Predictive Factors of Fever After Aneurysmal Subarachnoid Hemorrhage and Its Impact on Delayed Cerebral Ischemia and Clinical Outcomes

Accepted Manuscript Predictive factors of fever after aneurysmal subarachnoid hemorrhage and its impact on delayed cerebral ischemia and clinical outcomes Yung Ki Park, M.D., Hyeong-Joong Yi, M.D., Kyu-Sun Choi, M.D., Young-Jun Lee, M.D., Hyoung-Joon Chun, M.D., Sae Min Kwon, M.D. PII:

S1878-8750(18)30508-4

DOI:

10.1016/j.wneu.2018.03.030

Reference:

WNEU 7642

To appear in:

World Neurosurgery

Received Date: 3 January 2018 Revised Date:

3 March 2018

Accepted Date: 5 March 2018

Please cite this article as: Park YK, Yi H-J, Choi K-S, Lee Y-J, Chun H-J, Kwon SM, Predictive factors of fever after aneurysmal subarachnoid hemorrhage and its impact on delayed cerebral ischemia and clinical outcomes, World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.03.030. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title: Predictive factors of fever after aneurysmal subarachnoid hemorrhage and its impact on delayed cerebral ischemia and clinical outcomes

Yung Ki Park M.D.1, Hyeong-Joong Yi M.D.1*, Kyu-Sun Choi M.D.1, Young-Jun Lee M.D.2, Hyoung-Joon

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Chun M.D.1, Sae Min Kwon M.D.1

Department of Neurosurgery, Hanyang University Medical Center, Seoul, Korea

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Department of Radiology, Hanyang University Medical Center, Seoul, Korea

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Hanyang University Medical Center

E-mail: Yung Ki Park: [email protected] Hyeong-Joong Yi: [email protected]

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Kyu-Sun Choi: [email protected]

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222 Wangsimniro, Seongdong-gu, Seoul 133-792, Republic of Korea

Young-Jun Lee: [email protected]

Hyoung-Joon Chun: [email protected]

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Sae Min Kwon: [email protected]

Corresponding author’s name and current institution:

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Hyeong-Joong Yi, M.D., Ph.D.

Department of Neurosurgery, Hanyang University Medical Center 222 Wangsimniro, Seongdong-gu, Seoul 133-792, Republic of Korea Tel: +82-2-2290-8499

Fax: +82-2-2281-0954 Corresponding author’s e-mail: [email protected]

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Authors’ highest academic degrees: Yung Ki Park M.D., Hyeong-Joong Yi Ph.D., Kyu-Sun Choi Ph.D., Young-Jun Lee Ph.D., Hyoung-Joon Chun Ph.D., Sae Min Kwon M.D.

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Key words: Fever; Subarachnoid Hemorrhage; Brain Ischemia; Anterior Communicating Artery Aneurysm

Abbreviations: SAH, Subarachnoid hemorrhage; DCI, Delayed cerebral ischemia; MCA, Middle cerebral artery; ICP, Intracranial pressure; TCD, Transcranial Doppler; CT, Computed tomography; TMAX, Maximal

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temperature; UTI, Urinary tract infection; CSF, Cerebrospinal fluid; HTN, Hypertension; DM, Diabetes mellitus; BMI, Body mass index; ACoA, Anterior communicating artery; IVH, Intraventricular hemorrhage; ICH,

Systemic inflammatory response syndrome

Declarations of interest: none

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Intracerebral hemorrhage; mRS, modified Rankin scale; IQR, Interquartile range; CI, Confidence indices; SIRS,

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not-for-profit sectors.

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Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or

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Objective: Fever is relatively common and worsens neurologic injury after aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to display the time course of body temperature, identify

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predictive factors of fever after SAH, and evaluate its impact on delayed cerebral ischemia (DCI) and clinical outcomes.

Methods: Four hundred twelve patients with SAH and ruptured aneurysms who were treated at our institution between January 2007 and December 2016 were retrospectively analyzed. The febrile group was defined as

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patients having a TMAX ≥ 38.0°C for 2 consecutive days or for more than 3 days within 2 weeks after SAH, and the remaining patients comprised the afebrile group. The impact of fever on delayed cerebral ischemia (DCI)

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and clinical outcomes were assessed.

