Serum Anticholinergic Activity Research Articles

Serum anticholinergic activity and cerebral cholinergic dysfunction: An EEG study in frail elderly with and without delirium

BackgroundDelirium increases morbidity, mortality and healthcare costs especially in the elderly. Serum anticholinergic activity (SAA) is a suggested biomarker for anticholinergic burden and delirium risk, but the association with cerebral cholinergic function remains unclear. To clarify this relationship, we prospectively assessed the correlation of SAA with quantitative electroencephalography (qEEG) power, delirium occurrence, functional and cognitive measures in a cross-sectional sample of acutely hospitalized elderly (> 80 y) with high dementia and delirium prevalence.Methods61 consecutively admitted patients over 80 years underwent an extensive clinical and neuropsychological evaluation. SAA was determined by using radio receptor assay as developed by Tune, and standard as well as quantitative EEGs were obtained.Results15 patients had dementia with additional delirium (DD) according to expert consensus using DSM-IV criteria, 31 suffered from dementia without delirium (D), 15 were cognitively unimpaired (CU). SAA was clearly detectable in all patients but one (mean 10.9 ± 7.1 pmol/ml), but was not associated with expert-panel approved delirium diagnosis or cognitive functions. Delirium-associated EEG abnormalities included occipital slowing, peak power and alpha decrease, delta and theta power increase and slow wave ratio increase during active delirious states. EEG measures correlated significantly with cognitive performance and delirium severity, but not with SAA levels.ConclusionIn elderly with acute disease, EEG parameters reliable indicate delirium, but SAA does not seem to reflect cerebral cholinergic function as measured by EEG and is not related to delirium diagnosis.

Randomized, Placebo‐Controlled Trial of the Cognitive Effect, Safety, and Tolerability of Oral Extended‐Release Oxybutynin in Cognitively Impaired Nursing Home Residents with Urge Urinary Incontinence

Determine the cognitive effect, safety, and tolerability of oral extended-release oxybutynin in cognitively impaired older nursing home residents with urge urinary incontinence. Randomized, double-blinded, placebo-controlled trial. Twelve skilled nursing homes. Fifty women aged 65 and older with urge incontinence and cognitive impairment. Four-week treatment with once-daily oral extended-release oxybutynin 5 mg or placebo. Withdrawal rates and delirium or change in cognition from baseline at 1, 3, 7, 14, 21, and 28 days after starting treatment using the Confusion Assessment Method (CAM), Mini-Mental State Examination (MMSE), and Severe Impairment Battery (SIB). The Brief Agitation Rating Scale, adverse events, falls incidence, and serum anticholinergic activity change with treatment were also assessed. Participants' mean age +/-standard deviation was 88.6+/-6.2, and MMSE baseline score was 14.5+/-4.3. Ninety-six percent of subjects receiving oxybutynin (n=26) and 92% receiving placebo (n=24) completed treatment (P=.50). The differences in mean change in CAM score from baseline to all time points were equivalent between the oxybutynin and placebo groups. Delirium did not occur in either group. One participant receiving oxybutynin was withdrawn because of urinary retention, which resolved without treatment. Mild adverse events occurred in 38.5% of participants receiving oxybutynin and 37.5% receiving placebo (P=.94). Short-term treatment using oral extended-release oxybutynin 5 mg once daily was safe and well tolerated, with no delirium, in older female nursing home participants with mild to severe dementia. Future research should investigate different dosages and long-term treatment.

EEG changes and serum anticholinergic activity measured in patients with delirium in the intensive care unit

The aim of this study was to examine whether serum anticholinergic activity (SAA) is a reliable indicator of delirium in the ICU, and whether there is a significant correlation between SAA and quantitative electroencephalographic (EEG) data in delirious patients. In a prospective cohort study, we assessed ICU patients diagnosed with delirium (n = 37). EEG measurements and blood analysis including SAA were performed 48 h following ICU admission. The presence of delirium was evaluated using the Confusion Assessment Method for critically ill patients in ICU (CAM-ICU). The SAA level was measured using a competitive radioreceptor binding assay for muscarinergic receptors and quantitative EEG was measured using the CATEEM system. We found that, under comparable conditions, patients in the delirium group showed a higher relative EEG theta power and a reduced alpha power (n = 17) than did the non-delirious patients (n = 20). No difference in measured SAA levels were seen; therefore, there was no correlation between SAA and EEG measurements in delirious patients. We conclude that, in contrast to the EEG, the SAA level cannot be proposed as a tool for diagnosing delirium in ICU patients.

