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Central fever: a challenging clinical entity in neurocritical care

Fever is probably the most frequent symptom observed in the neurointensive care unit (NICU) by healthcare providers. An oral temperature greater than 37.5°C is considered a fever [1,2]. Hyperpyrexia is usually a diagnosis of exclusion, with temperatures exceeding 41°C and nonresponsiveness to antipyretic treatment [3,4]. Fever is seen in almost 70% of neurocritically ill patients [5-10]. Fever of central origin was first described by in the journal Brain by Erickson [11] in 1939. A significant number of these patients have fever from noninfectious causes (47% in Kilpatrick et al. [6] and 25% in Commichau et al. [7]), but this is ofCentral fever: a challenging clinical entity in neurocritical care Keshav Goyal, MD, DM; Neha Garg, MD; Parmod Bithal, MD Department of Neuroanaesthesiology and Critical Care, Neurosciences Centre, All India Institute of Medical Sciences, New Delhi, India Institute of Liver and Biliary Science, Delhi, India Department of Anesthesiology, King Fahd Medical City, Riyadh, Saudi Arabia Review Article

INTRODUCTION minalis, or from hormonal changes (progesterone, prostaglandin) modifying the firing rate of temperature-sensitive neurons in the medial preoptic nucleus [40].
Posttraumatic hyperthermia, also known as neurogenic fever, is another common cause of fever. Stimulation studies have suggested that the mechanism involves an imbalance between the hypothalamus and the various temperature regulating centers in the brainstem and spinal cord [41]. Won and Lin [42], in their study conducted on rabbits, found that inhibition of five hydroxytryptamine receptors in the anterior hypothalamus increased heat production and decreased heat loss, leading to hyperthermia. Suggested mechanisms for this effect include increased metabolic rate, increased carbon dioxide production, decreased cerebral blood flow, acidosis, brain edema exacerbation, excitotoxic neurotransmitter release, and blood-brain barrier breakdown. Disease-specific mechanisms are also described in Table 1.

Subarachnoid hemorrhage
SAH may cause impairment of hypothalamic thermoregulation due to the presence of clots in the suprasellar cistern. It may also lead to an intense activation of the sympathetic nervous system, leading to peripheral vasoconstriction and thus diminishing the heat-dissipating mechanisms [43].

Intracerebral hemorrhage
Intraventricular hemorrhage (IVH) is thought to elevate the temperature set point in the hypothalamus by direct damage to the thermoregulatory centers in the preoptic region, stimulation of prostaglandin production, or decreased inhibitory feedback from the lower midbrain which suppresses thermogenesis [39].

Tumors
It is hypothesized that a tumor, or its necrotic products, may lead to inflammation of leptomeninges, thus triggering fever [44].

Traumatic brain injury
While TBI can affect all seven pituitary hormones [45], growth hormone (GH) deficiency is most frequently reported [46,47]. Patients with GH deficiency have a reduced sweating capacity which increases the risk of developing hyperthermia [48]. TBI-induced hypothalamic-pituitary damage may be due to direct injury to the hypothalamic-pituitary area, a secondary injury from hypoxia, or increased intracranial pressure [49]. CF in patients with TBI can also be caused by direct injury to the hypothalamus [15,50]. The development of CF is associated with inflammatory changes within the hypothalamus [51].

RISK FACTORS
Various predisposing factors have been defined for the occurrence of CF in the NICU. Independent predictors of CF on multivariate analysis include blood transfusion, SAH, IVH, tumor, or onset of fever within 72 hours of hospital admission [57]. Intraventricular catheterization is a risk factor for unexplained fever, which suggests a role for ventricular hemorrhage in the pathogenesis of CF [7]. Risk factors among various acute neurological conditions are re-ported as follows (Table 1).

Subarachnoid hemorrhage
Disease severity, amount of blood in the subarachnoid space, and IVH are strong risk factors for the development of fever [7,58,59].

