Central Nervous System Conditions

Chapter 9
Fever
Yvonne M. Shevchuk, BSP, PharmD, FCSHP

Fever, which is a regulated elevation in core body a narrow range by balancing heat production by
temperature, is generally considered to be caused muscle and liver tissues with heat dissipation from
by infection; however, noninfectious causes include skin and lungs. With fever, the thermoregulatory
inflammatory diseases, neoplasms and immunologi- set point is elevated.1,2 Endothelial cells of the
cally mediated conditions such as some drug fevers.1,2 organum vasculosum laminae terminalis, a network
The definition of fever varies; anything above the of enlarged capillaries surrounding the hypothalamus,
normal range for body temperature can be defined as release arachidonic acid metabolites when exposed
fever.1,2 Fever in children is most often defined as rectal to pyrogens in the circulation. Prostaglandin E2,
temperature >38°C if the child is appropriately dressed released by the hypothalamus, is thought to be
and resting.3 In adults and children, an individual’s the major substance producing an elevation of the
body temperature varies with the time of day (normal thermoregulatory set point. Initially, with an elevated
circadian variation); it is lowest at approximately 6 set point, there is vasoconstriction of peripheral blood
a.m. and highest between 4 and 6 p.m.1 The mean vessels to conserve heat, shivering to increase heat
amplitude of variability is 0.5°C. Oral temperatures production and behavioural changes such as seeking
>37.2°C in early morning or ≥37.8°C any time during warmer environments and clothing. When the set point
the day may also be used to define fever.1,4 Outside is reduced, for example, by administering antipyretics
the neonatal period, children generally have a higher or disappearance of pyrogens, the reverse occurs;
temperature than adults; however, this is poorly vasodilation and sweating to dissipate heat, as well as
documented.5,6 Basal core temperatures decrease behavioural changes such as removal of clothing.2
toward the adult range by 1 year of age and continue
to decline until puberty. In children, the height of Sources of pyrogens, substances that cause fever, are
the temperature elevation has been correlated to the both exogenous and endogenous.1,2 The most common
likelihood of serious bacterial infection. Children with exogenous sources are microorganisms, their products
temperatures >41.1°C have an increased likelihood of or toxins (e.g., lipopolysaccharide endotoxin of gram-
serious bacterial infections.3,6 The degree of response negative bacteria). Exogenous pyrogens induce forma-
to antipyretics does not distinguish serious bacterial tion and release of endogenous pyrogens. Endogenous
infections from viral infections.3 pyrogens or pyrogenic cytokines are polypeptides pro-
duced by host cell macrophages, monocytes and other
Mild elevations in body temperature occur with exer- cells. The most common are interleukin 1α and 1β (IL
cise, ovulation, pregnancy, excessive clothing (over- 1α and 1β), tumor necrosis factor alpha (TNF α), IL-6,
bundling of infants), ingestion of hot foods or liquids ciliary neurotropic factor (CNF) and interferon gamma
and chewing gum or tobacco.1 (IFN γ).
Rectal temperatures are approximately 0.6°C higher
and axillary temperatures approximately 0.5–1°C Goals of Therapy
lower than oral temperatures.3 A high fever is usually
defined as a temperature >40.5°C. Fever is a regulated ■ Provide patient comfort
physiologic response and temperatures >41ºC are ■ Reduce parental anxiety
rare.2,7 ■ Reduce metabolic demand caused by fever in
patients with cardiovascular or pulmonary disease
Pathophysiology ■ Prevent or alleviate fever-associated mental dys-
The thermoregulatory centre in the anterior hypo- function in the elderly (common practice but
thalamus normally controls core temperature within evidence is unclear)

Copyright © 2010 Canadian Pharmacists Association. All rights reserved. Patient Self-Care, 2010
 Chapter 9: Fever 81
Patient Assessment (Figure 1) backache, myalgia, arthralgia, somnolence, chills and
rigors may also be associated with fever.
Fever is a symptom or sign of illness, not a disease,
and the reason for fever should be determined.3 Most Drug-induced fever is a symptom of hypersensitivity
commonly it is due to infection, often viral. Fever per- but can occur with other symptoms such as myalgia,
sisting longer than 3 days in those >6 months, recurrent chills and headache. Table 1 lists several medications
fever or high fever (>40.5°C) should be evaluated by a associated with drug-induced fever.9,10,11
physician.
Fever differs from hyperthermia, which is an increase
Once fever is established, the body initiates processes in core temperature without an increase in hypotha-
to permit homeostasis. Peripheral vasodilation causes lamic set point. If hyperthermia is suspected, refer the
the skin to feel hot. Sweating may occur. Malaise and patient to a physician; antipyretics are not useful (see
fatigue may be seen at higher temperatures. Headache, Chapter 10, Heat-related Disorders).

