Download pathophysiology of fever

17 May 2013
No. 17
ITS GETTING HOT IN HERE!!
Is antipyretic therapy necessary in
critically ill ICU patients?
H Somaroo
Commentator: AA Sader
Moderator: H Cassimjee
Discipline of Anaesthetics
CONTENTS
INTRODUCTION ................................................................................................... 3
IMPORTANT DEFINITIONS ................................................................................. 4
PATHOPHYSIOLOGY OF FEVER ....................................................................... 5
BENEFICIAL EFFECTS OF FEVER ..................................................................... 8
DETRIMENTAL EFFECTS OF FEVER ................................................................. 9
TREATMENT OF FEVER ................................................................................... 10
Paracetamol .................................................................................................... 11
NSAIDs ............................................................................................................ 12
PHYSICAL COOLING METHODS ...................................................................... 13
TEMPERATURE CURVE COMPLEXITY............................................................ 13
CONCLUSION .................................................................................................... 16
REFERENCES.................................................................................................... 17
APPENDIX .......................................................................................................... 19
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Is antipyretic therapy necessary in critically ill ICU patients?
INTRODUCTION
The practice of treating fever is said to predate 2000BC, when Emperor Shen
Nung of China is reported to have first described the antipyretic properties of the
antialarial herb ch’ang shan (Dichroa febrifuga). (2)
Hipprocrates was quoted more than twenty three thousand years ago as saying
“Give me the power to produce fever, and I will cure all disease,” (17), here alluding
to his ideas regarding the significance of fever and implications thereof. He was
known to have used heat therapy in his routine clinical practice.
Fever is a common,non-specific response to various types of infectious or noninfectious stimuli (16) and has been associated with increased mortality in adult
patients admitted to adult intensive care units (ICUs).(3) The incidence in ICUs
has been reported to range from 23 to 70%, and in half of these cases it was
found to be due to an infective cause. (6)
The routine control of fever, by pharmacological and physical methods, in critically
ill patients has become widespread practice in many ICUs, including our own.
However, the use of antipyretic therapy in critically ill patients remains
inconsistent. Evidence exists both for and against the treatment of fever. It has
also been postulated that the adequate treatment of fever may help reduce
excessive investigation, antimicrobial therapy and cost of care in the ICU setting.
As compared to with normothermic patients, patients with fever were found to
require longer durations of mechanical ventilation and length of ICU stay. (13) The
question remains when and who should we treat it? And are there any criteria to
highlight this?
Arguments against the control of fever view pyrexia as a beneficial, adaptive
response to stress, and consider the important adverse effects of of antipyretic
therapy. Certain animal studies have also shown an increased mortality in
subjects with viral, bacterial and parasitic infections following the treatment of
fever with antipyretic drug therapy.(2)
Conversely, proponents for the control of fever consider the detrimental effects of
fever in increasing oxygen consumption, energy deficit and hypoxic tissue injury;
the decreased risk of precipitating multi-system organ failure; and the benefits of
increased patient comfort. Fever has also been found to be a predictor of higher
mortality in neurological ICU patients. The advantages of antipyretic therapy or
induced hypothermia have also been investigated and has been shown to be of
benefit in acute respiratory distress syndrome, following cardiac arrest, and in
neurological injuries.
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There are presently no standardised recommendations regarding when and how
to approach the treatment of fever in critically ill patients; to understand this it is
important to understand the pathogenesis of fever, the specific clinical indications
and contraindications to treatment and to consider the risk-vs-benefit of using
specific treatment modalities.
IMPORTANT DEFINITIONS
Fever in ICU patients is defined as a core body temperature ≥ 38.3 degrees
celcius (°C) or 101 degrees Fahrenheit (°F), associated with an elevated
hypothalamic set point. Fever can have an infectious or non-infectious aetiology.
(Refer to appendix – table A).
Most abnormal temperature increases are due to fever, however abnormally
elevated body temperatures may also occur in association with a normal
hypothalamic set point, in which case it is defined as hyperthermia. This can be
due to:
1. environmental causes (eg. heatstroke)
2. drug induced (eg. malignant hyperthermia
3. endocrine causes (eg. thyrotoxicosis)
I will not go into more detail regarding hyperthermia, as this is not in the scope of
this talk.
