Skip Navigation


Age and Ageing Advance Access originally published online on November 17, 2006
Age and Ageing 2007 36(2):222-225; doi:10.1093/ageing/afl121
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
36/2/222    most recent
afl121v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Macdonald, A.
Right arrow Articles by Martin, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Macdonald, A.
Right arrow Articles by Martin, F.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © The Author 2007. Published by Oxford University Press on behalf of the British Geriatrics Society.

C-reactive protein levels predict the incidence of delirium and recovery from it

Introduction

SIR—Delirium (acute confusional state, a sudden onset, fluctuating state of cognitive decrement and disordered consciousness) is a very common condition that complicates the hospital treatment of many older people, particularly in the specialties of medicine, orthopaedics, and general and cardiovascular surgery. It is greatly distressing, life-shortening, and associated with longer hospital stays and residual cognitive impairment [1]. No laboratory test exists to assist in the diagnosis of delirium and thus its diagnosis depended only on clinical observations [2] and is often missed even in specialist centres [3]. The most consistent known risk factor is pre-existing dementia, suggesting that delirium is actually a part of the syndrome of dementia itself [4]. Its mechanism is unknown and, although anticholinergic activity has been given precedence as a basis for specific therapeutics for many years, no randomised controlled trials of cholinergic enhancement have been published. A possible neuroinflammatory basis for delirium is also emerging and low levels of insulin-like growth factor I (IGF-I) have recently been found as a risk factor for incident delirium [5].

The acute phase protein, C-reactive protein (C-RP), which has traditionally been used as a marker of infection, inflammation, and tissue injury [6], may also be implicated in the cause and outcome of delirium. One previous study investigated the kinetics of C-RP in post-operative elderly patients and reported significantly higher levels of C-RP in those with complications (infections, cardiovascular problems, and delirium) [7]. C-RP has also been correlated with poor cognitive performance and accelerated cognitive decline in a number of community studies [8, 9]. Some authors have found an increased C-RP concentration in older people [10–12] and have suggested that this represents sub-clinical illnesses [13]. Two large epidemiological studies (in Rotterdam and Honolulu) found that increased levels of C-RP were associated with all dementias [14, 15]. C-RP appears to predict coronary events and incident stroke independently of atherosclerosis severity or other cardiovascular risk factors [16, 17], and it appears to be an independent predictor of survival after stroke [18].

We therefore tested C-RP as both a predictor of incident delirium and recovery from delirium as part of a preliminary observational study of a series of 94 acutely ill patients aged 70 or older admitted to a medical unit for older people in a university teaching hospital.

Methods

All 94 patients were initially assessed within 3 days of admission with (i) a standard bedside test of cognitive function, the Mini Mental State Examination (MMSE) [19]: the MMSE score was standardized to give a maximum score of 30 if the patients could not complete sections because of serious disability, e.g. visual ((item score/items completed) x30); (ii) the confusion assessment method (CAM) to determine the presence or absence of delirium [20]; (iii) the Acute Physiological Score of APACHE-II (APS) [21] to measure severity of acute physical illness (arterial pH and oxygen saturation were omitted as arterial blood sampling was not feasible); and (iv) the Katz ADL scale [22] to measure disability. C-RP was measured routinely in all acute admissions on the day of the first ‘battery’ of assessments, almost always within 1 day. Presence of delirium was determined by CAM every 3 (plus or minus 1) days until the 18th day of hospitalisation and finally on the 28th day of hospitalisation. Incident delirium was defined as occuring when the initial CAM assessment was negative and any subsequent one was positive, and recovery from delirium was identified when a CAM-positive assessment was followed by CAM-negatives until discharge or death.

The study had ethical approval from the Guy's and St Thomas' Research Ethics Committee.