Figure 1: Assessment of Patients with Fever1,3,6,8

Patient Self-Care, 2010 Copyright © 2010 Canadian Pharmacists Association. All rights reserved.
82 Central Nervous System Conditions

Table 1: Selected Drugs Associated with Nonpharmacologic Therapy

Fever9,10,11
Nonpharmacologic interventions include removal of
Allopurinol Doxepin NSAIDs (e.g., excess clothing and bedding, increased fluid intake
Amphotericin Ba Epinephrine ibuprofen, to replace increased insensible water loss in fever,
Antacids Folic acid naproxen)
maintenance of ambient temperatures around 20–21°C
Antibacterials/ Furosemide Neuroleptics
and avoidance of physical exertion.8
antibiotics (e.g., Griseofulvin Nifedipine
cephalosporins, Heparin Oral Sponging increases evaporation to promote heat loss.
penicillins, contraceptives Tepid water sponging may be useful to reduce body
SMX/TMP) Hydralazine
Hydrochloroth-
Phenytoin temperature; however, it does not reset the hypotha-
Anticholinergics Procainamidea lamic set point.29 Therefore, to maintain the elevated
iazide
Antihistamines Propylthiouracil temperature the body actually works harder by shiv-
H2-receptor
Antineoplastics Quinidinea ering (results in increased oxygen consumption). As
antagonists (e.g.,
(e.g., cisplatin,
cimetidine) Quininea well, sponging often causes significant patient dis-
hydroxyureaa)
Insulin Rifampin comfort.30 Studies show no additional benefit from
Atropine
Interferon Salicylates sponging after antipyretic administration.31,32,33 If used,
Azathioprinea
Iodides Streptokinase administer antipyretics 30 minutes before sponging to
Barbiturates
Isoniazid Sulfasalazine reduce hypothalamic set point.
Carbamazepine
Iron dextran Sulindac
Clofibrate
Metoclopramide
Tepid sponging, if performed, should be done with
Tacrolimus
Corticosteroids
Methyldopaa
water only. Isopropyl alcohol has resulted, rarely, in
Triamterene
Cyclosporine
MAOIs Vitamins hypoglycemia, intoxication and coma as a result of
Digoxin Mycophenolate absorption through the skin or inhalation of fumes and
Diltiazem is not recommended.30,34
a Drugs associated with >5 case reports of drug fever.
Abbreviations: MAOIs = monoamine oxidase inhibitors;
NSAIDs = nonsteroidal anti-inflammatory drugs; SMX/TMP =
Pharmacologic Therapy
sulfamethoxazole/trimethoprim
There are many arguments against treating a
fever.1,2,35,36,37
Measurement of Body Temperature
■ Fever is an important defence mechanism; it
For available products consult Home Testing Prod- enhances the immune response.
ucts: Thermometers in Compendium of Self-Care ■ Use of antipyretics may impair the use of tempera-
Products. ture as an important clinical tool for monitoring the
progress of an infection or response to antibiotics.
There are a number of ways to measure temperature in
an ambulatory setting—oral, rectal, axillary, tympanic ■ Fever is usually self-limited and the most common
membrane, temporal artery and transcutaneous routes consequences of fever are generally harmless—mild
(Table 2).8 Oral, rectal and axillary temperatures may dehydration, febrile delirium, febrile seizures and
be taken with an electronic thermometer with a digital discomfort.
display (digital probe). Standard mercury in glass ther- Therefore, the decision to use antipyretics must be
mometers are no longer recommended due to potential individualized. Reduction of fever, not “normal” body
toxicity if they break,8 environmental concerns and temperature, may be the goal. Assessment of the
problems with proper use including long equilibration patient should not depend solely on the elevation of
times, difficulty reading them properly and failure to temperature (Figure 1).
reset the thermometer. Electronic thermometers are
safer and easier to use because they are faster, easier to Acetaminophen, ASA, ibuprofen and naproxen sodium
read and avoid the environmental concerns of mercury. are all currently indicated to reduce fever. These drugs
Generally, equilibration times require 30–60 seconds, reduce body temperature in febrile patients by decreas-
while up to 10 minutes are required for standard glass ing prostaglandin synthesis in the brain and reducing
thermometers. the hypothalamic set point.1,35 They do not lower nor-
mal body temperature. Short-term treatment with these
Normal temperature ranges associated with various drugs is associated with few side effects. Intermit-
routes and recommended routes based on age are listed tent administration of antipyretics may result in drug-
in Table 3 and Table 4. induced fluctuations in temperature and concomitant

Copyright © 2010 Canadian Pharmacists Association. All rights reserved. Patient Self-Care, 2010
 Chapter 9: Fever 83
shivering which may make the individual feel worse. not been evaluated and the dose is an initial dose only;
Use at regular intervals may improve patient discom- subsequent doses should be 10–15 mg/kg. Do not
fort and reduce the risk of increased metabolic demand recommend a loading dose to parents. Acetaminophen
with shivering. overdose resulting in hepatotoxicity remains a concern.
Acetaminophen is a relatively safe and effective The Food and Drug Administration in the USA
antipyretic with few contraindications, and can be is considering a number of warnings and changes
used in any age group.38,39 Many years of clinical regarding acetaminophen41 while Health Canada
experience is also an advantage. Using a loading dose has developed a labelling standard which includes
of acetaminophen has been studied.40 A 30 mg/kg warnings regarding hepatotoxicity and maximum
loading dose in children 4 months to 9 years of package sizes for pediatric products.42 It is the preferred
age resulted in a more rapid and sustained response agent in those with renal dysfunction or risk factors for
and a greater reduction in temperature compared to GI bleeding.
15 mg/kg. Although this strategy is used in some Standard dosing is provided in Table 5.
emergency departments, the safety of this practice has

