AACN Advanced Critical Care
Volume 25, Number 3, pp. 237-248
Fever in Acute and Critical Care
A Diagnostic Approach
Nancy Munro, RN, MN, CCRN, ACNP-BC
ABSTRACT
Determining the underlying cause of a fever
can be a daunting task. Multiple reasons
have been found for a patient to have a fever,
but the use of an organized approach will
assist clinicians in reaching a correct diagno-
sis. The first step in this process is a com-
plete assessment, including a thorough
physical assessment and an evaluation of
the history of present illness as well as a
detailed review of all the patient’s medica-
tions. Infection should always be a primary
F ever is a signal of a disruption of one of the
body’s defense mechanisms. The cause of
the disruption can be either infectious or non-
infectious, and the challenge is to discover the
underlying cause (see Figure 1). In the acute
and critical care setting, fever is a common
physical finding that must be addressed. Fever
is thought to occur in approximately 50% of
patients in the intensive care unit (ICU) and is
associated with adverse outcomes, including
death with high fever.1 The search for the cause
of fever can lead to increased diagnostic test-
ing, which incurs more cost and, at times,
increased risk to the patient. Practitioners need
to understand the mechanism of fever and how
to properly measure it and develop a compre-
hensive method to analyze the cause.
Thermoregulation Theory
A rise in temperature is only one part of the
febrile response. Although not thoroughly
understood, the febrile response is believed to
be an adaptive mechanism. It involves a
cytokine-mediated rise in core temperature, the
generation of acute phase reactants, and the
activation of some of the endocrine and immune
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NCI-D-14-00019.indd 237
© 2014 AACN
consideration for the cause of a fever. Evalu-
ating each body system can match symp-
toms with a possible cause for fever, and
proper testing and imaging can be pursued.
Noninfectious causes of fever need to be
included in the differential diagnostic pro-
cess. This article provides an analytic
approach to fever in adult patients in the
acute and critical care environment.
Key words: cytokines, fever, inflammation,
intensive care unit, temperature
mechanisms.2 To generate heat, cells must
engage in chemical reactions involving catabo-
lism. The body will maintain a level of heat pro-
duction in its normal functions, and the heat is
distributed throughout the body by the circula-
tory system. The control of temperature is dele-
gated to the nervous system, and although
centered in the hypothalamus, also includes the
limbic system, the lower brainstem and reticular
formation, the spinal cord, and sympathetic
ganglia. This group of structures involved in
thermoregulation is referred to as the preoptic
region.2 Temperature-sensitive cells in this area
control body temperature by integrating signals
from thermal sensors in the skin and core areas.
Warm and cold sensing neurons respond to
feedback from the peripheral sensors and bal-
ance their signaling to maintain a set temperature
Nancy Munro is Senior Acute Care Nurse Practitioner, National
Institutes of Health, Critical Care Medicine Department/
Pulmonary Consult Service, 10 Center Dr, Building 10-CRC,
Room 3-3677, Bethesda, MD 20892 (munronl@cc.nih.gov).
The author declares no conflicts of interest.
DOI: 10.1097/NCI.0000000000000041
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Fever
Infectious
Other Inflammatory
Head/neck Drug
Chest Transfusion reaction
Abdomen/pelvis Endocrine
Postoperative (> 96 hours) DVT
Postoperative (< 96 hours)
Figure 1. Causes of fever.3,50 Abbreviations: ARDS, acute respiratory distress syndrome; CVA, cerebral
vascular accident; DVT, deep vein thrombosis; GI, gastrointestinal; MI, myocardial infarction; PE, pulmonary
embolism; TBI, traumatic brain injury.
point of 37.0°C (98.6°F) through a negative
feedback loop. Heat loss responses such as vas-
odilation and sweating assist with lowering
body temperature, whereas heat retention
responses and heat production mechanisms
such as shivering increase catabolism and raise
body temperature.2
The thermal set point is thought to be con-
trolled within a very narrow range. Endoge-
nous and exogenous pyrogens can alter this set
point. Endogenous pyrogens are cytokines
released by phagocytic leukocytes into the
blood as a result of various stimuli. They either
cross the blood-brain barrier or cause release
of other mediators, in particular prostaglandin
E2, which interact with neuron receptors in the
preoptic area. This interaction causes a change
in firing rate and leads to an elevation of the
thermal set point.2 Exogenous pyrogens are
substances that are released by microbes and
are thought to trigger macrophages to produce
endogenous pyrogens, resulting in the same
end point of increasing the set point. The sign-
aling system with these pyrogens is complex
because of the large number and types of cells
involved. The most common pyrogenic
cytokines include interleukin 1 (IL-1), tumor
necrosis factor α, IL-6, and interferon γ.2 These
cytokines are thought to interact with the
receptors on the preoptic area neurons, liberat-
ing arachidonic acid and ultimately releasing
prostaglandin E2. Thus, the neuron firing rate
is changed and the set point is increased.2
Experts theorize that the febrile response is
an adaptive mechanism that has allowed
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NCI-D-14-00019.indd 238
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Noninfectious
Other Inflammatory (System)
Neuro (CVA, TBI, Seizure)
Cardiac (MI, Pericarditis)
Pulmonary (PE, ARDS)
GI (Pancreatitis, Acalculous
Cholecystitis, Ischemic colitis)
humans to survive. The acute phase response is
considered part of the febrile response. The same
cytokines that reset the thermal set point will
cause other physiological reactions, including
somnolence, anorexia, change in plasma protein
synthesis, and altered synthesis of multiple hor-
mones (eg, corticotropin-releasing hormone,
glucagon, insulin, hydrocortisone, aldosterone,
and many others).2 Many positive and negative
acute phase proteins (APPs) are considered a
major part of the acute phase response. Some
of these proteins play an active role in the
inflammatory process and tissue repair. C-reac-
tive protein is a positive APP that increases in
the acute phase response to bind with phos-
pholipid components of pathogenic bacteria as
well as necrotic host cells, activating the com-
plement system to eliminate these cells.2 Albu-
min is a negative APP that decreases with
inflammation and is thought to allow for
greater production of positive APPs. Some
endogenous cryogens also are cytokines that
have antipyretic activity to help maintain the
upper limit for temperature resetting. Exam-
ples of these cryogens are arginine vasopressin
and α-melanocyte-stimulating hormone, whose
cytokine activity assists in maintaining the
upper temperature limit of 41.0°C (105.8°F).2
The acute phase response is a complex series of
reactions and counteractions in the mainte-
nance of homeostasis.
