Analytic Review

Journal of Intensive Care Medicine

2017, Vol. 32(2) 124-129
Neurogenic Fever: The Author(s) 2016
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Review of Pathophysiology, DOI: 10.1177/0885066615625194
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Evaluation, and Management

Kevin Meier, MD1 and Kiwon Lee, MD, FCCM1

Abstract
Fever is a relatively common occurrence among patients in the intensive care setting. Although the most obvious and concerning
etiology is sepsis, drug reactions, venous thromboembolism, and postsurgical fevers are all on the differential diagnosis. There is
abundant evidence that fever is detrimental in acute neurologic injury. Worse outcomes are reported in acute stroke, sub-
arachnoid hemorrhage, and traumatic brain injury. In addition to the various etiologies of fever in the intensive care setting,
neurologic illness is a risk factor for neurogenic fevers. This primarily occurs in subarachnoid hemorrhage and traumatic brain
injury, with hypothalamic injury being the proposed mechanism. Paroxysmal sympathetic hyperactivity is another source of
hyperthermia commonly seen in the population with traumatic brain injury. This review focuses on the detrimental effects of fever
on the neurologically injured as well as the risk factors and diagnosis of neurogenic fever.

Keywords
neurogenic fever, neuroscience ICU, paroxysmal sympathetic hyperactivity