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PATHOPHYSIOLOGY OF FEVER
Fever is an evolutionary response to various kinds of infectious and non-infectious
stimuli, which, via different mechanisms induce an up-regulation of the
thermostatic setpoint in the preoptic area of the hypothalamus, resulting in fever.
Activation of the hypothalamus can occur via three ways (refer to figure 3):
1. The classical method, whereby exogenous pyrogens (such as exotoxins and
viruses) timulate leucocytes, to produce cytokines (or endogenous pyrogens),
mainly IL-1β, TNFα, and IL-6. These act on the central nervous system at the
level of the organum vasculosum of the laminae terminalis (OVLT) to induce
the production of prostaglandin E2 (PGE2). The OVLT is located below the
preoptic area of the hypothalamus, and forms part of the circumventricular
system of the brain ie. sites which do not possess a blood-brain barrier, at
which endogenous pyrogens act. PGE2 acts directly on the cells of the preoptic nucleus, to induce a febrile response.(18)
Figure 1: Midsagittal view of the brain, demonstrating hormonal pathways through the
circumventricular organs (18)
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The febrile response is thus controlled by neurons in or near the OVLT, which
monitor circulating cytokines and and input to areas in the hypothalamus and
brainstem, to elicit autonomic, endocrine and behavioural responses which are
involved in fever. (illustrated in figure 2)
Figure 2: Mechanism for the action of cytokines on the brain that induce
Fever (18)
2. The second mechanism is also mediated by IL-1β, which induces ceramide
production by the enzymatic shingomelinase pathway. Ceramide acts as a 2nd
messenger, inducing an early increase in core temperature.(16)
3. The third method is a neuronal mechanism, whereby Kuppfer cells in the liver
are stimulated by lipopolysaccharide to produce prostaglandin E2, which
stimulates a neural pathway involving the vagus nerve and nucleus tractus
solitarius, which then in turn elicits a hypothalamic febrile response. (16)
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Figure 3: Mechanism of activation of the hypothalamus
(16)
The Immune Response to Fever
Fever is known to induce changes in effector cells of the immune system, as well
as induce the heat shock response, which is a complex reaction ultimately
resulting in the production of heat shock proteins (HSPs), which are a class of
proteins crucial to cellular survival.(6)
Hyperthermic preconditioning has been investigated in animal models, and it was
found that pre-treated subjects showed a significantly lower mortality and
decreased organ damage following subsequent endotoxin infection. This was
also associated with increased levels of HSPs measured in these subjects.
Severe sepsis is thought to be associated with a decreased heat shock response.
The septic response in re-infection may however be modulated by heat shock
response, and is associated with higher levels of HSPs.(6)
HSPs have an anti-inflammatory effect, resulting in reduced levels of TNFα, IL-1,
IL-6 and IL-10 in vitro. Recent studies have also shown that the heat shock
response decreases the activity of NF-κβ, which is a potent modulator of the proinflammatory response. NF-κβ activity has been found to be associated with
increased mortality in septic shock patients. .(6)
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Hyperthermia has been found to induce the heat shock response, thus it plays a
role in modulating the immune response to sepsis.
The heat shock response leads to the eventual inhibition of NF-κβ activation, and
to a decreased cytokine production. (6) This demonstrates a protective role of
fever in sepsis, and brings challenges the routine practice of using antipyretic
therapy in critically ill patients.
BENEFICIAL EFFECTS OF FEVER
How fever could influence the outcome in septic patients is critical. However, it is
an issue which remains debated because of the limited value of studies that
include a heterogeneous population of patients with different levels of severity of
sepsis (16).
Several observations have been made regarding the beneficial effects of fever,
which include effects on:
1. the invading microorganism
2. accelerating the immune response and
3. attenuating the immune response, thus preventing collateral tissue damage.
