Supplementary Table 2: Detailed characteristics of human studies evaluating the role of interleukin-6 after subarachnoid hemorrhage

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Supplementary Table 2: Detailed characteristics of human studies evaluating the role of interleukin-6 after subarachnoid hemorrhage Study No. of

patients

Study design

IL-6

measurements

Relation to DCVS

Relation to DCI/DIND

Relation to outcome

Study result

Mathiesen et al., 1993 [72]

12 Prospective cohort study

CSF, plasma - Mean CSF IL-6 in

patients with DCI increased significantly

- IL-6 showed a marked

increase in CSF (up to 300- fold) after SAH. This was not paralleled by a systemic increase of IL-6 in plasma Kikuchi et

al., 1995 [53]

7 Prospective

cohort study

CSF, serum - - - Marked increase of CSF IL-

6 from early phase to middle phase after SAH.

Serum IL-6 concentrations were extremely low

compared with those of CSF Hirashima

et al., 1997 [48]

Plasma - IL-6 levels

significantly increased in patients suffering from delayed ischemic deficit

- IL-6 and the coagulating factor PAF concentrations increased within the first 4 days after SAH and

remained elevated up to 14 days

Patients with delayed ischemic deficit displayed the highest levels of PAF and the coagulation factors vWF and thrombin-

antithrombin III complex

McKeating 10 Prospective Serum - - - Increased jugular venous

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et al., (1997) [75]

cohort study serum concentrations of IL-

6 relative to arterial concentrations after SAH, suggesting a significant production of IL-6 in the intracranial compartment Gaetani et

al., 1998 [42]

CSF Significant

increase of IL-6

predictive for DCVS

- - Significant increase of IL-6

in the early stage after SAH

Osuka et al., 1998 [89]

CSF, plasma Patients with symptomatic DCVS had significant higher CSF IL-6 values compared with patient without symptomatic DCVS

- - CSF concentrations of IL-6

after SAH were thousands of times higher than in plasma or in control of CSF samples

IL-6 level remained high until the chronic stages

Fassbender et al., 2001 [38]

CSF, plasma Development of CBFVs

≥210 cm/s associated with increased CSF

Patient with CT signs of DCI showed a Non- significant trend toward increased CSF IL-6 concentrations

CSF IL-6 concentration at day 5 were significantly increased in patients with

CSF concentrations of IL-6 were increased up to 10,000 folds after SAH compared with control group

Plasma IL-6 concentrations after SAH were

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concentration s

poor (GOS 1- 2) compared with those with moderate (GOS3-5) outcome.

significantly lower in plasma compared with CSF

Kwon et al., 2001 [55]

CSF - IL-6 level 4-fold higher

in patient with DCI compared with patient without

No correlation with outcome on GOS

Significantly increased CSF IL-6 level after SAH compared with controls

Naredi et al., 2006 [83]

Plasma - - - Plasma level of IL-6

significantly elevated at 48 h, 72 h, and 7-10 days after SAH

No relationship between magnitude of sympathetic activation and IL-6

Schoch et al., 2007 [107]

CSF CSF IL-6

level >2000 pg/ml on day after SAH yielded an 11.72-fold higher relative risk of

developing DCVS

Significant correlation between IL-6 CSF and DCI

No significant correlation with Rankin scale

Mean CSF IL-6 values were 500-fold greater in SAH patients compared with controls

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Nakahara et al., 2009 [82]

CSF - - IL-6

significantly increased in patients with unfavorable outcome

HMGB1 levels increase after SAH and correlate with IL-6 levels

Sarrafzade h et al.

2010 [103]

CSF, plasma, ECF

- Cerebral but not

plasma IL-6 levels are predictive for DCI in symptomatic patients

- High IL-6 levels in CSF, ECF and plasma were found in all patients, reflecting a pronounced local

inflammatory response after SAH

Muroi et al., 2011 [79]

Plasma Higher IL-6

levels in patients developing DCVS

- - Aneurysmatic SAH patients

had significantly higher IL- 6 values compared with peri- mesencephalic SAH patients

Ni et al., 2011 [85]

CSF Patients with

DCVS demonstrated statistically significant higher median values of IL-6 CSF on day 1, 2, 3, 5, and 7

- - IL-6 CSF a reliable early

marker for predicting DCVS after SAH on days 3 (cut-off value 400 pg/ml) after treatment

Chou et al., 2012 [26]

Plasma No

association

- No association

between IL-6 No association between IL-

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between IL-6 plasma levels and DCVS

plasma levels

and outcome 6, DCVS and outcome

Muroi et al., 2013 [81]

Plasma - Higher IL-6 levels in

the early phase (day 3- 7 after SAH) are associated with occurrence of DCI

Higher IL-6 level

independent risk factor for poor outcome

High systemic IL-6 levels are independent risk factor for unfavorable outcome and occurrence of secondary cerebral infarction

McMahon et al., 2013 [76]

Plasma - Average increase per

day of IL-6 showed a significant association with DCI

- Leukocytosis and change in IL-6 before DCI reflect impending cerebral ischemia

Wu et al., 2016 [123]

