Pyrexia

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Pyrexia
Table of Contents
 Preface
 Introduction
 Assessing And Measuring Fever In ICU
 Assessment of fever of recent onset
 Clinical appraisal
 Fever – notable features and measurement
 Laboratory appraisal
 Imaging
 Culture techniques
 Molecular techniques
 Microbiology
 Systemic inflammatory response syndrome (SIRS)
 Determining The Cause Of Fever In The Critically Ill Patient
 Infective causes
 Non infective causes
 Fever In Specific Categories Of Critically Ill Patient
 The surgical critical care patient – determining the cause of fever
 Fever in immunocompromised patients
 Fever in neurological disease
 Identifying special forms of fever
 Understanding And Treating Fever
 Pathogenesis and pathophysiology
 Treating fever
 Malignant hyperthermia, neuroleptic malignant syndrome and lethal
catatonia
 Conclusion
 
https://collaboration.esicm.org/Pyrexia%3A+Preface?page_ref_id=2056
https://collaboration.esicm.org/Pyrexia%3A+Introduction?page_ref_id=2057
https://collaboration.esicm.org/Pyrexia%3A+Assessing+And+Measuring+Fever+In+ICU?page_ref_id=2058
https://collaboration.esicm.org/Pyrexia%3A+Assessing+And+Measuring+Fever+In+ICU%3A+Assessment+of+fever+of+recent+onset?page_ref_id=2059
https://collaboration.esicm.org/Pyrexia%3A+Assessing+And+Measuring+Fever+In+ICU%3A+Clinical+appraisal?page_ref_id=2060
https://collaboration.esicm.org/Pyrexia%3A+Assessing+And+Measuring+Fever+In+ICU%3A+Fever+%E2%80%93+notable+features+and+measurement?page_ref_id=2061
https://collaboration.esicm.org/Pyrexia%3A+Assessing+And+Measuring+Fever+In+ICU%3A+Laboratory+appraisal?page_ref_id=2062
https://collaboration.esicm.org/Pyrexia%3A+Assessing+And+Measuring+Fever+In+ICU%3A+Imaging?page_ref_id=2063
https://collaboration.esicm.org/Pyrexia%3A+Assessing+And+Measuring+Fever+In+ICU%3A+Culture+techniques?page_ref_id=2064
https://collaboration.esicm.org/Pyrexia%3A+Assessing+And+Measuring+Fever+In+ICU%3A+Molecular++techniques?page_ref_id=2775
https://collaboration.esicm.org/Pyrexia%3A+Assessing+And+Measuring+Fever+In+ICU%3A+Microbiology?page_ref_id=2065
https://collaboration.esicm.org/Pyrexia%3A+Assessing+And+Measuring+Fever+In+ICU%3A+Systemic+inflammatory+response+syndrome+%28SIRS%29?page_ref_id=2066
https://collaboration.esicm.org/Pyrexia%3A+Determining+The+Cause+Of+Fever+In+The+Critically+Ill+Patient?page_ref_id=2067
https://collaboration.esicm.org/Pyrexia%3A+Determining+The+Cause+Of+Fever+In+The+Critically+Ill+Patient%3A+Infective+causes?page_ref_id=2068
https://collaboration.esicm.org/Pyrexia%3A+Determining+The+Cause+Of+Fever+In+The+Critically+Ill+Patient%3A+Non+infective+causes?page_ref_id=2069
https://collaboration.esicm.org/Pyrexia%3A+Fever+In+Specific+Categories+Of+Critically+Ill+Patient?page_ref_id=2070
https://collaboration.esicm.org/Pyrexia%3A+Fever+In+Specific+Categories+Of+Critically+Ill+Patient%3A+The+surgical+critical+care+patient+%E2%80%93+determining+the+cause+of+fever?page_ref_id=2071
https://collaboration.esicm.org/Pyrexia%3A+Fever+In+Specific+Categories+Of+Critically+Ill+Patient%3A+Fever+in+immunocompromised+patients?page_ref_id=2072
https://collaboration.esicm.org/Pyrexia%3A+Fever+In+Specific+Categories+Of+Critically+Ill+Patient%3A+Fever+in+neurological+disease?page_ref_id=2073
https://collaboration.esicm.org/Pyrexia%3A+Fever+In+Specific+Categories+Of+Critically+Ill+Patient%3A+Identifying+special+forms+of+fever?page_ref_id=2074
https://collaboration.esicm.org/Pyrexia%3A+Understanding+And+Treating+Fever?page_ref_id=2075
https://collaboration.esicm.org/Pyrexia%3A+Understanding+And+Treating+Fever%3A+Pathogenesis+and+pathophysiology?page_ref_id=2076
https://collaboration.esicm.org/Pyrexia%3A+Understanding+And+Treating+Fever%3A+Treating+fever?page_ref_id=2077
https://collaboration.esicm.org/Pyrexia%3A+Understanding+And+Treating+Fever%3A+Malignant+hyperthermia%2C+neuroleptic+malignant+syndrome+and+lethal+catatonia?page_ref_id=2078
https://collaboration.esicm.org/Pyrexia%3A+Conclusion?page_ref_id=2079
Pyrexia
 
Current Status 2017
Completed 
This module is updated and maintained by the (INF) section
Latest Update
Second Edition
Systemic Inflammation and Sepsis
Chair
Ricard Ferrer Roca
Deputy
Massimo Girardis MD, Department of Anaesthesiology and Intensive Care, University
of Modena and Reggio Emilia and University Hospital of Modena, Lgo del Pozzo,
Modena
Section Editor
Nathan D. Nielsen MD, M.Sc., FCCM, Associate Professor, Division of Pulmonary,
Critical Care and Sleep Medicine, University of New Mexico School of Medicine,
Albuquerque, United States; Editorial Board and Sepsis Section Editor, ESICM
Academy
ELearning Committee
Chair
Kobus Preller Dr., Consultant, John Farman ICU, Cambridge University Hospitals NHS
Foundation Trust, Cambridge, UK
Deputy
Mo Al-Haddad MD, Consultant in Anaesthesia and Critical Care, Queen Elizabeth
University Hospital; Honorary Clinical Associate Professor University of Glasgow,
Glasgow UK
Project Manager
Estelle Pasquier , European Society of Intensive Care Medicine
Second Edition 2017
Module Authors
George Dimopoulos , PhD, Assoc. Professor Critical Care Medicine, Dept Critical
Care, ATTIKON University Hospital, Athens Greece, Medical School, National and
Kapodistrian University of Athens, Greece
Juan Jose Garcia Martinez MD, MBBS, Senior Registrar, Intensive Care Service,
Geneva University Hospitals, Geneva, Switzerland
Mohan Gurjar MD, Additional Professor, Department of Critical Care Medicine, Sanjay
Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), India
Elisabeth Paramythiotou MD, PhD, Intensive Care Unit, General University Hospital
"Attikon ", Haidari, Athens, Greece
Module Reviewers
Saad Nseir , PhD, Critical Care Center, University Hospital of Lille, and Medicine
School, Lille University, Lille, France
Section Editor
Saad Nseir , PhD, Critical Care Center, University Hospital of Lille, and Medicine
School, Lille University, Lille, France
CoBaTrICE Mapping Contributors
Cristina Santonocito MD, Dept. of Anesthesia and Intensive Care, IRCSS-ISMETT-
UPMC, Palermo, Italy
Co-Ordinating Editor
Stephanie C. Cattlin MBBS, Bsc, FRCA, FFICM, Consultant in Intensive Care,
Imperial College Healthcare NHS Trust, London, UK
Executive Editor
Mo Al-Haddad MD, Consultant in Anaesthesia and Critical Care, Queen Elizabeth
University Hospital; Honorary Clinical Associate Professor University of Glasgow,
Glasgow UK
Update 2011
Module Authors
George Dimopoulos , PhD, Assoc. Professor Critical Care Medicine, Dept Critical
Care, ATTIKON University Hospital, Athens Greece, Medical School, National and
Kapodistrian University of Athens, Greece
Johan Groeneveld , Dept of Intensive Care, Free University Hospital, Amsterdam, the
Netherlands
First Edition 2001
Module Authors
Roberto Fumagalli , Dept of Anaesthesiology & ICU, Azienda Osp, Riuniti di Bergamo,
Bergamo, Italy
Johan Groeneveld , Dept of Intensive Care, Free University Hospital, Amsterdam, the
Netherlands
Module Reviewers
Pedro Povoa MD, PhD, Coordinator of the Polyvalent Intensive Care Unit, Hospital de
Sao Francisco Xavier, CHLO, Lisbon, Associate Professor NOVA Medical School,
CEDOC, New University of Lisbon, Portugal, Adjunct Professor, Centre for Clinical
Epidemiology and Research Unit of Clinical Epidemiology, OUH Odense University
Hospital, Denmark; Chair of Infection (INF) Section, ESICM
Janice Zimmerman Dr., Dept of Internal Medicine Division of Critical Care The
Methodist Hospital Houston, Texas, USA
Update Info 
 
