is not completely understood, but the disorder is probably caused by an inflammatory reaction and the release of cytokines and neutrophil activation (Greenberg et al., 2015).

Polymer fume fever is caused by the inhalation of fumes produced when polymer-containing compounds such as Teflon® are heated. The pathogenesis of polymer fume fever is not understood, but it is thought to be the same as that of metal fume fever (Greenberg et al., 2015).

There is essentially no difference in the clinical presentation between metal fume fever and polymer fume fever. It is a self-limiting illness, but long-term pulmonary sequelae are possible (Greenberg et al., 2015). The treatment is symptomatic and supportive.

Signs and Symptoms of Fever

The typical signs of fever are chills, diaphoresis, flushing, shivering, and tachycardia. Arthralgias, malaise and myalgias are also common. Most people who have a simple febrile illness such as influenza will be uncomfortable, and they may not feel well enough to work, but they will perform basic activities of daily living.

Someone who has a fever will have noticeable signs and symptoms. The patient looks and feels sick, and there a body temperature that is > 38°C. However, a febrile illness presentation can be vastly different and less obvious in two populations: the elderly and the young. There is also a complication of febrile illnesses, febrile seizures, which happens only to children; this will be discussed separately.

Signs and Symptoms of Fever in the Elderly

Infection is a common source of illness and fever in the elderly (Mody, 2017). Still, advancing age increases the possibility of a medical condition, a non-infectious source, or a drug as the fever's cause. The second consideration is that the elderly who have a febrile illness may present differently, and the presence of a fever is more likely to indicate a serious illness.

Another important point is that the febrile response in elderly persons can be absent. Approximately 20-50% of elderly patients with a serious infection, such as bacteremia or meningitis, may not have a fever (Loby, 2017). An elderly person's fever response can also be blunted, meaning the temperature may not reach 38°C or the temperature may be essentially normal. Still, the patient's baseline core temperature is lower than average; therefore, the temperature elevation does not meet the fever's standard definition (Loby, 2017). Some part or parts of the febrile response are not normal. Although the phenomenon of an altered febrile response in the elderly is well known and well described, it is still unclear why it happens. Perhaps the hypothalamus's sensitivity may be decreased, the quantity and activity of the endogenous pyrogens may be diminished, or the level of prostaglandin E2 produced is not sufficient.

Finally, the elderly patient with a febrile illness may not have typical fever signs, such as chills, diaphoresis, or flushing. Confusion, shortness of breath, or decreased activity or mobility may indicate a febrile illness. The safest and most sensible approach is to keep in mind the possibility of an infectious process if an elderly patient has a sudden change in his/her mental or physical functioning.

The Infectious Disease Society of America recommends a clinical evaluation if a long-term care facility resident has a fever. Their definition of fever in this situation is provided below (Loby, 2017).

  • A single oral temperature > 37.8°C/100°F
  • Repeated oral temperatures > 37.2°C/ 99°F or rectal temperatures >37.5°C/ 99.5°F
  • Persistent tympanic temperature > 37.2°C/ 99°F
  • An increase in temperature of > 1.1°C/ 2°F over the baseline temperature

Fever, Neonates and Infants, and Febrile Seizures

Evaluation of febrile neonates or infants is far more important than fever reduction (Smitherman et al., 2017; Ward, 2016), but it is also challenging. Because of their age and level of development, the physical exam is a somewhat limited tool. There are fewer behavioral clues that can determine the severity of the illness or determine the child's illness. This patient population is more difficult to evaluate than older children. Also, a fever in these age groups is more likely to indicate the presence of a serious bacterial infection (SBI), and an infection in the first week of life is likely to be from vertical transmission from the mother. Febrile neonates and infants are at risk for febrile seizures.

