Fever among patients in the neurologic intensive care unit (ICU) is common and is associated with worse outcomes. Such fevers are likely due to infection or neurologic injury. Measures to control fever include pharmacologic and mechanical methods, and though such measures are effective, the literature is unclear on whether these interventions improve patient outcomes. The choice of intervention should be carefully considered for febrile neuro ICU patients and weighed against potential adverse effects. Further research on how temperature management affects outcomes in this population is needed to better inform management.
Key points
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Fever is common among neurocritically ill patients and associated with worse outcomes.
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Fever among neurocritically ill patients is commonly either from an infection or of neurogenic origin.
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There are a variety of pharmacologic and nonpharmacologic options for management, though whether such interventions improve outcomes remains unclear.
Introduction
Fever in the neurologically injured patient may come from a variety of sources and is associated with a longer length of stay, increased mortality, and worsening neurologic examination. , Infectious and noninfectious causes of fever may be present. Often, an accurate diagnosis of the causative factor may be challenging, as fever after acute brain injury can occur in up to 70% of cases. Risk factors for fever in this patient population include the presence of subarachnoid hemorrhage (SAH), intraventricular catheterization, and increased length of stay.
Fundamentally, a fever is when the body’s temperature exceeds its physiologic set point, often in response to a stressor. The temperature at which this becomes a fever varies among sources, but a common definition for fever is a core body temperature greater than 38.3°C. The appropriate treatment for fever in the neuro-intensive care unit (ICU) involves evaluation of the source of fever, correction of the temperature abnormality, and treatment of the underlying cause.
Causes of fever in neurocritically ill patients
Fever in a neurologically ill patient can be due to an infectious cause or due to the brain injury itself, which is often referred to as a central or neurogenic fever. Approximately, half of fevers in neuro ICU patients are found to have an infectious cause, with the most common infections being pneumonia and bronchitis. , The common causes of fever are briefly summarized in Table 1 .
| Cause | Presentation | Further Considerations |
|---|---|---|
| Central fever | Fever in the absence of infection, VTE, or other non-neurogenic cause Often occurs after insult to the brain, such as TBI or stroke | Consider patient factors and fever severity when deciding on a choice of treatment, if any |
| Infectious | CNS infection: headache, fever, neck rigidity, altered mental status, seizures Non-CNS infection: look for common signs of pneumonia or urinary tract infection | Consider starting empiric antibiotic therapy early due to the risk of mortality |
| Venous thromboembolism | Patients with immobility, venous catheters, increased coagulation | Many ICU patients will have these risk factors, so VTE should be considered for all patients with fever of unclear origin |
| Medication-induced | Fever after other causes have been ruled out among patients taking salicylates, anticonvulsants, anticholinergics, barbiturates, penicillins, cephalosporins, and sulfonamides, among many other medications | Depending on the medication, its indication, degree of clinical suspicion, switching, and/or temporarily halting the suspected medication can help evaluation |
Neurologic Infections
Neurologic infections may be spontaneous or related to trauma or surgery. Postoperative meningitis/ventriculitis occurs in up to 8.6% of craniotomy patients and up to 22% of patients with external ventricular drains (EVD). , Longer duration of catheterization and placement of a second EVD are associated with an increased risk of cerebrospinal fluid (CSF) infection, although prophylactic catheter exchange does not decrease the risk of infection , and long-term prophylactic antibiotics are not recommended. Coagulase-negative staphylococci is the most common pathogen in ventriculostomy-related infection. In patients with an EVD when fever or clinical signs of infection develop, CSF sampling, including Gram stain and culture, is appropriate.
Various methods to mitigate postsurgical or post-EVD infection risk have been investigated. Care bundles, which include preoperative antibiotics, barrier dressing, surgical site cleaning, and glycemic control protocols, have been shown to reduce the incidence of surgical site infections; however, , bundles for patients with EVDs/ventriculostomies have yielded mixed results.
Spontaneous infection of the nervous system may be present as well. These may include bacterial, viral, or fungal pathogens. CSF analysis may be useful for differentiating pathogens responsible for central nervous system (CNS) infection. Bacterial meningitis often presents with increased protein and neutrophils and decreased glucose on CSF analysis, with increased CSF opening pressure. Common bacterial pathogens include Streptococcus pneumoniae (accounting for nearly half of cases in the United States), Neisseria meningitidis , Group B streptococcus, Listeria monocytogenes , and Haemophilus influenzae . In contrast, viral meningitis may result in increased protein and lymphocytes in CSF with minimal change in glucose or opening pressure. Common causes of viral CNS infections include enteroviruses, herpes simplex virus (HSV), and arboviral encephalitis. Finally, fungal meningitis may result in increased lymphocytes and protein in CSF with decreased glucose. Common fungal pathogens include cryptococcus, histoplasmosis, and coccidioidomycosis. Further, checking β-d-glucan and galactomannan in CSF can help if a fungal pathogen is suspected. Patients with meningitis frequently present with at least 2 of the following symptoms: headache, fever, neck stiffness, and altered mental status. Encephalitis can be more difficult to diagnose as CSF findings may not follow a consistent pattern. Examination findings may include seizures and focal neurologic deficits, though these findings are often nonspecific among neuro ICU patients. Accordingly, a detailed history of travel and environmental exposures is particularly helpful in these cases.