Learning Objectives
After studying this module on Pyrexia, you should be able to:
1. Assess fever in the ICU and initiate an appropriate evaluation
2. Determine common causes of fever in the critically ill patient
3. Manage special forms of fever
4. Decide how and when to treat fever
 
eModule Information
Expiry date: 
COBATrICe competencies covered in this module:
Competencies
Undertakes timely and appropriate investigations
Obtains appropriate microbiological samples and interprets results
Interprets chest x-rays
Liaises with radiologiststo organise and interpret clinical imaging
Integrates clinical findings with laboratory investigations to form a differential diagnosis
Faculty Disclosures: 
The authors of this module have not reported any disclosures.
Duration: 7 hours
Copyright©2017. European Society of Intensive Care Medicine. All rights reserved. 
ISBN 978-92-95051-59-1 - Legal deposit D/2005/10.772/6
https://collaboration.esicm.org/tracker54
1. Introduction
Thirty per cent of patients will become febrile, while up to 90% of patients with sepsis will
experience fever, during a stay in the intensive care unit (ICU). Fever in critically ill patients
may be of infective, non-infective, or mixed origin. The confirmation of the source of fever is
often difficult, which leads to a diagnostic dilemma and a difficult decision (to treat or not to
treat) often resulting in a variability of treatment response from the medical and nursing
staff.
 Note
Fever in the ICU is an alarm signal most frequently indicating an activated host
defence
The Society of Critical Care Medicine practice parameters define fever in the ICU as a (core)
temperature above 38.3°C. The condition is caused by an imbalance between heat
production and heat loss. In the clinical context, excessive heat generation is much more
common than defective heat loss. The resulting disturbance may be transient and/or trivial
or it may portend serious illness.
This module focuses on the differential diagnosis of fever rather than on the antimicrobial
treatment of infection.
For current information on fever:
Website of the Centers for Disease Control and Prevention (CDC) where current
information on infection statistics and other relevant information is given.
Website of the journal Emerging Infectious Diseases, published by the CDC
Website of the Infectious Diseases Society of America, and the Emerging Infections
Network
Website of the European Society of Clinical Microbiology and Infectious Diseases
Sepsis Resource Center and critical care pages
In text References 
(Niven et al. 2012; Laupland 2009; Cunha and Shea. 1996; Marik 2000; Circiumaru, Baldock
and Cohen. 1999; Ryan and Levy. 2003; Dimopoulos. 2007; OGrady et al. 2008;
Dimopoulos and Falagas. 2009) 
 
 References
Niven DJ, Léger C, Stelfox HT, Laupland KB., Fever in the critically ill: a review of
epidemiology, immunology, and management., 2012, PMID:21441283
http://www.cdc.gov/
http://www.cdc.gov/eid
http://www.idsociety.org/
http://www.escmid.org/
http://www.medscape.com/
https://www.ncbi.nlm.nih.gov/pubmed/21441283
Laupland KB, Fever in the critically ill medical patient., 2009, PMID:19535958
Cunha BA, Shea KW., Fever in the intensive care unit., 1996, PMID:8698990
Marik PE, Fever in the ICU., 2000, PMID:10713016
Circiumaru B, Baldock G, Cohen J., A prospective study of fever in the intensive
care unit., 1999, PMID:10470569
Ryan M, Levy MM., Clinical review: fever in intensive care unit patients., 2003,
PMID:12793871
Dimopoulos G. , Approach to the Febrile Patient in the Intensive Care Unit. In:
Rello J, Kollef M, Diaz E, et al., editors. Infectious diseases in critical care. 2nd
ed. , 2007, ISBN:9783540344056
OGrady NP, Barie PS, Bartlett JG, Bleck T, Carroll K, Kalil AC, Linden P, Maki
DG, Nierman D, Pasculle W, Masur H, 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., 2008,
PMID:18379262
O'Grady NP, Barie PS, Bartlett JG, Bleck T, Carroll K, Kalil AC, Linden P, Maki
DG, Nierman D, Pasculle W, Masur H, 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., 2008,
PMID:18379262
Dimopoulos G, Falagas ME., Approach to the febrile patient in the ICU., 2009,
PMID:19665078
https://www.ncbi.nlm.nih.gov/pubmed/19535958
https://www.ncbi.nlm.nih.gov/pubmed/8698990
https://www.ncbi.nlm.nih.gov/pubmed/10713016
https://www.ncbi.nlm.nih.gov/pubmed/10470569
https://www.ncbi.nlm.nih.gov/pubmed/12793871
https://www.ncbi.nlm.nih.gov/pubmed/18379262
https://www.ncbi.nlm.nih.gov/pubmed/18379262
https://www.ncbi.nlm.nih.gov/pubmed/19665078
2. Assessing And Measuring Fever In ICU
Fever in an ICU patient is always a concern. The first and immediate priority is to determine
its clinical significance.
2. 1. Assessment of fever of recent onset
Fever has many causes depending on age, underlying illness, and the environment of the
patient. Fever in a healthy adult is commonly considered as a result of viral infections such
as influenza but in the hospital environment is considered of non-viral origin. In the critically
ill, mechanically ventilated patient, for instance, the most common causes are a bacterial or
fungal infection, unless proven otherwise. Non-infective causes of fever include
thromboembolism, trauma, and others. The distinction between these various causes is
important because of the difference in treatment and prognosis. In both medical and surgical
critically ill patients, fever is caused by infective and non-infective conditions in roughly
equal proportions. The latter tends to be confirmed once infective causes are ruled out; non-
infective causes may include cerebral conditions affecting thermoregulation. Fever above
38.9°C is more likely to be due to infective than non-infective causes, and vice versa. Fever
surpassing 41.1ºC are usually noninfectious. Possible causes include neuroleptic malignant
syndrome, drug fever, malignant hyperthermia, transfusion reactions, adrenal insufficiency,
thyroid storm and stroke. The higher the fever, the more likely it is to be of infective origin,
but a temperature above 41.1°C can be of neurological origin.
 Note
The presence of risk factors for nosocomial microbial infection in the critically ill
patient render non-infective causes less likely. In fact, nosocomial infection
complicates the hospital course of approximately 30% of critically ill patients, and
fever of recent onset in the ICU is caused by nosocomial infection in more than half of
cases. 
Ventilator-associated pneumonia, catheter related sepsis and sinusitis are the three
major contributors to ICU fever of recent onset
Risk factors for microbial infection include:
1. Advanced age
2. Severe underlying disease
3. Neutropenia
4. Immunosuppression
5. Intravascular catheters
6. Intubation and mechanical ventilation
7. Prolonged ICU stay
8. Prostheses
9. Foreign bodies
10. Prior surgery
11. Bladder catheters and wound drains
12. Nasogastric tubes
13. Neurological disease with impaired consciousness
Stress ulcer prophylaxis is considered a risk factor for nosocomial infections associated with
gastric colonisation by enteric organisms. In a large, hospital based pharmaco-
epidemiologic cohort, acid-suppressive medication use was associated with 30% increased
odds of hospital-acquired pneumonia while in subset analyses, statistically significant risk
was demonstrated only for proton pump inhibitor use. More importantly, the presence of
invasive devices predisposes to infection. Intravascular catheters are associated with
catheter-related blood stream infections. Endotracheal intubation and mechanical ventilation
are risk factors for ventilator-associated pneumonia and the presence of a nasogastric or
nasotracheal tube is a risk factor for sinusitis. Yeast and fungal infections are common in
patients with severe underlying disease, in neutropenia, diabetes mellitus, renal failure,
diabetes and after multiple courses of antibiotics. Furthermore, gastrointestinal surgery,
open wounds, and a prolonged ICU stay, are risk factors for deep fungal infections. Risk
factors for nosocomial infections in the critically ill are studied in:
In text References
(Girouet al. 1998; Herzig et al. 2009; MacLaren et al. 2017) 
Appropriate investigations of a patient with fever should not involve an undirected battery of
imaging, laboratory and microbiological tests but should be selected on the basis of a
thorough clinical evaluation and targeted toward suspected sources of infection. Expeditious
diagnosis is key to early effective therapy. In the diagnostic investigation of fever, the
following sequence represents reasonable practice.
 References
Girou E, Stephan F, Novara A, Safar M, Fagon JY., Risk factors and outcome of
nosocomial infections: results of a matched case-control study of ICU patients.,
1998, PMID:9563733
Herzig SJ, Howell MD, Ngo LH, Marcantonio ER., Acid-suppressive medication
use and the risk for hospital-acquired pneumonia., 2009, PMID:19470989
MacLaren G, Spelman D, Manaker S, Finlay G. , Fever in the intensive care unit,
2017, https://www.uptodate.com/contents/fever-in-the-intensive-care-unit
2. 2. Clinical appraisal
https://www.ncbi.nlm.nih.gov/pubmed/9563733
https://www.ncbi.nlm.nih.gov/pubmed/19470989
https://www.uptodate.com/contents/fever-in-the-intensive-care-unit
Clinical assessment starts with a full history and complete physical examination.
Assessment of fever of recent onset in the critically ill raises a number of questions:
1. When did the fever start and did it relate to any clinical events e.g. to drainage of an
infected collection or after removal of a central venous catheter (CVC), when
catheter-related infection is suspected?
2. Is there a clinically recognisable focus of infection?
3. What are the likely micro-organisms involved?
4. How high is the temperature?
5. Are there risk factors for microbial infection?
6. Are there possible non-infective causes?

In a recent onset fever, what are the important items in the clinical
history and why?
COMPLETE TASK THEN CLICK TO REVEAL THE ANSWER
 In the case of nosocomial infection, important history might include
prior haematological disease e.g. acquired immunodeficiency syndrome
(AIDS), since chronic infective disease may flare up in the presence of a
decreased immunocompetence. Other items from the history are the
duration of tracheal or nasal intubation, mechanical ventilation and
indwelling central venous catheters. You will want to know how long these
different foreign bodies have been in place as a pointer to the likelihood of
infection.
The physical signs of nosocomial infections can be subtle particularly in the patient with
neutropenia or other causes of immune-suppression. In mechanically ventilated patients, the
physical signs of ventilator-associated pneumonia may be manifested primarily by purulent
sputum on tracheal suction. A decrease in oxygenation may suggest pneumonia or
pulmonary embolism. Catheter-related infection may be accompanied by redness and
discharge from the insertion site but occurs in the absence of such signs. In surgical
patients, wound dressings should be removed to inspect wounds if they have not been seen
by clinical staff during a scheduled dressing change on that day. Wounds may need to be
opened in case of suspected infection. Drain fluids should be examined for turbidity.
Clostridium difficile infection and pseudomembranous colitis should be considered in any
patient with fever and diarrhoea.