Effects on the invading microorganism
Fever impacts on invading microorganisms by reducing their growth or prolonging
their growth time. Human infectious pathogens usually grow optimally between
temperatures of 35-37 °C. In studies of meningitis it was found that an increased
body temperature resulted in an increased pneumococci growth time in
cerebrospinal fluid, as opposed to when the febrile response was blunted.
In vitro studies on Plasmodium falciparum also demonstrated inhibited parasite
growth at febrile temperatures.
Febrile temperatures have also shown to be associated with increased antibiotic
sensitivity and a reduced minimum inhibitory concentration.
Effects on accelerating the immune response
Fever also results in an increased immune response, by modulating the cellular
immune response and inducing the heat shock response.
Hyperthermic preconditioning has been demonstrated to reduce the severity of
infection, inhibit lymphocyte cell reduction (CD4 lymphocytes and B cells) and also
resulted in reduced serum levels of TNFα.
Febrile temperatures have also been shown to induce an increase in:
- the mobility of polymorphonuclear cells
- the speed of phagocytosis
- the adherence of T-helper lymphocytes
- immunoglobulin levels
- TNFα cytotoxicity
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Effects on attenuating the immune response
Fever also proves beneficial by attenuating the immune response and thus
preventing collateral tissue damage.
This accomplished by an increase in heat shock proteins, which are vital for
reducing endothelial and end organ damage during various stressors, including
fever (16). Heat shock proteins also cause a decrease of NF-κβ, which in turn
reduces cytokine production (TNFα and INFγ ) and thus reduces the immune
response. Animal studies have shown a decreased mortality and reduced organ
injury following hyperthermic preconditioning.(16)
Human clinical studies have also shown similar results. A significantly higher
survival rate has been demonstrated in patients with Gram-negative bacilli
infections, who mounted a febrile response on the day of bacteraemia, as
opposed to those who did not. .(16) A fever > 38.2°C was also shown to be
protective against invasive Candida species infections in ICU patients. The
benefits of fever have also been demonstrated indirectly in clinical trials which
show the benefits of not treating fever eg. in children infected with P.falciparum
malaria, treatment with the antipyretic agent paracetamol was shown to prolong
the parasite clearance time, as compared with those children who were not
treated.(6)
DETRIMENTAL EFFECTS OF FEVER
Though the febrile response does confer many advantages, it does also have
numerous harmful effects on clinical outcome as well. These include:
1. increased metabolic demand and oxygen consumption
2. patient discomfort
3. seizures in children
4. harmful collateral tissue damage
The febrile process causes an increased metabolic demand and oxygen
consumption on organ systems, particularly of note in the brain and heart, which
worsens pre-existing disease. In neurological pathology, fever is a recognised
cause of secondary cerebral insult, and is associated with a worsening clinical
outcome. (16, 18) This is discussed further below.
Myocardial injuries are another pathological state in which fever is associated with
a deterioration in clinical outcome. Patients with pre-existing cardiac conditions,
especially those with coronary artery disease and ischaemic cardiomyopathy, are
more at risk to the systemic effects of fever, as a result of the increased oxygen
consumption it induces. An increase in temperature up to 39°C has been shown
to increase infarct size in an acute myocardial infarction model.(18)
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Conversely, a reduction in fever from 39 to 37°C has been shown to decrease
oxygen consumption, lessening the stress on the cardiorespiratory system, and
improving oxygen delivery in febrile, critically ill patients with impaired oxygen
delivery.(6,16,18) Studies have also shown that the treatment and resolution of fever
without antipyretic therapy increased the left ventricular stroke volume index, and
that left ventricular performance was improved with the abatement of the fever.(18)
Another negative effect is patient discomfort from fever, which can either stem
from the febrile process itself, or due to neuro-endocrine or metabolic pathways,
triggered in response to infection.(16) Patient discomfort is often the justification
clinicians use when opting to treat for fever.
Febrile seizures in children is another recognised undesired complication of fever.
Preventative treatment for this, however, remains a contentious issue, as
antipyretic therapy has never been shown to prevent febrile seizures (11).
