www.medigraphic.org.
mx
Trabajo de revisión
Fiebre en la unidad de cuidados intensivos
Jesús Salvador Sánchez Díaz,* Cecilia Rodríguez Zárate,** Enrique Monares Zepeda,***
Alejandro Díaz Esquivel,* Janet Aguirre Sánchez,**** Juvenal Franco Granillo*****
RESUMEN
Antecedentes: La fiebre es un signo común en la unidad de
cuidados intensivos. Ésta implica el reto de descubrir la causa
subyacente; puede tener un origen infeccioso o no infeccioso. El
Colegio Americano de Medicina de Cuidados Críticos y la Socie-
dad de Enfermedades Infecciosas de América definen «fiebre»
en pacientes en estado crítico como la temperatura igual o ma-
yor a 38.3 oC, lo que implica investigar la causa. En la unidad de
cuidados intensivos, la temperatura puede medirse utilizando
diferentes técnicas, entre las cuales tenemos el catéter en la ar-
teria pulmonar (estándar de oro), catéter vesical, sonda rectal,
sonda esofágica, infrarrojo en membrana timpánica y termó-
metro de arteria temporal. Un episodio nuevo de temperatura
mayor o igual a 38.3 oC debe ser evaluado clínicamente, pero no
necesariamente con estudios de laboratorio y gabinete. Existe
controversia acerca del tratamiento de la fiebre. El abordaje an-
tipirético debe ser reservado para los sujetos con inestabilidad
hemodinámica o individuos de alto riesgo; deben llevarse a cabo
la evaluación diagnóstica y la toma de hemocultivos. Objetivo:
Diferenciar causas infecciosas de no infecciosas que común-
mente condicionan fiebre en la unidad de cuidados intensivos.
Métodos: Se realizó un estudio de revisión del tema «fiebre
en la unidad de cuidados intensivos». Se hizo la búsqueda en
bases electrónicas (PubMed, MD Consult) hasta septiembre de
2014. Se incluyeron las revisiones sistemáticas consideradas las
más importantes de los últimos 14 años. Resultados: A tra-
vés de esta revisión nos fue posible proponer dos algoritmos en
relación con este tema, el primero hace referencia a las causas
de fiebre y el segundo, al abordaje diagnóstico de la misma; lo
importante de esto es la utilización y correcta aplicación de los
mismos. Conclusión: En la unidad de cuidados intensivos, la
temperatura puede medirse utilizando diferentes técnicas; el
catéter en la arteria pulmonar es el estándar de oro. El 50% de
www.medigraphic.org.mx
* Adscrito al Departamento de Medicina Crítica «Dr. Mario Shapiro».
** Adscrita al Servicio de Urgencias. Centro Médico ABC. Santa Fe.
*** Adscrito al Departamento de Medicina Crítica «Dr. Mario Shapiro», Jefe de
Terapia Intensiva del Hospital San Ángel Inn Universidad.
**** Subjefe del Departamento de Medicina Crítica «Dr. Mario Shapiro».
***** Jefe Corporativo de Medicina Crítica «Dr. Mario Shapiro».
Centro Médico ABC.
Recibido para publicación: 21/04/2015. Aceptado: 25/02/2016.
Este artículo puede ser consultado en versión completa en:
http://www.medigraphic.com/analesmedicos
Anales
Médicos
Vol. 61, Núm. 1
Ene. - Mar. 2016
p. 33 - 38
Fever in the Intensive Care Unit
ABSTRACT
Background: Fever is a common sign in the intensive care
unit; this involves the challenge of discovering the underlying
cause, since it may have an infectious or non-infectious origin.
The American College of Critical Care Medicine and the Infec-
tious Diseases Society of America define «fever» in critically
ill patients as a temperature equal to or greater than 38.3 oC,
which involves investigating the cause. In the intensive care
unit, temperature can be measured using different techniques,
among which are the pulmonary artery catheter (gold stan-
dard), bladder catheter, rectal probe, gavage, infrared tympanic
thermometer and temporal artery thermometer. A new episode
of temperature equal to or greater than 38.3 oC should be cli-
nically evaluated, but not necessarily with laboratory studies.
There is controversy about the treatment of fever. The antipyre-
tic approach should be reserved for patients with hemodynamic
instability or those high-risk; a diagnostic evaluation and blood
cultures should be performed. Objective: To differentiate infec-
tious causes from noninfectious ones that commonly cause fever
in the intensive care unit. Methods: A review was conducted
on the topic «fever in the intensive care unit». The search was
performed in electronic databases (PubMed, MD Consult) until
September 2014. Systematic reviews considered the most impor-
tant of the last 14 years were included. Results: Through this
review, we were able to propose two algorithms in relation to this
issue, the first refers to the causes of fever and the second, to the
diagnostic approach of fever; their importance lies in their use
and correct application of thereof. Conclusion: In the intensive
care unit, temperature can be measured using different techni-
ques, being the pulmonary artery catheter the gold standard.
50% of the patients in the intensive care unit present fever; only
Correspondencia: Dr. Jesús Salvador Sánchez Díaz
Departamento de Medicina Crítica,
Centro Médico ABC.
Sur 136 Núm. 116,
Col. Las Américas,
Del. Álvaro Obregón, 01120, México, D.F.
Tel: 5230 8000, ext. 8588.
E-mail: chavita_amerika@hotmail.com
Abreviaturas:
IDSA = Sociedad de Enfermedades Infecciosas de América (Infectious Diseases
Society of America).
 Sánchez DJS y cols. Fiebre en la unidad de cuidados intensivos
34 An Med (Mex) 2016; 61 (1): 33-38
los individuos presentará fiebre en la unidad de cuidados in-
tensivos; de éstos, sólo la mitad será de origen infeccioso. El
tratamiento antipirético debe ser reservado para los sujetos con
lesión neurológica aguda, inestabilidad hemodinámica y pacien-
tes de alto riesgo.
Palabras clave: Fiebre, causa infecciosa o no infecciosa, uni-
dad de cuidados intensivos, técnicas de medición, tratamiento.
Nivel de evidencia: IV
INTRODUCCIÓN
La fiebre es un signo común en la unidad de cuidados
intensivos; ésta implica el reto de descubrir la causa
subyacente, que puede tener un origen infeccioso o
no infeccioso. El 50% de los pacientes que ingresan
a la unidad de cuidados intensivos presentará fiebre;
de éstos, sólo la mitad será de origen infeccioso. In-
vestigar el origen de la fiebre incluye un mayor nú-
mero de estudios diagnósticos, lo que genera mayor
costo, tiempo y riesgos para el enfermo.1 Existen ar-
gumentos a favor y en contra del tratamiento de la
fiebre, y en la actualidad, la literatura no admite be-
neficio en individuos sin lesión neurológica aguda.2
OBJETIVO
Diferenciar causas infecciosas de no infecciosas que
comúnmente condicionan fiebre en la unidad de cui-
dados intensivos.
MÉTODOS
Se realizó un estudio de revisión del tema «fiebre en
la unidad de cuidados intensivos». La búsqueda se
efectuó en bases electrónicas (PubMed, MD Consult)
hasta septiembre de 2014. Se incluyeron las revisio-
nes sistemáticas consideradas las más importantes
de los últimos 14 años.
DEFINICIONES www.medigraphic.org.mx
Se considera 37 oC como la temperatura corporal nor-
mal. Existen variaciones normales de aproximada-
mente 0.5 a 1 oC en las personas dependiendo de la
hora del día, con disminución por la mañana y un pico
por la tarde. Tomando en cuenta lo anterior, existen
múltiples definiciones de fiebre en la literatura.3
El Colegio Americano de Medicina de Cuidados
Críticos y la Sociedad de Enfermedades Infecciosas de
half of them with an infectious origin. The antipyretic treatment
should be reserved for patients with acute neurological injury,
hemodynamic instability and those high risk.
Key words: Fever, infectious or noninfectious cause, intensive
care unit, measurement techniques, treatment.
Nivel de evidencia: IV
América (IDSA, por sus siglas en inglés), definen «fie-
bre» en pacientes en estado crítico como la temperatu-
ra igual o mayor a 38.3 oC, lo que implica investigar la
causa. Temperaturas menores a 36 oC sin causa conoci-
da también deben ser indagadas. Algunos sujetos mere-
cen consideración especial debido a su incapacidad para
manifestar una respuesta febril normal, tales como los
individuos inmunocomprometidos y los ancianos.1
Hipertermia y fiebre son dos conceptos difíciles
de diferenciar a la cabecera del enfermo.3 La hiper-
termia puede estar asociada a daño hipotalámico di-
recto; no respeta el ciclo circadiano y se caracteriza
por temperatura muy elevada, constante y con pobre
respuesta a los antipiréticos.4
MÉTODOS UTILIZADOS PARA MEDIR LA
TEMPERATURA EN ORDEN DE PRECISIÓN
En la unidad de cuidados intensivos, la temperatura
puede medirse utilizando diferentes técnicas: termis-
tor en arteria pulmonar, catéter en vejiga urinaria,
sonda esofágica, sonda rectal, sonda oral, termómetro
infrarrojo de oído, termómetro de la arteria temporal,
termómetro axilar y chemical dot (Cuadro I). No se
recomienda utilizar termómetros orales o axilares.
Existen diferencias de resultados en la toma de
temperatura dependiendo de la técnica utilizada. En
caso de que una medición no sea lógica, siempre será
conveniente corroborarla con un segundo dispositivo.3
La técnica ideal para medir la temperatura debe
ser cómoda, segura, confiable y reproducible. Cual-
quier dispositivo utilizado debe estar calibrado co-
rrectamente; además, se deben tomar las medidas
necesarias para que no sea un facilitador en la propa-
gación de agentes patógenos.5
CAUSAS
Las principales causas de fiebre en los individuos
críticamente enfermos son los síndromes de hiper-
 Sánchez DJS y cols. Fiebre en la unidad de cuidados intensivos

An Med (Mex) 2016; 61 (1): 33-38

35

termia, las causas infecciosas y las causas no infec- como principal causa de fiebre de origen infeccioso
ciosas (Figura 1). Los síndromes de hipertermia son a las infecciones del tracto respiratorio (casi en el
condicionados por golpe de calor, fármacos (neuro- 50% de los casos) y a la fiebre postoperatoria como
léptico maligno, hipertermia maligna, serotoninér- principal causa de origen no infeccioso, principal-
gico) y causas endocrinas (tirotoxicosis, feocromo- mente en cirugía cardiaca. Cuando se presenta fie-
citoma, crisis adrenal). Algunos estudios reportan bre prolongada (> cinco días), la causa en la mayo-
ría de los casos es infección y se asocia con mayor
mortalidad. Los pacientes no quirúrgicos presentan
Cuadro I. Variación de la temperatura. fiebre con mayor frecuencia que los que tuvieron
una cirugía previa, así como el género masculino y
Sitio de medición Variación los sujetos jóvenes.
• Catéter en la arteria pulmonar • Estándar de oro La fiebre persistente habitualmente se asocia a
• Oral • < 0.4 oC infección por bacterias Gram negativas o daño en el
• Arteria temporal • < 0.4 oC sistema nervioso central. Fiebre 48 horas después de
• Recto • < 0.3 oC intubación orotraqueal puede estar condicionada por
• Vejiga • < 0.2 oC neumonía asociada a la ventilación mecánica y/o son-
• Esófago • < 0.1 oC da vesical; si se presenta cinco a siete días después de

Lesión cerebral Causas Síndromes de hipertermia

de fiebre

Daño hipotalámico No infecciosas Infecciosas

• Golpe de calor
• Síndrome neuroléptico maligno
• Hipertermia maligna
• Síndrome serotoninérgico
• Fiebre postoperatoria (< 48 horas) • Neumonía asociada a la ventilación • Tirotoxicosis
• Hipersensibilidad a medicamentos mecánica • Feocromocitoma
• Alcohol • Infección relacionada con dispositivos • Crisis suprarrenal
• Supresión de drogas intravenosos
• Trombosis venosa profunda/embolismo pulmonar • Infecciones del sistema nervioso central
• Hematomas • Infecciones del tracto urinario
• Colecistitis alitiásica • Sinusitis
• Pancreatitis • Diarrea por Clostridium difficile
• Isquemia intestinal • Sepsis abdominal
• Hemorragia gastrointestinal • Infección del sitio quirúrgico
• Rechazo a trasplantes • Fiebre postoperatoria (> 48 horas,

• Neumonitis por aspiración www.medigraphic.org.mx

• Síndrome de dificultad respiratoria aguda considerar infección)
• Siempre considerar bacterias, virus,
• Embolismo graso hongos y protozoos
• Enfermedades de la colágena
• Insuficiencia suprarrenal
• Neoplasias
• Gota/pseudogota
• Evento vascular cerebral
• Infarto agudo del miocardio
• Tromboflebitis Figura 1.
• Reacción a contraste
Causas de fiebre.
 Sánchez DJS y cols. Fiebre en la unidad de cuidados intensivos
36 An Med (Mex) 2016; 61 (1): 33-38

una cirugía puede estar relacionada a un absceso, y
de diez a catorce días después del inicio de antibióti-
cos, a infecciones por hongos.3
EVALUACIÓN
Un episodio nuevo de temperatura mayor o igual a
38.3 oC debe ser evaluado clínicamente, pero no ne-
cesariamente con estudios de laboratorio o gabinete.
La hipotermia (temperatura < 36 oC) sin causa cono-
cida (hipotiroidismo, manta térmica, medio ambien-
te) también requiere una evaluación clínica, pero no
necesariamente estudios paraclínicos.5
Siempre debemos considerar los cultivos del sitio
apropiado, de manera ideal, antes del inicio de la te-
rapia con antibióticos, situación difícil en la unidad
de cuidados intensivos, pues en la mayoría de los ca-
sos la terapia con antibióticos ya fue iniciada.6
Los cultivos, a pesar de muchos falsos negativos,
pueden identificar no sólo el sitio del problema
sino la aparición de gérmenes de tipo oportunista
no esperados.

Fiebre (temperatura ≥ 38.3 oC)

Evaluación clínica

Hemocultivos

Síndromes de hipertermia Lesión cerebral aguda

Tratamiento
Tratamiento específico (beneficio probado)

Antipirético ¿?
Causas no infecciosas Causas infecciosas Enfriamiento externo ¿?

< 48 horas > 48 horas Sitio evidente Estudio diagnóstico y

tratamiento adecuado

Considerar:
Observar Considerar infección Sitio no evidente * Accesos vasculares
* Sondas

Causas infecciosas Remover ¿?

Estudio diagnóstico y tratamiento adecuado

www.medigraphic.org.mx
• Neumonía asociada a la ventilación mecánica
• Infección relacionada con dispositivos intravenosos
• Infecciones del sistema nervioso central
• Infecciones del tracto urinario
• Sinusitis
• Diarrea por Clostridium difficile
• Sepsis abdominal
• Infección del sitio quirúrgico
• Fiebre postoperatoria (> 48 horas, considerar infección)

Figura 2. Abordaje diagnóstico de la fiebre.


CULTIVOS DE SANGRE
• Obtener de tres a cuatro hemocultivos dentro de
las primeras 24 horas de la aparición de la fiebre.
• El sitio de punción debe limpiarse con gluconato
de clorhexidina al 2%, alcohol isopropílico al 70%
(30 segundos de secado) o alcohol yodado al 2% (2
minutos de secado). Las botellas deben limpiarse
con alcohol al 70-90%. Se debe evitar el yodo.
• Se deben obtener 20-30 mL de sangre en un solo
tiempo por cultivo.
• Los hemocultivos deben ser claramente etiqueta-
dos con la hora exacta, la fecha, el sitio de donde
se extrae la sangre y los antibióticos utilizados.5
TRATAMIENTO
Existe controversia con relación al tratamiento de la
fiebre. La controversia radica en la teoría de que ésta
es un proceso adaptativo y de defensa del huésped;
además, puede hacer que algunos patógenos sean
más susceptibles.1 Niven y colaboradores realizaron
un metaanálisis publicado en el año 2013 donde con-
cluyen que el tratamiento de la fiebre en pacientes
sin lesión neurológica aguda no mejora la mortalidad
en la unidad de cuidados intensivos, aunque puede
contribuir a la disminución del malestar y síntomas
en general del sujeto. Actualmente, la evidencia no
apoya el beneficio de tratar la fiebre en poblaciones
sin lesión neurológica aguda.2
Los que están a favor de tratar la fiebre en indi-
viduos sin lesión neurológica aguda argumentan el
beneficio del enfermo al mejorar su confort, reducir
la demanda metabólica de oxígeno y reducir el estrés
cardiovascular, aunque estos aparentes beneficios
no han demostrado disminuir la mortalidad de la
unidad de cuidados intensivos en estudios clínicos.
Investigaciones han demostrado que los pacientes
con choque séptico que presentan hipotermia tienen
mayor mortalidad que aquéllos con choque séptico y
fiebre.3
www.medigraphic.org.mx
En el estudio de Schulman y su grupo, publicado
en el año 2005 y llevado a cabo en una unidad de cui-
dados intensivos de trauma, los participantes fueron
aleatorizados en dos grupos (control agresivo de la
fiebre versus control permisivo de la fiebre). El grupo
de control agresivo de la fiebre presentó mayor nú-
mero de infecciones, más días de uso de antibióticos
y mayor mortalidad.7
El tratamiento antipirético debe ser reservado
para los individuos con inestabilidad hemodinámi-
ca o sujetos de alto riesgo; deben llevarse a cabo la
Sánchez DJS y cols. Fiebre en la unidad de cuidados intensivos
An Med (Mex) 2016; 61 (1): 33-38
37
evaluación diagnóstica y la toma de hemocultivos. En
enfermos con sepsis, la terapia con antibióticos den-
tro de la primera hora del diagnóstico se asocia con
disminución de la mortalidad.5
Byung Ho Lee y colegas, en su estudio publicado
en el año 2012, valoraron la asociación de fiebre y
uso de antipiréticos como factor independiente de
mortalidad en pacientes sépticos y no sépticos. En-
contraron que el tratamiento de la fiebre con antiin-
flamatorios no esteroideos o paracetamol incrementa
la mortalidad a los 28 días en los individuos sépticos,
pero no en los sujetos no sépticos.8
Los datos anteriores sugieren que la fiebre de ori-
gen infeccioso no debería ser tratada a menos que
el enfermo presentara reserva cardiopulmonar dis-
minuida, y que los pacientes con lesión neurológica
aguda evidentemente se benefician con el tratamien-
to de la fiebre. Las mantas de enfriamiento deben
ser utilizadas para inducir hipotermia en individuos
con lesión neurológica aguda siempre y cuando esté
indicada; cuando éstas se utilizan para control de la
fiebre su uso es controvertido.
La fiebre no se asocia con mayor mortalidad en
la unidad de cuidados intensivos, pero la fiebre alta
(temperatura igual o mayor a 39.5 oC) incrementa
el riesgo de muerte. Debemos interpretar lo ante-
rior siempre tomando en cuenta el tiempo de evolu-
ción de la fiebre, su causa y la población en la que
se presenta.9
DISCUSIÓN
Sabemos bien que la fiebre es la señal de un trastorno
en los mecanismos de defensa del cuerpo. La presencia
de la misma de manera frecuente nos conduce a rea-
lizar exámenes diagnósticos e intervenciones terapéu-
ticas y esto, a su vez, incrementa los costos médicos,
expone al paciente a riesgos innecesarios y, por si fue-
ra poco, al uso inapropiado de antibióticos. La mitad
de los individuos que ingresan a la unidad de cuidados
intensivos presentará fiebre en algún momento, por lo
que es importante el correcto abordaje diagnóstico. En
este caso, lo primero que debemos pensar es la causa
de la fiebre, haciendo referencia a su origen, ya sea
infeccioso, no infeccioso, e incluso, no descartar la po-
sibilidad de que la fiebre esté condicionada por lesión
cerebral o algún síndrome de hipertermia. En esta re-
visión recomendamos dos algoritmos para el correcto
abordaje y diagnóstico de la fiebre, basados en la lite-
ratura «clásica» y «actual» que hace referencia a este
tema tan importante. Paul E. Marik,6 uno de los médi-
cos más reconocidos de la medicina crítica y miembro
 Sánchez DJS y cols. Fiebre en la unidad de cuidados intensivos
38 An Med (Mex) 2016; 61 (1): 33-38
de varias sociedades médicas de importancia mundial,
mostró su interés en este tema publicando un artículo
«clásico» al hablar del tema en el año 2000, sin de-
jar de mencionar que existen guías de práctica clínica
para la evaluación de la fiebre en pacientes críticos
publicadas por el Colegio Americano de Medicina de
Este documento
Cuidados es elaborado
Críticos por Medigraphic
y la Sociedad de Enfermedades In-
fecciosas de América.5 No dejemos de recordar que la
Sociedad de Cuidados Críticos dice: «right care right
now» (tratamiento correcto y de inmediato).
A través de esta revisión nos fue posible proponer dos
algoritmos en relación con este tema, el primero hace re-
ferencia a las causas de fiebre y el segundo al abordaje
diagnóstico de la misma fiebre. Lo importante de esto es
la utilización y correcta aplicación de los mismos.
CONCLUSIÓN
En la unidad de cuidados intensivos, la temperatura
puede medirse utilizando diferentes técnicas; el caté-
ter en la arteria pulmonar es el estándar de oro. El
50% de los pacientes presentará fiebre en la unidad
de cuidados intensivos; de éstos, sólo la mitad será
de origen infeccioso. El tratamiento antipirético debe
ser reservado para los individuos con lesión neuro-
lógica aguda, inestabilidad hemodinámica y aquéllos
de alto riesgo.
www.medigraphic.org.mx
BIBLIOGRAFÍA
1. Munro N. Fever in acute and critical care. AACN Adv Crit
Care. 2014; 25 (3): 237-248.
2. Niven DJ, Laupland KV, Tabah A, Vesin A, Rello J, Koulenti D
et al. Diagnosis and management of temperature abnormality
in ICUs: a EUROBACT investigators’ survey. Crit Care. 2013;
17 (86): R289. [Consultado: 20 de marzo de 2015]. Disponible
en: http://ccforum.com/content/17/6/R289
3. Laupland KB. Fever in the critically ill medical patient. Crit
Care Med. 2009; 37 [7 Suppl.]: S273-S278.
4. Thompson HJ, Tkacs NC, Saatman KE, Raghupathi R, Mc-
Intosh TK. Hyperthermia following traumatic brain injury: a
critical evaluation. Neurobiol Dis. 2003; 12 (3): 163-173.
5. O’Grady NP, Barie PS, Bartlett JG, Bleck T, Carroll K, Kalil
AC et al. Guidelines for evaluation of new fever in critically
ill adult patients: 2008 update from the American College of
Critical Care Medicine and the Infectious Diseases Society of
America. Crit Care Med. 2008; 36 (4): 1330-1349.
6. Marik PE. Fever in the ICU. Chest. 2000; 117 (3): 855-869.
7. Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhad-
dad H et al. The effect of antipyretic therapy upon outcomes
in critically ill patients: a randomized, prospective study. Surg
Infect (Larchmt). 2005; 6 (4): 369-375.
8. Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J et al. As-
sociation of body temperature and antipyretic treatments
with mortality of critically ill patients with and without sep-
sis: multi-centered prospective observational study. Crit Care.
2012; 16 (1): R33. [Revisado: marzo 2015]. Disponible en:
http://ccforum.com/content/16/1/R33
9. Laupland KB, Shahpori R, Kirkpatrick AW, Ross T, Gregson
DB, Stelfox HT et al. Occurrence and outcome of fever in criti-
cally ill adults. Crit Care Med. 2008; 36 (5): 1531-1535.
 Available online http://ccforum.com/content/7/3/221

Review
Clinical review: Fever in intensive care unit patients
Michael Ryan1 and Mitchell M Levy2

1Fellow, Brown Medical School/Rhode Island Hospital, Pulmonary/Critical Care Division, Providence, Rhode Island, USA
2Associate Professor, Brown Medical School/Rhode Island Hospital and Medical Director of MICU, Rhode Island Hospital, Pulmonary/Critical Care
Division, Providence, Rhode Island, USA

Correspondence: Mitchell M Levy, mitchell.levy@brown.edu

Published online: 8 March 2003 Critical Care 2003, 7:221-225 (DOI 10.1186/cc1879)
This article is online at http://ccforum.com/content/7/3/221
© 2003 BioMed Central Ltd (Print ISSN 1364-8535; Online ISSN 1466-609X)

Abstract
Fever is a common response to sepsis in critically ill patients. Fever occurs when either exogenous or
endogenous pyrogens affect the synthesis of prostaglandin E2 in the pre-optic nucleus. Prostaglandin
E2 slows the rate of firing of warm sensitive neurons and results in increased body temperature. The
febrile response is well preserved across the animal kingdom, and experimental evidence suggests it
may be a beneficial response to infection. Fever, however, is commonly treated in critically ill patients,
usually with antipyretics, without good data to support such a practice. Fever induces the production
of heat shock proteins (HSPs), a class of proteins critical for cellular survival during stress. HSPs act
as molecular chaperones, and new data suggest they may also have an anti-inflammatory role. HSPs
and the heat shock response appear to inhibit the activation of NF-κβ, thus decreasing the levels of
proinflammatory cytokines. The anti-inflammatory effects of HSPs, coupled with improved survival of
animal models with fever and infection, call into question the routine practice of treating fever in
critically ill patients.