Intracerebral hemorrhage
ICH with intraventricular extension and larger hematoma volumes (86.7 ± 66.5 mL CF vs. 33.7 ± 54.4 mL in no fever) are associated with an increased probability of developing CF [18]. There were no significant differences related to the anatomical location of hematoma and presence of CF, but involvement of the basal ganglia and thalamus showed a trend towards an increased chance of CF [18]. Third ventricular shift in ICH patients is associated with fever within 72 hours of admission and high discharge mortality [59].

Tumors
CF is more frequently associated with tumors located in the sella, diencephalon, and intraventricular regions [52,57].

Traumatic brain injury
Patients with DAI, as shown via imaging, and frontal lobe injuries were independently associated with the presence of CF [60,61]. Other risk factors were young age, low Glasgow Coma Scale on presentation, skull fracture, presence of blood in the parenchyma/ ventricles, and acute brain injury [62]. CF is more common in severely ill TBI patients with diffuse white matter damage, brain edema, hyperglycemia, leukocytosis, and hypotension [61]. Frontal lobe injury may serve as an indication of hypothalamic injury, given the nature of mechanical forces within the skull during injury and the proximity of the hypothalamus to the ventricles. Location of the skull fracture in proximity to the hypothalamic region (for example, the anterior fossa) may increase this risk [60].

Ischemic stroke
Magnetic spectroscopy indicates that the temperature of the ischemic zone is higher than in normal areas of the brain. Therefore, larger ischemic infarcts are likely to increase the chance of CF [63].

Traumatic spine injury
CF is also reported after traumatic spine injury, with a mean incidence of 8% [55]. Cervical and thoracic level injuries are more commonly associated with fever, as compared to lumbar injuries. Complete spine injuries have a higher incidence than incomplete injuries [55]. The etiology of fever following spine injury is not thoroughly understood.

Age
CF generally occurs in the younger population, as compared to infectious fever [57].

Level of consciousness
Depressed level of consciousness has also been identified as an independent predisposing factor for noninfectious fever, mainly attributed to immobilization and the increased atelectasis found in these patients [7].

CLINICAL FEATURES OF CENTRAL FEVER
This is a diagnosis of exclusion. CF occurs early, typically within 72 hours of admission after acute brain injury. All the cultures are negative and the chest radiograph is normal. Fever is disproportionately high and persistent. The temperature peak is higher when the fever starts earlier, and will be higher when compared to infectious fever [18]. There is generally less fever-free period and the cumulative fever load is high, accounting for a longer stay in the NICU. Generally, CF is continuous in nature without diurnal variations, plateau-like, and without spikes. Patients with CF have relative bradycardia with a notable absence of perspiration. Sustained fever is another factor in favor of CF [57]. Fever is also resistant to antipyretic medications [62,[64][65][66][67].
Continuous fever, lasting longer than 6 hours for 2 or more consecutive days, has been considered persistent [57]. The combination of negative cultures; absence of infiltrate on chest radiographs; diagnosis of SAH, IVH, or tumor; and onset of fever within 72 hours of admission, predict CF with a probability of 0.90 [57]. In a study conducted by Thompson et al. [15], fever persisted for weeks to months in 4% to 37% of patients with TBI. Vasospasm with SAH is also predictive of CF [22].
The criteria for systemic inflammatory response syndrome and leukocytosis are similar to central and infectious fever. This underscores the difficulty in differentiating central and infectious fever prospectively in the critically ill population. The extreme physiologic stress provoked by acute neurologic injury can cause a rise in inflammatory markers and increased sympathetic response [21,22]. The percentage of neutrophils is higher in patients with infectious fever, suggesting that while leukocytosis may not be a reliable clinical variable to decide whether to use empirical antibiotics or discontinue antibiotics early, the presence of a left shift remains useful [57].  [38] Following hemispherectomies [53] Following hemidecortication [54] Traumatic spine injury [55] Basilar artery occlusion [56] https://doi.org/10.18700/jnc.190090 Extreme hyperpyrexia, defined as fever ≥ 41.1℃ (106°F), is usually noninfectious. Examples include CF, drug fever, malignant hyperthermia, transfusion reactions, adrenal insufficiency, thyroid storm, neuroleptic malignant syndrome, heat stroke, acalculous cholecystitis, mesenteric ischemia, acute pancreatitis, deep vein thrombosis, and pulmonary embolism [68,69]. A single fever spike of 102°F is classical for noninfectious disorders and is never due to infection. Fever associated with blood transfusions are usually transient, that is, they present as a single fever spike within < 1 week [68,70].

