Fever Management in SAH

Neurocrit Care
DOI 10.1007/s12028-011-9588-6

REVIEW

Fever Management in SAH

V. Scaravilli • G. Tinchero • G. Citerio •
The Participants in the International Multi-disciplinary Consensus
Conference on the Critical Care Management of Subarachnoid Hemorrhage

Ó Springer Science+Business Media, LLC 2011

Abstract An electronic literature search through August outcome and increased length of stay [1], with detrimental
2010 was performed to obtain articles describing fever effects independent of vasospasm. Fever has also been
incidence, impact, and treatment in patients with sub- linked to symptomatic vasospasm independent of hemor-
arachnoid hemorrhage. A total of 24 original research rhage severity or the presence of infection [2, 3]. This
studies evaluating fever in SAH were identified, with association could be due to inflammatory activation after
studies evaluating fever and outcome, temperature control SAH [4], which might be implicated in the development of
strategies, and shivering. Fever during acute hospitalization both phenomena. In addition to disease severity and to the
for subarachnoid hemorrhage was consistently linked with amount of blood in the subarachnoid space, intraventricular
worsened outcome and increased mortality. Antipyretic hemorrhage [5] is a strong risk factor for fever develop-
medications, surface cooling, and intravascular cooling ment [6]. Fever exacerbates ischemic injury [7], worsens
may all reduce temperatures in patients with subarachnoid cerebral edema, and increases intracranial pressure [8] and
hemorrhage; however, benefits from cooling may be offset may lead to decreased level of consciousness. Even a
by negative consequences from shivering. single episode of fever after SAH is associated with poorer
outcomes, even in best-grade patients [9]. Fever may be
Keywords Cooling Á Fever Á SAH Á Normothermia Á controlled in SAH using both medications and non-drug
Shivering Á Temperature therapies [10].

Introduction How fever impacts outcome is largely unknown [11].
While fever might precipitate secondary neurological
In the acute phase following aneurysmal subarachnoid injury, researchers have often noted that it is impossible to
hemorrhage (SAH), alterations of body temperature regu- rigorously exclude the possibility that fever might simply
lation are common. Fever in SAH is associated with worse be a marker for other critical events. This review was
designed to evaluate available data on the role of fever in
The Participants in the International Multi-disciplinary Consensus SAH and the effect of different therapies on controlling
Conference: Michael N. Diringer, Thomas P. Bleck, Nicolas Bruder, fever and improving outcome.
E. Sander Connolly, Jr., Giuseppe Citerio, Daryl Gress, Daniel
Hanggi, J. Claude Hemphill, III, MAS, Brian Hoh, Giuseppe Lanzino, Methods
Peter Le Roux, David Menon, Alejandro Rabinstein, Erich
Schmutzhard, Lori Shutter, Nino Stocchetti, Jose Suarez, Miriam An electronic Medline literature search was performed on
Treggiari, MY Tseng, Mervyn Vergouwen, Paul Vespa, Stephan August 16, 2010, using the key word ‘‘subarachnoid
Wolf, Gregory Zipfel. hemorrhage’’ with at least one key word from each of the
following groups: (1) ‘‘fever,’’ ‘‘temperature,’’ ‘‘hyper-
V. Scaravilli Á G. Tinchero Á G. Citerio (&) thermia,’’ or ‘‘pyrexia’’ and (2) ‘‘induced hypothermia,’’
Neurorianimazione, Anestesia e Rianimazione II, Ospedale San ‘‘therapeutic hypothermia,’’ ‘‘hypothermic therapy,’’
Gerardo, Via Pergolesi 33, 20900 Monza, Italy ‘‘thermoregulation,’’ ‘‘thermoregulatory,’’ ‘‘diclofenac,’’
e-mail: [email protected]