Keywords fever, heat shock proteins, intensive care unit, nuclear factor-κB, sepsis

Fever occurs commonly in hospitalized patients. It is estimated
that nosocomial fevers occur in approximately one-third of all
medical patients at some time during their hospital stay [1]. In
patients admitted to the intensive care unit (ICU) with severe
sepsis, the incidence of fever is more than 90% [2]. As there
is variation in the incidence of reported fevers, the etiology of
fever in critically ill patients is similarly diverse—both infectious
and noninfectious etiologies are common [1,3,4].
The definition of fever is arbitrary. The mean body tempera-
ture (oral) in healthy individuals is approximately 36.8°C
(98.2°F), with a range of 35.6°C (96°F) to 38.2°C (100.8°F)
and a slight diurnal variation [5]. The Society of Critical Care
Medicine and the Infectious Disease Society of America, in a
recent consensus statement, suggested that a temperature of
above 38.3°C (101°F) should be considered a fever and
should prompt a clinical assessment [4].
Physician and staff response to fever varies institutionally.
Besides evaluating the patient and initiating a workup
based on the clinical evaluation, it is common for the
patient to receive either pharmacologic or mechanical
antipyretic therapy. However, there is little evidence that
would support such routine practice. The traditional view,
at least in pediatrics, is that an exuberant febrile response
is inherently dangerous and can, in the worse case, lead to
seizures and brain damage [6]. Adult nonhealthcare
workers (i.e. patient family members) also have significant
misconceptions regarding the perceived detrimental
effects of fever [7]. In this complicated psychosocial
setting, it is easy for the physician to merely treat the fever.
However, there are costs associated with such therapies. It
is estimated that when either paracetamol, icepacks or
cooling blankets are used, it can cost one 18-bed ICU
between $10,000 and $29,000 per year [8]. Pharmacolog-
ical means to reduce fever cause renal and hepatic dys-
function in patients who are volume depleted or who have
underlying kidney or liver disease [9]. Additionally, there is
evidence, at least in animal models, that fever is a benefi-
cial host response to infection [10–12].

COX-2 = cyclooxygenase-2; HSF = heat shock factor; HSP = heat shock protein; ICU = intensive care unit; IL = interleukin; NF = nuclear factor;
OVLT = organum vasculosum of the laminae terminalis; TNF-α = tumor necrosis factor alpha. 221
 Critical Care June 2003 Vol 7 No 3 Ryan and Levy
The goal of the present review is to question, by critically
evaluating the literature, the practice of routinely treating fever
in the ICU patient. The pathophysiology of fever will be
reviewed, the animal and human data that have evaluated the
role and the potential beneficial effects of fever in disease
states will be examined, and the hemodynamic and metabolic
costs of fever will be summarized.
The physiology of fever
Fever is extremely well preserved throughout evolution. It has
been found in numerous phyla and is estimated to be more
than four million years old [13]. Fever is seen in mammals,
reptiles, amphibians, and fish as well as in some inverte-
brates. Not only is it found in endothermic (warm-blooded)
animals, it is also seen in ectothermic (cold-blooded) animals
[11]. In response to infection, lizards will elevate their body
temperature by selecting a warmer microclimate [14]. The
febrile response, defined by Plaisance and Mackowiak, is a
“complex physiologic reaction to disease involving a cytokine
mediated rise in core temperature, generation of acute-phase
reactants, and activation of numerous physiologic endocrino-
logic and immunologic systems” [15].
Exogenous stimuli, such as endotoxin, staphylococcal erytho-
toxin and viruses, induce white blood cells to produce
endogenous pyrogens. The most potent of these endo-
genous pyrogens are IL-1 and tumor necrosis factor alpha
(TNF-α) [16]. Other endogenous pyrogens that are integral in
the febrile response include IL-6 and the interferons [17].
These endogenous pyrogens act on the central nervous
system at the level of the organum vasculosum of the laminae
terminalis (OVLT). The OVLT is surrounded by the medial and
lateral portions of the pre-optic nucleus, the anterior hypo-
thalamus and the septum pallusolum [18].
The exact mechanism of how circulating cytokines in the
systemic circulation effect neural tissue remains unclear. It
has been hypothesized that a leak in the blood–brain barrier
at the level of the OVLT allows the central nervous system to
sense the presence of endogenous pyrogens. Additional pro-
posed mechanisms include active transport of cytokines into
the OVLT or activation of cytokine receptors in endothelial
cells of the neural vasculature, which than transduce signals
to the brain [19].
The OVLT synthesizes prostaglandin, especially prosta-
glandin E2, in response to endogenous pyrogens. Prosta-
glandin E2 acts directly on the cells of the pre-optic nucleus
to reduce the rate of firing of warm sensitive neurons, and it is
one of the downstream products of the arachidonic acid
pathway [20,21]. There is ample evidence that cyclooxyge-
nase-2 (COX-2) in neural vasculature is important in the for-
mation of fever. Induction of the febrile response by
lipopolysaccharide, TNF-α, and IL-1β resulted in increased
COX-2 mRNA in the cerebral vasculature of numerous exper-
222 imental models of fever [22]. In a murine model COX-2
knockout mice were unable to mount a febrile response to
endotoxin, and in humans COX-2 selective inhibitors were
shown to reduce fever [23,24]. In fact, over 30 years ago, the
NSAIDS were shown to inhibit the action of COX-2 [25].
Shortly afterwards, a similar mechanism was discovered for
acetaminophen, but this effect was only found in neural COX-
2 enzymes; thus explaining why acetaminophen is a strong
anti-pyretic but devoid of anti-inflammatory effects [26].
Fever and clinical outcomes
Although the febrile response has existed for millions of years,
controlled studies evaluating the benefits of fever do not exist.
Most of the studies in humans evaluating clinical outcomes,
fever and infection have been case–control series. For
example, in the pre-antibiotic era, artificial fever was used,
with limited success and without controlled trials, to treat
neurosyphilis [27,28]. Evaluation of fever in animal models is
confounded by the fact that stressed animals often increase
their body temperature several degrees with handling and is
confounded by questions about the appropriate pyrogenic
stimulus in a particular species [11]. It has been postulated
that a behavior so widely preserved, yet metabolically expen-
sive, must convey some net benefit to the host or it would not
have been retained during evolution [11].
In vitro and animal data evaluating the effect of temperature
on survival during infection suggest that fever may be benefi-
cial to the host. Increased survival with fever has been
demonstrated in animal studies [29,30]. In fact, the majority
of studies (14 out of 21 studies) evaluated in one review
demonstrated a deleterious effect of lowering body tempera-
ture [11]. Additionally, increasing temperature has effects on
the minimum inhibitory concentration of antibiotics to bacte-
ria. As the experimental temperature increased past 38.5°C,
the authors of one study found reductions in the minimum
inhibitory concentrations, representing a progressive increase
in the antimicrobial activity of antibiotics [31].
While in vitro data and animal data seems to suggest that
treatment of fever does not favorably impact morbidity and
mortality, human studies in this area are lacking. In a study
with 218 patients who had gram-negative bacteremia, fever
correlated positively with survival [32]. However, this data is
confounded by the fact that the majority of afebrile septic
patients who died did not receive appropriate antibiotic
therapy. Additionally, another retrospective case series
showed that failure to mount a febrile response within the first
24 hours was associated with increased mortality [33]. When
patient comfort was evaluated as a primary outcome variable,
there was no difference in the comfort level of patient who
had fever treated versus control [8].
Fever and the immune response
Increased temperature is known to induce changes in many
of the effector cells of the immune response. In addition to
these changes, fever induces the heat shock response. The

heat shock response is a complex reaction to fever, to
cytokines, or to numerous other stimuli. The end result of this
reaction is production of heat shock proteins (HSPs), a class of
proteins crucial to cellular survival [34]. Ritossa first reported
the heat shock response in 1962 when he noticed changes in
the Drosphilia chromosome in response to increased tempera-
ture [35]. The protein products of these chromosomal changes
were subsequently isolated and called HSPs [36].
The heat shock response provides a cell or organism with ther-
motolerance. When a cell is subjected to a sublethal heat
stress, this sublethal stress protects the organism from a sub-
sequent potentially lethal heat stress [37]. This response
seems to not only function to provide protection from heat, but
can, by a mechanism called cross-tolerance, be induced by a
particular stressor (e.g. heat) and can protect against cell death
from an entirely different lethal stress (e.g. endotoxin) [34].
HSPs have subsequently been found in numerous organisms,
and the DNA sequencing and subsequent protein structure is
highly preserved between organisms [38]. Because they are
so well preserved throughout nature, it is postulated that
HSPs are critical for cell survival. They are molecular chaper-
ones that escort proteins marked for translocation throughout
the organelles of a cell, they participate in refolding proteins
that have become denatured during cellular stress, and they
transport severely damaged proteins to proteolytic organelles
for destruction [39]. Additionally, HSPs also are important in
the apoptotic response, modulating the immune response,
and in regulating steroid hormone receptors.
Inducible HSPs exist in the cytosol, bound to proteins called
heat shock factors (HSFs) [34]. A stress causes HSPs to dis-
sociate from HSFs, and the HSFs are then phosphorylated .
These phosphorylated HSFs form a trimer that enters the
nucleus of the cell and, after further phosphorylation, bind to
the cellular DNA on a sequence called a heat shock element.
The heat shock element is a promoter sequence for the HSP.
Binding of the HSF to the heat shock element causes tran-
scription of HSP mRNA. Translation of the mRNA occurs,
and further HSPs are produced [39].
This system is regulated on several levels. HSPs bind to dis-
sociated HSFs in the cytosol, preventing the formation of
further HSF trimers to act as DNA promoters. Additionally,
there is evidence of post-transcriptional regulation of HSP
production [34]. In vitro experiments show that while HSP
mRNA is increased secondary to a stressor, the amount of
HSPs produced is variable and is dependent on the magni-
tude of the stressor [40].
Heat shock response: clinical implications in
sepsis
The importance of the heat shock response in vivo has been
demonstrated in numerous experiments. Ryan and colleagues
heated rats from 39°C to 42.5°C and then, 24 hours later,
Available online http://ccforum.com/content/7/3/221
administered a lethal dose of endotoxin to the animals [10].
The mortality in the control group at 48 hours was 71.4%,
while no rats died in the heat-treated group. Villar and col-
leagues showed that, during intra-abdominal sepsis, previous
heat treatment significantly impacted mortality and reduced
organ injury [12]. In this study, rats underwent heat treatment
18 hours before cecal ligation and puncture. Survival at
7 days was noted, and rats were sacrificed at various times
after the cecal ligation and puncture to examine the organ his-
tology. The HSP-72 levels increased in the lungs and the
heart of heat-treated animals shortly after heat treatment.
Animals that underwent cecal ligation and puncture without
previous heat treatment had no detectable expression of
HSP-72 at any time in the course of their illness. The heat-
treated rats had improved mortality, had less organ damage,
and had less evidence of acute lung injury.
Interestingly, severe sepsis may be associated with a dimin-
ished heat shock response. Lymphocytes obtained from a
group of patients with severe sepsis were compared with lym-
phocytes obtained from critically ill postoperative patients and
healthy volunteers [41]. At baseline, all three groups had similar
percentages of lymphocytes expressing HSP-70. When the
lymphocytes were given an endotoxin challenge, however, the
percentage of lymphocytes that expressed HSP-70 was signifi-
cantly less in the septic group. If patients recovered from
severe sepsis, there was an increase in the percentage of their
lymphocytes that produced HSP-70 to endotoxin challenge.
This may suggest that HSPs modulate the septic response.
There is strong evidence that HSPs have anti-inflammatory
roles. In vitro studies have shown that the heat shock
response reduces levels of TNF-α, IL-1, IL-6, and IL-10 [42].
This effect is not isolated to cell cultures, as it has also been
demonstrated in murine models of sepsis [43,44]. The ability
of the heat shock response to inhibit a wide array of inflam-
matory mediators implies that it must modulate the septic
response at one or more key regulatory steps. Indeed, recent
data has demonstrated that induction of the heat shock
response downregulates the activity of NF-κB.
κB
Heat shock response and NF-κ
NF-κB is a nuclear transcription factor that, when activated,
binds to DNA promoter regions that encode for the mRNA of
numerous inflammatory molecules. The effect of this binding
is to enhance the expression of these inflammatory mediators
[45]. NF-κB, therefore, is a potent upstream modulator of the
proinflammatory response. NF-κB is a dimer composed of
two proteins from the ReL family. It is contained in the cytosol
of the cell, bound to an inhibitory protein called I-κB. During
the process of NF-κB activation, I-κB is phosphorylated by a
kinase called IKK [38]. This causes the I-κB to dissociate
from NF-κB, uncovering the nuclear translocation signal on
the NF-κB dimer. Unbound NF-κB is than able to serve its
role as a DNA promoter to enhance the transcription of
mRNA, which codes for the inflammatory molecules. 223
 Critical Care June 2003 Vol 7 No 3 Ryan and Levy
NF-κB activity has been reported to correlate with mortality in
septic shock patients. Borher and colleagues followed daily
NF-κB activity obtained from nuclear extracts of peripheral
blood monocytes. They found that survivors of septic shock,
when compared with patients who died, had significantly less
increases in their daily NF-κB activity. In fact, all five patients
who died had a doubling of their baseline NF-κB activity [46].
In a similar study, Paterson and colleagues showed that there
was increased nuclear activity of NF-κB in both monocytes
and neutrophils of septic patients when compared with
healthy controls [47]. The patients who died from sepsis had
increased levels of NF-κB activity in the nucleus of mono-
cytes, as compared with patients who survived sepsis.
The exact mechanism by which hyperthermia, via induction of
the heat shock response, appears to modulate the immune
response to sepsis is thought to be through inhibition of IKK
proteins [45]. As mentioned earlier, IKK has been shown to
be an important regulator of NF-κB activity. This protein phos-
phorylates I-κB and allows the regulatory protein to disassoci-
ate from NF-κB, thus allowing NF-κB to migrate into the
nucleus of the cell [38,45]. Inhibition of IKK will therefore lead
to decreased NF-κB activation and, ultimately, to less down-
stream proinflammatory cytokine gene expression.
After induction of the heat shock response with TNF-α,
human respiratory and alveolar cells had less production of
inflammatory cytokines, had less phosphorylated I-κB, had
higher total levels of I-κB, and had less IKK activity [48]. Addi-
tionally, recent in vitro experiments in human endothelial cells
have duplicated this work, showing that the heat shock
response reduces the activation of IKK, thereby reducing the
phosphorylation of the inhibitory protein I-κB and preventing
activation of NF-κB [49].
These data, which link fever and heat shock response to inhi-
bition of NF-κB, and thus decreased downstream cytokine
production, raise an important question about the wisdom of
treating hypothermia in septic patients.
Summary
Fever in the ICU, and especially in patients with sepsis, is
extremely common. It occurs from activity of endogenous
pyrogens that enhance prostaglandin E2 production in the
pre-optic region of the hypothalamus. Drugs that inhibit
COX-2, as well as measures that promote active cooling, are
effective at suppressing fever and are frequently used during
critically illness. Despite their widespread use, there is data
that suggest fever is beneficial to animals with infection, and
there is no evidence that treating fever changes mortality.
There is theoretical benefit that, through the heat shock
response and subsequent reduction of NF-κB, fever may play
a protective role in the survival of patients with severe sepsis.
In the absence of meaningful evidence for the beneficial
effects of fever reduction, the commonplace reduction of
224 fever in critically ill patients must be called into question.
Competing interests
None declared.
References
1. Cunha BA, Shea KW: Fever in the intensive care unit. Infect Dis
Clin North Am 1996, 10:185-209.
2. Arons MM, Wheeler AP, Bernard GR, Christman BW, Russell J A,
Schein R, Summer WR, Steinberg KP, Fulkerson W, Wright P,
Dupont WD, Swindell BB: Effects of ibuprofen on the physiol-
ogy and survival of hypothermic sepsis. Ibuprofen in Sepsis
Study Group. Crit Care Med 1999, 27:699-707.
3. Marik PE: Fever in the ICU. Chest 2000, 117:855-869.
4. O’Grady NP, Barie PS, Bartlett J, Bleck T, Garvey G, Jacobi J,
Linden P, Maki DG, Nam M, Pasculle W, Pasquale MD, Tribett DL,
Masur H: Practice parameters for evaluating new fever in criti-
cally ill adult patients. Task Force of the American College of
Critical Care Medicine of the Society of Critical Care Medicine
in collaboration with the Infectious Disease Society of
America. Crit Care Med 1998, 26:392-408.
5. Mackowiak PA, Wasserman SS, Levine MM: A critical appraisal
of 98.6 degrees F, the upper limit of the normal body temper-
ature, and other legacies of Carl Reinhold August Wunderlich.
JAMA 1992, 268:1578-1580.
6. Ipp M, Jaffe D: Physicians’ attitudes toward the diagnosis and
management of fever in children 3 months to 2 years of age.
Clin Pediatr (Phila) 1993, 32:66-70.
7. Fletcher JL, Jr., Creten D: Perceptions of fever among adults in
a family practice setting. J Fam Pract 1986, 22:427-430.
8. Gozzoli V, Schottker P, Suter PM, Ricou B: Is it worth treating
fever in intensive care unit patients? Preliminary results from
a randomized trial of the effect of external cooling. Arch Intern
Med 2001, 161:121-123.
9. Plaisance KI: Toxicities of drugs used in the management of
fever. Clin Infect Dis 2000, 31 (Suppl 5):S219-S223.
10. Ryan AJ, Flanagan SW, Moseley PL, Gisolfi CV: Acute heat
stress protects rats against endotoxin shock. J Appl Physiol
1992, 73:1517-1522.
11. Kluger MJ, Kozak W, Conn CA, Leon LR, Soszynski D: The adap-
tive value of fever. Infect Dis Clin North Am 1996, 10:1-20.
12. Villar J, Ribeiro SP, Mullen JB, Kuliszewski M, Post M, Slutsky AS:
Induction of the heat shock response reduces mortality rate
and organ damage in a sepsis-induced acute lung injury
model. Crit Care Med 1994, 22:914-921.
13. Mackowiak PA: Physiological rationale for suppression of
fever. Clin Infect Dis 2000, 31 (Suppl 5):S185-S189.
14. Bernheim HA, Kluger MJ: Fever and antipyresis in the lizard
Dipsosaurus dorsalis. Am J Physiol 1976, 231:198-203.
15. Plaisance KI, Mackowiak PA: Antipyretic therapy: physiologic
rationale, diagnostic implications, and clinical consequences.
Arch Intern Med 2000, 160:449-456.
16. Leon L: Cytokine regulation of fever: studies using gene
knockout mice. J Appl Physiol 2002, 92:2648-2655.
17. Netea MG, Kullberg BJ, Van der Meer JW: Circulating cytokines
as mediators of fever. Clin Infect Dis 2000, 31 (Suppl 5):S178-
S184.
18. Boulant JA: Role of the preoptic-anterior hypothalamus in
thermoregulation and fever. Clin Infect Dis 2000, 31 (Suppl 5):
S157-S161.
19. Luheshi GN: Cytokines and fever. Mechanisms and sites of
action. Ann N Y Acad Sci 1998, 856:83-89.
20. Katsuura G, Arimura A, Koves K, Gottschall PE: Involvement of
organum vasculosum of lamina terminalis and preoptic area
in interleukin 1 beta-induced ACTH release. Am J Physiol
1990, 258:E163-E171.
21. Saper CB, Breder CD: The neurologic basis of fever. N Engl J
Med 1994, 330:1880-1886.
22. Simmons DL, Wagner D, Westover K: Nonsteroidal anti-inflam-
matory drugs, acetaminophen, cyclooxygenase 2, and fever.
Clin Infect Dis 2000, 31 (Suppl 5):S211-S218.
23. Li S, Wang Y, Matsumura K, Ballou LR, Morham SG, Blatteis CM:
The febrile response to lipopolysaccharide is blocked in
cyclooxygenase-2(-/-), but not in cyclooxygenase-1(-/-) mice.
Brain Res 1999, 825:86-94.
24. Schwartz JI, Chan CC, Mukhopadhyay S, McBride KJ, Jones TM,
Adcock S, Moritz C, Hedges J, Grasing K, Dobratz D, Cohen RA,
 Available online http://ccforum.com/content/7/3/221

