eISSN 2508-1349

J Neurocrit Care 2020;13(1):19-31

https://doi.org/10.18700/jnc.190090

Central fever: a challenging clinical

entity in neurocritical care
Review Article
Keshav Goyal, MD, DM1; Neha Garg, MD2; Parmod Bithal, MD3
Received: July 18, 2019
1
Department of Neuroanaesthesiology and Critical Care, Neurosciences Centre, All India Institute Revised: December 12, 2019
of Medical Sciences, New Delhi, India Accepted: December 13, 2019
2
Institute of Liver and Biliary Science, Delhi, India
3
Department of Anesthesiology, King Fahd Medical City, Riyadh, Saudi Arabia Corresponding Author:
Keshav Goyal, MD, DM
Department of Neuroanaesthesiology
and Critical Care, Neurosciences
Centre, All India Institute of Medical
Sciences, 710, New Delhi 110029, India
Tel: +91-11-26588700-4111
E-mail: [email protected]

Fever is probably the most frequent symptom observed in neurointensive care by healthcare providers. It is seen in almost 70% of
neurocritically ill patients. Fever of central origin was first described in the journal Brain by Erickson in 1939. A significant number of
patients develop this fever due to a noninfectious cause, but are often treated as having an infectious fever. Unjustified use of antibi-
otics adds to the increased cost of treatment and the emergence of resistant strains, contributing to additional morbidity. Since fever
has a detrimental impact on the recovery of the acutely injured brain and contributes to an increased stay in the neurointensive care
unit (NICU), timely and accurate diagnosis of the cause of fever in the NICU is imperative. Here, we try to understand the underlying
mechanism, risk factors, clinical characteristics, diagnosis and management options of the central fever. We also make an attempt to
differentiate two noninfectious causes of fever in the NICU: paroxysmal sympathetic hyperactivity and central fever.

Keywords: Humans; Fever; Brain; Intensive care units; Ant-bacterial agents

INTRODUCTION ten treated as infectious fever. Unjustified use of antibiotics adds

to the increased cost of treatment and the emergence of resistant
Fever is probably the most frequent symptom observed in the strains, contributing to additional morbidity. Since fever has a
neurointensive care unit (NICU) by healthcare providers. An detrimental impact on the recovery of the acutely injured brain
oral temperature greater than 37.5℃ is considered a fever [1,2]. [12-15] and contributes to an increase in length of stay in NICU
Hyperpyrexia is usually a diagnosis of exclusion, with tempera- [8]; timely and accurate diagnosis of the cause of fever in the
tures exceeding 41℃ and nonresponsiveness to antipyretic treat- NICU is imperative.
ment [3,4]. Fever is seen in almost 70% of neurocritically ill pa- Here, we try to understand the underlying mechanism, risk fac-
tients [5-10]. Fever of central origin was first described by in the tors, clinical characteristics, diagnosis and management options of
journal Brain by Erickson [11] in 1939. A significant number of central fever (CF). We also make an attempt to differentiate two
these patients have fever from noninfectious causes (47% in Kil- noninfectious causes of fever in NICU, paroxysmal sympathetic
patrick et al. [6] and 25% in Commichau et al. [7]), but this is of- hyperactivity and CF.

© 2020 The Korean Neurocritical Care Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/)
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www.e-jnc.org 19
Keshav Goyal, et al. • Central fever

EPIDEMIOLOGY minalis, or from hormonal changes (progesterone, prostaglandin)