Results: Anterior communicating artery (ACoA) aneurysm, Hunt and Hess grade, SAH sum score, IVH sum score, and BMI were independent predictive factors for fever after SAH. A larger SAH and fever were independent risk factors for DCI. A worse Hunt and Hess grade, concomitant intracerebral hemorrhage, DCI, old age, and fever were independent risk factors for unfavorable outcomes.

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Conclusion: Predictors of fever after SAH were a worse clinical status at admission, larger SAH and IVH, ACoA aneurysm, and higher BMI. Fever itself was an independent risk factor for DCI and unfavorable

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outcomes after aneurysmal SAH.

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Introduction

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Fever after aneurysmal subarachnoid hemorrhage (SAH) is relatively common compared to other brain pathology and known to exacerbate brain injury.1 Some studies reported that postoperative fever occurs in 70% of patients after SAH, and 50% of these cases have a non-infectious etiology.2,3 Other studies showed that fever might be associated with unfavorable outcomes in various brain pathology such as aneurysmal SAH, acute

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ischemic stroke and traumatic brain injury.4–9 Postoperative fever is also known to be associated with angiographic vasospasm and delayed ischemic neurological deficits after SAH.9,10

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Some authors have suggested that SAH triggers systemic inflammation, and fever is a component of this response.11 Fever depends on humoral cues from the body, controlled by the anterior hypothalamus, and involves coordination of a wide range of autonomic, endocrine, and behavioral responses.12 As a component of systemic inflammation, fever can play an important role in predicting delayed cerebral ischemia (DCI) and unfavorable outcomes in patients with SAH.

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In the period of postoperative management after SAH, distinguishing infectious and non-infectious fever is challenging and leads to overuse of antibiotics and other medical problems such as multi-drug resistance and pseudomembranous colitis. Understanding the predictive factors of fever after SAH could be useful in clinical practice. A prospective study of patients with aneurysmal SAH showed that ventriculostomy, symptomatic

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vasospasm, and older age were predictive factors for fever occurrence.10 However, the study size was relatively

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small (n = 92), and concrete radiologic data were missing. We tried to overcome these problems with more specific data in the current study. The purpose of this study was to display the time course of body temperature, to evaluate the predictive factors of fever, and to clarify the impact of fever on DCI and clinical outcomes in patients with aneurysmal SAH.

Material and methods

Patient selection and general management 4

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We retrospectively reviewed patients with non-traumatic SAH who were treated in our institution from January 2007 to December 2016. Of the 498 consecutive patients with SAH and ruptured aneurysms, 412 patients were included in this study. Patients, aged between 18 and 80 years, with ruptured aneurysm treated within 72 hours after symptom onset were included in the current study. Aneurysm obliteration 3 days after onset, in-hospital

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death before 14 days, therapeutic hypothermia, incomplete medical records, early discharge before 14 days, and patients lost to follow-up were excluded from this study. This study was approved by the Institutional Review Board at the author’s institute (HYUH IRB 2017-10-006-001).

The surgical procedure was determined by the neurosurgical team according to age, aneurysm location, initial

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mental status, neck/dome presentation, and preexisting comorbidities. Middle cerebral artery (MCA) aneurysm was typically treated with microsurgical neck clipping and posterior circulation including the basilar and

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vertebral artery system with endovascular coiling. After the surgical procedure, the patient was placed in the neurocritical care unit for close observation with strict blood pressure control, fluid balance, and intracranial pressure (ICP) management. In most patients, oral or intravenous nimodipine was administered to avoid vasospasm. In patients with suspected vasospasm, transcranial Doppler (TCD), computed tomography (CT) angiography, or cerebral angiography was performed. Intra-arterial nimodipine injection was performed for

Fever management

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cases of moderate to severe vasospasm.

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In febrile patients, antipyretic drugs such as acetaminophen or nonsteroidal anti-inflammatory drug and cooling blankets were used to reduce the fever. Axillary temperature was obtained every hour in the neurocritical care unit and every 4 to 6 hours in the general ward. Daily maximal temperature (TMAX) was recorded every 24 hours

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from day 1 to day 14 in all patients. Day 0 was defined as the day of the SAH event. Patients with fever (≥ 38.0°C) were examined thoroughly to identify the infection source, and antibiotics were administrated according to the condition. Pneumonia was defined as a new focal infiltrate and at least two of the following criteria: (1) temperature of > 38.0°C, (2) leukocytosis > 10,000 cells/mm3, and (3) purulent respiratory secretions.13 Urinary tract infection (UTI) was defined as a positive urine culture with pyuria. Catheter-related infection was defined as blood or catheter tip culture positive with fever ≥ 38.0°C. Cerebrospinal fluid (CSF) infection was defined as positive culture with fever ≥ 38.0°C.

