Patricia W. Slattum

Incidence and risk factors for postoperative cognitive dysfunction in older adults undergoing major noncardiac surgery: A prospective study

Background & Aims: Postoperative cognitive dysfunction (POCD) is a decline in cognitive function that occurs after surgery. The purpose of this study was to estimate the incidence and identify potential risk factors of POCD in older adults undergoing major noncardiac surgery. Materials and Methods: A total of 69 patients aged 65 years or older undergoing major noncardiac surgery were enrolled. Patients’ cognitive function was assessed before and 3 months after surgery using a computerized neurocognitive battery. A nonsurgical control group of 54 older adults was recruited to adjust for learning effects from repeated administration of neurocognitive tests. Data about potential risk factors for POCD were collected before, during, and after surgery, including patient, medication, and surgery factors. The incidence of POCD was calculated using the Z-score method. A multivariable logistic regression model was used to identify risk factors for POCD. Results: POCD was present in eleven patients (15.9%, 95% confidence interval [CI] = 7.3-24.6) 3 months after major noncardiac surgery. Carrying the apolipoprotein E4 (APOE4) genotype (odds ratio [OR] = 4.74, 95% CI = 1.09-22.19), using one or more highly anticholinergic or sedative-hypnotic drugs at home prior to surgery (OR = 5.64, 95% CI = 1.35-30.22), and receiving sevoflurane for anesthesia (OR = 6.43, 95% CI = 1.49-34.66) were associated with the development of POCD. Conclusions: POCD was observed in 15.9% of older adults after major noncardiac surgery. Risk factors for POCD in these patients were carrying the APOE4 genotype, using one or more highly anticholinergic or sedative-hypnotic drugs prior to surgery, and receiving sevoflurane for anesthesia.

Comparison of methods for the assessment of central nervous system stimulant response after dextroamphetamine administration to healthy male volunteers

The objective of this investigation was to evaluate a series of potential pharmacodynamic measures of central nervous system stimulation, including quantitative electroencephalography (EEG) and neuroendocrine, mood, and psychomotor performance measures. The reproducibility and sensitivity of the measures were compared. The study was conducted in two parts. The first part investigated the interindividual and intraindividual variability associated with a series of potential pharmacologic response measures under baseline (i.e., drug‐free) conditions. It was an open‐label, three‐period pilot study in which healthy male volunteers underwent a series of tests (EEG, a visual continuous performance task, a finger tapping task, and self‐rated mood scales) repeatedly during each study period. The second part evaluated the sensitivity of a series of potential response measures to detect the effects of dextroamphetamine, and was a double‐blind, placebo‐controlled, four‐period crossover study in nine healthy male volunteers. Subjects received 5 mg, 10 mg, or 20 mg of dextroamphetamine or placebo orally and underwent the same series of tests as in Part I in addition to blood collection for determination of serum prolactin and dextroamphetamine levels. Peripheral response to dextroamphetamine was assessed by heart rate and blood pressure measurement. The greatest variability among days, within days, and among participants was associated with the quantitative electroencephalographic parameters studied. First‐session effects were apparent for several of the tests, including EEG. Consistent response on EEG (increased alpha power) to dextroamphetamine was observed only in the three subjects who had a baseline alpha activity greater than 35%. Serum prolactin levels were inversely associated with the amount of dextroamphetamine administered, with the largest decrease in serum prolactin levels observed after the 5‐mg dose, and this finding was statistically significant. Mood scales showed that three of nine participants experienced dysphoria after at least one dose level of dextroamphetamine. The effect on mood was generally greater as the dose increased. Doses could not be distinguished based on the results of the performance tests. Serum prolactin concentration was the most sensitive measure of central nervous system stimulation on EEG produced by dextroamphetamine under these study conditions. Cardiovascular measures were more sensitive measures of dextroamphetamine effects than the central nervous system measures.

Medication-Related Dizziness in the Older Adult

With increased medication use among the older adult population, adverse drug events and polypharmacy can be significant causes of dizziness in the elderly. The evidence evaluated in this review is helpful in clinical practice but requires an additional detailed investigation into the agents discussed to understand the risk/benefit ratio associated with medications. Examples of medications highly associated with dizziness in older adults and discussed in this review include cardiovascular and central nervous system agents. Several other medication classes associated with dizziness are among the medications most commonly used by older patients.