Is fundoscopy or other specific physical examination procedure useful
in the ‘septic work-up’ (see below) and why?
Figure 1:Approach to the febrile patient in
the ICU
COMPLETE TASK THEN CLICK TO REVEAL THE ANSWER
 
Fundoscopic and skin examination may point to evidence of (septic) emboli.
Candidaemia may be more likely if there is widespread Candida infection
and endophthalmitis. There may be evidence of decubitus ulcers and/or skin
fold infection. The appearance of a new murmur may suggest endocarditis. 
The septic work-up or diagnostic approach to new onset fever in the critically
ill can be summarised as above.
In text References
(Dimopoulos and Falagas. 2009) 
This figure, and a number of the figures used below, are slides in the recommended ESICM
Flash Conference:
George Dimopoulos. Late fever in an ICU patient, Barcelona, 2010.
 
https://collaboration.esicm.org/dl1153?display
Figure 2:
 
 References
Dimopoulos G, Falagas ME., Approach to the febrile patient in the ICU., 2009,
PMID:19665078
2. 3. Fever – notable features and measurement
Prior to assessment, you will wish to confirm the presence of fever and determine its
severity. Body temperature is an important diagnostic component of ICU severity scores and
helps the diagnosis of sepsis, SIRS,VAP etc. Response to fever varies with age. In children
between the ages of six months and six years, febrile convulsions may occur. Elderly
patients are unable to regulate their body temperature to the same degree as young adults,
making them susceptible to extremes of temperature – older patients with serious infections
have a substantial prevalence of apyrexia (20% to 30%) and a lower febrile response than
younger patients. A lack of fever may contribute to lower resistance to infection, delayed
recovery, and suboptimal outcome while lower febrile responses to infection are associated
with a higher mortality rate and poorer prognosis especially in ICU patients with traumatic
brain injury or postoperative patients. Hypothermia has also other negative effects such as
electrolyte disorders, insulin resistance, arrhythmias and coagulation disorders. Core
temperature measurement is, of course, the gold standard and several methods may be
used in the ICU, involving the placement of a thermistor or similar device in the pulmonary
(or femoral) artery, the bladder or the oesophagus. In practice, however, surrogate site
(rectal, oral or axillary) temperature measurement is often used (Table 1).
Table 1: Measurement of fever using different techniques at different body sites
Site Method Comments
Potential
problems
https://collaboration.esicm.org/dl1154?display
https://www.ncbi.nlm.nih.gov/pubmed/19665078
Pulmonary artery catheter, PICCO
Mixed venous
blood
Core
temperature
but pulmonary
artery catheter
required,
aseptic
insertion
Blood stream
infection
Bladder measurement Thermometer
Core
temperature
but ‘Foley’
catheter
required,
aseptic
insertion
The effect of
oliguria unknown
Oesophageal measurement Probe
Core
temperature
but difficult to
insert, training
required
Fluids passing
may alter the
temperature
Infrared ear Thermometer
Values a few
tenths below
values in the
pulmonary
artery catheter
and brain
Rectal temperature
Mercury
thermometer
or electrical
probe, should
be placed 4
cm inside
rectum
A few tenths
higher than
(and lags
behind) core
temperature.
Unpleasant and
intrusive for
patients
Not proper for
rapid temperature
variations
Oral measurement
Thermometer,
should be
placed in
posterior
sublingual
pocket
Influenced by
warmed gases
delivered by
respiratory
devices, by
eating and
drinking
Accuracy is not
affected by oral or
mouth breathing,
administration of
oxygen
Axillary measurement Thermometer
Underestimates
core
temperature,
lacks
reproducibility
Possibly affected
by ambient
temperature, local
factors such as
local blood flow,
sweat,
inappropriate
placement of
probe
Whether shell or ‘non-core’ temperature can be considered a practical equivalent to core
temperature is controversial. Rectal temperature (although sometimes classified as a ‘core’
temperature) may lag behind rapid changes in actual core temperature and therefore is not
regarded as a ‘real-time’ measurement of core temperature. Axillary and oral methods are
less reliable in reflecting core temperature. Cold liquids, among others, may confound oral
temperatures. Infrared tympanic membrane temperature measurement devices have gained
some popularity but in the study below, oral thermometry was found to be more accurate
when a pulmonary artery core measurement was not available. In addition, in patients with
head injury or cerebral bleeding/stroke, brain and thus tympanictemperature may exceed
core temperature, but the clinical significance is unknown.
Challenge
Review the practice in your department concerning temperature measurement. When
exploring the pros and cons, how do you rate the practice in your ICU?
In text References 
(Stavem, Saxholm and Smith-Erichsen. 1997; Giuliano et al. 1999) 
Anecdote
An 86-year-old lady with multiple trauma receiving mechanical ventilation for two weeks
develops fever (green line, °C), without tachycardia (blue line, b/min). The recording is from
the bedside computer monitor, visualising continuous measurements (vertical lines are
days). There is a diurnal pattern. The diagnosis made was ventilator-associated pneumonia
attributable to Pseudomonas aeruginosa. The blue arrow indicates the day of starting
piperacillin and tobramycin, and the ‘lytic’ resolution of the fever is illustrated.
Figure 3: Heart rate b/min and Body temperature
C
 
 References
https://collaboration.esicm.org/dl1155?display
Stavem K, Saxholm H, Smith-Erichsen N., Accuracy of infrared ear thermometry
in adult patients., 1997, PMID:9037647
Giuliano KK, Scott SS, Elliot S, Giuliano AJ., Temperature measurement in
critically ill orally intubated adults: a comparison of pulmonary artery core,
tympanic, and oral methods., 1999, PMID:10548205
2. 4. Laboratory appraisal
The clinical assessment is supplemented by selected laboratory measurements. The
commonest of these is the leukocyte and differential counts, as signs of infection include
leukocytosis and a ‘left shift’. Investigators have searched for specific ‘sepsis’ markers
including circulating C-reactive protein, procalcitonin and the cytokine, interleukin-6.
Although the exact predictive values remain uncertain, some of these plasma factors can
help to forecast the likelihood of microbial infection in a patient with fever, before the results
of Gram stains, and particularly microbiological cultures, are available. On day six after
trauma or surgery, development of fever and persistently high circulating IL-6 and C-reactive
protein levels may be predictive for nosocomial infection. Similarly, the detection of
endotoxaemia by means of rapid assay techniques may be of some predictive value in
Gram-negative infection/bacteraemia and its associated morbidity.
The following papers address the (limited) value of surrogate indicators of microbial
infection.
In text References
(Fassbender et al. 1993; Ugarte et al. 1999; Heyland et al. 2011; Samraj, Zingarelli and
Wong. 2013) 
 
 References
Fassbender K, Pargger H, Müller W, Zimmerli W., Interleukin-6 and acute-phase
protein concentrations in surgical intensive care unit patients: diagnostic signs in
nosocomial infection., 1993, PMID:8339583
Ugarte H, Silva E, Mercan D, De Mendonça A, Vincent JL., Procalcitonin used as
a marker of infection in the intensive care unit., 1999, PMID:10199528
Heyland DK, Johnson AP, Reynolds SC, Muscedere J., Procalcitonin for reduced
antibiotic exposure in the critical care setting: a systematic review and an
economic evaluation., 2011, PMID:21358400
Samraj RS, Zingarelli B, Wong HR., Role of biomarkers in sepsis care., 2013,
PMID:24088989
https://www.ncbi.nlm.nih.gov/pubmed/9037647
https://www.ncbi.nlm.nih.gov/pubmed/10548205
https://www.ncbi.nlm.nih.gov/pubmed/8339583
https://www.ncbi.nlm.nih.gov/pubmed/10199528
https://www.ncbi.nlm.nih.gov/pubmed/21358400
https://www.ncbi.nlm.nih.gov/pubmed/24088989
2. 5. Imaging
Bedside chest radiography is routinely used to detect new pulmonary infiltrates in the ICU.
In this condition and in sinusitis, CT scan is associated with fewer false negative results than
plain radiography. The benefits of CT, however, only rarely outweigh the inconvenience and
risk of transferring the patient to the radiology department (see later sections for further
discussion). 
Other imaging techniques include ultrasonography. Transoesophageal echocardiography
can be of help for detecting pulmonary emboli and valvular lesions in endocarditis. Nuclear
techniques can supplement other imaging studies, including CT and ultrasound, but are
rarely used in critically ill patients with fever of unknown origin.
In text References
(Dumarey et al. 2006) 
 References
Dumarey N, Egrise D, Blocklet D, Stallenberg B, Remmelink M, del Marmol V,
Van Simaeys G, Jacobs F, Goldman S., Imaging infection with 18F-FDG-labeled
leukocyte PET/CT: initial experience in 21 patients., 2006, PMID:16595496
2. 6. Culture techniques
Specimens from sites of suspected infection, together with blood samples when indicated,
should be obtained as a matter of course for Gram stain, culture and sensitivity
determinations. Taking cultures should precede the use of empirical antibiotics unless undue
delays are anticipated. Aspiration of pleural fluid or ascites may indicate potential sites of
infection. Aspiration of localised fluid collections or abscesses can be guided by
ultrasonography or CT scans.
 Think
What are the indications for these types of radiological investigations and who is the
best person to approach for advice in your institution?
Blood should be obtained percutaneously via venepuncture (or via ‘clean-stick’, newly
introduced arterial or central venous catheters), and 10 ml placed in each of two bottles for
aerobic/anaerobic cultures. At least two to three sets, 10 minutes apart, should be taken,
after proper skin preparation.
In text References
https://www.ncbi.nlm.nih.gov/pubmed/16595496
(Shafazand and Weinacker. 2002) 
 References
Shafazand S, Weinacker AB., Blood cultures in the critical care unit: improving
utilization and yield., 2002, PMID:12426278
2. 7. Molecular techniques
The importance of timely diagnosis of severe infections has been often emphasised
especially in recent sepsis guidelines. Blood culture diagnosis often delay or they produce
false negative results. To overcome these limitations, molecular diagnostic techniques have
been developed. Based on Polymerase Chain Reaction (PCR) these methods may offer the
advantage of diagnosis in 6 hours also providing some important information about the
presence of resistant mechanisms. The place of these diagnostic methods in the ICU
remains to be defined.
 