modifying the firing rate of temperature-sensitive neurons in the
Overall in the intensive care unit (ICU), at least 50% of fever are medial preoptic nucleus [40].
reported to be due to noninfectious causes [16]. The incidence of Posttraumatic hyperthermia, also known as neurogenic fever, is
noninfectious fever in the neurology ICU is 23% while in the neu- another common cause of fever. Stimulation studies have suggest-
rosurgical ICU it is 47% [6]. Of these, the highest rates of febrile ed that the mechanism involves an imbalance between the hypo-
episodes occur in patients with subarachnoid hemorrhage (SAH; thalamus and the various temperature regulating centers in the
50% to 65%), followed by traumatic brain injury (TBI; 4% to brainstem and spinal cord [41]. Won and Lin [42], in their study
40%) and intracerebral hemorrhage (ICH; 31%), with no cause conducted on rabbits, found that inhibition of five hydroxytrypt-
of fever identified in 28% of patients, suggesting fever of central amine receptors in the anterior hypothalamus increased heat pro-
origin [7,10,17,18]. Hyperthermia is a frequent complication of duction and decreased heat loss, leading to hyperthermia. Sug-
acute ischemic stroke in 50% of these patients and carries a poor gested mechanisms for this effect include increased metabolic
prognosis [19]. rate, increased carbon dioxide production, decreased cerebral
blood flow, acidosis, brain edema exacerbation, excitotoxic neu-
PATHOPHYSIOLOGY rotransmitter release, and blood-brain barrier breakdown. Dis-
ease-specific mechanisms are also described in Table 1.
An abnormal rise in temperature may be physiological, environ-
mental, or even drug-related, rather than due to infection. The Subarachnoid hemorrhage
mechanism of CF in the NICU is not well defined but the litera- SAH may cause impairment of hypothalamic thermoregulation
ture suggests some probable mechanisms. Inflammatory markers due to the presence of clots in the suprasellar cistern. It may also
causing fever may be triggered by extreme physiologic stress in lead to an intense activation of the sympathetic nervous system,
acute neurologic injury [20,21]. Brain injury may also lead to the leading to peripheral vasoconstriction and thus diminishing the
disruption of the mesencephalic-diencephalic mechanisms re- heat-dissipating mechanisms [43].
sponsible for the inhibition of thermogenesis [22]. Monocytes
and macrophages produce the cytokines interleukin 1 (IL-1), IL- Intracerebral hemorrhage
6, and tumor necrosis factor α (TNF-α), which act on the orga- Intraventricular hemorrhage (IVH) is thought to elevate the tem-
num vasculosum of laminae terminalis. This in turn leads to the perature set point in the hypothalamus by direct damage to the
release of prostaglandin E2 (PGE2) via activation of the cycloox- thermoregulatory centers in the preoptic region, stimulation of
ygenase-2 (COX-2) enzyme. PGE2 acts on the preoptic area of prostaglandin production, or decreased inhibitory feedback from
the hypothalamus leading to an increase in the set point of the hy- the lower midbrain which suppresses thermogenesis [39].
pothalamus, thereby increasing the body temperature [23-34].
Systemic pyrogens, such as IL-1, appear to enter the brain at re- Tumors
gions where there is an incomplete blood-brain barrier (circum- It is hypothesized that a tumor, or its necrotic products, may lead
ventricular organs) and act on the preoptic area of the hypothala- to inflammation of leptomeninges, thus triggering fever [44].
mus to induce fever [24,35-38]. Various neurological events that
take place in febrile patients affect this pathway. Direct hemotoxic Traumatic brain injury
damage to thermoregulatory centers in the preoptic region, inter- While TBI can affect all seven pituitary hormones [45], growth
ference with tonic inhibitory inputs from lower midbrain that or- hormone (GH) deficiency is most frequently reported [46,47].
dinarily suppresses thermogenesis, and stimulation of prostaglan- Patients with GH deficiency have a reduced sweating capacity
din production leading to temperature set point elevation, have all which increases the risk of developing hyperthermia [48]. TBI-in-
been implicated in the causation of CF [39]. CF is speculated to duced hypothalamic-pituitary damage may be due to direct injury
result from damage to the hypothalamus, midbrain, or pons, and to the hypothalamic-pituitary area, a secondary injury from hy-
be enhanced by increased sympathetic activity, opening of the poxia, or increased intracranial pressure [49]. CF in patients with
ventricles, damage to the frontal lobes, physical distortion, diffuse TBI can also be caused by direct injury to the hypothalamus
axonal injury (DAI), or toxic blood metabolites [39]. CF may [15,50]. The development of CF is associated with inflammatory
also be due to the selective loss of warm-sensitive neurons, the os- changes within the hypothalamus [51].
motic changes detected by the organum vasculosum laminae ter-

20 https://doi.org/10.18700/jnc.190090
Table 1. Various neurological diseases and their relation with central fever
Disease Probable mechanisms Risk factors Effects on outcome
TBI 1. GH deficiency 1. Diffuse axonal Injury 1. A negative association between early
peak fever greater than 39℃ and hospital
mortality
2. Direct injury to the hypothalamic-pituitary 2. Frontal lobe injuries 2. Possibility of antibiotic overuse, with the
area or secondary injury from hypoxia or associated risk of the emergence of
increased intracranial pressure. resistant microorganisms
3. Young age, low GCS on presentation, 3. Prolonged coma or unawareness, diabetes
skull fracture, presence of blood in the insipidus and poor outcomes
parenchyma/ventricles, and acute brain
injury.
4. Location of the skull fracture in proximity
to the hypothalamic region (for example,
anterior fossa)
ICH 1. Direct damage to thermoregulatory centres 1. ICH with intraventricular extension 1. High mortality and poor functional outcome
in the preoptic region, stimulation of at 3 months on modified Rankin Scale
prostaglandin production, and decreased
inhibitory feedback from the lower
midbrain which suppresses thermogenesis
2. Larger hematoma volumes 2. Duration of fever was independently
associated with poor outcome in those
who survived past 72 hours.
3. Basal ganglia and thalamic involvement
4. Third ventricular shift