Table 2: Methods of Measuring Body Temperature

Rectal Instructions for use in children8
Is considered the most accurate and the standard against which other • Place the infant on his back with knees bent
routes of temperature measurement is compared.1,7,12 or lay infant or young child face down across
This route is preferred for newborns, in children less than 4–5 years old parent’s lap or in fetal position on flat surface.
when an axillary temperature is not sufficient, and when the oral route is • Lubricate anus and thermometer with petroleum
not suitable due to mouth breathing. May be less acceptable to toddlers. jelly (pea-size quantity).
It is contraindicated in premature infants,1 the immunocompromised7 and • With one hand gently insert thermometer 2–3
in the presence of rectal anomalies, recent anorectal surgery or severe cm into rectum.
hemorrhoids. A rare complication is perforation of the rectum. This route • Hold buttocks closed against thermometer with
may also transmit infections.7 other hand.
• Leave thermometer in place until it beeps and
temperature is displayed.
Oral Instructions for use8
This route can be used in children over 5 years old and adults;7 younger • Place thermometer on either side of mouth
children may bite the thermometer or have difficulty keeping it in the (between gum and cheek) or under the tongue.
closed mouth. This may also be a problem for individuals who have • Hold in place with lips or fingers (not the teeth).
difficulty understanding instructions, e.g., the mentally impaired or elderly
with dementia.1 • Breathe through nose with mouth closed.
• Leave thermometer in place until it beeps and
Avoid the oral route when nasal breathing is difficult (e.g., due to viral
temperature is displayed.
upper respiratory tract infection); mouth breathing will cause spuriously
low temperatures. Beverages, either hot or cold, and smoking should be
avoided for at least 10 minutes prior to taking an oral temperature.1,7
Armpit Instructions for use8

Axillary (armpit) temperatures have many disadvantages.7 They take a • Place thermometer in apex of axilla.
longer time to measure and are affected by a number of factors including • Hold elbow against chest to stabilize the
hypotension, cutaneous vasodilation and prior cooling of the patient. thermometer.
Axillary temperature may be a poor alternative to rectal temperatures in • Leave thermometer in place until it beeps and
children aged 3 months to 6 years.13,14 temperature is displayed.
Although axillary temperatures are generally considered to be
approximately 0.5°C lower than oral temperatures, reliable data are
not available to correlate axillary with oral or rectal temperatures. The
advantages of axillary temperatures are that this route is very accessible,
safe and less frightening to children than rectal temperatures.7
The reading should be confirmed via another route if the axillary
temperature is >37.2°C.

(cont’d)

Patient Self-Care, 2010 Copyright © 2010 Canadian Pharmacists Association. All rights reserved.
84 Central Nervous System Conditions

Table 2: Methods of Measuring Body Temperature (cont’d)

Ear Instructions for use20
Tympanic thermometers (TT) measure infrared emissions from the • Follow specific manufacturers’ directions as they
tympanic membrane.1,15 may vary.
Because the tympanic membrane and the hypothalamus share the • Apply a clean probe tip.
same blood supply, these thermometers are considered to reflect core • Gently tug on ear, pulling it back. This helps to
temperature measurements.1 The temperature is then converted by straighten the ear canal so an accurate reading
the thermometer to reflect oral or rectal temperatures, which may lead can be obtained.
to some inaccuracy in the temperature reading. The aiming of the ear
• Gently insert the thermometer into the ear until
probe and proper placement in the ear canal are important for accurate
the ear canal is fully sealed off.
measurements.6 Improper placement can result in a lower temperature
reading from a lower outer ear canal wall temperature.6 There may be • Squeeze and hold down the button for 1 second
a poor correlation of TT with rectal temperatures and this route may (or until the device beeps).
not be sensitive enough to screen for fever in pediatric patients16,17,18 • Remove from the ear and read temperature.
although performance was good in adults, including the elderly.19 It is not
recommended for children less than 2 years of age by the Canadian
Paediatric Society.8
The advantages of TT include simplicity, speed and patient acceptance.7
Less than 2 seconds is needed to obtain a reading. Other advantages
include lack of external influences such as hot beverage ingestion,
and no mucous membrane contact, therefore minimal risk of disease
transmission.7 Acute otitis media and nonobstructive cerumen do not
appear to affect the accuracy of TT.15
A disadvantage is high cost.
Plastic colour-changing strips (transcutaneous) Instructions for use
One transcutaneous route uses a plastic strip that is placed on the • Place on forehead for 1 minute.
forehead for 1 minute and indicates temperature by changing colour.21 • Use not recommended in children.
The strip contains encapsulated thermophototropic esters of cholesterol
(called liquid crystals) that change colour in response to temperature
changes. They are easier to read and require less time than a standard
thermometer, but are less reliable because skin temperature is not a
reliable indicator of core temperature.1,6,7,8,21,22 The strip incorporates
a correction factor for this but assumes the factor is the same in all
individuals. When studied in emergency departments, they were poor
predictors of fever.22,23 Their accuracy is affected by ambient temperature
(e.g., cold hands holding the strip and nearby heat sources such as a
lamp). Because they can register afebrile temperatures in a truly febrile
child, possibly delaying medical attention, their use is not recommended.
Temporal artery (Forehead) Instructions for use28
Like the tympanic thermometer, the temporal artery thermometer (TAT) • Follow specific manufacturers’ directions as they
uses infrared technology to measure the temperature using a heat may vary.
balance method.24 • Remove dirt, hair or sweat from forehead area.
Infrared sensors compute a temporal artery temperature by rapid, • Turn unit on.
repeated measures to synthesize skin surface and ambient temperature.
• Press button a second time.
It has similar advantages as the TT in that it is very quick (3 seconds)
and avoids any mucous membrane contact.24 • Place thermometer probe gently and flush onto
the area approximately 1.25 cm above the centre
It may be prone to less error than the TT25 but is not considered as
of the eyebrow.
accurate as rectal temperatures in children.25,26,27
• Sweep the skin from above eyebrow to temple
until you hear a beep.
• Read the temperature display.
Abbreviations: TAT = temporal artery thermometer; TT = tympanic thermometer