In text References 
(Dark et al. 2015; Vincent et al. 2015) 
 References
Dark P, Blackwood B, Gates S, McAuley D, Perkins GD, McMullan R, Wilson C,
Graham D, Timms K, Warhurst G., Accuracy of LightCycler(®) SeptiFast for the
detection and identification of pathogens in the blood of patients with suspected
sepsis: a systematic review and meta-analysis., 2015, PMID:25416643
Vincent JL, Brealey D, Libert N, Abidi NE, ODwyer M, Zacharowski K,
Mikaszewska-Sokolewicz M, Schrenzel J, Simon F, Wilks M, Picard-Maureau M,
Chalfin DB, Ecker DJ, Sampath R, Singer M,Rapid Diagnosis of Infections in the
Critically Ill Team., Rapid Diagnosis of Infection in the Critically Ill, a Multicenter
Study of Molecular Detection in Bloodstream Infections, Pneumonia, and Sterile
Site Infections., 2015, PMID:26327198
2. 8. Microbiology
The commonly identified micro-organisms causing infections in the ICU include Gram-
negative bacilli (mainly Enterobacteriaceae, Klebsiella, Pseudomonas, Acinetobacter and
Serratia spp.), Gram-positive bacteria such as coagulase-negative staphylococci and S.
aureus and Candida albicans.
 Note
Organisms should always be considered in the specific clinical context when making
‘best guess’ therapeutic decisions.
https://www.ncbi.nlm.nih.gov/pubmed/12426278
https://www.ncbi.nlm.nih.gov/pubmed/25416643
https://www.ncbi.nlm.nih.gov/pubmed/26327198
Blood culture results with S. epidermidis are considered clinically ‘significant’, if present in
more than one bottle and are rapidly growing in culture. Candida spp. may cause catheter-
related blood stream infections, wound infections, and peritonitis. Culture of Candida spp.
may, of course, represent colonisation as opposed to infection, but there are no commonly
accepted criteria to separate these conditions. Candiduria exceeding105 colony forming
units/mL in two urine specimens taken before and after change of a bladder catheter in a
patient with clinical signs of sepsis may point to Candida as the aetiology. A high Candida
colony count in urine, recovery from two or more otherwise sterile sites (excluding urine and
sputum) may point to Candida sepsis in the febrile ICU patient with leukocytosis (>12.0 x
109/L). Candidaemia (e.g. after change of intravascular catheters) is indicative of infection.
Candida endophthalmitis, oesophagitis, suppurative thrombophlebitis or wound
infections/peritonitis (‘open abdomen’) may be the source of deep Candida infections.
Further relevant details are to be found in the following reference.
In text References
(Holley et al. 2009) 
Viral infections causing pneumonia, even in critically ill, immunocompromised (or
immunocompetent) patients, are rare. Herpes virus, cytomegalo, adeno- or respiratory
syncytial viruses or Chlamydia spp. are considered the most frequent causes.
In text References
(Jaber et al. 2005; Limaye et al. 2008; Chiche et al. 2009) 
 Think
about the common clinical contexts relevant to these specific organisms. When do
you think viral reactivation is harmful and when not?
Why is viral reactivation important in clinical management?
COMPLETE TASK THEN CLICK TO REVEAL THE ANSWER
 In order to make an informed decision as to appropriate ‘best guess’
antibiotic treatment.
 Note
Rare fungal infections developing in the critically ill may include Aspergillus fumigatus
lung infections after near drowning or in the neutropenic/organ transplant patient with
underlying haematologic malignancy or immunosuppression. A rare cause of bilateral
sinusitis may be infection with Rhizopus (mucormycosis), particularly in diabetics, as
illustrated in the references below.
For further insight into the evolution of microbiology of nosocomial bacteraemia in the ICU
and opportunistic infections in surgical patients
In text References
(Gans et al. 1989; Dimopoulos and Vincent. 2002; Fishman 2007; Edgeworth, Treacher and
Eykyn. 1999; Dunn 2000) 
 References
Holley A, Dulhunty J, Blot S, Lipman J, Lobo S, Dancer C, Rello J, Dimopoulos
G., Temporal trends, risk factors and outcomes in albicans and non-albicans
candidaemia: an international epidemiological study in four multidisciplinary
intensive care units., 2009, PMID:19167196
Jaber S, Chanques G, Borry J, Souche B, Verdier R, Perrigault PF, Eledjam JJ.,
Cytomegalovirus infection in critically ill patients: associated factors and
consequences., 2005, PMID:15653989
Limaye AP, Kirby KA, Rubenfeld GD, Leisenring WM, Bulger EM, Neff MJ, Gibran
NS, Huang ML, Santo Hayes TK, Corey L, Boeckh M., Cytomegalovirus
reactivation in critically ill immunocompetent patients., 2008, PMID:18647984
Chiche L, Forel JM, Roch A, Guervilly C, Pauly V, Allardet-Servent J, Gainnier M,
Zandotti C, Papazian L., Active cytomegalovirus infection is common in
mechanically ventilated medical intensive care unit patients., 2009,
PMID:19384219
Gans RO, Strack van Schijndel RJ, Laarman DA, Stilma JS, Thijs LG., Fatal
rhinocerebral mucormycosis and diabetic ketoacidosis., 1989, PMID:2492643
Dimopoulos G, Vincent JL. , Candida and Aspergillus infections in critically ill
patients, 2002, https://www.tandfonline.com/doi/abs/10.3109/tcic.13.1.1.12?
journalCode=icic20
Fishman JA, Infection in solid-organ transplant recipients., 2007, PMID:18094380
Edgeworth JD, Treacher DF, Eykyn SJ., A 25-year study of nosocomial
bacteremia in an adult intensive care unit., 1999, PMID:10470744
Dunn DL, Diagnosis and treatment of opportunistic infections in
immunocompromised surgical patients., 2000, PMID:10695740
2. 9. Systemic inflammatory response syndrome (SIRS)
 
In any patient with fever, one has to consider the likelihood of microbial infection and sepsis
as opposed to SIRS which has been defined as:
1. Fever (>38°C) or hypothermia (<36°C)
2. Tachycardia (>90 b/min)
3. Tachypnoea (>20/min), or fall in arterial PCO2 (<32mmHg)
4. Leukocytosis (>12.0 x 109/L) or leukopenia (<4.0 x 109/L) or >10% immature (band)
forms.
See module on Sepsis and Septic Shock .
https://www.ncbi.nlm.nih.gov/pubmed/19167196
https://www.ncbi.nlm.nih.gov/pubmed/15653989
https://www.ncbi.nlm.nih.gov/pubmed/18647984
https://www.ncbi.nlm.nih.gov/pubmed/19384219
https://www.ncbi.nlm.nih.gov/pubmed/2492643
https://www.tandfonline.com/doi/abs/10.3109/tcic.13.1.1.12?journalCode=icic20
https://www.ncbi.nlm.nih.gov/pubmed/18094380
https://www.ncbi.nlm.nih.gov/pubmed/10470744
https://www.ncbi.nlm.nih.gov/pubmed/10695740
https://collaboration.esicm.org/Sepsis%20and%20Septic%20Shock
 
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host
response to infection. Infection is indicated by a host response to micro-organisms or the
invasion of otherwise sterile host tissues by (replicating) microorganisms. However, the
predictive value of SIRS for severe microbial infection may be poor; specificity is low and
sensitivity high. For example, the criteria are often met in trauma patients even in the
absence of microbial infection. Hence, the clinical value of SIRS is in doubt. Nevertheless,
meeting severe sepsis (organ dysfunction associated with sepsis) septic shock criteria, a
clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain
MAP ≥65 mmHg and having a serum lactate level >2 mmol/L (18 mg/dL) despite adequate
volume resuscitation, or hypotension below 90mmHg in sepsis despite volume resuscitation,
carries a higher mortality rate than meeting SIRS criteria alone, so that the latter
classifications may have prognostic (rather than diagnostic) significance.
 Think
The usefulness of SIRS and sepsis criteria in patients with fever remains unclear. The
sensitivity of the syndrome may be too high and specificity too low for microbial
infection, even when supplemented by other ‘sepsis signs’.
In text References
(Pittet et al. 1995; Bossink et al. 2001; Levy et al. 2001; Singer et al. 2016) 
Challenge
Determine the prevalence (number of cases per total number of patients) and incidence
(number of new cases per total number in a given time period) of SIRS and sepsis in your
ICU population over three days, assuming that criteria must be met within a six-hour time
window. What percentage is associated with positive culture?
 