SAH 1. Impair hypothalamic thermoregulation Disease severity, amount of blood in the 1. Even a single episode of fever after SAH is
due to presence of clots in suprasellar subarachnoid space and associated IVH associated with poorer outcomes even in
cistern. best-grade patients.
2. Intense activation of the sympathetic 2. ↑Vasospasm associated with CF
nervous system
3. More severe functional disability and
cognitive impairment among survivors
Tumours Tumour or its necrotic products may lead More prone with tumours located in the Poor outcome
to inflammation of leptomeninges, thus sella, diencephalon, and intraventricular
triggering fever. region
AIS Hypothalamic dysfunction It is probable, larger the ischemia more the 1. May increase volume of the ischemic
chances of CF zone
2.↑ Mortality in stroke patients
TBI, traumatic brain injury; GH, growth hormone; GCS, Glasgow Coma Scale; ICH, intracerebral hemorrhage; SAH, subarachnoid hemorrhage; IVH,
intraventricular hemorrhage; CF, central fever; AIS, acute ischemic stroke.

Etiology ported as follows (Table 1).

CF can occur following any acute brain injury (Table 2) [38,52-
56]. Subarachnoid hemorrhage
Disease severity, amount of blood in the subarachnoid space, and
RISK FACTORS IVH are strong risk factors for the development of fever [7,58,59].

Various predisposing factors have been defined for the occurrence Intracerebral hemorrhage
of CF in the NICU. Independent predictors of CF on multivariate ICH with intraventricular extension and larger hematoma vol-
analysis include blood transfusion, SAH, IVH, tumor, or onset of umes (86.7 ± 66.5 mL CF vs. 33.7 ± 54.4 mL in no fever) are asso-
fever within 72 hours of hospital admission [57]. Intraventricular ciated with an increased probability of developing CF [18]. There
catheterization is a risk factor for unexplained fever, which suggests were no significant differences related to the anatomical location
a role for ventricular hemorrhage in the pathogenesis of CF [7]. of hematoma and presence of CF, but involvement of the basal
Risk factors among various acute neurological conditions are re- ganglia and thalamus showed a trend towards an increased chance

https://doi.org/10.18700/jnc.190090 21
Keshav Goyal, et al. • Central fever

Table 2. Causes of central fever injuries [55]. The etiology of fever following spine injury is not
Subarachnoid haemorrhage thoroughly understood.
Intraventricular haemorrhage
Intracerbral haemorrhage Age
Tumours: sella, diencephalon, and intraventricular region [52]
CF generally occurs in the younger population, as compared to
Traumatic brain injury
infectious fever [57].
Ischemic stroke
Pontine haemorrhage
Tuberculous meningitis [38] Level of consciousness
Following hemispherectomies [53] Depressed level of consciousness has also been identified as an in-
Following hemidecortication [54] dependent predisposing factor for noninfectious fever, mainly at-
Traumatic spine injury [55] tributed to immobilization and the increased atelectasis found in
Basilar artery occlusion [56] these patients [7].