57 Case control study

CSF DCVS

patients showed elevated IL-6 compared with non- DCVS patients

- - IL-6 and TNFalpha levels in

CSF of SAH patients markedly higher compared with controls. IL-6 CSF levels correlated with the increasing disease severity based on Hunt-Hess grade in SAH patients

Niwa et al., 2016 [87]

CSF - - Poor outcome

patients showed higher IL-6

concentrations compared with good outcome

CSF IL-6 concentration significantly increased during the acute stage the disease

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patients Chaudhry

et al., 2017 [22]

Serum Higher IL-6

levels in patient with DCVS

Delayed increase of IL- 6 in patients with DCI

Serum IL-6 levels were independently associated with poor clinical outcome

Serum IL-6 levels were found to be significantly elevated in SAH patients presenting with higher Hunt and Hess grades, increasing age, and both

intraventricular and intracerebral hemorrhage IL-6 was also significantly raised in patients who developed seizures and chronic hydrocephalus Chamling

et al., 2017 [14]

Plasma - IL-6 levels

significantly associated with DCI

-

Leucocyte count associated with occurrence of DCI Savarraj et

al., 2017 [105]

45 Retrospectiv e

observation al study

Plasma - - - Systemic inflammatory

activity peaks at 24 to 48 hours after SAH. IL-6 in plasma peaked between 24 to 48 hours and decreased to baseline 6 to 8 days after SAH

Duris K. et al., 2018 [33]

CSF, plasma No

association between IL-6

- Significant

association between IL-6

CSF IL-6 levels massively increased after SAH up to 72 hours, with an additional

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levels and DCVS was found

and GOS for both overall levels of IL-6 and their dynamics

increase in later phases (after 72 hours)

No association was found between Fisher grade and IL-6 and modality of treatment

Plasmatic levels of IL-6 increased slightly

Savarraj et al., 2018 [104]

71 Prospective observation al study

Plasma - - IL-6,

independently associated with clinical

severity

IL-6 was elevated in

patients with global cerebral ischemia, in patients with higher subarachnoid hemorrhage early brain edema score and higher Hunt-Hess-score

Ahn et al., 2019 [1]

Plasma - No significant

association between IL- 6 and DCI was found

Early

elevations of IL-6 after SAH were

independently associated with poor functional outcomes at 3 months

IL-6 sequentially expressed in CSF after SAH

Al-Tamimi et al., 2019 [3]

CSF, plasma - No significant

difference in CSF IL-6 levels between patient

Day 3 plasma IL-6 levels predicted poor

CSF levels of IL-6 showed significant increase in the days after SAH compared

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with or without DIND outcome at six months, but not

independently of clinical grade.

with controls

Plasma IL-6 levels were significantly higher on days 5 and 7 than controls

Rasmussen et al., 2019 [97]

Plasma No

association between plasma IL-6 and DCVS

No association between plasma IL-6 and DCI

No association between plasma IL-6 and outcome at 3 months

Plasma levels of IL-6 were not associated with DCI, DCVS, or clinical outcome at 3 months

Ridwan et al., 2019 [98]

CSF, serum - - IL-6 CSF

levels showed a significant positive impact on HRQOL

Early IL-6 levels may predict patients' HRQOL after SAH. CSF IL-6 level significantly higher than serum IL-6 levels

Vlachogian nis et al., 2019 [118]

CSF, plasma Patients with DCVS showed a trend toward higher IL-6 CSF

concentration s

Patients with DCI showed a trend toward higher IL-6 CSF concentrations

Patients with unfavorable outcome showed a trend toward higher IL-6 CSF concentrations

CSF IL-6 levels were significantly elevated from day 1 to days 4 and 10, whereas plasma IL-6 showed a different trend at lower levels

Higher Fisher grade showed a trend of higher CSF IL-6 CSF IL-6 levels

significantly higher than

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Plasma IL-6, this suggests endogenous cytokine production within the CNS after SAH

Ridwan et al., 2021 [99]

CSF, serum Correlation between CSF IL-6 and secondary vasospastic infarcts

Significant correlation between CSF IL-6 and DCI

Baseline CSF IL-6 levels following SAH predictors of DCI No correlations between individual serum IL-6 peak levels and DCI

High CSF IL-6 levels

corresponded to worse outcome on modified Rankin scale

CSF IL-6 levels higher than serum level. correlation between elevated CSF IL-6 levels and secondary vasospastic infarcts

IL-6, interleukin-6; DCVS, delayed cerebral vasospasm; DCI, delayed cerebral ischemia; DIND, delayed ischemic neurological deficit; CSF, cerebrospinal fluid; SAH, subarachnoid hemorrhage; PAF, platelet activating factor; vWF, von Willebrand factor; CBVF, cerebral blood flow velocities; GOS, Glasgow Outcome Scale; HMGB1, High-mobility group box 1 protein; ECF, extracerebral fluid; TNFalpha, tumor necrosis factor alpha; HRQOL, health-related quality of life