 References
Pittet D, Rangel-Frausto S, Li N, Tarara D, Costigan M, Rempe L, Jebson P,
Wenzel RP., Systemic inflammatory response syndrome, sepsis, severe sepsis
and septic shock: incidence, morbidities and outcomes in surgical ICU patients.,
1995, PMID:7650252
Bossink AW, Groeneveld AB, Koffeman GI, Becker A., Prediction of shock in
febrile medical patients with a clinical infection., 2001, PMID:11176153
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal
SM, Vincent JL, Ramsay G; International Sepsis Definitions Conference., 2001
SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.,
2001, PMID:12664219
https://www.ncbi.nlm.nih.gov/pubmed/7650252
https://www.ncbi.nlm.nih.gov/pubmed/11176153
https://www.ncbi.nlm.nih.gov/pubmed/12664219
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M,
Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM,
Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL,
Angus DC., The Third International Consensus Definitions for Sepsis and Septic
Shock (Sepsis-3)., 2016, PMID:26903338
https://www.ncbi.nlm.nih.gov/pubmed/26903338
3. Determining The Cause Of Fever In The Critically
Ill Patient
Causes of fever of recent onset in the critically ill patient may be infective or non-infective.
Infective causes 
Common:
1. Ventilator-associated pneumonia (VAP) / hospital acquired pneumonia (HAP)
2. Catheter-related infection (CRIs)
3. Ventilator-associated tracheobronchitis (VAT)
Less common:
1. Upper respiratory tract infection and sinusitis
2. Gastrointestinal infection: Clostridium difficile3. Urinary tract infection
4. Acalculous cholecystitis
5. Primary Gram-negative bacteraemia
6. Candidaemia
7. Intra-abdominal infection / peritonitis
8. Decubitus ulcers
9. Wound infection / cellulitis
10. Endocarditis
11. Pericarditis
12. Empyema
13. Infected implants (like pacemaker)
14. Tropical infection (malaria or others).
Non-infective causes 
Common:
1. Acute respiratory distress syndrome (ARDS)
2. Pulmonary aspiration
3. Postoperative fever (<48h)
4. Phlebitis / thrombophlebitis
5. Febrile non-haemolytic red cell and platelet transfusion reactions
6. Alcohol withdrawal
7. Acute pancreatitis.
8. Trauma
9. Haematoma
10. Cerebral disease, including subarachnoid haemorrhage
11. Thromboembolism
12. Gastrointestinal bleeding
13. Neoplasia, including lymphoma
Less common:
1. Drug-induced fever
2. Drug withdrawal
3. Ischaemia of the bowel / ischaemic colitis
4. Fat embolism
5. Systemic lupus erythematosus
6. Neurogenic fever after acute traumatic spinal cord injury
7. Neuroleptic malignant syndrome
8. Serotonin syndrome
9. Malignant hyperthermia
10. Gout
11. Transplant rejection
12. Myocardial infarction
13. Addisonian crisis, acute adrenocortical insufficiency
In text References
(Vincent et al. 2009; OGrady et al. 2008; Rehman and deBoisblanc. 2014; Niven and
Laupland. 2016; Dimopoulos. 2011) 
 References
OGrady NP, Barie PS, Bartlett JG, Bleck T, Carroll K, Kalil AC, Linden P, Maki
DG, Nierman D, Pasculle W, Masur H, 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., 2008,
PMID:18379262
Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, Moreno R, Lipman
J, Gomersall C, Sakr Y, Reinhart K, EPIC II Group of Investigators., International
study of the prevalence and outcomes of infection in intensive care units., 2009,
PMID:19952319
Rehman T, deBoisblanc BP., Persistent fever in the ICU., 2014, PMID:24394828
Niven DJ, Laupland KB., Pyrexia: aetiology in the ICU., 2016, PMID:27581757
Dimopoulos G. , Fever in critically ill patients. , 2011,
https://www.escmid.org/escmid_publications/escmid_elibrary/material/?mid=904
3. 1. Infective causes
3. 1. 1. Ventilator-associated pneumonia / Hospital-acquired pneumonia
The longer the duration of stay in ICU / on mechanical ventilation, there are greater the risk
of developing HAP / VAP. Early diagnosis and effective treatment is associated with a lower
morbidity and mortality. Recently, the concept of healthcare-associated pneumonia (HCAP)
has been removed.
https://www.ncbi.nlm.nih.gov/pubmed/18379262
https://www.ncbi.nlm.nih.gov/pubmed/19952319
https://www.ncbi.nlm.nih.gov/pubmed/24394828
https://www.ncbi.nlm.nih.gov/pubmed/27581757
https://www.escmid.org/escmid_publications/escmid_elibrary/material/?mid=904
There is still no gold standard test for diagnosing VAP / HAP. Confirmation of the clinical
diagnosis includes developing fever, leukocytosis or leukopenia, impaired oxygenaton,
purulent sputum and a new infiltrate on chest radiography.
As per international clinical practice guidelines for the management of HAP and VAP 2017
international guidelines by European Respiratory Society (ERS), European Society of
Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious
Diseases (ESCMID) and Asociacion Latinoamericana del Torax (ALAT), and 2016 clinical
practice guidelines by the Infectious Diseases Society of America (IDSA) and the American
Thoracic Society (ATS), recommendations are:
Diagnosis of VAP / HAP:
Sampling for microbiological culture:
As per European guidelines: For VAP, obtain a lower respiratory tract sample (distal
quantitative or proximal quantitative or qualitative culture), preferably prior to any antibiotic
treatment (in stable patients).
As per American guidelines: For VAP, non-invasive respiratory sampling (endotracheal
aspiration) with semi-quantitative cultures is preferred, rather than quantitative cultures on
samples collected via either non-invasive method or invasive methods (i.e. bronchoalveolar
lavage (BAL), protected specimen brush (PSB) and blind bronchial sampling i.e. mini-BAL).
For HAP diagnosis, consider non-invasive methods to collect respiratory samples, which
may include spontaneous expectoration, sputum induction or nasotracheal suctioning.
Role of biomarkers to diagnose VAP / HAP:
Use clinical criteria alone to diagnose VAP / HAP, rather than using clinical criteria plus
biomarkers (Procalcitonin (PCT), Soluble Triggering Receptor Expressed on Myeloid Cells
(sTREM) or C-Reactive Protein CRP).
Role of the Clinical Pulmonary Infection Score (CPIS) to diagnose VAP/ HAP:
Use clinical criteria alone to diagnose VAP / HAP, rather than using clinical criteria plus CPIS
to decide whether or not to initiate antimicrobials.
Initial treatment of VAP / HAP: 
It is recommended that use clinical criteria alone, rather than using clinical criteria plus
CPIS/ biomarkers to decide whether or not to initiate antibiotic therapy.
There is recommendation that all hospitals should generate and disseminate a local
antibiogram on regular basis, which will help in tailoring in selection of an empiric antibiotic
regimen. It is also recommended that empiric treatment should have coverage for S. aureus,
Pseudomonas aeruginosa, and other Gram-negative bacilli.
If invasive quantitative cultures are available, and are below the threshold (PSB with <103
CFU/ml or BAL with <104CFU/ml), then antibiotics should be withheld rather than continued.
Also, antibiotic therapy should not be given for ventilator-associated tracheobronchitis (VAT).
In absence of risk factors for multidrug-resistant pathogens, use empiric antibiotic active
against methicillin-sensitive S. aureus (MSSA), not MRSA, like piperacillin+tazobactam,
cefepime, levofloxacin, imipenem or meropenem. Consider prior intravenous antibiotic use
within 90 days, as a risk factor for multidrug-resistant pathogen. Other risk factors for
multidrug-resistant pathogens includes: presence of septic shock, ARDS, more than 5 days
of hospitalisation or on renal replacement therapy. In these patients with VAP / HAP, select
empiric antibiotic to cover MRSA (vancomycin or linezolid) and MDR Pseudomonas
(antipseudomonal activity β-lactam-based agents or Non-β-lactam-based agents). Also,
ICUs where >10%-20% of S. aureus isolates are methicillin resistant, coverage for MRSA
should be considered. Similarly, ICUs where >10% of gram-negative isolates are MDR,
consider to use 2 antipseudomonal antibiotics.
Antibiotic dosing should be determined by pharmacokinetic/ pharmacodynamic (PK/PD)
data.
Tailoring antibiotics after culture report: 
Guidelines suggest for tailoring antibiotic therapy once microbiological susceptibility report is
available.
If initial combination antibiotic therapy is started, then narrow to single agent as per culture
report. Consider continuation of combination therapy in patients with extensively drug
resistant (XDR, i.e. susceptibility to only one or two classes of antibiotics), or pan-drug
resistant (PDR, i.e. not susceptible to any antibiotic) or non-fermenting Gram-negative
bacteria, or Carbapenem-resistant Enterobacteriaceae (CRE) isolates. 
Avoid aminoglycoside / polymyxins, if alternative agents with gram-negative activity are
available. In patients with VAP due to gram-negative bacilli that are susceptible to only
aminoglycosides or polymyxins, consider for both inhaled and systemic antibiotics, rather
than systemic antibiotics alone.
Duration of antibiotics: 
In stable patients having HAP (no clinical deterioration within 72 hours at symptoms onset),
avoid routine use of antibiotic for more than 3 days.
In patients having VAP, including non-fermenting Gram-negative, Acinetobacter spp. and
MRSA, use 7-8 days course of antibiotic instead of 14 days.
Consider longer duration of antibiotictherapy in patients with immunodeficiency, cystic
fibrosis, empyema, lung abscess, cavitation, necrotising pneumonia, XDR/ PDR pathogen,
carbapenem-resistant Acinetobacter spp., CRE, MRSA bacteremia or initial inappropriate
antibiotic therapy.
Routine measurement of serial serum PCT is not recommended to reduce duration of
antibiotic therapy. Experts suggest that in patients requiring longer duration of antibiotic
therapy (in specific population), serial serum PCT levels together with clinical assessment
could be considered with the aim of reducing antibiotic therapy duration.
Selective oral decontamination (SOD) or selective digestive decontamination (SDD)
for VAP prevention: 
European guidelines do not recommend the use of non-absorbable antibiotic/ chlorhexidine
to perform SOD, or non-absorbable antimicrobials as SDD, in patients requiring mechanical
ventilation for >48 hours, to reduce incidence of VAP.
However, experts suggest the use of SOD, but not SDD, in settings with low rates of
antibiotic-resistant bacteria (<5%) or where there is low antibiotic consumption in the ICU
(<1000 daily doses per 1000 admission days).
In text References
(Torres et al. 2017; Kalil et al. 2016; Kalil et al. 2016) 