Effect of Renin-Angiotensin System Inhibition on Cardiovascular Events in Older Hypertensive Patients with Metabolic Syndrome

OBJECTIVE Metabolic syndrome (MetS) is associated with cardiovascular disease (CVD). Insulin resistance has been hypothesized as the underlying feature of MetS. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are widely used antihypertensives that may improve insulin sensitivity. The aim of the study is to evaluate the effect of ACEI/ARB on incident CVD events in older hypertensive patients with MetS. MATERIALS/METHODS We used the Cardiovascular Health Study, a prospective cohort study of individuals>65years of age to evaluate ACEI/ARB use and time to CVD events (including coronary and cerebrovascular events). The study included 777 subjects who had hypertension and ATP III-defined MetS, but free of CVD and diabetes at baseline. Cox regression models were used to evaluate the effect of ACEI/ARB as compared to other antihypertensives on the time to the first CVD events. RESULTS ACEI/ARB use was associated with a decreased risk of CVD events (adjusted HR=0.658, 95 % C.I. [0.436-0.993]) compared to other antihypertensives. When CVD endpoints were evaluated separately, use of ACEI/ARB was associated with lower rates of angioplasty and coronary events (HR of 0.129 and 0.530 respectively, with 95 % CI [0.017-0.952] and [0.321-0.875]). CONCLUSIONS ACEI/ARB use was associated with a lower risk of CVD events in older hypertensive patients with MetS, primarily due to a reduction in coronary events. The potential protective effect of ACEI/ARB on CVD events in older individuals with MetS will need further confirmation from prospective studies.

Warfarin Use in Nursing Home Residents: Results from the 2004 National Nursing Home Survey

BACKGROUND Practice guidelines recommend anticoagulation therapy with warfarin for stroke prevention in patients with atrial fibrillation (AF). Despite this, warfarin is underused in older adults. OBJECTIVE The purpose of this study was to determine the prevalence of AF in nursing home (NH) residents and the use of warfarin or other antiplatelet medications in NH residents with AF who have indications for and no contraindications against warfarin use. The secondary objective was to determine the factors associated with warfarin use in NH residents with AF. METHODS Cross-sectional analysis of prescription and resident data files from the 2004 National Nursing Home Survey was performed. Residents with a diagnosis of AF were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, and prescriptions of warfarin and antiplatelet medications were identified using Long-Term Care Drug Database System (LTCDDS) codes. Resident characteristics, stroke risk factors, and potential bleeding risk factors significant at P < 0.10 in χ(2) analyses were entered in the final multiple logistic regression model to determine the factors associated with warfarin use. RESULTS From 13,507 NH residents, 1904 (14%) had a diagnosis of AF and 1767 (13%) had a diagnosis of AF with indications for and no contraindications against warfarin use. Of these 1767 residents, 537 (30%) were prescribed warfarin, and of the remaining 1230 residents who were not prescribed warfarin, 283 (23%) received either aspirin or clopidogrel. Thus, of 1767 residents with AF, with indications for and no contraindications to warfarin use, 947 (54%) residents did not receive any antithrombotic therapy in the form of warfarin, aspirin, clopidogrel, or a combination of these medications. Factors that were significantly associated with increased odds of receiving warfarin were congestive heart failure, previous stroke or transient ischemic attack, deep vein thrombosis or peripheral embolus, valvular heart disease, and total number of medications ≥ 6. Factors that were significantly associated with reduced odds of receiving warfarin were nonwhite race, history of gastrointestinal bleeding, and use of antiplatelets (ie, clopidogrel). CONCLUSIONS AF is common in NH residents, and more than half of the residents with AF who had indications for and no contraindications against warfarin use were not prescribed either warfarin or antiplatelets, such as aspirin or clopidogrel, suggesting that antithrombotic therapy may be underused in NH residents with AF.

Clinical Pharmacokinetics in the Elderly

Clinical response to medication in an individual patient is the net result of the interaction of a number of complex processes. These processes can be categorized into two broad areas: those affecting pharmacokinetics or the relationship between the administered dose and the concentrations of the drug in the systemic circulation, and those affecting pharmacodynamics or the relationship between concentrations of the drug in the systemic circulation and the observed pharmacologic response. Absorption, distribution, metabolism, and excretion of a drug determine its pharmacokinetics. Drug-receptor interactions, concentrations of the drug at the receptor, and homeostatic compensatory mechanisms determine a drug’s pharmacodynamics. Pharmacokinetics and pharmacodynamics are affected by a number of patient-specific factors including age, sex, ethnicity, genetics, disease processes, and prior and present drug exposure. This chapter focuses on the effects of advanced age on pharmacokinetics.