Results

C-RP levels were available for 86 patients. Their mean age was 82.7 (SD 6.6) years and 37 (43%) of them were male. Admission MMSE scores had a mean of 18.1 (SD 8.2), a median of 19 and an interquartile range of 13. Fifty-four (62.8%) subjects remained non-delirious throughout their admission, 26 subjects (30.2%) were cases of prevalent delirium, and 6 subjects (7%) became CAM-positive after their first assessment (incident delirium). Overall, 37.2% had delirium at some point. From among those with delirium at any point, 14 (43.8%) recovered from delirium before death or discharge and 18 (56.3%) did not. In the patients who remained CAM-negative throughout their admission, the mean C-RP was 52.4 mg/l (SD 55.8), in those already CAM-positive at initial assessment (prevalent delirium) it was 64.8 mg/l (SD 54.5), and in those who were negative at first assessment but who later became positive (incident delirium) it was 148.6 mg/l (SD 82.6). Although a significant difference in the levels of C-RP between the three groups (with prevalent delirium, incident delirium, or never had delirium) was evident (Kruskal–Wallis test, chi-square 10.746, DF 2, p = 0.005), there was no significant difference in the levels of C-RP between those with delirium and those without delirium at first assessment (Mann–Whitney test, p = 0.112). In a binary logistic analysis, including age, sex, initial MMSE, APS scale score, disability score and C-RP, only the C-RP level predicted the incidence of delirium (Wald 5.56, DF 1, p = 0.018). For CAM-negative patients at first assessment, a receiver operator characteristics (ROC) curve for initial C-RP level against incident delirium is shown (dashed line) in Figure 1. The likelihood ratio for incident delirium by initial C-RP level in this group is shown in Figure 2 (dashed line, right hand Y axis). In a further binary logistic regression, only a higher (better) initial MMSE score and a low C-RP predicted recovery from the CAM-positive status at any time (Wald statistic 6.49 DF 1p = 0.011, Wald statistics 5.67 DF 1p = 0.017, respectively). In these patients, an ROC curve against recovery to CAM-negative status is also shown (solid line) in Figure 1. The likelihood ratio for their recovery by initial C-RP level is shown in Figure 2 (solid line, left-hand Y axis). The two figures together appear to confirm that the association between C-RP and incident delirium was stronger than that with recovery, at least in this small sample.


Figure 1
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1. Receiver operator characteristics curves of C-RP with incident delirium (higher C-RP = more incidence) and recovery from incident or prevalent delirium (lower C-RP = more recovery)

 

Figure 2
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2. Likelihood ratios for each value of initial C-RP against incident delirium and recovery from delirium

 
Discussion

This is the first report of a possible link between C-RP levels, which is a marker of acute inflammatory response, and delirium in acute medical inpatients. C-RP levels appear to be highly predictive of both incident delirium and recovery even in the small numbers in this study and are independent of our measures of physical illness and disability. C-RP is thought to reflect the intensity of the acute phase response, but we found that the effect was independent of our measures of physical illness and disability, in contrast to that seen in post-operative patients [7]. Evidence has recently emerged of the relationship of C-RP with neuroinflammatory processes; for instance, it is associated in the activation of vascular endothelial cells, a process that may explain the vulnerability of patients with organic brain disease to delirium caused by systemic inflammatory conditions [23]. Considering that C-RP is elevated in inflammation and infection, and its production is under the control of other cytokines [16], it may be that the levels of more specific cytokines are even more closely correlated with such processes and their relationship with delirium. Alternatively, after initiation as a host defence mechanism, C-RP may act as a proinflammatory factor [6] with deleterious effects, as shown in animal studies [24]. Although it could be argued that CAM is quicker than the measurement of C-RP, the fact is that the C-RP measurement is quicker. This may help focus clinical attention on those most at risk of developing delirium and enable the initiation of well-known, evidence-based but expensive preventative measures.

The present study could not determine the mechanisms leading to delirium, and a further study in a new cohort is underway. Given the complex interplay between predisposing and precipitating causes, especially in the presence of multiple conditions that may or may not be relevant, it was not possible to ascertain the illnesses or other factors that were causal in this study. There are always limitations in the applicability of results from small samples to other cohorts of patients; however, in view of the widespread use of C-RP in medical practice, this preliminary finding should be easily replicable. Larger studies in several settings would be needed to determine the best cut-off points for using C-RP as a predictor of delirium incidence and recovery.

