Cytokine changes in cerebrospinal fluid and plasma after emergency orthopaedic surgery

Abstract

Neuroinflammation after surgery and its contribution to peri-operative neurocognitive disorders (PND) is not well understood. Studying the association between central and peripheral cytokines and neuroinflammation is a prelude to the development of treatments for PND. Here, we investigate the hypotheses that there is a greater cytokine response in cerebrospinal fluid (CSF) than plasma after orthopaedic surgery, and that plasma cytokine levels are directly related to CSF cytokine levels, indicating that plasma cytokine levels may have potential as biomarkers of neuroinflammation. Patients admitted with a fractured neck of femur were invited to participate in this study. Participants had a spinal catheter inserted just prior to induction of anaesthesia. Samples of blood and CSF were taken before, immediately after, and on the first day following emergency surgery. The catheter was then removed. Samples were analysed for the presence of ten cytokines by immunoassay. A spinal catheter was successfully inserted in 11 participants during the 18-month study period. Five plasma cytokines (IL-4, IL-6, IL-10, IL-12p70 and IL-13) rose significantly following surgery, whereas all ten CSF cytokines rose significantly (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IFN-γ and TNF-α) (adjusted-p < 0.05). Central (CSF) cytokine levels were consistently higher than their peripheral (plasma) counterparts after surgery, with some patients having a particularly marked neuroinflammatory response. The greatest increases occurred in IL-8 in CSF and IL-6 in plasma. There were significant, strong positive correlations between several of the measured cytokines in the CSF after surgery, but far fewer in plasma. There was no significant correlation between cytokine levels in the plasma and CSF at each of the three time points. To our knowledge, this is the first study to analyse paired samples of plasma and CSF for cytokine levels before and after emergency orthopaedic surgery. This study demonstrates that following surgery for a fractured neck of femur, there is a far greater rise in cytokines in the CSF compared to plasma. The lack of correlation between peripheral and central cytokines suggests measurement of peripheral cytokines are not necessarily related to which patients may have a large neuroinflammatory response.

Putative Involvement of Cytokine Modulation in the Development of Perioperative Neurocognitive Disorders

“… Danielson et al 2020 67 27 Knee or hip replacement Spinal Elective Nil 0, 4, 8, 24, 32 and 48 hours after surgery IL-6, IL-8, CXCL6, CCL3, CCL8 Higher CSF levels of IL-6, IL-8, CCL3, CCL8, and CXCL6 were found at 48 hours after surgery in patients with long-term cognitive decline. Fertleman et al 2022 65 11 Surgery for a broken hip Spinal Emergency Nil 0, after surgery and day 1 after surgery IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IFN-γ, TNF-α Cytokine rises were greater in CSF than plasma, with the largest increase in IL-8. Hirsch et al 2016 61 10 Major knee surgery Spinal Elective Nil 0, 3, 6 and 18 hours after surgery 14 cytokines Increases in pro-inflammatory cytokines were found in patients’ plasma and CSF after surgery.…”

“…While preoperative cytokine levels can be difficult to detect, it is possible to measure CSF cytokine levels in the post-operative period by leaving a spinal catheter in situ for 24 hours after an operation. 61 , 65 Numerous cytokines have been shown to increase in the CSF after an operation, with greater increases in the cytokines IL-6 and IL-8 in the CSF than in serum, as summarised in Table 2 . While these studies are informative, they have only been performed in patients undergoing cardiac, orthopaedic or vascular surgery, and the numbers involved are small.…”

“…This suggests that a combination of fracture, pain, dehydration and a catabolic state do not drive neuroinflammation in the same way that surgery does. 65 …”

“… 48 In 11 patients undergoing hip fracture repair, 3 patients had similarly pronounced CSF cytokine responses following surgery. 65 It remains to be seen whether those patients with a more pronounced CSF cytokine response are those that go on to develop PND. Of note, animal models suggest this may be the case, as in rats undergoing abdominal surgery, the magnitude of neuroinflammation was correlated with POD.…”

“…It has consistently been shown that plasma or serum cytokines do not correlate with CSF cytokines in the post-operative period, with no association found between IL-6, 45 , 70 IL-8 60 and 10 pro-inflammatory cytokines. 65 This is disappointing as the use of blood-based biomarkers is more attractive than CSF biomarkers due to the fact that obtaining CSF involves a more invasive process, which carries some risk. 71 …”