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Cerebrospinal fluid cortisol and cytokines in delirium after hip fracture
R. Reynolds / Psychoneuroendocrinology 61 (2015) 1–78
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Cerebrospinal fluid cortisol and cytokines in delirium after hip fracture
Cortisol diurnal rhythm and inflammation in delirium after hip fracture
R.J. Hall 1,∗ , L.O. Watne 2 , I. Robertson 1 , J. Witlox 3 , K. Kalisvaart 4 , J.R. Seckl 5 , V. Juliebø 2,6 , T.B. Wyller 2 , A.M.J. MacLullich 5
R.J. Hall 1,∗ , D. Davis 2 , T.O. White 1 , I. Robertson 1 , J.R. Seckl 3 , A.M.J. MacLullich 3
1
2
Lothian University Hospitals Trust, Scotland, UK 2 University of Oslo, Oslo, Norway 3 Medical Center Alkmaar, Alkmaar, The Netherlands 4 Kennemer Gasthuis, Haarlem, The Netherlands 5 University of Edinburgh, Edinburgh, UK 6 Oslo University Hospital, Oslo, Norway
Introduction: Delirium is a serious and common condition affecting older people. The pathophysiology is incompletely understood and there are no specific treatments. Current hypotheses suggest involvement of exaggerated cortisol release in response to stressors, and a magnified central nervous system (CNS) inflammatory response to peripheral insults. The aim of this collaborative research project was to test the hypotheses that delirium is associated with increased cortisol, increased pro-inflammatory and reduced anti-inflammatory cytokines in cerebrospinal fluid (CSF). Methods: Participants with acute hip fracture were recruited at the Royal Infirmary of Edinburgh and Oslo University Hospital. They were assessed for delirium pre-operatively, and at regular intervals for two weeks post-operatively. CSF was collected at the spinal anaesthetic performed for their fracture repair. Cortisol was measured by Enzyme-linked immunosorbent assay, and a highsensitivity panel of cytokines by Luminex assay (Interleukin(IL)-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IFN-␥, GM-CSF and TNF-␣). Group comparisons were with Kruskal–Wallis or Student’s t-test, and logistic regression analysis was used to adjust for potential confounders. Results: Delirium was diagnosed in 68/148 participants (46%) in the cortisol assay and 38/76 (50%) in the cytokine assay. CSF cortisol was higher in those with prevalent delirium (median 36.5 nmol/L, IQR 26.3–53.1) than incident (30.0 nmol/L (16.8–39.2)) or never delirium (27.2 nmol/L (18.8–39.3)), p = 0.023. CSF cortisol level above the median was still associated with delirium after adjusting for confounders. There were no differences observed in the levels of most cytokines between groups, but IL-5 was low in those with pre-operative delirium. Conclusions: These findings support the hypothesis that delirium is associated with exaggerated cortisol release, but provide little evidence of an exaggerated CNS inflammatory response. Prolonged high cortisol increases neuronal vulnerability to damage or death from various insults. Whether high cortisol is a cause or consequence of delirium merits further detailed investigation. http://dx.doi.org/10.1016/j.psyneuen.2015.07.523
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Lothian University Hospitals Trust, Scotland, UK University College London, London, UK 3 University of Edinburgh, Edinburgh, UK Introduction: Delirium is a serious and common condition affecting older people. The pathophysiology is incompletely understood and there are no specific treatments. Current hypotheses suggest involvement of exaggerated and prolonged cortisol and pro-inflammatory cytokine release in response to stressors. This study aimed to test the hypotheses that delirium is associated with increased cortisol levels and loss of cortisol diurnal rhythm, and with increased pro-inflammatory cytokines. Methods: Participants with acute hip fracture were recruited at the Royal Infirmary of Edinburgh. They were assessed for delirium pre-operatively, and regularly for two weeks postoperatively. Morning serum and diurnal saliva samples were collected pre-operatively and on post-operative days 4 and 10–14, with additional saliva samples on day 7. Cortisol was measured by Enzyme-linked immunosorbent assay, and a panel of cytokines by Luminex assay (Interleukin(IL)-1, IL-1ra, IL-5, IL-6, IL-8, IL10, MCP-1, MIP-1␣, MIP-1, and TNF-␣). Group comparisons were with Mann–Whitney U test. Logistic regression modelling was used to examine the relationship between delirium and longitudinal logtransformed cortisol level and cortisol AM:PM ratio, adjusting for confounders. Results: Delirium was diagnosed in 42/104 participants (40.4%). Serum cortisol was higher in the delirium group, and this was significant for those with active delirium on day 4. PM salivary cortisol was significantly higher in the delirium group on days 4 and 7. Morning cortisol was associated with delirium after adjusting for age, gender, illness severity, co-morbidity and dementia. The delirium group had higher levels of serum IL-1ra, IL-6, IL-8 and TNF-␣, and a higher pro:anti-inflammatory ratio. Conclusions: These findings support the hypothesis that delirium is associated with increased cortisol and attenuation of the normal nadir of cortisol diurnal rhythm, and that there is a shift towards a pro-inflammatory state. Future studies could investigate ways to attenuate this, such as the use of 11- hydroxysteroid dehydrogenase inhibitors. http://dx.doi.org/10.1016/j.psyneuen.2015.07.524