Risk of Fracture and the Concomitant Use of Bisphosphonates With Osteoporosis-Inducing Medications

Objective: To review the literature on the concomitant use of bisphosphonates and medications that can influence bone metabolism and potentially attenuate bisphosphonate antifracture efficacy. Data Sources: MEDLINE and CINAHL were searched for articles published in English through December 2014 using the following terms: bisphosphonates, bone density conservation agents, acid-suppressive therapy, levothyroxine, thiazolidinediones (TZDs), selective serotonin reuptake inhibitors (SSRIs), bone fractures. Study Selection and Data Extraction: Studies were included if they reported results of concomitant use of any listed medications with bisphosphonates and risk of fractures and focused on women. Articles that focused generally on the use of one of the listed medications and fractures without explicitly examining the potential antifracture efficacy or attenuation of bisphosphonates were excluded. Data Synthesis: A total of 6 relevant studies were identified. Four epidemiological studies reported a statistically significant dose-dependent increase in the risk of fractures when bisphosphonates and acid-suppressive drugs were used together. One post hoc analysis of clinical trial data suggested no attenuation of the antifracture effects of bisphosphonates when used concomitantly with acid-suppressive therapy. One study involving bisphosphonates and SSRIs noted a statistically significant association between fracture risk and SSRI use. No study examining TZDs or levothyroxine with bisphosphonates was identified. Conclusions: Existing research suggests potential attenuation of bisphosphonate antifracture efficacy among patients taking acid-suppressive medications. Based on their pharmacological actions, TZDs, SSRIs, and levothyroxine have similar implications. The paucity of evidence in the literature associating the attenuation of bisphosphonate antifracture efficacy when combined with other medications suggests that further investigation is needed.

The role of epigenomics in personalized medicine

ABSTRACT Introduction: Epigenetics is the study of reversible modifications to chromatin and their extensive and profound effects on gene regulation. To date, the role of epigenetics in personalized medicine has been under-explored. Therefore, this review aims to highlight the vast potential that epigenetics holds. Areas covered: We first review the cell-specific nature of epigenetic states and how these can vary with developmental stage and in response to environmental factors. We then summarize epigenetic biomarkers of disease, with a focus on diagnostic tests, followed by a detailed description of current and pipeline drugs with epigenetic modes of action. Finally, we discuss epigenetic biomarkers of drug response. Expert commentary: Epigenetic variation can yield information on cellular states and developmental histories in ways that genotype information cannot. Furthermore, in contrast to fixed genome sequence, epigenetic patterns are plastic, so correcting aberrant, disease-causing epigenetic marks holds considerable therapeutic promise. While just six epigenetic drugs are currently approved for use in the United States, a larger number is being developed. However, a drawback to current therapeutics is their non-specific effects. Development of locus-specific epigenetic modifiers, used in conjunction with epigenetic biomarkers of response, will enable truly precision interventions.

A Core Process in Receptor Function, General Anesthesia, Sleep, and Aging

The diffusion of ligands and proteins was proposed to be guided by chreodes in water organized by protein‐surface side chains with varying hydropathic states. These chreodes are proposed to be the target of volatile general anesthetic agents. The similarity between this effect and sleep deprivation leads to a proposal of an external agent responsible for sleep. This agent is elemental nitrogen. An extension of this effect is the concept that elemental nitrogen is a core factor in aging.

Improving Therapeutics to Better Care for Older Adults and the Young: Report From the American College of Clinical Pharmacology Workshop

About 50 years ago, Harry Shirkey MD, a pediatrician coined the term that infants and children are “therapeutic or pharmaceutical orphans.”1 This is because many of the drugs approved in the 1960s carry an “orphaning”clause, such as “not to be used in children” or “is not recommended for use in infants and young children.”1 In contrast to years past when few studies were conducted in this age group, we are currently witnessing tremendous progress in pediatric drug development. In that context, in the workshop, Drs. Burckart, Stegemann, and Eissing as well as Schlender presented materials related to improving therapeutics to better care for the young. At the other end of the age spectrum, older adult patients are relatively “neglected” with regard to consideration during drug development.2,3 Persons 65 years and above will be the fastest-growing segment of the population in the United States for the next 4 decades primarily because of the migration of the baby boom generation into this age group with a steadily increasing life expectancy. From 2012 to 2050, the projected number of people in the United States aged 65 years and above will almost double to 83.7 million, corresponding to more than 20% of the population.4 This aging trend is consistent with that of developed countries like Japan, Germany, Italy, France, Spain, the United Kingdom, Canada, Ukraine, Poland, and Russia.4 The oldest-old (aged 85 years) segment of the United States is increasing even faster and will triple by 2060.5 Similar aging trends exist in the 3 other most populated countries in the world, namely, China, India, and Indonesia.4 This segment of the older adult population is frailer and is more likely to have significant sensory impairment (hearing and vision), cognitive impairment, and multiple chronic illnesses. Similarly, the incidence of nursing home placement is much higher than among the general older adult population. Although older adults currently account for only 13.1% of the United States population, they consume an estimated 30%–40% of all medications,6 indicating that pharmacotherapy is an important medical intervention for the care of older adult patients. These patients usually have more disease burden and thus receive multiple drug therapies. In that context, in the workshop Drs. Golden, Abernethy, Stegemann, Slattum, and Eissing as well as Schlender presented materials related to improving therapeutics to better care for older adults.