Twenty-four-hour, weekly and annual patterns in serious falls of non-institutionalized independent Spanish seniors.

OBJECTIVE: The study aimed to explore clock hour, day-of-week, and month-of-year patterns of serious falls experienced by non-institutionalized Spanish seniors (age ≥65 years) in relation to associated conventional intrinsic and extrinsic factors. PATIENTS AND METHODS: Intake emergency department records from January 1 to December 31, 2013 of a tertiary hospital of southern Spain were abstracted for particulars of falls, including the time of occurrence, experienced specifically by non-institutionalized seniors. Chi-squares and Single and Multiple-Component Cosinor (time series) Analyses were applied to determine the statistical significance of observed 24-hour, 7-day, and annual variation. RESULTS: Falls were ~2.5-fold more numerous in older women than older men and ~7-fold more frequent between 12:00 and 14:00 hours than ~02:00 hours, respectively, the time spans corresponding to the absolute peak and trough of the 24-hour pattern in falls. The midday/early afternoon peak primarily represented incidents of women ≥75 years of age that occurred inside the home while walking, standing, or moving on stairs. A late evening less prominent excess of mostly inside-the-home incidents of women ≥75 years of age, largely due to fragility, slipping, stumbling, or tripping, was additionally detected. Cosinor Analysis substantiates statistical significance of the 24-hour patterning of falls of men and women (both p<0.001). Day-of-week differences, with prominent Thursday peak and Sunday minimum, were additionally detected, but only for falls of women occurring outside the home (Cosinor Analysis: p=0.007). Day-of-week discrepancy in female/male sex ratio (SR) of fallers was demonstrated, arising from day-of-week disparity in the SR of inside-the-home incidents, with ~4.5-fold more elderly women than elderly men falling Thursday than any other day of the week (p=0.005). Non-statistically significant month-of-year difference in falls, lowest in autumn and highest (~60% more) in winter, was observed and explained by prominent seasonal difference in incidents by elderly women. CONCLUSIONS: Serious falls of non-institutionalized independent seniors are characterized according to intrinsic and extrinsic factors by prominent 24-hour and 7-day patterning. These findings complement the understanding of the epidemiology of falls of the elderly and further inform fall prevention programs.

Sleep-time ambulatory blood pressure as a novel therapeutic target for cardiovascular risk reduction.

Diagnosis of hypertension and clinical decisions regarding its treatment are typically based upon daytime clinic blood pressure (BP) measurements, occasionally supplemented by wake-time patient self-assessment. Yet, correlation between BP level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is higher for ambulatory BP monitoring (ABPM) measurements. Numerous studies consistently reveal CVD events are better predicted by the asleep than awake or 24 h BP means. In addition, when the asleep BP mean is adjusted by the awake mean, only the former is a significant independent predictor of outcome. Endogenous circadian rhythms explain statistically and clinically significant ingestion time differences in efficacy, duration of action, safety and/or effects on the daily BP pattern of most hypertension medications and their combinations. Bedtime versus morning-time ingestion of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, independent of drug terminal half-life, both better reduces asleep BP and normalizes the daily BP profile into a more normal dipper pattern. The recently completed prospective outcome MAPEC Study verifies therapeutic restoration of the normal sleep-time BP decline, a novel therapeutic goal most effectively achieved by ingestion of the entire daily dose of ⩾ 1 conventional hypertension medications at bedtime, best decreases CVD morbidity and mortality. Our findings indicate around-the-clock ABPM is a clinical necessity to accurately detect abnormal sleep-time BP and assess CVD risk, and that hypertension ought to be managed by a bedtime therapeutic strategy, preferably one including medication that antagonizes the activities and actions of the renin-angiotensin-aldosterone system.

Circadian rhythms and clinical medicine with applications to hypertension.

Circadian (24-h) rhythms are important to the practice of medicine. The phasing and amplitude of key physiologic and biochemical circadian rhythms contribute to predictable-in-time patterns in the manifestation and exacerbation of most medical conditions. Moreover, body rhythms can significantly affect responses of patients to diagnostic tests and medications. Rhythmicity in the pathophysiology of medical conditions is the rationale for chronotherapeutics--that is purposeful variance of the concentration of medicines in synchrony with biologic rhythm determinants of disease activity--to optimize treatment outcomes. This article discusses the concept of biologic time structure and its relevance to the practice of medicine, with a focus on hypertension and cardiovascular issues.

Circadian rhythm of double (rate-pressure) product in healthy normotensive young subjects.