Randomised controlled studies investigating ibuprofen compared with a placebo,
and similar studies with acetaminophen, showed no reduction in the recurrence
rate of febrile seizures with prophylactic antipyretic treatment.(9,16) At high fever
level (> 40 to 41°C), the beneficial immunomodulatory effect may be outweighed
by the harmful metabolic/inflammatory effect of fever(16). By inducing enhanced
microbicidal mechanisms, fever can result in inadvertent collateral tissue damage.
In an animal model of Gram negative bacterial pneumonia, fever was found to
decrease survival, even in the face of improved innate host response mechanisms
and pathogen elimination.(16)
This decreased survival was found to be associated with increased pulmonary
vasculature injury, increased aggregation of neutrophils, and increased levels of
cytokines found in the broncho-alveolar lavage(19). Thus this enhanced response
is also capable of causing injury to collateral host tissue, illustrating that the
ultimate effect of fever is in fact determined by the balance between the
accelerated clearance of pathogens and the damage to collateral tissue.
TREATMENT OF FEVER
Treatment modalities for fever in our ICUs involves either pharmacological
interventions or physical cooling methods. The assumption made by most clinical
workers is that fever is noxious (11) and that the suppression of fever will reduce or
eliminate the detrimental effects. However, these interventions are by no means
innocuous, and the benefit vs the risk of treatment needs to be considered.
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PHARMACOGICAL TREATMEANT
In our practice, the common pharmacological agents used are paracetamol and
NSAIDs, so these will be discussed further, with emphasis on paracetamol, as it
forms the mainstay of our antipyretic pharmacological practice. Indications for
their use include a decrease in morbidity and mortality in febrile patients, the relief
of patient discomfort, the contentious notion that they play a role in the preventing
febrile seizures, reducing cognitive impairment, preventing secondary injury, and
improving outcome in patients with neurological injuries.
Paracetamol
Pharmacodynamics
Paracetamol acts centrally, and two mechanisms are responsible for it’s
antipyretic and analgesic properties:
1. selective inhibition of cyclo-oxygenase (COX) in the central nervous system, via
a tissue-specific inhibitory effect on the COX enzyme, in the presence of low
peroxide levels, as is encountered in intact neuronal cells. This peroxidedependent specificity accounts for the relatively poor anti-inflammatory and
antiplatelet properties, and also the better side-effect profile, as compared to the
NSAIDS.
2. an indirect effect on cannabinoid and vanilloid receptors in the thermoregulatory
and nociceptive pathways in the central nervous system. Paracetamol is a
prodrug of the fatty acid amide N-arachidonoylphenolamine (AM404).
AM404 has been demonstrated to:
- inhibit in-vitro COX activity and PGE2 formation, resulting in a resetting of the
thermoregulatory set-point.
- increase levels of the endogenous cannabinoid neurotransmitter,
anandamide, which act to lower temperature and modify nociceptive signals
(4)
.
There is also evidence for a synergistic relationship existing between paracetamol
and endogenous opioid analgesic pathways at a spinal and supraspinal level.
Pharmacokinetics
The pharmacokinetics of paracetamol in critically ill patients is variable, due to
different pathological processes(4). Nasogastric administration leads to delayed
absorption, however absorption following post-pyloric administration results is
rapid; rectal absorption is poor. The volume of distribution is also found to be
increased in ICU patients. The clinical significance of these differences is not
clear.
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Adverse effects
- Hepatic necrosis following paracetamol overdose is the most serious, lifethreatening side effect. This leads to hepatocellular injury related to
accumulation of its toxic metabolite N-aceto-þ-benzo-quinone imine, when
glutathione reserves are exceeded. In normal patients paracetamol is
considered safe, however acute hepatitis may occur in ICU patients who have
a diminished glutathione reserve eg. malnourished patients and alcoholics.
- Evidence also suggests the same pathway implicated in the kidney, causing
paracetamol-associated nephropathy.
- Serum increases in ALT of > three times has also been demonstrated; the
clinical significance of this requires further investigation (16).
- Paracetamol does not usually affect platelet function, however intravenous
paracetamol has been demonstrated to inhibit platelet COX-1 enzyme in a
dose dependent manner.