Febrile seizures are a complication of common febrile illnesses occurring in children, and febrile seizures are the most common cause of seizures in the pediatric population. The definition of a febrile seizure is seizures occurring in a child aged 6-60 months with a temperature ≥ 38 degrees C (100.4 degrees F) and no central nervous system infection, metabolic disturbance, or history of afebrile seizure (Ganzales, 2016).

Febrile seizures are the most common cause of seizures in children (Feng et al., 2016). The exact incidence of febrile seizures is unknown, but it has been estimated to be 2%-5% (Feng et al., 2016; Gonzales, 2016; Nilsson et al., 2016). Febrile seizures are most often associated with common infectious illnesses such as otitis media and upper respiratory infections. The most powerful risk factor for febrile seizures is age (Whelan et al., 2017). Other factors that may contribute to an increased risk for febrile seizures include (Gonzales, 2016; Sharawat et al., 2016).

  • Antenatal complications
  • Daycare attendance
  • Developmental delay
  • Family history of febrile seizure
  • Male gender
  • High peak body temperature
  • Hypocalcemia
  • Hypoglycemia
  • Iron
  • Selenium and zinc deficiency
  • Microcytic hypochromic anemia

Childhood vaccinations have been associated with an increased risk for febrile seizures, but the risk is small (Francis et al., 2016; Gonzales, 2016).

Most febrile seizures are what are called simple febrile seizures. The seizure is generalized; the seizure duration is < 15 minutes; there is only one seizure in 24 hours; there are no post-seizure complications or sequelae. The child has no history of neurological disease (Whelan et al., 2017). Serious neurological sequelae can occur, albeit rarely, after a simple febrile seizure, especially if the seizure was particularly long or severe. The child had an extremely high fever, or the seizure was caused by infection with measles or salmonella (Whelan et al., 2017).

Febrile seizures may occur once, or they may be recurrent. The risk of recurrent febrile seizures is approximately 30%-35% (Millchap et al., 2016). The risk of recurrence varies considerably. Risk factors are: (Millchap et al., 2016)

  • Very young children
  • First-degree relative who had febrile seizures
  • A brief period between the onset of fever and the first febrile seizure

There are also complex febrile seizures and febrile status epilepticus (Whelan et al., 2017). Complex febrile seizures are seizures that focal or localized with a duration longer than 15 minutes but less than 30 minutes or involve recurrence of seizures in 24 hours; 20–25% of febrile seizures are complex (Whelan et al., 2017).

Approximately one-third of febrile seizures are complex febrile seizures and are associated with a risk of developing epilepsy (Feng et al., 2016). This risk has been estimated at 6%-7% but varies widely. Some research has not found an association between complex febrile seizures and epilepsy (Whelan et al., 2017).

Febrile status epilepticus is a prolonged seizure, lasting longer than 30 minutes (Whelan et al., 2017; Millchap et al., 2016). Children who have febrile status epilepticus appear to have the same basic risk factors for febrile seizures as children who have simple febrile seizures (Millchap et al., 2017).

Febrile seizures are treated on an individual basis. Simple febrile seizures do not require specific care, and they usually resolve spontaneously. Complex febrile seizures may be treated with antiepileptic medications (Millchap et al., 2016). Antipyretics can make the child more comfortable, but they will not prevent a recurrence (Millchap et al., 2016).

Hyperthermia

Three clinical conditions can cause a very elevated body temperature distinct from the infectious processes and non-infectious medical conditions that were previously discussed. These conditions are hyperthermia, malignant hyperthermia, and neuroleptic malignant syndrome.

These conditions differ from the typical febrile illness in the following ways:

  1. They are not mediated by the effects of cytokines on the hypothalamus, so antipyretics are not useful
  2. The body temperature is often much higher than a fever caused by an infection
  3. Associated with high rates of morbidity and mortality

Hyperthermia

Hyperthermia is defined as a body temperature > 40.1°C/104°F. Hyperthermia is caused by:

  • High environmental heat
  • Greatly increased metabolic activity or muscular activity
  • Decreased functioning of the body's heat loss mechanisms
  • A combination of these mechanisms

Heatstroke and drugs are common causes of hyperthermia. Hyperthermia is extremely dangerous. Body temperatures this high can denature proteins in the central nervous system and can cause irreversible brain damage. Hyperthermia can cause systemic effects like acid-base-disturbances, coagulation disorders, liver damage, rhabdomyolysis, and seizures.