Definition of Fever
Variation exists in the literature about quantita-
tive values to define fever. Temperature values
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range from a single measurement of 38.0°C
(100.4°F) to 2 consecutive elevations of greater
than 38.3°C (101.0°F), with other qualifiers in
the description including route of measure-
ment, immunological state, and rate of temper-
ature elevation.3 These variations are justified
when considering the complexity of the con-
cept of fever. Variables that must be accounted
for include age, sex, immunological status, cir-
cadian rhythms, and environmental factors as
well as pharmacological and external interven-
tions, that is, extracorporeal membrane oxy-
genation and continuous renal replacement
therapy. To provide a general standard for clin-
ical practice, the American College of Critical
Care Medicine and the Infectious Diseases
Society of America (IDSA) have published and
updated guidelines for evaluation of new fever
in critically ill adult patients.3,4 Patients who
have a temperature of 38.3°C (100.9°F) or
higher are considered febrile, and an investiga-
tion for the cause of the temperature elevation
should be pursued.3
Patients who are immunocompromised
deserve special consideration, because their
immunological system is abnormal and is una-
ble to manifest a normal febrile response.
Hughes et al5 recommend that patients with
neutropenia are febrile when a temperature ele-
vation higher than 38°C (100.4°F) is present for
more than 1 hour. Although patients with neu-
tropenia are obviously immunologically com-
promised, a high prevalence of unrecognized
immune dysfunction is present in critically ill
patients.6 Patients who have recently received
or are currently being treated with steroids or
patients with Cushing syndrome with high lev-
els of cortisol are examples of patients with
atypical immune suppression. The elderly are
another population that can be included in this
category. A temperature of less than 36.0°C
(96.8°F) without a known cause for the
decrease also should be a trigger to investigate
the cause.3 Hypothermia occurs in more severe
cases of sepsis and septic shock.7 The mecha-
nism for hypothermia with sepsis is not clear
but thought to be induced by bacterial lipopol-
ysaccharide in rat models.7,8 This research has
led to the discovery of new lipid-derived media-
tors, referred to as endocannabinoids, that
interact with cannabinoid-1 and other recep-
tors.7 The cannabinoid-1 receptors are thought
to be expressed by leukocytes, microgliocytes,
and neurons.7 Temperature can, therefore, be
another indicator of immunosuppression that
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NCI-D-14-00019.indd 239
D IAGNOST IC A P P ROACH TO FE VE R
can alert practitioners caring for acute and
critically ill patients.
Measurement of Temperature
Multiple methods are available to measure
temperature, but clinicians should understand
the accuracy and limitations of each method
and device. The criterion standard remains the
measurement of core temperature using a pul-
monary artery catheter.3,9 Core temperature is
the best evaluation of body temperature
because it is the least influenced by environ-
mental and other factors and maintains a sta-
ble temperature.10 The issues with using the
pulmonary artery catheter are that it is inva-
sive and its use has decreased significantly over
the years. The distal esophagus, bladder, poste-
rior nasopharynx, and tympanic membrane
are other sites of core temperature measure-
ment.9 The alternative methods are noninva-
sive and measure peripheral temperature,
which can be influenced by extreme environ-
ment and physiological conditions. The site
and instrument used for noninvasive measure-
ment are the most important factors when
considering accuracy. Accuracy is affected by
common sources of error, including operator
technique, anatomic site, and calibration and
inherent instrument error.10 Research evaluat-
ing methods and accuracy for temperature
measurement compared with core temperature
consider the end result accurate if the mean
difference in temperature obtained was
±0.3°C and the instrument to be accurate if
the standard deviation was from 0.3°C to
0.5°C.9 Table 1 compares the different temper-
ature modes, variations from core tempera-
ture, and the advantages and disadvantages of
each method.