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‘‘NSAID,’’ ‘‘temperature control,’’ ‘‘heat exchange,’’ severe functional disability and cognitive impairment
‘‘cooling,’’ ‘‘prognosis,’’ ‘‘prognostic,’’ ‘‘predictor,’’ ‘‘pre- among survivors [5]. Cumulative fever burden, defined as
dict,’’ ‘‘outcome,’’ or ‘‘incidence.’’ Articles were included the sum of time with temperatures >38.3°C in the first
if they focused on clinical management of fever in patients 13 days, is associated with worse outcome and with later,
with SAH. Titles and abstracts were screened, with but often incomplete, recovery in good-grade patients and
potentially relevant articles identified. Candidate articles potential late recovery in poor-grade patients [35]. More-
were evaluated if the full manuscript was available in over, fever induces cerebral metabolic distress, with
English. Additional references were sought by evaluating elevated levels of lactate/pyruvate ratio documented using
bibliographies from selected articles. microdialysate measurements during febrile episodes. In a
cohort study, Oddo found an association between fever and
Summary of the Literature cerebral metabolic distress, with distress reduced in SAH
patients managed with fever control, independent of
A total of 24 original research studies evaluating fever in intracranial pressure [36]. In fact, induced normothermia
SAH were identified: 9 studies evaluating fever and out- was related to a significant reduction in lactate/pyruvate
come (Table 1) [1–3, 5, 9, 12–15], 12 studies evaluating ratio and with fewer episodes of cerebral metabolic crisis,
temperature control strategies (Table 2) [16–27], and 3 supporting the view that fever control may be ‘‘neuropro-
shivering (Table 3) [29, 30]. Outcome data included 4 tective.’’ This evidence suggests that fever could be
prospective studies, with the remainder cohort data or detrimental and its control could reduce metabolic distress.
retrospective analyses. Among studies evaluating temper-
ature control, 10 studies were prospective and 7 studies Pharmacological Interventions
provided moderate- to high-quality evidence. All studies
evaluating shivering described observational data collected Antipyretics are traditionally first-choice therapy for con-
prospectively. Study sizes were small, with only one high- trolling fever. They block cerebral prostaglandin-E
quality study. Details from these studies are provided in synthesis, which lowers the hypothalamic set point. This
each Table. activates the body’s two principal mechanisms for heat
dissipation: vasodilatation and sweating. The effectiveness
Patients with SAH who experience fever were consis- of antipyretic agents is tightly linked to conditions where
tently more likely to experience a more negative outcome thermoregulation is intact. Therefore, they are likely to be
and increased mortality risk. Antipyretic medications, less effective in brain-damaged patients with impaired
surface cooling, and intravascular cooling could all reduce thermoregulatory mechanisms, such as SAH patients.
temperatures in patients with subarachnoid hemorrhage;
however, benefits from cooling could be offset by negative Limited data are available to determine the efficacy of
consequences from shivering. Additional articles were also antipyretics in patients with SAH. Data extrapolated from
identified that provided important supplemental informa- series of ischemic stroke patients indicate low efficacy of
tion on incidence, impact, and treatment of fever in patients non-steroidal anti-inflammatory drugs (NSAIDs) in con-
after SAH or other neurointensive care populations. These trolling temperature elevation [37–39]. In patients with
studies are summarized below. acute stroke, acetaminophen has been the therapy most
widely studied in an attempt to maintain normothermia.
Fever After SAH Kasner et al. [40] observed a clinically and statistically
insignificant difference of 0.2°C in body temperature in
Fever, defined as a body temperature C38.3°C (101°F), favor of treatment with acetaminophen (approximately 4 g/
occurs in up to 72% of aneurysmal SAH patients [2, 5, 8, 9, day) compared with placebo. Two recent phase II studies
31, 32]. Non-infectious fever is common in patients with showed that a higher acetaminophen dose (6 g/day) was
SAH [33]; nevertheless, infections should always be more effective in maintaining normothermia and prevent-
excluded in febrile patients [34] because they are not ing fever [38, 39]. A randomized, controlled study in adult
infrequent [9] and demand prompt antibiotic treatment. patients with brain injury demonstrated that ibuprofen
Non-infectious fever tends to start earlier than fever from (2,400 mg/day) was no better than acetaminophen or pla-
infection, usually starting within the first 3 days after SAH. cebo for maintaining normothermia after ischemic stroke
Patients, with mostly intraventricular hemorrhage [6], [38]. Nevertheless, the efficacy in maintaining normother-
typically have body temperatures persistently increased mia in the published series is poor, and the extrapolation of
instead of spikes. this information to SAH patients requires caution.