Copyright © 2010 Canadian Pharmacists Association. All rights reserved. Patient Self-Care, 2010
 Chapter 9: Fever 85
Table 3: Normal Pediatric Temperature Ranges tion with Reye’s syndrome in influenza and varicella.
Associated with Measurement Reye’s syndrome consists of acute encephalopathy
Technique8 with cerebral edema, fatty infiltration of the liver and
Measurement metabolic derangements such as hypoglycemia. It
Technique Normal Temperature Range occurs in otherwise previously healthy children. Since
Rectum 36.6°C–38°C (97.9°F–100.4°F) the cause of fever is unknown initially in many cir-
cumstances, avoid ASA in children.53,54,55
Mouth 35.5°C–37.5°C (95.9°F–99.5°F)
Armpit 34.7°C–37.3°C (94.5°F–99.1°F)
Naproxen sodium is the most recent nonprescription
NSAID available for fever. It has a longer half-life with
Ear 35.8°C–38°C (96.4°F–100.4°F) a corresponding less frequent administration schedule.
Source: Canadian Paediatric Society, 2008. “Fever and Temperature There are no data on the use of naproxen sodium for
Taking”. For more information, visit www.caringforkids.cps.ca. treatment of fever in children.
Table 4: Recommendations for Temperature Alternating Antipyretics
Measuring Techniques8
Age Recommended Technique
In the past, alternating acetaminophen with ASA
for management of fever unresponsive to a single
Birth to 2 y First choice: Rectum (for an exact agent was recommended. Since ASA is no longer
reading)
recommended in children and adolescents because of
Second choice: Armpit (to check for an association with Reye’s syndrome, this practice
fever)
has been abandoned. However, recommendations
Not Tympanic membrane to alternate acetaminophen with ibuprofen have
recommended: thermometers
emerged.56,57 Alternating or combining acetaminophen
Between 2 First choice: Rectum and ibuprofen has not been shown to be either safe or
and 5 y more effective than a single antipyretic.49,58,59,60,61 This
Second choice: Ear, armpit recommendation is often confusing to caregivers and
Older than 5 y First choice: Mouth could result in increased dosing errors.62,63
Second choice: Ear, armpit Table 5 outlines dosing, side effects, contraindications,
Source: Canadian Paediatric Society, 2008. “Fever and Temperature
precautions and toxicity in overdose of ASA,
Taking”. For more information, visit www.caringforkids.cps.ca. acetaminophen, ibuprofen and naproxen sodium.
Ibuprofen is an alternative to acetaminophen when
there are no contraindications to its use. There is
Fever in Specific Patient Groups
less experience with it and it is more expensive, but Children
with short-term use in children there appears to be
no difference in adverse event rates compared to Young children have an immature central nervous sys-
acetaminophen.44,45,46,47 However, renal failure in chil- tem thermoregulatory system, and in the first 2 months
dren has been reported, particularly when the child is of life may have minimal or no fever during an infec-
dehydrated, therefore avoid in children with diarrhea tious illness. Since neonates and infants are less able to
and vomiting.8,48 In one study, time without fever in mount a febrile response, when they do become febrile,
the first 4 hours after administration was greater with it is more likely to indicate a major illness. After 3
ibuprofen than acetaminophen and time to fever clear- months of age, the degree of fever more closely approx-
ance was shorter with ibuprofen.49 A meta-analysis imates that seen in older children.64
showed that ibuprofen (5–10 mg/kg) as compared to Fever is common in children and is usually due to bac-
acetaminophen (10–15 mg/kg) was a better antipyretic terial or viral infection. Because children have had less
producing greater temperature reductions at 2, 4 and 6 exposure than adults to infectious agents, they are more
hours after dosing.50 Ibuprofen may also have a longer susceptible upon initial contact. Reactions to vaccina-
duration of action50 than acetaminophen and is less tions may also be a cause of fever. Compared to adults,
toxic in overdose.51,52 children are more sensitive to ambient temperature (due
ASA should be avoided in children less than 18 years to a greater body surface area for heat exchange) and at
old who have a viral illness because of its associa- higher risk for dehydration.64

Patient Self-Care, 2010 Copyright © 2010 Canadian Pharmacists Association. All rights reserved.
 86
Copyright © 2010 Canadian Pharmacists Association. All rights reserved.

Table 5: Drug Therapy for Fever

For available products consult Analgesic Products: Internal Analgesics and Antipyretics; Baby Care Products: Antipyretics in Compendium
of Self-Care Products.

