Chapter 10
Fever
Lebanese International University
School of Pharmacy
Non-Prescription Drugs
Fall 2013 - 2014
Katia Iskandar, PharmD, MHM (Course coordinator)
Samar Younes , PharmD
Fouad Sakr, PharmD
Introduction
Defined as a body temperature higher than the normal core
temperature of 37.8°C.
It is important to distinguish "fever" from "hyperthermia" and
"hyperpyrexia“.
Fever is a regulated rise in body temperature maintained by
the hypothalamus in response to a pyrogen.
Introduction
Fever is a sign of an increase in the body's thermoregulatory
set point.
Hyperthermia represents a malfunctioning of the normal
thermoregulatory process at the hypothalamic level.
Hyperpyrexia is a body temperature greater than 41.1°C that
typically results in mental and physical consequences.
Introduction
Most fevers are self-limited and nonthreatening unless the oral
temperature is greater than 41.1°C
◦ However can cause a great deal of discomfort
May indicate serious underlying pathology (e.g., acute
infectious process)
The principal reason for treating fever is to alleviate
discomfort
◦ The underlying cause should be identified before treatment
Introduction
The average temperature is usually maintained between
36.4°C and 37.2°C.
Temperature maintained in this range is considered to be the
"set point“.
Introduction
Normal body temperature varies throughout the day :
◦ Peaking daily between 4 pm and 6 pm.
◦ Reaching its lowest point at approximately 6 am.
◦ Healthy infants aged 3 to 4 months on average experience the highest
temperatures just before bedtime, and their temperature falls more than a
degree during actual sleep.
◦ Normal body temperature in adults is higher on average in the evening
compared with the morning; a similar diurnal pattern has also been reported
in elderly adults.
Etiology
Idiopathic
Most febrile episodes are caused by microbial infections (i.e., viruses,
bacteria, fungi, yeasts, or protozoa).
There is no basis for differentiating viral from bacterial infections
according to the magnitude of the fever or the temperature reduction from
antipyretic drug therapy.
Fever is often less pronounced in elderly patients than in younger
individuals. Consequently, infection may not be recognized easily in older
patients if fever is the primary assessment criterion.
Etiology
Non-infectious pathologic processes
◦ e.g., malignancies, MI, surgery, dehydration, gout and
hyperthyroidism
Drugs
Vigorous activity
Selected Medications That Induce Hyperthermia
Anti-Infectives Antineoplastics Cardiovascular CNS Agents Other Agents
Aminoglycosides Bleomycin Epinephrine Amphetamines Allopurinol
Amphotericin B Chlorambucil Hydralazine Barbiturates Atropine
Cephalosporins Cytarabine Methyldopa Benztropine Azathioprine
Clindamycin Daunorubicin Nifedipine Carbamazepine Cimetidine
Chloramphenicol Hydroxyurea Procainamide Haloperidol Corticosteroids
Imipenem l-Asparaginase Quinidine Lithium Folate
Isoniazid 6-Mercaptopurine Streptokinase MAOIs Inhaled anesthetics
Macrolides Procarbazine Nomifensine Interferon
Mebendazole Streptozocin Phenytoin Iodides
Nitrofurantoin Phenothiazines Metoclopramide
Para- SSRIs Propylthiouracil
aminosalicylic acid
Penicillins Trifluoperazine Prostaglandin E2
Rifampin Thioridazine Salicylates
Streptomycin TCAs Tolmetin
Sulfonamides
Tetracyclines
Vancomycin
Management of drug fever
The management of drug fever involves discontinuing the
suspected medication whenever possible.
If feasible, all medications should be temporarily discontinued.
If the hyperthermia is drug induced, the patient's temperature will
generally decrease within 24 to 72 hours after the offending agent
is withdrawn.
After patient safety and identification of the offending medication
have been considered, each medication may be restarted, one at a
time, while monitoring for fever recurrence.