Extracranial Infection
Extracranial infections are also common among neuro ICU patients and are a frequent source of fever. The incidence of pneumonia among ICU patients is approximately 30%. , Intubation, polytrauma, and severe neurologic dysfunction increase the risk of nosocomial pneumonia. Staphylococcus aureus , H influenzae , and Streptococcus pneumoniae commonly cause early nosocomial respiratory infections while Pseudomonas , Actinobacteria , and methicillin-resistant S aureus may be more likely to cause respiratory infections that develop later. Urinary tract infections (UTIs) may also occur among these patients and are strongly associated with urinary catheterization. Common causes of UTI in the neuro ICU include Escherichia coli , Pseudomonas aeruginosa , and Enterococcus . Analysis has found bloodstream infections in up to 16% of neuro ICU patients and is associated with prolonged central venous catheter insertion. , Bloodstream infections are more commonly caused by Staphylococcus epidermidis , S aureus , and Enterococcus.
Traumatic Brain Injury
Fever among patients with traumatic brain injury (TBI) may be the result of neurologic dysfunction or infection. TBI has been identified as an independent predictor of fever among neuro ICU patients through downregulation of the immune responses and increased susceptibility to infection.
The incidence of fever after TBI is high with one analysis finding nearly 80% of TBI patients admitted to the ICU experience a fever with an even higher incidence in postcraniotomy TBI patients. Fever after TBI is associated with worse outcomes and increased mortality among older patients, hence aggressive fever control may be beneficial among patients with severe TBI. ,
Venous Thromboembolism
Venous thromboembolism (VTE) is a common fever etiology among ICU patients, which may manifest as a pulmonary embolism (PE). Though there is a robust link between VTE and fever, the precise mechanism and rate of fever in patients with VTE is unclear, with one study finding that 9.1% of patients with deep vein thrombosis (DVT) had a fever. Fever in patients with DVT and/or PE is associated with increased morbidity and mortality. , Therefore, avoidance of immobility and venous catheter use as well as the use of compression stockings and prophylactic enoxaparin or heparin may reduce the rate of VTE. ,
Evaluation
New onset of fever in a neurologically injured patient should start with an infectious workup. In the absence of previous cranial surgery or procedures, open wounds, or meningismus, a systemic workup including chest imaging, sputum cultures, urinary studies, and blood cultures should be performed. In the trauma patient, all open wounds should be inspected. In the presence of new-onset headaches, worsening mental status, nausea, and/or lethargy with or without previous cranial surgery, CNS infection should be suspected. The workup should include CSF studies with consideration of imaging, including MRI with and without contrast, especially in postoperative patients. If an intraventricular drain is present, CSF sampling should be performed with any significant fever; however, routine CSF sampling in the absence of fever or neurologic signs is not recommended. Procalcitonin may be used as a biomarker for infection, with one meta-analysis showing it has a 93.9% sensitivity and 47.7% specificity. C-reactive protein (CRP) and erythrocyte sedimentation rate may also be used to monitor infection. Notably, both are markers of inflammation and demonstrate poor specificity for detecting underlying infection and should be evaluated in the context of other clinical findings and the patient’s history. ,
In the presence of fever with leukocytosis and elevated inflammatory markers but an otherwise negative workup, more rare or nonbacterial infections should be investigated. This is particularly important in immunocompromised patients, such as human immunodeficiency virus patients. Respiratory viruses such as influenza or COVID-19 should also be considered.
VTE is another relatively common cause of fever and should be part of the differential diagnosis for any patient with noninfectious fever in the ICU. In the presence of unilateral extremity swelling or erythema, Doppler ultrasonography is indicated. However, one analysis found that Doppler ultrasounds ordered for neuro ICU patients with fever detected DVTs at a similar rate compared with patients without fever. Therefore, fever alone may not be an indication for DVT screening.