A fever caused by an excess of drugs is relatively common. Antipyretics are not useful for treating hyperthermia because alteration of the hypothalamic setpoint does not cause elevated body temperature.

Malignant Hyperthermia

Malignant hyperthermia is a life-threatening condition caused by volatile inhalational anesthetics such as halothane and the non-depolarizing muscle relaxer succinylcholine (Prasad, 2016). These medications can cause a massive calcium release from the sarcoplasmic reticulum that leads to a complex systemic hypermetabolic state. The patient's body temperature can rapidly rise as high as 45°C. This drug reaction is an inherited metabolic disorder. Malignant hyperthermia can also be an idiosyncratic event (Prasad, 2016). Patients with malignant hyperthermia should be given dantrolene and treated with symptomatic, supportive care (Lexicomp®, 2017; Prasad, 2016).

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially dangerous reaction to typical or atypical antipsychotics such as haloperidol and risperidone. These drugs are dopamine receptor antagonists. NMS is thought to be initiated by a drastic blockade of dopamine activity in the central nervous system (Oruch et al., 2017; Rae-Grant, 2016). The decrease in dopamine activity causes intense muscular contraction, affects the hypothalamus's thermoregulatory center, and hyperthermia is possible. There appears to be a genetic component to NMS (Oruch et al., 2017). Neuroleptic malignant syndrome is very uncommon. The onset of NMS is usually within the first two weeks after starting therapy with a neuroleptic, but it can happen after one dose and after many years of taking the same drug.

NMS's classic signs are autonomic dysfunction, delirium, hyperthermia, metabolic changes, muscular rigidity; a body temperature of 40°C is not unusual during NMS. A patient who has NMS must be treated with aggressive supportive care, including cooling methods. Amantadine, bromocriptine, and dantrolene have been prescribed as antidotes for NMS. However, there is limited evidence for or against their use that they are effective (Oruch et al., 2017).

When to Treat a Fever

When and how should a fever be treated? The only reasonable answer is it depends. Fever reduction should not be routinely done, and fever reduction should be subject to the same considerations as any therapy. There should be an indication for fever reduction. The patient should be considered individually to determine if he will benefit or suffer from fever reduction. The advantages and potential adverse effects of fever reduction should be factored into using or not using cooling techniques.

Most patients who have a fever, either adults or children, have an infectious illness quickly diagnosed and treated. They have a non-serious, self-limiting illness such as influenza. In the first case, specific therapies are more important than fever reduction, and in the second case, the illness, and the fever last at most a few days, and neither the illness nor the fever require specific therapies. There is no evidence that treating fever in either of these situations will decrease the illness's length. There is some evidence that suggests that antipyretics and cooling techniques may prolong the course of illness. So, treating a fever would be a comfort measure and not a vital part of these patients' therapy.

Nevertheless, there can be times when reducing a fever can be beneficial. Treating a fever can increase patient comfort, and that can be helpful. If the patient has a fever and has chronic cardiac or pulmonary disease, fever reduction should be considered. These patients have limited physical reserves, and the increased metabolic demand and oxygen consumption caused by a fever could be harmful. The use of fever reduction in specific clinical situations is described below.

Neonates and Infants

Because of their age, these infants are more difficult to evaluate than older children; the physical exam is a somewhat limited tool. There are fewer behavioral clues that can determine the severity of the illness or what illness the infant has.

Fever evaluation in these patients is more important than fever reduction. The American Academy of Pediatrics recommends that acetaminophen and ibuprofen should not be used in febrile children < six months of age. Fever may be the only sign of serious infection in a young infant. Infections should be excluded before symptomatic treatment of fever is initiated (Ward, 2016).