Clinical Presentation
Nonspecific
Elevated temperature
Other accompanying signs and symptoms
Clinical Presentation
Signs and symptoms that typically accompany fever and cause a
great deal of discomfort include:
Headache
Arthralgia
Diaphoresis Myalgia
Generalized malaise Irritability
Chills
Anorexia
Tachycardia
Complications
The presence of fever is a cause of great concern, although in
most cases fever may be self-limiting and serious
complications are rare.
Overall, the major risks of fever are rare but may include
acute complications such as seizures, dehydration, and change
in mental status.
Elderly patients are at a higher risk for fever-related
complications because of their decreased thirst perception and
perspiration ability.
Complications: Febrile seizures
Seizures are defined as a seizure accompanied by fever in infants or children
who do not have an intracranial infection, a metabolic disturbance, or a defined
cause.
These seizures occur in 2% to 5% of all children from the ages of 6 months to 5
years, with the peak occurrence in children aged 18 to 24 months.
Risk factors for a first febrile seizure include day care attendance,
developmental delay, a family history of febrile seizure, and a neonatal hospital
stay of more than 30 days.
The risk of recurrence is increased in children who have had multiple febrile
seizures, are younger than 1 year at the time of their first seizure, and have a
family history of epilepsy.
Antipyretics are generally recommended to make the child more comfortable,
although they do not reduce the risk of recurrent febrile seizures.
Prophylaxis against simple febrile seizures with antiepileptic or antipyretic
drugs is not recommended by the American Academy of Pediatrics.
Detection of Fever
With a thermometer using proper technique
Core temperature is estimated with various types of
thermometers used at the rectal, axillary, oral, temporal, or ear
canal sites
The rectal method is considered the gold standard
measurement
◦ Most patients prefer other methods of temperature
measurement because of comfort and ease of use
Detection of Fever
Temperature is considered elevated if:
Rectal temperature > 38.0°C
Oral temperature > 37.6°C
Axillary temperature > 37.4°C
◦ Rectal temperatures are 0.4°C–1.0°C higher than oral
readings
◦ Oral temperature may be up to 0.9°C higher than tympanic
readings
◦ Axillary temperatures range from 0.4°C–2°C lower than
rectal temperatures
Detection of Fever
Site of
Normal Range Fever
Measurement
Rectal 36.6°C – 38°C > 38.0°C Most sensitive
Oral 35.5°C – 37.5°C > 37.6°C
Axillary 34.7°C – 37.3°C > 37.4°C Least sensitive
Tympanic 35.7°C – 37.7°C > 37.8°C
Goals of Therapy
Alleviate the discomfort of fever
Reducing the body temperature to a normal level
Exclusions for Self Treatment
Patients > 6 months of age Risk for hyperthermia
with rectal temperature ≥
40ºC or equivalent Impaired oxygen utilization
(e.g., severe COPD,
Children < 6 months of age respiratory distress, heart
with rectal temperature ≥ failure)
38ºC
Impaired immune function
Severe symptoms of (e.g., HIV, cancer)
infection that are not self-
limiting
Exclusions for Self Treatment
CNS damage (e.g., head Child who refuses to drink
trauma, stroke) any fluids
Children with history of Child who is very sleep,
febrile seizure or seizures irritable, or hard to wake up
Fevers that persist > 3 days Child who is vomiting and
with or without treatment cannot keep down fluids
Child who develop spots or
rash
General Treatment Approach
Fever exceeding 38.3°C orally may be treated with antipyretic
agents (as well as nonpharmacologic measures)
Treatment with antipyretics may also be indicated at lower
temperatures if the patient is experiencing discomfort or is of
advanced age.
Treatment should also involve identification and, if possible,
treatment of the underlying cause.
Nonpharmacologic Therapy
Body sponging with tepid water may facilitate heat dissipation,
but:
◦ Sponging or baths have limited utility in the management of
fever .
◦ Not routinely recommended for those with a temperature
less than 40°C.
◦ Sponging is usually uncomfortable and often induces
shivering, which could further raise the temperature.