Look at the chest radiographs of this ICU patient who developed fever
of 38.5 °C and a deterioration in their oxygenation. The initial CXR is on
the left and shows right lower lobe volume loss and some patchy
infiltrates; the CXR on the right was taken 48 hours later. The patient
was a 72-year-old male with cerebellar haemorrhage, a tracheal tube for
mechanical ventilation and his sputum had become purulent. Interpret
the CXRs and give your presumptive diagnosis.
Figure 4:
COMPLETE TASK THEN CLICK TO REVEAL THE ANSWER
 The chest radiograph two days later (right), shows the development of
a pleural effusion. Taking the radiological infiltrates together with the clinical
signs (purulent secretions, gas-exchange deterioration and fever), there is
presumptive evidence of VAP.
 How would you prove a diagnosis of VAP?
https://collaboration.esicm.org/dl1156?display
COMPLETE TASK THEN CLICK TO REVEAL THE ANSWER
 Other than clinical signs and symptoms for VAP, microbiological proof
may be obtained by a positive culture from noninvasive respiratory sampling
(endotracheal aspiration). In this instance, the cultures of tracheal aspirate
and pleural fluid yielded Serratia marcescens which was subsequently
successfully treated by piperacillin+tazobactam.
3. 1. 2. Central venous catheter-related infections
Central line: As per the CDC (Centers for Disease Control and Prevention), a central line is
defined as an intravascular catheter that terminates at, close to the heart, or in one of the
great vessels, that is used for infusion, withdrawal of blood, or haemodynamic monitoring. 
Examples for great vessels include: superior vena cava, inferior vena cava, brachiocephalic
veins, internal jugular veins, subclavian veins, external iliac veins, common iliac veins,
femoral veins, the aorta, and the pulmonary artery. 
As per the CDC, arterial catheters*, intra-aortic balloon pump (IABP) devices, non-accessed
central line (not accessed nor inserted during the hospitalisation) are not considered a
central line. Pacemaker wires and other non-lumened devices inserted into central blood
vessels or the heart are not considered central lines, because fluids are not infused,
pushed, nor withdrawn through such devices.
 Note
As per the ECDC (European Centre for Disease Prevention and Control), arterial
catheters are considered as catheters for defining catheter-related blood stream
infection.
Common commensal organism: CDC/ National Hospital Safety Network (NHSN) uses the
term “common commensal organisms” that includes, but is not limited to, coagulase
negative staphylococci (including S. epidermidis), viridans group streptococci, Aerococcus
spp, diphtheroids Corynebacterium spp., Bacillus (not B. anthracis) spp., Propionibacterium
spp and Micrococcus spp.
Eligible central line: A central line that has been in place for more than two consecutive
calendar days (on or after central line day 3), following the first access of the central line, in
an inpatient location, during the current admission. Such lines are eligible for central line-
associated blood stream infection (CLABSI) events and remain eligible for CLABSI events
until the day after removal from the body or patient discharge, whichever comes first.
Central line-associated blood stream infection (CLABSI): A laboratory confirmed
bloodstream infection (BSI) where an eligible BSI organism is identified and an eligible
central line is present for the laboratory confirmed BSI or was present the day before.
Catheter-related blood stream infection (CRBSI): CRBSI is defined as:
1. Clinical manifestation (patient has at least one of the following signs or symptoms:
fever (>38°C), chills, or hypotension)
2. No other apparent source of infection
3. At least one positive blood culture from a peripheral vein
4. Same organism (species and antibiogram) is isolated from the catheter segment
and a peripheral blood sample either positive semi-quantitative (>15 CFU/catheter
segment) or quantitative (>103 CFU/catheter segment) culture.
OR 
Simultaneous quantitative cultures of blood samples with a ratio of ≥3:1 (CVC vs. peripheral)
OR 
Differential delay of positivity of blood cultures: central line blood sample culture positive two
hours or more before peripheral blood culture (blood samples drawn at the same time). 
OR 
Positive culture with the same microorganism from pus from insertion site.
 Note
Ratio CVC blood sample/peripheral blood sample >5. As per ECDC (Surveillance of
healthcare-associated infections and prevention indicators in European intensive care
units. May 2017)
 Note
This criteria as per ECDC,
Local CVC-related infection (no positive blood culture): 
Quantitative CVC culture >103 CFU/ml or semi-quantitative CVC culture >15 CFU 
AND 
Pus/ inflammation at the insertion site or tunnel
General CVC-related infection (no positive blood culture): 
Quantitative CVC culture >103 CFU/ml or semi-quantitative CVC culture >15 CFU 
AND 
Clinical signs that improve within 48 hours after catheter removal
In text References
(Centers for Disease Control and. 2018; European Centre for Disease Prevention and
Control ). 2017) 
Incidence of CRBSI 
Depending on the type of unit and patient, among other factors, the rate of catheter-related
blood stream infection varies between 0 and 33% (mean 5%) of catheters, or an incidence
density of 2.8 to 12.8 episodes per 1000 catheter days.
 Note
Central venous catheter-related sepsis is preventable!
Implementation of a multiple approach prevention strategy can decrease the number of
catheter blood stream infections from 11.3 episodes per 1000 patient days to 3.8 episodes.
Prevention of catheter-related infection is of utmost importance.
In text References
(OGrady et al. 2011; O'Grady et al. 2011; Miller, OGrady and Society of Interventional. 2012;
Eggimann et al. 2000; Pronovost et al. 2006) 
Challenge
What is the incidence of central venous catheter-related infection in your unit and does this
necessitate a change of insertion and maintenance policy? 
Complications of catheter-related infection other than severe sepsis and septic shock
include endocarditis, and metastatic abscesses, thrombosis and suppurative phlebitis.
Management of CRI 
Treatment is outside the scope of this module but the guidelines on the management of CRI
of the Infectious Diseases Society of America (IDSA) is recommended and is available
(Mermel et al. 2009) .
3. 1. 3. Sinusitis
Nasogastric and nasotracheal tubes are important risk factors, and should be removed if
present during treatment of sinusitis. Prolonged nasotracheal intubation is particularly
associated with sinusitis; this type of airway is often converted to an oral tube when
prolonged intubation is anticipated. Sinusitis is a risk factorfor ventilator-associated
pneumonia (VAP). Hence, a search for and treatment of sinusitis in febrile patients may
prevent VAP and associated mortality. Fever and purulent nasal discharge in the presence
of nasal tubes may point to nosocomial sinusitis. The maxillary sinuses are most commonly
affected, but sphenoidal or ethmoidal sinusitis, whether or not accompanied by maxillary
sinusitis, is increasingly recognised.
The diagnosis is difficult, even in the case of maxillary sinusitis, since bedside plain
radiograms (Caldwell and Waters’ view) may not be sensitive and specific. This may be
overcome by a CT scan. Opacification or fluid-air levels necessitate needle aspiration,
microscopy and culture of secretions to confirm a radiologic diagnosis. Only half the patients
with a radiological diagnosis are confirmed to have sinusitis on aspiration. A radiological
diagnosis is confirmed on aspiration if staining and culture yield neutrophils and micro-
organisms at a concentration >103 CFU/ml. Gram-negative bacteria are often involved, and
polymicrobial infections are relatively common.
Endoscopically directed middle meatal cultures have been found better in comparison to
computed tomographic scans in the diagnosis of sinusitis. A-mode ultrasound also, has
been found useful in evaluation of maxillary sinusitis.
Treatment of maxillary sinusitis includes needle aspiration, lavage and, sometimes, systemic
antibiotics. The clinical and radiographic features of infection should abate within a few
days, following the start of appropriate treatment. Rarely, persistent or recurrent sinusitis
http://www.idsociety.org/Index.aspx
may necessitate surgical exploration.
In text References
(van Zanten et al. 2005; Konen et al. 2000; Elwany et al. 2012; Boet et al. 2010; Vargas et
al. 2006) 

Considering the risks involved in transporting a critically ill patient to
the radiology department, in what circumstances might it be justified to
perform a CT examination to confirm a diagnosis of sinusitis?
COMPLETE TASK THEN CLICK TO REVEAL THE ANSWER
 If the patient has to be transported for investigation of another major
problem. Some institutions may also perform a CT scan when sinusitis
persists or recurs despite adequate treatment (drainage and lavage) for 72h.