Introduction fevers with no evidence of infection. The very same surgical

Fevers are a relatively common occurrence among critically ill
patients. A prospective study in a general intensive care unit
(ICU) setting revealed that 70% of admissions were febrile at
some point during their hospital course.1 The fever response is
a physiologic mechanism to raise the core body temperature.2
This can be accomplished by both increased heat production
and decreased heat loss. Rats were observed to generate heat
through shivering and conserve heat through vasoconstriction
in their tail.3 Similar mechanisms are present in humans.2
The idea of a neurogenic, or centrally mediated, fever has
been around for many years. In 1936, it was first noticed that
damage to the anterior hypothalamus in cats would produce a
fever.4 This was subsequently demonstrated in other animals5
and was not associated with any signs or evidence of infection.
In 1940, it was reported that noninfectious fevers would
develop in humans sustaining damage to the hypothalamus
during neurosurgical interventions.6,7 Further studies supported
the hypothalamus as the thermoregulatory center of the brain.2
The anterior hypothalamus contains distinct populations of
neurons that respond to temperature differences and initiate
behaviors to raise or lower the body temperature. The reference
temperature to which these neurons compare is called the set
point and can be modified in certain physiologic conditions.2
If the set point is raised, specific neurons will be activated that
induce heat generation and conservation.8
In 1977, it was observed in rats that surgical lesions of the
anterior hypothalamus and preoptic region would generate
lesions would also cause an increase in local prostaglandin
levels. 3 They further demonstrated that prostaglandin E
injected into the rostral hypothalamus, without the surgical
lesion, would cause a similar febrile response. Their conclusion
was that it was the prostaglandin E, not the surgical lesion
directly, that mediated the fever. This was further demonstrated
when indomethacin, a prostaglandin inhibitor, attenuated the
fever caused by the anterior hypothalamic lesion.5
Numerous microbial proteins have been shown to cause
fevers.2 In response to these exogenous pyrogens, phago-
cytes are activated to produce endogenous pyrogens, which
initiate a cascade of events, including prostaglandin produc-
tion, leading to the change in the temperature set point.2,8,9
The endogenous pyrogen was initially felt to be a solitary
chemical, pyrexin, secreted by bone marrow-derived
1
Department of Neurosurgery, The University of Texas Medical School at
Houston, Houston, TX, USA
Received May 05, 2015. Received revised November 16, 2015. Accepted
for publication December 11, 2015.
Corresponding Author:
Kiwon Lee, Department of Neurosurgery for Critical Care, Neurosurgery and
Neurology, Division of Critical Care, Neuroscience and Neurotrauma ICU,
Mischer Neuroscience Institute, Memorial Hermann, Texas Medical Center,
The University of Texas Medical School at Houston, 6431 Fannin St MSB 7.152,
Houston, TX 77030, USA.
Email: kiwon.lee@uth.tmc.edu
Meier and Lee
phagocytes, but further studies have revealed that several
inflammatory cytokines can act as endogenous pyrogens,
most potently interleukin 1.9
Impact of Fever on Patients With Brain Injury
There is evidence that fever is more common in the patient
with acute brain injury than the general intensive care popu-
lation.10,11 It has also been suggested that fevers in the general
medical population may be a beneficial response to infec-
tion2,12 and that aggressive fever reduction may not be indi-
cated. One such study showed that antipyretic usage
increased mortality among patients with sepsis but not unin-
fected patients.13 However, strong evidence supports the con-
clusion that in the population with brain injury, fevers are
associated with increased mortality.12,14-17 Mortality was
shown to be increased in patients with traumatic brain injury
and stroke with early fevers but not in patients with central
nervous system (CNS) infections.15 A study of 390 patients
with stroke showed that higher body temperatures were sta-
tistically associated with worse outcome, with a relative risk
increase of 2.2 for every 1 C increase in body temperature.18
They also showed that elevated body temperatures were asso-
ciated with larger infarct sizes. A rat model of middle cerebral
artery occlusions showed that final infarct size was affected
by brain temperature manipulations.19 Isolated to subarach-
noid hemorrhage (SAH), of 580 patients, 54% had fevers and
showed an odds ratio (OR) of 2 for predicting poor outcome.20
Finally, a meta-analysis of 14 431 patients with brain injury,
primarily stroke, associated fever with worse outcome in 7 dif-
ferent outcome measures.17
There are several possible explanations for why fevers
affect the injured brain differently and why mortality
increases in these patients. It has been shown that brain tem-
perature is not only slightly higher than core temperature but
also that the difference increases with increased core tempera-
ture.21 Hyperthermia increases metabolic demand, which can
be detrimental to ischemic neurons.22 Increased brain tem-
perature has been shown to be associated with significant
increases in intracranial pressure.21 Hyperthermia increases
the inflammation, cytokines, and neutrophils present in
injured brain tissue.23,24 Other possible mechanisms of brain
injury include excitatory damage, breakdown of the blood
brain barrier, and decreased protein stability and function.17
Oddo et al compared metabolic profiles during fever and
induced normothermia in 18 patients with SAH. They found
a decrease in the lactatepyruvate ratio and fewer episodes of
lactate/pyruvate >40, labeled a metabolic crisis, in normother-
mic patients.25
Given the impact of fever on the injured brain, it is
crucial to quickly and accurately identify the etiology and
initiate appropriate treatment. When indicated, appropriate
antibiotics are lifesaving. However, early and accurate diag-
noses of central fever could potentially save patients from
unnecessary antibiotics and the many associated risks and
complications.
125
Fever in the Neuroscience ICU
Although common in the general intensive care setting, it has
been shown that neurologically ill patients are more likely to be
febrile. One study showed that 70% of patients with brain
injury will have fevers during their hospital course compared
to only 30% to 45% of postsurgical ICU patients. Further, only
about half of the fevers in patients with brain injury will be
infectious in nature.10
Among patients in the neurologic ICU, patients with SAH
were at highest risk for developing fevers during their hospital
course, both infectious and noninfectious.26 Other risk factors
for noninfectious fevers included length of stay and ventricular
catheterization.26 Of 428 patients in the neurologic ICU, 93%
of patients with a stay over 14 days had fevers and 59% of
patients with SAH were febrile at some point.27 Specifically, in
subarachnoid patients, poor Hunt and Hess grade, presence of
intraventricular blood, larger aneurysm, SAH sum score, and
level of consciousness were all associated with fevers.14
Fever of Noninfectious Etiology
Of febrile patients, a certain percentage will not have any
identifiable infection. Among neurologic ICU patients, only
50% of fevers were associated with an infection.10 In a general
intensive care setting, the most common noninfectious etiology
for fever is felt to be postsurgical.1 Other possible noninfec-
tious etiologies of fever include medications, venous throm-
boembolisms, and acalculous cholecystitis.8 Among the many
medications that have been reported to cause fevers, commonly
used medications in the ICU include antibiotics, phenytoin, and
barbiturates.28 Possible mechanisms include hypersensitivity
reactions, heat production, and idiosyncratic reactions.28
Neurogenic Fever
Despite a thorough fever evaluation, a subset of patients
will not have an identifiable etiology, infectious or noninfec-
tious. In up to 29% of neurologic intensive care patients, the
etiology of the fever may remain a mystery.29,30 Specifically, in
SAHs, of 92 patients, 26% developed unexplained fevers.29 In
traumatic brain injuries, 4% to 37% of patients will have fevers
thought to be neurogenic in origin, after ruling out other pos-
sible causes.31
As mentioned previously, the concept of a neurogenic fever
is not new.4,6,7 Lesions in the hypothalamus with correspond-
ing elevations in prostaglandin E have been implicated in their
etiology.5 One study in rabbits showed hyperthermia and
increased prostaglandin E in the cerebrospinal fluid after hemo-
globin was injected into the ventricles.32 This correlates with
the many observations that intraventricular blood is a risk fac-
tor for noninfectious fever.14,26 Noninfectious fevers also tend
to occur earlier in the hospital course,30 suggesting that the
initial injury is pyrogenic. In traumatic brain injury, diffuse
axonal injury and frontal lobe damage are risk factors for a
central fever.31 The authors hypothesized that frontal lobe
126 Journal of Intensive Care Medicine 32(2)