Key points

  • High levels of C-RP independently predicted the incidence of delirium.
  • A higher initial MMSE score and low C-RP predicted the recovery from delirium at any time during hospitalisation for patients with delirium.
  • Elevated C-RP should alert clinicians to the possibility of incident delirium.
  • C-RP in acute illness merits further investigation as a marker for potential precipitating or perpetuating mechanisms for delirium.

Conflicts of interest

The authors have no conflicts of interest to declare.

Funding

The project was supported by the Bosher Memorial Bequest. No-one connected with the bequest played any role in the design, execution, analysis and interpretation of data, or preparation of the study.

Alastair Macdonald1,*, Dimitrios Adamis2, Adrian Treloar2 and Finbarr Martin3

1 Institute of Psychiatry, Psychological Medicine, London, UK
2 Oxleas NHS Trust, Old Age Psychiatry, London, UK
3 Guy's and St Thomas' NHS Foundation Trust, Elderly Care Unit, London, UK

* To whom correspondence should be addressed Email: alastair.macdonald{at}iop.kcl.ac.uk

References

  1. Burns A, Gallagley A, Byrne J. (2004) Delirium. J Neurol Neurosurg Psychiatry 75 362–67.[Abstract/Free Full Text]
  2. American Psychiatric Association. (1999) Practice guideline for the treatment of patients with delirium. Am J Psychiatry 156 1–20.[Free Full Text]
  3. Elie M, Rousseau F, Cole M, Primeau F, McCusker J, Bellavance F. (2000) Prevalence and detection of delirium in elderly emergency department patients. CMAJ 163 977–81.[Abstract/Free Full Text]
  4. Macdonald AJ and Treloar A. (1996) Delirium and dementia; are they distinct? J Am Geriatr Soc 44 1001–2.[Web of Science][Medline]
  5. Wilson K, Broadhurst C, Diver M, Jackson M, Mottram P. (2005) Plasma insulin growth factor-1 and incident delirium in older people. Int J Geriatr Psychiatry 20 154–59.[CrossRef][Web of Science][Medline]
  6. Pepys MB and Hirschfield GM. (2003) C-reactive protein: a critical update. J Clin Invest 111 1805–12.[CrossRef][Web of Science][Medline]
  7. Beloosesky Y, Grinblat J, Pirotsky A, Weiss A, Hendel D. (2004) Different C-reactive protein kinetics in post-operative hip-fractured geriatric patients with and without complications. Gerontology 50 216–22.[CrossRef][Web of Science][Medline]
  8. Tilvis RS, Kahonen-Vare MH, Jolkkonen J, Valvanne J, Pitkala KH, Strandberg TE. (2004) Predictors of cognitive decline and mortality of aged people over a 10-year period. J Gerontol A Biol Sci Med Sci 59 268–74.
  9. Yaffe K, Kanaya A, Lindquist K, et al. (2004) The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 292 2237–42.[Abstract/Free Full Text]
  10. Caswell M, Pike LA, Bull BS, Stuart J. (1993) Effect of patient age on tests of the acute-phase response. Arch Pathol Lab Med 117 906–10.[Web of Science][Medline]
  11. Ballou SP, Lozanski FB, Hodder S, et al. (1996) Quantitative and qualitative alterations of acute-phase proteins in healthy elderly persons. Age Ageing 25 224–30.[Abstract/Free Full Text]
  12. Lehtimaki T, Ojala P, Rontu R, et al. (2005) Interleukin-6 modulates plasma cholesterol and C-reactive protein concentrations in nonagenarians. J Am Geriatr Soc 53 1552–58.[CrossRef][Web of Science][Medline]
  13. Hutchinson WL, Koenig W, Frohlich M, Sund M, Lowe GD, Pepys MB. (2000) Immunoradiometric assay of circulating C-reactive protein: age-related values in the adult general population. Clin Chem 46 934–38.[Abstract/Free Full Text]
  14. Engelhart MJ, Geerlings MI, Meijer J, et al. (2004) Inflammatory proteins in plasma and the risk of dementia: the Rotterdam Study. Arch Neurol 61 668–72.[Abstract/Free Full Text]
  15. Schmidt R, Schmidt H, Curb JD, Masaki K, White LR, Launer LJ. (2002) Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol 52 168–74.[CrossRef][Web of Science][Medline]
  16. Gabay C and Kushner I. (1999) Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340 448–54.[Free Full Text]
  17. Cao JJ, Thach C, Manolio TA, et al. (2003) C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the cardiovascular health study. Circulation 108 166–70.
  18. Muir KW, Weir CJ, Alwan W, Squire IB, Lees KR. (1999) C-reactive protein and outcome after ischemic stroke. Stroke 30 981–85.[Abstract/Free Full Text]
  19. Folstein MF, Folstein SE, McHugh PR. (1975) "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12 189–98.[CrossRef][Web of Science][Medline]
  20. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. (1990) Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med 113 941–48.[Abstract/Free Full Text]
  21. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. (1985) APACHE II: a severity of disease classification system. Crit Care Med 13 818–29.[Web of Science][Medline]
  22. Katz S, Downs TD, Cash HR, Grotz RC. (1970) Progress in development of the index of ADL. Gerontologist 10 20–30.[Web of Science][Medline]
  23. Uchikado H, Akiyama H, Kondo H, et al. (2004) Activation of vascular endothelial cells and perivascular cells by systemic inflammation-an immunohistochemical study of postmortem human brain tissues. Acta Neuropathol (Berl) 107 341–51.[CrossRef][Medline]
  24. Gill R, Kemp JA, Sabin C, Pepys MB. (2004) Human C-reactive protein increases cerebral infarct size after middle cerebral artery occlusion in adult rats. J Cereb Blood Flow Metab 24 1214–18.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Age AgeingHome page
J. McManus, R. Pathansali, H. Hassan, E. Ouldred, D. Cooper, R. Stewart, A. Macdonald, and S. Jackson
The course of delirium in acute stroke
Age Ageing, July 1, 2009; 38(4): 385 - 389.
[Abstract] [Full Text] [PDF]