◦ Ice-water baths or sponging with hydroalcoholic solutions
(e.g., isopropyl or ethyl alcohol) is uncomfortable,
dangerous, and not recommended.
Nonpharmacologic Therapy
Alcohol poisoning can result from cutaneous absorption or
inhalation of topically applied alcohol solutions.
Infants and children are at a higher risk of alcohol poisoning
because of their smaller body mass.
Unlike acetaminophen and nonsteroidal anti-inflammatory drugs
(NSAIDs), sponging does not reduce the hypothalamic set point;
therefore, sponging should follow oral antipyretic therapy by 1 hour
to permit the appropriate reduction of the hypothalamic set point
and a more sustained temperature-lowering response.
Nonpharmacologic Therapy
Adequate fluid intake to prevent dehydration.
Wearing lightweight clothing
Removing blankets
Maintaining a room temperature at 25.6°C
Pharmacologic Therapy
Antipyretics inhibit PGE2 synthesis reduce the
hypothalamic set point during fever
All antipyretics decrease the production of PGE2 by inhibiting
the cyclooxygenase (COX) enzyme
NSAIDs and Aspirin inhibit the COX enzyme in the periphery
and CNS
Acetaminophen mainly inhibits the COX enzyme in the CNS
Pharmacologic Therapy: Acetaminophen
Reaches maximum temperature reduction at 2 hours at the usual recommended
dose
Acetaminophen is also available as a rectal suppository
◦ May be an advantage for caregivers who have problems giving their children
oral medications or for children who are vomiting or having a febrile seizure
◦ But absorption is erratic and studies on its antipyretic activity are conflicting
◦ Recommended weight based pediatric dose: 10-15 mg/kg, individual dose
may be repeated every 4-6 hours as beeded not to exceed 5 doses per 24
hours.
Pharmacologic Therapy: NSAIDs
Ibuprofen is the most common NSAID used as an antipyretic
Reaches a maximum temperature reduction at 2 hours at the
recommended dosing of 5 to 10 mg/kg per dose every 6 to 8
hours with a maximum of four doses per day
Ibuprofen is approved in only patients older than 6 months for
the reduction of fever
Pharmacologic Therapy
Acetaminophen may interact with :
Alcohol → increased risk of hepatotoxicity
Warfarin → increased risk of bleeding
Ibuprofen and other NSAIDs may interact with:
Aspirin → decreased antiplatelet effect of aspirin
Phenytoin
Bisphosphonates → increased risk of GI ulceration
Anticoagulant and Alcohol → increased risk of GI bleeding
Medication errors
Overdosing or duplicating therapy when using multiple products
with similar ingredients
Inappropriate dosing for pediatric patients attributed to
mathematical errors in calculating a weight-based dose
◦ the pharmacist should provide appropriate counseling to the
patient or caregiver and make sure that parents :
◦ Understand which product to use
◦ Know the appropriate weight-based dose for each child
◦ Know the correct dosing frequency
◦ Use and appropriate measuring device
Special population
Pregnancy: Acetaminophen is considered safe .
Breast feeding: Acetaminophen , Ibuprofen and Naproxen are
considered compatible with breast feeding.
Pediatric patients: Dosing of Acetaminophen or Ibuprofen is
based on body weight not age.
Pharmacotherapeutic Comparison
Efficacy and safety between Acetaminophen and Ibuprofen are
similar in recommended dosages.
Slightly more benefit shown with ibuprofen in terms of onset of
action and fever reduction.
Other NSAIDS such as naproxen and aspirin may also be
appropriate as an antipyretic in adults.
Alternating doses of acetaminophen and ibuprofen is not
recommended because of the risk of overdose , medication errors
resulting from the complexity of regimens and increased side effects.
Outcome Evaluation
The primary monitoring parameters for febrile patients include
temperature and discomfort
Most patients demonstrate a reduction in temperature after
each individual dose of an antipyretic but it may take up to 1
day for temperature lowering to occur.
If symptoms are not improving or are worsening over the
course of 3 days with self-treatment a health care provider
should be consulted
