By: Dr. Geoffrey Modest
A recent study found a significant relationship between inflammatory markers and the development of delirium post-operatively (see doi:10.1093/gerona/glv083). This study assessed 566 patients >70yo undergoing major noncardiac surgery from the Successful Aging after Elective Surgery Study (SAGES), and compared 12 different cytokine levels in those patients who developed delirium vs not. Funded by the National Institute on Aging.
Background:
- Inflammatory markers have been linked to a variety of outcomes in the elderly, including frailty, dementia and cognitive decline, as well as several medical diseases (diabetes, heart disease…)
- Delirium is associated with systemic inflammatory states (eg, infections), perhaps related to inflammation-related breakdown of blood-brain barrier, microglial activation, and neuroinflammation.
Details of this study:
- Mean age 77, 56% female, vascular comorbidity approx 45%, General Cognitive Performance mean of 55 (this is a composite measure reflecting vulnerability to delirium, which to my reading is a scale normalized to 50 for the elderly, with a score of 50 roughly correlating to an MMSE of 26, and a score of 55 correlating with 28)
- Cytokines were measured at 4 times in all patients: pre-op (PREOP), post-anesthesia (PACU), post-op day 2 (POD2), and post-op day 30 (POD1M)
- This was a case-control study matched for age, sex, surgery type, baseline cognition, vascular comorbidity, apo E genotype
- Delirium was assessed by the Confusion Assessment Method algorithm
- There was a 3-stage approach: a discovery cohort (n=272, comparing 39 matched pairs of delirium cases vs no-delirium controls), a replication cohort (36 matched pairs from the remaining SAGES sample), and a combo of these 2 (with 75 matched pairs).
- Results:
- The most consistently elevated statistically significant cytokines in the different cohorts:
- IL-2, especially on POD2
- IL-6 (the most elevated, and dramatically so), esp POD2
- IL-12 was decreased, mostly POD1M
- TNF-a (tumor necrosis factor alpha) and VEGF (vascular endothelial growth factor): both peaking on POD2
- The association was found in all the cohorts, though less impressively in the replication cohort
- The most consistently elevated statistically significant cytokines in the different cohorts:
This study confirms some previous studies finding an association between cytokines and delirium. In other studies IL-6 has been found to be associated with age-related frailty and dementia. IL-2 regulates growth and differentiation of T cells and affects the development of the immune system and also seems to induce blood-brain barrier dysfunction. A strength of the current study is that it had a real baseline cytokine measurement (some of the studies of patients with hip fractures could have had cytokine increases based on the trauma. This study was in patients getting elective surgery). Also, the cytokines measured in the current study did not include acute phase reactants.
So, delirium is a pretty awful disease for patients and family, with increased mortality, increased hospital stays with their attendant morbidity and cost, high rates of institutional placement, and perhaps even high risk of subsequent dementia. This study provides both a potential means to identify patients at high risk of delirium early, and could ultimately lead to new medications to prevent delirium (all to be determined). I did send out a previous blog on the efficacy of melatonin-like meds in preventing delirium (see https://stg-blogs.bmj.com/bmjebmspotlight/2015/05/11/primary-care-corner-with-geoffrey-modest-md-melatonin-and-delirium-prevention/ )