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Method of data collection Patients were categorized into two groups. The febrile group was defined as those having a TMAX ≥ 38.0°C for 2 consecutive days or for more than 3 days between day 1 and day 14, and the remaining patients composed the

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afebrile group. Baseline demographic features and radiologic findings were recorded for all patients. Demographic features included sex, age, operation type (clip or coil), aneurysm location and size (maximal diameter), Hunt and Hess grade,14 hypertension (HTN), diabetes mellitus (DM), smoking, and body mass index (BMI). Aneurysm location consisted of the internal carotid artery (ICA), the anterior communicating artery

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(ACoA), the MCA, and the posterior circulation. An ICA aneurysm was defined as proximal to the carotid T bifurcation, and posterior circulation was defined as the vertebral and basilar artery system. Radiologic findings

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included the modified Fisher scale15, intraventricular hemorrhage (IVH), concomitant intracerebral hemorrhage (ICH), initial bicaudate index,16 SAH sum score,17 and IVH sum score.18 The modified Fisher scale was categorized into two groups according to the amount of SAH (1&2 versus 3&4). The bicaudate index was measured by CT scan on admission to evaluate acute hydrocephalus. The amount of SAH on initial CT scan was calculated by the mean Hijdra score, which is a semi-quantitative scale according to extravasated blood. A total

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of 10 cistern or fissure points (0 to 3 points each) were added, according to the amount of blood, and the score ranged from 0 to 30.17 The amount of IVH on the initial CT scan was calculated by the mean Graeb score according to the amount of blood within each ventricle. The lateral ventricle was scored 0 to 4, and the third and

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fourth ventricle were scored 0 to 2 according to blood volume, with the score ranging from 0 to 12.18 All radiologic findings were recorded by one neuroradiologist (Y.-J.L.) in a blind fashion. Angiographic vasospasm was defined as moderate to severe arterial narrowing (>50%), not caused by atherosclerosis, catheter induced

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spasm or vessel hypoplasia.19 Evaluation of cerebral vasculature was performed by CT angiography, magnetic resonance angiography or trans-femoral cerebral angiography. DCI was defined as the occurrence of focal neurological impairment or a decrease of at least 2 points on the Glasgow Coma Scale score or one of its individual components lasting at least 1 hour that could not be attributed to other causes.20 The modified Rankin scale (mRS)21 was used to evaluate the clinical outcomes 3 months after SAH, and the patients were divided into 2 groups, the favorable (mRS 0 to 2) and unfavorable (mRS 3 to 6) outcomes groups. Evaluation of clinical outcome was performed and recorded by neurosurgeon, usually at outpatient clinic.

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Statistical methods Non-parametric data were compared using the chi-square and Fisher’s exact test. Parametric variables with normal distribution were compared by the independent t-test, and those without normal distribution were

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compared using the Mann-Whitney U test. Descriptive summaries were reported as mean (±standard deviation) for continuous variables with normal distribution, median [interquartile range (IQR)] for continuous variables without normal distribution, and frequency (percentage) for categorical variables. Variables with a value of p < 0.10 in univariate analysis were re-entered into the multivariate logistic regression model in a backward

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stepwise method. Odds ratios and 95% confidence indices (CI) were reported for statistically significant factors (p < 0.05). All data were analyzed with R version 3.3.2 (https://www.r-project.org/; R Foundation for Statistical

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Computing, Vienna, Austria).

Results

Febrile and afebrile groups

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A total of 412 patients with aneurysmal SAH were enrolled and divided into the febrile group (n = 203) and the afebrile group (n = 209). The mean TMAX of the febrile and afebrile groups is graphed in Figure 1A. In the afebrile group, the temperature tended to rise continuously with a peak at day 6 (37.31 ± 0.43°C) and slowly

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decreased until day 14. In the febrile group, the temperature tended to increase rapidly beginning at day 2 (37.41 ± 0.51°C) and maintained a high plateau from day 6 (37.77 ± 0.64°C) until day 11 (37.84 ± 0.57°C) and then slowly decreased. The highest mean TMAX in the febrile group was on day 8 (37.90 ± 0.54°C), two days later

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than that in the afebrile group.