injury and diffuse axonal damage are good indicators of con-

comitant hypothalamic injury. A cadaveric study showed that
hypothalamic injury occurred in 42.5% of traumatic brain
injuries.33
Several studies have looked for specific indicators and pre-
dictors of central fever in the neurologically critically ill
patients. It has been suggested that time of fever occurrence
could help elucidate the etiology. Noninfectious fevers typi-
cally occurred earlier in the hospital course, one study showing
that fever within 72 hours and subarachnoid blood were the
strongest predictors of a noninfectious etiology.30 A study of
526 patients found that subarachnoid blood, intraventricular
blood, malignancy, onset within 72 hours, and a longer fever
duration all predicted a central fever.34 Another study associ-
ated prolonged length of stay, ventricular catheterization, and
SAH with unexplained fevers.26 The authors proposed that as
ventricular catheterization was more common in intraventricu-
lar hemorrhages, the blood was the more likely risk factor.

Diagnostic Evaluation
The ability to differentiate infectious from noninfectious fevers
is crucial in the care of neurologically ill patients. As impend-
ing sepsis is the most dangerous condition, a thorough infec-
tious workup should be performed. This should include
evaluation for urinary, pulmonary, and blood stream infections.
Many patients will have an intraventricular drain, which can act
as a source of a CNS infection. If indicated, cerebrospinal fluid
can be sent for analysis. If the concern for infection is high or
the patient is unstable, antibiotic administration should be
started as soon as possible (Figure 1).
Another possible tool in the diagnostic evaluation of fevers
includes serum biomarkers of infection. Procalcitonin, one
such possible biomarker, has been widely studied for its
potential role in diagnosing sepsis and guiding antibiotic ther-
apy. A meta-analysis in 2007 showed a sensitivity and speci-
ficity of about 71% over 18 studies.35 The studies were varied
in their location and the procalcitonin cutoff value used.
Procalcitonin-guided antibiotic therapy could theoretically
lessen the duration of treatment. A recent meta-analysis com-
piled 7 studies, including 1075 patients, and showed that
procalcitonin-guided antibiotic therapy did not affect mortal-
ity, while significantly decreasing the duration of antibiotic
therapy.36
In addition to an infectious workup, a review of the patients
medications should be performed looking for medications
known to cause fever.28 Should the patient continue to be feb-
rile despite antibiotic coverage or no microbial source is found,
consideration should be given to screening for venous throm-
bosis, both clinically and via upper and lower extremity ultra-
sound.37 A postoperative febrile patient could potentially be
watched for resolution, but surgical site infection should be
considered in the setting of persistent fevers. Atelectasis is
frequently mentioned as a cause of noninfectious fever,
although several studies have been unable to find an associa-
tion.38 Acalculous cholecystitis can be life threatening and
Figure 1. Sample fever workup algorithm. See text for details.
requires a high index of suspicion to diagnose given the vague
symptomatology.39 Diagnosis can be made with abdominal
ultrasound.
Only after thoroughly ruling out infection and the above-
mentioned noninfectious etiologies and in the appropriate clin-
ical setting, should the diagnosis of central fever be given
(Table 1). As mentioned, certain neurologic conditions are
more prone to central fever.26,31,34 Aneurysmal SAH appears
to be the most prominent risk factor, followed by intraventri-
cular hemorrhage.34 Of patients with traumatic brain injury,
patients with diffuse axonal injury and frontal lobe damage
appear to be at highest risk.31
Continued fevers despite treatment 34 and onset within
72 hours34,30 are suggestive of central etiology. Central fevers
may not be associated with the tachycardia and diaphoresis that
usually accompany infectious fevers and can be resistant to
typical antipyretics.33
Ultimately, the diagnosis relies on a thorough evaluation for
and elimination of other etiologies. Although it is desirable to
avoid unnecessary antibiotics given possible side effects,
avoiding antibiotics in a patient with sepsis could be fatal.
Meier and Lee 127