Home page
 Age AgeingHome page
D. Adamis, M. Lunn, F. C. Martin, A. Treloar, N. Gregson, G. Hamilton, and A. J. D. Macdonald
Cytokines and IGF-I in delirious and non-delirious acutely ill older medical inpatients
Age Ageing, May 1, 2009; 38(3): 326 - 332.
[Abstract] [Full Text] [PDF]

Home page
 Age AgeingHome page
S. Speciale, G. Bellelli, F. Guerini, and M. Trabucchi
C-reactive protein levels and delirium in a rehabilitation ward
Age Ageing, January 1, 2008; 37(1): 122 - 123.
[Full Text] [PDF]

Home page
 Age AgeingHome page
S. White, E. Eeles, S. O'Mahony, and A. Bayer
Delirium and C-reactive protein
Age Ageing, January 1, 2008; 37(1): 123 - 124.
[Full Text] [PDF]

Home page
 Age AgeingHome page
D. Adamis, A. Treloar, F.-Z. Darwiche, N. Gregson, A. J. D. Macdonald, and F. C. Martin
Associations of delirium with in-hospital and in 6-months mortality in elderly medical inpatients
Age Ageing, November 1, 2007; 36(6): 644 - 649.
[Abstract] [Full Text] [PDF]

Home page
 Age AgeingHome page
A. Morandi, I. Sleiman, R. Rozzini, and M. Trabucchi
C-reactive protein and delirium in acute ill elderly patients
Age Ageing, July 1, 2007; 36(4): 473 - 473.
[Full Text] [PDF]

This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
36/2/222    most recent
afl121v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Macdonald, A.
Right arrow Articles by Martin, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Macdonald, A.
Right arrow Articles by Martin, F.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?