Significant correlation between plasma and CSF anticholinergic activity in presurgical patients

Previous studies have suggested a possible link between cognitive impairment and anticholinergic burden as reflected by high serum anticholinergic activity (SAA). Thus, we hypothesized a close relationship between anticholinergic activity in cerebral spinal fluid (CSF) and blood. However, it has never been convincingly demonstrated that peripheral anticholinergic activity correlates with central anticholinergic levels in presurgical patients. Therefore, anticholinergic activity was measured in blood and CSF from 15 patients with admission scheduled for urological surgery to compare peripheral and central anticholinergic level. Blood and CSF probes were taken after routine premedication and before spinal anesthesia. Anticholinergic activity was determined by competitive radioreceptor binding assay for muscarinergic receptors. Correlation analysis was conducted for peripheral and central anticholinergic levels. The mean anticholinergic levels were 2.4 ± 1.7 in the patients’ blood and 5.9 ± 2.1 pmol/mL of atropine equivalents in CSF. Interestingly, the anticholinergic activity in CSF was about 2.5-fold higher than in patients’ blood. A significant linear correlation was detected between blood and CSF levels. Therefore we conclude that SAA levels adequately reflect central anticholinergic activity. When patients receiving or not receiving anticholinergic medication were compared, anticholinergic activity tended to increase in blood and CSF after receiving anticholinergic medication ≥4 weeks ( p > 0.05).

Serum anticholinergic activity in patients following cardiac surgery and healthy individuals following amitriptyline application

The serum anticholinergic activity (SAA) is used as a marker for cognitive impairment. Here, two studies have been performed characterizing the SAA profile. In Study 1 the endogenous SAA in relation to the total serum protein concentration was monitored for 24 h in five healthy individuals and compared with that in four inpatients following cardiac surgery. In Study 2 the SAA of seven healthy individuals was assessed following a single amitriptyline dose. In both studies SAA was assessed by an ex vivo assay. In Study 1, the absolute SAA varied in a wide range of 1.2 and 14.5 atropine equivalents (AEs) over 24 h. A circadian pattern was not observed. The mean total serum protein concentration, but not the SAA, was significantly lower in inpatients than in healthy individuals. In Study 2, the SAA increased following amitriptyline to a maximum. The mean SAA increased by 6.39 AE at the amitriptyline peak concentration. High SAA variability showed a low statistical relation to amitriptyline concentrations. Both studies characterize the SAA as an individual parameter not affected per se by surgery or clinical care and poorly correlated with the total serum protein concentration. The relation with amitriptyline concentration helps to quantify SAA values towards a better understanding of the clinical implications and limitations of SAA changes.

Serum Anticholinergic Activity and Motor Performance in Elderly Persons

Medications prescribed to elderly persons often have an anticholinergic effect, as do many commonly used over-the-counter drugs. Anticholinergic medications are known to produce psychomotor slowing, especially in older persons. The present study examined whether the cumulative anticholinergic load present in the serum of community volunteers was associated with decrements on tests of psychomotor performance (gait speed and simple manual response time) known to predict falls in elderly persons. Serum anticholinergic activity (SAA) was relatively low in this group; however, an elevated SAA was associated with a significant slowing in both gait speed and simple response time. Cumulative anticholinergic burden may be one of the factors contributing to an increased risk of falls in the older population.