Davidson MH,Bachmann KA, Gertz BJ: Cyclooxygenase-2 inhi- bilization of I kappa B alpha through preventing I kappa B
bition by rofecoxib reverses naturally occurring fever in kinase activation in respiratory epithelial cells. J Immunol
humans. Clin Pharmacol Ther 1999, 65:653-660. 2000, 164:5416-5423.
25. Vane JR: Inhibition of prostaglandin synthesis as a mecha- 49. Kohn G, Wong HR, Bshesh K, Zhao B, Vasi N, Denenberg A,
nism of action for aspirin-like drugs. Nat New Biol 1971, 231: Morris C, Stark J, Shanley TP: Heat shock inhibits tnf-induced
232-235. ICAM-1 expression in human endothelial cells via I kappa
26. Flower RJ, Vane JR: Inhibition of prostaglandin synthetase in kinase inhibition. Shock 2002, 17:91-97.
brain explains the anti-pyretic activity of paracetamol (4-
acetamidophenol). Nature 1972, 240:410-411.
27. Duffell E: Curative power of fever. Lancet 2001, 358:1276.
28. Styrt B, Sugarman B: Antipyresis and fever. Arch Intern Med
1990, 150:1589-1597.
29. Muschenheim C, Duerschrer DR, Hardy JD: Hypothermia in
experimental infections: III. The effect of hypothermia on
resistance to experimental pneumococcus infection. J Infect
Dis 1943, 72:187-196.
30. Strouse S: Experimental studies on pneumococcus infections.
J Exp Med 1909, 11:743-761.
31. Mackowiak PA, Marling-Cason M, Cohen RL: Effects of temper-
ature on antimicrobial susceptibility of bacteria. J Infect Dis
1982, 145:550-553.
32. Bryant RE, Hood AF, Hood CE, Koenig MG: Factors affecting
mortality of gram-negative rod bacteremia. Arch Intern Med
1971, 127:120-128.
33. Kreger BE, Craven DE, McCabe WR: Gram-negative bac-
teremia. IV. Re-evaluation of clinical features and treatment in
612 patients. Am J Med 1980, 68:344-355.
34. Kregel KC: Heat shock proteins: modifying factors in physio-
logical stress responses and acquired thermotolerance. J
Appl Physiol 2002, 92:2177-2186.
35. Ritossa F: A new puffing pattern induced by temperature
shock and DNP in Drosophila. Experientia 1962, 18:571-573.
36. Tissieres A, Mitchell HK, Tracy UM: Protein synthesis in salivary
glands of Drosophila melanogaster: relation to chromosome
puffs. J Mol Biol 1974, 84:389-398.
37. Gerner EW, Schneider MJ: Induced thermal resistance in HeLa
cells. Nature 1975, 256:500-502.
38. Malhotra V, Wong HR: Interactions between the heat shock
response and the nuclear factor-kappaB signaling pathway.
Crit Care Med 2002, 30 (Suppl 1):S89-S95.
39. Kiang JG, Tsokos GC: Heat shock protein 70 kDa: molecular
biology, biochemistry, and physiology. Pharmacol Ther 1998,
80:183-201.
40. Mizzen LA ,Welch WJ: Characterization of the thermotolerant
cell. Effects of protein synthesis activity and the regulation of
heat-shock 70 protein expression. J Cell Biol 1988, 106:1105-
1116.
41. Schroeder S, Lindemann C, Hoeft A, Putensen C, Decker D, von
Ruecker AA, Stuber F: Impaired inducibility of heat shock
protein 70 in peripheral blood lymphocytes of patients with
severe sepsis. Crit Care Med 1999, 27:1080-1084.
42. Flohe S, Dominguez Fernandez E, Ackermann M, Hirsch T, Borg-
ermann J, Schade FU: Endotoxin tolerance in rats: expression
of TNF-alpha, IL-6, IL-10, VCAM-1 AND HSP 70 in lung and
liver during endotoxin shock. Cytokine 1999, 11:796-804.
43. Hauser GJ, Dayao EK, Wasserloos K, Pitt BR, Wong HR: HSP
induction inhibits iNOS mRNA expression and attenuates
hypotension in endotoxin-challenged rats. Am J Physiol 1996,
271:H2529-H2535.
44. Klosterhalfen B, Hauptmann S, Offner FA, Amo-Takyi B, Tons C,
Winkeltau G, Affify M, Kupper W, Kirkpatrick CJ, Mittermayer C:
Induction of heat shock protein 70 by zinc-bis-(DL-hydroge-
naspartate) reduces cytokine liberation, apoptosis, and mor-
tality rate in a rat model of LD100 endotoxemia. Shock 1997,
7:254-262.
45. Sun Z, Andersson R: NF-kappaB activation and inhibition: a
review. Shock 2002, 18:99-106.
46. Bohrer H, Qiu F, Zimmermann T, Qiu F, Zimmermann T, Zhang Y,
Jllmer T, Mannel D, Bottiger BW, Stern DM, Waldherr R, Saeger
HD, Ziegler R, Bierhaus A, Martin E, Nawroth PP: Role of NFkap-
paB in the mortality of sepsis. J Clin Invest 1997, 100:972-
985.
47. Paterson RL, Galley HF, Dhillon JK, Webster NR: Increased
nuclear factor kappa B activation in critically ill patients who
die. Crit Care Med 2000, 28:1047-1051.
48. Yoo CG, Lee S, Lee CT, Kim YW, Han SK, Shim YS: Anti-inflam-
matory effect of heat shock protein induction is related to sta- 225
Young and Saxena Critical Care 2014, 18:206
http://ccforum.com/content/18/2/206
REVIEW
Fever management in intensive care patients with
infections
Paul J Young1*, Manoj Saxena2
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2014 and co-published as a series
in Critical Care. Other articles in the series can be found online at http://ccforum.com/series/annualupdate2014. Further information about the
Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.
Introduction
‘Humanity has but three great enemies:
fever, famine and war; of these by far the greatest,
by far the most terrible, is fever’ [1].
Fever is one of the cardinal signs of infection and, nearly
120  years after William Osler’s statement in his address
to the 47th annual meeting of the American Medical
Association [1], infectious diseases remain a major cause
of morbidity and mortality. Despite this, it is unclear
whether fever itself is truly the enemy or whether, in fact,
the febrile response represents an important means to
help the body fight infection. Furthermore, it is unclear
whether the administration of antipyretic medications or
physical cooling measures to patients with fever and
infection is beneficial or harmful [2], [3]. Here, we review
the biology of fever, the significance of the febrile
response in animals and humans, and the current
evidence-base regarding the utility of treating fever in
intensive care patients with infectious diseases.
The biology of fever
Regulation of normal body temperature
Thermoregulation is a fundamental homeostatic mecha-
nism that maintains body temperature within a tightly
regulated range. The ability to internally regulate body
temperature is known as endothermy and is a charac-
teristic of all mammals and birds. The thermoregulatory
system consists of an afferent sensory limb, a central
processing center, and an efferent response limb. In
humans, the central processing center controlling the
thermoregulatory set-point is the hypothalamus. Both
warm-sensitive and cold-sensitive thermoreceptors are
*Correspondence: paul.young@ccdhb.org.nz
1
Intensive Care Unit, Wellington Regional Hospital, Wellington, New Zealand
Full list of author information is available at the end of the article
© 2010 BioMed Central Ltd © 2014 Springer-Verlag Berlin Heidelberg and BioMed Central
involved in the afferent limb. Stimulation of the cold-
sensitive receptors activates efferent responses relayed
via the hypothalamus that reduce heat loss and increase
heat production. These responses include reducing blood
flow to the peripheries and increasing heat production by
mechanisms including shivering. Conversely, stimulation
of warm-sensitive receptors ultimately increases heat loss
through peripheral vasodilation and evaporative cooling
caused by sweating.
The cellular and molecular basis of the febrile response
Upward adjustment of the normal hypothalamic thermo-
regulatory set-point leading to fever is typically part of a
cytokine-mediated systemic inflammatory response
syndrome that can be triggered by various infectious
etiologies including bacterial, viral, and parasitic infec-
tions as well as by a range of non-infectious etiologies
including severe pancreatitis and major surgery.
In patients with sepsis, the febrile response involves
innate immune system activation via Toll-like receptor 4
(TLR-4). This activation leads to production of pyrogenic
cytokines including interleukin (IL)-1β, IL-6, and tumor
necrosis factor (TNF)-α. These pyrogenic cytokines act
on an area of the brain known as the organum vascu-
losum of the laminae terminalis (OVLT) leading to the
release of prostaglandin E2 (PGE2) via activation of the
enzyme cyclo-oxygenase-2 (COX-2). PGE2 binds to
receptors in the hypothalamus leading to an increase in
heat production and a decrease in heat loss until the
temperature in the hypothalamus reaches a new, elevated,
set-point. Once the new set-point is attained, the
hypothalamus maintains homeostasis around this new
set-point by the same mechanisms involved in the
regulation of normal body temperature. However, in
addition, there are a number of important specific
negative feedback systems in place that prevent excessive
elevation of body temperature. One key system is the
glucocorticoid system, which acts via nuclear
Young and Saxena Critical Care 2014, 18:206
http://ccforum.com/content/18/2/206
factor-kappa B (NF-κB) and activator protein-1 (AP-1).
Both these mediators have anti-inflammatory properties
and downregulate the production of pyrogenic cytokines,
such as IL-1β, IL-6, and TNF-α. The febrile response is
further modulated by specific antipyretic cytokines
including IL-1 receptor antagonist (IL-1RA), IL-10, and
TNF-α binding protein.
Heat shock proteins and the febrile response
The negative feedback systems outlined above are not the
only mechanisms that exist to protect cells from being
damaged by the febrile response. In addition, the heat
shock proteins (HSPs) provide intrinsic resistance to
thermal damage. Genes encoding the HSPs probably first
evolved more than 2.5  billion years ago. They represent
an important system providing protection to cells, not
only against extremes of temperature, but also against
other potentially lethal stresses including toxic chemicals
and radiation injury. During heat-stress, transcription
and translation of HSPs is upregulated. HSPs can then
trigger refolding of heat-damaged proteins preserving
them until heat-stress has passed or, if necessary, can
transport denatured proteins to organelles for intra-
cellular degradation. As well as providing protection
against cellular damage from the thermal stress induced
by fever, the HSPs may themselves be important
regulators of the febrile response. For example, HSP  70
inhibits pyrogenic cytokine production via NF-κB. HSPs
also inhibit programmed cell death, which might
otherwise be induced by an invading pathogen.
The physiological consequences of fever
The febrile response leads to a marked increase in
metabolic rate. In humans, generating fever through
shivering increases the metabolic rate above basal levels
by six-fold [4]. In critically ill patients with fever, cooling
reduces oxygen consumption by about 10  % per °C
decrease in core temperature and significantly reduces
cardiac output and minute ventilation [5]. Any potential
benefit of the febrile response needs to be weighed
against this substantial metabolic cost.
The immunological consequences of fever
Temperatures in the physiological febrile range stimulate
the maturation of murine dendritic cells. This is
potentially important because dendritic cells act as the
key antigen presenting cells in the immune system.
Human neutrophil cell motility and phagocytosis are
enhanced by temperatures in the febrile range, and
growth of intracellular bacteria in human macrophages
in vitro is reduced by temperatures in the febrile range
compared to normal temperatures. Murine macrophages
demonstrate a range of enhanced functions at tempera-
tures in the febrile range. These effects include enhanced
Page 2 of 8
expression of the Fc receptors that are involved in
mediating antibody responses, and enhanced phago-
cytosis. Temperatures in the physiological febrile range
enhance binding of human lymphocytes to the vascular
endothelium. This L-selectin-mediated binding is
important in facilitating lymphocyte migration to sites of
tissue inflammation or infection. In mice, T lymphocyte-
mediated killing of virus-infected cells is increased by
temperatures in the febrile range and helper T-cell
potentiation of antibody responses is enhanced. In
contrast to other cells of the immune system, the
cytotoxic activity of natural killer cells is reduced by
temperatures in the febrile range compared to normal
body temperature. Although their functions are
enhanced by temperatures in the physiological febrile
range (38–40  °C), neutrophils and macrophages have
substantially reduced function at temperatures of ≥ 41 °C.
The effects of fever on the viability of microbial
pathogens
Temperatures in the human physiological febrile range
cause direct inhibition of some viral and bacterial
organisms such as influenza virus [6], Streptococcus
pneumonia [7], [8], and Neisseria meningitides [9] which
can all cause life-threatening illnesses. For influenza, the
degree of heat sensitivity appears to be a determinant of
virulence, such that strains with a shut-off temperature of
≤38  °C cause mild symptoms, whereas strains with a
shut-off temperature of ≥39  °C cause severe symptoms
[6]. The susceptibility of a pathogen to heat may have
significance in terms of its pathogenicity in a particular
host. For example, Campylobacter jejuni is not
pathogenic in birds (body temperature 42  °C) but is
pathogenic in humans (body temperature 37 °C) and the
growth and chemotactic ability of C. jejuni in vitro are
greater at 37 °C than at 42 °C [10].
The significance of fever in animals with infections
The febrile response to infection is seen in a range of
animal species including not only endotherms, such as
mammals and birds, but also ectotherms, including
reptiles, amphibians, and fish. The febrile response can
be blocked by inhibition of COX in a diverse range of
species including desert iguanas [11] and bluegill sunfish
[12], as well as higher animals like humans. As COX
catalyzes the generation of prostaglandins from
arachidonic acid, this suggests that the pivotal role of
PGE2 in the regulation of the thermostatic set-point may
be preserved in these species as well as in higher animals.
Such a common biochemical mechanism to regulate
fever across such a diverse group of animals raises the
possibility that the febrile response may have evolved in a
common ancestor. If this is the case, then fever probably
emerged as an evolutionary response more than 350 million
Young and Saxena Critical Care 2014, 18:206
http://ccforum.com/content/18/2/206
years ago [13]. As the febrile response comes at a
significant metabolic cost [4], [5], its persistence across
such a broad range of species provides strong
circumstantial evidence that the response has some
evolutionary advantage. Furthermore, given that the
response appears ubiquitous, it logically follows that the
components of the immune system would have evolved
to function optimally in the physiological febrile range.
In experimental models in mammals, the febrile
response appears to offer a survival advantage across a
range of viral infections. Newborn mice infected with
coxsackie virus, which are allowed to develop a fever
have a much lower mortality than mice which are
prevented from developing a fever [14]. Similarly,
increasing the environmental temperature from 23–26 °C
to 38  °C increases the core temperature of Herpes
simplex-infected mice by about 2  °C and increases their
survival from 0  % to 85  % [15]. A meta-analysis of the
effect of antipyretic medications on mortality in animal
models of influenza infection demonstrated that
antipyretic treatment was associated with an increased
mortality risk [OR 1.34 (95 % CI 1.04-1.73)] [16].
Studies in mammalian models of bacterial infections
have generally yielded similar results. In rabbits infected
with Pasteurella multocida, the presence of a mild fever
of up to 2.25  °C above normal was correlated with the
greatest chance of survival compared to either
normothermia or fever of >  2.25  °C above normal [17].
Although mice are predominantly endothermic, they
appear to require external sources of heat to generate a
fever. If mice are allowed to position themselves in a cage
with a temperature gradient, they increase their ambient
temperature preference and elevate their core tempera-
ture by 1.1 °C after a lipopolysaccharide (LPS) challenge
[18]. Housing mice at 35.5 °C rather than 23 °C increases
their core body temperature by about 2.5  °C, alters
cytokine expression, and improves survival in Klebsiella
pneumoniae peritonitis [19]. In this model, the elevated
body temperature seen with increased ambient
temperature was associated with a 100,000-fold
reduction in the intraperitoneal bacterial load [19]. A
recently published systematic review and meta-analysis
of the effects of antipyretic medications on mortality in S.
pneumoniae infection identified four animal studies
comparing aspirin to placebo and demonstrated that the
administration of aspirin was associated with an
increased risk of death [OR 1.97 (95 %CI 1.22-3.19)] [20].
The significance of fever in humans with infection
Fever, hyperthermia, and antipyresis in non-ICU patients
with infections
Viral infections
Two double blind randomized placebo-controlled trials
in 45 volunteers inoculated with either rhinovirus type 21
Page 3 of 8
(study one) or rhinovirus type 25 (study two) demon-
strated that administration of aspirin did not alter the
proportion of patients who developed clinical illness or
significantly alter the frequency or severity of symptoms
[21]. Although the administration of aspirin significantly
increased the shedding of rhinovirus in these trials, only
one of the 45 patients developed fever so this increase in
shedding was probably not attributable to the antipyretic
effect of aspirin [21]. A similar study of 60 volunteers
inoculated with rhinovirus and randomized to aspirin,
paracetamol, ibuprofen, or placebo showed that the use
of either aspirin or paracetamol was associated with
suppression of the serum antibody response and a rise in
circulating monocytes [22]. There were no significant
differences in viral shedding among the four groups.
However, the subjects treated with aspirin or paracetamol
had a significant increase in nasal symptoms and signs
compared to the placebo group [22]. In rhinovirus-
infected volunteers treated with pseudoephedrine, the
addition of ibuprofen had no effect on symptoms or on
viral shedding or viral titers [23]. Again, only two of the
58 subjects developed a fever. A randomized controlled
trial of children aged six months to six years with
presumed non-bacterial infection and a fever of ≥ 38 °C
demonstrated that administration of paracetamol
increased the children’s activity but not their mood,
comfort or appetite [24].
Overall, the data from clinical studies in non-ICU
patients do not support the hypothesis that antipyresis has
a clinically significant beneficial or detrimental impact on
the course or severity of minor viral illnesses. Although
antipyretic medicines may increase the duration of
rhinovirus shedding and time until crusting of chicken pox
lesions, these effects seems unlikely to be attributable to
antipyresis and are of uncertain clinical importance.
Bacterial infections
There are no randomized controlled trial data examining
strategies of fever management on patient-centered
outcomes in non-ICU patients with bacterial infections.
However, there are historical examples of dramatic
responses to treatment with therapeutic hyperthermia in
some infectious diseases. It has been known since the
time of Hippocrates that progressive paralysis due to
neurosyphilis sometimes resolves after an illness
associated with high fever. This observation led Julius
Wagner-Jauregg to propose, in 1887, that inoculation of
malaria might be a justifiable therapy for patients with
‘progressive paralysis’. His rationale was that one could
substitute an untreatable condition for a treatable one –
malaria being treatable with quinine. In 1917, he tested
his hypothesis in nine patients with paralysis due to
syphilis by injecting them with blood from patients
suffering from malaria. Three of the patients had
Young and Saxena Critical Care 2014, 18:206 Page 4 of 8
http://ccforum.com/content/18/2/206

Table 1 Summary of key observational studies of fever and fever management in ICU patients
Design, setting, and participants Key findings

Laupland et al. 2008 [30] Retrospective cohort study of patients admitted to • Fever of ≥ 38.3 °C developed during 44 % of ICU admissions and
four ICUs in Calgary between 2000 and 2006; high fever ≥ 39.3 °C during 8 % of admissions
n = 24,204 ICU admissions in 20,466 patients • Fever was not associated with increased ICU mortality but high
fever was associated with a significantly increased risk of death

Young et al. 2011 [31] Inception cohort study in three tertiary ICUs in • 9 % of patients admitted to ICU had or developed a fever and
Australia and New Zealand over six weeks in 2010 known or suspected infection
identifying patients with fever ≥ 38 °C and known or • Paracetamol was administered to about 2/3 of patients with fever
suspected infection; n = 565 and known or suspected infection on any given day

Selladurai et al. 2011 [32]
Retrospective cohort study of patients admitted to
a single tertiary ICU in Australia with sepsis between
December 2009 and August 2010; n = 106
• 69 % of septic patients received paracetamol at least once
during their first seven days in ICU
• 88 % of septic patients with a fever > 38 °C received
paracetamol during their first seven days in ICU
• Septic patients with a fever > 38 °C were 6.8 times (95 % CI
1.9-24.7) more likely to receive paracetamol than septic patients
who were not febrile

Lee et al. 2012 [33]
Inception cohort study of consecutive patients
admitted to 25 ICUs in Japan and Korea for more
than 48 hours over three months in 2009; n = 1,425
• NSAID use independently associated with increased 28-day
mortality in patients with sepsis (adjusted OR 2.61; 95 % CI
1.11-6.11; p = 0.03) but with a trend towards a decreased 28-day
mortality in patients without sepsis (adjusted OR 0.22; 95 % 0.03-
1.74; p = 0.15)
• Paracetamol use independently associated with increased
28-day mortality in patients with sepsis (adjusted OR 2.05; 95 %
CI 1.19-3.55; p = 0.01) but with a trend towards a decreased 28-
day mortality in patients without sepsis (adjusted OR 0.58; 95 %
0.06-5.26; p = 0.63)

Laupland et al. 2012 [34] Inception cohort study of patients admitted to • 25.7 % of patients had a fever of ≥ 38.3 °C at ICU presentation
French ICUs contributing to the Outcomerea • Fever was not associated with increased mortality but
database between April 2000 and November 2010; hypothermia was an independent predictor of death in medical
n = 10,962 patients

Young et al. 2012 [35] Retrospective cohort study of 636,051 patients in • Elevated body temperature in the first 24 hours in ICU was
Australia, New Zealand and the UK admitted to the associated with an increased risk of mortality in patients without
ICU between 2005 until 2009 infections and a decreased risk of mortality in patients with
infections