Infectious fever in febrile patients Of the 412 patients, 49.3% (n = 203) developed fever after SAH. Of the 203 febrile patients, 38.4% (n = 78) had the infectious source identified. Pneumonia was the most common infectious source (52.6%) in febrile patients, and the most common pathogen was Staphylococcus aureus. The second most common infectious source was UTI (33.3%), followed by catheter-related infection (12.8%), and CSF infection (7.7%). Multiple sources of

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Predictive factors of fever after SAH Comparison of demographic and radiologic findings between the febrile and afebrile groups is shown in Table 1.

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The mean age was higher in the febrile group (57.1 ± 11.8) than in the afebrile group (54.6 ± 12.3), with statistical significance (p = 0.039). ACoA aneurysm was more frequent in the febrile group than in the afebrile group (36.9% versus 25.8%), with statistical significance (p = 0.020). The highest mean TMAX difference between ACoA and non-ACoA patients was 0.21 ± 0.07°C on day 6 (p = 0.007), and the time course of TMAX

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between the two groups is shown in Fig. 1D. Concomitant IVH and ICH occurred more frequently in the febrile group than in the afebrile group, with a significant statistical difference (p < 0.001 and p = 0.031, respectively)

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for both factors. Bicaudate index, SAH, and IVH sum score were all higher in the febrile group than in the afebrile group, with statistical significance (p = 0.030, p < 0.001 and p < 0.001, respectively). BMI was higher in the febrile group (23.7 [21.3; 26.0]) than in the afebrile group (22.9 [20.8; 25.2]), with statistical significance (p = 0.022).

The results of multivariate analysis for fever after SAH are shown in Table 2. Five variables remained

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statistically significant after adjusting for confounding factors: (1) ACoA aneurysm (OR 1.70, 95% CI = 1.082.567, p = 0.0221), (2) Hunt and Hess grade (OR 1.35, 95% CI = 1.05-1.75, p = 0.0188), (3) SAH sum score (OR 1.03, 95% CI = 1.01-1.06, p = 0.0070), (4) IVH sum score (OR 1.12, 95% CI = 1.03-1.21, p = 0.0101) and

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(5) BMI (OR 1.07, 95% CI = 1.00-1.15, p = 0.0381).

Angiographic vasospasm and DCI

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Angiographic vasospasm was observed in 156 out of 412 patients (37.9%). Angiographic vasospasm was more frequent in the febrile group than in the afebrile group, with statistical significance (45.8% versus 30.1%, p=0.001) DCI occurred in 62 out of 412 (15.0%) patients. The time course of mean TMAX between the DCI and non-DCI groups is displayed in Fig 1C. In patients with DCI, the temperature increased rapidly and peaked at day 8 (38.00 ± 0.56°C), and the highest mean TMAX difference compared to that in the non-DCI group was 0.50 ± 0.08°C on the same day. The mean TMAX difference between the two groups was statistically significant (p < 0.05) for all 14 days after SAH. Univariate and multivariate analysis of DCI is shown in Table 3. The modified

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Fisher scale and Hunt and Hess grade were not significantly associated with the occurrence of DCI. Concomitant IVH was observed more frequently in the DCI group than in the non-DCI group (67.7% versus 53.4%; p = 0.051) but did not show a significant difference after adjusting for confounding factors. In multivariate analysis, the SAH sum score (OR 1.04; 95% CI = 1.00-1.07; p = 0.0440) and the febrile group (OR

Relationship between fever and clinical outcomes

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3.42; 95% CI = 1.86-6.61; p = 0.0001) remained significant predictors for the occurrence of DCI.