When infectious causes have been eliminated, other noninfectious etiologies for fever should be investigated, such as medications. Common fever-inducing medications are salicylates, barbiturates, and antibiotics, such as penicillins, cephalosporins, and sulfonamides. For patients in the neuro ICU, the most common offending agents include phenytoin and carbamazepine. Changing or stopping the medication is the primary means of ruling out this source of fever.
Should the above etiologies be ruled out, a central fever can be diagnosed. Among neuro ICU patients, central fever is likely to account for about half of fevers and is more likely to occur within the first 72 hours of admission. , One analysis found that negative blood cultures, absence of chest infiltrate on X ray, presence of SAH, IVH, or brain tumor, and fever onset within 72 hours predicted central fever 90% of the time. However, care should be taken with this diagnosis, especially in the presence of new-onset fever. In the patient with severe neurologic injury, intermittent episodes of fever with tachycardia, hypertension, increased tone, and motor posturing would favor paroxysmal sympathetic activation.
Treatment
Pharmacologic
The treatment for fever includes treatment of the underlying cause as well as the fever itself. At the initiation of the fever workup, antibiotics should be considered and are indicated in patients with hemodynamic compromise or high suspicion of CNS infection. These antibiotics should include broad-spectrum coverage with meningitis dosages to start. These antibiotics may then be tailored to the specific organisms when the cultures result. Acyclovir should be considered in patients with concern for HSV infection while awaiting the polymerase chain reaction (PCR) results. If a surgical infection is suspected, antibiotics should be held until intraoperative cultures are taken if the patient is stable to wait.
Pharmacologic treatments for fever are based on disrupting particular steps in the cyclooxygenase pathway. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, inhibit cyclo-oxygenase, thereby preventing the formation PGE2. NSAIDs lower the hypothalamic setpoint, leading to increased sweating and vasodilation. Common NSAIDs that have been investigated include ibuprofen, which is effective for reducing fever among critically ill patients. ,
Acetaminophen is another common antipyretic and is believed to interfere with the cyclo-oxygenase pathway in the CNS, though the precise mechanism remains unclear. Studies on the effect of acetaminophen have yielded mixed results. A randomized control trial among neuro ICU patients demonstrated that treatment with both acetaminophen and ibuprofen significantly lowered body temperature compared with either medication alone. One advantage to acetaminophen is that there is no theoretic increased risk of hemorrhage when compared with NSAIDs. However, acetaminophen may result in or exacerbate liver dysfunction in critically ill patients and should be used with caution.
Notably, regardless of the pharmacologic intervention, even in studies where there is a decrease in body temperature, there may not be a clinical benefit. Accordingly, further analysis is needed to understand how pharmacologic treatment of fever among neuro ICU patients influences overall outcomes.
Nonpharmacologic
In the presence of infection, source control is essential. If a surgical site infection is present, surgical exploration with debridement and washout is often needed. If an EVD infection is present, then the catheter should be removed or replaced based on the patient’s need for CSF diversion. Often abscess formation in neurologic and non-neurological locations will require incision and drainage to achieve fever and source control, as well as to get a specimen to tailor the antibiotics appropriately.
Although antipyretic therapy is the first-line treatment, it may not be effective. In such cases, external cooling methods may be utilized. The most common measures for nonpharmacologic cooling are ice packs and cooling blankets, but these measures are inconsistent. Sponging with ice water was found to be more effective than pharmacologic treatment and was also associated with decreased energy expenditure. However, for neuro ICU patients, water-circulating pads applied to the patients’ trunks and thighs outperformed cooling blankets, with a 75% reduction in fever burden.
Intravascular (IV) cooling is also an effective means of fever control. Cooling with 4°C IV saline can lower body temperature by 2.5°C in 1 hour in healthy patients. Automated IV cooling devices allow for highly accurate temperature measurements and regulation and are preferred over boluses of cold IV saline.
However, there are drawbacks to using these techniques to reduce fever. For one, external cooling may induce vasoconstriction, further preventing heat loss. Other concerns include increased temperature fluctuations and overshooting the target temperature. Localized skin breakdown may be present with surface cooling, and intravenous cooling devices have complications related to long-term intravenous access including infection and thrombosis.
Shivering is a common reaction to nonpharmacological treatments of fever. , One analysis found that 39% of patients treated with induced normothermia experienced shivering. Risk factors included being male, hyponatremia, and hypomagnesemia. Shivering increases metabolic expenditure and myocardial oxygen demand, as well as patient discomfort. , Shivering patients also had less improvement in Glasgow Coma Scale (GCS) compared with nonshivering patients and is associated with decreased brain tissue oxygenation and elevated intracranial pressure. As such, shivering should be avoided in neurocritically ill patients.