- Intravenous paracetamol has been shown to induce increases in skin blood
flow, due to its antipyretic action, with a consequent drop in systemic vascular
resistance, which may be associated with significant hypovolaemia in critically
ill patients, in whom baroreceptor reflexes may be dysfunctional or cardiac
reserve limited. (21) The fall in blood pressure observed may be severe
enough to warrant treatment in some critically ill patients.
NSAIDs
Non steroidal anti-inflammatory drugs are also sometimes used to treat pyrexia in
ICU patients. They work by inhibiting COX enzymes, with those with a higher
affinity for COX-1 being ten times more likely to induce gastrointestinal (GIT)
toxicity.(16) Selective COX-2 inhibitors have fewer GIT side effects, but they lack
the cardio-protective effect shared by non-selective and COX-1 inhibitors.(16)
Adverse effects of this group include:
- GIT toxicity, which may be divided into three categories, viz. mucosal lesions,
GIT discomfort (eg dyspepsia) and severe GIT complications (including GIT
bleeding and perforated ulceration). Patients at risk for these include those on
high doses of NSAIDs, advanced age, a prior history of peptic ulcer disease or
GIT bleeding, concomitant use of steroids or anticoagulants, and a short
duration of therapy.
- NSAIDs are also known to have nephrotoxic adverse effects, which can
manifest as fluid and electrolyte disturbances, acute renal failure, acute
interstitial nephritis and analgesic drug-associated nephropathy.(11) Studies
have shown a markedly decreased creatinine clearance in patients taking
NSAID therapy, more especially in those on diuretic or angiotensin-converting
enzyme inhibitors.
- These drugs have also been known to cause vasospasm in patients with preexisting coronary artery disease. (16)
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PHYSICAL COOLING METHODS
Physical cooling is also utilised as an antipyretic modality in critically ill pyrexial
patients. Methods employed include external air and water blanket techniques,
internal cold gastric lavage and cold fluid infusions.(1) However, its practice is
controversial, due to certain adverse effects, viz:
- its ability to induce sympathetic system activation, thus opposing attempts to
lower core temperature, by thermoregulatory mechanisms;
- cutaneous vasodilation and
- shivering, which results in increased oxygen consumption, up to 40%.of
normal (16)
These also contribute to worsening levels of patient discomfort.
Hypothermia blankets have also been used in febrile ICU patients, but have been
found to induce large temperature fluctuations and rebound hypothermia.
TEMPERATURE CURVE COMPLEXITY
The measurement of body temperature is a long used, reliable clinical tool, and
fever is considered to be a reliable index of illness in patients. However fever
provides little in the way of diagnostic or prognostic information.
In theory, temperature is a quantitative variable used, but in practice it behaves as
a dichotomous variable, with poorly a delineated cutoff point. (21) It is however,
the culmination of an intricate, complex system, and may provide useful
physiological information in both patients with and without a fever. Using nonlinear
dynamics and complexity analysis, with approximate entropy used as a measure
of complexity, disturbances in the thermoregulatory system can be represented
by the temperature curve, in patients with or without fever.
The clinical status of critically ill patients with multiorgan failure has been found to
have an inverse association to the complexity of the temperature curve,
expressed as approximate entropy. (21) Thus a reduced complexity is associated
with a poor prognosis. Complexity of the temperature curve was also found to
decrease significantly with age.
The advantages of this assessment is it is non-invasive, cost effective and it
allows for the real-time, continuous monitoring of clinical status (21), which is
useful especially in critically ill patients.
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Figure 4: Receiver operating characteristic (ROC) curves of complexity measures and SOFA
scores to predict death. (23)
...IS ANTIPYRETIC THERAPY NECESSARY?
Despite the magnitude of evidence demonstrating the the beneficial effects of
fever as part of the host response to fever, antipyretic therapy is still commonly
utilised in febrile critically ill patients. This somewhat contradictory practice has
triggered various studies reviewing fever in intensive care unit patients, what
levels of fever should warrant antipyretic therapy, the morbidity and mortality
related to various forms of antipyretic therapy and the differences encountered in
critically ill patients with infectious and non-infectious pathologies. However there
are as yet no established guidelines for fever in the critically ill demographic.