Oral thermometry was thought to be influ-
enced by oxygen therapy, warmed and cooled
inspired gases, and respiratory rates, but multi-
ple analyses demonstrate that these factors
have no statistical influence if the oral temper-
ature is taken in the left or right posterior (buc-
cal) pocket.10,26,27 Even oral intubation has been
tested as to its effect on temperature accuracy
and does not influence the value.13 Tympanic
thermometry is commonly used, most likely
because of ease, despite studies that were
poorly designed and did not address proper
technique and instrument testing.10 Esophageal
temperature monitoring, which is a good
measurement of core temperature, is used pri-
marily in the operating room, but could be a
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Table 1: Summary of Different Temperature Modes, Variation From Core Temperature,

Clinical Advantages, and Disadvantagesa
Site of Variation
Temperature From Core Best Practice: Advantages (+)
Measurement Temperature and Disadvantages (−)
Pulmonary Reference standard + True core temperature
artery − Highly invasive
Oral <0.4°C + Ease of use
+ Oxygen up to 6 L and endotracheal tube do not influence
accuracy11-13
+ Research has shown that administration of warmed gases
and oxygen through an endotracheal tube does not cause
significantly different oral temperature compared with core
temperature13,14
− Accurate placement of probe in the mouth (posterior
sublingual pocket) is necessary for correct temperature
reading10,11,12,15
− May be influenced by fluids and tachypnea16
Esophagus <0.1°C + Correlates closely with pulmonary artery temperature.15,17,18
Optimal placement requires the esophageal temperature
probe to be positioned at the point of maximal heart tones
(left atrium) in the distal part of the esophagus11,17 and at an
insertion depth between 32 and 38 cm.18
+ Minimal lag time for temperature measurement15,17
− Temperature fluctuates according to depth of probe; accu-
rate placement is key18
Bladder <0.2°C + Easy to perform with urinary catheterization; low risk of
dislocation
+ Temperature is accurate during dates of increased diuresis19
− Accuracy of temperature influenced by low urine flow17,18
− Lag time estimated up to 20 min during therapeutic hypo-
thermia interventions18
Rectum <0.3°C + Easy to perform
− Invasive; placed in rectal vault; may be expelled with intes-
tinal motility
− Lag time estimated up to 15 min17,18
− Accuracy of readings influenced by stool in the rectum
Temporal <0.4° C + Minimally invasive temperature closely correlated with core
artery temperature
+ Temporal artery is not significantly affected by thermoregula-
tory changes; therefore, perfusion should be stable in most
conditions and closely reflect core temperature.16,17,20
− Current research has provided mixed results as to accuracy
of this device in different practice settings, patient popula-
tions, and physiological conditions.
− Diaphoresis may influence accuracy of temperature readings.
− Accuracy of temperature measurement procedure required
for correct temperature reading from the forehead and be-
hind the ear.16,21
Tympanic Not recommended for − Tested in multiple populations of patients; however, user
membrane temperature error and patient’s anatomy reduce accuracy of temperature
monitoring3,10,12,15,17, 22 obtained.10,12,15,17,23
a
Based on evidence from Hooper and Andrews,10 Sessler,17 Crawford et al,24 Torossian,11 Forbes et al,15 Bridges and Thomas,23 Hooper
et al,12 Polderman and Herold,18 O’Grady et al,3 Exacon Scientific,25 Konopad et al,14 and Fallis.19 Reprinted with permission from Flynn Makic
MB, VonRueden KT, Rauen CA et al. Evidence-based practice habits: putting more sacred cows out to pasture. Crit Care Nurse. 2011;31:38–62.

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 VOL UME 2 5 • N U MBER 3 • JULY–SEPTEM BER 2014
modality used in the ICU once postoperative
patients are transferred to that setting.
Advanced practice practitioners must be
knowledgeable about the methods of ther-
mometry used in their practice setting to make
informed treatment decisions.
Infectious Causes of Fever
Assessment of fever begins with a thorough
history of the patient’s illness, including expo-
sure to people who are or have been sick, travel
history both inside (with attention to areas
that are sources of specific infections) and out-
side the United States, and environmental
exposures, such as construction where mold
and other microbe exposures are common.
Animals are also sources of infection and the
inquiry should not be limited to domestic pets
but also should include farm animals and more
exotic animals, including monkeys, reptiles,
and others. A thorough physical examination
is an integral part of the diagnostic process and
should include inspection of all devices, the
sites of insertion, and all skin areas, especially
the back and sacrum. Laboratory testing
should include serial complete blood cell count
with a differential to evaluate for leukocytosis
or leucopenia as well as a review of the per-
centage of various types of white blood cells
(WBCs), especially neutrophils, lymphocytes,
and eosinophils. Leukocytosis is a common
finding with infection, but it could also indi-
cate a hematologic disorder such as leukemia
or lymphoma. A high eosinophil count could
indicate an allergic reaction. The patient’s
medication list should be reviewed; a clinical
pharmacist is a great resource for any ques-
tions about medications. All these data should
be considered in this diagnostic process.