Treatment-refractory fever during the first 10 days after One small study, including SAH patients, testing the
SAH is associated with increased mortality and more efficacy of paracetamol compared with external means
(fanning, evaporative cooling using cool cloths and

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Table 1 Fever and outcome

References Design Patient number Main findings

Hanafy et al. [12] Retrospective review of prospectively 850 Fever at admission, significant predictor of poor-grade
collected database patients.

Consecutive SAH patients Mitigating the inflammatory response to aneurysmal rupture
in the hyper-acute setting may improve the admission clinical
Claassen et al. [13] Prospective observational 413 grade, which may in turn improve outcomes
Diringer et al. [1]
Consecutive SAH patients admitted to SIRS scores higher in patients with death or severe disability
neuroscience intensive care unit at at 3 months
tertiary care academic center
SIRS score and APACHE II physiologic subscore did not add
Retrospective review of prospectively 4,295 (298 predictive value

collected data of patients in SAH) Additional 7.4 intensive care unit days and 9.7 total hospital
days in SAH patients with fever
neurology/neurosurgery intensive
Temperature independently associated with longer intensive
care at academic tertiary care center care and hospital stays, higher mortality rate, and worse
outcome. Percent discharged to home decreased with each
Fernandez et al. [5] Cohort 353 increase in temperature level

Maximum daily temperature recorded Poor HH grade and intraventricular hemorrhage were
for consecutive patients between days strongest predictors of fever
0 and 10
Treatment-refractory fever during the first 10 days after SAH
Oliveira-Filho et al. Prospective 92 increased mortality with more functional disability and
[3] cognitive impairment among survivors
Neurologic intensive care patients
with non-traumatic SAH Patients with symptomatic vasospasm had increased risk of
developing fever independently of disease severity or
Wartenberg et al. [2] Cohort 580 presence of infection. Increased risk of poor outcome for
Naidech et al. [14] 122 each day that a patient had fever, independent of disease
Todd et al. [9] Neurological intensive care patients 1000 severity, vasospasm, or infection
were treated according to standard
management protocols Fever affected 54% of patients—most frequent complication

Prospective cohort Fever, anemia, and hyperglycemia affect 30–54% of patients
with SAH and are significantly associated with mortality and
Baseline characteristics, poor functional outcome
complications, and length of stay
analyzed Fever likely drives length of stay

Prospective Fever reported in 41% of patients. In 97%, fever occurred in
postoperative period
Incident fever and relationship to
outcome assessed in intraoperative Fever associated with worse outcome in surgical SAH
hypothermia for aneurysm surgery patients but dependent on covariates used in the analysis
trial (particularly operative events and delayed ischemic
neurological deficits)
Kirkness et al. [15] Prospective 86
Elevated mesors, blunted amplitudes, and delayed and
Diurnal temperatures and variables of dispersed acrophases consistent with clinical features of
circadian rhythm measured in SAH diurnal temperature pattern
patients

Acrophase time at which daily peak temperature rhythm occurs, APACHE II acute physiology and chronic health evaluation II, HH hunt and hess
score, mesor mean level around which temperature oscillates, SAH subarachnoid hemorrhage, SIRS systemic inflammatory response syndrome

sponging, ice packs, and cooling blanket) reported a traumatic brain injury and SAH patients [16]. Although no
reduction in body core temperature in 57% of patients adverse effects rates were reported, larger studies are
receiving paracetamol [19]. Two other studies including needed before this therapy can be routinely recommended.
SAH patients demonstrated efficacy in controlling tem-
perature elevation with very low doses of continuously Non-pharmacologic Interventions
infused diclofenac [16, 17]. For example, a small, ran-
domized study reported that a continuous infusion of External cooling with surface cooling devices has been tes-
diclofenac sodium (0.04 mg/kg/h) was effective in reduc- ted in SAH population, with poor efficacy reported with the
ing the burden of fever and number of febrile events in use of fanning, evaporative cooling, cool cloths, sponging,