CLINICAL FEATURES OF CENTRAL

of CF [18]. Third ventricular shift in ICH patients is associated FEVER
with fever within 72 hours of admission and high discharge mor-
tality [59]. This is a diagnosis of exclusion. CF occurs early, typically within
72 hours of admission after acute brain injury. All the cultures are
Tumors negative and the chest radiograph is normal. Fever is dispropor-
CF is more frequently associated with tumors located in the sella, tionately high and persistent. The temperature peak is higher
diencephalon, and intraventricular regions [52,57]. when the fever starts earlier, and will be higher when compared to
infectious fever [18]. There is generally less fever-free period and
Traumatic brain injury the cumulative fever load is high, accounting for a longer stay in
Patients with DAI, as shown via imaging, and frontal lobe injuries the NICU. Generally, CF is continuous in nature without diurnal
were independently associated with the presence of CF [60,61]. variations, plateau-like, and without spikes. Patients with CF have
Other risk factors were young age, low Glasgow Coma Scale on relative bradycardia with a notable absence of perspiration. Sus-
presentation, skull fracture, presence of blood in the parenchyma/ tained fever is another factor in favor of CF [57]. Fever is also re-
ventricles, and acute brain injury [62]. CF is more common in se- sistant to antipyretic medications [62,64-67].
verely ill TBI patients with diffuse white matter damage, brain Continuous fever, lasting longer than 6 hours for 2 or more
edema, hyperglycemia, leukocytosis, and hypotension [61]. Fron- consecutive days, has been considered persistent [57]. The com-
tal lobe injury may serve as an indication of hypothalamic injury, bination of negative cultures; absence of infiltrate on chest radio-
given the nature of mechanical forces within the skull during inju- graphs; diagnosis of SAH, IVH, or tumor; and onset of fever with-
ry and the proximity of the hypothalamus to the ventricles. Loca- in 72 hours of admission, predict CF with a probability of 0.90
tion of the skull fracture in proximity to the hypothalamic region [57]. In a study conducted by Thompson et al. [15], fever persist-
(for example, the anterior fossa) may increase this risk [60]. ed for weeks to months in 4% to 37% of patients with TBI. Vaso-
spasm with SAH is also predictive of CF [22].
Ischemic stroke The criteria for systemic inflammatory response syndrome and
Magnetic spectroscopy indicates that the temperature of the isch- leukocytosis are similar to central and infectious fever. This un-
emic zone is higher than in normal areas of the brain. Therefore, derscores the difficulty in differentiating central and infectious fe-
larger ischemic infarcts are likely to increase the chance of CF ver prospectively in the critically ill population. The extreme
[63]. physiologic stress provoked by acute neurologic injury can cause a
rise in inflammatory markers and increased sympathetic response
Traumatic spine injury [21,22]. The percentage of neutrophils is higher in patients with
CF is also reported after traumatic spine injury, with a mean inci- infectious fever, suggesting that while leukocytosis may not be a
dence of 8% [55]. Cervical and thoracic level injuries are more reliable clinical variable to decide whether to use empirical antibi-
commonly associated with fever, as compared to lumbar injuries. otics or discontinue antibiotics early, the presence of a left shift re-
Complete spine injuries have a higher incidence than incomplete mains useful [57].

22 https://doi.org/10.18700/jnc.190090
 Extreme hyperpyrexia, defined as fever ≥ 41.1℃ (106°F), is tious from noninfectious causes, including serum procalcitonin
usually noninfectious. Examples include CF, drug fever, malignant (PCT) assays, endotoxin detection systems, triggering receptor
hyperthermia, transfusion reactions, adrenal insufficiency, thyroid expressed on myeloid cells-S (TREM-1), C-reactive protein,
storm, neuroleptic malignant syndrome, heat stroke, acalculous TNF-α, and IL-6. PCT of 0.5 ng/mL or greater was useful in dif-
cholecystitis, mesenteric ischemia, acute pancreatitis, deep vein ferentiating infectious fever from CF in SAH and ICH patients
thrombosis, and pulmonary embolism [68,69]. A single fever [73]. This test is shown to have high specificity and a reasonably
spike of 102°F is classical for noninfectious disorders and is never high negative predictive value. A decision tree has been suggested
due to infection. Fever associated with blood transfusions are usu- by Hocker et al. [57], but no specific diagnostic paradigm has
ally transient, that is, they present as a single fever spike within < 1 been suggested for universal usage.
week [68,70].
DIFFERENTIAL DIAGNOSIS
TEMPERATURE PULSE RELATIONSHIP
Some common differential diagnoses are important to be distin-
Relative bradycardia is a feature of CF. The following applies to guished before making a diagnosis of CF, since it a diagnosis of ex-
adult patients with temperatures > 102°F and when pulse is taken clusion. Nonresponse to antibiotics in CF may lead to misdiagno-
simultaneously with temperature. Normally, the pulse rises in sis of antibiotic failure or resistance in CF (Table 4).
concert with the temperature, (e.g., for every degree Fahrenheit
temperature is increased, the pulse should rise 10 beats/min). If Bacteremia
the pulse rate is lower than predicted from a given temperature Bacteremia should be investigated by sending at least three blood
( > 102°F), then relative bradycardia is present, unless the patient cultures within 24 hours of suspected infection. Each culture
is on a beta-blocker, verapamil or diltiazem, or has a pacemak- should be sent from a separate venepuncture site or intravascular
er-induced rhythm or heart block. In absence of these exclusion device. Intravascular catheters should be suspected as an infection
criteria, relative bradycardia in neurosurgical ICU patients with risk in young nonimmune compromised patients with abrupt on-
fever strongly suggests a central or drug fever (Table 3) [71]. set of septicemia. These patients may have inflammation at the
site of insertion that can provide a clue to the diagnosis, though
Diagnosis this is absent in 60% of patients. Difficulty in drawing a sample
A high index of suspicion is needed for the diagnosis of CF. Diag- from the line may be another indicator of intravenous catheter-re-
nosis of CF is a diagnosis of exclusion in predisposed patients lated infection.
with neurological injury. The practice guidelines from the task
force of the Society for Critical Care Medicine suggest a “careful Ventilator-associated pneumonia
clinical assessment” and “cost-conscious approach” for obtaining a Ventilator-associated pneumonia is the second most common
diagnosis through laboratory and radiological tests [72]. The clin- cause of infectious fever in any ICU. It is distinguished by a culture
ical signs of pneumonia, bacteremia, sinusitis, urinary tract infec- of respiratory secretion which can be obtained by various tech-
tion, catheter site infection, meningitis, or ventriculitis should be niques, including expectoration, nasopharyngeal washing, saline
investigated. A chest radiograph, culture of blood, urine and tra- induction, deep tracheal suctioning, bronchoscopic specimen/
chea are the baseline tests done in all cases. Any long-standing ve- brush samples, aspiration, and bronchoscopic or nonbroncho-
nous line or catheter should also be removed. scopic lavage (mini-BAL). Chest radiography for abscess, atelecta-
Certain biomarkers have been developed to differentiate infec- sis, effusion, and consolidation should also be done.