The double product (DP), systolic blood pressure multiplied by heart rate, is a surrogate measure of myocardial oxygen demand and cardiac workload used increasingly today in medicine. The double product is more strongly correlated with left ventricular mass than the daily blood pressure mean. The purpose of this study was to describe the normative circadian pattern of the double product in healthy normotensive young adults. We studied 125 men and 75 women, 23.0+/-3.3 (mean +/- SD) years of age, without medical history of hypertension and 24h ambulatory systolic/diastolic blood pressure mean consistently below 135/85 mm Hg. Subjects underwent ambulatory blood pressure monitoring at 30-minute intervals for 48 consecutive hours once each season of the year, yielding 930 protocol-correct blood pressure and heart rate time series. Subjects maintained their usual routine of diurnal activity and nocturnal sleep and avoided use of over-the-counter and other medication. Circadian rhythmicity in the double product was established by population multiple-component analysis. The double product rose rapidly from the lowest value, attained 3h before awaking from sleep at night, to a markedly elevated level at the commencement of morning activity. The double product was highest in the afternoon, roughly 7h after the commencement of diurnal activity. In both men and women, the shape of the high-amplitude circadian rhythm in the double product was best described by a complex model composed of three cosine curves having periods of 24h, 12h, and 6h. The 24h mean in the double product of 8092.51+/-42.76 (mean +/- SD) in men was significantly lower than that of 8353.17+/-37.48 in women (P < .001). The circadian double amplitude of the rhythm was statistically significantly greater (P < .001) in men (50% of the 24h mean) than women (44% of the 24h mean). The double product did not differ between seasons in women, but it did in men (P = .017) due to reduced heart rate in summer. The circadian pattern of large amplitude in the double product and its gender differences must be taken into account when using this variable to assess cardiac workload, risk of left ventricular hypertrophy, and efficiency of antihypertensive therapy.

Day-night variation in aggressive behavior among psychiatric inpatients.

Self-directed aggressive behaviors of human beings show a 24h pattern. The aim of this study was to evaluate if violence of psychiatric inpatients against one another and hospital staff varies over the 24h. The clock time occurrence of 334 episodes of assault behaviors by 119 psychiatric inpatients (78 males and 41 females, mean age 34.8+/-11.3 years) committed during a 5-year span in the psychiatric unit of the university-based hospital of Ferrara, Italy, was evaluated. The clock time of each event was categorized by hour during the 24h and into one of four 6h intervals for analysis of temporal variation by cosinor and chi2 tests, respectively. A significant 24h variation, characterized by an early afternoon peak, was detected irrespective of gender and number (single vs. repeated) of episodes committed. Changes during the 24h in ward activity, patient contact, and endogenous circadian rhythms are likely to contribute to the observed 24h pattern, although further study is needed to confirm our findings and to define causal factors.

The birth of chronobiology: Julien Joseph Virey 1814.

Julien-Joseph Virey (1775-1846) held the position of pharmacist-in-chief at the Val-de-Grâce, a military hospital. He was an innovative pharmacist, naturalist, anthropologist, and philosopher and a prolific author. His writings encompassed a wide range of topics, although many of his ideas were sometimes harshly questioned. Interest in Virey's work today stems from renewed appreciation of his doctoral thesis in medicine, which was completed in 1814 in Paris and was the first devoted to biological rhythms. Virey envisioned biological rhythms to be innate in origin and controlled by living clocks entrained by periodic environmental changes, such as the day-night alternation in light and darkness. He also reported that the effects of drugs vary according to their administration time. But, above all, he collected and published quantified time series that demonstrated human circadian and annual mortality rhythms. Statistical analysis of Virey's data using modern time series methods confirms his deduction that human mortality exhibits rhythmicity. Comparison of his findings with those derived from analyses of more recent human mortality time series shows the characteristics of these rhythms have changed little since 1807 despite differences in environmental conditions. Virey deserves credit for establishing the field of chronobiology based on his insights and writings.

Circadian rhythms in medicine.

Circadian (24-hour) rhythms are important to the practice of medicine. The phasing and amplitude of key physiologic and biochemical circadian rhythms contribute to predictable-in-time patterns in the manifestation and exacerbation of most medical conditions. Moreover, body rhythms can significantly affect responses of patients to diagnostic tests and medications. Rhythmicity in the pathophysiology of medical conditions is the rationale for chronotherapeutics--the purposeful variance of the concentration of medicines in synchrony with biological rhythm--determinants of disease activity--to optimize treatment outcomes. This article discusses the concept of biological time structure and its relevance to the practice of medicine, with a focus on neurologic issues.

Seasonal variation in the effect of a fixed dose of heparin on activated clotting time in patients prepared for open-heart surgery.

