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Evaluation and
Management of Fever in
the Critically-Ill Patient.
David Oxman MD
Assistant Professor of Medicine
Division of Pulmonary & Critical Care Medicine
Thomas Jefferson University
Fever in the ICU
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Fever very common in the critically ill.
Can be symptom of life-threatening illness
or relatively harmless process.
Competing concerns:
 Not delaying diagnosis and treatment.
 Not performing unnecessary tests and
procedures
Pathophysiology of Fever
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Fever complex response to many disparate diseases.
Febrile response not only includes elevation of body temp.
but activation of physiological, endocrinologic and
immunologic systems.
Neural regulation of body temperature involves several
different parts of the brain but preoptic and anterior
regions of the hypothalamus have greatest role
Pyrogens – either endogenous or exogenous –stimulate
cytokines (such IL-1, IL-6, TNF-α, IFN-γ) or act directly
on hypothalamic neurons
 decrease their firing rate
 Leads to physiological responses that decrease heat loss
and increase heat production.
Das Verhalten der Eingenwarme in Krankenheiten
“The Behavior of Self-Warmth in Diseases”
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Wunderlich
1 million observations in
25,000 subjects.
Mostly axillary temps and
no more than twice/day.
Called 98.6 or 37 C normal.
100.4 or 38.0 C as upper
limit normal.
Definitions of Fever
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Definition fever somewhat arbitrary.
Study of healthy volunteers (Mackowiak, JAMA 1992)
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Temperatures ranged from 35.6 C (96.0F) to 38.5C (100.8)
Mean of 36.8 + 0.4C (98.2 + 0.7 F)
SCCM defines fever in as temp. > 38.3 (>101F)
Reasonable to use lower threshold for immunosuppressed and elderly.
Measuring Temperature
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Conventional means includes intravascular,
intravesical, rectal, oral, and tympanic.
Axillary and tympanic are inaccurate in
critically ill patients and should not be used.
The gold standard is the thermistor on a
pulmonary artery catheter.
Whichever method is employed should be
used consistently and the site of
measurement documented.
How Common is Fever in ICU?
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Retrospective cohort study by Laupland
>24,000 ICU admissions.
Incidence of at least one documented fever
during ICU course was 44%.
Incidence of “high fever” (>39.5) only 8%.
Crit Care Med, 2008
Incidence of Fever by ICU Population
Laupland, Critical Care Medicine 2008
Fever Evaluation in ICU
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Main dilemma: infectious vs. noninfectious causes.
Fever from infectious cause:
generally treatable
 worse outcomes if diagnosis treatment
delayed.
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Fever from non-infectious cause:
often unmodifiable
 not necessarily worse outcomes.
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Causes of Fever in the ICU
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Infectious
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Catheter infection
VAP
Sinusitis
UTI
Wound Infection
C. Difficile Colitis
Non-Infectious
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Post operative
Transfusions
Drug fever
Thromboembolic disease
Acalculous cholecystitis
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Cerebral Hemmorrhage
ARDS
Adrenal insufficiency
Thyroid storm
Vasculitis
Atelectasis (?)
Pancreatitis
Hematoma
Gout
ETOH withdrawl
Tumor fever
Burns
Myocardial Infarction
 ..and
more !!!
The Fever Work-up Menu
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Blood Cultures
Chest x-ray
Sputum exam
Urinanalysis/culture
LE ultrasound/CTA
CT sinuses
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CT abdomen
CT chest
Lumbar puncture
Right Upper Quadrant
U/S
White Blood Cell Scan
Procalcitonin/CRP
ID Consult
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Perils
The “Fever Workup”
Perils & Pitfalls
Costly.
 Risk in procedures and tests.
 Can lead to unnecessary treatments.
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Goal
Clinically appropriate to patient.
 Know strengths and weakness of tests
employed.
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Issues in Fever Evaluation and
Management
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Common Evaluation Problems
Ventilator-Associated Pneumonia
 Bacteremia/Intravascular Catheter Infection
 Urinary Tract Infection
 Sinusitis
 Meningitis
 DVT/PE
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Treatment/Outcomes of Fever in Critically-ill
Ventilator-Associated Pneumonia
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Common ICU-acquired infection.
Suspected in intubated patient with fever
infiltrate, leukocytosis, and purulent
secretions.
Difficult to diagnose definitively
CXR in ICU patient non-specific.
 Upper respiratory tract colonized with bacteria.
 Non-infectious reasons for worsened gas
exchange
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Common cause of unnecessary antibiotics
Overdiagnosis of VAP
Klompas, JAMA
Bacteremia/Intravascular Catheter
Infection
 Important
to diagnose
 Potentially life-threatening condition
 Generally easily treatable
 Difficulties
 Blood cultures not particularly sensitive
 Contamination leads to false positives
 Newer technologies (e.g. PCR) may
improve sensitivity
Bacteremia: Perils and Pitfalls
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Draw before initiation of antibiotics
Don’t draw through peripheral IV: 3x the false
positive rate!!!
