Clinical Review & Education
From The JAMA Network
Fever in Critical Neurologic Illness Paul M. Vespa, MD
JAMA NEUROLOGY Indicators of Central Fever in the Neurologic Intensive Care Unit
infection treated with antibiotics. Remaining patients were considered to have central fever. Continuous fever lasting longer than 6 hours for 2 or more consecutive days was considered persistent.
Sara E. Hocker, MD; Lin Tian; Guangxi Li; James M. Steckelberg, MD; Jay N. Mandrekar, PhD; Alejandro A. Rabinstein, MD IMPORTANCE Fever is common in critically ill neurologic patients. Knowledge of the indicators of central fever may allow greater antibiotic stewardship in this era of rapidly developing super-resistant microorganisms.
OBJECTIVE To develop a model to differentiate central from
infectious fever in critically ill neurologic patients with fever of an undetermined cause. DESIGN, SETTING, AND PARTICIPANTS Retrospective data collection from January 1, 2006, through December 31, 2010, at a 20-bed neurologic intensive care unit of a large teaching hospital. Consecutive patients 18 years and older admitted for 48 hours or longer with a core body temperature higher than 38.3°C on at least 1 measurement for 2 consecutive days. Patients with alternative identified causes of noninfectious fever were excluded. In total, 526 patients were included in the final analysis.
MAIN OUTCOMES AND MEASURES Percentage incidence and odds ratios of variables associated with central fever. Fever was classified as infectious if there was culture growth of a pathogenic species or documented clinical diagnosis of
Fever is a common medical complication for many types of critical neurologic illnesses, including acute ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and brain trauma. In prospective observational studies, fever has been found in nearly 75% of patients.1 Fever is a form of secondary injury and independently worsens neurologic outcome and increases the mortality in neurologic patients.1 Hence, fever is a therapeutic target that needs to be identified, understood, and treated. Measuring temperature and determining the presence of fever is straightforward, but the differential diagnosis of infectious vs noninfectious (or central) fever is quite challenging and is more art than science. It is well known that patients with intracranial blood may have noninfectious (or central) fever in the absence of objective signs of clinical infection. The criteria and methodological approach to making the distinction between infectious and noninfectious fever are subject to considerable variation among practitioners. 1456
RESULTS Fever was central in 246 patients (46.8%). Patients with infectious fever were older (mean, 57.4 vs 53.5 years; P = .01) and had a longer length of stay in the neurologic intensive care unit (mean, 12.1 vs 8.8 days; P < .001). Central fever was more likely to occur within 72 hours of admission to the neurologic intensive care unit (76.4% vs 60.7%; P < .001) and tended to be persistent (26.4% vs 18.6%; P = .04). Blood transfusion (odds ratio [OR], 3.06; 95% CI, 1.63-5.76); absence of infiltrate on chest x-ray (3.02; 1.81-5.05); diagnosis of subarachnoid hemorrhage, intraventricular hemorrhage, or tumor (6.33; 3.72-10.77); and onset of fever within 72 hours of hospital admission (2.20; 1.23-3.94) were independent predictors of central fever on multivariable analysis. The combination of negative cultures; absence of infiltrate on chest radiographs; diagnosis of subarachnoid hemorrhage, intraventricular hemorrhage, or tumor; and onset of fever within 72 hours of admission predicted central fever with a probability of .90.
CONCLUSIONS AND RELEVANCE We provide a reliable model to differentiate central fever from infectious fever in critically ill neurologic patients, allowing clinicians to select patients in whom antibiotics may be safely discontinued despite ongoing fever.
JAMA Neurol. 2013;70(12):1499-1504. doi:10.1001/jamaneurol.2013.4354.
This variability likely results in some antibiotic overusage, which can have adverse effects on the patient in question and on microbial resistance across a larger cohort of patients. Hence, it is crucial to be able to determine infectious from noninfectious fever. In an article in JAMA Neurology by Hocker et al,2 determinants of noninfectious fever were identified from a large single-center neurocritical care cohort of patients with a wide variety of critical neurologic illnesses, ranging from subarachnoid hemorrhage, intraventricular hemorrhage, and tumors to status epilepticus. The authors performed a retrospective analysis to design a classification tree schema of which patients are likely to have infectious fever. Noninfectious fever occurring within 72 hours of admission was determined to be present in 46% of patients. Blood transfusions were another independent factor associated with noninfectious fever. The authors proposed a step-wise selection tree method for determining the cause of fever.