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Table 2 Efficacy of temperature control strategies

References Design Patient number Quality of Main findings

(SAH) evidence Good efficacy. Hemodynamics, hepatic, renal
function unaffected. No effects on ICP, GOS at
Cormio and Randomized, prospective 22 (10) Moderate 6 months
Citerio [16] 12 (5) Moderate
Low-dose continuous diclofenac 4 (2) Very low Lower mean temperature after diclofenac, ICP
versus NSAIDs boluses 67 (?) Very low reduced, no hemodynamic effects, hepatic and
47 (28) High renal function unaffected
Cormio et al. Retrospective
[17] Good efficacy
Efficacy and safety of low-dose Shivering developed in all patients
continuous diclofenac infusion
Poor efficacy in external means
Carhuapoma Cohort, prospective
et al. [18] Treatment group experienced 75% reduction in
Efficacy and safety of water- fever burden, spent less time febrile, attained
circulating cooling device normothermia faster. No difference in shivering

Price et al. [19] Randomized, prospective Low efficacy of pharmacological approach
Better temperature control with external cooling
Efficacy of paracetamol vs external device, but longer intensive care length of stay and
means. higher rate of tracheostomy and need for sedation
for shivering control. Also, worse outcome at
Mayer et al. [20] Randomized, prospective 14 days and 3 month; better outcome after
12 months
Efficacy of water-circulating surface Catheter did not increase risk above that for central
cooling system versus conventional
blanket catheter
Very efficient in fever control
Badjatia et al. Case–control 40 (40) plus 80 High Catheter did not increase risk above that for central
[21] (80)
Surface cooling device versus catheter
historical cohort conventional fever Better efficiency in maintaining normothermia
management compared with conventional management
No significant difference in mortality and neurologic
Schmutzhard Uncontrolled, prospective 51 (19) Low long-term follow-up
et al. [22] High Good efficiency in reducing fever and maintaining
Safety and efficacy of novel
Broessner et al. intravascular cooling device Low normothermia
[23] High No infectious or bleeding complications; 2 deep
Randomized, prospective 102 (51) Moderate venous thrombosis requiring filter placement)
Low Lower fever burden
Safety and efficacy of an intravascular No difference in infection, mortality, major or minor
cooling device (prophylactic adverse events, or 30-day complications
normothermia) versus conventional
fever management Good efficiency
No difference in side effects
Badjatia et al. Cohort, prospective 9 (9) Higher costs
[24]
Safety and efficacy of intravascular No difference in adverse effect
cooling device Temperature decline higher in water-circulating
blankets, gel-pads, intravascular cooling compared
Diringer [25] Randomized, prospective 296 (124) with conventional cooling and air-circulating
blankets
Hinz et al. [26] Paracetamol plus blanket compared
with acetaminophen plus blanket plus
Hoedemaekers intravascular cooling device
et al. [27]
Randomized, non-blinded, prospective 26 (21)

Efficacy and therapeutic costs of
intravascular cooling device versus
conventional treatment

Randomized, controlled, prospective 50 (8)

Compared efficacy in speed of cooling
by different means

GOS glasgow outcome scale, ICP intracranial pressure

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Table 3 Effects of shivering Shivering treatment Patient Quality Main findings
References Design number of
(SAH) evidence