The Centers for Disease Control and Pre-
vention (CDC) has recently published a
10-state point-prevalence survey on hospital-
acquired infections performed in 2011 that
revealed that 1 in every 25 patients in the acute
care setting has a hospital-acquired infection.28
The most common infections are pneumonia
(not ventilator associated; 21.8%) and surgical
site infections (21.8%) followed by gastroin-
testinal tract infections (17.1%), with the most
common pathogen being Clostridium difficile.
Urinary tract infections (UTIs; 12.9%) and pri-
mary bloodstream infections (9.9%) com-
pleted the top 5 infections discovered in this
prevalence survey.28 Data from national surveys
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NCI-D-14-00019.indd 241
D IAGNOST IC A P P ROACH TO FE VE R
and data banks can inform clinicians about
patterns of infections.
Bacteremia and Central Line–
Associated Bloodstream Infections
Bacteremia is the presence of bacteria or path-
ogens in the blood. Bacteria remain a major
concern in the development of bloodstream
infections, but the presence of fungi in blood is
becoming more prevalent. The most common
pathogens involving bloodstream infections
reported in the CDC multistate prevalence sur-
vey were (1) Candida species (11%) including
C albicans, C parapsilosis, and C glabrata; (2)
coagulase-negative Staphylococcus species (9%);
and (3) Staphylococcus aureus (7%) as well as
other pathogens.28
Central line–associated bloodstream infec-
tions can be a cause of fever. If the patient has
an abrupt onset of signs and symptoms and
has no other local site of infection, an intra-
vascular catheter infection should be a pri-
mary consideration as the fever source. The
types of catheters associated with the highest
risk of infection are short-term, noncuffed
central venous catheters, with short-term
hemodialysis catheters having an even higher
risk.3 The site of insertion should be examined
for inflammation and purulent drainage, but
these findings may not always be present. At
least 2 sets of blood cultures (1 culture set
from the suspected central catheter and 1 set
from a peripheral blood draw if able) should
be collected, and at least 20 mL of blood
should be added to each bottle. The volume of
blood is important to optimize possible patho-
gen growth.3,29 If the catheter is thought to be
the source of infection, it should be removed,
and the tip can be cultured. However, cultur-
ing the tip of the catheter is controversial
because up to 20% of removed central venous
catheters are colonized at removal and can
lead to unnecessary therapies as well as extra
cost for laboratory testing if the tip culture
data are not interpreted appropriately.3 If the
suspected central catheter is a long-term cen-
tral catheter, removal of the catheter has other
ramifications. When virulent pathogens such
as S aureus are detected, the catheter should
be removed. Other pathogens found in multi-
ple blood cultures such as Corynebacterium
jeikeium, Bacillus species, atypical mycobac-
teria, or Malassezia species suggest an intra-
vascular catheter device infection.3
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Central Nervous System Infections
Once artificial devices are addressed as a source
of infection, using a body system approach is
useful for organizing the diagnostic process.
Central nervous system infections should be a
consideration when a change occurs in level of
consciousness or new focal deficits appear in
patients with fever in the acute and critical care
setting. Diagnostic tests that are most useful
with central nervous infections are the lumbar
puncture and imaging studies. Noncontrast
head computed tomography (CT) is usually the
first imaging to be performed because it will
give adequate information about mass lesions
or obstructive hydrocephalus.3 It also will help
assess for increased intracranial pressure and
whether clinicians can safely perform a lumbar
puncture and not risk herniation. The brain
parenchyma can be further assessed using mag-
netic resonance imaging.
Cerebral spinal fluid obtained from a lum-
bar puncture should be sent for cell counts and
differential, glucose and protein concentra-
tions, gram-negative stains, and bacterial cul-
tures. Protein content of cerebral spinal fluid
can vary depending on where the fluid is
obtained.3 Further testing for fungi or viruses
with polymerase chain reaction tests also can
be performed. Lumbar punctures have a low
yield for positive results unless the patient is
immunocompromised or has instrumentation
such as a ventriculostomy, ventriculoperitoneal
shunt, or Ommaya reservoir.30 If spinal cord
involvement is suspected, neurosurgery should
be consulted before sampling cerebral spinal
fluid. Meningitis is the primary diagnosis when
infection is suspected. Empiric antimicrobial
coverage can be started for virulent microor-
ganisms such as Streptococcus pneumonia,
Neisseria meningitidis, and Listeria monocy-
togenes (especially in older adults) while the
diagnostic process proceeds.31 A thorough
physical examination should be performed to
include not only the neurological examination
but also the site of any devices.