JAMA October 8, 2014 Volume 312, Number 14
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/11/2015
jama.com
From The JAMA Network Clinical Review & Education
This report confirms previous observations that noninfectious fever is common but expands current knowledge and presents a useful algorithm for diagnosis. The term central fever does imply dysfunction of the hypothalamus and the thermoregulatory control mechanisms. That term is a bit more specific than the data would permit, and other factors such as neuroinflammation, cytokinemediated fever, and other mechanical causes such as atelectasis or venous thromboembolic disease could be at play. Despite these caveats, the article confirms that noninfectious fever may be common in patients with critical neurologic illness. Acknowledging that noninfectious fever exists is important because treatment with antibiotics will not resolve the temperature and other treatment modalities, both pharmacologic and nonpharmacologic, are necessary. In modern neurointensive care units, an expanding array of temperature control methods are being used. These include surface cooling blankets and body-conformed wraps, intravascular cooling devices, head-only cooling caps, inhaled perfluorocarbon cooling systems, and pharmacologic agents designed to lower temperature.3 Much has already been written comparing these various devices, yielding a few important summary lessons. First, intravascular cooling provides rapid reduction to a target temperature with the least amount of overshoot and temperature variability.4 Next, second-generation devices, both surfacebased and intravascular, are much better than a basic cooling blanket. Third, water- or coolant-based systems are more capable of temperature control than air-convection devices. Fourth, prevention of shivering is an important therapeutic measure to gain temperature control. Several important features of fever control remain understudied and therefore controversial. The ideal temperature is not curARTICLE INFORMATION Author Affiliation: David Geffen School of Medicine, University of California, Los Angeles. Corresponding Author: Paul M. Vespa, MD, David Geffen School of Medicine, University of California, Los Angeles, 757 Westwood Blvd, Room 6236A, Los Angeles, CA 90095 ([email protected] .edu). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. Rincon F, Patel U, Schorr C, et al. Brain injury as a risk factor for fever upon admission to the intensive care unit and association with in-hospital case fatality: a matched cohort study [published online
rently known. The recent publication outlining that mild hypothermia (or normothermia at 36°C) may be as neuroprotective as formal hypothermia to 32°C to 34°C has raised the possibility that modest prevention of fever is sufficient for neuroprotection.5,6 The optimal duration of fever control in neurologic patients is not well studied, but outcomes are better when the duration of fever is minimized. There is little evidence that fever prevention is harmful. The ideal population for temperature control is also presently unknown, but patients with subarachnoid hemorrhage appear to be prone to fever at the onset of vasospasm.7 Hence, the vasospasm period may be a rational time window for induced normothermia. Extension of temperature control to other critically ill neurologic patients with brain trauma, stroke, and intracerebral hemorrhage appears reasonable too. The final consideration is how best to follow the fever decision tree by Hocker et al,2 which can be applied to patients with neurologic disorders to help limit antibiotic use or overuse. For example, if fever occurs early in the absence of radiologic or microbial evidence of infection, antibiotics may be withheld. More judicious use of antibiotics may translate into less colonization of nosocomial antibiotic-resistant super bugs such as acinetobacter. This may offset the ongoing antibiotics arms race against increasingly resistant organisms. Given the recent revisions to surveillance and diagnostic methods for hospital-acquired infections,8 this new decision tree may become a useful tool for clinicians and should be considered by health quality experts too. The focus on fever control in critically ill neurologic patients should be a top-tier goal for intensivists and neurologists alike. A daily deliberate effort should be made to monitor for fever and take steps to return the patient to normothermia.
October 16, 2013]. J Intensive Care Med. doi:10.1177 /0885066613508266.
management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206.
2. Hocker SE, Tian L, Li G, Steckelberg JM, Mandrekar JN, Rabinstein AA. Indicators of central fever in the neurologic intensive care unit. JAMA Neurol. 2013;70(12):1499-1504.
6. Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA. 2014;311(1):45-52.
3. Diringer MN; Neurocritical Care Fever Reduction Trial Group. Treatment of fever in the neurologic intensive care unit with a catheter-based heat exchange system. Crit Care Med. 2004;32(2):559564. 4. Flint AC, Hemphill JC, Bonovich DC. Therapeutic hypothermia after cardiac arrest: performance characteristics and safety of surface cooling with or without endovascular cooling. Neurocrit Care. 2007;7(2):109-118.
7. Scaravilli V, Tinchero G, Citerio G; Participants in the International Multi-Disciplinary Consensus Conference on the Critical Care Management of Subarachnoid Hemorrhage. Fever management in SAH. Neurocrit Care. 2011;15(2):287-294. 8. Magill SS, Klompas M, Balk R, et al. Developing a new, national approach to surveillance for ventilator-associated events. Crit Care Med. 2013;41 (11):2467-2475.