TEMPERATURE PULSE RELATIONSHIP
Relative bradycardia is a feature of CF. The following applies to adult patients with temperatures > 102°F and when pulse is taken simultaneously with temperature. Normally, the pulse rises in concert with the temperature, (e.g., for every degree Fahrenheit temperature is increased, the pulse should rise 10 beats/min). If the pulse rate is lower than predicted from a given temperature ( > 102°F), then relative bradycardia is present, unless the patient is on a beta-blocker, verapamil or diltiazem, or has a pacemaker-induced rhythm or heart block. In absence of these exclusion criteria, relative bradycardia in neurosurgical ICU patients with fever strongly suggests a central or drug fever (Table 3) [71].

Diagnosis
A high index of suspicion is needed for the diagnosis of CF. Diagnosis of CF is a diagnosis of exclusion in predisposed patients with neurological injury. The practice guidelines from the task force of the Society for Critical Care Medicine suggest a "careful clinical assessment" and "cost-conscious approach" for obtaining a diagnosis through laboratory and radiological tests [72]. The clinical signs of pneumonia, bacteremia, sinusitis, urinary tract infection, catheter site infection, meningitis, or ventriculitis should be investigated. A chest radiograph, culture of blood, urine and trachea are the baseline tests done in all cases. Any long-standing venous line or catheter should also be removed.
Certain biomarkers have been developed to differentiate infec-tious from noninfectious causes, including serum procalcitonin (PCT) assays, endotoxin detection systems, triggering receptor expressed on myeloid cells-S (TREM-1), C-reactive protein, TNF-α, and IL-6. PCT of 0.5 ng/mL or greater was useful in differentiating infectious fever from CF in SAH and ICH patients [73]. This test is shown to have high specificity and a reasonably high negative predictive value. A decision tree has been suggested by Hocker et al. [57], but no specific diagnostic paradigm has been suggested for universal usage.

DIFFERENTIAL DIAGNOSIS
Some common differential diagnoses are important to be distinguished before making a diagnosis of CF, since it a diagnosis of exclusion. Nonresponse to antibiotics in CF may lead to misdiagnosis of antibiotic failure or resistance in CF (Table 4).

Bacteremia
Bacteremia should be investigated by sending at least three blood cultures within 24 hours of suspected infection. Each culture should be sent from a separate venepuncture site or intravascular device. Intravascular catheters should be suspected as an infection risk in young nonimmune compromised patients with abrupt onset of septicemia. These patients may have inflammation at the site of insertion that can provide a clue to the diagnosis, though this is absent in 60% of patients. Difficulty in drawing a sample from the line may be another indicator of intravenous catheter-related infection.

Ventilator-associated pneumonia
Ventilator-associated pneumonia is the second most common cause of infectious fever in any ICU. It is distinguished by a culture of respiratory secretion which can be obtained by various techniques, including expectoration, nasopharyngeal washing, saline induction, deep tracheal suctioning, bronchoscopic specimen/ brush samples, aspiration, and bronchoscopic or nonbronchoscopic lavage (mini-BAL). Chest radiography for abscess, atelectasis, effusion, and consolidation should also be done.

Urinary tract infection
Urinary tract infection is the next leading cause of fever. Diagnosis is excluded by sending urine for direct microscopic examination, staining, and culture.

Diarrhea
Diarrhea is another important cause of fever in the ICU. It should be suspected in any patient with diarrhea and who has been given antibiotic treatment or chemotherapy in the past 60 days. The most common organism implicated is Clostridium difficile [74,75]. It can be excluded by enzyme immunosorbent assay (EIA) for detecting toxins A and B, or by culture (though it is more time consuming).