Pulmonary Infections
Pulmonary infection in acute and critical care
patients has been a focus in the literature with
the advent of the ventilator-associated pneu-
monia (VAP) bundle introduced by the Insti-
tute for Healthcare Improvement in 2005.32
Much controversy has arisen about the validity
of the VAP bundle in the literature, which has
resulted in the CDC convening a board of
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NCI-D-14-00019.indd 242
W W W.A ACNA DVA NCE D CRIT ICA LCA RE .COM
experts and organizations to help address some
of the issues with the bundle.33 This contro-
versy has demonstrated the difficulty with
standardizing a definition for VAP. Radiologi-
cal confirmation of an infiltrate in pneumonia
is required, and other clinical findings have
similar appearance on a chest radiograph,
including atelectasis, effusion, heart failure,
and acute respiratory distress syndrome, which
can confound the diagnosis.3 Overdiagnosis of
VAP is now becoming a concern.34 Although
the sample size was small in the CDC point
prevalence study, pneumonia rather than VAP
may be the more prominent issue currently.28
Consideration must be given as to whether the
infection was acquired in the hospital setting,
that is, hospital-acquired pneumonia, or
whether infection developed in the community
setting, that is, community-acquired pneumo-
nia. Different organisms are primary patho-
gens in these different settings, so making this
determination is an important step. Multiple
drug-resistant organisms, especially methicil-
lin-resistant S aureus, are now automatically
included in this decision-making process.
Carbapenem-resistant Enterobacteriaceae is
another group of virulent bacteria that are an
increasing infection threat, especially in hospi-
tal settings. The CDC provides an epidemiology
perspective on multidrug-resistant organisms
and has many resources available to assist with
prevention.35 The IDSA has developed guide-
lines for both hospital-acquired pneumonia
and community-acquired pneumonia that are
excellent resources for practice.36,37
The 3 components of an initial evaluation
for a pulmonary infection include physical
examination, chest radiograph, and examina-
tion of pulmonary secretions.3 Physical assess-
ment is a valuable tool but can be misleading,
even for experienced clinicians. To optimize the
chest radiograph’s information, clinicians must
use the best technique in performing the test.
The best inspiratory effort of the patient must
be captured as well as optimal exposure and
patient position. The posterior-anterior tech-
nique in the radiology department will usually
produce a better image than the portable chest
radiograph if the patient is stable. The other
important concept is that changes on the image
should be seen on serial chest radiographs; 1
image is not sufficient.3 Chest CT scans provide
more specific information about the lung
parenchyma, but patient acuity may limit the
ability to perform this type of imaging.
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Sputum characteristics should be assessed
for change in color and volume. If feasible, a
sputum sample should be sent before starting
any antimicrobial medications. The sample
should be sent to the laboratory within 2 hours
of collection for optimal microbiological
assessment.3 The method of sputum collection
will vary depending on the status of the
patient. Bronchoalveolar lavage (BAL) is con-
sidered the better method to sample sputum,
because it is performed under direct visualiza-
tion using fiberoptic technology and allows
sampling of a larger number of alveolar units.
Clinicians should understand that the sensitiv-
ity of quantitative BAL fluid cultures ranges
from 42% to 93%, implying that BAL fluid is
not diagnostic for VAP in approximately 25%
of cases.38 The specificity of quantitative BAL
fluid cultures ranges from 45% to 100%,
which implies that an incorrect diagnosis
(a false-positive result) occurs in 20% of cases.38
Reasons for the varying sensitivity and speci-
ficity are related to standardization of the pro-
cedure, dilutional effects, technique, choice of
sampling site, and other variables. Urine anti-
gen testing is available for Legionella pneu-
mophila type 1 and S pneumoniae. The
limitation with antigen testing is that it can
identify only 1 species.
Interpretation of sputum cultures can be
challenging, especially when determining
whether the microbe is a pathogen or colonizer.
Many organisms are usually pathogens if found
in the pulmonary system, such as Legionella,
Chlamydia, Mycobacterium tuberculosis, influ-
enza and parainfluenza virus, respiratory syncy-
tial virus, and others. Enterococci, Streptococcus
viridians or coagulase-negative staphylococci,
and Candida species are rarely the cause of res-
piratory dysfunction.3 Normal flora of the
upper respiratory tract, such as Pseudomonas
aeruginosa, S pneumoniae, S aureus, and Hae-
mophilus influenza, may be found in sputum
culture results. For clinicians to determine
whether these flora are true pathogens versus
colonizers, gram-negative organisms should be
the main organism on the direct gram-negative
stain or the culture should report moderate to
heavy growth of gram-negative organisms.3
Drawing blood cultures or polymerase chain
reaction tests may assist with determining the
cause of pneumonia.
Pleural effusions are hidden sources of infec-
tion. An infiltrate can cause an inflammatory
process that irritates the adjacent pleura, and
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NCI-D-14-00019.indd 243
D IAGNOST IC A P P ROACH TO FE VE R
an exudative effusion could result. Aspiration
of the fluid under ultrasound guidance can be
performed, and the sample should be sent for
gram-negative stain and routine culture.3 Glu-
cose, protein, lactate dehydrogenase, amylase,
pH, and cell count with differential can also
help determine whether the effusion is exuda-
tion or transudative in nature, especially if
fluid overload is present.