We investigated the effect of an injected bolus of 5 mg kg(-1) heparin at one circadian stage (08:30 to 11:00) on blood coagulation during different months of the year. Activated clotting times (ACTs) were assessed before and 5 min after heparin dosing to ensure extracorporeal circulation during open-heart surgery. The ACT data of 1083 presumably day-active Turkish patients (816 men and 267 women, mostly older than 46 years) who underwent coronary bypass surgery between 08:30 and 11:00 in the years from 1994 to 1997 were analyzed for annual rhythmicity. The ACT values obtained just before and 5 min after heparinization were subjected to cosinor analysis using a 365.25-day period to assess seasonality in basal ACT level and heparin effect. A small-amplitude annual rhythm with a wintertime peak was documented in the morning ACT in the group of 1083 patients. Rhythms of similar magnitude and staging were also detected in heparin effect on ACT in the 1083 patients and in subgroups categorized by gender. Circannual rhythmicity in the heparin effect on ACT was also documented in the elderly (> or = 45 years old), but not young (18-45 years old) patients. The annual mean effect of heparin on the ACT was statistically significantly greater in younger than older patients. The relatively low-amplitude circannual rhythm in heparin effect on ACT (approximately 10% of the annual mean) is not viewed as being meaningful in patient preparation for bypass surgery for the 5 mg kg(-1) level of heparin dose.

Hypertension, chronotherapy, and patient management.

This article highlights information from a symposium held at the 1999 National Conference for Nurse Practitioners, Washington, D.C., November 11, 1999, sponsored by The Nursing Institute and supported by an unrestricted educational grant from Schwarz Pharma Inc. "Hypertension" was the first topic and was discussed by Elijah Saunders, MD, FACC, FACP. "Medical Chronobiology and Chronotherapy" was the second topic and was discussed by Michael H. Smolensky, PhD. The third topic, "The Nurse Practitioner and the Hypertensive Patient," was discussed by Helen C. Noel, ANP, PhD. Dr. Noel also served as chair of the symposium.

Day-night pattern in accidental exposures to blood-borne pathogens among medical students and residents.

The purpose of this study was to determine whether the occurrence of accidental blood-borne pathogen exposure incidents in medical students and residents in training varies during the 24 h. A retrospective review of reported exposures was conducted in a large urban teaching institution--the University of Texas Health Science Center in Houston--between November 1993 and July 1998. Professional level (year of student or level of resident), time of exposure, means/route of exposure (needle stick, laceration, or splash), and type of medical service were recorded. Analysis of the clock time of the 745 reported blood-borne pathogen exposures showed they occurred more frequently during the day than night. Over the nearly 5-year span, 531 incidents took place between 06:00 and 17:59 in comparison to only 214 between 18:00 and 05:59. To account for the day-night difference in medical student and resident hospital staffing, the data were reexpressed as exposure rates, that is, in terms of the number of events per hour per 1000 medical students and residents. Based on the total number of reported exposures over the almost 5-year span of data collection, the average rate was 40 accidents per hour per 1000 doctors in training during the 12 h daytime span (6:00-17:59). It was 50% greater at night (18:00-05:59), with 60 incidents per hour per 1000 doctors in training. The day-night difference in rate of exposures was statistically significant (p < .04). The relative risk ratio for residents and students when working during the day shift compared to working the night shift was 0.67. This means that doctors in training are at a 1.50 higher risk of sustaining a blood-borne pathogen exposure when working nights than when working days.

Clinical chronobiology and chronotherapeutics with applications to asthma.

The concept of homeostasis (i.e., constancy of the milieu interne) has long dominated the teaching and practice of medicine. Concepts and findings from chronobiology, the scientific study of biological rhythms, challenge this construct. Biological processes and functions are not at all constant; rather, they are organized in time as rhythms with period lengths that range in duration from as short as a second or less to as long as a year. It is the body's circadian (24 h) rhythms that have been researched most intensely. The peak and trough of these rhythms are ordered rather precisely in time to support the biological requirements of activity during the day and sleep at night. The timing of the peak and trough plus the magnitude of variation (amplitude) of physiological and biochemical functions during the 24 h give rise to predictable-in-time, day-night patterns in the manifestation and exacerbation of many common medical conditions. Circadian rhythms also can influence the response of patients to diagnostic tests and therapeutic interventions according to their timing with reference to body rhythms. Rhythms in the pathophysiology of medical conditions and patient tolerance to medications constitute the basis for chronotherapeutics, the timing of treatment in relation to biological rhythm determinants as a means of optimizing beneficial effects and safety. The article discusses recent advances in medical chronobiology and chronotherapeutics and their relevance to clinical medicine in general and the management of asthma in particular. Indeed, since asthma is a disease that exhibits rather profound circadian rhythmicity, investigation of its pathophysiology and therapy necessitates a chronobiologic approach.