Urinary tract infection

Table 3. Temperature pulse relationship Urinary tract infection is the next leading cause of fever. Diagnosis
Temperature (°F) Appropriate pulse response (/min) Relative bradycardia is excluded by sending urine for direct microscopic examination,
106 150 <140 staining, and culture.
105 140 <130
104 130 <120 Diarrhea
103 120 <110 Diarrhea is another important cause of fever in the ICU. It should
102 110 <100 be suspected in any patient with diarrhea and who has been given

https://doi.org/10.18700/jnc.190090 23
Keshav Goyal, et al. • Central fever

Table 4. Differential diagnosis of fever in neurointensive care unit

Infectious causes Deep venous thrombosis
Ventilator-associated pneumonia Pulmonary emboli
Sinusitis Neurological diseases
Meningitis Increased intracranial pressure
Encephalitis Nonconvulsive status epilepticus
Catheter-related sepsis Autonomic dysreflexia
Sepsis Cushing response
Clostridium difficile diarrhea Agitation
Abdominal sepsis Dystonia
Complicated wound infections Malignant catatonia
Urinary tract infection Stiffman syndrome
Acute respiratory distress syndrome, both late and fibro-proliferative Paroxysmal sympathetic hyperactivity
stage Mixed autonomic hyperactivity syndrome
Systemic inflammatory response syndrome Drugs/Toxins
Noninfectious causes Delirium
Alcohol/drug withdrawal Serotonin syndrome
Postoperative fever (48 hours postoperative) Acute drug withdrawal (intrathecal baclofen, dopamine agents)
Post-transfusion fever Narcotic withdrawal
Drug fever Neuroleptic syndrome
Connective tissue disease Malignant hyperthermia
Myocardial infarction Scorpion envenomation
Pancreatitis Gamma hydroxybutyrate intoxication
Acalculous cholecystitis Fenfluramine-phentirmine overdose
Ischemic bowel (without primary peritonitis) Drug overdoses (e.g., aspirin, anticholinergic drugs)
Gastrointestinal bleed Endocrine diseases
Aspiration pneumonitis
Pheochromocytoma
Fat emboli
Thyroid storm
Gout/pseudo gout
Adrenal insufficiency
Transplant rejection
Other diseases
Hematoma
Cirrhosis Carotid sinus injury
Decubitus ulcer Baroreceptor failure
Phlebitis/thrombophlebitis Renal artery stenosis
Intravenous contrast reaction Irukandji syndrome
Neoplastic fever

antibiotic treatment or chemotherapy in the past 60 days. The Surgical site infection
most common organism implicated is Clostridium difficile [74,75]. Surgical site infection accounts for 3% of fever in the ICU, which
It can be excluded by enzyme immunosorbent assay (EIA) for can easily be diagnosed by local inspection and cultures from the
detecting toxins A and B, or by culture (though it is more time wound site [77,78]. Abscess in the lung, abdomen or any other
consuming). region may also be a cause of fever.