Paroxysmal Sympathetic Hyperactivity
In patients with paroxysmal sympathetic hyperactivity after brain injury, pharmacologic methods can be used to downregulate sympathetic output and its effects. Such treatments include opioids, anesthetics, benzodiazepines, β-adrenergic blockers, and α-2 agonists. Other drugs with neuromodulating effects, such as bromocriptine, dantrolene, and gabapentin, have been used with varying efficacy. External cooling methods may also be used to more aggressively control hyperthermia in these patients. However, literature on the efficacy of treatment options for paroxysmal sympathetic hyperactivity is limited. Additionally, episodes during paroxysmal sympathetic hyperactivity often occur in response to a stimulus, such as pain, movement, or urinary retention. As such, avoiding these triggers is particularly important for management.
Outcomes
There are several possible mechanisms through which fever may predispose patients to worse outcomes. Such mechanisms include weakening the blood-brain barrier, increased free radical production, and increased excitatory neurotransmitter release. More downstream, these effects result in increased metabolic rate and oxygen consumption, resulting in worsening hypoxemia and exacerbating neuronal injury. As such, there is much effort to control fever and prevent these effects.
Despite the importance of fever management in the neuro ICU, the outcomes have been variable. Ideally, treatment would control a patient’s fever, resulting in shortened ICU admission and improved neurologic status. However, even in such cases where fever is controlled, it is unclear whether improved outcomes necessarily follow. Further, such interventions, particularly external cooling methods, may create additional complications, such as shivering, pneumonia, arrhythmias, and coagulation abnormalities, resulting in a prolonged clinical course and worse outcomes. , , While there is good evidence indicating the efficacy of cooling methods for lowering body temperature and such methods are widely accepted, evidence that such interventions improve patient outcomes is lacking. , Additionally, therapeutic hypothermia has not shown benefit. A recent meta-analysis failed to demonstrate the efficacy of therapeutic hypothermia. Additionally, therapeutic hypothermia may be associated with increased rates of pneumonia, cardiac arrhythmia, and coagulation abnormalities. , ,
Non-neurological benefits of fever
Fever is a physiologic response to an infection, making the body inhospitable to foreign pathogens. Numerous studies on the use of NSAIDs and acetaminophen among patients with viral infections indicate that antipyretics may increase viral shedding, prolong infections, and suppress antibody responses. Another study found that a fever response is associated with improved mortality among patients with community-acquired pneumonia. Though there are no randomized control studies on the matter, one analysis found fever was associated with positive outcomes for patients with gram-negative bacteremia, and several animal studies demonstrate fever is associated with prolonged survival during infection. , Additionally, antibiotic medications may have improved activity against pathogens at higher temperatures. Overall, the literature on the benefits of routine antipyretic therapy for infection is mixed, and potential therapy should be carefully weighed against the possible adverse effects, particularly in light of the lack of supporting evidence. However, in the neurologically injured patient, the deleterious effects of fever are significant and should be mitigated, particularly when the fever is not a physiologic response to an infection.
Summary
Fever is a common and significant concern among neurologic and neurosurgical ICU patients. Fevers within this population may be due to infection, thermoregulatory dysfunction, or other causes such as DVT. While fever is thoroughly associated with worse outcomes, it is unclear which patients may benefit from interventions targeted at reducing core body temperatures. Accordingly, further research is needed to understand how temperature reduction, whether via antipyretic therapy or external/IV cooling, influences patient outcomes.
Clinics care points
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Evaluation of febrile patients with neurologic injury should start with a workup for infectious etiologies. About half of fevers in the neuro ICU will have an infectious cause.
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In the absence of infection, VTE, or fever-inducing medication, a neurogenic fever can be diagnosed.
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The fever treatment should be tailored to the specific cause, such as antibiotics for bacterial infections and should also include pharmacologic and nonpharmacologic methods of decreasing the temperature.
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For patients with paroxysmal sympathetic hyperthermia, opioids, anesthetics, benzodiazepines, β-adrenergic blockers, and α-2 agonists may be useful. There should be careful attention to avoidance of triggers, such as pain, movement, and urinary retention.
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Fever is the neurologically injured patient is associated with worse outcomes. However, cooling mechanisms may not improve patient outcomes despite controlling the fever.
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Fever may have a physiologic benefit in the setting of certain types of infections, and such benefits should be weighed against the deleterious effects of fever when deciding management.
Related posts:
Fundamentals of Acute Care for Patients with Traumatic Spinal Cord Injury
Challenges in Pulmonary Management after Traumatic Brain and Spinal Cord Injury
Thrombosis and Coagulopathy
Endocrinopathy and Dysautonomia
Fluids, Electrolytes, and Nutrition in the Critically Ill Patient with Neurotrauma
Sudden Neurologic Worsening
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