Niven et al. 2012 [36] Interrupted time series analysis of cumulative fever • The cumulative incidence of fever ≥ 38.3 during ICU admission
incidence in ICUs in Calgary from 2004–2009 decreased from 50.1 % to 25.5 % over the 5.5 years of the study
CI: confidence interval; ICU: intensive care unit; NSAIDs: non-steroidal anti-inflammatory drugs; OR: odds ratio

remission of their paralysis. This led to further experi-
ments and clinical observations on more than a thousand
patients with remission occurring in 30  % of patients
with neurosyphilis-related progressive paralysis ‘treated’
with fever induced by malaria compared to spontaneous
remission rates of only 1  %. This work on fever therapy
led to Julius Wagner-Jauregg being awarded the Nobel
Prize in Physiology or Medicine in 1927 [25]. Subse-
quently, fever therapy was shown to be effective in
treating gonorrhea. Inducing a hyperthermia of 41.7  °C
for six hours in the ‘Kettering hypertherm chamber’ led
to cure in 81 % of cases [26].
A number of observational studies have examined the
association between body temperature and outcome in
patients with various bacterial infections, including
pneumonia [27], spontaneous bacterial peritonitis [28],
and Gram-negative bacteremia [29]. These studies show
that the absence of fever is a sign of poor prognosis in
patients with bacterial infections. Overall, the design of
these studies does not allow one to distinguish between
the absence of fever as a marked of disease severity or
impaired host resilience rather than the presence of fever
as a protective response.
Fever in ICU patients with infections
Observational studies of fever and fever management in ICU
patients
The epidemiology of fever in ICU patients and the
frequency and utility of antipyretic use in ICU patients
has been evaluated in a number of observational studies.
The most important of the studies are summarized in
Table 1.
The incidence of fever attributable to infection in
observational studies in various critical care settings
Young and Saxena Critical Care 2014, 18:206
http://ccforum.com/content/18/2/206
varies from 8 % to 37 % [31], [34], [36]–[41]. These
studies use a variety of definitions of fever and a range of
methods to record temperature, making comparisons
between studies difficult. In these studies, the presence of
fever was associated with either an increased risk of
death [30], [39]–[41] or no difference in mortality risk
compared to a normal temperature [34]. Only two studies
have evaluated the mortality risk of patients with sepsis
separately from patients without sepsis [33], [35]. In the
first study, fever was associated with an increased 28-day
mortality risk in patients without sepsis but not in
patients with sepsis [33] raising the possibility that the
presence of infection might be an important determinant
of the significance of the febrile response in ICU patients.
Similarly, in a retrospective cohort study [35]
(n  =  636,051) using two independent, multicenter,
geographically distinct and representative databases we
found that peak temperatures above 39.0 °C in the first
24  hours after ICU admission were generally associated
with a reduced risk of in-hospital mortality in patients
with an admission diagnosis of infection. Conversely,
higher peak temperatures were associated with an
increased risk of in-hospital mortality in patients with a
non-infection diagnosis.
Overall, although one recent study suggests that the
incidence of fever is decreasing over time [36], existing
observational data suggest that fever is a commonly
encountered abnormal physical sign in ICU patients.
Unfortunately, because of the potential for unmeasured
confounding factors, it is impossible to establish whether
treating fever in ICU patients with an infection is beneficial
or harmful on the basis of observational studies.
Interventional studies of fever management in ICU patients
Two recently published meta-analyses found no evidence
that antipyretic therapy was either beneficial or harmful
in non-neurologically injured ICU patients [2], [3].
Nearly all of the patients included in these meta-analyses
had known or suspected sepsis and one of the meta-
analyses only included patients with infection [3]. In both
meta-analyses, the authors noted that existing studies
lacked adequate statistical power to detect clinically
important differences and recommended that large
randomized controlled trials were urgently needed. The
details of published interventional studies of fever
management strategies in ICU patients are summarized
in Table 2.
The largest published randomized controlled trial
evaluated the use of ibuprofen in critically ill patients
with sepsis [43]. Patients with severe sepsis were
randomized to receive 10 mg/kg of ibuprofen or placebo
every six hours for a total of eight doses. Although the
use of ibuprofen significantly reduced body temperature,
it did not alter 30-day mortality, which was 37  % in the
Page 5 of 8
ibuprofen-treated group and 40 % in the placebo group.
This study was designed to evaluate the use of ibuprofen
as an anti-inflammatory rather than as an anti-pyretic
and, while the use of ibuprofen significantly reduced
temperature compared to placebo, the study included
patients who were hypothermic as well as patients who
were febrile. An additional confounding factor was that
patients assigned to the ibuprofen group were treated
with paracetamol more often than those assigned to the
control group. On the basis of this [43] and other smaller
studies [45], [46] of non-steroidal anti-inflammatory
drugs (NSAIDs) in critically ill patients, it is clear that
NSAIDs are effective at reducing temperature in febrile
ICU patients. However, there is no consistent mortality
signal from the existing studies of NSAIDs. Some studies
show trends towards benefit [42]–[44] with the use of
NSAIDs and others show trends towards harm [45], [46].
The second largest published study of temperature
management in febrile ICU patients evaluated the use of
external cooling [49]. This study randomized 200 febrile
patients with septic shock requiring vasopressors,
mechanical ventilation, and sedation to external cooling
to normothermia (36.5-37 °C) for 48 hours or no external
cooling. The primary endpoint was the proportion of
patients with a 50  % decrease in vasopressor use at
48  hours after randomization. There was no significant
difference between the treatment groups for the primary
endpoint, which was achieved in 72  % of the patients
assigned to external cooling and 61  % of the patients
assigned to standard care. This study had a large number
of secondary endpoints including mean body tempera-
ture, the proportion of patients who achieved 50  %
reduction in vasopressors at 2 hours, 12 hours, 24 hours,
and 36  hours as well as day-14, ICU, and hospital
mortality. The secondary endpoints generally favored
external cooling and day-14 mortality was noted to be
significantly lower in the external cooling group (19 % vs.
34  %; p  =  0.0013). This difference in mortality was not
evident by the time of ICU or hospital discharge and
caution should be exerted in interpreting these endpoints
as it is possible that they were affected by a type 1 error
due to a lack of statistical power.
Another trial compared temperature control strategies
in a tertiary trauma ICU and randomized patients to
either aggressive temperature control or a permissive
strategy [47]. Patients assigned to the aggressive
treatment arm received regular paracetamol once the
temperature exceeded 38.5  °C and physical cooling was
added when the temperature exceeded 39.5  °C. Patients
assigned to the permissive treatment arm received
paracetamol and cooling when the temperature reached
40  °C. This trial originally aimed to enroll 672 patients;
however, it was stopped by the Data Safety Monitoring
Board after enrolment of 82 patients due to a trend
Young and Saxena Critical Care 2014, 18:206 Page 6 of 8
http://ccforum.com/content/18/2/206

Table 2 Summary of randomized controlled trials investigating the management of fever in critically ill adults
Design, setting, and participants Key findings
Bernard et al. 1991 [42] Double blind placebo-controlled trial of ibuprofen in • Ibuprofen significantly reduced temperature, heart rate, and
patients with severe sepsis; n = 30 peak airway pressure
• There was no significant difference between ibuprofen and
placebo in terms of in-hospital mortality rate (18.8 % ibuprofen-
treated group vs. 42.9 % placebo-treated group)

Bernard et al. 1997 [43]
Double blind placebo-controlled trial of ibuprofen in
patients with severe sepsis in seven centers in North
America; n = 455
• Ibuprofen significantly reduced temperature, heart rate, oxygen
consumption, and lactic acidosis in patients with severe sepsis
• Ibuprofen did not alter the incidence or duration of shock or
ARDS and had no significant effect on 30-day mortality (37 %
ibuprofen-treated group vs. 40 % placebo-treated group)

Memis et al. 2004 [44] Double blind placebo-controlled trial of lornoxicam • No significant difference between lornoxicam and placebo
in patients with severe sepsis in one center in Turkey; was demonstrated in terms of hemodynamic parameters,
n = 40 biochemical parameters, cytokine levels, or ICU mortality (35 %
lornoxicam-treated group vs. 40 % placebo-treated group)

Morris et al. 2011 [45]
Multicenter, randomized trial comparing the
antipyretic efficacy of a single dose of placebo,
100 mg, 200 mg, or 400 mg of i. v. ibuprofen in
hospitalized patients of whom > 90 % had infections;
n = 120 (53 critically ill)
• All doses of ibuprofen tested were effective in lowering
temperature
• There were no significant difference between treatment groups
with respect to ventilation requirements, length of stay or
in-hospital mortality (4 % placebo, 3 % 100 mg ibuprofen, 7 %
200 mg ibuprofen, 6 % 400 mg ibuprofen)

Haupt et al. 1991 [46] Multicenter, placebo-controlled randomized trial of • Ibuprofen significantly reduced body temperature
ibuprofen in patients with severe sepsis; n = 29 • There was no significant difference between the treatment
groups in terms of in-hospital mortality (30.8 % in the placebo
group vs. 56.3 % in the ibuprofen group)

Schulman et al. 2006 [47] Single center, unblinded, randomized trial of • There was no significant difference between the treatment arms
aggressive vs. permissive temperature management in terms of the number of new infections
in febrile patients in a trauma ICU; n = 82 • The in-hospital mortality was 15.9 % in the aggressive treatment
group and 2.6 % in the permissive treatment group (p = 0.06)

Niven et al. 2012 [48] Multicenter, unblinded randomized trial of • The mean daily temperature was lower in the patients assigned
aggressive vs. permissive temperature management to aggressive fever management
in febrile ICU patients; n = 26 • The in-hospital mortality was 21 % in the aggressive treatment
group and 17 % in the permissive treatment group (p = 1.0)

Schortgen et al. 2012 [49] Multicenter, randomized controlled trial of external
cooling in patients with fever and septic shock
receiving mechanical ventilation in seven centers in
France; n = 200
ARDS: acute respiratory distress syndrome; ICU: intensive care unit.
• External cooling significantly reduced body temperature
• External cooling did not alter the proportion of patients who
had a 50 % reduction in vasopressor dose after 48 hours
• Day-14 mortality was significantly lower in the patients assigned
to external cooling but there was no significant difference
between the groups in terms of ICU or in-hospital mortality

towards increased mortality in the aggressive treatment
group. While all deaths were attributed to septic causes,
conventional stopping rules were not used and
differences between the study treatment arms could be
due to chance. This study had other major limitations
including a lack of blinding or placebo-control, and
potential confounding from the uncontrolled use of other
antipyretic drugs and per-protocol use of external
cooling. A similar open-label randomized study enrolled
26 febrile ICU patients and assigned them to aggressive
or permissive temperature management [48]. In this
study, the aggressive fever control group received
paracetamol 650 mg enterally every 6  hours when the
temperature was ≥ 38.3 °C and received physical cooling
for temperature ≥ 39.5 °C. The permissive group did not
receive paracetamol until the temperature was ≥ 40 °C
and did not receive physical cooling until the temperature
reached ≥  40.5  °C. All patients assigned to aggressive
temperature management had an infectious etiology of
fever and 75  % of patients assigned to the permissive
management arm had an infectious etiology at baseline.
The 28-day all cause mortality was not significantly
different between the two groups.
The safety and efficacy of using paracetamol to treat
fever in ICU patients with infections is being evaluated in
a 700-patient phase IIb, multicenter, randomized
placebo-controlled trial (the HEAT trial), which is due to
complete enrolment in November 2014 [50].
Young and Saxena Critical Care 2014, 18:206
http://ccforum.com/content/18/2/206
Conclusion
There is a significant body of animal data demonstrating
that fever is an important component of the host
response to infection and confers a survival advantage in
a number of animal species. The conservation of a
metabolically costly response across a broad range of
animal species suggests that the response probably has an
evolutionary advantage. There are some interesting
historical examples of hyperthermia being employed to
treat infectious diseases. However, in the modern era the
relevance of these examples is questionable. Furthermore,
arguments based on the evolutionary importance of the
febrile response do not necessarily apply to critically ill
patients who are, by definition, supported beyond the
limits of normal physiological homeostasis. Humans are
not adapted to critical illness. In the absence of modern
medicine and intensive care, most critically ill patients
with fever and infection would presumably die. Among
critically ill patients, it is biologically plausible that there
is a balance to be struck between the potential benefits of
reducing metabolic rate that come with fever control and
the potential risks of a deleterious effect on host defense
mechanisms. Remarkably, at present, we do not know
what effect treating fever in critically ill patients with
infections has on patient-centered outcomes. These
treatments include commonly used interventions such as
paracetamol and physical cooling. This area of research is
of high priority given the global epidemiology of fever in
critically ill patients and the generalizability of the
candidate interventions.
List of abbreviations used
AP-1: activator protein-1; ARDS: acute respiratory distress syndrome; CI:
confidence interval; COX-2: cyclo-oxygenase; HSPs: heat shock proteins;
ICU: intensive care unit; IL: interleukin; IL-1RA: IL-1 receptor agonist; LPS:
lipopolusaccharide; NF-κB: nuclear factor-kappa B; NSAIDs: non-steroidal
anti-inflammatory drugs; OR: odds ratio; OVLT: organum vasculosum of the
laminae terminalis; PGE2: prostaglandin E2; TLR-4: Toll-like receptor 4; TNF:
tumor necrosis factor.
Competing interests
The authors declare that they have no competing interests.
Declarations
Funding for publication of this article comes from Public Hospital Funds that
are allocated for Training, Education and Study Leave purposes.
Author details
1
Intensive Care Unit, Wellington Regional Hospital, Wellington, New Zealand.
2
Department of Intensive Care Medicine, St. George Hospital, Kogarah,
Australia
Published: 18 March 2014
References
1. Osler W: The study of the fevers of the south. JAMA 1986, XXVI:1001–1004.
2. Niven DJ, Stelfox HT, Laupland KB: Antipyretic therapy in febrile critically ill
adults: A systematic review and meta-analysis. J Crit Care 2013, 28:303–310.
3. Jefferies S, Weatherall M, Young P, Eyers S, Perrin KG, Beasley CR: The effect of
antipyretic medications on mortality in critically ill patients with infection:
a systematic review and meta-analysis. Crit Care Resus 2011, 13:125–131.
4. Horvath SM, Spurr GB, Hutt BK, Hamilton LH: Metabolic cost of shivering.
J Appl Physiol 1956, 8:595–602.
Page 7 of 8
5. Manthous CA, Hall JB, Olson D, Singh M, Chatila W, Pohlman A, Kushner R,
Schmidt GA, Wood LD: Effect of cooling on oxygen consumption in febrile
critically ill patients. Am J Respir Crit Care Med 1995, 151:10–14.
6. Chu CM, Tian SF, Ren GF, Zhang YM, Zhang LX, Liu GQ: Occurrence of
temperature-sensitive influenza A viruses in nature. J Virol 1982,
41:353–359.
7. Small PM, Tauber MG, Hackbarth CJ, Sande MA: Influence of body
temperature on bacterial growth rates in experimental pneumococcal
meningitis in rabbits. Infect Immun 1986, 52:484–487.
8. Enders JF, Wu CJ, Shaffer MF: Studies on natural immunity to
pneumococcus type III: IV. Observations on a non-type specific humoral
factor involved in resistance to pneumococcus type III. J Exp Med 1936,
64:425–438.
9. Moench M: A study of the heat sensitivity of the meningococcus in vitro
within the range of therapeutic temperatures. J Lab Clin Med 1926,
57:665–676.
10. Khanna MR, Bhavsar SP, Kapadnis BP: Effect of temperature on growth and
chemotactic behaviour of Campylobacter jejuni. Lett Appl Microbiol 2006,
43:84–90.
11. Bernheim HA, Kluger MJ: Fever: effect of drug-induced antipyresis on
survival. Science 1976, 193:237–239.
12. Reynolds WW: Fever and antipyresis in the bluegill sunfish, Lepomis
macrochirus. Comparative biochemistry and physiology. Comp Biochem
Physiol C 1977, 57:165–167.
13. Kluger M: The evolution of fever. In Fever: Its Biology, Evolution, and
Function, 1st edn.Edited by Kluger M Princeton University Press, New Jersey,
1979: 106–127.
14. Strouse S: Experimental Studies on Pneumococcus Infections. J Exp Med
1909, 11:743–761.
15. Armstrong C: Some recent research in the field of neurotropic viruses with
especial reference to lymphocytic choriomeningitis and herpes simplex.
Mil Surg 1942, 91:129–145.
16. Eyers S, Weatherall M, Shirtcliffe P, Perrin K, Beasley R: The effect on mortality
of antipyretics in the treatment of influenza infection: systematic review
and meta-analysis. J R Soc Med 2010, 103:403–411.
17. Kluger MJ, Vaughn LK: Fever and survival in rabbits infected with
Pasteurella multocida. J Physiol 1978, 282:243–251.
18. Akins C, Thiessen D, Cocke R: Lipopolysaccharide increases ambient
temperature preference in C57BL/6J adult mice. Physiol Behav 1991,
50:461–463.
19. Jiang Q, Cross AS, Singh IS, Chen TT, Viscardi RM, Hasday JD: Febrile core
temperature is essential for optimal host defense in bacterial peritonitis.
Infect Immun 2000, 68:1265–1270.
20. Jefferies S, Weatherall M, Young P, Eyers S, Beasley R: Systematic review and
meta-analysis of the effects of antipyretic medications on mortality in
Streptococcus pneumoniae infections. Postgrad Med J 2012, 88:21–27.
21. Stanley ED, Jackson GG, Panusarn C, Rubenis M, Dirda V: Increased virus
shedding with aspirin treatment of rhinovirus infection. JAMA 1975,
231:1248–1251.
22. Graham NM, Burrell CJ, Douglas RM, Debelle P, Davies L: Adverse effects of
aspirin, acetaminophen, and ibuprofen on immune function, viral
shedding, and clinical status in rhinovirus-infected volunteers. J Infect Dis
1990, 162:1277–1282.
23. Sperber SJ, Sorrentino JV, Riker DK, Hayden FG: Evaluation of an alpha
agonist alone and in combination with a nonsteroidal antiinflammatory
agent in the treatment of experimental rhinovirus colds. Bull N Y Acad Med
1989, 65:145–160.
24. Kramer MS, Naimark LE, Roberts-Brauer R, McDougall A, Leduc DG : Risks and
benefits of paracetamol antipyresis in young children with fever of
presumed viral origin. Lancet 1991, 337:591–594.
25. Wagner-Jauregg J: The treatment of dementia paralytica by malaria
innoculation. In Nobel Lectures: Physiology or Medicine 1922–1941. Elsevier,
New York, 1927: 159–169
26. Owens C: The value of fever therapy for gonorrhea. JAMA 1936,
107:1942–1946.
27. Ahkee S, Srinath L, Ramirez J: Community-acquired pneumonia in the
elderly: association of mortality with lack of fever and leukocytosis. South
Med J 1997, 90:296–298.
28. Weinstein MP, Iannini PB, Stratton CW, Eickhoff TC: Spontaneous bacterial
peritonitis. A review of 28 cases with emphasis on improved survival and
factors influencing prognosis. Am J Med 1978, 64:592–598.
Young and Saxena Critical Care 2014, 18:206
http://ccforum.com/content/18/2/206
29. Bryant RE, Hood AF, Hood CE, Koenig MG: Factors affecting mortality of
gram-negative rod bacteremia. Arch Intern Med 1971, 127:120–128.
30. Laupland KB, Shahpori R, Kirkpatrick AW, Ross T, Gregson DB, Stelfox HT:
Occurrence and outcome of fever in critically ill adults. Crit Care Med 2008,
36:1531–1535.
31. Young P, Saxena M, Eastwood GM, Bellomo R, Beasley R: Fever and fever
management among intensive care patients with known or suspected
infection: a multicentre prospective cohort study. Crit Care Med 2011,
13:97–102.
32. Selladurai S, Eastwood GM, Bailey M, Bellomo R: Paracetamol therapy for
septic critically ill patients: a retrospective observational study. Crit Care
Resus 2011, 13:181–186.
33. Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsegu K,
Uehara K, Dote K, Tajimi K, Morita K, Matsuo K, Hoshino K, Hosokawa K, Lee
KH, Lee KM, Takatori M, Nishimura M, Sanui M, Ito M, Egi M, Honda N,
Okayama N, Shime N, Tsuruta R, Nogami S, Yoon SH, Fujitani S, Koh SO, Takeda
S, Saito S, Hong SJ, Yamamoto T, Yokoyama T, Yamaguchi T, Nishiyama T,
Igrashi T, Kakihana Y, Koh Y, Fever and Antipyretic in Critically il patients
Evaluation (FACE) Study Group: Association of body temperature and
antipyretic treatments with mortality of critically ill patients with and
without sepsis: multi-centered prospective observational study. Crit Care
2012, 16:R33.
34. Laupland KB, Zahar JR, Adrie C, Schwebel C, Goldgran-Toledano D, Azoulay E,
Garrouste-Orgeas M, Cohen Y, Jamali S, Souweine B, Darmon M, Timsit JF:
Determinants of temperature abnormalities and influence on outcome of
critical illness. Crit Care Med 2012, 40:145–151.
35. Young PJ, Saxena M, Beasley R, Bellomo R, Bailey M, Pilcher D, Finfer S,
Harrison D, Myburgh J, Rowan K: Early peak temperature and mortality in
critically ill patients with or without infection. Intensive Care Med 2012,
38:437–444.
36. Niven DJ, Stelfox HT, Shahpori R, Laupland KB: Fever in adult ICUs: An
interrupted time series analysis. Crit Care Med 2013, 41:1863–1869
37. Kiekkas P, Velissaris D, Karanikolas M, Aretha D, Samios A, Skartsani C,
Baltopoulos GI, Filos KS: Peak body temperature predicts mortality in
critically ill patients without cerebral damage. Heart Lung 2010,
39:208–216.
38. Moran JL, Peter JV, Solomon PJ, Grearly B, Smith T, Ashforth W, Wake M, Peake
SL, Peisach AR: Tympanic temperature measurements: are they reliable in
the critically ill? A clinical study of measures of agreement. Crit Care Med
2007, 35:155–164.
39. Circiumaru B, Baldock G, Cohen J: A prospective study of fever in the
intensive care unit. Intensive Care Med 1999, 25:668–673.
40. Peres Bota D, Lopes Ferreira F, Melot C, Vincent JL: Body temperature
alterations in the critically ill. Intensive Care Med 2004, 30:811–816.
Page 8 of 8
41. Barie PS, Hydo LJ, Eachempati SR: Causes and consequences of fever
complicating critical surgical illness. Surg Infect (Larchmt) 2004, 5:145–159.
42. Bernard GR, Reines HD, Halushka PV, Higgins SB, Metz CA, Swindell BB, Wright
PE, Watts FL, Vrbanac JJ: Prostacyclin and thromboxane A2 formation is
increased in human sepsis syndrome. Effects of cyclooxygenase
inhibition. Am Rev Respir Dis 1991, 144:1095–1101.
43. Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP,
Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB:
The effects of ibuprofen on the physiology and survival of patients with
sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med 1997,
336:912–918.
44. Memis D, Karamanlioglu B, Turan A, Koyuncu O, Pamukcu Z: Effects of
lornoxicam on the physiology of severe sepsis. Crit Care 2004, 8:R474–R482.
45. Morris PE, Promes JT, Guntupalli KK, Wright PE, Arons MM: A multi-center,
randomized, double-blind, parallel, placebo-controlled trial to evaluate
the efficacy, safety, and pharmacokinetics of intravenous ibuprofen for
the treatment of fever in critically ill and non-critically ill adults. Crit Care
2010, 14:R125.
46. Haupt MT, Jastremski MS, Clemmer TP, Metz CA, Goris GB: Effect of ibuprofen
in patients with severe sepsis: a randomized, double-blind, multicenter
study. The Ibuprofen Study Group. Crit Care Med 1991, 19:1339–1347.
47. Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, Lasko D,
Amortequi J, Dy CJ, Dlugasch L, Baracco G, Cohn SM: The effect of
antipyretic therapy upon outcomes in critically ill patients: a randomized,
prospective study. Surg Infect (Larchmt) 2005, 6:369–375.
48. Niven DJ, Stelfox HT, Leger C, Kubes P, Laupland KB: Assessment of the safety
and feasibility of administering antipyretic therapy in critically ill adults: A
pilot randomized clinical trial. J Crit Care 2013, 28:296–302.
49. Schortgen F, Clabault K, Katsahian S, Devaquet J, Mercat A, Deye N,
Dellamonica J, Bouadma L, Cook F, Beji O, Brun-Buisson C, Lemaire F: Fever
control using external cooling in septic shock: a randomized controlled
trial. Am J Respir Crit Care Med 2012, 185:1088–1095.
50. Young PJ, Saxena MK, Bellomo R, Freebairn RC, Hammond NE, van Haren FM,
Henderson SJ, McArthur CJ, McGuiness SP, Mackle D, Myburgh JA, Weatherall
M, Webb SA, Beasley RW, ANZICS Clinical Trials Group: The HEAT trial: a
protocol for a multicentre randomised placebo-controlled trial of IV
paracetamol in ICU patients with fever and infection. Crit Care Resus 2012,
14:290–296.
doi:10.1186/cc13773
Cite this article as: Young PJ, Saxena M: Fever management in intensive care
patients with infections. Critical Care 2014, 18:206.
 CHEST Postgraduate Education Corner
CONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