Draw proper number - Never draw one set!
Draw proper volume: minimum 10ml but 20
preferred.
Try not to draw through intravascular device
(unless indicated).
Consider more than two sets of patients with high
pretest probability.
Detection of Fungemia
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Fungal Isolator
Not necessary for routine use.
Candida species grow well on
routine bacterial culture media.
Consider in immunocompromised
patients at risk of uncommon fungal
(e.g cryptococcus, fusarium) or
mycobacterial bloodstream
infection.
Evaluation of Urinary Tract Infection
 UTIs
reported to be common in ICU
 But no consistent definition – most
studies equate isolation of
bacteria/yeast with infection.
 Genuine UTIs in ICU probably
uncommon.
SCCM Guidelines 2008
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“Cultures from catheterized patients
showing >103 cfu/mL represent true
bacteruria or candiuria, but neither higher
counts, nor the presence of pyuria alone are
of much value in determining if (this) is
cause of a patient’s fever; in most cases, it is
not the cause of fever (level1).”
Urinary Tract Infection:
Take Home
Routine evaluation in febrile ICU patient of
questionable benefit.
 UA/culture hard to interpret in catheterized
patient
 Patients at high risk of complication with UTI
(neutropenia, urinary obstruction, pregnancy)
should have testing and presumptive treatment.
 Everyone else: WHO KNOWS?
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Sinusitis
Sinusitis
True incidence hard to know
 Many ICU patients have fluid in
sinuses
 How many ICU patients with fever are
DUE TO sinusitis?
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Sinusitis
Hospital-acquired sinusitis is a common cause
of fever of unknown origin in orotracheally
intubated critically ill patients.
(Critical Care 2005 R583-R590. )
OR
Occult fever in surgical intensive care unit
patients is seldom caused by sinusitis.
(Am J Surg 1992; 164 (5):412-5)
Diagnosis of Sinusitis
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Difficult to diagnose in
ICU patients.
Clinical signs symptoms
not reliable
Fluid in sinuses
common
Nasal swabs not
diagnostic
Aspiration of sinuses
rarely done
Nosocomial Sinusitis in Patients in the
Medical Intensive Care Unit:
A Prospective Epidemiological Study
George, CID 1998
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366 intubated patients with fever and/or
purulent nasal discharge
All patients with radiographic signs of sinus
fluid had maxillary sinus aspiration.
28 (7.6%) met criteria for sinusitis
RR of nasoenteric feeding with orotracheal
intubation 26.7 (3.7-194.5) <.0001
Sinusitis: Take Home
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Sinusitis is common in critically-ill patients
Common cause of FUO in critically-ill: ???
High risk patients:
nasoenteric feeding with oral intubation
 facial trauma
 immunocompromised (fungal)
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Treatment:
removal nasoenteric tube
 decongestants
 brief course antibiotics
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Meningitis in the ICU or
“Do I have to LP all my patients with
fever.”
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Dyad of fever and
altered mental
status very
common in ICU.
Teaching: “If you
think about LP, do
one”
Tremendous
variability in
diagnostic
practice.
What’s the Data Say?
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Addelson-Mitty 1:
70 non-neurosurgical SICU patients
 Most LPs performed to evaluate fever and
mental status change (“r/o meningitis”)
 No cases meningitis diagnosed.
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Metersky 2
52 LPs to rule out nosocomial meningitis
 None positive
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1. Addelson-Mitty, Intensive Care Med 1997
2. Metersky. Clinical Infectious Diseases 1997
LP for Fever in ICU:
Take Home
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ICU-acquired meningitis very rare.
Data does not support routine LP for ICUacquired fever/altered mental status.
Exceptions:
Neurosurgical patients.
 Intracranial device.
 Severe immune compromise (including cancer).
 ? Undiagnosed community-acquired
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DVT/PE as Cause of Fever in
the ICU
DVT common in ICU patients (1030%)
 But how common is DVT/PE as
cause of fever.
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Clinical Data
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Fever and DVT
RIETE Registry >14,000 patients with DVT
 707 (4.9%) with temp >38 C. at presentation
 ??? % with other signs of DVT
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AbuRhama (Surgery 1997)
114 Duplexes for FUO
 DVT considered cause of FUO in 5 (6%)
 $450 x 144 = $51,300 ; $10,260 per case DVT
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PIOPED
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311 with angiographically proven pulmonary
embolism.
43 (14%) had temp > 100.0 and no other
cause.
19 (6.1 %)) had temp >38.3ºC and no other
source.
5 (1.6 percent) had a temperature of >38.9ºC.
DVT/PE Bottom Line
 In
ICU patients with FUO and no
other sign of thromboembolic
disease, DVT/PE examination low
yield.
 Might be useful to know
 Cost-effective ??
Does Magnitude of Fever Mean
Anything?
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High fever definition varies, often greater
than 39.5 (103F).
? more likely in certain conditions.
<102 - ??????