Central Nervous System Conditions

Acetaminophen Ibuprofen ASA Naproxen Sodium
Dose
Adults 325–650 mg Q4-6H po/pr 200–400 mg Q4-6H po PRN 325–650 mg Q4-6H po PRN 220 mg Q8-12H po PRN
PRN (maximum 4 g/day) (maximum 1.2 g/day) (maximum 4 g/day) (maximum 440 mg/day)
Age >65: 220 mg Q12H po

Children 10–15 mg/kg Q4-6H 5–10 mg/kg Q6-8H po Use not recommended ≥12 y: adult dose
po/pr PRN (no greater (maximum 4 doses per day
than 5 doses per day or or 40 mg/kg/day)
65 mg/kg/day)
Dosing in renal ClCr 10–50 mL/min: extend No adjustment in renal ClCr 10–50 mL/min: extend Avoid if ClCr <30 mL/mina
dysfunction interval from Q4 to Q6H dysfunction requireda interval from Q4 to Q6H
ClCr <10 mL/min: Q8H Avoid if ClCr <10 mL/mina
Onset of effect 30 min Within 1 h Within 1 h 20 min (pain relief; no data
for fever)
Time to peak effect 3h 2–4 h 3h No data
Duration 4–6 h 6–8 h 4–6 h No data
Adverse effects Repeated dosing at or Dyspepsia, heartburn, Dyspepsia, heartburn, Dyspepsia, heartburn,
slightly above upper limit of abdominal pain, diarrhea abdominal pain, abdominal pain, diarrhea
recommended doses may GI bleeding diarrhea, rectal irritation GI bleeding
result in severe hepatic (suppositories)
Dizziness, headache, Dizziness, headache,
toxicity GI bleeding
nervousness, fatigue, lightheadedness,
irritability Skin rash drowsiness, insomnia
Skin rash Allergic reactions Skin rash
Allergic reactions Sodium and water retention Allergic reactions
Reduced renal function, Platelet dysfunction Reduced renal function,
acute renal failure acute renal failure
Sodium and water retention Sodium and water retention
Platelet dysfunction Platelet dysfunction
Patient Self-Care, 2010
Patient Self-Care, 2010

For available products consult Analgesic Products: Internal Analgesics and Antipyretics; Baby Care Products: Antipyretics in Compendium
of Self-Care Products.
Acetaminophen Ibuprofen ASA Naproxen Sodium
Contraindications/ Hypersensitivity Peptic ulcer disease, GI Children <18 y Peptic ulcer disease, GI
Precautions Chronic alcohol consumption perforation or bleeding perforation or bleeding, IBD
Active GI lesions
Malnutrition/fasting Hypersensitivity History of recurrent GI History of asthma, urticaria
Bleeding disorders lesions or allergic-type reactions
Concomitant alcohol use Bleeding disorders after taking ASA or other
NSAIDs
Individuals who rely Thrombocytopenia
on vasodilatory renal Severe liver impairment or
ASA hypersensitivity active liver disease
prostaglandins for renal
Concomitant alcohol use Severe renal impairment
function (HF, hepatic
cirrhosis with ascites, chronic Individuals who rely (<30 mL/min)
renal failure, hypovolemia) on vasodilatory renal Severe cardiac impairment
prostaglandins for renal and a history of hypertension
function (HF, hepatic
cirrhosis with ascites, chronic Coagulation disorders
renal failure, hypovolemia) Individuals who rely
on vasodilatory renal
prostaglandins for renal
function (HF, hepatic
cirrhosis with ascites, chronic
renal failure, hypovolemia)
Drug interactions Alcohol: increased risk of Alcohol and corticosteroids: Alcohol and corticosteroids: Alcohol and corticosteroids:
hepatotoxicity increased risk of GI increased risk of GI increased risk of GI
Copyright © 2010 Canadian Pharmacists Association. All rights reserved.

Enzyme inducers (e.g., pain/ulceration pain/ulceration pain/ulceration

phenytoin, barbiturates, Antagonism of hypotensive Antagonism of hypotensive Antagonism of hypotensive
carbamazepine, isoniazid) effects of ACEI, diuretics, effects of ACEI, diuretics, effects of ACEI, diuretics,
decrease acetaminophen beta-blockers beta-blockers beta-blockers
levels Anticoagulants: increased Anticoagulants: increased Anticoagulants: increased
risk of bleeding risk of bleeding risk of bleeding
Increased levels of Increased levels of Increased levels of
cyclosporine and risk of methotrexateb cyclosporine and risk of
nephrotoxicity ASA may decrease nephrotoxicity
Increased levels of lithium, therapeutic effect Increased levels of lithium,

Chapter 9: Fever
methotrexateb of uricosuric agents methotrexateb
Reduction of ASA’s (probenecid, sulfinpyrazone) Reduction of ASA’s
antiplatelet effects43 antiplatelet effects43

(cont’d)

87
 88
Copyright © 2010 Canadian Pharmacists Association. All rights reserved.

Table 5: Drug Therapy for Fever (cont’d)

For available products consult Analgesic Products: Internal Analgesics and Antipyretics; Baby Care Products: Antipyretics in Compendium
of Self-Care Products.