Hata et al. Observational, prospective Sequential shivering treatment: (1) 10 (1) Very Reduction in temperature
[28] low No difference in VO2, VCO2,
Effect of shivering on VO2 during no treatment, (2) hand warming, ventilation, HR, MAP
induced normothermia by external (3) facial warming, and (4) Despite shivering treatment, 50%
had shivering
cooling meperidine 12.5–25 mg 10 min Non-shivering patients had
reduction in VO2 with cooling, with
Arctic sun to 36° then indirect to a maximum of 150 mg no reduction in shivering patients
During active shivering, VO2 and
calorimetry (DeltaTrac) No neuromuscular blockade VCO2 ventilation were higher
Shivering associated with reduced
Oddo et al. Observational, prospective Sequential shivering treatment: (1) 15 (5) Low
High PbtO2, higher ICP, lower CPP,
[29] Effect of shivering on brain tissue air warming, (2) buspirone and lower temperature
15–30 mg three times daily to
oxygenation (PbtO2) during BSAS associated with
induced normothermia by external maximum 60 mg, (3) meperidine hypermetabolic index, VO2,
12.5 mg three times daily to resting energy expenditure,
cooling VCO2. Low serum magnesium
maximum 300 mg, and (4) was independently associated
Arctic sun to 37° for 72 h in sedation with propofol/fentanyl with the presence of shivering
refractory fever, then PbtO2
(LICOX) No neuromuscular blockade

Badjatia Observational, prospective Acetaminophen (650 mg 6 times 50 (34)
et al. daily), buspirone (30 mg three
[30] Validation of grading shivering times daily), skin
scale against continuous counterwarming (BAIR) protocol.
assessments of resting energy Subsequent use of propofol,
expenditure, VO2, VCO2 by dexmedetomidine, meperidine, or
indirect calorimetry fentanyl at clinician discretion

Cooling by intravascular
(CelsiusControl) or external
cooling (Arctic sun) device

CPP cerebral perfusion pressure, ICP intracranial pressure, PbtO2 partial pressure of brain tissue oxygen, VCO2 carbon dioxide production, VO2
oxygen consumption

ice packs, and cooling blankets [19]. Forty consecutive devices was obtained very slowly, after 120 min [18]. The
febrile patients who underwent ‘‘advanced fever control’’ efficacy of a water-circulating surface cooling system was
(AFC, target temperature 37°C) with a surface cooling compared in a randomized, controlled trial with conven-
device during the first 14 days after SAH were compared tional measures for treating fever in neurointensive care unit
with a matched a group of 80 historical SAH patients who patients [20]. Patients were randomly assigned to 24 h of
underwent conventional fever control (CFC: acetamino- treatment with a conventional water-circulating cooling
phen, 650 mg every 4–6 h orally, with or without the use of a blanket placed over the patient or to hydrogel-coated water-
water-circulating cooling blanket) [21]. The average daily circulating energy transfer pads applied directly to the trunk
temperature burden for the first 2 weeks after SAH was and thighs. Patients randomized to this latter group experi-
significantly lower in the AFC patients compared with the enced a 75% reduction in fever burden, spent less percent
CFC patients. This study confirms the low efficacy of the time febrile, and attained normothermia faster, but experi-
standard pharmacological approach and a better temperature enced a higher incidence of shivering. Therefore, while
control with an external cooling device. Nevertheless, AFC surface cooling devices are able to reduce temperature, the
patients had a longer intensive care length of stay and a time of induction of normothermia is usually slow and
higher rate of tracheostomy. These interim outcomes may problematic shivering may occur.
have been driven by the need for prolonged sedation and
prolonged mechanical ventilation leading to tracheostomy Invasive temperature control with intravascular systems
needed to achieve shiver control in AFC patients. AFC was a may be more efficacious than external cooling devices [27].
significant predictor of good outcome only after 12 months. Diringer tested the effectiveness of a catheter-based heat
Another cohort study likewise reported problematic shiver- exchange system in reducing elevated temperatures in
ing, even if temperature reduction with surface cooling neurologically critically ill patients using a prospective
randomized, non-blinded trial [25]. In that study,