Anticholinergic Drugs and Physical Function Among Frail Elderly Population

Increasing evidence from experimental studies and human observations suggests that drugs with anticholinergic properties can cause physical and mental impairment. The aim of this study was to evaluate the relationship between the use of drugs with anticholinergic activity and measures of physical performance, muscle strength, and functional status in persons aged 80 years or older. Data are from baseline evaluation of 364 subjects enrolled in the ilSIRENTE study. The ilSIRENTE study is a prospective cohort study performed in the mountain community living in the Sirente geographic area (L'Aquila, Abruzzo) in Central Italy. Physical performance was assessed using the physical performance battery score (Short Physical Performance Battery), which is based on three timed tests: 4-meter walking speed, balance, and chair stand tests. Muscle strength was measured by hand grip strength. We defined as anticholinergic drugs all medications for which serum anticholinergic activity was previously demonstrated. Analyses of covariance were performed to evaluate the relationship of anticholinergic drugs with physical function. In the unadjusted model, all the physical performance, muscle strength, and functional measures showed significant associations with the anticholinergic drug use. After adjustment for potential confounders (age, gender, smoking, physical activity level, cognitive performance score, living alone, body mass index, congestive heart failure, lung diseases, diabetes), these associations were weaker but still statistically significant (physical performance battery score: non-users anticholinergic drugs 6.9, SE 0.1, users anticholinergic drugs 6.1, SE 0.2, P=0.05; hand grip strength: non-users anticholinergic drugs 31.3 kg, SE 0.8, users anticholinergic drugs 28.8 kg, SE 1.0, P=0.05; Activities of Daily Living scale score: non-users anticholinergic drugs 1.2, SE 0.1, users anticholinergic drugs 1.6, SE 0.1, P=0.03; Instrumental Activities of Daily Living scale score: non-users anticholinergic drugs 2.7, SE 0.1, users anticholinergic drugs 3.4, SE 0.1, P<0.001). The use of medication with anticholinergic properties is common among community older subjects in Italy. Our results suggest that among old-old subjects the use of anticholinergic drugs is associated with impaired physical performance and functional status.

The Anticholinergic Drug Scale as a Measure of Drug‐Related Anticholinergic Burden: Associations With Serum Anticholinergic Activity

Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.

Review Article: Serum Biomarkers for Delirium

This narrative review examines serum biomarkers for the diagnosis and monitoring of delirium. Serum biomarkers for delirium fall into three major groups: 1) those that are present or elevated prior to disease onset-risk markers, 2) those that rise with onset and fall with recovery-disease markers, and 3) those that rise in proportion to the consequences of disease-end products. As risk markers, we examine serum chemistries and genetic risk markers. As disease markers, we examine serum anticholinergic activity, amino acids, melatonin, cytokines, cortisol, and gene expression. As end products of delirium, we examine markers of neuronal injury. Finally, we discuss methodological and biostatistical considerations for future biomarker studies. Identifying accurate biomarkers for delirium may shed further light into its pathophysiology and on the interrelationship between delirium and dementia.

Bench-to-bedside review: Critical illness-associated cognitive dysfunction – mechanisms, markers, and emerging therapeutics

Cognitive dysfunction is common in critically ill patients, not only during the acute illness but also long after its resolution. A large number of pathophysiologic mechanisms are thought to underlie critical illness-associated cognitive dysfunction, including neuro-transmitter abnormalities and occult diffuse brain injury. Markers that could be used to evaluate the influence of specific mechanisms in individual patients include serum anticholinergic activity, certain brain proteins, and tissue sodium concentration determination via high-resolution three-dimensional magnetic resonance imaging. Although recent therapeutic advances in this area are exciting, they are still too immature to influence patient care. Additional research is needed if we are to understand better the relative contributions of specific mechanisms to the development of critical illness-associated cognitive dysfunction and to determine whether these mechanisms might be amenable to treatment or prevention.