Table 1. Characteristic findings for different etiologies of fever. External cooling is frequently used when pharmacologic
interventions are inadequate. Although rapid cooling can be
Diagnosis Characteristic Findings
achieved, reflex shivering can attenuate the cooling
Infection Leukocytosis, SIRS, new oxygen need, and increase metabolic demand.23 In 2004, novel water-
altered mental status circulating cooling units, such as the Arctic Sun, were com-
Venous Swollen, tender extremity, new oxygen pared to conventional surface cooling blankets and shown to be
thromboembolism need superior with regard to fever burden and time to normother-
Drug related No improvement on antibiotics, on a
mia.44 Faster cooling times can be achieved with concomitant
reported medication
Postsurgical Recent surgery, rule out surgical site ice baths and cold intravenous saline.
infection Most recently, endovascular cooling catheters have been
Paroxysmal sympathetic Tachycardia, dystonic posturing, episodic, developed for rapid induction of hypothermia. Time to goal
hyperactivity associated with stimulation temperature and overall fever burden can be reduced, with a
Neurogenic Ruled out other etiologies, hypothalamic similar adverse event profile to central venous catheters.45
damage, SAH/IVH, recurrent, and Broessner et al showed significantly reduced fever burden with
resistant to treatment
no increase in adverse events in critically ill patients with cer-
Abbreviations: IVH, intraventricular hemorrhage; SAH, subarachnoid hemor- ebrovascular disease treated with endovascularly mediated nor-
rhage; SIRS, systemic inflammatory response syndrome. mothermia for 7 to 14 days.46

Table 2. Treatments for fever.