Sinusitis can be an underestimated cause of
fever in ICU patients. The most common rea-
son for a sinus infection is obstruction of the
ostia, especially of the maxillary sinuses.3
Obstruction is most commonly caused by nasal
intubation or insertion of gastric tubes and can
develop after 7 days of intubation. Maxillary
sinus trauma is another cause of sinusitis.3 Cli-
nicians should have a high index of suspicion
for sinusitis in patients who have a history of
sinus issues and no other source of infection is
apparent. The best imaging study for diagnos-
ing sinusitis is a CT of the facial sinuses. Opaci-
fication of the sinuses will be present on the
CT, and sampling of the fluid by needle punc-
ture may be indicated. Flora of the nasophar-
ynx, especially gram-negative bacilli, are
primarily responsible for 60% of bacterial
infections, particularly Pseudomonas aerugi-
nosa, whereas gram-positive cocci (S aureus
and coagulase-negative staphylococci) are
found in approximately 33% of cultures.39 The
IDSA has developed a clinical practice guide-
line that provides a comprehensive approach
for treating acute bacterial rhinosinusitis.40
Abdomen and Pelvis Infections
Diarrhea is a common problem in acute and
critically ill patients. In the ICU, the cause is
usually related to either enteral feedings or
drug therapy, especially clindamycin, cepha-
losporins, and fluoroquinolones.3 Infection is
an important part of the differential diagnos-
tic process for diarrhea and has become more
prominent in recent years. Definitions for
diarrhea can vary, but the 2008 guideline by
O’Grady et al3 defines diarrhea as more than
2 stools per day that conform to the container
in which they are placed. The most common
cause of enteric fever in the ICU is C difficile.3
If leukocytosis without an associated cause is
present, C difficile should be considered and
diagnosis pursued. Diarrhea may not always
be present, especially in postoperative
patients who can present with ileus or toxic
megacolon.3
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Testing for the C difficile toxin in stool is
quickly evolving. The initial test used was the
tissue culture assay, which takes 24 to 48 hours
to produce results, but more recent testing uses
the enzyme immunoassay because 2 toxins are
produced by the microbe, toxin A and B, and
2% to -3% of C difficile strains produce toxin
B, which the enzyme immunoassay can detect.3
A polymerase chain reaction test for C difficile
has been developed, which is fast and very sen-
sitive but also expensive. The test can be too
sensitive and may find genetic remnants of the
microbe when a true infection is no longer pre-
sent. Research continues in this area to try to
perfect the best test to detect C difficile and
help prevent outbreaks.41 The NAP1 strain is
causing epidemics in the United States, Canada,
and Europe, with serious consequences.3 Treat-
ment includes metronidazole and/or vancomy-
cin (preferably oral), depending on the clinical
situation. The situation has become so serious
that fecal microbiota transplantation is an
intervention for recurrent C difficile infection
and should be prescribed by specialists (usually
infectious disease) who have a special investi-
gational new drug permit.42 The IDSA guide-
lines for C difficile are helpful in making
clinical decisions.43
Other intra-abdominal infections can be
challenging to diagnose and treat. A basic
approach to the diagnostic process should be
followed and a surgery consult should be one
of the first interventions if the clinician sus-
pects an intra-abdominal process. A physical
examination revealing diffuse peritonitis is a
presentation that will probably require surgical
intervention. Patients with altered level of con-
sciousness, spinal cord injury, or immunocom-
promised state deserve a higher index of
suspicion.44 The preferred imaging is a CT of
the abdomen, and the need and type of con-
trast will be a decision dependent on the pres-
entation of the patient and the possibility of
perforation. Fluid resuscitation should be initi-
ated as soon as possible, and empiric antimi-
crobial coverage should be initiated. As with
pneumonia, community- versus hospital-
acquired infection is an important considera-
tion, as different pathogens may need to be
treated depending on the presenting situation.44
Community-acquired intra-abdominal infec-
tions should be covered empirically for enteric
gram-negative aerobic and facultative bacilli
and enteric gram-positive streptococci.44 With
hospital-acquired infections, more virulent
244
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NCI-D-14-00019.indd 244
W W W.A ACNA DVA NCE D CRIT ICA LCA RE .COM
organisms may be present, and coverage for
multidrug-resistant organisms, as well as for
Candida, should be included.44 The IDSA
guidelines for the diagnosis and management
of the complicated intra-abdominal infection
provide extensive guidance on this clinical
situation.44
Surgical wounds and their care can be costly
and represent the third most common infection
cited in the CDC point prevalence survey.28
Many factors influence a diagnosis of a surgi-
cal infection, including the medical comorbid-
ity of the patient, whether surgery was
prolonged or emergent, and the degree of con-
tamination of the incision.3 The incision should
be examined daily, and if an infection is sus-
pected, the wound should be opened and
gram-negative stain and cultures should be
sent. The most common pathogen is S aureus,
but gram-negative bacilli also can cause surgi-
cal site infections, depending on the location.3
No evidence supports the use of antibiotic
therapy in these cases, but the incision/wound
should be drained, irrigated, and treated with
local care.3 Additional information on skin and
soft tissue infections is available in the IDSA
practice guidelines.45
Urinary Tract Infections
In the acute and critical care setting, UTIs are
common but can present a clinical dilemma.