Examine this CT scan from a 54-year-old male admitted because of
respiratory insufficiency in the course of Legionella pneumonia. Day 11
of mechanical ventilation was complicated by fever, leukocytosis, and
purulent nasal discharge, in spite of systemic antibiotics. What is your
presumptive diagnosis and how would you prove it?
Figure 5:
COMPLETE TASK THEN CLICK TO REVEAL THE ANSWER
 The CT scan demonstrates fluid levels in both maxillary sinuses. The
diagnosis of sinusitis can be confirmed if aspiration reveals microscopic and
culture evidence for bacterial infection. Specimens obtained by aspiration
https://collaboration.esicm.org/dl1157?display
revealed some leukocytes on Gram staining and Gram-positive cocci.
Cultures from both sinuses grew Candida albicans. The condition cleared
following repeated lavages.
3. 1. 4. Urinary tract infections
Most critically ill patients will have indwelling urinary bladder catheters. Nevertheless, a
urinary tract infection is rarely the cause of fever in the critically ill, even though colonisation
(bacteriuria at >105 CFU/ml) is common. Fever, leukocytosis, pyuria and a known pathogen
in urine with the same pathogen cultured from blood points to a urinary tract infection in the
febrile critically ill patient that should be treated by antibiotics. 
As per IDSA (Infectious Diseases Society of America) guidelines, catheter-associated
urinary tract infection (CA-UTI) is defined by the presence of symptoms or signs compatible
with UTI with no other identified source of infection, along with ≥103 CFU/ml of ≥1 bacterial
species in a single catheter urine sample. While catheter associated asymptomatic
bacteriuria (CA-ASB) is defined by the presence of ≥105 CFU/ml of ≥1 bacterial species in a
single catheter urine sample without presence of symptoms compatible with UTI. The urine
culture should be obtained from the freshly placed catheter. 
Empirical antibiotic treatment does not improve outcome in CA-UTI. Obstructed catheters
should be replaced.
In text References
(Sampathkumar 2017; Babich T Zusman et al. 2017; Hooton et al. 2010) 
3. 1. 5. Acute acalculous cholecystitis
After multiple trauma, burns, severe sepsis and major surgery, the gallbladder may become
inflamed in the absence of gall stones. This inflammation, called acalculous cholecystitis,
has an estimated incidence of 1.5% especially in septic patients or in patients recovering
from abdominal sepsis. The low incidence is probably because of the non-specific clinical
signs (pain in the right upper quadrant and nausea) and laboratory work-up. The detected
wall thickness >3 mm, intramural lucencies, gallbladder distension, pericholecystic fluid, and
intramural sludge are helpful radiological findings, while hepatobiliaryscintigraphy is
characterised by a high false-positive rate (>50%). Frequently, the diagnosis is delayed and
the disease progresses to ischaemia, gangrene and perforation, indicating the necessary
high index of suspicion while the treatment of choice is cholecystectomy. However, in very
unstable patients, radiologic percutaneous drainage (cholecystostomy) may be preferred as
a temporary measure and has replaced surgical cholecystectomy as a first choice treatment
in many centres. In many patients, antibiotics will be prescribed, aimed at the causative
organism, identified after percutaneous puncture and culture of the bile. Recent studies
have questioned routine use of abdominal ultrasonography to look for acalculous
cholecystitis in ICU patients.
In text References
(Myrianthefs et al. 2012; Boland et al. 2000) 
3. 1. 6. Clostridium difficile infection (CDI)
Clostridium difficile infection (CDI) has become a prevalent problem in many ICUs. In milder
forms of the infection, diarrhoea may be the only feature. C. difficile -related diarrhoea is a
relatively frequent occurrence in the critically ill, particularly if there has been treatment with
multiple courses of broad-spectrum antibiotics. Other features of the disease includes ileus,
toxic megacolon (>6 cm in transverse width of colon), pseudomembranous colitis diagnosed
during endoscopy, shock, marked leukocytosis, decreased serum albumin and elevated
creatinine.
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) suggest that
at least all submitted unformed stool samples (formed stool in case of paralytic ileus) from
patients (3 years or older) should be tested for CDI. As per current recommendations for the
diagnosis of CDI, a 2-step algorithm is used. Step 1: highly sensitive test NAAT (nucleic acid
amplification test) or GDH (glutamate dehydrogenase) enzyme immunoassays; Step 2:
highly specific test Toxin A/B enzyme immunoassays.
Oral metronidazole (500 mg three times daily for 10 days) is recommended only for non-
severe disease, and should not be used for severe CDI. For severe disease, use either
vancomycin orally (125 mg four times daily) or fidaxomicin orally (200 mg twice daily) for 10
days. A test of cure is not recommended. In cases of colonic perforation or condition
refractory to antibiotic therapy, surgical treatment (total abdominal colectomy with ileostomy)
should be performed.
The bacteria can be transmitted from patient to staff and vice versa. Alcohol hand cleansing
is regarded as inadequate to clear C difficile spores; a (traditional) physical hand wash is
required.
In text References
(Crobach et al. 2016; Debast et al. 2014; Cohen et al. 2010) 
3. 1. 7. Other causes
Be aware of central nervous system infections in patients with (internal or external)
neurosurgical monitoring or draining devices. Coagulase-negative Staphylococci is often
involved. Suspected infection should prompt obtaining cerebrospinal fluid (CSF) forGram
stain and culture.
 References
Crobach MJ, Planche T, Eckert C, Barbut F, Terveer EM, Dekkers OM, Wilcox
MH, Kuijper EJ., European Society of Clinical Microbiology and Infectious
Diseases: update of the diagnostic guidance document for Clostridium difficile
infection., 2016, PMID:27460910
Debast SB, Bauer MP, Kuijper EJ, European Society of Clinical Microbiology and
Infectious Diseases., European Society of Clinical Microbiology and Infectious
Diseases: update of the treatment guidance document for Clostridium difficile
infection., 2014, PMID:24118601
Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepin J,
Wilcox MH, Society for Healthcare Epidemiology of America, Infectious Diseases
Society of America., Clinical practice guidelines for Clostridium difficile infection
https://www.ncbi.nlm.nih.gov/pubmed/27460910
https://www.ncbi.nlm.nih.gov/pubmed/24118601
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Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB,
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File TM Jr, Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek
JL., Management of Adults With Hospital-acquired and Ventilator-associated
Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society
of America and the American Thoracic Society., 2016, PMID:27418577
Torres A, Niederman MS, Chastre J, Ewig S, Fernandez-Vandellos P, Hanberger
H, Kollef M, Li Bassi G, Luna CM, Martin-Loeches I, Paiva JA, Read RC, Rigau
D, Timsit JF, Welte T, Wunderink R., International ERS/ESICM/ESCMID/ALAT
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associated pneumonia: Guidelines for the management of hospital-acquired
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2017, PMID:28890434
Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB,
Napolitano LM, OGrady NP, Bartlett J, Carratalà J, El Solh AA, Ewig S, Fey PD,
File TM Jr, Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek
JL., Executive Summary: Management of Adults With Hospital-acquired and
Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the
Infectious Diseases Society of America and the American Thoracic Society.,
2016, PMID:27521441
Centers for Disease Control and Prevention., Bloodstream Infection Event
(Central Line-Associated Bloodstream Infection and Non-central Line Associated
Bloodstream Infection), 2018,
https://www.cdc.gov/nhsn/pdfs/pscmanual/4psc_clabscurrent.pdf
European Centre for Disease Prevention and Control (ECDC). , Surveillance of
healthcare-associated infections and prevention indicators in European intensive
care units. HAI-Net ICU protocol, version 2.2. , 2017,
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OGrady NP, Alexander M, Burns LA, Dellinger EP, Garland J, Heard SO, Lipsett
PA, Masur H, Mermel LA, Pearson ML, Raad II, Randolph AG, Rupp ME, Saint S,
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O'Grady NP, Alexander M, Burns LA, Dellinger EP, Garland J, Heard SO, Lipsett
PA, Masur H, Mermel LA, Pearson ML, Raad II, Randolph AG, Rupp ME, Saint S,
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Miller DL, OGrady NP, Society of Interventional Radiology., Guidelines for the
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Eggimann P, Harbarth S, Constantin MN, Touveneau S, Chevrolet JC, Pittet D.,
Impact of a prevention strategy targeted at vascular-access care on incidence of
infections acquired in intensive care., 2000, PMID:10866442
Pronovost P, Needham D, Berenholtz S, Sinopoli D, Chu H, Cosgrove S, Sexton
B, Hyzy R, Welsh R, Roth G, Bander J, Kepros J, Goeschel C., An intervention to
decrease catheter-related bloodstream infections in the ICU., 2006,
PMID:17192537
Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, OGrady NP, Raad II, Rijnders
BJ, Sherertz RJ, Warren DK., Clinical practice guidelines for the diagnosis and
management of intravascular catheter-related infection: 2009 Update by the
Infectious Diseases Society of America., 2009, PMID:19489710
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., 2005, PMID:16277722
Konen E, Faibel M, Kleinbaum Y, Wolf M, Lusky A, Hoffman C, Eyal A, Tadmor
R., The value of the occipitomental (Waters) view in diagnosis of sinusitis: a
comparative study with computed tomography., 2000, PMID:11069741