Antipyretic Comments
Tylenol Dose cautiously in liver failure, IV preparation
available, safe in intracranial hemorrhage
NSAIDs Caution in renal failure, caution in intracranial
hemorrhage or if already on aspirin, consider GI
prophylaxis
Surface cooling Pads can be expensive, monitor for skin breakdown,
may use counter rewarming
Intravascular Expensive, increased risk for DVT, will likely need to
cooling treat shivering
Abbreviations: DVT, deep vein thrombosis; GI, gastrointestinal; NSAIDs, non-
steroidal anti-inflammatory drugs.
Therapeutic Options
As fevers are caused by a prostaglandin-induced elevation in
the hypothalamic set point,2 an appropriate intervention is to
block this process (see Table 2). Typical antipyretics, including
acetaminophen and nonsteroidal anti-inflammatory drugs, are
believed to interfere with prostaglandin synthesis.23 Several
studies have shown a fever reduction associated with these
medications,40,41 without showing a mortality benefit. In the
Paracetamol (Acetaminophen) in Stroke trial, patients with
stroke were given 6 g paracetamol daily compared to pla-
cebo.42 In patients with body temperature between 36 C and
39 C, average body temperature was lowered 0.26 C in those
receiving paracetamol. They showed a nonsignificant improve-
ment in outcome. A post hoc analysis showed that among
patients with body temperature 37 C to 39 C, those receiving
paracetamol showed a slightly larger reduction in body tem-
perature, 0.30 C, and a significant improvement in outcome
(OR: 1.43, 95% confidence interval: 1.02-1.97).
Reports have suggested that neurogenic fevers are some-
what resistant to traditional pharmacologic therapies.33 One
study showed that only 7% of patients with traumatic brain
injury and 11% of patients with SAH defervesced with the
antipyretics used.43
Paroxysmal Sympathetic Hyperactivity
Although a separate entity than the central fever that has
been discussed thus far, paroxysmal sympathetic hyper-
activity (PSH) deserves mention, as patients are often
hyperthermic during episodes. First described by Penfield
in 1929, 47 PSH involves episodes of symptomatically
increased sympathetic output.48 It can affect 8% to 33%
of patients with traumatic brain injury, and although several
types of brain injury can cause PSH, 79.4% of patients who
experience PSH have acute traumatic brain injury.49 Char-
acteristically, the episodes are triggered by external stimuli
and start quite abruptly.48
The symptoms are characteristic of increased sympathetic
discharge. An analysis of 9 studies that published diagnostic
criteria for PSH showed that tachycardia, diaphoresis, and
increased motor activity were ubiquitous in their involve-
ment.49 Seven of the studies included hyperthermia. Another
study reviewed 53 cases of PSH, and more than 71% of those
patients had fever during the episodes.50 Ninety-eight percent
had tachycardia; and diaphoresis, hypertension, and tachypnea
were as frequent as fevers.
The underlying mechanism is still unclear.51 A prevailing
early hypothesis, including that of Penfield, involved epileptic
discharges.47,48 The currently proposed mechanism involves a
disrupted balance between inhibitory and stimulatory sympa-
thetic pathways.48 There are centers in the brainstem and dien-
cephalon that inhibit sympathetic outflow. If damaged, spinal
cord circuits may be allowed to amplify, through positive feed-
back loops, mild peripheral stimulation and initiate an exag-
gerated sympathetic response.50 Magnetic resonance imaging
has shown injury to deep brain structures, the brainstem, or
diffuse axonal injury in these patients.48
Current treatment is centered on prevention, with agitation
and pain control.48 The primary treatment options highlight the
mechanism of increased sympathetic discharge. Beta-blockers
are the mainstay of treatment, propranolol being the most com-
monly used. Clonidine is a presynaptic a-2 agonist that
128
decreases sympathetic outflow and is a good choice for blood
pressure control.48
Future Research
As it is the temperature of the brain that, mechanistically, cre-
ates an environment that is harmful to the injured brain, it is
reasonable to postulate that fevers of any origin should affect
outcome in a similar fashion. This has not been studied, how-
ever. If at-risk patients could be identified, it would be inter-
esting to see whether neurogenic fevers could be prevented. It
would also be very beneficial to have a sensitive and specific
biomarker to distinguish noninfectious from infectious fevers.
This could potentially save patients from needless antibiotics.
As most of the work regarding procalcitonin has been in the
general intensive care setting, data specific to the patient with
acute brain injury could be insightful.
Conclusion
Fevers are a common occurrence among critically ill patients,
and appropriate evaluation is a necessary skill for the medical
practitioner. An injured brain is especially sensitive to
increased temperatures, and numerous data prove that fevers
negatively affect outcome in the patient with acute brain injury.
Neurologic illness will sometimes even be the cause of those
fevers. Subarachnoid hemorrhage, intraventricular blood, and
certain types of traumatic brain injury are all risk factors for a
centrally mediated fever. This should only be a diagnosis of
exclusion, after a thorough workup has excluded other treatable
causes. Treatment options include pharmacologic antipyretics
as well as surface and endovascular cooling devices.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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