 102-106:
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? more commonly infection
 Laupland: more culture + patients.
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>106 :
likely non-infectious
 Patients do worse
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Empiric Antibiotics
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Not every fever needs new antibiotic!
Those who do: High risk of bad outcome
Deteriorating condition
 Incipient Shock
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Compromised Host
neutropenic
 ventricular assist device
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Fever ≥102ºF (as most infectious) ????
For other patients with new fever  WAIT
In Defense of Fever
Fever itself typically seen as harmful to
patient.
 Yet questionable evidence if treating
fever beneficial.
 Could treating fever be bad for patient?
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In Defense of Fever
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Highly preserved evolutionary response.
Number of conditions where fever
associated with bad outcomes
Other situations could be beneficial
Experimental Data
 Protective
in mouse and sheep
models of sepsis.
induces heat shock response critical for cellular protection
 reduces endothelial and organ damage
 downregulates activity of NF-κB, modulating the immune
response
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 In
vitro effect on antibiotics.
growth time bacteria prolonged
 MIC reduced
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Ozveri et al Intensive Care Med 1999, 25:1155-1159.
Mackowiak , et al J Infect Dis 1982, 145:550-553.
Clinical Data
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Uncontrolled and Retrospective
Higher survival from gram-negative bacteremia
in patients with fever 1.
 elderly patients with CAP > mortality rate with
no fever (29% vs. 4%) 2.
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Prospective and Controlled
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44 Trauma ICU patients 3.
Randomized to treatment vs permissive fever.
7 deaths in treatment vs 1 death permissive
1. Bryant et al Arch Intern Med 1971, 127:120-128
2. Ahkee et al SouthMed J 1997, 90:296-298.
3. Schulman et al. Surg Infect (Larchmt) 2005, 6:369-375.
ICU FEVER AND MORTALITY
Laupland CCM 2008
Bad Effects of Fever
in ICU Patient
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Appears to worsen outcomes in traumatic
brain injuries.
Increases cardiac output, O2 consumption
and CO2 production.
Poorly tolerated in patients with low cardiorespiratory reserve.
Specific hyperthermias (e.g. NMS,
malignant hyperthermia, heat stroke) need
treatment.
Treatment of Fever: Take Home
 Effect
of fever on outcomes unclear
 Evidence that in infections may be
beneficial
 Several specific conditions where
fever detrimental.
Overall Conclusions
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Fever, especially low grade, is very common in
ICU patients.
Unexplained fever merits some clinical
assessment.
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Blood cultures perhaps only mandatory investigation.
Other tests should be appropriate to patient
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Important to know something about performance of test.
Interpret with entire clinical picture
Many non-infectious causes have benign course
Not every fever needs an antibiotic
Treatment of fever only proven benefit in specific
populations.
References
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Circiumaru, et. al. Prospective study of fever in the intensive care unit. Intensive
Care Med 1999: 25(7):668-73.
Mackowiak, et. al. Critical appraisal of 98.6F, the upper limit of normal body
temperature, and other legacies of Carl Reinhold August Wunderlich; JAMA
1992:268 (12): 1578-80.
Kane, et. Al The detection of microbial DNA in the blood: a sensitive method for
diagnosing bacteremia and/or bacterial translocation in surgical patients. Ann
Surg 1998 Jan;227(1):1-9
Galicier and Richet. Prospective study of postoperative fever in a general surgery
department. Infect Control 1985: 6:487-90
Engeron M. Lack of association between atelectasis and fever. Chest 1995: 107
(1): 81-4.
Kisala JM Am J Physiol Regul Integr Comp Physiol 264: R610-164 1993.
Marik et. al. Incidence of deep venous thrombosis in ICU patients. Chest 1997:
111 (3): 661-4.
Fagon et. al. Evaluation of clinical judgement in identification and treatment
nosocomial pneumonia in ventilated patients. Chest 1993; 102 (2):547-53
Fabregas, et. al. Clinical diagnosis of ventilator associated pneumonia revisited.
Thorax 1999; 54 (10):867-73
Marik PE, Fever in the ICU. Chest 2000; 117;855-869.
Peres BD; Melot C, et al. Crit Care Med 2003 Nov;31(11):2579-84.
Infectious causes fever in ICU
Prevalence of nosocomial infection in
ICU quoted as from 3-31%. 8
 True numbers difficult because of
varying definitions.
 Strong correlation between ICU length
of stay and likelihood infection.
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Post-operative Fever
 Well-recognized
but poorly defined
syndrome.
 Magnitude of trauma correlated with
degree fever response.
 Cytokine release from tissue trauma.
 ? Elevated levels bacterial endotoxins and
exotoxins.
Post-operative Fever
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Prospective study 800 surgical patients, 81
(9%) developed fever with no cause.
Those with fever within 48 hours much less
likely to be infectious.
> 96 hours post-op infection much more
likely.
Practice of deferring workup 48 hours
probably sound.
Galicier and Richet. Infect Control 1985