Central Nervous System Conditions

Acetaminophen Ibuprofen ASA Naproxen Sodium
Overdose Nausea, vomiting, GI disturbances, bleeding, Tinnitus, hyperpyrexia, Drowsiness, dizziness,
hepatotoxicity, death CNS depression, metabolic hyperventilation, acid-base disorientation, heartburn,
acidosis, hypotension, disturbances, nausea, indigestion, epigastric pain,
bradycardia, seizures, vomiting, dehydration, abdominal discomfort,
drowsiness, diaphoresis, coma, seizures, bleeding, nausea, vomiting, transient
liver dysfunction, death. hepatotoxicity, renal failure, alterations in liver function,
Serious toxicity from hyper- or hypoglycemia, hypoprothrombinemia,
overdose is unusual death renal dysfunction, metabolic
acidosis, apnea and seizures
Other comments Rectal products slowly and Take with food Take with food Drink a full glass of water
incompletely absorbed Avoid in 3rd trimester of Rectal products slowly and with each dose
Preferred agent in pregnancy pregnancy incompletely absorbed Take with food
and breastfeeding May be used while Avoid in 3rd trimester Food slightly delays
breastfeeding of pregnancy and while absorption
In patients on long-term ASA breastfeeding Avoid in 3rd trimester of
for cardioprotection take pregnancy
ibuprofen at least 30 minutes May be used while
after ASA ingestion or at breastfeeding although
least 8 hours before ASA shorter acting NSAIDs
ingestion to avoid a potential (ibuprofen) may be preferred
interaction43
Only give to children if they
are drinking reasonably well8
a NSAIDs are generally avoided in the presence of renal dysfunction because of the risk of renal toxicity. Dosing is provided if acetaminophen is contraindicated and benefit is seen
to outweigh risk.
b More likely to occur with antineoplastic doses of methotrexate.

Abbreviations: ACEI = angiotensin converting enzyme inhibitor; CNS = central nervous system; GI = gastrointestinal; HF = heart failure; IBD = inflammatory bowel disease;
NSAIDs = nonsteroidal anti-inflammatory drugs
Patient Self-Care, 2010
 Chapter 9: Fever 89
In children ages 3 months to 5 years, seizures occur if ASA is ingested by the mother within 7 days of
with 2–5% of febrile episodes.65 Although simple delivery and salicylates displace bilirubin from protein
febrile seizures are rarely associated with neurologic binding sites. Increased bleeding has been reported in
damage or permanent seizure disorders, they concern both mothers and infants if ASA is ingested close to
and frighten parents. For this reason, antipyretics are the time of delivery.51 See Appendix V, Pregnancy and
often recommended for children in this age group, Breastfeeding: Nonprescription Therapy for Common
particularly those with previous febrile seizures or Conditions.
neurologic problems. Recommending antipyretics at
the first sign of fever is not effective in preventing Fever Phobia
recurrent febrile seizures even though this practice is
frequently recommended.65,66,67 The term “fever phobia” describes unrealistic concerns
and misconceptions parents and health professionals
Patients with Cardiovascular or Pulmonary have regarding fever in children.74,75,76,77,78 Health care
Disorders professionals should undertake educational interven-
Increased metabolic demands which occur during tions to ensure appropriate management of fever and
the chill phase (increased metabolic rate, nore- rational use of antipyretics.
pinephrine-mediated peripheral vasoconstriction,
increased arterial blood pressure) may aggravate Optimizing Dosing and Administration
comorbid disease states in patients with heart failure,
Review the following points with all parents when rec-
coronary, pulmonary or cerebral insufficiency. Fever
ommending an antipyretic preparation:
may result in deterioration in cognitive function and
delirium.1 ■ Ensure parents/caregivers understand that fever is
rarely harmful and does not have to be treated.
The Elderly
■ Explain that comfort is the goal and not achievement
Older individuals exhibit less intense fevers in response of an arbitrary “normal” temperature.
to infection compared to younger individuals.68 They ■ Assist the parent in calculating the correct mg/kg
also become hypothermic more often when infected dose of the drug and ensure they know the maxi-
and have greater morbidity and mortality from infec- mum number of doses that can be administered in a
tions.68 Fever in individuals older than 60 is less likely 24-hour period.
to be a benign febrile illness than it is in younger indi-
viduals;69 therefore, it is important to carefully assess – In a study of 100 caregivers given a mock dosing
fever in the elderly. The elderly are more likely to have scenario that required the caregiver to determine
the cardiovascular and pulmonary conditions described and measure a correct dose of acetaminophen for
above. Acetaminophen is safer in older individuals their child, only 40% stated an appropriate dose
with risk factors predisposing to GI and renal toxicity for their child.79
of NSAIDs. – Of 118 children given an antipyretic at home and
subsequently brought to the emergency depart-
Pregnancy ment, only 47% had been given a proper dose.80
Studies in humans suggest that exposure to fever Underdosing may be a cause of unnecessary
and other heat sources during the first trimester of emergency department visits.81 This also leads to
pregnancy is associated with increased risk of neural added stress for both the parent and sick child.82
tube defects and multiple congenital abnormalities.70,71 ■ Ask what form of product they have at home and cal-
Although one study indicated a possible benefit72 of culate the appropriate number of millilitres or tablets
antipyretic therapy others have not.73 for the child.
Acetaminophen crosses the placenta and is relatively – Multiple miscalculated overdoses of
safe for short-term use in pregnancy when therapeutic acetaminophen given by parents account for an
doses are used. Use of ASA and NSAIDs can result important cause of acetaminophen toxicity.83,84,85
in a number of problems. Since these drugs inhibit – Use of incorrect measuring devices, differences
prostaglandin synthesis, they may interfere with labor in medication concentrations (e.g., pediatric
and cause premature closure of the ductus arteriosus drops vs suspensions), use of adult formula-
resulting in persistent pulmonary hypertension in the tions for pediatric patients and unrecognized
infant. Platelet aggregation is inhibited in the newborn acetaminophen content in multiple ingredient