5. Nielsen N, Wetterslev J, Cronberg T, et al; TTM Trial Investigators. Targeted temperature
jama.com
JAMA October 8, 2014 Volume 312, Number 14
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/11/2015
1457
From The JAMA Network
Fever in Critical Neurologic Illness Paul M. Vespa, MD
JAMA NEUROLOGY Indicators of Central Fever in the Neurologic Intensive Care Unit
infection treated with antibiotics. Remaining patients were considered to have central fever. Continuous fever lasting longer than 6 hours for 2 or more consecutive days was considered persistent.
Sara E. Hocker, MD; Lin Tian; Guangxi Li; James M. Steckelberg, MD; Jay N. Mandrekar, PhD; Alejandro A. Rabinstein, MD IMPORTANCE Fever is common in critically ill neurologic patients. Knowledge of the indicators of central fever may allow greater antibiotic stewardship in this era of rapidly developing super-resistant microorganisms.
OBJECTIVE To develop a model to differentiate central from
infectious fever in critically ill neurologic patients with fever of an undetermined cause. DESIGN, SETTING, AND PARTICIPANTS Retrospective data collection from January 1, 2006, through December 31, 2010, at a 20-bed neurologic intensive care unit of a large teaching hospital. Consecutive patients 18 years and older admitted for 48 hours or longer with a core body temperature higher than 38.3°C on at least 1 measurement for 2 consecutive days. Patients with alternative identified causes of noninfectious fever were excluded. In total, 526 patients were included in the final analysis.
MAIN OUTCOMES AND MEASURES Percentage incidence and odds ratios of variables associated with central fever. Fever was classified as infectious if there was culture growth of a pathogenic species or documented clinical diagnosis of
Fever is a common medical complication for many types of critical neurologic illnesses, including acute ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and brain trauma. In prospective observational studies, fever has been found in nearly 75% of patients.1 Fever is a form of secondary injury and independently worsens neurologic outcome and increases the mortality in neurologic patients.1 Hence, fever is a therapeutic target that needs to be identified, understood, and treated. Measuring temperature and determining the presence of fever is straightforward, but the differential diagnosis of infectious vs noninfectious (or central) fever is quite challenging and is more art than science. It is well known that patients with intracranial blood may have noninfectious (or central) fever in the absence of objective signs of clinical infection. The criteria and methodological approach to making the distinction between infectious and noninfectious fever are subject to considerable variation among practitioners. 1456
RESULTS Fever was central in 246 patients (46.8%). Patients with infectious fever were older (mean, 57.4 vs 53.5 years; P = .01) and had a longer length of stay in the neurologic intensive care unit (mean, 12.1 vs 8.8 days; P < .001). Central fever was more likely to occur within 72 hours of admission to the neurologic intensive care unit (76.4% vs 60.7%; P < .001) and tended to be persistent (26.4% vs 18.6%; P = .04). Blood transfusion (odds ratio [OR], 3.06; 95% CI, 1.63-5.76); absence of infiltrate on chest x-ray (3.02; 1.81-5.05); diagnosis of subarachnoid hemorrhage, intraventricular hemorrhage, or tumor (6.33; 3.72-10.77); and onset of fever within 72 hours of hospital admission (2.20; 1.23-3.94) were independent predictors of central fever on multivariable analysis. The combination of negative cultures; absence of infiltrate on chest radiographs; diagnosis of subarachnoid hemorrhage, intraventricular hemorrhage, or tumor; and onset of fever within 72 hours of admission predicted central fever with a probability of .90.
CONCLUSIONS AND RELEVANCE We provide a reliable model to differentiate central fever from infectious fever in critically ill neurologic patients, allowing clinicians to select patients in whom antibiotics may be safely discontinued despite ongoing fever.
JAMA Neurol. 2013;70(12):1499-1504. doi:10.1001/jamaneurol.2013.4354.
This variability likely results in some antibiotic overusage, which can have adverse effects on the patient in question and on microbial resistance across a larger cohort of patients. Hence, it is crucial to be able to determine infectious from noninfectious fever. In an article in JAMA Neurology by Hocker et al,2 determinants of noninfectious fever were identified from a large single-center neurocritical care cohort of patients with a wide variety of critical neurologic illnesses, ranging from subarachnoid hemorrhage, intraventricular hemorrhage, and tumors to status epilepticus. The authors performed a retrospective analysis to design a classification tree schema of which patients are likely to have infectious fever. Noninfectious fever occurring within 72 hours of admission was determined to be present in 46% of patients. Blood transfusions were another independent factor associated with noninfectious fever. The authors proposed a step-wise selection tree method for determining the cause of fever.