Sinusitis
Sinusitis is an uncommon cause of fever in the ICU, but may have a grave impact on patient outcomes. Risk factors include obstruction of the ostia draining the sinuses, nasal intubation of trachea, or the passage of a nasogastric tube. Though occult, it can spread to the brain, lungs, and blood, leading to serious consequences [76]. It can be ruled out by a radiograph, ultrasound, magnetic resonance imaging or computed tomography scan transnasal puncture.

Surgical site infection
Surgical site infection accounts for 3% of fever in the ICU, which can easily be diagnosed by local inspection and cultures from the wound site [77,78]. Abscess in the lung, abdomen or any other region may also be a cause of fever.

Drug fever
Drug fever is caused by some commonly used drugs in the NICU, such as phenytoin, salicylates, barbiturates, methyldopa, furosemide, penicillin, cephalosporin, sulfonamide, amphotericin B, rarely corticosteroids, clindamycin, tetracycline, macrolide. Onset of fever is usually within 1 to 2 weeks of drug initiation, and it can easily be diagnosed by stopping the drug. Suspicion of drug fever can also arise from relative bradycardia and the patient being inappropriately well for the degree of fever. Fever usually disappears within 3 days of stopping drugs or antibiotics in such cases [71,79].
Other differential diagnoses are listed in Table 4.

PAROXYSMAL SYMPATHETIC HYPERACTIVITY VS. CENTRAL FEVER
Both are diagnoses of exclusion in patients with neurological injuries during their stay in neurocritical care. They both occur in the NICU in acute brain-injury patients. Differentiating one from the other is very crucial in proper care and appropriate management, and thus ultimately affects patient outcomes. Differentiating features are listed in Table 5.

Impact on outcome
Fever predisposes the brain to harmful effects by disrupting the blood-brain barrier, an increasing excitatory amino acid release, and increasing the production of free radicals [80]. There is an exacerbation of neuronal injury in fever. The permeability of the blood-brain barrier is related to body temperature and higher temperatures increase the extravasation of proteins [81,82]. There is a lack of literature for a definitive association between the duration of fever and increased mortality. Studies conducted by Circiumaru et al. [83] and Peres Bota et al. [84] found that fever lasting longer than 5 days was associated with increased mortality. These results are in contrast to a study conducted by Schulman et al. [85], who found increased patient mortality when fever was aggressively controlled, although it should be noted that these were nonneurological trauma patients. Fever is also found to increase the length of ICU stay [8,9]. 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 in the metabolic rate [86]. Increased body temperature causes permanent neuronal damage and worsens prognosis in animal models of ischemic brain injury [40,[87][88][89][90][91]. Fever is also known to increase delirium and agitation [92,93]. However, fever is not found to increase intracranial pressure [94]. Fever also increases cardiac output, oxygen consumption, and heart rate [95]. This increased demand on the heart is poorly compensated in patients with previously compromised cardiac function and in sepsis [96]. Fever has also been associated with increased multiorgan dysfunction and mortality [97]. Higher temperature is further associated with cell protein denaturation, susceptibility to acid-base and electrolyte disturbances, and impaired oxygen release [98].

Subarachnoid hemorrhage
Even a single episode of fever after SAH is associated with poorer outcomes, even in good-grade patients [99]. Vasospasm in SAH patients is associated with CF, independent of hemorrhage severity or the presence of infection [7,12,22,57,[100][101][102]. Treatment-refractory fever during the first 10 days after SAH is associ- ated with increased mortality, more severe functional disability, and cognitive impairment among survivors [58]. Cumulative fever burden, defined as the sum of time with temperatures > 38.3℃ in the first 13 days, is associated with worse outcomes, including incomplete recovery in good-grade SAH patients and potentially late recovery in poor-grade patients [102].

Intracerebral hemorrhage
The presence of CF leads to poor outcomes and is an independent risk factor for mortality in ICH patients [18]. This results in high mortality and poor functional outcomes at 3 months on the modified Rankin Scale. In one study, the presence of CF led to unfavorable outcomes in 100% cases at 90 days postictus, while the absence of fever was associated with unfavorable outcomes in only 46.9% of patients [18]. In a retrospective study of 251 patients with spontaneous ICH, the duration of fever was independently associated with poor outcomes in those who survived past 72 hours [14].