According to the modified Rankin scale (mRS), the patients were categorized into two groups. Of the 412

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patients, favorable outcomes (mRS 0 to 2) occurred in 259 patients (62.9%), and unfavorable outcomes (mRS 3 to 6) occurred in 153 patients (37.1%). The time course of the mean TMAX between the favorable and

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unfavorable outcome groups is shown in Fig. 1B. A high fever plateau was observed from day 6 (37.76 ± 0.63°C) until day 11 (37.79 ± 0.58°C) with a peak on day 9 (37.84 ± 0.59°C) in patients with unfavorable outcomes. The mean TMAX difference between the two groups was statistically significant on all 14 days (p < 0.001) and was particularly higher during the second week after SAH. The results of univariate and multivariate analysis are shown in Table 4. In univariate analysis, age, microsurgical clipping, MCA aneurysm, aneurysm size, Hunt and

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Hess grade, concomitant IVH, ICH, SAH, and IVH sum scores, occurrence of DCI, HTN, and DM, and the febrile group were correlated with unfavorable outcomes. In multivariate analysis, five variables remained significant predictors for unfavorable outcomes: (1) Hunt and Hess grade (OR = 3.81, 95% CI = 2.68-5.58, p <

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0.0001), (2) concomitant ICH (OR = 3.83, 95% CI = 2.06-7.25, p < 0.0001), (3) occurrence of DCI (OR = 3.71, 95% CI = 1.75-8.05, p = 0008), (4) age (OR = 1.05, 95% CI = 1.02-1.07, p = 0007) and (5) febrile group (OR

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3.02, 95% CI = 1.69-5.49, p = 0.0003).

Discussion

In an animal model, hemoglobin released in the subarachnoid space increases core temperature, which was accompanied by a significant release in cerebrospinal prostaglandin E2.22 Blood metabolites, such as oxyhemoglobin, methemoglobin, and coagulation factors after SAH, trigger glial cell activation. This leads to a cascade of events including production of pro-inflammatory cytokines, impaired blood flow regulation, and

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increased glutamate levels.23 In a prospective study of 194 patients with SAH, the amount of ventricular blood was associated with fever. The amount of cistern blood tended to be greater in the febrile group, but this was not statistically significant.24 In the current study, fever was associated with the severity of SAH indicated by the Hunt and Hess grade and the amount of SAH and IVH.

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Interestingly, ACoA aneurysms were related to fever after SAH in the current study. A prospective study by Oliveira-Filho et al. reported that patients with ACoA aneurysms developed higher incidence of fever (29% versus 19%) compared to patients with aneurysms in other locations, but there was no statistical significance (p = 0.31).10 To our knowledge, this is the first report that reveals the relationship between ACoA aneurysms and

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fever after aneurysmal SAH. In a neuro-pathologic study of hypothalamic lesions of SAH by Crompton et al, ischemic necrosis, macro- and micro-hemorrhage in the hypothalamus were seen in 68% of patients.

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Furthermore, anterior hypothalamic lesions were found in 22 out of 32 (68.8%) patients with ruptured ACoA aneurysm.25 A possible explanation for these lesions is obstruction of venous drainage due to increased pressure in the chiasmatic cistern after hemorrhage and direct damage to the perforating artery to the hypothalamus during the surgical procedure. Moreover, vasoconstriction of the vessel to the hypothalamus can result in ischemia.26 Damage to the anterior hypothalamus might result in dysregulation of body temperature, resulting in

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fever. The ACoA is the structure most adjacent to the anterior hypothalamus compared to other aneurysm locations, and this could explain fever after SAH. In the current study, ACoA aneurysm was an independent predicting factor for fever, but it did not lead to the occurrence of DCI and unfavorable outcomes.

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In the current study, a higher BMI was related to the occurrence of fever, but it did not affect DCI or unfavorable outcomes. Obesity is regarded as a chronic state of low-grade inflammation and leads to diabetes mellitus, hypertension, and dyslipidemia.27 Obesity is associated with increased circulating inflammatory markers such as

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C-reactive protein, interleukin-6, and fibrinogen, which can lead to vascular disease.28 Another study reported that excess weight elevates the risk of cerebral infarction but does not affect clinical outcomes in patients with aneurysmal SAH.28 Patients with a state of chronic inflammation can react more sensitively and may be more likely to develop fever after SAH insult. Fever was the strongest independent predictive factor for DCI in the current study. The febrile group had 3.4 times the risk for DCI after adjusting for confounding factors. In comparison to patients without DCI, fever occurred 2 to 3 days later, spiking at day 8, and lasted longer in patients with DCI (Fig. 1C). This period is

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consistent with the timing of vasospasm. Other studies focused on the relationship between systemic inflammatory response syndrome (SIRS) and functional outcomes after SAH. SIRS is a complex clinical response to a variety of insults using temperature (< 36°C or > 38°C), heart rate (> 90 bpm), respiratory rate (> 20 breaths /minute), and white blood cell count (< 4000/mm3 or > 12000/mm3). Yoshimoto et al. showed that

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SIRS is associated with vasospasm related neurological deterioration, normal-pressure hydrocephalus, and unfavorable outcomes.11 Dhar et al. showed that 85% of patients developed SIRS within 4 days after SAH, and these factors predict symptomatic vasospasm and worse clinical outcomess.29 Fever is one component of systemic inflammation and might be useful in predicting vasospasm and DCI in clinical practice.