Urinary tract infections can be asymptomatic,
are discovered incidentally, and usually are not
treated except in certain circumstances such as
future transurethral resection of prostate.46
Guidelines for managing asymptomatic UTIs
have been developed by the IDSA to try to pro-
vide guidance and avoid unnecessary treat-
ment.46 Cystitis or lower UTIs can be
uncomplicated when symptoms are present,
including dysuria and vaginal discharge.
Assessment for infection should start with a
urinalysis. The presence of WBCs, leukocyte
esterase, and nitrate (substances released by
WBCs) can indicate a UTI and should prompt
obtaining a urine culture and Gram stain. Bac-
teriuria is defined as 2 consecutive voided urine
specimens with isolation of the same bacterial
strain in quantitative counts of 105 colony-
forming units/mL.46 The quantitative count is
important to help determine whether the bac-
teria is a colonizer or a pathogen. A degree of
contamination from the gastrointestinal tract
will be present, especially in women as a result
of the proximity of the anus. Escherichia coli is
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 VOL UME 2 5 • N U MBER 3 • JULY–SEPTEM BER 2014
the single most common organism leading to
UTIs. If the integrity of the urinary tract is
disrupted, that is, from surgery, injury, or
instrumentation, the infection is considered
complicated.
A Foley catheter is the most frequent device
used that can lead to infection. The best inter-
vention is to use catheters only when needed
and remove them as soon as possible.47 In
patients with short-term indwelling urethral
catheterization, use of antimicrobial (silver
alloy or antibiotic) coated urinary catheters
may be considered to reduce or delay the onset
of catheter-associated bacteriuria.47 When col-
lecting a urine sample from a catheter system,
the urine should be collected from the sam-
pling port and sent to the laboratory within 1
hour of collection.3 The IDSA guidelines for
catheter-associated urinary tract infections are
helpful in dealing with this infection, which is
one of the most common hospital-acquired
infections.47 The CDC also has guidelines to
help in operationalizing a process improve-
ment program.48 Patient presentation does not
usually include fever in cystitis, but if the infec-
tion progresses to the upper urinary tract
(above the bladder), pyelonephritis is a consid-
eration. Common pathogens include gram-
negative bacilli other than E coli, Enterococcus
species, and yeasts.3 Cystitis and pyelonephritis
can be very complicated in women and have
warranted an additional set of guidelines from
the IDSA.49
Postoperative Fever
Postoperative fever can be either infectious or
noninfectious in nature. The key factor to con-
sider is the time interval when fever appears.
Fever is common in the first 48 hours postoper-
atively and is usually inflammatory in nature,
unless improper sterile technique or pulmonary
aspiration is suspected.3 Atelectasis has been a
common explanation for acute postoperative
fever, but little evidence supports this theory.
Multiple studies have been conducted to
attempt to demonstrate a relationship between
postoperative fever and atelectasis by various
methods, including measuring cytokine levels,
but no relationship can be established.50 Marvos
et al51 state that little evidence supports any con-
nection between atelectasis and fever. However,
postoperative fever that occurs after 96 hours
should be evaluated with infection as the cause.3
Another consideration for the cause of postop-
erative fever is deep vein thrombosis, superficial
245
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NCI-D-14-00019.indd 245
D IAGNOST IC A P P ROACH TO FE VE R
thrombophlebitis, or pulmonary embolism.
Patients who preoperatively were sedentary,
had a history of cancer, or were taking oral con-
traceptives also may generate a fever.3
Noninfectious Causes
of Fever
Noninfectious causes of fever are inflamma-
tory conditions that will activate the cytokine
system and trigger a systemic inflammatory
response syndrome. The cytokines involved in
systemic inflammatory response syndrome are
the same or similar to those involved in devel-
oping a fever. These conditions can be obvious,
such as a blood component transfusion reac-
tion, or more subtle when fever is generated
with a deep vein thrombosis. Infection should
always be the first consideration when clini-
cians evaluate fever, but inflammation should
not be ignored (see Figure 1). These conditions
are challenging because treatment can be com-
plicated.
Drug fever is an example of a noninfectious
source and can occur for different reasons.
One cause for drug fever is a hypersensitivity
reaction that is influenced by the severity of the
reaction. Other causes are drugs that stimulate
heat production (thyroxine), drugs that limit
heat dissipation (vasoconstrictors), and drugs
that alter thermoregulation (phenothiazines).3
Drugs that produce a cytokine storm will logi-
cally produce a fever. Monoclonal antibodies
are being used more frequently for treating
malignancies as well as other diseases, and cli-
nicians should expect fever with these drugs.
Suspicion of index should begin when examin-
ing the list of medications and establishing a
temporal relationship between fever and drug
introduced. Drug fever can vary in length from
1 day to more than 7 days.3 Table 2 provides a
list of drug categories that commonly produce
drug fever, but it is not exhaustive.