Children

In most febrile children, fever is caused by a self-limiting viral illness, so lowering body temperature is unnecessary. However, fever reduction can make the child more comfortable, help him maintain an adequate hydration state, and antipyretics have an analgesic effect (Ward, 2016).

Carefully evaluate each febrile child on a case-by-case basis. Fever can be one of the signs of a serious illness in a child (Ward, 2016; Hague, 2015), or if the febrile child has a pre-existing condition like a cardiac abnormality, reducing a fever may be wise.

Acute Brain Injury

Fever reduction is recommended for patients who have had an acute brain injury (Chiumello et al., 2016; Doyle et al., 2016).

Sepsis

Fever increases the inflammatory response of sepsis, but it helps decrease the pathogen load (Doyle et al., 2016). Current literature reviews indicate that fever reduction in a septic patient may be beneficial and unlikely to be harmful. Fever reduction should not be routinely done but considered on a case-by-case basis and recognizing the benefits and risks (Chiumello et al., 2016; Doyle et al., 2016).

Status Epilepticus

Fever decreases the seizure threshold, and fever reduction is commonly recommended for patients having status epilepticus reduction (Doyle et al., 2016; Ehrlich, 2017).

Stroke

Fever has been identified as a risk factor for poor outcomes in patients who have had a stroke (Chiumello et al., 2016). Fever reduction is recommended by the American Heart Association/American Stroke Association guidelines, and other authoritative sources commonly recommend it. However, there is no definitive evidence that fever reduction for adult or pediatric stroke patients is beneficial (Chiumello et al., 2016; Doyle et al., 2016; Grelli et al., 2016).

Learning Break:
Reducing fever in critically ill patients who have a neurological injury has many positive effects. It can decrease cerebral edema, decrease the brain's metabolic rate and oxygen demand, enhance cellular function, decrease the risk of seizures, and reduce intracranial pressure. However, the line between benefits and risks of fever reduction in this situation appears to be small and not well defined.

Fever Management: Birth to 90 Days Old

A child who has a fever and is three months old or younger is more likely to have a serious bacterial infection (SBI) than an older child; the incidence of SBI neonates has been estimated to be 12% (Starr, 2016). The most common source of SBI in children aged 90 days and younger is a urinary tract infection, but sepsis, meningitis, cellulitis, sinusitis, and pneumonia are possible, as well (Smitherman et al., 2017; Starr, 2016). These illnesses are serious in this age group because children who are three months old or younger have a relatively weak immune response to infection and fewer barriers against pathogens.

Risk factors for an SBI are this population include: (Smitherman et al., 2017)

  • Age, especially < 28 days old
  • Antibiotic use in the recent past
  • No immunizations
  • An ill-appearing child
  • Fever > 38.6°C/101.5°F
  • Maternal infections, e.g., genital herpes
  • Prematurity

Evaluation of the presence of an SBI in these patients is complicated. Criteria that can be used to distinguish febrile children 90 days old and younger who have an SBI from those who simply have a self-limiting viral illness have been developed, e.g., Boston, Milwaukee, Philadelphia, and Rochester criteria. However, these criteria do not have good specificity, and they require extensive laboratory testing (Smitherman et al., 2017). Smitherman et al. (2017) recommend that instead of using these tools, the following approach should be applied.

The evaluation aims to determine which febrile children have an SBI and need testing and treatment and which children have a simple, self-limiting viral illness. The evaluation is particularly difficult because of the child's age and level of behavioral development.