Human Muscarinic Receptor Binding Characteristics of Antimuscarinic Agents to Treat Overactive Bladder

We characterized the binding affinities of several antimuscarinic agents in human muscarinic receptors. Competitive inhibitory effects of antimuscarinic agents on specific NMS [H] (PerkinElmer Life Sciences, Boston, Massachusetts) binding were examined in human tissue homogenates and in CHO-K1 cell membranes expressing human muscarinic receptor subtypes. Oxybutynin, propiverine, tolterodine, the respective metabolites DEOB, DPr-P-4(N-->O) and 5-HM, and darifenacin inhibited in concentration dependent fashion specific [(3)H]NMS binding in homogenates of the human bladder and parotid gland as well as in membranes of CHO-K1 cell lines expressing human muscarinic M(1) to M(5) receptor subtypes. Based on inhibition constant values the inhibitory effects of tolterodine, 5-HM and DPr-P-4(N-->O) were 1.4 to 1.7 times greater in the bladder than in the parotid gland, whereas the inhibitory effects of oxybutynin, DEOB, propiverine and darifenacin were 2 to 10 times greater in the parotid gland. Consequently tolterodine, 5-HM and DPr-P-4(N-->O) compared with oxybutynin, DEOB, propiverine and darifenacin were found to show 3 to 4 times greater affinity to muscarinic receptors in the human bladder than in the parotid gland. Tolterodine and 5-HM were 2-fold more potent for inhibiting specific [(3)H]NMS binding at cell membranes expressing the M(2) vs the M(3) subtype. Conversely oxybutynin, DEOB, propiverine, DPr-P-4(N-->O) and darifenacin showed 2 to 22 times higher affinity to the M(3) than to the M(2) subtype. Compared with oxybutynin, tolterodine, 5-HM and DPr-P-4(N-->O) may bind more selectively to muscarinic receptors in the human bladder than in the parotid gland.

Serum anticholinergic activity, white matter hyperintensities, and cognitive performance

The authors investigated whether the cognitive impairments associated with white matter hyperintensities (WMH) in normal elderly subjects are exacerbated by any anticholinergic medications being taken by the subjects. Results showed serum anticholinergic activity (SAA) and WMH volume to have a synergistic interaction such that the cognitive decrements associated with increasing WMH volume were greatest in those older individuals in the highest quartile of the SAA distribution.

Potential mechanisms and markers of critical illness-associated cognitive dysfunction

To review the current understanding of the potential mechanisms of critical illness-associated cognitive dysfunction and to provide insight into markers that could be used to evaluate the influence of specific mechanisms in individual patients. Cognitive dysfunction is common in critically ill patients, not only during the acute illness but also long after its resolution. Several pathophysiologic mechanisms are thought to underlie critical illness-associated cognitive dysfunction, including neurotransmitter abnormalities and occult diffuse brain injury. Markers that could be used to evaluate the influence of specific mechanisms in individual patients include serum anticholinergic activity, certain brain proteins, and tissue sodium concentration determination by way of high-resolution three-dimensional magnetic resonance imaging. Although recent advances in this area are exciting, they are still too immature to influence patient care. Additional research is needed to provide a better understanding of the relative contribution of specific mechanisms to the development of critical illness-associated cognitive dysfunction and to determine whether these mechanisms might be amenable to treatment or prevention.

Assessment of pharmacological toxicity using serum anticholinergic activity in a patient with dementia

Assessment of pharmacological toxicity using serum anticholinergic activity in a patient with dementia

Serum Anticholinergic Activity and Cognition in Patients With Moderate-to-Severe Dementia

The authors investigated the association between serum anticholinergic activity (SAA) and cognitive performance in a group of patients with moderate-to-severe dementia. SAA and cognitive performance were assessed in 26 patients admitted to a geropsychiatric unit for the treatment of behavioral disturbances associated with dementia. SAA was measured by radioreceptor competitive binding assay. Cognition was tested with the Mini-Mental State Exam and the Severe Impairment Battery. Higher SAA was associated with lower cognitive performance. This study extends to patients with moderate-to-severe dementia the finding that higher SAA is associated with lower cognitive performance.