Elwany S, Helmy SA, El-Reweny EM, Harfoush R, Sobhy A., Endoscopically
directed middle meatal cultures vs computed tomographic scans in the diagnosis
of bacterial sinusitis in intensive care units., 2012, PMID:21798708
Boet S, Guene B, Jusserand D, Veber B, Dacher JN, Dureuil B., A-mode
ultrasound in the diagnosis of maxillary sinusitis in ventilated patients., 2010,
PMID:21090159
Vargas F, Bui HN, Boyer A, Bébear CM, Lacher-Fougére S, De-Barbeyrac BM,
Salmi LR, Traissac L, Gbikpi-Benissan G, Gruson D, Hilbert G., Transnasal
puncture based on echographic sinusitis evidence in mechanically ventilated
patients with suspicion of nosocomial maxillary sinusitis., 2006, PMID:16614810
Sampathkumar P, Reducing catheter-associated urinary tract infections in the
ICU., 2017, PMID:28858916
Babich T Zusman O, Elbaz M, Ben-Zvi H, Paul M, Leibovici L, Avni T., Empirical
Antibiotic Treatment Does Not Improve Outcomes in Catheter-Associated Urinary
Tract Infection: Prospective Cohort Study., 2017, PMID:29020203
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S, Schaeffer AJ, Tambayh PA, Tenke P, Nicolle LE, Infectious Diseases Society of
America., Diagnosis, prevention, and treatment of catheter-associated urinary
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Infectious Diseases Society of America., 2010, PMID:20175247
Myrianthefs P, Evodia E, Vlachou I, Petrocheilou G, Gavala A, Pappa M,
Baltopoulos G, Karakitsos D., Is routine ultrasound examination of the gallbladder
justified in critical care patients?, 2012, PMID:22649716
Boland GW, Slater G, Lu DS, Eisenberg P, Lee MJ, Mueller PR., Prevalence and
significance of gallbladder abnormalities seen on sonography in intensive care
unit patients., 2000, PMID:10749232
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https://www.ncbi.nlm.nih.gov/pubmed/20175247
https://www.ncbi.nlm.nih.gov/pubmed/22649716
https://www.ncbi.nlm.nih.gov/pubmed/10749232
3. 2. Non-infective causes
Half of fever episodes in the ICUare of non-infective origin without the temperature usually
exceeding 38.3 ºC. The medical history, including recent interventions along with the
physical examination aids the clinician in narrowing down the differential diagnosis.
However, the type of ICU population (e.g. medical versus surgical patients), the specific type
of patients (e.g. immunocompromised, elderly), the history of recent epidemics and the local
epidemiology must be taken into account.
Drug-fever has an unknown incidence (3%-7% of febrile episodes are attributed to drug
reactions but many cases remain undiagnosed), a temperature range from 38.8 ºC (102 ºF)
to 40 ºC (104 ºF) and is a difficult diagnosis (usually established by exclusion because of the
non-specific signs and laboratory tests), shaking chills and spiking temperatures. A
concomitant maculopapular rash makes the diagnosis simple but accompanies fever in only
5%-10% of cases. Rarely an increased leukocyte count with a left shift, peripheral
eosinophilia, a moderate elevation of serum transaminases, and a markedly elevated
erythrocyte sedimentation rate (>100 mm/h) are recorded.
The signs that are associated with drug-fever are a lack of appropriate pulse rate response
and a relative bradycardia in the absence of intrinsic conduction defects or beta-blockade.
Any drug can cause fever due to hypersensitivity producing fever alone, with local
inflammation at the site of administration (phlebitis, sterile abscess, soft tissue reaction) or
because of the delivery systems (diluent intravenous fluid, intravascular delivery
devices).The high-risk agents for drug-fever are all antibiotics (especially β-lactams), anti-
epileptic drugs (especially phenytoin), antiarrhythmics (mainly quinidine and procainamide),
antihypertensives (α-methyldopa), diuretics, and stool softeners. Antibiotics with a lower risk
for drug-fever development are: clindamycin, vancomycin, chloramphenicol, aztreonam,
doxycycline, erythromycin, imipemen, quinolones, and aminoglycosides. 
The time between initiating a drug and fever appearance is estimated to be 21 days (median
8 days), while the fever resolves usually within 72 hours after removing the offending drug.
When a rash is present it may persist for days or weeks. The usual scenario of drug-fever in
the ICU, includes a patient in whom an already diagnosed infection is resolving and after an
initial defervescence in temperature, a recurrence of fever is noticed. In this type of patient,
the antibiotics should be discontinued if the infection has resolved or another infected site
has not been detected. If the patient is stable, but the infection has not resolved,
sensitivities, according to the spectrum of pathogens should be performed. then the
presumed offending agent should be removed and antibiotic therapy modified accordingly. 
Alcohol withdrawal is often seen in the first 48 to 72 hours following hospitalisation and can
often result in confusion with infection. Infection, hepatitis or pancreatitis should therefore be
sought and excluded. Alcohol withdrawal leads to autonomic disturbances with sweating
and fever. Benzodiazepines are the drug of choice for treatment. 
Blood transfusions may elicit acute febrile reactions, even in the absence of bacterial
contamination or haemolysis. Both acute, but more often, delayed haemolytic transfusion
reactions may also be responsible for the fever. (Sub) acute febrile reactions without
haemolysis (negative direct antiglobulin test) are caused by antibodies present in the
recipient’s plasma and directed against HLA antigens on leukocytes in the donor’s blood.
Occasionally, the donor’s blood is contaminated by micro-organisms and elicits fever in the
recipient. Acute or subacute febrile reactions during red cell and platelet infusions should
lead to discontinuation of the transfusion. Both donor and recipient blood should be sent for
culture and haematological investigation.
 Note
Onset of fever during blood transfusion is a medical emergency 
In cardiac care units (CCUs), the main causes of non-infective fever include: myocardial
infarction, Dressler’s syndrome with pericarditis, thromboembolism, thrombolytic therapy
with haemorrhagic complications, antiarrhythmic medication (e.g. procainamide, quinidine),
and deep venous thrombosis. 
In a neurosurgical ICU, posterior fossa syndrome is a common cause of non-infective fever
that mimics meningitis, with stiff neck, low level of glucose/increased level of protein in
cerebrospinal fluid, and predominance of polymorphonuclear leukocytes in cerebrospinal
fluid (CSF) as a result of blood leakage into CSF. The differential diagnosis from bacterial
meningitis is based on the negative cultures and the gradual lessening of meningeal
symptoms as the number of red blood cells decreases in the CSF with time. 
Other causes are: central fever (caused by intracranial lesion or trauma affecting the brain
or hypothalamus that is resistant to antipyretics, exceeds 39 ºC or 106 ºF and is
characterised by absence of perspiration); the use of anticonvulsive medications; deep
venous thrombosis and fat embolism syndrome in trauma patients. In the acute phase after
head injury, the appearance of pyrexia is extremely frequent and deleterious to cerebral
perfusion (CPP) and intracranial pressure (ICP); while lack of treatment by antipyretics has
been correlated with a longer ICU stay. Other causes of nosocomial fever in the ICU include
adrenal insufficiency, acute pancreatitis, decubitus ulcers and gastrointestinal haemorrhage.
In text References
(Wood 1998; Spies and Rommelspacher. 1998; Rabinstein and Sandhu. 2007; Stein et al.
2000; Stocchetti et al. 2002) 
 References
Wood AJ, Adverse Drug Reactions. In: Harrison’s Principles of Internal Medicine.
14th ed, 1998, ISBN: 007912013X
Spies CD, Rommelspacher H., Alcohol withdrawal in the surgical patient:
prevention and treatment., 1998, PMID:10195555
Rabinstein AA, Sandhu K., Non-infectious fever in the neurological intensive care
unit: incidence, causes and predictors., 2007, PMID:17940175
Stein PD, Afzal A, Henry JW, Villareal CG., Fever in acute pulmonary embolism.,
2000, PMID:10631196
https://www.ncbi.nlm.nih.gov/pubmed/10195555
https://www.ncbi.nlm.nih.gov/pubmed/17940175
https://www.ncbi.nlm.nih.gov/pubmed/10631196
Stocchetti N, Rossi S, Zanier ER, Colombo A, Beretta L, Citerio G., Pyrexia in
head-injured patients admitted to intensive care., 2002, PMID:12415441
https://www.ncbi.nlm.nih.gov/pubmed/12415441
4. Fever In Specific Categories Of Critically Ill Patient
Some categories of critical care patients deserve special mention. In some centres, surgical
ICU is a separate entity but even where surgical patients are part of a general critical care
population, some distinctive considerations pertain particularly in the early postoperative
period. Fever in the immune suppressed and in neurological patients is also included here.
4. 1. The surgical critical care patient – determining the cause of fever
The normal response to trauma and surgery includes release of proinflammatory mediators
and an elevation of body temperature that usually does not exceed 38.5 °C and does not
last longer than two days, unless the surgery was done for infection itself, e.g. peritonitis.
Hence, any elevation of temperature above 38.5 °C, lasting longer than two days or
developing on the third day, may indicate concomitant microbial infection and sepsis. About
10% of trauma patients develop a nosocomial infection.
 Note
Trauma has some immunodepressant effect thereby increasing the risk for infection.
Other risk factors relate to advanced age, diabetes, immune suppression, obesity,
catheterisation, postoperative ventilation and extent of trauma and surgery. Risk factors also
include prolonged hypotension, haematoma, foreign bodies and blood transfusion.
Repeated and careful searches for a source and micro-organisms are mandatory in these
patients. Gram-negative pneumonia and wound infection are among the most common
sources.