JAMA October 8, 2014 Volume 312, Number 14
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/11/2015
jama.com
From The JAMA Network Clinical Review & Education
This report confirms previous observations that noninfectious fever is common but expands current knowledge and presents a useful algorithm for diagnosis. The term central fever does imply dysfunction of the hypothalamus and the thermoregulatory control mechanisms. That term is a bit more specific than the data would permit, and other factors such as neuroinflammation, cytokinemediated fever, and other mechanical causes such as atelectasis or venous thromboembolic disease could be at play. Despite these caveats, the article confirms that noninfectious fever may be common in patients with critical neurologic illness. Acknowledging that noninfectious fever exists is important because treatment with antibiotics will not resolve the temperature and other treatment modalities, both pharmacologic and nonpharmacologic, are necessary. In modern neurointensive care units, an expanding array of temperature control methods are being used. These include surface cooling blankets and body-conformed wraps, intravascular cooling devices, head-only cooling caps, inhaled perfluorocarbon cooling systems, and pharmacologic agents designed to lower temperature.3 Much has already been written comparing these various devices, yielding a few important summary lessons. First, intravascular cooling provides rapid reduction to a target temperature with the least amount of overshoot and temperature variability.4 Next, second-generation devices, both surfacebased and intravascular, are much better than a basic cooling blanket. Third, water- or coolant-based systems are more capable of temperature control than air-convection devices. Fourth, prevention of shivering is an important therapeutic measure to gain temperature control. Several important features of fever control remain understudied and therefore controversial. The ideal temperature is not curARTICLE INFORMATION Author Affiliation: David Geffen School of Medicine, University of California, Los Angeles. Corresponding Author: Paul M. Vespa, MD, David Geffen School of Medicine, University of California, Los Angeles, 757 Westwood Blvd, Room 6236A, Los Angeles, CA 90095 ([email protected] .edu). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. Rincon F, Patel U, Schorr C, et al. Brain injury as a risk factor for fever upon admission to the intensive care unit and association with in-hospital case fatality: a matched cohort study [published online
rently known. The recent publication outlining that mild hypothermia (or normothermia at 36°C) may be as neuroprotective as formal hypothermia to 32°C to 34°C has raised the possibility that modest prevention of fever is sufficient for neuroprotection.5,6 The optimal duration of fever control in neurologic patients is not well studied, but outcomes are better when the duration of fever is minimized. There is little evidence that fever prevention is harmful. The ideal population for temperature control is also presently unknown, but patients with subarachnoid hemorrhage appear to be prone to fever at the onset of vasospasm.7 Hence, the vasospasm period may be a rational time window for induced normothermia. Extension of temperature control to other critically ill neurologic patients with brain trauma, stroke, and intracerebral hemorrhage appears reasonable too. The final consideration is how best to follow the fever decision tree by Hocker et al,2 which can be applied to patients with neurologic disorders to help limit antibiotic use or overuse. For example, if fever occurs early in the absence of radiologic or microbial evidence of infection, antibiotics may be withheld. More judicious use of antibiotics may translate into less colonization of nosocomial antibiotic-resistant super bugs such as acinetobacter. This may offset the ongoing antibiotics arms race against increasingly resistant organisms. Given the recent revisions to surveillance and diagnostic methods for hospital-acquired infections,8 this new decision tree may become a useful tool for clinicians and should be considered by health quality experts too. The focus on fever control in critically ill neurologic patients should be a top-tier goal for intensivists and neurologists alike. A daily deliberate effort should be made to monitor for fever and take steps to return the patient to normothermia.
October 16, 2013]. J Intensive Care Med. doi:10.1177 /0885066613508266.
management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206.
2. Hocker SE, Tian L, Li G, Steckelberg JM, Mandrekar JN, Rabinstein AA. Indicators of central fever in the neurologic intensive care unit. JAMA Neurol. 2013;70(12):1499-1504.
6. Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA. 2014;311(1):45-52.
3. Diringer MN; Neurocritical Care Fever Reduction Trial Group. Treatment of fever in the neurologic intensive care unit with a catheter-based heat exchange system. Crit Care Med. 2004;32(2):559564. 4. Flint AC, Hemphill JC, Bonovich DC. Therapeutic hypothermia after cardiac arrest: performance characteristics and safety of surface cooling with or without endovascular cooling. Neurocrit Care. 2007;7(2):109-118.
7. Scaravilli V, Tinchero G, Citerio G; Participants in the International Multi-Disciplinary Consensus Conference on the Critical Care Management of Subarachnoid Hemorrhage. Fever management in SAH. Neurocrit Care. 2011;15(2):287-294. 8. Magill SS, Klompas M, Balk R, et al. Developing a new, national approach to surveillance for ventilator-associated events. Crit Care Med. 2013;41 (11):2467-2475.
5. Nielsen N, Wetterslev J, Cronberg T, et al; TTM Trial Investigators. Targeted temperature
jama.com
JAMA October 8, 2014 Volume 312, Number 14
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/11/2015
1457