Persistent Fever in the ICU

Tayyab Rehman, MD; and Bennett P. deBoisblanc, MD

Disorders of elevated body temperature may be classified as either fever or hyperthermia. Fever
is caused by a pyrogen-mediated upward adjustment of the hypothalamic thermostat; hyper-
thermia results from a loss of physiologic control of temperature regulation. Fever in the ICU can
be due to infectious or noninfectious causes. The initial approach to a febrile, critically ill patient
should involve a thoughtful review of the clinical data to elicit the likely source of fever prior to
the ordering of cultures, imaging studies, and broad-spectrum antibiotics. Both high fever and
prolonged fever have been associated with increased mortality; however, a causal role for fever
as a mediator of adverse outcomes during non-neurologic critical illness has not been established.
Outside the realm of acute brain injury, the practice of treating fever remains controversial. To
generate high-quality, evidence-based guidelines for the management of fever, large, prospec-
tive, multicenter trials are needed. CHEST 2014; 145(1):158–165

Abbreviations: CDI 5 Clostridium difficile infection; CFU 5 colony-forming units; CLABSI 5 central line-associated
blood stream infection; CVC 5 central venous catheter; CXR 5 chest radiograph; NMS 5 neuroleptic malignant syn-
drome; SSRI 5 selective serotonin reuptake inhibitor; TCA 5 tricyclic antidepressant; UTI 5 urinary tract infection;
VAP 5 ventilator-associated pneumonia

Fever is a ubiquitous finding among patients admitted

to the ICU. The clinical significance of fever var-
ies with its context. On one hand, fever may represent
a response to a serious perturbation in the steady
state, such as when an infection is present. On the
other, fever may occur as a nonspecific physical sign
accompanying critical illness, as is often the case in
postoperative patients. Single temperature elevations
that resolve without treatment are seldom of signifi-
cance; however, persistently elevated temperature has
major implications for the care of critically ill patients.1
Not infrequently, the finding of fever in the ICU trig-
gers an unfocused, multimodal diagnostic workup and
empirical dispensation of antimicrobial agents. Such
an approach contributes to disruption of care, patient
discomfort, antimicrobial resistance, and increased
Manuscript received November 21, 2012; revision accepted July 22,
2013.
Affiliations: From the Section of Pulmonary & Critical Care Medi-
cine (Drs Rehman and deBoisblanc), Department of Medicine,
LSU Health Sciences Center, New Orleans, LA.
Correspondence to: Bennett P. deBoisblanc, MD, Section of
Pulmonary & Critical Care Medicine, Department of Medicine,
LSU Health Sciences Center, 1901 Perdido St, MEB, Ste 3205,
New Orleans, LA 70112; e-mail: bdeboi@lsuhsc.edu
© 2014 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.12-2843
cost.2 This article recapitulates the salient aspects of
febrile critical illness; discusses recent advances in its
epidemiology, evaluation, and treatment; and advocates
for a rational approach to its management.
Pathophysiology of Thermoregulation
As homeothermic organisms, humans must tightly
regulate their core body temperature to maintain opti-
mal conditions for fundamental biologic processes.3
The target temperature that the thermoregulatory sys-
tem aims to achieve (ie, the set point) is determined
in the preoptic region of the hypothalamus. To mini-
mize variation from the set point, the hypothalamus
integrates processes that generate, conserve, or dissi-
pate heat to the environment.
Abnormally elevated body temperature can result
from two pathophysiologically distinct disorders of
thermoregulation:
1. Fever results from an upward adjustment in the
thermoregulatory set point. Pyrogens (eg, bacte-
rial lipopolysaccharide, tumor necrosis factor-a,
IL-1) induce the synthesis of prostaglandin E2,
which raises the set point in the anterior hypo-
thalamus. The hypothalamus, in turn, activates
heat generation (through shivering and increased