Sinusitis Drug fever

Sinusitis is an uncommon cause of fever in the ICU, but may have Drug fever is caused by some commonly used drugs in the NICU,
a grave impact on patient outcomes. Risk factors include obstruc- such as phenytoin, salicylates, barbiturates, methyldopa, furose-
tion of the ostia draining the sinuses, nasal intubation of trachea, mide, penicillin, cephalosporin, sulfonamide, amphotericin B,
or the passage of a nasogastric tube. Though occult, it can spread rarely corticosteroids, clindamycin, tetracycline, macrolide. Onset
to the brain, lungs, and blood, leading to serious consequences of fever is usually within 1 to 2 weeks of drug initiation, and it can
[76]. It can be ruled out by a radiograph, ultrasound, magnetic easily be diagnosed by stopping the drug. Suspicion of drug fever
resonance imaging or computed tomography scan transnasal can also arise from relative bradycardia and the patient being inap-
puncture. propriately well for the degree of fever. Fever usually disappears
within 3 days of stopping drugs or antibiotics in such cases

24 https://doi.org/10.18700/jnc.190090
Table 5. Paroxysmal sympathetic hyperactivity vs. central fever
Feature PSH CF
Onset Usually after a week of ABI and may last up to 1 year. Occurs within 72 hours of ABI
Generally seen after cessation of ICU sedation
Associated signs and symptoms Tachycardia, hypertension, tachypnoea, dystonia, diaphoresis No such association
Fever At least one episode per day for 3 consecutive days (2–3 Unusually high fever remains for most of the time
cycles/day) (plateau-like with no diurnal variation)
Trigger Essential diagnostic criteria (mostly nonnoxious stimuli) No such trigger defined
Mechanism Excitatory-inhibitory model: most commonly accepted Inflammatory cytokines increase the set point of
hypothalamus
Leukocytosis Generally absent Present
Heart rate Tachycardia Relative bradycardia
Sweating Generally present Absent
Posturing/Dystonia Generally present (one of the diagnostic criteria) Absent
Pupil size Usually increased Normal
Paroxysmal nature Yes No
Most common pathology TBI SAH
Diagnostic criteria Defined by multidisciplinary international committee No such diagnostic criteria
(diagnostic likelihood tool)
Core clinical features Six core sympathetic and motor clinical features No such clinical features
PSH, paroxysmal sympathetic hyperactivity; CF, central fever; ABI, acute brain injury; ICU, intensive care unit; TBI, traumatic brain injury; SAH,
subarachnoid hemorrhage.

[71,79]. [85], who found increased patient mortality when fever was ag-
Other differential diagnoses are listed in Table 4. gressively controlled, although it should be noted that these were
nonneurological trauma patients. Fever is also found to increase
PAROXYSMAL SYMPATHETIC the length of ICU stay [8,9].
HYPERACTIVITY VS. CENTRAL FEVER The brain injury patient is at risk of secondary injury from fever,
as for every 1°C rise in body temperature there is a 13% increase
Both are diagnoses of exclusion in patients with neurological inju- in the metabolic rate [86]. Increased body temperature causes
ries during their stay in neurocritical care. They both occur in the permanent neuronal damage and worsens prognosis in animal
NICU in acute brain-injury patients. Differentiating one from the models of ischemic brain injury [40,87-91]. Fever is also known
other is very crucial in proper care and appropriate management, to increase delirium and agitation [92,93]. However, fever is not
and thus ultimately affects patient outcomes. Differentiating fea- found to increase intracranial pressure [94]. Fever also increases
tures are listed in Table 5. cardiac output, oxygen consumption, and heart rate [95]. This in-
creased demand on the heart is poorly compensated in patients
Impact on outcome with previously compromised cardiac function and in sepsis [96].
Fever predisposes the brain to harmful effects by disrupting the Fever has also been associated with increased multiorgan dysfunc-
blood-brain barrier, an increasing excitatory amino acid release, tion and mortality [97]. Higher temperature is further associated
and increasing the production of free radicals [80]. There is an ex- with cell protein denaturation, susceptibility to acid-base and
acerbation of neuronal injury in fever. The permeability of the electrolyte disturbances, and impaired oxygen release [98].
blood-brain barrier is related to body temperature and higher
temperatures increase the extravasation of proteins [81,82]. There Subarachnoid hemorrhage
is a lack of literature for a definitive association between the dura- Even a single episode of fever after SAH is associated with poorer
tion of fever and increased mortality. Studies conducted by Circi- outcomes, even in good-grade patients [99]. Vasospasm in SAH
umaru et al. [83] and Peres Bota et al. [84] found that fever lasting patients is associated with CF, independent of hemorrhage severi-
longer than 5 days was associated with increased mortality. These ty or the presence of infection [7,12,22,57,100-102]. Treat-
results are in contrast to a study conducted by Schulman et al. ment-refractory fever during the first 10 days after SAH is associ-