A distinction should be made between fever
and hyperthermia. Hyperthermia is the unreg-
ulated rise in body temperature and a failure of
the thermoregulatory homeostasis, whereas
fever is an adaptive mechanism to reset the
thermostat.2 Malignant hyperthermia, neuro-
leptic malignant syndrome, and serotonin syn-
drome are conditions that produce a high
temperature. Malignant hyperthermia is associ-
ated with anesthetic agents, including halothane
and succinylcholine, and is thought to be a
genetic disorder that causes a dysregulation of
cytoplasmic calcium control of the skeletal
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 MU N R O
Table 2: Drugs That Can Cause Fevera
Antimicrobials, especially β-lactam drugs
Antiepileptic drugs, especially phenytoin
Antiarrhythmics, especially quinidine and
procainamide
Antihypertensives, especially methyldopa,
hydralazine
H1 and H2 blocking antihistamines
Iodides
Anti-Parkinson drugs
Phenothiazines
Butyrophenones, especially haloperidol
Thyroxine
Drugs producing cytokine storm, especially
monoclonal antibodies
Penicillins
Antimalarials
a
Based on data from O’Grady et al.3
muscle and results in a severe increase in mus-
cle activity, thereby producing a high fever.3
This syndrome occurs most frequently in the
operating room but can be exhibited up to 24
hours after anesthesia if steroids were adminis-
tered preoperatively.3 Dantrolene is the muscle
relaxant used to treat malignant hypothermia.
Neuroleptic malignant syndrome is most com-
monly associated with antipsychotic drugs,
especially haloperidol, which is commonly
used in the ICU setting. This drug reaction also
produces abnormal increased muscle activity,
resulting in fever. Serotonin syndrome is related
to excessive stimulation of the 5-hydroxy-
tryptamine 1A receptor and is commonly
confused with neuroleptic malignant syn-
drome.3 It is associated with serotonin reup-
take inhibitors and produces increased muscle
activity, which is more twitching in nature.
Supportive care is given when these syndromes
occur, and patients usually require ICU care.
Updates for Fever Treatment
and Diagnosis
The debate about treating a fever remains
unanswered. The theory that fever is an adap-
tive evolutionary process and is an important
host defense is a core tenet in this debate.50
“Evidence seems to suggest that temperature in
the usual fever range increases host defense
246
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NCI-D-14-00019.indd 246
W W W.A ACNA DVA NCE D CRIT ICA LCA RE .COM
activity and may make some pathogens more
susceptible.”50(p864) Proponents for treating fever
argue that prolonged fever may cause increased
oxygen consumption and could possibly lead
to organ failure.50 Some researchers have sug-
gested that fever may affect the mortality rate
in the ICU population, but a meta-analysis and
systematic review by Niven et al52 found no evi-
dence that fever treatment influences the mor-
tality rate in critically ill adults without acute
neurological injury. A few randomized con-
trolled trials have been conducted; however,
studies with small sample sizes, differences in
interventions, and variable follow-up duration
make it difficult to draw appropriate clinical
practice conclusions from the current data.
Interventions to treat fever include antipy-
retic therapy (nonsteriodal anti-inflammatory
drugs and/or acetaminophen as well as physi-
cal cooling mechanisms), but they are not
without adverse effects. Nonsteroidal anti-
inflammatory drugs can be very effective but
can contribute to renal dysfunction, especially
if the renal dysfunction is not recognized.
Acetaminophen dosing of 4 g in a 24-hour
period has been associated with transamini-
tis.53 Caution also must be taken when giving
acetaminophen that all sources of the drug be
included in the daily total dose calculation.
Pain medications that are narcotic and aceta-
minophen combinations often are forgotten in
the calculation. The advent of intravenous
acetaminophen has been helpful in providing
another route of administration, but it is
expensive. Therapeutic physical cooling meth-
ods are available and can be efficient but cause
discomfort for patients.
The use of biomarkers along with fever assess-
ment to detect microbiological infection is
becoming more accepted in clinical practice,
although the supportive evidence is variable. Var-
ious markers have been studied including C-reac-
tive protein, tumor necrosis factor α, and IL-6,
but their use has not been validated. Another
biomarker, procalcitonin, is a precursor to calci-
tonin, which plays a role in calcium homeostasis.
The procalcitonin level is thought to increase
with a proinflammatory stimulus, especially
those that are bacterial in origin. A procalcitonin
level greater than 0.65 ng/mL is associated with
high risk of microbial infection, whereas a level
less than 0.65 ng/mL may indicate a low risk of
infection.54 However, patient safety and efficacy
are not clear in the current evidence.55
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 VOL UME 2 5 • N U MBER 3 • JULY–SEPTEM BER 2014
Summary
Fever is common in acute and critical care set-
tings. A disciplined approach to patient evalua-
tion will increase the chances of arriving at an
accurate diagnosis. The process should start
with a thorough physical examination as well
as a review of the patient’s history and medica-
tion list. The method of measuring temperature
as well as the strengths and weaknesses of the
method must be understood. Each body system
should be reviewed, and proper testing and
imaging should be ordered. A balance needs to
be maintained in today’s health care environ-
ment, so that clinicians can assess the patient’s
condition properly and can order the appropri-
ate tests using the best evidence available while
maintaining a cost-conscious approach.
Acknowledgment
This activity was supported in part by the Intra-
mural Research Program of the National Insti-
tutes of Health (NIH), Critical Care Medicine
Department, NIH Clinical Center.
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