158 Postgraduate Education Corner

Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2015

 metabolism) and heat conservation (through
peripheral vasoconstriction) to bring up the body
temperature.4
2. Hyperthermia is a pathophysiologic state of
uncontrolled heat production (eg, malignant
hyperthermia) and/or impaired heat dissipation
(eg, heat stroke). There is no adjustment of the
hypothalamic set point during hyperthermic
syndromes.5
Definition of Fever
Normal oral temperature is approximately 36.8°C
(98.2°F) with an amplitude of variability of 0.5°C
between the morning and the evening.6 During critical
illness, the variability can be even greater due to dis-
ruption of circadian rhythm, autonomic disturbances,
drugs, the ICU environment, and artifacts. Selecting
a single threshold to identify fever in the ICU involves
a tradeoff between sensitivity and specificity, with sig-
nificant implications for care. In the interest of stan-
dardization, a joint task force of the American College
of Critical Care Medicine (ACCM) and the Infectious
Diseases Society of America (IDSA) defined ICU fever
as a core body temperature ⱖ 38.3°C (101°F).7 Impor-
tantly, the task force emphasized that any threshold is
arbitrary unless informed by the clinical context.
Temperature Measurement
Historically, the pulmonary artery catheter therm-
istor has constituted the gold standard for the mea-
surement of the core body temperature.8 Rectal probe,
bladder thermistor, and infrared tympanic thermom-
eter have been shown to closely approximate core tem-
perature measurements.9 In contrast, the oral and
the axillary sites are unreliable in critically ill patients
and should be avoided. Serial temperature measure-
ments should be performed using the same site, the
same instrument, and the same technique, and these
specifics should be clearly documented in the patient’s
medical record.
Epidemiology
The prevalence of ICU fever ranges from 26% to
70% depending on the population studied and the
definition of fever used.10-13 Infectious and noninfec-
tious causes are equally represented.10,11 Young age,
male sex, septic shock, trauma, emergent surgery, and
neurocritical illness are associated with the develop-
ment of fever.11-13 Prolonged fever (lasting . 5 days)
and high fever (ⱖ 39.3°C) are more likely to be infec-
tious.10,13 In surgical ICUs, fever occurs most com-
monly on postoperative day 1.11
Both fever and admission hypothermia are associ-
ated with an increased ICU length of stay.12 Prolonged
journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2015
fever10 and high fever13,14 are also associated with a
significantly increased risk of death. Whether fever
plays a causal role in mediating adverse outcomes in
nonneurologic critical illness remains to be elucidated.
Differential Diagnosis
The approach to fever in the ICU is at times reflex-
ive, equating fever with infection. The finding of ele-
vated body temperature triggers an order set that
includes culturing of several body sites (eg, blood,
urine, sputum), imaging of the chest and/or abdomen
and the initiation of broad-spectrum antibiotics. To
promote a more rational approach, a joint American
College of Critical Care Medicine and Infectious Dis-
eases Society of America guideline was issued in 2008.7
Recognizing that the sources of fever may be either
infectious or noninfectious, the guideline panel recom-
mended that “any unexplained temperature elevation
merits a clinical assessment by a healthcare profes-
sional that includes a review of the patient’s history
and a focused physical examination before any labo-
ratory tests or imaging procedures are ordered.”7 The
goal is to promote individualized management based
on consideration of factors unique to each patient. A
head-to-toe approach, such as the one suggested in
Table 1, can provide a framework for the formulation
of a probable differential diagnosis and cost-effective
workup.
Selected Infectious Causes of Fever
Approximately 50% of fevers in the ICU are due to
infections.10 Nearly all patients in the ICU undergo
placement of devices (eg, central venous catheters
[CVCs], arterial lines, urinary catheters, endotracheal
tubes, and nasogastric tubes) that bypass natural host
defenses and provide easy portals of entry to microor-
ganisms. The use of a “daily goals” checklist to assess
ongoing need of these devices is an effective strategy
to reduce the rates of ICU-acquired infections.
When clinical evidence makes infection the likely
source of fever, culturing of the blood should be per-
formed, preferably prior to initiating antibiotics.15
Three blood cultures achieve a 99% detection rate
of true bacteremia.16,17 All blood cultures can be
drawn simultaneously, as the yield is not increased
by serial draws.18 However, a separate venipuncture
site should be used for each blood culture.17 A blood
volume of ⱖ 20 mL per culture is required for opti-
mal yield.17
Central Line-Associated Blood Stream Infection
For surveillance purposes, a blood stream infec-
tion in a patient with a CVC of ⱖ 48 h duration is
considered as a central line-associated blood stream
CHEST / 145 / 1 / JANUARY 2014 159
 Table 1—Common Causes of Persistent Fever in the ICU: A Head-to-Toe Approach to Differential Diagnosis
Site Infectious
Head and neck Meningitis
Otitis media
Sinusitis
CVC-related blood stream infection
Chest Infective endocarditis
Ventilator-associated tracheobronchitis
Ventilator-associated pneumonia
Empyema
Abdomen and pelvis Intraabdominal infections (eg, SBP, abscesses)
Clostridium difficile infection
Pyelonephritis
Catheter-related UTI
Perineal or perianal abscess
Extremities Femoral line/PICC-related blood stream infection
Septic arthritis
Skin and back Cellulitis
Infected pressure ulcer
Surgical site infection
Miscellaneous … Drugs
CVC 5 central venous catheter; PICC 5 peripherally inserted central catheter; SBP 5 spontaneous bacterial peritonitis; SLE 5 systemic lupus ery-
thematosus; UTI 5 urinary tract infection.
infection (CLABSI) provided that it is not related to
an infection at another site (eg, pneumonia, pyelo-
nephritis).19 Using this definition, the rate of CLABSI
in the ICU is estimated to vary from 1.4 to 5.5 per
1,000 catheter-days.20
In evaluating a patient in the ICU with fever, a
detailed examination of the CVC insertion site should
be performed, looking for signs of local inflammation
or purulence. Any exudate should be swabbed and
sent for Gram staining and culture. In hemodynami-
cally stable patients, a CVC without local signs of
infection can be left in place awaiting culture results.
However, in unstable patients, it is best to remove the
suspicious catheter without waiting for microbiologic
confirmation.21 Vascular access in these cases should
be secured using a fresh catheter insertion site prior
to the removal of the old line.
Paired blood cultures, from the catheter and from
a peripheral venipuncture, should be drawn simulta-
neously. If the blood culture from the catheter becomes
positive ⱖ 2 h before the one obtained from the
peripheral site and both cultures show growth of the
same organism (differential time to positivity method),
the diagnosis of CLABSI is established.22 Alterna-
tively, a quantitative blood culture showing a greater
than fivefold higher colony count from the catheter also
suggests CLABSI.21 Finally, semiquantitative culturing
of 5 cm of the catheter tip (roll-plate method) should
be performed on all CVCs removed from patients
160
Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2015
Noninfectious
Cerebrovascular accident
Seizure disorder
Traumatic brain injury
Myocardial infarction
Pericarditis
Pulmonary embolism
ARDS
Pancreatitis
Acalculous cholecystitis
Ischemic colitis
Gout
DVT
Drug eruptions
Transfusion reactions
Endocrine disorders (eg, thyrotoxicosis, adrenal insufficiency)
Malignancy
Inflammatory disorders (eg, SLE)
with suspected CLABSI. Isolation of , 15 colony-
forming units (CFU) is consistent with contamination,
while ⱖ 15 CFU per catheter tip represents catheter
colonization.23 A diagnosis of CLABSI is confirmed
only if catheter colonization is accompanied by a
positive peripheral blood culture with an identical
organism.24 Though not widely available, quantitative
culturing of catheter segments (sonication method)
provides more accurate results, especially for cathe-
ters that have been in place for a longer time.24,25
Ventilator-Associated Respiratory Infection
Mechanical ventilation with an endotracheal tube
increases the risk of pneumonia sixfold to 20-fold.26,27
The attributable mortality from ventilator-associated
pneumonia (VAP) is estimated around 10%.28 Impor-
tantly, VAP is preventable, and appropriate and timely
therapy can improve outcomes.27
More recent data suggest that on-demand chest radi-
ography is as safe as routine daily chest radiography
for patients undergoing mechanical ventilation.29,30 In
the presence of fever, leukocytosis, purulent secretions,
and declining Pao2/Fio2, a chest radiograph (CXR) is
indicated. There is no radiographic pattern diagnos-
tic of VAP, but the finding of a new or progressive
pulmonary infiltrate is supportive. When symptoms
and signs of lower respiratory tract infection are pre-
sent but the CXR does not demonstrate an infiltrate,
Postgraduate Education Corner
 the preferred diagnostic label is ventilator-associated
tracheobronchitis. Ventilator-associated tracheobron-
chitis is increasingly viewed as a precursor to VAP.31
Evaluation of lower respiratory secretions is central
to the diagnostic workup of VAP. The precise sampling
approach (noninvasive vs invasive) remains controver-
sial. Noninvasive approaches include tracheobronchial
aspiration and blind mini-BAL. Invasive approaches
use bronchoscopy to perform sampling via BAL or
protected specimen brushing. A large multicenter trial
demonstrated the equivalency of endotracheal aspi-
ration to bronchoscopic BAL sampling.32 However,
the study excluded patients infected or colonized with
Pseudomonas species and methicillin-resistant Staph-
ylococcus aureus, somewhat limiting its external validity.33
A 2012 meta-analysis concluded that invasive strat-
egies do not result in reduced mortality, reduced time
in the ICU or on mechanical ventilation, or higher rates
of antibiotic change when compared with noninva-
sive strategies.34
Urinary Tract Infection
An overwhelming majority of urinary tract infec-
tions (UTIs) in the ICU are catheter related, with an esti-
mated incidence of nine to 11 per 1,000 catheter-days.
Secondary bacteremia occurs in only 1% to 5% of
these cases.35 Although ICU-acquired UTI is associ-
ated with increased length of stay, cost, and crude mor-
tality, it is not an independent risk factor for death.36
Typical symptoms of UTI (ie, dysuria, urgency, pelvic
discomfort, or flank pain) are infrequently reported
by patients with catheters in the ICU and have little
predictive value.37 Moreover, neither fever nor leuko-
cytosis is associated with a positive urine culture
during the first 14 days of ICU stay.38 Results of rou-
tine urinalysis are insensitive but relatively specific
for UTI in critically ill patients who are catheterized.39,40
In the evaluation of ICU fever, it is recommended
to restrict urine cultures to patients with catheters and
no other obvious source of fever. The urine sample
should be obtained from the catheter port, not from
the urine bag.41 Any growth ⱖ 102 CFU/mL of urine in
a patient with a catheter is abnormal and indicates at
least colonization of the urinary tract.41 The tradition-
ally used criterion of ⱖ 105 CFU/mL is too insensitive
for patients with catheters. As a general guideline, we
recommend empirical antibiotics for presumed UTI
in febrile patients with catheters when the results of
urinalysis are positive and no other source of fever or
infection is obvious. The results of the urine culture
should be used to guide rapid antibiotic de-escalation.
Clostridium difficile Infection
By definition, patients with well-formed stools do
not have Clostridium difficile infection (CDI). How-
journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2015
ever, a patient in the ICU who has fever, leukocy-
tosis, and diarrhea should be assessed for CDI. Fever
is noted in 30% and leukocytosis in 50% of docu-
mented CDI cases.42 Severe CDI may also present
with abdominal pain, ileus, and a systemic inflamma-
tory response.42
Laboratory assessment of suspected CDI includes
enzyme immunoassay for toxin A and toxin B (rapid
and widely available but insensitive), cell cytotoxicity
assay (highly specific, but of limited availability with a
turnaround time of ⱖ 48 h), and stool culture (costly
and time consuming, with frequent false-positive
results).43,44 Real-time polymerase chain reaction test-
ing for toxin A or toxin B genes is both rapid and
accurate and has become the preferred option in the
ICU setting.45 In severe cases, endoscopic finding of
pseudomembranes and CT scan evidence of colonic
wall thickening, pericolonic stranding, and megaco-
lon are also supportive of the diagnosis.46
Oral vancomycin, either alone or in combination
with metronidazole, is recommended for critically
ill patients with severe CDI. When ileus is present,
vancomycin retention enemas should be added.
Colectomy should be considered for patients with
fulminant CDI characterized by one or more of the
following: septic shock, toxic megacolon, acute abdo-
men, serum lactate . 5 mM, and peripheral blood
WBC . 50,000/mL.43
Nosocomial Sinusitis
The paranasal sinuses can become colonized and
infected if there is anatomic obstruction of ostial drain-
age. Nasogastric tubes, nasotracheal tubes, and nasal
packs are major risk factors for nosocomial sinusitis.47
While oral placement of gastric and endotracheal tubes
can reduce the incidence of nosocomial sinusitis, the
risk remains elevated compared with patients without
such devices.47 In a prospective study of orotracheally
intubated patients with a new-onset fever . 48 h after
ICU admission, sinusitis was found to be the sole cause
of fever in 16% of patients and a contributory cause
in 30% of patients.48
In the presence of risk factors for nosocomial sinus-
itis, purulent nasal drainage, and no other explanation
of fever, a CT scan of the sinuses should be performed.
The finding of an air-fluid level or complete opacifi-
cation of a sinus constitutes radiographic sinusitis.
The diagnostic accuracy of CT scan is . 90% when
accompanied by the finding of purulence in the middle
meatus.49 Ultrasonography is not as accurate as CT scan-
ning but has the advantage of point-of-care testing
with real-time interpretation of results and is the pre-
ferred imaging modality in patients who cannot be
safely transported outside the ICU. However, ultra-
sonography is highly operator dependent and does not
CHEST / 145 / 1 / JANUARY 2014 161
 provide adequate assessment of the frontal, ethmoid,
and sphenoidal sinuses.50,51
Febrile, critically ill patients with radiographic sinus-
itis should undergo diagnostic sampling of the sinus
fluid prior to the initiation of antibiotics. Endoscopic-
guided middle meatus aspiration is the modality of
choice for this purpose and is recommended in prefer-
ence to the conventional sinus puncture and aspiration.52
Selected Noninfectious Causes of Fever
About one-half of all fevers in the ICU are due to
noninfectious etiologies.2,10 A major goal of the evalua-
tion of persistent fever is to search for clinical clues of
noninfectious sources of fever. Infectious and nonin-
fectious fever may occur together in the same patient.
Hyperthermic Syndromes
While pathophysiologically distinct, hyperthermic syn-
dromes can clinically mimic fever. Commonly encoun-
tered examples include environmental heat-related
illness, malignant hyperthermia, serotonin syndrome and
neuroleptic malignant syndrome (NMS). In addition,
recreational drug use (eg, cocaine, methamphetamines,
mephedrone [bath salts]), and agitated withdrawal from
alcohol, opiates, or benzodiazepines can also cause
significant elevations of the core body temperature.2
Environmental heat-related illness results from a
failure of heat dissipation. The spectrum of illness ranges
from minor heat cramps, heat syncope, or heat exhaus-
tion to the potentially life-threatening heat stroke
(core body temperature . 40°C with significant CNS
dysfunction).5 During climatic heat waves, the elderly
with limited mobility and chronic medical conditions
constitute a cohort at particularly high risk.
Malignant hyperthermia is a pharmacogenetic syn-
drome associated with the administration of succinyl-
Table 2—Neuroleptic Malignant Syndrome vs Serotonin Syndrome
Feature Neuroleptic Malignant Syndrome
Mechanism Dopamine receptor antagonism
Causative drugs Neuroleptic agents (eg, haloperidol,
phenothiazines, clozapine)
Type of ADR Idiosyncratic
Onset Over days to weeks
Clinical manifestations
Altered mental status Agitation, disorientation, delirium
Dysautonomia Tachycardia, labile blood pressure
Neuromuscular hyperactivity Rigidity, bradyreflexia, tremor
Hyperthermia 92% of cases
Treatment Discontinuation of all antidopaminergic agents
Bromocriptine
Dantrolene (for severe rigidity and hyperthermia)
Time to recovery Over days (average 9 d)
ADR 5 adverse drug reaction; SSRI 5 selective serotonin reuptake inhibitor; TCA 5 tricyclic antidepressant.
162
Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2015
choline or inhalational anesthetics.53 In susceptible
individuals, these drugs induce dysregulation of cal-
cium homeostasis in the skeletal muscles, resulting in
intense tonic contraction and uncontrolled thermogen-
esis. The syndrome is clinically obvious within 30 min
of drug administration, although presentations delayed
up to 24 h have been reported. Treatment includes
prompt discontinuation of the offending agent, exter-
nal cooling, IV fluids, and dantrolene.
Serotonin syndrome is caused by the overactivation
of 5-HT1a and 5-HT2a receptors. It commonly occurs
in patients taking selective serotonin reuptake inhibi-
tors (SSRIs) or tricyclic antidepressants (TCAs) who
then receive either another drug that possesses seroto-
nergic activity or that interferes with the cytochrome
P450 metabolism of SSRIs or TCAs.54 Clinically, the
syndrome manifests as a triad of altered mental status,
autonomic hyperactivity, and neuromuscular abnor-
malities. Discontinuation of the offending agent can
lead to rapid resolution of symptoms. Benzodiazepines
and the serotonin antagonist, cyproheptadine, are used
to treat severe cases.
NMS is precipitated by the antidopaminergic activity
of neuroleptic agents.54 The clinical presentation of
NMS resembles that of serotonin syndrome (Table 2).
NMS can develop at any time during treatment, while
serotonin syndrome usually develops within minutes
to hours after exposure to the offending drug. In
addition to stopping neuroleptic medications, bro-
mocriptine, a central dopamine agonist, is used for
treatment.
Drug Fever
Almost any drug can cause fever, but the ones
most commonly implicated in the ICU include anti-
biotics (especially b-lactams), anticonvulsants (diphe-
nylhydantoins), and antiarrhythmics (quinidine and
Serotonin Syndrome
5-HT1a and 5-HT2a receptor activation
Serotonin agonists (eg, SSRI, TCA)
Predictable
Within 24 h of drug use
Anxiety, agitation, disorientation
Tachycardia, hypertension, flushing, diarrhea
Tremor, hyperreflexia, clonus (particularly
lower extremities)
34% of cases
Discontinuation of all serotonergic agents
Benzodiazepines
Cyproheptadine (in severe cases)
, 24 h
Postgraduate Education Corner
 procainamide).55 No fever pattern is characteristic of
drug fever. Relative bradycardia, rash, and eosinophilia
are seen in a minority of cases.56 The temporal associ-
ation between the initiation of a drug and the onset of
fever or discontinuation of a suspected drug and res-
olution of fever provides helpful clues. Drug fever
remains a diagnosis of exclusion.
Postoperative Fever
Fever is common in the first 72 h after surgery and
is predominantly noninfectious. A rational approach
to postoperative fever is to clinically assess for infec-
tious sources, but initiate a workup only if clues other
than fever or leukocytosis point toward an infection.
The yield of a nonfocused approach is low and adds
significantly to cost of care. Routine chest radiography
and sputum analysis in the early postoperative period
are not indicated, as they fail to prompt a change in
management.57 In a retrospective review of 537 patients
undergoing major gynecologic surgery, the preva-
lence of early postoperative fever was 39%.58 Of the
77 patients evaluated with blood cultures, none had a
positive result. In a separate cohort of 1,100 patients
who had undergone orthopedic surgery, the diagnos-
tic yield of CXRs, blood cultures, and urine cultures
was 2%, 6%, and 22%, respectively; however, the yield
increased substantially for fever occurring after postop-
erative day 3 (OR, 23.3), for high fever ⱖ 39°C (OR,
2.4), and for persistent or recurrent fever (OR, 8.6).59
The average cost of a fever evaluation was $960, while
the cost associated with a change in treatment was
$8,208.59 More recent studies have found no associa-
tion between fever and postoperative atelectasis.60
VTE
In the PIOPED (Prospective Investigation of Pul-
monary Embolism Diagnosis) study, fever ⱖ 37.8°C
without an alternative cause was noted in 14% of
patients with pulmonary embolism.61 VTE-related fever
is usually low grade, short-lived, and resolves with
anticoagulation therapy.62 VTE-related fever is asso-
ciated with an increased 30-day mortality.63
Acalculous Cholecystitis
Spontaneous ischemic or inflammatory injury of
the gall bladder may develop during critical illness.
Occlusion of the cystic duct, bile stasis, distension, and
secondary infection can lead to gangrene and perfo-
ration of the gall bladder.64 The diagnosis should be
suspected in any patient with fever, leukocytosis, and
a right upper quadrant pain. Bedside ultrasonography
has a sensitivity and specificity of . 80%.65 CT scan-
ning performs slightly better but is limited by the
journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2015
need to transport critically ill patients to the radiology
suite.65 In patients at high surgical risk, percutaneous
cholecystostomy can prove a life-saving intervention.66
Treatment of Fever
To lower the core body temperature, two approaches
can be used: pharmacologic agents, such as acetamin-
ophen and nonsteroidal antiinflammatory drugs; and
physical measures, such as ice packs, cooling blan-
kets, and endovascular cooling devices.
The choice of antipyretic agent should be informed
by the presence or absence of hepatic and renal injury,
and the risk of GI bleeding.67 Acetaminophen should
be avoided in patients with liver failure, but may be
preferred over ibuprofen in the setting of coagulopa-
thy, GI bleeding, and kidney injury. Physical measures
offer more reliable temperature control68 and can suc-
cessfully lower temperature even when pharmacologic
antipyretic therapy has failed.69 External cooling can
provoke shivering, which may necessitate the use of
sedatives, and even paralytics.
While a standard practice in patients with acute brain
injury,70 the value of treatment of fever in patients
with nonneurologic critical illness remains obscure.
In a randomized, controlled trial, 82 trauma patients
with fever (ⱖ 38.5°C) but without brain injury were
treated with either an “aggressive” or a “permissive”
fever control strategy.71 Patients in the “aggressive”
arm received acetaminophen 650 mg q6h for temper-
ature ⱖ 38.5°C, with the addition of a cooling blanket
for temperature ⱖ 39.5°C. Patients in the “permis-
sive” arm were not treated unless the core temperature
was ⱖ 40°C, at which point they received acetamino-
phen and cooling blankets to lower their temperature
below 40°C. The study was stopped after an interim
analysis revealed a trend toward higher mortality and
higher rates of infection in the “aggressive” arm (seven
deaths vs one death; P 5 .06).
In a multicenter trial, 200 febrile (ⱖ 38.3°C) patients
with respiratory failure and vasopressor-dependent
septic shock were randomized to either external cool-
ing targeting normothermia (36.5°C-37°C) or to usual
care without cooling.72 The primary end point, a
50% reduction in the baseline vasopressor dose at 48 h,
was not significantly different between the two groups.
However, a few secondary end points favored the
external cooling strategy, including a lower vasopres-
sor dose at 12 h and greater shock reversal. Impor-
tantly, the mortality was not significantly different
either at ICU or at hospital discharge. Similarly, a
2013 meta-analysis including 399 patients from five
randomized trials found no survival benefit for antipy-
retic therapy in febrile critical illness (acute neurologic
injury excluded).73
CHEST / 145 / 1 / JANUARY 2014 163
 Conclusions
Fever in the ICU is a common clinical entity. High
fever and prolonged fever are associated with an
increased risk of death, although a causal relationship
has not been established. The reflexive practice of
equating fever with infection should be replaced with
one that begins with a thoughtful clinical assessment
and takes into account both infectious and noninfec-
tious etiologies of elevated body temperature. With
the exception of acute brain injury and hyperthermic
syndromes, the practice of temperature control in the
ICU remains controversial. To develop an evidence-
based approach to the management of ICU fever, mul-
ticenter, randomized controlled trials are needed.
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported
to CHEST that no potential conflicts of interest exist with any
companies/organizations whose products or services may be dis-
cussed in this article.
References
1. Marik PE. Fever in the ICU. Chest. 2000;117(3):855-869.
2. Rizoli SB, Marshall JC. Saturday night fever: finding and con-
trolling the source of sepsis in critical illness. Lancet Infect
Dis. 2002;2(3):137-144.
3. Nakamura K. Central circuitries for body temperature regu-
lation and fever. Am J Physiol Regul Integr Comp Physiol.
2011;301(5):R1207-R1228.
4. Cooper KE. The role of the hypothalamus in the genesis of
fever. Proc R Soc Med. 1965;58(9):740.
5. Lugo-Amador NM, Rothenhaus T, Moyer P. Heat-related ill-
ness. Emerg Med Clin North Am. 2004;22(2):315-327.
6. Mackowiak PA, Wasserman SS, Levine MM. A critical appraisal
of 98.6 degrees F, the upper limit of the normal body tempera-
ture, and other legacies of Carl Reinhold August Wunderlich.
JAMA. 1992;268(12):1578-1580.
7. O’Grady NP, Barie PS, Bartlett JG, et al; American College of
Critical Care Medicine; Infectious Diseases Society of America.
Guidelines for evaluation of new fever in critically ill adult
patients: 2008 update from the American College of Critical
Care Medicine and the Infectious Diseases Society of America.
Crit Care Med. 2008;36(4):1330-1349.
8. Nierman DM. Core temperature measurement in the inten-
sive care unit. Crit Care Med. 1991;19(6):818-823.
9. Jefferies S, Weatherall M, Young P, Beasley R. A systematic
review of the accuracy of peripheral thermometry in esti-
mating core temperatures among febrile critically ill patients.
Crit Care Resusc. 2011;13(3):194-199.
10. Circiumaru B, Baldock G, Cohen J. A prospective study of
fever in the intensive care unit. Intensive Care Med. 1999;
25(7):668-673.
11. Barie PS, Hydo LJ, Eachempati SR. Causes and consequences
of fever complicating critical surgical illness. Surg Infect
(Larchmt). 2004;5(2):145-159.
12. Peres Bota D, Lopes Ferreira F, Mélot C, Vincent JL. Body
temperature alterations in the critically ill. Intensive Care
Med. 2004;30(5):811-816.
13. Laupland KB, Shahpori R, Kirkpatrick AW, Ross T, Gregson DB,
Stelfox HT. Occurrence and outcome of fever in critically ill
adults. Crit Care Med. 2008;36(5):1531-1535.
164
Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2015
14. Laupland KB, Zahar JR, Adrie C, et al. Determinants of tem-
perature abnormalities and influence on outcome of critical
illness. Crit Care Med. 2012;40(1):145-151.
15. Wilson ML, Weinstein MP. General principles in the laboratory
detection of bacteremia and fungemia. Clin Lab Med. 1994;
14(1):69-82.
16. Lee A, Mirrett S, Reller LB, Weinstein MP. Detection of
bloodstream infections in adults: how many blood cultures
are needed? J Clin Microbiol. 2007;45(11):3546-3548.
17. Cockerill FR III, Wilson JW, Vetter EA, et al. Optimal testing
parameters for blood cultures. Clin Infect Dis. 2004;38(12):
1724-1730.
18. Li J, Plorde JJ, Carlson LG. Effects of volume and periodicity
on blood cultures. J Clin Microbiol. 1994;32(11):2829-2831.
19. O’Grady NP, Alexander M, Burns LA, et al; Healthcare Infec-
tion Control Practices Advisory Committee. Guidelines for
the prevention of intravascular catheter-related infections.
Am J Infect Control. 2011;39(4)(suppl 1):S1-S34.
20. Edwards JR, Peterson KD, Mu Y, et al. National Healthcare
Safety Network (NHSN) report: data summary for 2006 through
2008, issued December 2009. Am J Infect Control. 2009;37(10):
783-805.
21. Mermel LA, Allon M, Bouza E, et al. Clinical practice guide-
lines for the diagnosis and management of intravascular catheter-
related infection: 2009 Update by the Infectious Diseases
Society of America. Clin Infect Dis. 2009;49(1):1-45.
22. Raad I, Hanna HA, Alakech B, Chatzinikolaou I, Johnson MM,
Tarrand J. Differential time to positivity: a useful method for
diagnosing catheter-related bloodstream infections. Ann Intern
Med. 2004;140(1):18-25.
23. Maki DG, Weise CE, Sarafin HW. A semiquantitative culture
method for identifying intravenous-catheter-related infection.
N Engl J Med. 1977;296(23):1305-1309.
24. Raad I, Hanna H, Maki D. Intravascular catheter-related
infections: advances in diagnosis, prevention, and management.
Lancet Infect Dis. 2007;7(10):645-657.
25. Safdar N, Fine JP, Maki DG. Meta-analysis: methods for diag-
nosing intravascular device-related bloodstream infection.
Ann Intern Med. 2005;142(6):451-466.
26. Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J
Respir Crit Care Med. 2002;165(7):867-903.
27. American Thoracic Society; Infectious Diseases Society of
America. Guidelines for the management of adults with hospital-
acquired, ventilator-associated, and healthcare-associated pneu-
monia. Am J Respir Crit Care Med. 2005;171(4):388-416.
28. Melsen WG, Rovers MM, Koeman M, Bonten MJ. Estimating
the attributable mortality of ventilator-associated pneumonia
from randomized prevention studies. Crit Care Med. 2011;
39(12):2736-2742.
29. Hejblum G, Chalumeau-Lemoine L, Ioos V, et al. Comparison
of routine and on-demand prescription of chest radiographs in
mechanically ventilated adults: a multicentre, cluster-randomised,
two-period crossover study. Lancet. 2009;374(9702):1687-1693.
30. Oba Y, Zaza T. Abandoning daily routine chest radiography in
the intensive care unit: meta-analysis. Radiology. 2010;255(2):
386-395.
31. Craven DE, Hjalmarson KI. Ventilator-associated tracheo-
bronchitis and pneumonia: thinking outside the box. Clin
Infect Dis. 2010;51(Suppl 1):S59-S66.
32. Canadian Critical Care Trials Group. A randomized trial of
diagnostic techniques for ventilator-associated pneumonia.
N Engl J Med. 2006;355(25):2619-2630.
33. Kollef MH. Diagnosis of ventilator-associated pneumonia.
N Engl J Med. 2006;355(25):2691-2693.
34. Berton DC, Kalil AC, Teixeira PJ. Quantitative versus quali-
tative cultures of respiratory secretions for clinical outcomes
Postgraduate Education Corner
 in patients with ventilator-associated pneumonia. Cochrane
Database Syst Rev. 2012;1:CD006482.
35. Laupland KB, Bagshaw SM, Gregson DB, Kirkpatrick AW,
Ross T, Church DL. Intensive care unit-acquired urinary
tract infections in a regional critical care system. Crit Care.
2005;9(2):R60-R65.
36. Bagshaw SM, Laupland KB. Epidemiology of intensive care
unit-acquired urinary tract infections. Curr Opin Infect Dis.
2006;19(1):67-71.
37. Tambyah PA, Maki DG. Catheter-associated urinary tract infec-
tion is rarely symptomatic: a prospective study of 1,497 cath-
eterized patients. Arch Intern Med. 2000;160(5):678-682.
38. Golob JF Jr, Claridge JA, Sando MJ, et al. Fever and leukocy-
tosis in critically ill trauma patients: it’s not the urine. Surg
Infect (Larchmt). 2008;9(1):49-56.
39. Tambyah PA, Maki DG. The relationship between pyuria and
infection in patients with indwelling urinary catheters: a pro-
spective study of 761 patients. Arch Intern Med. 2000;160(5):
673-677.
40. Schwartz DS, Barone JE. Correlation of urinalysis and dip-
stick results with catheter-associated urinary tract infections
in surgical ICU patients. Intensive Care Med. 2006;32(11):
1797-1801.
41. Wilson ML, Gaido L. Laboratory diagnosis of urinary tract
infections in adult patients. Clin Infect Dis. 2004;38(8):
1150-1158.
42. Bobo LD, Dubberke ER, Kollef M. Clostridium difficile in the
ICU: the struggle continues. Chest. 2011;140(6):1643-1653.
43. Cohen SH, Gerding DN, Johnson S, et al; Society for Health-
care Epidemiology of America; Infectious Diseases Society of
America. Clinical practice guidelines for Clostridium difficile
infection in adults: 2010 update by the society for healthcare
epidemiology of America (SHEA) and the infectious diseases
society of America (IDSA). Infect Control Hosp Epidemiol.
2010;31(5):431-455.
44. Leclair MA, Allard C, Lesur O, Pépin J. Clostridium difficile
infection in the intensive care unit. J Intensive Care Med.
2010;25(1):23-30.
45. Stamper PD, Alcabasa R, Aird D, et al. Comparison of a com-
mercial real-time PCR assay for tcdB detection to a cell cul-
ture cytotoxicity assay and toxigenic culture for direct detection
of toxin-producing Clostridium difficile in clinical samples.
J Clin Microbiol. 2009;47(2):373-378.
46. Riddle DJ, Dubberke ER. Clostridium difficile infection in
the intensive care unit. Infect Dis Clin North Am. 2009;23(3):
727-743.
47. Rouby JJ, Laurent P, Gosnach M, et al. Risk factors and clin-
ical relevance of nosocomial maxillary sinusitis in the critically
ill. Am J Respir Crit Care Med. 1994;150(3):776-783.
48. van Zanten AR, Dixon JM, Nipshagen MD, de Bree R, Girbes
AR, Polderman KH. Hospital-acquired sinusitis is a common
cause of fever of unknown origin in orotracheally intubated
critically ill patients. Crit Care. 2005;9(5):R583-R590.
49. Kountakis SE, Burke L, Rafie JJ, Bassichis B, Maillard AA,
Stiernberg CM. Sinusitis in the intensive care unit patient.
Otolaryngol Head Neck Surg. 1997;117(4):362-366.
50. Tiedjen KU, Becker E, Heimann KD, Knorz S, Hildmann H.
Value of B-image ultrasound in diagnosis of paranasal sinus dis-
eases in comparison with computerized tomography [in German].
Laryngorhinootologie. 1998;77(10):541-546.
51. Zagólski O, Strek P. Ultrasonography of the nose and paranasal
sinuses [in Polish]. Pol Merkur Lekarski. 2007;22(127):32-35.
52. Talmor M, Li P, Barie PS. Acute paranasal sinusitis in critically
ill patients: guidelines for prevention, diagnosis, and treatment.
Clin Infect Dis. 1997;25(6):1441-1446.
journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2015
53. Denborough M. Malignant hyperthermia. Lancet. 1998;
352(9134):1131-1136.
54. McAllen KJ, Schwartz DR. Adverse drug reactions resulting
in hyperthermia in the intensive care unit. Crit Care Med.
2010;38(6)(Suppl):S244-S252.
55. Mackowiak PA. Drug fever: mechanisms, maxims and mis-
conceptions. Am J Med Sci. 1987;294(4):275-286.
56. Mackowiak PA, LeMaistre CF. Drug fever: a critical appraisal
of conventional concepts. An analysis of 51 episodes in two
Dallas hospitals and 97 episodes reported in the English litera-
ture. Ann Intern Med. 1987;106(5):728-733.
57. Simon SD, Castle EP, Ferrigni RG, Andrews PE. Routine
postoperative chest x-ray following laparoscopic nephrectomy.
JSLS. 2005;9(2):205-207.
58. Fanning J, Neuhoff RA, Brewer JE, Castaneda T, Marcotte MP,
Jacobson RL. Yield of postoperative fever evaluation. Prim
Care Update Ob Gyns. 1998;5(4):146.
59. Ward DT, Hansen EN, Takemoto SK, Bozic KJ. Cost and effec-
tiveness of postoperative fever diagnostic evaluation in total joint
arthroplasty patients. J Arthroplasty. 2010;25(6)(suppl):43-48.
60. Mavros MN, Velmahos GC, Falagas ME. Atelectasis as a
cause of postoperative fever: where is the clinical evidence?
Chest. 2011;140(2):418-424.
61. Stein PD, Afzal A, Henry JW, Villareal CG. Fever in acute
pulmonary embolism. Chest. 2000;117(1):39-42.
62. Nucifora G, Badano L, Hysko F, Allocca G, Gianfagna P,
Fioretti P. Pulmonary embolism and fever: when should
right-sided infective endocarditis be considered? Circulation.
2007;115(6):e173-e176.
63. Barba R, Di Micco P, Blanco-Molina A, et al. Fever and deep
venous thrombosis. Findings from the RIETE registry. J Thromb
Thrombolysis. 2011;32(3):288-292.
64. Huffman JL, Schenker S. Acute acalculous cholecystitis: a
review. Clin Gastroenterol Hepatol. 2010;8(1):15-22.
65. Kiewiet JJ, Leeuwenburgh MM, Bipat S, Bossuyt PM, Stoker J,
Boermeester MA. A systematic review and meta-analysis
of diagnostic performance of imaging in acute cholecystitis.
Radiology. 2012;264(3):708-720.
66. Chung YH, Choi ER, Kim KM, et al. Can percutaneous chole-
cystostomy be a definitive management for acute acalculous
cholecystitis? J Clin Gastroenterol. 2012;46(3):216-219.
67. Plaisance KI. Toxicities of drugs used in the management of
fever. Clin Infect Dis. 2000;31(suppl 5):S219-S223.
68. Hoedemaekers CW, Ezzahti M, Gerritsen A, van der Hoeven JG.
Comparison of cooling methods to induce and maintain
normo- and hypothermia in intensive care unit patients: a
prospective intervention study. Crit Care. 2007;11(4):R91.
69. Carhuapoma JR, Gupta K, Coplin WM, Muddassir SM, Meratee
MM. Treatment of refractory fever in the neurosciences crit-
ical care unit using a novel, water-circulating cooling device.
A single-center pilot experience. J Neurosurg Anesthesiol.
2003;15(4):313-318.
70. Diringer MN, Reaven NL, Funk SE, Uman GC. Elevated
body temperature independently contributes to increased length
of stay in neurologic intensive care unit patients. Crit Care
Med. 2004;32(7):1489-1495.
71. Schulman CI, Namias N, Doherty J, et al. The effect of antipyretic
therapy upon outcomes in critically ill patients: a randomized,
prospective study. Surg Infect (Larchmt). 2005;6(4):369-375.
72. Schortgen F, Clabault K, Katsahian S, et al. Fever control using
external cooling in septic shock: a randomized controlled trial.
Am J Respir Crit Care Med. 2012;185(10):1088-1095.
73. Niven DJ, Stelfox HT, Laupland KB. Antipyretic therapy
in febrile critically ill adults: A systematic review and meta-
analysis. J Crit Care. 2013;28(3):303-310.
CHEST / 145 / 1 / JANUARY 2014 165
 
©
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT 2013 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other

REVIEW

A clinical outline to fever

in intensive care patients
S. ÖNCÜ

Department of Infectious Diseases and Clinical Microbiology, Adnan Menderes University Medical Faculty, Aydin,
Turkey

ABSTRACT
Fever is a common symptom in intensive care unit (ICU) patients and is caused by a wide variety of infectious and
noninfectious disorders. The presence of fever often results in the act of diagnostic tests and procedures that consid-
erably increase medical costs and expose the patient to inappropriate use of antibiotics which eventually results in
antibiotic resistance. Thus, evaluation of the febrile patient in the ICU requires a meticulous and attentive approach.
Currently, managing ICU patients with fever should be towards a more restrictive approach than simply starting
antibiotic therapy. This review summarizes the common causes of fever in ICU patients and outlines a clinical ap-
proach to the management of these patients. (Minerva Anestesiol 2013;79:408-18)
Key words: Fever, physiopathology - Intensive care units - Infection.

