Elevated Systemic IL-6 Levels in Patients with Aneurysmal Subarachnoid Hemorrhage Is an Unspecific Marker for Post-SAH Complications

Shafqat Rasul Chaudhry, Birgit Stoffel-Wagner, Thomas Mehari Kinfe, Erdem Güresir, Hartmut Vatter, Dirk Dietrich, Alf Lamprecht, Sajjad Muhammad, Shafqat Rasul Chaudhry, Birgit Stoffel-Wagner, Thomas Mehari Kinfe, Erdem Güresir, Hartmut Vatter, Dirk Dietrich, Alf Lamprecht, Sajjad Muhammad

Abstract

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is still a fatal and morbid disease, although bleeding aneurysms can be secured in almost all cases. Occurrence of post-SAH complications including cerebral vasospasm, delayed cerebral ischemia, hydrocephalus, epilepsy, and infections are the main determinants of clinical outcome. Hence, it is important to search for early predictors for specific post-SAH complications to treat these complications properly. Both cellular and molecular (cytokines) inflammation play a key role after aSAH during the phase of occurrence of post-SAH complications. Interleukin-6 (IL-6) is a well-known cytokine that has been extensively analyzed in cerebrospinal fluid (CSF) of patients after aSAH, but detailed studies exploring the role of systemic IL-6 in aSAH associated complications and its impact on early clinical outcome prediction are lacking. The current study aims to analyze the systemic IL-6 levels over two weeks after bleeding and its role in post-SAH complications. Methods: We recruited 80 aSAH patients prospectively who underwent peripheral venous blood withdrawal in serum gel tubes. The blood was centrifuged to harvest the serum, which was immediately frozen at -80 °C until analysis. Serum IL-6 levels were quantified using Immulite immunoassay system. Patient records including age, gender, post-SAH complications, aneurysm treatment, and clinical outcome (modified Rankin scale and Glasgow outcome scale) were retrieved to allow different subgroup analysis. Results: Serum IL-6 levels were significantly raised after aSAH compared to healthy controls over the first two weeks after hemorrhage. Serum IL-6 levels were found to be significantly elevated in aSAH patients presenting with higher Hunt and Hess grades, increasing age, and both intraventricular and intracerebral hemorrhage. Interestingly, serum IL-6 was also significantly raised in aSAH patients who developed seizures, cerebral vasospasm (CVS), and chronic hydrocephalus. IL-6 levels were sensitive to the development of infections and showed an increase in patients who developed pneumoniae. Intriguingly, we found a delayed increase in serum IL-6 in patients developing cerebral infarction. Finally, IL-6 levels were significantly higher in patients presenting with poor clinical outcome in comparison to good clinical outcome at discharge from hospital. Conclusion: Serum IL-6 levels were elevated early after aSAH and remained high over the two weeks after initial bleeding. Serum IL-6 was elevated in different aSAH associated complications, acting as a non-specific marker for post-SAH complications and an important biomarker for clinical outcome at discharge.

Keywords: aneurysm; clinical outcome; inflammation; interleukin-6 (IL-6); post-SAH complications; subarachnoid hemorrhage.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Comparison of serum IL-6 levels among healthy controls and aneurysmal subarachnoid hemorrhage (aSAH) patients. HC = Healthy controls, n = 10, aSAH = Aneurysmal subarachnoid hemorrhage, n = 80, D1–D13 = Day 1–Day 13, Unpaired t test, p < 0.001 (***), error bars represent SEM.
Figure 2
Figure 2
Comparison of serum interleukin-6 (IL-6) levels among aSAH patients with different characteristics. (A) Comparison of serum IL-6 levels in aSAH patients undergoing repair of aneurysm by neurosurgical clipping (n = 39) or endovascular coiling (n = 41); (B) Comparison of serum IL-6 levels in male (n = 30) and female (n = 50) aSAH patients; (C) Comparison of serum IL-6 levels among aSAH patients with anterior circulation aneurysms (n = 69) and posterior circulation aneurysms (n = 11); (D) Comparison of serum IL-6 levels among aSAH patients below (n = 37) and above 55 years of age (n = 43); (E) Comparison of serum IL-6 levels among aSAH patients with good Hunt and Hess (H&H) grades (n = 29) and poor H&H grades (n = 51); (F) Comparison of serum IL-6 levels among aSAH patients showing no intraventricular hemorrhage and intracerebral bleeding (IVH + ICB) (n = 43) and IVH (n = 10). Unpaired t test to compare the two groups, p < 0.05 (*), p < 0.01 (**), p < 0.001 (***), error bars represent SEM.
Figure 3
Figure 3
(A) Comparison of serum IL-6 levels among aSAH patients showing no IVH + ICB (n = 43) and ICB (n = 16). (B) Comparison of serum IL-6 levels among aSAH patients showing no IVH + ICB (n = 43) and both IVH + ICB (n = 11). (C) Comparison of serum IL-6 in patients displaying delayed ischemic neurological deficits (DIND) (n = 28) and no DIND (n = 52). (D) Comparison of serum IL-6 in aSAH patients who developed cerebral vasospasm (CVS) (n = 44) and no CVS (n = 36). (E) Comparison of serum IL-6 in aSAH patients who developed seizures (n = 24) and no seizures (n = 56). (F) Comparison of serum IL-6 in aSAH patients who developed chronic hydrocephalus (n = 25) and no chronic hydrocephalus (n = 55). Unpaired t test to compare the two groups, p < 0.05 (*), p < 0.01 (**), p < 0.001 (***), error bars represent SEM.
Figure 4
Figure 4
(A) Comparison of serum IL-6 levels in aSAH patients with infections (n = 30) and without infections (50). (B) Comparison of serum IL-6 levels in aSAH patients presenting with only pneumonia (n = 14) and no infections (n = 50). (C) Comparison of serum IL-6 levels in aSAH patients presenting with only meningitis (n = 7) and no infections (n = 50). (D) Comparison of serum IL-6 levels in aSAH patients presenting with other infections (n = 9) and no infections (n = 50). (E) Comparison of serum IL-6 levels among patients with cerebral ischemia (CI) (n = 33) and no CI (n = 47). (F) Comparison of serum IL-6 levels in patients with delayed cerebral ischemia (DCI) (n = 16) and no CI (n = 47). Unpaired t test to compare the two groups, p < 0.05 (*), p < 0.01 (**), p < 0.001 (***), error bars represent SEM.
Figure 5
Figure 5
(A) Comparison of serum IL-6 levels among patients with good clinical outcome (GOS 4–5 = 39) and poor clinical outcome (GOS 1–3 = 41) as assessed by GOS. (B) Comparison of serum IL-6 levels among aSAH patients with good clinical outcome (mRS 0–2 = 35) and poor clinical outcome (mRS 3–6 = 45) as assessed by modified Rankin scale. Unpaired t test to compare the two groups, p < 0.05 (*), p < 0.001 (***), error bars represent SEM.

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