Traumatic brain injury
In a cohort of more than 100,000 patients, a negative association was observed between early peak fever greater than 39℃ and hospital mortality in patients with TBI [103]. Further, this correlation was not seen in patients with central nervous system infection. Because CF starts earlier and lasts longer than infectious fever, there is a high risk of antibiotic overuse and the associated risk of the emergence of resistant microorganisms [57]. CF may be associated with prolonged coma or unawareness, diabetes insipidus, and overall poor outcomes [50,64,65,67,104].

TREATMENT
Although many treatment regimens have been suggested, none have been identified as superior to others in the treatment of fever [65,105]. However, controlling fever is an important part of management in CF, owing to its detrimental effects on the brain. Pharmacologic methods include acetaminophen, acetylsalicylic acid, and other nonsteroidal antiinflammatory medications and corticosteroids [106,107]. Other methods to decrease temperature include rotary fans, sponging, and surface cooling devices. However, these have had limited efficacy and are uncomfortable for the patient. Surface cooling devices have also been reported to increase the incidence of shivering, increase oxygen consumption and even cause thermal burns [107,108]. Hypothermia blankets can lead to large temperature fluctuations [109,110]. Air blankets have been increasingly used and are found to have better efficacy and produce better patient comfort [110]. Some authors have suggested the use of sand body-conformed wraps, intravascular cooling devices, head-only cooling caps, or inhaled perfluorocarbon cooling systems [111].
Several studies have tried intravenous infusion of cold saline, showing promising results and no increase in complications [112]. A few studies have tried local (brain) cooling. This may prevent the side effects of global hypothermia, such as impaired coagulation, arrhythmias and deep vein thrombosis [113][114][115][116]. However, no large multicentre trial is available, leading to no definitive conclusions on the use of selective brain cooling.
IL-1 antagonists have been shown to produce significant improvements in rat models of TBI [117], although no human trials have been conducted. However, it has been shown that even a small temperature decrease in febrile patients can improve neurologic outcomes [118].

Morphine
Remission of CF is reported with morphine post-TBI [119].

Chlorpromazine
Sometimes, when traditional management fails, chlorpromazine has been tried with variable success. Chlorpromazine produces antipyretic actions because of its ability to render the patient thermolabile and its effect on thermoregulation [120,121]. Hyperpyrexia following hemispherectomy has been reported to respond to chlorpromazine [121].

Baclofen
Baclofen successfully abolished prolonged central hyperthermia in a patient with basilar artery occlusion leading to brain stem infarction [56].

Bromocriptine
There are anecdotal case reports of the successful use of bromocriptine for treatment of CF [122,123].

Growth hormone therapy
Successful treatment of CF by GH therapy has been reported, with the mechanism related to the improvement of sweat production [124].

FUTURE DIRECTIONS
There are no guidelines or directions to help differentiate CF from other noninfectious causes of fever in the NICU. The literature is sparse and unclear. The diagnostic criteria are not well defined and not standardized. Treatment modalities for this clinical entity have been symptomatic only and mostly rely on over the counter drugs. No standard therapy has been defined in the literature. Multicentre large studies are required to better define CF, understand its pathophysiology, and guide standard management protocols in neurocritical care settings.

CONCLUSION
CF is an important diagnosis in neurocritical care. It not only prevents unnecessary antibiotic use, but its early recognition would also help improve patient management and prevent delayed discharge from the hospital. The current key to diagnosis in a predisposed patient is a high index of suspicion, along with thorough clinical examination, radiological, microbiological, and biochemical tests. Immediate attainment of normothermia is the current recommendation, as fever worsens the brain insult. Treatment includes various pharmacological agents and surface cooling methods to decrease body temperature. Studies are lacking on the best methods for diagnosis, treatment, and prevention of CF. Thus, more human trials are needed in this field to make any definitive recommendations.