Patient Self-Care, 2010 Copyright © 2010 Canadian Pharmacists Association. All rights reserved.
90 Central Nervous System Conditions

cough and cold products contribute to this prob- Suggested Readings

lem.84
■ Ensure the parent has and will use an appropriate American Academy of Pediatrics. Committee on
measuring device. Drugs. Acetaminophen toxicity in children. Pedi-
atrics 2001;108:1020-4.
– In the mock dosing study reported above, only
67% of caregivers accurately measured the Aronoff DM, Neilson EG. Antipyretics: mechanisms
amount they intended to give. Forty-three of action and clinical use in fever suppression. Am
percent measured out a correct amount of J Med 2001;111:304-15.
acetaminophen; however, 30% of these did so by Canadian Paediatric Society. Caring for Kids. Fever
accident by inaccurately measuring an improper and temperature taking [cited 2009 Jul 23]. Avail-
dose.79 able from: www.cps.ca/caringforkids/whensick/
■ Ask about other preparations, particularly cough fever.htm.
and cold products, they may be coadministering and Crocetti M, Moghbeli N, Serwint J. Fever phobia re-
ensure they are aware of the antipyretic content of visited: have parental misconceptions about fever
these products. The coadministration of these prod- changed in 20 years? Pediatrics 2001;107:1241-6.
ucts should be carefully monitored to ensure the cu- Mayoral CE, Marino RV, Rosenfeld W et al. Alternat-
mulative dose is within the recommended range. ing antipyretics: is this an alternative? Pediatrics
2000;105:1009-12.
Monitoring of Therapy
Plaisance KI. Toxicities of drugs used in the manage-
Recommendations for frequent monitoring of tempera- ment of fever. Clin Infect Dis 2000;31:S219-23.
ture likely contribute to parental concern and fever pho- Simon HK, Weinkle DA. Over-the-counter medica-
bia. The temperature should be taken if the patient feels tions. Do parents give what they intend to give?
warm or looks ill to determine the initial temperature.
Arch Pediatr Adolesc Med 1997;151:654-6.
Subsequently, temperatures need not be taken more
than 2–4 times daily unless the patient has recently Steering Committee on Quality Improvement and
received chemotherapy. If the fever persists for 24 Management, Subcommittee on Febrile Seizures.
hours without an apparent cause, or for more than 3 Febrile seizures: clinical practice guideline for the
days, medical attention should be sought. The degree long-term management of the child with simple
of illness and not the temperature should guide therapy febrile seizures. Pediatrics 2008;121:1281-6.
and referral. References
Monitor: 1. Mackowiak PA. Fever. In: Mandell GL, Bennett JE, Dolin R,
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■ All patients given antipyretics for development of tice of infectious diseases. 7th ed. Philadelphia: Churchill Liv-
rash or other allergic reactions. ingstone/Elsevier; 2010.
■ Patients with pre-existing comorbid illness for 2. Mackowiak P. Concepts of fever. Arch Intern Med
1998;158:1870-81.
edema and decreased urine output. 3. Alpern ER, Henretig FM. Fever. In: Fleisher GR, Ludwig
■ For other common side effects, such as GI intoler- S, Henretig FM, editors. Textbook of pediatric emergency
ance and tinnitus (Table 5). medicine. 5th ed. Philadelphia: Lippincott Williams & Wilkins;
2006. p. 295-306.
■ To ensure appropriate doses, products and measur- 4. Mackowiak PA, Wasserman SS, Levine MM. A critical appraisal
ing devices are being used, and the patient is not of 98.6 degrees F, the upper limit of the normal body tempera-
receiving excessive amounts of antipyretics through ture, and other legacies of Carl Reinhold August Wunderlich.
JAMA 1992;268:1578-80.
use of cough and cold or analgesic products. 5. Mackowiak PA, Bartlett JG, Borden EC et al. Concepts of
■ To ensure the patient is not receiving interacting fever: recent advances and lingering dogma. Clin Infect Dis
medications (Table 5). Recommend avoiding alco- 1997;25:119-38.
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8. Canadian Paediatric Society. Caring for Kids. Fever and
temperature taking [cited 2009 Jul 23]. Available from:
www.cps.ca/caringforkids/whensick/fever.htm.