https://doi.org/10.18700/jnc.190090 25
Keshav Goyal, et al. • Central fever

ated with increased mortality, more severe functional disability, cooling devices have also been reported to increase the incidence
and cognitive impairment among survivors [58]. Cumulative fe- of shivering, increase oxygen consumption and even cause ther-
ver burden, defined as the sum of time with temperatures mal burns [107,108]. Hypothermia blankets can lead to large
> 38.3℃ in the first 13 days, is associated with worse outcomes, temperature fluctuations [109,110]. Air blankets have been in-
including incomplete recovery in good-grade SAH patients and creasingly used and are found to have better efficacy and produce
potentially late recovery in poor-grade patients [102]. better patient comfort [110]. Some authors have suggested the
use of sand body-conformed wraps, intravascular cooling devices,
Intracerebral hemorrhage head-only cooling caps, or inhaled perfluorocarbon cooling sys-
The presence of CF leads to poor outcomes and is an indepen- tems [111].
dent risk factor for mortality in ICH patients [18]. This results in Several studies have tried intravenous infusion of cold saline,
high mortality and poor functional outcomes at 3 months on the showing promising results and no increase in complications
modified Rankin Scale. In one study, the presence of CF led to [112]. A few studies have tried local (brain) cooling. This may
unfavorable outcomes in 100% cases at 90 days postictus, while prevent the side effects of global hypothermia, such as impaired
the absence of fever was associated with unfavorable outcomes in coagulation, arrhythmias and deep vein thrombosis [113-116].
only 46.9% of patients [18]. In a retrospective study of 251 pa- However, no large multicentre trial is available, leading to no de-
tients with spontaneous ICH, the duration of fever was inde- finitive conclusions on the use of selective brain cooling.
pendently associated with poor outcomes in those who survived IL-1 antagonists have been shown to produce significant im-
past 72 hours [14]. provements in rat models of TBI [117], although no human trials
have been conducted. However, it has been shown that even a
Acute ischemic stroke small temperature decrease in febrile patients can improve neuro-
Pyrexia in experimental animals may increase the volume of the logic outcomes [118].
ischemic zone [40,84-87]. Also, fever greater than 39℃ increases
mortality in stroke patients [103]. Morphine
Remission of CF is reported with morphine post-TBI [119].
Traumatic brain injury
In a cohort of more than 100,000 patients, a negative association Chlorpromazine
was observed between early peak fever greater than 39℃ and hos- Sometimes, when traditional management fails, chlorpromazine
pital mortality in patients with TBI [103]. Further, this correla- has been tried with variable success. Chlorpromazine produces
tion was not seen in patients with central nervous system infec- antipyretic actions because of its ability to render the patient ther-
tion. Because CF starts earlier and lasts longer than infectious fe- molabile and its effect on thermoregulation [120,121]. Hyperpy-
ver, there is a high risk of antibiotic overuse and the associated risk rexia following hemispherectomy has been reported to respond to
of the emergence of resistant microorganisms [57]. CF may be as- chlorpromazine [121].
sociated with prolonged coma or unawareness, diabetes insipidus,
and overall poor outcomes [50,64,65,67,104]. Baclofen
Baclofen successfully abolished prolonged central hyperthermia
TREATMENT in a patient with basilar artery occlusion leading to brain stem in-
farction [56].
Although many treatment regimens have been suggested, none
have been identified as superior to others in the treatment of fever Bromocriptine
[65,105]. However, controlling fever is an important part of man- There are anecdotal case reports of the successful use of bro-
agement in CF, owing to its detrimental effects on the brain. Phar- mocriptine for treatment of CF [122,123].
macologic methods include acetaminophen, acetylsalicylic acid,
and other nonsteroidal antiinflammatory medications and corti- Growth hormone therapy
costeroids [106,107]. Successful treatment of CF by GH therapy has been reported,
Other methods to decrease temperature include rotary fans, with the mechanism related to the improvement of sweat produc-
sponging, and surface cooling devices. However, these have had tion [124].
limited efficacy and are uncomfortable for the patient. Surface