F ever, which is frequently encountered in inten-

sive care unit (ICU) patients, is caused by a
wide variety of infectious and noninfectious dis-
orders. The presence of fever results in the act of
diagnostic tests and measures that considerably
increase medical costs and may subject the patient
to unnecessary invasive procedures.1 Also, its pres-
ence is usually perceived as a sign of infection and
is among the main reason for inappropriate anti-
biotic prescription. This may expose the patient to
serious drug side effects and is the leading cause to
the development of antibiotic resistance.2, 3 There-
fore, rationale approach to the febrile patient in
ICU is of critical importance for the healthcare
or other proprietary information of the Publisher.
Among the mediators that stimulate a rise in the
normal core temperature set point are interleukin
1 (IL-1), tumor necrosis factor (TNF-α), inter-
leukin 6 (IL-6), and interferon γ (IFN-γ).4, 5 They
are released primarily by monocytes and macro-
phages in response to invasion by various patho-
gens and by other inflammatory stimuli. These
cytokines bind to their specific receptors located
in the preoptic region of the anterior hypotha-
lamus.6 Here, the cytokine receptor interaction
activates phospholipase A2 which in turn stimu-
lates the cyclo-oxygenase pathway to produce in-
creased levels of prostaglandin E2. This small lipid
mediator diffuses across the blood brain barrier,

workers. This review summarizes the common
causes of fever in ICU patients and outlines a clini-
cal approach to the management of these patients.
Pathophysiology of fever
Fever is a consequence of the anterior hypoth-
alamus responding to inflammatory mediators.
where it acts to decrease the rate of firing of pr-
eoptic warm-sensitive neurons, leading to activa-
tion of responses designed to decrease heat loss
and increase heat production.6, 7 Fever is charac-
terized by beneficial and deleterious effects. It ap-
pears to be an adaptive reaction that has evolved
to save the host against invading pathogens. El-
evated body temperature has been shown to aug-

408 MINERVA ANESTESIOLOGICA April 2013

 ©
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT 2013 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
A CLINICAL OUTLINE TO FEVER IN INTENSIVE CARE PATIENTS ÖNCÜ
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
ment some parts of immune function, including
T-cell activation, antibody production, and neu-
trophil/macrophage function6. Increased sur-
vival with fever has been demonstrated in animal
studies.8, 9 Additionally, one in-vitro study found
reductions in the minimum inhibitory concen-
trations (MIC) with increasing temperature,
representing an improvement in the antimicro-
bial activity of antibiotics.10 While in vitro and
animal data seems to suggest that fever favorably
impacts morbidity and mortality, human studies
are sparse in this area. Nevertheless, in some of
these studies, a positive correlation between el-
evated temperature and survival was reported.8,
11-13 An elevated body temperature may, however,
be associated with a number of harmful effects.
Increased heart rate and cardiac output, elevated
oxygen consumption, and increased serum cat-
echolamine production are accompanying adap-
tive responses to fever, aiming to enhance oxygen
delivery to meet the raised tissue demands.3, 14, 15
These changes may not be adequately tolerated
in patients with limited cardio-respiratory reserve
in the ICU. In addition, moderate elevations of
brain temperature may deteriorate the resulting
injury in patients who have head injuries and cer-
ebrovascular accidents.6, 16
Definition of fever
The definition of fever is arbitrary and depends
on the purpose for which it is defined.17 The
mean body temperature in healthy individuals
is approximately 36.8°C (98.2 °F), with a range
of 35.6 °C (96 °F) to 38.2 °C (100.8 °F) and a
slight diurnal variation.18 A joint task force from
the American College of Critical Care Medicine
and the Infectious Diseases Society of America
has defined fever as a body temperature of 38.3
ºC (101 ºF) or higher.6, 17 Accordingly, unless the
patient has other features of an infectious disease,
or other proprietary information of the Publisher.
only a temperature higher than 38.2 °C (101 °F)
warrants further investigation in ICU.
Causes of fever in the ICU
Any disease process that results in the release of
inflammatory cytokines may produce fever. De-
spite the common perception of “fever indicates
Vol. 79 - No. 4 MINERVA ANESTESIOLOGICA 409
infection”, about half of the fever in ICU is elic-
ited by non-infectious causes. Hence, a rationale
approach should be paid to differentiate infec-
tious from non-infectious cause of fever. Other-
wise increased expenditure, antibiotic resistance
and side effects are inevitable. Those infectious
and non-infectious disorders that should be con-
sidered in ICU patients with fever are summa-
rized in systematic order and listed in Table I.
Non-infectious causes of fever in the ICU
Many patients admitted to the ICU have un-
derlying illnesses and dysfunction of multiple or-
gan systems. They commonly go through several
diagnostic/therapeutic procedures and are treated
with numerous medications during their stay in
the ICU. It is not astonishing that patients in
these conditions develop fever, but it is not nec-
essarily the case that the fever will be due to an
infection. Abundant number of noninfectious
disorders may result in tissue injury with inflam-
mation and a febrile reaction.15 The clinical ap-
proach to the noninfectious disorders with fever
is usually relatively straightforward since they are
easily diagnosable by history, physical examina-
tion, routine laboratory tests or radiological im-
aging. The complexity usually becomes apparent
when the patient has a diversity of conditions and
distinguishing the infectious from the noninfec-
tious causes can be an overwhelming work. The
level of fever may simply be a clue to differenti-
ate the cause of fever in ICU. With the exception
of malignant hyperthermia, adrenal insufficiency,
intracranial hemorrhage, drug fever and heat
stroke most of the noninfectious disorders usu-
ally lead to a fever that is usually less than 38.9 °C
(102 °F).19 Thus, in case the temperature is be-
low this threshold noninfectious diseases should
be included more extensively in the differential
diagnosis of fever. On the other hand, it is well
known that low level or absence of fever may ac-
company serious infections in ICU and therefore
should never exclude infection from diagnosis.20
Hyperthermia
In contrast to fever, hyperthermia is character-
ized by an increase of the core body temperature
 ©
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT 2013 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is

ÖNCÜ A CLINICAL OUTLINE TO FEVER IN INTENSIVE CARE PATIENTS

This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other

Table I.—Main causes of fever in ICU.

Body system
Cardiovascular system
Central nervous system
Endocrine system
Gastrointestinal system
Respiratory system
Skin/Soft tissue
Urinary system
Other
Non-Infectious etiology Infectious etiology
–– Deep vein thrombosis –– Bacteremia
–– Dressler’s syndrome –– Endocarditis
–– Embolism –– Intravascular device infection
–– Myocardial infarction –– Septic thrombophlebitis
–– Postpericardiotomy syndrome
–– Thrombophlebitis
–– Cerebral infarction –– Meningitis
–– Intracranial hemorrhage
–– Posterior fossa syndrome
–– Seizure
–– Adrenal insufficiency
–– Hyperthyroidism
–– Acalculous cholecystitis –– Cholecystitis/Cholangitis
–– Diffuse hepatitis –– Diarrhea (C.difficile)
–– Gastrointestinal bleeding –– Intraabdominal abscess
–– Ischemia of bowel –– Peritonitis
–– Pancreatitis
–– ARDS –– Empyema
–– Aspiration pneumonitis –– Pneumonia
–– Atelectasis –– Sinusitis
–– Mediastinitis –– Tracheobronchitis
–– Pulmonary embolism/infarction
–– Burn –– Cellulitis
–– Decubitus ulcer –– Wound infection
–– Catheter associated UTI
–– Pyelonephritis
–– Pyonephrosis
–– Blood/blood product transfusion –– Surgical site infection
–– Drug fever
–– Drug/alcohol withdrawal
–– Collagen vascular/autoimmune disease
–– Fat embolism
–– Hematoma
–– Hyperthermia
–– IV contrast reaction
–– Jarisch-Herxheimer reaction
–– Malignancy
–– Postoperative/interventional fever
–– Transplant rejection

without an alteration in the hypothalamic set postoperative day 1 may be safely assumed not
point and occurs essentially owing to failure to to be due to MH.22, 23
dissipate heat in relation to its rate of produc-
tion.21 Common causes include heat stroke, ma- Exacerbation of underlying chronic disease
lignant hyperthermia (MH) and the neuroleptic
malignant syndrome (NMS).15 These disorders Many patients requiring intensive care have
or other proprietary information of the Publisher.

should be kept in mind in critically ill patients
when the body temperature is especially high of-
ten exceeding 42 oC (107.6 oF). NMS has been
strongly associated with antipsychotic neurolep-
tic medications. MH can be caused by succinyl-
choline and inhaled anesthetics administration
(especially halothane). As it generally becomes
apparent intraoperatively, fever beginning on
underlying chronic diseases that may mani-
fest with systemic symptoms including fever.
Malignancies, connective tissue disorders and
other autoimmune diseases are among those
diseases which may be the sole cause of fever
in ICU. 24 Serious manifestation of these un-
derlying diseases may be the primary reason
for ICU requirement. Not only fever but oth-

410 MINERVA ANESTESIOLOGICA April 2013

 ©
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT 2013 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
A CLINICAL OUTLINE TO FEVER IN INTENSIVE CARE PATIENTS ÖNCÜ
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
er organ system involvements (arthritis, rash,
pneumonitis, diarrhea etc) of the relevant
disease are the likely presentations. Hence,
while exploring the cause of fever underlying
illnesses should be excluded as the possible
etiology.
Cardiovascular disorders
The non-infectious causes of fever include
myocardial infarction, Dressler’s syndrome
with pericarditis, dissecting aortic aneurism,
thromboembolism, deep venous thrombosis
and postpericardiotomy syndrome.25 Post-
pericardiotomy syndrome, characterized by
inflammatory reaction involving pleuroperi-
cardium is a frequent complication of open-
heart surgery and may present with fever in
addition to chest pain and pleuropericardial
effusions.26 Hemorrhagic complications due
to thrombolytic therapy and administration
of antiarrhythmic medication (procainamide,
quinidine) are other potential causes of fever
in cardiac care units.27
Central nervous system disorders
Patients with central nervous system trau-
ma or intracranial lesion frequently have fe-
ver while in the ICU. This kind of fever is
thought to be caused by disruption in the
hypothalamic set point. The temperature is
characteristically very high, has a plateau-
like curve (no diurnal variation) and resist-
ant to antipyretic medications. 28 Posterior
fossa syndrome is another cause of noninfec-
tious origin of fever in neurosurgical patients.
It mimics meningitis with clinical signs and
laboratory findings. The differential diagno-
sis from infectious meningitis is based on the
negative microbiological test results of cer-
or other proprietary information of the Publisher.
ebrospinal fluid (CSF).29 Convulsion, acute
cerebral infarction and hemorrhage are other
possible causes of fever related to CNS.28
Endocrine disorders
Two endocrine disorders can present with
fever in ICU patients: thyroid storm and adre-
Vol. 79 - No. 4 MINERVA ANESTESIOLOGICA 411
nal insufficiency.17 An ICU patient with hyper-
thyroidism may precipitate thyroid storm, an
acute febrile illness and hyperdynamic state, by
physiological stress such as surgery or a critical
illness. Acute adrenal insufficiency may occur in
patients who have chronic adrenal insufficiency
in whom steroid therapy is interrupted, or in the
setting of stress or adrenal injury. It may present
with a sudden onset of high fever, hypotension
and a hyperdynamic state that is indistinguish-
able from septic shock.30
Gastrointestinal disorders
Acalculous cholecystitis which results from
gallbladder ischemia and bile stasis, is a relative-
ly uncommon ‘noninfectious’ cause of fever in
critically ill patients. The clinical findings (pain
in the right upper quadrant, nausea, vomiting,
fever) and laboratory workup are, however, of-
ten nonspecific. Radiologic investigations are re-
quired for a presumptive diagnosis.31 Fever is an
important sign in patients with acute pancreati-
tis. The timing of fever is essential in determin-
ing its cause and importance. Fever in the first
week of acute pancreatitis is as a result of acute
inflammation and is mediated by inflammatory
cytokines. Fever in the second or third week in
patients with acute necrotizing pancreatitis is
usually attributable to infection of the necrotic
tissue and is much more vital.32 Gut ischemia,
resulting from inefficient perfusion that is com-
monly encountered in intensive care requiring
patients, is one of the possible causes of fever in
ICU.21 Abdominal pain and rectal bleeding are
the most common symptoms, but the signs and
symptoms may overlap with other colonic dis-
eases.
Respiratory disorders
In the absence of pulmonary infection, acute
respiratory distress syndrome (ARDS) may cause
fever resulting from the inflammatory-fibrotic
process present in the airspace.33 Aspiration
pneumonitis which progress rapidly and within
hours after aspiration of regurgitated contents
of the stomach usually presents with respiratory
distress symptoms and also fever.34 Although at-
 ©
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT 2013 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
ÖNCÜ A CLINICAL OUTLINE TO FEVER IN INTENSIVE CARE PATIENTS
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
electasis is commonly implicated as a cause of
fever, the available evidence regarding the asso-
ciation of atelectasis and fever is scarce35. Hence
it should be a diagnosis of exclusion. Pulmonary
embolism/infarct and pulmonary hemorrhage
are among the reason of elevated body tempera-
ture in the ICU.36
Skin/soft tissue disorders
Virtually all burn patients have elevated core
body temperatures secondary to the systemic in-
flammatory response to burn injury. Thus, fever
after burn is a common finding and not a reli-
able indicator of infection.37 Disruption of skin
and underlying tissues is a common issue in ICU
patients due to unrelieved pressure usually over
bony prominence. Prolonged pressure on the af-
fected area cuts off the blood supply which even-
tually leads to tissue necrosis with consequential
fever.38
Postoperative fever
Fever is a common phenomenon during the
initial 72 hours after surgery, usually caused
by the release of endogenous pyrogens into the
bloodstream. It should be remembered that fe-
ver in this early postoperative period is usually
noninfectious in origin, assuming that extraordi-
nary breaks in sterile technique did not occur.39
Detailed workup is usually not necessary during
this postoperative time period if the patient is
clinically stable. Nevertheless, this type of fever
warrants a careful evaluation to rule out infec-
tion, which is increasingly likely with time.
Drug fever
Although the precise incidence is unknown,
drug fever should be considered in patients
or other proprietary information of the Publisher.
with an otherwise unexplained fever. Drugs can
cause fever due to hypersensitivity in ICU, and
it is most often attributed to antibiotics (espe-
cially β-lactams and sulfonamides), anti-epilep-
tic drugs (particulary phenytoin), antiarrhyth-
mics (mainly quinidine and procainamide),
antihypertensives (a-methyldopa), nonsteroidal
anti-inflammatory drugs (NSAIDS), sulpha-
412 MINERVA ANESTESIOLOGICA April 2013
containing drugs (diuretics and stool softeners)
and antidepressants/tranquilizers.40 Neverthe-
less, even though unusual in comparison to
aforementioned drugs, it should be remem-
bered that any drug may elicit fever in ICU.
The signs that are associated with drug-fever are
a lack of appropriate pulse rate response and a
relative bradycardia. A concomitant maculo-
papular rash and eosinophilia makes the diag-
nosis simple but accompanies the fever in only
minority.41, 42 Fever does not invariably occur
immediately after drug administration; instead
it may be days after administration that fever
arises and many more days before the fever sub-
sides.17 Contrary to drug fever, withdrawal of
drug/alcohol may also cause fever and should
always be considered in a patient with a history
of substance abuse.23 As clinicians may not be
informed about abuse history, clinical suspicion
should be high.
Transfusion related fever
Febrile reactions complicate about 0.5% of
blood transfusions. It is most often attributed to
the presence of granulocytes and platelets, but
could also be caused by plasma factors such as
exogenous immunoglobulins.43 Febrile reactions
usually begin within 30 min to 2 h after transfu-
sion. The fever generally lasts between 2 h and
24 h and may be preceded by chills.
Hematoma
Whatever the cause and wherever it presents
in the body, hematoma is one of the well known
etiologies of fever.19 Accordingly, hematoma
should be at the top differential diagnosis list of
fever in an ICU patient with bleeding diathesis,
trauma and postsurgery.
Infectious causes of fever in ICU
Infections now concern 25% to 33% of ICU
patients.44 The most common causes are lower
respiratory tract infection associated with me-
chanical ventilation, intra-abdominal infections
following trauma or surgery, and intravascular
catheter infection.
 ©
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT 2013 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
A CLINICAL OUTLINE TO FEVER IN INTENSIVE CARE PATIENTS ÖNCÜ
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
Intravascular catheter-related infection
Infection  remains the main complication of
intravascular  catheters  in critically ill patients.
Catheter-related infections (CRI) have been re-
ported to occur in 3 to 8% of inserted catheters
and are the first cause of nosocomial bloodstream
infection in ICUs.45 All type of catheters may
cause infection, but the risk is increased with
central venous catheters especially those which
are non-tunneled.46 Although purulent dis-
charge at the insertion site is a clue of infection,
most catheter-related bloodstream infections
present without this infection sign. As the diag-
nosis of CRI requires microbiological workup, at
the beginning it is a diagnosis of exclusion. Fe-
ver appearing during or after treatment through
catheter, as in dialysis and infusion, should raise
suspicion of intraluminal originating CRI.47
Presence of risk for CRI such as inappropriate
catheter care should also put these infections for-
ward as a cause of fever.45
Central nervous system infections
Fever is a common finding in neurocritical pa-
tients, but substantial of these fevers are of non-
infectious origin. CNS infections are fortunately
rare in ICU patients, thus through differential
diagnostic workup should be performed to ex-
clude other possible source of fever. But, special
attention should be given for post-neurosurgical
and intracranial device applied patients since
CNS infection rates are considerable higher in
this group of patients.48 Altered consciousness,
focal neurological signs and fever are the most
common signs of infectious pathology. Evalua-
tion of CSF is the simplest and most efficient
way to rule out CNS infection as a cause of fever.
Diarrhea
or other proprietary information of the Publisher.
Many patients in the ICU have diarrhea,
which is often caused by drugs or enteral feed-
ings. Fever and other inflammation signs are not
likely with this kind of diarrhea. The commonest
cause of febrile diarrhea in critically ill patients
is pseudomembraneous enterocolitis caused by
Clostridium difficile, which should be suspect-
Vol. 79 - No. 4 MINERVA ANESTESIOLOGICA 413
ed in any patient who received an antibacterial
agent or chemotherapy within 60 days before
the onset of inflammatory diarrhea.49 The physi-
cian should be aware that some patients, espe-
cially those who are postoperative, may present
with ileus or toxic megacolon without diarrhea
as the manifestation of C. difficile disease.17
Infective endocarditis
Infective endocarditis (IE) requires a high in-
dex of suspicion particularly in patients predis-
posed to IE. Prosthetic valve, cardiac surgery and
long-term indwelling intravascular devices are
the main risk factors for ICU acquired IE.50 In
addition to fever; peripheral thromboembolism,
neurological complications such as stroke or in-
tracranial hemorrhage; new or changing cardiac
murmur, heart failure and acute kidney injury
are IE suggesting findings. Also, sustained fever
with accompanying bacteremia/fungemia de-
spite efficient antimicrobial therapy should alert
the physician for the possible IE.
Intra-abdominal infections
The abdomen can harbour a broad range of
infectious disorders with minimal evidence of
their presence but fever. The clinical setting is
the most important clue to recognize the possi-
ble cause of infection. Patient with ascites should
be evaluated for primary peritonitis as the source
of fever. Prior abdominal surgery should raise
the outlook of an unrecognized complication ei-
ther directly related to the procedure itself such
as anastomotic dehiscences or to the laparotomy
undertaken to perform the procedure. Perfora-
tion of an ulcer is also a possible complication of
major surgical intervention and stress, particu-
larly in the patient with known peptic ulcer dis-
ease. These surgical complications are the main
cause of secondary peritonitis and intraabdomi-
nal abscess which are not uncommon infectious
cause of fever in ICU patient.51 Biliary tract is
another common source for infection and there-
by fever. Obstructive pathology and existence of
stent in biliary tract are the principal risk factors
that should focus the physician on cholangitis as
the source of fever. Other invasive devices within
 ©
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT 2013 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
ÖNCÜ A CLINICAL OUTLINE TO FEVER IN INTENSIVE CARE PATIENTS
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
the peritoneal cavity such as peritoneal dialysis
cannulae, are as well prone to infection. Finally,
infection may complicate the later course of a
disease such as pancreatitis, which is initially a
sterile process.52
Respiratory infections
The condition that most dramatically increas-
es the risk of lower respiratory tract infection is
mechanic ventilation. New onset of fever in ICU
patients, especially that are mechanically venti-
lated, should raise suspicion on pneumonia.
Various combinations of clinical, radiographic,
and laboratory criteria are frequently used to
make the diagnosis. These criteria include fever,
leukocytosis or leukopenia, purulent tracheal
secretions, and the presence of a new or wors-
ening radiographic infiltrate. The differential
diagnosis includes ARDS, left ventricular failure
(LVF), pulmonary hemorrhage and aspiration
pneumonitis owing to the similar pattern of the
radiographic pulmonary infiltrates. Quantitative
cultures of tracheal aspirate, bronchoalveolar la-
vage, and protected specimen brush can aid in
the diagnosis.53 Tracheobronchititis is another
lower respiratory tract infection that may cause
fever in ICU. The diagnostic criteria are similar
to VAP in exception of radiographic signs of new
pneumonia.54
Sinusitis
Nosocomial sinusitis is a frequent but under-
diagnosed complication of ICU care. Nasal intu-
bation is thought to play a major role in patho-
genesis, but the lack of sinus ventilation, pooling
and stagnation of fluid in the sinuses of patients
with depressed mental status who remain in
the supine position may also contribute to the
pathogenesis of this infection. Clinical manifes-
or other proprietary information of the Publisher.
tations of infection may be minimal. They in-
clude purulent nasal discharge and fever without
an obvious source.55
Skin-soft tissue infections
Any type of skin-soft tissue infection (SSTI)
may develop in ICU patient. The good point
414 MINERVA ANESTESIOLOGICA April 2013
of these infections is that they can be diagnosed
easily with cautious inspection. Special attention
should be paid for pressure areas and device in-
sertion sites as those parts are prone to infection.
Decubitus ulcer is a cause of fever on its own,
but appending infection aggravates systemic in-
flammatory reaction, so necessitates urgent anti-
infective management.56 Local inflammation,
common in the insertion site of medical devices,
can progress to cellulites and even other SSTI
that are possible causes of fever in ICU patient.
Fever is a frequent symptom in burned patients,
but it is not discriminative for burn infection.
Other clinical and laboratory findings should
guide to differentiate the cause of fever in this
patient group.57
Surgical site infections
Surgical site infections are a devastating and
common complication of hospitalization, oc-
curring in 2% to 11% of patients undergoing
surgery.58 Therefore, new onset fever in a patient
who had surgical operation should be evaluated
with priority for possible SSIs. But, it is valuable
to remember that fever in early postoperative pe-
riod (<72 h) is usually noninfectious in origin
except for group A streptococcal infections and
clostridial infections, which can develop within
1-3 days after surgery.59 Inflammation signs and
purulent discharge at incision site are easy evi-
dence to diagnose SSIs. But radiologic screening
may be necessary to diagnostic workup for deep
or organ/space SSIs.
Urinary tract infections
Most ICU patients require an indwelling uri-
nary catheter for monitoring fluid balance and
renal function. In the absence of a catheter, uri-
nary tract is rarely a source of infection in this pa-
tient group. In ICUs, less than 3% of bacteremic
episodes are attributed to urinary infection.60
The majority of bacterial and fungal isolates from
catheterized patients represents colonization
rather than infection. In contrast to community-
acquired urinary tract infections, where pyuria
is predictive of significant bacteriuria, it is ubiq-
uitous in patients with indwelling catheters and
 ©
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT 2013 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
A CLINICAL OUTLINE TO FEVER IN INTENSIVE CARE PATIENTS ÖNCÜ
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
has no diagnostic value for differentiating infec-
tion from colonization. Hence, the diagnosis of
urinary tract infection (UTI) in ICU is usually
a clinical diagnosis and a diagnosis of exclusion.
The most common symptomatic presentation
of UTI for patients with indwelling catheters is
fever without localizing genitourinary findings.
Localizing signs and symptoms that are occa-
sionally present include catheter obstruction, he-
maturia, and costovertebral angle or suprapubic
pain or tenderness.61 Recent urologic manipula-
tion or surgery, especially in those patients with
known previous colonization, should also direct
the physician to this region as the source of fever.
Bacteremia
The vast majority of bloodstream infections in
ICU are secondary bacteremias and the source
is straightforwardly detected with attentive ap-
proach.62 But the source of the remaining bac-
teremia is of unknown origin and fever may be
the only presentation. Transient bacteremia en-
compasses the mainstream of unknown source
bacteremia. It is usually due to different inter-
ventions and invasive procedures.15 Endotracheal
suctioning, urinary catheter placement, infusion
through colonized i.v. catheter are some of the
interventions that may cause bacteremia. Such
transient bacteremias are unsustained and owing
to their short duration, they usually do not result
in sustaining infection. Hence, single fever spikes
that appear with transient bacteremia are a diag-
nostic rather than a therapeutic problem. Con-
sequently, query for the etiology of fever should
include very recent interventions and procedures.
Fungal infections
During the past decades, fungi have emerged
as serious nosocomial threat, particularly among
or other proprietary information of the Publisher.
patients in ICU. Fungi represent one of the lead-
ing causes of bloodstream infection in the ICU,
where up to 17% of nosocomial infection is at-
tributed to these pathogens.63 Fungal infections
should be considered in febrile ICU patients
who have certain risk factors for these opportun-
istic pathogens. Presence of CVC, particularly
in patients receiving total parenteral nutrition
Vol. 79 - No. 4 MINERVA ANESTESIOLOGICA 415
(TPN), and prolonged use of broad spectrum
antibiotics clearly increase the chance of fungal
infections.64 In addition, patients with malig-
nancy and transplantation have their own set of
risk factors beyond those associated with general
ICU admission.
Biomarkers
Several biomarkers are approved and proposed
to be used as adjunctive markers for the assess-
ment of fever, aiming to distinguish infection
from noninfectious diseases. Apart from bio-
markers that are in clinical use for years (Procal-
citonin-PCT, C-reactive protein-CRP, etc), novel
biomarkers have also been introduced with the
intention to improving the sensitivity and speci-
ficity of these tests. Some of these novel biomark-
ers include; triggering receptor expressed on my-
eloids cells-1 (TREM-1), pro-adrenomedullin,
pro-atrial natriuretic peptide, pro-vasopressin
(copeptin), various interleukins (IL 6, IL 8, IL
10 etc), interferon-γ, tumor necrosis factor α,
serum mRNAs and resistin.65, 66 Although some
promising results have been reported, none of
these novel biomarkers seem to fulfill the optimal
requirements yet. Instead, based on current evi-
dence, serum PCT still stays one step ahead for
the detection of bacterial infection/sepsis.65 Un-
fortunately, it also lacks the required precision to
be used without clinical judgment, which should
retain a crucial role in clinical diagnosis. This is
particularly important in patients who present
early in the course of illness or have focal rather
than systemic infection. Accordingly, biomarkers
may be better used to discard rather than decree
systemic infection in ICU patient, particularly if
repeated measures are used.66
Approach to fever in ICU
Evaluation of the febrile patient in the ICU
requires a meticulous and attentive approach.
The initial approach to the febrile patient should
include a through physical examination comple-
mented by a review of the patient’s history, all
medications, therapies, blood products, labora-
tory tests, culture results and imaging studies.
Characterizing fever magnitude, pattern, and
 ©
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT 2013 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is