Serum Anticholinergic Activity and Cognition in Patients With Moderate-to-Severe Dementia

Objective The authors investigated the association between serum anticholinergic activity (SAA) and cognitive performance in a group of patients with moderate-to-severe dementia. Methods SAA and cognitive performance were assessed in 26 patients admitted to a geropsychiatric unit for the treatment of behavioral disturbances associated with dementia. SAA was measured by radioreceptor competitive binding assay. Cognition was tested with the Mini-Mental State Exam and the Severe Impairment Battery. Results Higher SAA was associated with lower cognitive performance. Conclusions This study extends to patients with moderate-to-severe dementia the finding that higher SAA is associated with lower cognitive performance. The authors investigated the association between serum anticholinergic activity (SAA) and cognitive performance in a group of patients with moderate-to-severe dementia. SAA and cognitive performance were assessed in 26 patients admitted to a geropsychiatric unit for the treatment of behavioral disturbances associated with dementia. SAA was measured by radioreceptor competitive binding assay. Cognition was tested with the Mini-Mental State Exam and the Severe Impairment Battery. Higher SAA was associated with lower cognitive performance. This study extends to patients with moderate-to-severe dementia the finding that higher SAA is associated with lower cognitive performance.

Serum anticholinergic activity in a community-based sample of older adults: relationship with cognitive performance.

Serum anticholinergic activity (SAA), as measured by a radioreceptor assay, quantifies a person's overall anticholinergic burden caused by all drugs and their metabolites. In several small geriatric patient groups, SAA has been associated with cognitive impairment or frank delirium. To our knowledge, there has not yet been any systematic study of the prevalence of SAA and its effect on cognition in a community-based population. Serum anticholinergic activity was measured in 201 subjects who were randomly selected among the participants in an epidemiological community study, based on their age and sex. Cognitive performance was assessed with use of the Mini-Mental State Examination. The association between SAA and cognitive performance was examined using a univariate analysis and a multiple logistic regression model, adjusting for age, sex, educational level, and number of medications. Serum anticholinergic activity was detectable in 180 (89.6%) participants (range, 0.50-5.70 pmol/mL). Univariate testing showed a significant association between SAA and Mini-Mental State Examination scores. Logistic regression analysis indicated that subjects with SAA at or above the sample's 90th percentile (ie, SAA >/=2.80 pmol/mL) were 13 times (odds ratio, 1.08-152.39) more likely than subjects with undetectable SAA to have a Mini-Mental State Examination score of 24 (the sample's 10th percentile) or below. To our knowledge, this is the largest analysis of SAA and the first to examine its extent and relationship with cognitive performance in a community sample. Its results suggest that SAA can be detected in most older persons in the community and confirm that even low SAA is associated with cognitive impairment.

The Cholinergic Deficiency Syndrome and Its Therapeutic Implications

Cholinesterase inhibitors are licensed for treatment of dementia in Alzheimer’s disease. However, the effects of these drugs on the cognitive symptoms of dementia are very small. We suggest that symptoms like impairment of attention and concentration, anxiety, restlessness and hallucinations, delineate a specific central cholinergic deficiency syndrome (CDS), that may be a much better target for such treatment. Changes in the quantitative electroencephalogram, muscarinic subtype radioimaging and serum anticholinergic activity may potentially help to diagnose the CDS. CDS is suggested to occur in various neurodegenerative diseases like Alzheimer’s disease, Lewy body dementia and Parkinson’s disease and to respond well to cholinesterase inhibitor therapy.

Endogenous anticholinergic substances may exist during acute illness in elderly medical patients.

The purpose of this study was to determine if serum anticholinergic activity (SACA) arises from endogenous substances produced during illness. Elderly medical inpatients (N = 612) were screened for anticholinergic medication use in the week prior to the study by interviews of subjects and proxies and review of emergency room, hospital, and nursing home medication administration records. Of 24 subjects without a recent anticholinergic medication history, 15 were recruited and 10 completed the study. Serum samples were obtained on Day 2 of hospital admission. SACA was measured using a radionuclide displacement assay. Medications taken by subjects were assayed for central muscarinic receptor binding at therapeutic concentrations. Results. Eight of the ten subjects had SACA detectable in the serum. No medication used by these subjects had anticholinergic activity at usual therapeutic concentrations. Endogenous anticholinergic substances may exist during acute illness. Characterization of such substances may increase the depth of our understanding of delirium and lead to useful intervention strategies.

The muscarinic (hm 1-m 5) and neuronal-nicotinic receptors binding profile of some medicines reported to have serum anticholinergic activity

The muscarinic (hm 1-m 5) and neuronal-nicotinic receptors binding profile of some medicines reported to have serum anticholinergic activity