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A worse Hunt and Hess grade, concomitant ICH, DCI, and old age were associated with unfavorable outcomes, in agreement with earlier reports.30 Additionally, fever itself was an independent risk factor for unfavorable

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outcomes in the current study. A prospective study showed that the cumulative fever burden was associated with worse outcomes and late recovery in patients with SAH.31 Rossi et al. showed that intracranial temperature was about 0.33°C higher than body core temperature in patients with SAH.32 Furthermore, there was a significant relationship between the occurrence of febrile episodes and the increase in ICP. This indicates that a minimal increase of core temperature can possibly lead to a significant increase of ICP. Baseline temperature is already

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high in the acute stage of SAH, and a slight increase of body temperature can increase ICP, which can lead to severe brain damage. We should be aware of this mechanism and not underestimate the adverse effect of fever after SAH. Even in patients with mild fever, clinicians should pay close attention in order to avoid secondary

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brain damage.

Clinically, the biggest issue is the method of temperature management in patients with SAH to achieve better results. It is obvious that fever is associated with poor outcomes in patients with SAH, but the ideal target

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temperature (whether normothermia or hypothermia), duration of treatment, and cooling method are still uncertain. Badjatia et al. showed that induced normothermia using a surface cooling device during first 14 days after SAH is associated with improved outcomes.33 However, higher rates of hyperglycemia and arrhythmia were seen with no improvement in symptomatic vasospasm. Another study showed that induced normothermia is associated with reduction in an elevated lactate/pyruvate ratio, which is a marker of brain damage and cerebral metabolic crisis in patients with poor grade SAH.34 In a prospective randomized trial, hypothermia treatment reaching 33°C did not improve outcomes in patients with severe brain injury.35 Currently, it seems

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clear that maintaining a normal body temperature after SAH leads to better outcomes, but further study is needed on target temperature, duration of treatment, and cooling methods. Understanding risk factor of fever after aneurysmal SAH can be helpful to practitioner dealing with febrile patients. Unnecessary laboratory or radiologic test can be minimized and can help selecting appropriate

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treatment options to febrile patients. Furthermore, understanding fever pattern and feature can help predicting vasospasm, DCI, and clinical outcome. Regardless of the cause of fever, we suggest to maintain the normal body temperature in febrile patients. Physical examination with appropriate laboratory and radiologic test should be performed to reveal the cause of fever. Confirmed infection source should be eliminated promptly with

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appropriate antibiotics and treatment. In patients with aneurysmal SAH, brain damage can be accelerated by a small rise of body temperature. Therefore, careful observation and proper management of body temperature are

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necessary.

Limitations

This study has several limitations because of the nature of retrospective studies. In current study, patients who died before 14 days after SAH were excluded from study. The proportion of poor grade SAH patients (Grade IV-

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V) were lower than case series of SAH patients reported in literature. As a result, patients group of this study was mainly with good grade SAH patients (Grade I-III), which can be a potential source of selection bias. Evaluation of angiographic vasospasm and DCI was not performed using a standard method. Cerebral

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angiography was performed mostly in patients with clinical suspicion of vasospasm. This could underestimate the rate of DCI occurrence, especially in unconscious patients. Measurement of body temperature was estimated using surface axillary temperature which is less reliable than deep body temperature such as bladder temperature.

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Inflammatory parameters, such as white blood cells and C-reactive protein, were not measured daily after SAH. Further study is needed to overcome this limitation for more accurate results.

Conclusions

Predictive factors of fever after SAH were a worse clinical status at admission (Hunt and Hess grade), a greater amount of SAH and IVH, ACoA aneurysm, and a higher BMI. Fever itself was an independent risk factor for

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Acknowledgements: None

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Figure Legend

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Figure 1. Time course of mean highest temperature (TMAX) from Day 1 to Day 14.