Copyright © 2010 Canadian Pharmacists Association. All rights reserved. Patient Self-Care, 2010
 Chapter 9: Fever 91
9. Mackowiak PA, LeMaistre CF. Drug fever: a critical appraisal of 31. Newman J. Evaluation of sponging to reduce body temperature
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14. Craig JV, Lancaster GA,Williamson PR et al. Temperature mea- fever management? Arch Dis Child 2008;93:918-20.
sured at the axilla compared with rectum in children and young 38. Eccles R. Efficacy and safety of over-the-counter analgesics
people: systematic review. BMJ 2000;320:1174-8. in the treatment of common cold and flu. J Clin Pharm Ther
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frared emission detection tympanic thermometry. Ann Emerg 39. Goldman RD, Ko K, Linett JL et al. Antipyretic efficacy and
Med 1992;21:1483-92. safety of ibuprofen and acetaminophen in children. Ann Phar-
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17. Selfridge J, Shea SS. The accuracy of the tympanic membrane 15-mg/kg maintenance dose. Pediatrics 2000;108:E73.
thermometer in detecting fever in infants aged 3 months and 41. U.S. Food and Drug Administration. Acetaminophen
younger in the emergency department setting. J Emerg Nurs overdose and liver injury—background and options for
1993;19:127-30. reducing injury [cited 2009 Aug 30]. Available from:
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infrared ear thermometry for fever diagnosis in children finds 1-01-FDA.pdf.
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19. Onur OE, Guneysel O, Akoglu H et al. Oral, axillary, and tym- standard [cited 2010 Feb 13]. Available from: www.hc-
panic temperature measurements in older and younger adults sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/label_
with or without fever. Eur J Emerg Med 2008;15:334-7. stand_guide_ld-eng.php.
20. Vicks. Ear Thermometer package insert. 43. Antman EM, Bennett JS, Daugherty A et al. Use of nonsteroidal
21. Reisinger KS, Kao J, Grant DM. Inaccuracy of the Clinitemp anti-inflammatory drugs: an update for clinicians: a scientific
skin thermometer. Pediatrics 1979;64:4-6. statement from the American Heart Association. Circulation
22. Scholefield JH, Gerber MA, Dwyer P. Liquid crystal forehead 2007;115:1634-42.
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1982;136:198-201. fen use in infants and children. Pediatrics 1997;100:954-7.
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24. Titus MO, Hulsey T, Heckman J et al. Temporal artery ther- atrics 1999;104:e39.
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(Phila) 2009;48:190-3. atric ibuprofen. A practitioner-based randomized clinical trial.
25. Greenes DS, Fleisher GR. Accuracy of a noninvasive temporal JAMA 1995;273:929-33.
artery thermometer for use in infants. Arch Pediatr Adolesc Med 47. Southey ER, Soares-Weiser K, Kleijnen J. Systematic review
2001;155:376-81. and meta-analysis of the clinical safety and tolerability of
26. Hebbar K, Fortenberry JD, Rogers K et al. Comparison of tem- ibuprofen compared with paracetamol in paediatric pain and
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in pediatric intensive care unit patients. Pediatr Crit Care Med 48. Moghal NE, Hegde S, Eastham KM. Ibuprofen and acute renal
2005;6:557-61. failure in a toddler. Arch Dis Child 2004;89:276-7.
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tion with survival. J Toxicol Clin Toxicol 2000;38:55-7.

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53. Aspirin and Reye syndrome. Committee on Infectious Diseases. 69. Keating HJ, Klimek JJ, Levine DS et al. Effect of aging on the
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55. Waldman RJ, Hall WN, McGee H et al. Aspirin as a risk factor posure and neural tube defects. JAMA 1992;268:882-5.
in Reye’s syndrome. JAMA 1982;247:3089-94. 71. Edwards MJ. Review: hyperthermia and fever during preg-
56. Mayoral CE, Marino RV, Rosenfeld W et al. Alternating an- nancy. Birth Defects Res A Clin Mol Teratol 2006;76:507-16.
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57. Wright AD, Liebelt EL. Alternating antipyretics for fever reduc- diseases as possible causes of multiple congenital abnormalities:
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58. Erlewyn-Lajeunesse MD, Coppens K, Hunt LP et al. Ran- 73. Li Z, Ren A, Liu J et al. Maternal flu or fever, medication
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antipyretics: antipyretic efficacy of acetaminophen versus ac- 75. Schmitt BD. Fever phobia: misconceptions of parents about
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61. Schmitt BD. Concerns over alternating acetaminophen and tion. Pediatrics 1992;90:851-4.
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Copyright © 2010 Canadian Pharmacists Association. All rights reserved. Patient Self-Care, 2010
 Chapter 9: Fever 93

Fever — What You Need to Know

Hints to help you manage a fever: acetaminophen, ibuprofen or ASA. Be sure you are
■ Treat the person, not the fever. By itself, fever is not giving your child too much of these medicines.
rarely dangerous. It is not always necessary to use ■ Keep all medications out of reach of children.
drugs to lower a fever. ■ Encourage the person with fever to drink lots of flu-
■ Do not wake a sleeping child to give drugs for fever. ids.
■ Do not use fever medication for more than 3 days ■ Keep the person cool by removing excess clothing
without consulting a doctor. and bedding.
■ Use acetaminophen or ibuprofen for fever in chil- When should you contact your doctor?
dren and adolescents. Do not use ASA—it can
cause Reye’s syndrome, a serious liver disorder. ■ Contact the doctor for:
■ Use one drug only. Do not alternate acetaminophen – fever over 40.5°C
and ibuprofen. – children less than 2 months old who have fever
■ Read the labels carefully. Make sure you use the – a child who appears very ill, has a stiff neck, has
right form of medicine for your child (liquid or a seizure, is confused or delirious, or is crying
pills). Determine the dosage based on your child’s without stopping
weight. Use the proper measuring device to be sure ■ Contact the doctor if the person with a fever has
the amount is accurate. recently had chemotherapy.
■ Check other medications, especially medica-
tions for cough and cold, to see if they contain

Patient Self-Care, 2010 Copyright © 2010 Canadian Pharmacists Association. All rights reserved.