Evaluation of any febrile child 90 days old or younger should begin with assessing the vital signs. The child should then be completely undressed, and a physical exam performed. Take special note of skin color and temperature, activity level, responsiveness, lack of responsiveness to touch or handling, and examine the child carefully for local infection signs. After the vital signs and physical exam have been done, ask about the child's health and activity during the febrile illness. Has the child been especially agitated or lethargic? Has oral intake been significantly decreased, or does the child not tolerate feedings? Has the child been coughing or having difficulty breathing? If a cough has been present, ask about the duration and quality of the cough. Have the child's bladder or bowel habits been abnormal?

The child's prenatal and birth history should be reviewed, and the history of the child's health before the febrile illness should be reviewed. Ask the mother if she has had or has hepatitis B or C, infection with HIV, or a sexually transmitted disease. Ask the parent/parents if the child has been exposed to any adults or animals with an illness or recently arrived from another country.

Extensive evaluation depending on the child's:

  • Age
  • Clinical condition
  • Temperature
  • Findings of the physical examination
  • Medical conditions
  • Previous state of health

In the case of a well looking but febrile infant 29-60 days old with no focal bacterial infection, no risk factors for or findings of a herpes simplex virus infection, and a rectal temperature of <38.6°C (101.5°F) – the following tests should be done.

  • Blood culture
  • Chest radiograph in patients with signs of a respiratory illness
  • Complete blood count (CBC) with differential
  • C-reactive protein (CRP), but only if results are rapidly available, e.g., within 60 minutes
  • Procalcitonin (PCT), but only if results are rapidly available, e.g., within 60 minutes)
  • Urinalysis
  • Urine culture (by transurethral bladder catheterization or suprapubic aspiration)

A lumbar puncture should be performed depending on these tests' results, and empirical antibiotic therapy started.

Fever Management in Adults with Fever of Unknown Origin

Febrile illnesses in adults are often self-limiting viral illnesses, or there is a clear cause for the fever, or the cause can be quickly determined. If the febrile illness persists and despite a complete evaluation, no cause is found, this is called fever of unknown origin (FUO).

Table 5: Criteria for Fever of Unknown Origin in an Adult (Kasper et al., 2016)
  • Fever higher than 38.3ºC on several occasions
  • Duration of fever for at least three weeks
  • Uncertain diagnosis after one week of study in the hospital

FUO is usually caused by a common disease or disorder, but the presentation is atypical. The most common causes of FUO are: (Kasper et al., 2016; Bor, 2016)

  • Infections such as abscesses, diverticulitis, osteomyelitis, and tuberculosis
  • Malignancies such as malignant lymphoma
  • Non-infectious inflammatory diseases such a sarcoidosis
  • Connective tissue diseases such as rheumatoid arthritis or systemic lupus erythematosus

Neutropenic states, drug fever, and healthcare-associated infections should be considered. An FUO for which no cause can be found is very unusual (Bor, 2016).

Assessment of a patient who has FUO should begin with history taking and a physical examination. This point seems obvious, but as noted in Kasper et al. (2016), the diagnostics' most important step is searching for potential diagnostic clues (PDCs) through complete and repeated history taking and physical examination. Be sure to ask the patient about exposure to animals, travel experiences, recent or past use of drugs, prescription, illicit, or over-the-counter, use of supplements, or alternative medicines.

Suppose no cause can be found after the history and physical examination or from the results of basic laboratory/diagnostic tests (e.g., blood cultures, complete blood count, chest radiography, urinalysis). In that case, the following tests should be done: (Bor, 2016)

  • Antinuclear antibodies
  • Creatine phosphokinase
  • CT scan of the abdomen
  • CT scan of the chest
  • Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)
  • Heterophile antibody test in children and young adults
  • HIV antibody assay and HIV viral load for patients at high risk
  • Rheumatoid factor
  • Serum lactate dehydrogenase
  • Serum protein electrophoresis
  • Three routine blood cultures drawn from different sites for at least several hours without administering antibiotics, if not already performed
  • Tuberculin skin test or interferon-gamma release assay

If there is a strong suspicion that the patient has an illness such as tuberculosis, then empiric treatment can be started. Antipyretics should be used cautiously as they may make finding the cause of an FUO more difficult. (Bor, 2016)

Fever Reduction

Fever reduction can be done using antipyretics drugs, physical cooling techniques, or both. Antipyretics drugs reset the temperature-regulating center of the hypothalamus. Physical cooling techniques encourage heat loss. Both methods are effective. Physical cooling techniques work faster, but they are more complex and time-consuming to initiate and monitor than using antipyretics.