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A) TMAX graph of all patients, the febrile and afebrile groups. (B) TMAX graph of favorable and unfavorable outcomes. (C) TMAX graph of delayed cerebral ischemia (DCI) and non-DCI groups. (D) TMAX graph of anterior communicating artery (ACoA) and non-ACoA groups

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*indicates statistically significant difference (p<0.05) in daily TMAX between the two groups

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ACCEPTED MANUSCRIPT Table 1. Demographic features and radiologic findings of the febrile and afebrile groups after SAH Total (N = 412)

Afebrile group (N = 209)

Febrile group (N = 203)

p-value

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Female Sex 278 (67.5%) 145 (69.4%) 133 (65.5%) 0.465 Age 55.7 ± 12.2 54.6 ± 12.3 57.1 ± 11.8 0.039 Operation Type 0.369 Clip 293 (71.1%) 144 (68.9%) 149 (73.4%) Coil 119 (28.9%) 65 (31.1%) 54 (26.6%) Aneurysm location ICA 101 (24.5%) 53 (25.4%) 48 (23.6%) 0.772 MCA 107 (26.0%) 60 (28.7%) 47 (23.2%) 0.241 ACoA 129 (31.3%) 54 (25.8%) 75 (36.9%) 0.020 Post. circulation 34 (8.3%) 16 (7.7%) 18 (8.9%) 0.789 Aneurysm Size 5.2 [4.0; 7.0] 5.0 [4.0; 6.5] 5.2 [3.8; 7.2] 0.411 Hunt & Hess Grade < 0.001 I 36 (8.7%) 25 (12.0%) 11 (5.4%) II 174 (42.2%) 102 (48.8%) 72 (35.5%) III 117 (28.4%) 53 (25.4%) 64 (31.5%) IV 81 (19.7%) 28 (13.4%) 53 (26.1%) V 4 (1.0%) 1 (0.5%) 3 (1.5%) Modified Fisher scale 0.129 1&2 52 (12.6%) 32 (15.3%) 20 (9.9%) 3&4 360 (87.4%) 177 (84.7%) 183 (90.1%) IVH 229 (55.6%) 94 (45.0%) 135 (66.5%) < 0.001 ICH 117 (28.4%) 49 (23.4%) 68 (33.5%) 0.031 Bicaudate Index 16.7 [14.3; 19.8] 16.1 [14.3; 19.0] 17.4 [14.6; 20.2] 0.030 SAH sum score 19.0 [11.0; 27.0] 16.0 [9.0; 25.0] 24.0 [15.0; 28.0] < 0.001 IVH sum score 1.0 [0.0; 3.0] 0.0 [0.0; 2.0] 2.0 [0.0; 4.0] < 0.001 Hypertension 153 (37.1%) 72 (34.4%) 81 (39.9%) 0.297 Diabetes mellitus 28 (6.8%) 13 (6.2%) 15 (7.4%) 0.783 Smoking 107 (26.0%) 54 (26.0%) 53 (26.1%) 1.000 BMI 23.3 [21.0; 25.6] 22.9 [20.8; 25.2] 23.7 [21.3; 26.0] 0.022 ICA internal carotid artery, MCA middle cerebral artery, ACoA anterior communicating artery, IVH intraventricular hemorrhage, ICH intracerebral hemorrhage, SAH subarachnoid hemorrhage, BMI body mass index

ACCEPTED MANUSCRIPT Table 2. Multivariate logistic regression model of independent risk factor of fever after SAH Odds ratio

95% CI

p-value

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Hunt & Hess grade 1.35 1.05-1.75 0.0188 SAH sum score 1.03 1.01-1.06 0.0070 IVH sum score 1.12 1.03-1.21 0.0101 BMI 1.07 1.00-1.15 0.0381 ACoA aneurysm 1.70 1.08-2.67 0.0221 SAH subarachnoid hemorrhage, IVH intraventricular hemorrhage, BMI body mass index, ACoA anterior communicating artery, CI confidence interval

ACCEPTED MANUSCRIPT Table 3. Univariate and multivariate analysis of delayed cerebral ischemia Multivariate analysis

Univariate analysis

Age

Non-DCI (N = 350)