For critically ill patients with sepsis, a temperature ≥39.5°C is also associated with
increased mortality. Considering the mechanisms of fever as a normal and an
adaptive physiological process (18, 2), and that the febrile response to infection is
beneficial, as discussed before, at a cellular level with the direct inhibition of
micro-organisms, as well as the enhancement of the protective cellular and
immune responses; fevers less than this value should not be treated (1,18,16,4).
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Figure 5: Forest plot of odds ratio for death by antipyretic versus placebo treatment, in
septic patients (2)
Differences exist in the septic and non-septic patients. In non-septic patients it is
found that fever ≥39.5°C is independently associated with an increased mortality,
without the association of antipyretic therapy administration with mortality.
However, in septic patients the administration of antipyretic therapy is
independently associated increased mortality, without the association of fever with
mortality. (1) This indicates that fever and anti-pyretic therapy have different clinical
implications for patients with and without sepsis.
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4: Mean peak temperature observed in ICU patients with and without sepsis
However patient discomfort and the metabolic demands of fever, especially in
patients with a decreased cardiopulmonary reserve, also needs to be taken into
consideration here; and in certain cases the adaptive advantage of the febrile
response may need to be forfeited. At high grade fevers > 40°C, central nervous
system and other collateral tissue injury may actually warrant antipyretic
treatment. Treatment here needs to be individualised. In critically ill patients with
neurological injuries (including traumatic brain injury and stroke) fever is
associated with increased mortality, and in this demographic temperature control
with antipyretic therapy is essential. Fever in this setting results in unacceptable
pathophysiological changes, both locally (including increased proteolysis and free
radical production (4), and systemically, resulting in decreased cerebral perfusion
pressure. In these patients antipyretic therapy is therefore warranted.
CONCLUSION
Fever, triggered by infectious and non-infectious processes, is frequently
encountered in critically ill ICU patients. The balance of its benefit to harm is a
complex issue, and many factors including the presence and severity of infection,
the intensity of the cellular and immune response, the extent of collateral tissue
damage, and the pre-existing physiological reserve of the patient need to be
considered before deciding whether or not to institute antipyretic therapy. The
adequate treatment of fever may also help reduce excessive investigation,
antimicrobial therapy and cost of care in the ICU setting, and therefore further
investigation into this is certainly needed, to establish evidence based consensus
regarding its management.
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REFERENCES
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with and without sepsis: multi-centered prospective observational study. Crit
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5. Kiekkas B. Physical antipyresis in critically ill adults. The American journal of
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7. Gozzoli V. Randomized trial of the effect of antipyresis by metamizol,
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8. Young P. Early peak temperature and mortality in critically ill patients with or
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10.Rizoli S. Saturday night fever: finding and controlling the source of sepsis in
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16. Launey Y. Clinical review: fever in septic ICU patients--friend or foe?. Critical
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17. Bierman W. The History of Fever Therapy in the Treatment of Disease.
Bulletin of the New York Academy of Medicine (1925). 1942-01;18:65-75.
18. Saper C. The neurologic basis of fever. The New England journal of
medicine. 1994-06-30;330:1880-6.
19. Miller’s Anaesthesia, Neurosurgical anesthesia. 7th edition, Churchill,
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20. Krajčová A. Mechanism of paracetamol-induced hypotension in critically ill
patients: A prospective observational cross-over study. Australian critical
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21. Varela M. Clinical implications of temperature curve complexity in critically ill
patients. Critical care medicine. 2005-12;33:2764-71.
22. Boyle M. Paracetamol induced skin blood flow and blood pressure changes in
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23. Varela, Manuel;Churruca, et al. Temperature Curve Complexity Predicts
Survival in Critically Ill Patients. American Journal of Respiratory and Critical
Care Medicine. Aug 1, 2006; 174:290-298.
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APPENDIX
Table 1 – causes of fever
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