Antipyretics

The drugs used as antipyretics are nonsteroidal anti-inflammatories (NSAIDs) or acetaminophen. Aspirin is very seldom used, and the reason for this will be discussed later.

The NSAIDs inhibit the activity of cyclooxygenase-1 and cyclooxygenase-2 enzymes. Decreased activity of these enzymes decreases the amount of prostaglandin formed, and the setpoint of the temperature-regulating center is re-adjusted to the normal level. Acetaminophen's antipyretic mechanism is not completely understood, but it probably works through the hypothalamus' temperature regulating center. Either drug can be used for fever reduction, but ibuprofen is slightly more effective (Jayawardena et al., 2016). The safety profile of each drug is comparable. Ibuprofen is more likely to cause GI distress, and it should be used cautiously in people who are dehydrated or who have renal impairment. Acetaminophen therapeutic overdoses are a leading cause of liver failure.

Alternating acetaminophen and ibuprofen have often been recommended as a useful technique for lowering fever in children. There is no conclusive evidence that this technique is more effective than using a single drug.

Physical Cooling Methods

Physical cooling methods are: (Doyle et al., 2016; Salgado et al., 2016; Tunali et al., 2016)

  • Traditional methods such as fans, cool bathing, and ice packs
  • Air-circulating blankets
  • Water circulating blankets
  • Hydrogel-coated water circulating pads
  • Endovascular cooling devices, cold peritoneal lavage, rectal or nasal lavage, or infusion of cold IV fluids
  • Extracorporeal access and infusion of cold fluids

Some of these methods no longer appear to be in favor because they are:

  • Ineffective (fans)
  • Unpleasant
  • Short duration of action (cool bathing)
  • Labor and time-intensive (rectal or nasal lavage)

There are few reviews of comparisons of cooling methods. Doyle (2016) found that endovascular cooling devices are superior to external, surface cooling devices, and physical cooling is superior to pharmacologic cooling.

Side effects associated with or caused by cooling methods include: (Doyle et al., 2016)

  • Arrhythmias, bradycardia
  • Coagulation pathway impairment
  • Electrolyte disorders from intracellular shifts and renal excretion. Calcium magnesium, phosphate, and potassium levels can be affected
  • Insulin resistance with hyperglycemia
  • Patient discomfort, e.g., shivering, skin breakdown

Of these five, the first four seem concerning, but shivering sounds relatively benign by common definition. Shivering caused by cooling blankets and ice packs increased CO2 and blood pressure by 15%. Doyle et al. (2016) noted that shivering causes cardiovascular and respiratory stress response and increases cerebral metabolic stress.

Patient Education

Many laypersons have misconceptions about fever. They believe a fever is dangerous; the higher the temperature, the greater the danger; fever can cause brain damage, and; a fever will almost always cause febrile seizures (Elkon-Tamier et al., 2017; Purssell et al., 2016). Misconceptions about fever and how to treat it are also common in healthcare professionals (Martins et al., 2016).

These beliefs can be very upsetting at the least and, at the worst, can cause non-productive behaviors and are occasionally harmful (Peetoom et al., 2016). Emergency rooms see many patients who have a simple viral syndrome because of concern about high fever. Patients and parents may overuse antipyretics and over-the-counter cough and cold preparations. Therapeutic overuse of acetaminophen can cause liver damage. The excessive dosing of a cough and cold preparations used to treat febrile illness can cause serious harm (Acheampong et al., 2016; Bertille et al., 2016; Lancaster et al., 2015). Patient education about fever can avoid this emotional distress and encourage sensible treatment of a fever.