ÖNCÜ A CLINICAL OUTLINE TO FEVER IN INTENSIVE CARE PATIENTS

This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other

relation to pulse may provide some diagnostic and therapeutic intervention is required. If there
clues. But the reliability and consistency of these is no obvious source of infection and unless the
clues are low to make certain diagnosis. Early patient is clinically deteriorating continued ob-
diagnosis of infections is of critical importance servation and repeated assessment should be the
in ICU, as morbidity/mortality rates increases approach. However, all neutropenic patients with
proportionally with delay in treatment. By vir- fever and patients with severe or progressive signs
tue of this, with the onset of fever the threshold of sepsis should be started on broad-spectrum
for starting empirical antibiotic therapy is usually antimicrobial therapy immediately after obtain-
low in ICUs. This practice, however, carries the ing appropriate cultures. Withdrawal of central
risk of over-treatment, and endorsing the emer- lines, in the presence of risk for CRI, should be
gence of multidrug-resistant pathogens. Where- assessed in rapidly deteriorating patients with-
as, managing ICU patients with fever should be out an obvious source of infection. In case fever
towards a more restrictive approach than simply persists 48–96 hours after appropriate antibiotic
starting antibiotic therapy. In all febrile patients, treatment and without the source of the infection
unless there is an obvious noninfectious cause, being identified, the patient must be evaluated
at least two blood cultures from different sites for empirical antifungal therapy. Approach to pa-
should be obtained before initiation of any treat- tient with fever in ICU is outlined in figure 1.
ment. If a central venous catheter is present and
considered as the potential source of infection, Conclusions
a blood culture should also be drawn through
the catheter. Other cultures, instead of routine, Fever in ICU patients is extremely common
should only be obtained from the related site in and it occurs from activity of endogenous pyro-
clinical doubt of infection. In patients with an gens that are released in response to infectious or
obvious source of infection a focused diagnostic non-infectious process. It is crucial to exclude an

Fever (>38.2 oC)

-Review patient’s medical record, previous studies and cultures

-Perform physical examination and focused diagnostic test

Obvious source of non-infectious etiology Obvious source of infection Unidentified source

Take cultures (blood, etc) Take cultures (blood, etc)

Treat the cause

Progressive signs of sepsis

Start empirical antibiotic therapy or
Neutropenic patient (PMNL < 500 mm3)

Yes No

Remove i.v. catheters (if in place > 72 hours and -Await culture results
presence of risk factors for infection) -Reevaluate / examine patient daily for source of fever
-Perform focused diagnostic tests and procedures

Start empirical antibiotic therapy

Fever source identified
or other proprietary information of the Publisher.

Yes
Persistence of fever or
progressive sign of infection No
+ Treat the cause
presence of risk for fungal infection

-Remove i.v. catheters (if in place > 72 hours and presence of

risk factors for infection) and other devices (nasogastric and
Start empirical antifungal therapy endotracheal tube etc)
-Stop or change, if possible, suspicious drugs

De-escalate therapy according to the -Continue to monitor the patient for fever and any diagnostic clue
antibiotic susceptibility results -If sufficient suspicion of any disease arises start focused therapy

Figure 1.—Approach to patient with fever in ICU

416 MINERVA ANESTESIOLOGICA April 2013

 ©
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT 2013 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
A CLINICAL OUTLINE TO FEVER IN INTENSIVE CARE PATIENTS ÖNCÜ
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
infectious cause of the fever in the ICU because
of the potential for rapid deterioration with un-
treated infections. However, about half of the
fever in ICU is elicited by non-infectious causes
that are readily diagnosable by attentive history,
physical examination and laboratory workup.
Therefore, managing ICU patients with fever
should be towards a more restrictive approach
than simply starting antibiotic therapy.
Key messages
—— ICU patients frequently have multiple
infectious and noninfectious causes of fever,
which requires a systematic and comprehen-
sive diagnostic approach.
—— Fever in the ICU is defined as a tem-
perature greater than 38.2°C (101°F) and
accordingly unless the patient has other fea-
tures of an infectious process, only a tem-
perature higher than this threshold warrants
further investigation.
—— With the exception of malignant
hyperthermia, adrenal insufficiency, intracra-
nial hemorrhage, drug fever and heat stroke
most of the noninfectious disorders usually
lead to a lower grade of fever.
—— The most common causes infectious
fever are lower respiratory tract infection,
intra-abdominal infections and intravascular
device related infections.
—— Absence of fever should never exclude
infection from diagnosis.
—— Biomarkers may be better used to dis-
card rather than decree systemic infection in
ICU patients.
—— Managing ICU patients with fever
should be towards a more restrictive ap-
proach than simply starting empirical antibi-
otic therapy which should be reserved for the
high-risk or clinically deteriorating patients.
or other proprietary information of the Publisher.
References
  1. Young P, Saxena M, Eastwood GM, Bellomo R, Beasley R.
Fever and fever management among intensive care patients
with known or suspected infection: a multicentre prospec-
tive cohort study. Crit Care Resusc 2011;13:97-102.
  2. Toltzis P, Rosolowski B, Salvator A. Etiology of fever and
Vol. 79 - No. 4 MINERVA ANESTESIOLOGICA 417
opportunities for reduction of antibiotic use in a pediat-
ric intensive care unit. Infect Control Hosp Epidemiol
2001;22:499-504.
  3. Ferguson A. Evaluation and treatment of fever in intensive
care unit patients. Crit Care Nurs Q 2007;30:347-63.
  4. Conti B, Tabarean I, Andrei C, Bartfai T. Cytokines and
fever. Front Biosci 2004;9:1433-49.
  5. Ryan M, Levy MM. Clinical review: fever in intensive care
unit patients. Crit Care 2003;7:221-5.
  6. Marik PE. Fever in the ICU. Chest 2000;117:855-69.
  7. Mackowiak PA. Concepts of fever. Arch Intern Med
1998;158:1870-81.
  8. Launey Y, Nesseler N, Malledant Y, Seguin P. Clinical re-
view: fever in septic ICU patients--friend or foe? Crit Care
2011;15:222.
  9. Jiang Q, Cross AS, Singh IS, Chen TT, Viscardi RM,
Hasday JD. Febrile core temperature is essential for op-
timal host defense in bacterial peritonitis. Infect Immun
2000;68:1265-70.
10. Mackowiak PA, Marling-Cason M, Cohen RL. Effects of
temperature on antimicrobial susceptibility of bacteria. J
Infect Dis 1982;145:550-3.
11. Bryant RE, Hood AF, Hood CE, Koenig MG. Factors af-
fecting mortality of gram-negative rod bacteremia. Arch
Intern Med 1971;127:120-8.
12. Weinstein MP, Iannini PB, Stratton CW, Eickhoff TC.
Spontaneous bacterial peritonitis. A review of 28 cases with
emphasis on improved survival and factors influencing
prognosis. Am J Med 1978;64:592-8.
13. Mackowiak PA. Brief history of antipyretic therapy. Clin
Infect Dis 2000;31 Suppl 5:154-6.
14. Manthous CA, Hall JB, Olson D, et al. Effect of cooling on
oxygen consumption in febrile critically ill patients. Am J
Respir Crit Care Med 1995;151:10-4.
15. Dimopoulos G, Falagas ME. Approach to the febrile pa-
tient in the ICU. Infect Dis Clin North Am 2009;23:471-
84.
16. Ginsberg MD, Busto R. Combating hyperthermia in acute
stroke: a significant clinical concern. Stroke 1998;29:529-
34.
17. O’Grady NP, Barie PS, Bartlett JG, et al. Guidelines for
evaluation of new fever in critically ill adult patients: 2008
update from the American College of Critical Care Medi-
cine and the Infectious Diseases Society of America. Crit
Care Med 2008;36:1330-49.
18. Mackowiak PA, Wasserman SS, Levine MM. A critical ap-
praisal of 98.6 degrees F, the upper limit of the normal body
temperature, and other legacies of Carl Reinhold August
Wunderlich. JAMA 1992;268:1578-80.
19. Rizoli SB, Marshall JC. Saturday night fever: finding and
controlling the source of sepsis in critical illness. Lancet In-
fect Dis 2002;2:137-44.
20. Peres Bota D, Lopes Ferreira F, Melot C, Vincent JL. Body
temperature alterations in the critically ill. Intensive Care
Med 2004;30:811-6.
21. Kothari VM, Karnad DR. New onset fever in the intensive
care unit. J Assoc Physicians India 2005;53:949-53.
22. Heiman-Patterson TD. Neuroleptic malignant syndrome
and malignant hyperthermia. Important issues for the med-
ical consultant. Med Clin North Am 1993;77:477-92.
23. McAllen KJ, Schwartz DR. Adverse drug reactions resulting
in hyperthermia in the intensive care unit. Crit Care Med
2010;38:244-52.
24. Lemmen S, Lewalter K. Fever of unknown origin in the in-
tensive care unit. Dtsch Med Wochenschr 2012;137:1123-
5.
25. Wessman DE, Stafford CM. The postcardiac injury syn-
drome: case report and review of the literature. South Med
J 2006;99:309-14.
26. Imazio M, Brucato A, Ferrazzi P, Spodick DH, Adler Y.
Postpericardiotomy syndrome: a proposal for diagnostic
 ©
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT 2013 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
ÖNCÜ A CLINICAL OUTLINE TO FEVER IN INTENSIVE CARE PATIENTS
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
criteria. J Cardiovasc Med (Hagerstown) 2012 [Epub ahead
of print].
27. Murray KD, Vlasnik JJ. Procainamide-induced postopera-
tive pyrexia. Ann Thorac Surg 1999;68:1072-4.
28. Kilpatrick MM, Lowry DW, Firlik AD, Yonas H, Marion
DW. Hyperthermia in the neurosurgical intensive care unit.
Neurosurgery 2000;47:850-5.
29. Carmel PW, Greif LK. The aseptic meningitis syndrome: a
complication of posterior fossa surgery. Pediatr Neurosurg
1993;19:276-80.
30. Nieboer P, van der Werf TS, Beentjes JA, Tulleken JE, Zi-
jlstra JG, Ligtenberg JJ. Catecholamine dependency in a
polytrauma patient: relative adrenal insufficiency? Intensive
Care Med 2000;26:125-7.
31. Barie PS, Eachempati SR. Acute acalculous cholecystitis.
Gastroenterol Clin North Am 2010;39:343-57.
32. Toouli J, Brooke-Smith M, Bassi C, Carr-Locke D, Telford
J, Freeny P et al. Guidelines for the management of acute
pancreatitis. J Gastroenterol Hepatol 2002;17 Suppl:15-39.
33. Croce MA. Diagnosis of acute respiratory distress syndrome
and differentiation from ventilator-associated pneumonia.
Am J Surg 2000;179:26-9.
34. Marik PE. Aspiration syndromes: aspiration pneumonia
and pneumonitis. Hosp Pract 2010;38:35-42.
35. Mavros MN, Velmahos GC, Falagas ME. Atelectasis as a
cause of postoperative fever: where is the clinical evidence?
Chest 2011;140:418-24.
36. Stein PD, Afzal A, Henry JW, Villareal CG. Fever in acute
pulmonary embolism. Chest 2000;117:39-42.
37. Murray CK, Hoffmaster RM, Schmit DR, Hospenthal DR,
Ward JA, Cancio LC et al. Evaluation of white blood cell
count, neutrophil percentage, and elevated temperature as
predictors of bloodstream infection in burn patients. Arch
Surg 2007;142:639-42.
38. Parish LC, Lowthian P, Witkowski JA. The decubitus ulcer:
many questions but few definitive answers. Clin Dermatol
2007;25:101-8.
39. Ballestas HC. Postoperative fever: to what is the body really
responding? AORN J 2007;86:983-8; 9-92.
40. Vodovar D, Lebeller C, Megarbane B, Lillo-Le-Louet A,
Hanslik T. Drug Fever: a descriptive cohort study from
the French national pharmacovigilance database. Drug Saf
2012;35:759-67.
41. Patel RA, Gallagher JC. Drug fever. Pharmacotherapy
2010;30:57-69.
42. Clarke DE, Kimelman J, Raffin TA. The evaluation of fever
in the intensive care unit. Chest 1991;100:213-20.
43. Barton JC. Nonhemolytic, noninfectious transfusion reac-
tions. Semin Hematol 1981;18:95-121.
44. Malacarne P, Boccalatte D, Acquarolo A, Agostini F, Ang-
hileri A, Giardino M et al. Epidemiology of nosocomial
infection in 125 Italian intensive care units. Minerva Anes-
tesiol 2010;76:13-23.
45. Oncu S, Ozsut H, Yildirim A, Ay P, Cakar N, Eraksoy H
et al. Central venous catheter related infections: risk factors
and the effect of glycopeptide antibiotics. Ann Clin Micro-
biol Antimicrob 2003;2:3.
46. Oncu S. In vitro effectiveness of antifungal lock solutions
on catheters infected with Candida species. J Infect Che-
mother 2011;17:634-9.
or other proprietary information of the Publisher.
47. Oncu S, Ozturk B, Kurt I, Sakarya S. Elimination of intra-
luminal colonization by antibiotic lock in catheters. Tohoku
J Exp Med 2004;203:1-8.
Received on February 4, 2013 - Accepted for publication on March 1, 2013.
Corresponding author: Prof. S. Öncü, MD, Adnan Menderes University Medical Faculty, Department of Infectious Diseases and Clinical
Microbiology, 09100, Aydin, Turkey. E-mail: soncu@dr.com
418 MINERVA ANESTESIOLOGICA April 2013
48. Federico G, Tumbarello M, Spanu T, Rosell R, Iacoangeli
M, Scerrati M et al. Risk factors and prognostic indicators
of bacterial meningitis in a cohort of 3580 postneurosurgi-
cal patients. Scand J Infect Dis 2001;33:533-7.
49. Bartel B, Gau E. Nosocomial diarrhea: a review of patho-
physiology, etiology, and treatment strategies. Hosp Pract
2012;40:130-8.
50. Gilleece A, Fenelon L. Nosocomial infective endocarditis. J
Hosp Infect 2000;46:83-8.
51. Agarwal N, Saha S, Srivastava A, Chumber S, Dhar A, Garg
S. Peritonitis: 10 years’ experience in a single surgical unit.
Trop Gastroenterol 2007;28:117-20.
52. Barie PS, Hydo LJ, Eachempati SR. Longitudinal outcomes
of intra-abdominal infection complicated by critical illness.
Surg Infect 2004;5:365-73.
53. Kollef MH. Recognition of nosocomial pneumonia in
the intensive care unit: still a confusing issue. Respir Care
2011;56:1209-12.
54. Nseir S, Ader F, Marquette CH. Nosocomial tracheobron-
chitis. Curr Opin Infect Dis 2009;22:148-53.
55. Stein M, Caplan ES. Nosocomial sinusitis: a unique subset
of sinusitis. Curr Opin Infect Dis 2005;18:147-50.
56. Bansal C, Scott R, Stewart D, Cockerell CJ. Decubitus ul-
cers: a review of the literature. Int J Dermatol 2005;44:805-
10.
57. Greenhalgh DG, Saffle JR, Holmes JHt 4th, Gamelli RL,
Palmieri TL, Horton JW et al. American Burn Associa-
tion consensus conference to define sepsis and infection in
burns. J Burn Care Res 2007;28:776-90.
58. Hawn MT, Vick CC, Richman J, Holman W, Deierhoi RJ,
Graham LA et al. Surgical site infection prevention: time to
move beyond the surgical care improvement program. Ann
Surg 2011;254:494-9.
59. Goldstein EJ, Citron DM, Merriam CV, Abramson MA.
Infection after elective colorectal surgery: bacteriological
analysis of failures in a randomized trial of cefotetan vs. er-
tapenem prophylaxis. Surg Infect 2009;10:111-8.
60. Tambyah PA, Maki DG. Catheter-associated urinary tract
infection is rarely symptomatic: a prospective study of 1,497
catheterized patients. Arch Intern Med 2000;160:678-82.
61. Nicolle LE. Urinary catheter-associated infections. Infect
Dis Clin North Am 2012;26:13-27.
62. Maldini B, Antolic S, Sakic-Zdravcevic K, Karaman-Ilic M,
Jankovic S. Evaluation of bacteremia in a pediatric intensive
care unit: epidemiology, microbiology, sources sites and risk
factors. Coll Antropol 2007;31:1083-8.
63. Dimopoulos G, Karabinis A, Samonis G, Falagas ME. Can-
didemia in immunocompromised and immunocompetent
critically ill patients: a prospective comparative study. Eur J
Clin Microbiol Infect Dis 2007;26:377-84.
64. Leroy O, Gangneux JP, Montravers P, Mira JP, Gouin F,
Sollet JP et al. Epidemiology, management, and risk fac-
tors for death of invasive Candida infections in critical care:
a multicenter, prospective, observational study in France
(2005-2006). Crit Care Med 2009;37:1612-8.
65. Hoeboer SH, Alberts E, van den Hul I, Tacx AN, Debets-
Ossenkopp YJ, Groeneveld AB. Old and new biomarkers
for predicting high and low risk microbial infection in criti-
cally ill patients with new onset fever: a case for procalcito-
nin. J Infect 2012;64:484-93.
66. Kibe S, Adams K, Barlow G. Diagnostic and prognostic
biomarkers of sepsis in critical care. J Antimicrob Che-
mother 2011;66(Suppl 2):33-40.