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conventional fever treatment with acetaminophen and Shivering is also associated with a significant decrease
cooling blankets was compared with conventional treat- in brain tissue oxygenation, correlating with the intensity of
ment plus an intravascular catheter-based heat exchange cooling [29]. A significant correlation has been found
system. Fever burden was reduced by 64% in the catheter between the magnitude of shivering-associated decrease in
group, with no higher rate of infection or the use of seda- brain tissue oxygenation and circulating water temperature.
tives or antibiotics. The cooling catheter-related risk was Monitoring of therapeutic cooling with computerized
not different from a standard central catheter. A more thermoregulatory systems may help prevent shivering and
precise stability at set point has been documented with optimize the management of induced normothermia.
intravascular catheters [27]. Others have cautioned that,
although effective, intravascular cooling is more costly Because of the negative consequences of shivering,
[26]. uncontrolled shivering can eliminate any benefit of fever
control, making shiver control an essential component to
Recently, Broessner demonstrated the effectiveness and inducing and maintaining normothermia. The Bedside
safety of endovascular cooling to maintain normothermia Shivering Assessment Scale (BSAS) is a simple shivering
prophylactically in comparison with standardized, step- grading tool developed by assessing the correlation of
wise, escalating fever management in patients with severe bedside shivering and systemic metabolic stress quantified
cerebrovascular disease [23]. This prospective, random- by indirect calorimetry [30]. By clinically assessing mus-
ized, controlled trial used a blinded neurologic outcome cular involvement in the trunk and limbs, the BSAS
evaluation to compare prophylactic, catheter-based nor- provides an accurate representation of the metabolic impact
mothermia (i.e., body core temperature 36.5°C) and of shivering. The ability to accurately identify shivering
conventional, stepwise fever management with anti- intensity has distinct advantages when developing a step-
inflammatory drugs in the control group at 36.5°C. Overall, wise approach to treating shivering.
median total fever burden during the course of treatment
was 0.0 and 4.3°C h in the catheter and conventional Less sedating options (e.g., surface counterwarming) are
groups, respectively. preferred as initial interventions. Pharmacologic interven-
tions without significant sedating effects are the second step
Shivering and include buspirone and magnesium. Buspirone is a
serotonin (5-HT) 1A partial agonist that has shown special
Physical strategies for reducing fever have the serious anti-shivering activity by activating hypothalamic heat-loss
drawback of promoting shivering. Shivering and vasocon- mechanisms. Buspirone is only mildly sedating and provides
striction responses are dependent on deviations from the a good synergistic therapy when combined with other anti-
temperature set point, controlled by the preoptic nucleus of shivering interventions. The main disadvantage of buspirone
anterior hypothalamus. Sensors throughout the body both is that it is administered orally and therefore may not be
control temperature regionally and maintain a constant core reliably absorbed in critically ill patients. Hypomagnesemia
temperature. The overall goal of such tight control is to has been significantly linked with shivering [41]. Intrave-
reduce oxygen utilization and caloric expenditure to max- nous magnesium promotes both cutaneous vasodilatation
imize metabolic efficiency as well as protect crucial and mild muscle relaxation. Magnesium may also confer
enzymatic function. The shivering response, trying to keep some protection from tissue ischemia [42], although recent
body temperature at the set point when external cooling studies of its neuroprotective role have not been conclusive
strategies are applied, is a concerted reaction involving [43, 44]. Regardless, low serum magnesium levels have been
skeletal muscular contraction as well as peripheral vaso- shown to be a risk factor in the development of shivering, and
constriction. The incidence of shivering has been reported all efforts should be made to maintain serum levels between 3
to occur in up to 40% of patients undergoing therapeutic and 4 mg/dl. When these initial measures are not effective,
normothermia with physical strategies [20]. The metabolic more effective pharmacologic agents with more sedative
consequences of this response can be extensive. An properties are utilized. The most effective anti-shivering
important and consistent consequence is a dramatic pharmacologic agent is meperidine. Short-acting sedative
increase in resting energy expenditure, carbon dioxide agents could be used if first-line interventions fail.
production, and oxygen consumption. By affecting several
muscular groups for prolonged periods, shivering triggers Conclusions
increases in metabolic demand, which translates into higher
oxygen consumption combined with increased respiration. Fever affects up to three in every four patients with SAH,
Oxygen consumption increases from shivering are pro- with non-infectious fevers most likely to begin during the
portional to the affected muscular mass and can increase first 3 days. Patients with SAH with fever tend to have a
the basal rate of oxygen consumption two- to threefold. worse prognosis. Drugs, including acetaminophen and

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