PO75
PO76
Cerebrospinal fluid cortisol and cytokines in delirium after hip fracture
Cortisol diurnal rhythm and inflammation in delirium after hip fracture
R.J. Hall 1,∗ , L.O. Watne 2 , I. Robertson 1 , J. Witlox 3 , K. Kalisvaart 4 , J.R. Seckl 5 , V. Juliebø 2,6 , T.B. Wyller 2 , A.M.J. MacLullich 5
R.J. Hall 1,∗ , D. Davis 2 , T.O. White 1 , I. Robertson 1 , J.R. Seckl 3 , A.M.J. MacLullich 3
1
2
Lothian University Hospitals Trust, Scotland, UK 2 University of Oslo, Oslo, Norway 3 Medical Center Alkmaar, Alkmaar, The Netherlands 4 Kennemer Gasthuis, Haarlem, The Netherlands 5 University of Edinburgh, Edinburgh, UK 6 Oslo University Hospital, Oslo, Norway
Introduction: Delirium is a serious and common condition affecting older people. The pathophysiology is incompletely understood and there are no specific treatments. Current hypotheses suggest involvement of exaggerated cortisol release in response to stressors, and a magnified central nervous system (CNS) inflammatory response to peripheral insults. The aim of this collaborative research project was to test the hypotheses that delirium is associated with increased cortisol, increased pro-inflammatory and reduced anti-inflammatory cytokines in cerebrospinal fluid (CSF). Methods: Participants with acute hip fracture were recruited at the Royal Infirmary of Edinburgh and Oslo University Hospital. They were assessed for delirium pre-operatively, and at regular intervals for two weeks post-operatively. CSF was collected at the spinal anaesthetic performed for their fracture repair. Cortisol was measured by Enzyme-linked immunosorbent assay, and a highsensitivity panel of cytokines by Luminex assay (Interleukin(IL)-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IFN-␥, GM-CSF and TNF-␣). Group comparisons were with Kruskal–Wallis or Student’s t-test, and logistic regression analysis was used to adjust for potential confounders. Results: Delirium was diagnosed in 68/148 participants (46%) in the cortisol assay and 38/76 (50%) in the cytokine assay. CSF cortisol was higher in those with prevalent delirium (median 36.5 nmol/L, IQR 26.3–53.1) than incident (30.0 nmol/L (16.8–39.2)) or never delirium (27.2 nmol/L (18.8–39.3)), p = 0.023. CSF cortisol level above the median was still associated with delirium after adjusting for confounders. There were no differences observed in the levels of most cytokines between groups, but IL-5 was low in those with pre-operative delirium. Conclusions: These findings support the hypothesis that delirium is associated with exaggerated cortisol release, but provide little evidence of an exaggerated CNS inflammatory response. Prolonged high cortisol increases neuronal vulnerability to damage or death from various insults. Whether high cortisol is a cause or consequence of delirium merits further detailed investigation. http://dx.doi.org/10.1016/j.psyneuen.2015.07.523
49
1
Lothian University Hospitals Trust, Scotland, UK University College London, London, UK 3 University of Edinburgh, Edinburgh, UK Introduction: Delirium is a serious and common condition affecting older people. The pathophysiology is incompletely understood and there are no specific treatments. Current hypotheses suggest involvement of exaggerated and prolonged cortisol and pro-inflammatory cytokine release in response to stressors. This study aimed to test the hypotheses that delirium is associated with increased cortisol levels and loss of cortisol diurnal rhythm, and with increased pro-inflammatory cytokines. Methods: Participants with acute hip fracture were recruited at the Royal Infirmary of Edinburgh. They were assessed for delirium pre-operatively, and regularly for two weeks postoperatively. Morning serum and diurnal saliva samples were collected pre-operatively and on post-operative days 4 and 10–14, with additional saliva samples on day 7. Cortisol was measured by Enzyme-linked immunosorbent assay, and a panel of cytokines by Luminex assay (Interleukin(IL)-1, IL-1ra, IL-5, IL-6, IL-8, IL10, MCP-1, MIP-1␣, MIP-1, and TNF-␣). Group comparisons were with Mann–Whitney U test. Logistic regression modelling was used to examine the relationship between delirium and longitudinal logtransformed cortisol level and cortisol AM:PM ratio, adjusting for confounders. Results: Delirium was diagnosed in 42/104 participants (40.4%). Serum cortisol was higher in the delirium group, and this was significant for those with active delirium on day 4. PM salivary cortisol was significantly higher in the delirium group on days 4 and 7. Morning cortisol was associated with delirium after adjusting for age, gender, illness severity, co-morbidity and dementia. The delirium group had higher levels of serum IL-1ra, IL-6, IL-8 and TNF-␣, and a higher pro:anti-inflammatory ratio. Conclusions: These findings support the hypothesis that delirium is associated with increased cortisol and attenuation of the normal nadir of cortisol diurnal rhythm, and that there is a shift towards a pro-inflammatory state. Future studies could investigate ways to attenuate this, such as the use of 11- hydroxysteroid dehydrogenase inhibitors. http://dx.doi.org/10.1016/j.psyneuen.2015.07.524