DCI (N = 62)

p-value

55.8 ± 12.2

56.1 ± 11.5

0.669

OR

95% CI

p-value

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Clip 247 (70.6%) 46 (74.2%) 0.830 ACoA 107 (30.6%) 22 (35.5%) 0.535 Hunt & Hess grade 0.125 Modified Fisher 0.582 1&2 46 (13.1%) 6 (9.7%) 3&4 304 (86.9%) 56 (90.3%) Aneurysm size 5.8 ±2.9 5.6±3.0 0.704 IVH 187 (53.4%) 42 (67.7%) 0.051 ICH 99 (28.3%) 18 (29.0%) 1.000 SAH sum score 19.0 [10.0; 26.0] 26.0 [15.0; 28.0] 0.001 1.04 1.00-1.07 0.0440 IVH sum score 1.0 [0.0; 3.0] 1.0 [0.0; 3.0] 0.269 Smoking 86 (24.6%) 21 (34.4%) 0.144 Febrile group 156 (44.6%) 47 (75.8%) < 0.001 3.42 1.86-6.61 0.0001 DCI delayed cerebral ischemia, ACoA anterior communicating artery, IVH intraventricular hemorrhage, ICH intracerebral hemorrhage, SAH subarachnoid hemorrhage, OR odds ratio, CI confidence interval

ACCEPTED MANUSCRIPT Table 4. Univariate and multivariate analysis of clinical outcome Multivariate analysis

Univariate analysis Favorable outcome (N = 259)

Unfavorable outcome (N = 153)

p-value

OR

95% CI

p-value

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Age 53.7 ± 11.8 59.4 ± 11.7 < 0.001 1.05 1.02-1.07 0.0007 Clip 172 (66.4%) 121 (79.1%) 0.009 MCA 57 (22.0%) 50 (32.7%) 0.023 Hunt & Hess grade < 0.001 3.81 2.68-5.58 < 0.0001 Aneurysm size 5.0 [3.7; 6.5] 5.6 [4.2; 8.0] 0.003 IVH 119 (45.9%) 110 (71.9%) < 0.001 ICH 42 (16.2%) 75 (49.0%) < 0.001 3.83 2.06-7.25 < 0.0001 SAH sum score 16.0 [9.0; 25.5] 25.0 [16.0; 28.0] < 0.001 IVH sum score 0.0 [0.0; 2.0] 2.0 [0.0; 5.0] < 0.001 DCI 23 (8.9%) 39 (25.5%) < 0.001 3.71 1.75-8.05 0.0008 Hypertension 86 (33.2%) 67 (43.8%) 0.041 Diabetes mellitus 12 (4.6%) 16 (10.5%) 0.039 Febrile group 95 (36.7%) 108 (70.6%) < 0.001 3.02 1.69-5.49 0.0003 MCA middle cerebral artery, IVH intraventricular hemorrhage, ICH intracerebral hemorrhage, SAH subarachnoid hemorrhage, DCI delayed cerebral ischemia, OR odds ratio, CI confidence interval

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ACCEPTED MANUSCRIPT Highlights 1.

Rupture of anterior communicating artery aneurysm is related with fever after subarachnoid hemorrhage. Higher body mass index is related with fever after subarachnoid hemorrhage

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Fever after subarachnoid hemorrhage is an independent factor for delayed cerebral ischemia and worse

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clinical outcome.

ACCEPTED MANUSCRIPT Abbreviations List SAH: Subarachnoid hemorrhage DCI: Delayed cerebral ischemia

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MCA: Middle cerebral artery ICP: Intracranial pressure TCD: Transcranial Doppler

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CT: Computed tomography

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TMAX: Maximal temperature UTI: Urinary tract infection CSF: Cerebrospinal fluid HTN: Hypertension

BMI: Body mass index

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DM: Diabetes mellitus

ACoA: Anterior communicating artery

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IVH: Intraventricular hemorrhage

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ICH: Intracerebral hemorrhage mRS: modified Rankin scale IQR: Interquartile range CI: Confidence indices

SIRS: Systemic inflammatory response syndrome

ACCEPTED MANUSCRIPT The authors have no personal financial or institutional interest in this article. The study adheres strictly to all ethical principles and there is no financial support for this work that

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could have influenced its outcome.

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No conflicts of interest

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Hyeong-Joong Yi M.D.