26 https://doi.org/10.18700/jnc.190090
FUTURE DIRECTIONS 2. Laupland KB. Fever in the critically ill medical patient. Crit
Care Med 2009;37(7 Suppl):S273-8.
There are no guidelines or directions to help differentiate CF 3. Grunau BE, Wiens MO, Brubacher JR. Dantrolene in the treat-
from other noninfectious causes of fever in the NICU. The litera- ment of MDMA-related hyperpyrexia: a systematic review.
ture is sparse and unclear. The diagnostic criteria are not well de- CJEM 2010;12:435-42.
fined and not standardized. Treatment modalities for this clinical 4. Sharma HS. Neurobiology of hyperthermia. Amsterdam: Else-
entity have been symptomatic only and mostly rely on over the vier; 2007:175-7. 485.
counter drugs. No standard therapy has been defined in the litera- 5. Albrecht RF 2nd, Wass CT, Lanier WL. Occurrence of poten-
ture. Multicentre large studies are required to better define CF, tially detrimental temperature alterations in hospitalized pa-
understand its pathophysiology, and guide standard management tients at risk for brain injury. Mayo Clin Proc 1998;73:629-35.
protocols in neurocritical care settings. 6. Kilpatrick MM, Lowry DW, Firlik AD, Yonas H, Marion DW.
Hyperthermia in the neurosurgical intensive care unit. Neuro-
CONCLUSION surgery 2000;47:850-6.
7. Commichau C, Scarmeas N, Mayer SA. Risk factors for fever in
CF is an important diagnosis in neurocritical care. It not only pre- the neurologic intensive care unit. Neurology 2003;60:837-41.
vents unnecessary antibiotic use, but its early recognition would 8. Diringer MN, Reaven NL, Funk SE, Uman GC. Elevated body
also help improve patient management and prevent delayed dis- temperature independently contributes to increased length of
charge from the hospital. The current key to diagnosis in a predis- stay in neurologic intensive care unit patients. Crit Care Med
posed patient is a high index of suspicion, along with thorough 2004;32:1489-95.
clinical examination, radiological, microbiological, and biochemi- 9. Stocchetti N, Rossi S, Zanier ER, Colombo A, Beretta L, Cite-
cal tests. Immediate attainment of normothermia is the current rio G. Pyrexia in head-injured patients admitted to intensive
recommendation, as fever worsens the brain insult. Treatment in- care. Intensive Care Med 2002;28:1555-62.
cludes various pharmacological agents and surface cooling meth- 10. Laws C, Jallo J. Fever and infection in the neurosurgical inten-
ods to decrease body temperature. Studies are lacking on the best sive care unit. JHN J 2010;5:5.
methods for diagnosis, treatment, and prevention of CF. Thus, 11. Erickson TC. Neurogenic hyperthermia: a clinical syndrome
more human trials are needed in this field to make any definitive and its treatment. Brain 1939;62:172-90.
recommendations. 12. Oliveira-Filho J, Ezzeddine MA, Segal AZ, Buonanno FS,
Chang Y, Ogilvy CS, et al. Fever in subarachnoid hemorrhage:
ARTICLE INFORMATION relationship to vasospasm and outcome. Neurology 2001;
56:1299-304.
Conflict of interest 13. Rossi S, Zanier ER, Mauri I, Columbo A, Stocchetti N. Brain
No potential conflict of interest relevant to this article. temperature, body core temperature, and intracranial pressure
in acute cerebral damage. J Neurol Neurosurg Psychiatry
ORCID 2001;71:448-54.
Keshav Goyal, https://orcid.org/0000-0001-9139-0689 14. Schwarz S, Häfner K, Aschoff A, Schwab S. Incidence and
Neha Garg, https://orcid.org/0000-0003-4817-9807 prognostic significance of fever following intracerebral hemor-
Parmod Bithal, https://orcid.org/0000-0001-5348-2814 rhage. Neurology 2000;54:354-61.
15. Thompson HJ, Tkacs NC, Saatman KE, Raghupathi R, McIn-
Author contributions tosh TK. Hyperthermia following traumatic brain injury: a
Conceptualization: KG, NG, and PB. Data curation & Formal critical evaluation. Neurobiol Dis 2003;12:163-73.
analysis: KG, NG, and PB. Visualization & Writing–original draft: 16. Dimopoulos G, Falagas ME. Approach to the febrile patient in
KG and PB. Writing–review editing: KG and NG. the ICU. Infect Dis Clin North Am 2009;23:471-84.
17. Otawara Y, Ogasawara K, Kubo Y, Tomitsuka N, Ogawa A, Su-
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