Educating Parents

The following points about fever and febrile illnesses should be discussed with parents: (UpToDate; Ward, 2015)

  • Fever is a normal defense mechanism against illness, and fever may decrease the length of time a child is sick
  • The degree of fever does not correlate with the severity of the illness
  • Lowering a fever does not prevent febrile seizures
  • A high fever will not cause serious harm to a child, causing brain damage
  • The only reason to treat a fever is to make the child more comfortable and help him/her stay well hydrated
  • Lowering a fever will not decrease the amount of time the child is sick
  • An over-the-counter cough and cold medications, many of which contain an antipyretic, have no proven benefit, and the American Academy of Pediatrics and the Food and Drug Administration recommend that these products not be given to children
  • Most fevers are caused by simple, self-limiting illnesses such as influenza or a cold, and the fever will not harm your child. However, if your child has a fever, always discuss the situation with your pediatrician to get instructions specific to your child and the situation
  • Rest, fluids, and time are the best interventions for a child with a routine febrile illness
  • If you are instructed to give acetaminophen or ibuprofen, do not go outside the dosing directions. If the prescribed dose is not effective, more will not be better and can be harmful. Do not give a febrile child aspirin

Aspirin should not be given to a child with a fever or anyone 19 years of age or younger (Ward, 2015). Aspirin is an effective antipyretic, but its use in febrile children has been associated with an encephalopathic disease called Reye's syndrome. Reye's syndrome is quite rare, and the link between aspirin and Reye's syndrome is still somewhat controversial. Some authorities do not believe aspirin can cause Reye's, but Reye's syndrome is a serious disease. Acetaminophen and ibuprofen are as effective as aspirin, and if used correctly, they are much safer.

Other medications such as antibiotics, vitamin supplements, mineral supplements, and antihistamines will not be effective treatments for children who have a fever from a simple illness. Parents should never treat a febrile child with any medication unless the pediatrician has been consulted and approved its use.

Some children who have a fever have a serious illness, and some are susceptible to SBIs. If a child has a fever, parents should be instructed to bring the child to the pediatrician as soon as possible in these situations:

  • If the infant is ≤ 90 days old and has a rectal temperature of 38ºC/100.4ºF or higher, even if the infant appears well
  • If the child is between 3 and 36 months old and has a rectal temperature of 38ºC/100.4ºF or higher for more than three days. This situation is especially important if the child has been noticeably sick or has been refusing to take fluids
  • If the child is between 3 and 36 months old and has a rectal temperature of 38.9ºC/102 ºF or higher
  • Any child who has an oral, otic, rectal, or forehead temperature of 40 ºC/104ºF or higher or an axillary temperature of 39.4ºC/103ºF or higher
  • The child has a fever and has a seizure
  • The child has a fever and has a chronic medical problem, e.g., cancer, heart disease, sickle cell anemia
  • The child has a fever and develops a skin rash

Educating Adults

Much of the same information for parents applies to adults. Adults who have a fever should be instructed to rest and stay well hydrated. Over-the-counter cough and cold medications offer minimal benefit, and some of the ingredients they have can cause harmful interactions with many commonly used prescription medications. For example, dextromethorphan is an anti-tussive, and it can cause serotonin syndrome if used in combination with anti-depressants such as fluoxetine or paroxetine. Phenylephrine is a decongestant that is a sympathomimetic, and it should not be used cautiously by people who have cardiovascular disease.

Acetaminophen or ibuprofen can be used for fever control. But adults, especially older adults, should check with a physician before using these medications. Acetaminophen may not be safe for someone who has liver disease, and ibuprofen should be used cautiously by people who have gastric ulcers. Aspirin is an effective antipyretic, but even for adults, it is not the drug of choice. Acetaminophen and ibuprofen are safer alternatives, especially for elderly adults.

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