Biologic rhythms in the immune system.

In all of its components, the immune system shows regularly recurring, rhythmic variations in numerous frequencies; the circadian (about 24 h) rhythms are the best explored. The circadian variations in immunocompetent cells circulating in the peripheral blood are of a magnitude to require attention in medical diagnostics. Both the humoral arm and the delayed (cellular) arm of the immune system function in a rhythmic manner. The response of the immune system to introduction of an antigen and to challenge of the sensitized organism varies in extent in the circadian frequency range and also in lower frequencies, for example, of about a week (circaseptan) or seasonally (circannual). The medical application of the biologic rhythms of the immune system extends to diagnostic measures, as well as treatment.

Circadian rhythms in the pharmacokinetics and clinical effects of beta-agonist, theophylline, and anticholinergic medications in the treatment of nocturnal asthma.

Published asthma consensus reports now acknowledge that asthma is a nocturnal disease in as many as 75% of those afflicted by this medical condition. Nonetheless, the treatment of this chronic obstructive pulmonary disease in the clinic continues to be based primarily on homeostatic considerations in that it relies on long-acting bronchodilator and other therapies formulated and scheduled to ensure constant or near-constant levels of medication during the 24h. The need of asthma patients prone to nighttime attacks is not the same during the day and night; the therapeutic requirements of patients who experience nocturnal asthma, especially ones with the more severe forms of the disease, are often not satisfied by conventional medications. The therapeutic response and patient tolerance to bronchodilator medications can be improved markedly when the medications are proportioned during the 24h as a chronotherapy, that is, when more medication is delivered during nighttime sleep than daytime activity, as verified by numerous studies. This article reviews how the body's circadian rhythms influence the pharmacokinetics and effects of commonly prescribed asthma therapies and addresses why and how they must be taken into consideration to increase the effectiveness of asthma treatment.

Population studies of ambulatory blood pressure monitoring in Brazilian children.

BACKGROUND: The determination of hypertension in a given population depends on the knowledge of population norms for blood pressure. This is true for both casual blood pressure (CBP) measurements and the newest and most promising technology of ambulatory blood pressure monitoring (ABPM). OBJECTIVE: To design an ambitious multinational co-operative study to determine normal blood pressure data in Brazilian children. METHODS: The study was designed to determine normative data for CBP, using the Task Force technical recommendations for age-, sex- and height-percentile-specific blood pressure values. The proposed procedure is as follows. ABPM will be studied in a random subgroup of individuals, to develop similar normative data. These data will be correlated to CBP measurements and to echocardiographic findings as a measure of end-organ damage. All patients who are diagnosed by CBP measurement to be hypertensive will also be studied by ABPM, and studies of target-organ damage will be performed. Family and medical histories will be evaluated by questionnaire and first-degree relatives will be evaluated for CBP measurement. Hypertensive patients will form a cohort for long-term follow-up. These data will be the foundation for studies of hypertension in Brazilian children.

Chronopharmacology and chronotherapy of cardiovascular medications: relevance to prevention and treatment of coronary heart disease.

Biological functions and processes, including cardiovascular ones, exhibit significant circadian (24-hour) and other period rhythms. Ambulatory blood pressure assessment reveals marked circadian rhythms in blood pressure both in normotensive persons and hypertensive patients, whereas Holter monitoring substantiates day-night patterns in electrocardiographic events of patients with ischemic heart disease. The concept of homeostasis, that is, constancy of the milieu interne, which has dominated the teaching, research, and practice of medicine during the 20th century,is now being challenged by emerging concepts from the field of chronobiology-the science of biological rhythms. Epidemiologic studies document the heightened morning-time risk of angina, myocardial infarction, and stroke. Circadian rhythms in coronary tone and reactivity, plasma volume, blood pressure, heart rate, myocardial oxygen demand, blood coagulation, and neuroendocrine function plus day-night patterns in the nature and strength of environmental triggers all contribute to this morning vulnerability. Homeostatically devised pharmacotherapies, that is, medications formulated to ensure a near-constant drug concentration, may not be optimal to adequately control diseases that vary in risk and severity during the 24 hours. Moreover, circadian rhythms in the physiology of the gastrointestinal tract, vital organs, and body tissues may give rise to administration-time differences in the pharmacokinetics and effects of therapies. Thus the same medication consumed in the same dose under identical conditions in the evening and morning may not exhibit comparable pharmacokinetics and dynamics. New technology makes possible chronotherapy, that is, increase of the efficiency and safety of medications by proportioning their concentrations during the 24 hours in synchrony with biological rhythm determinants of disease. The chronotherapy of peptic ulcer disease achieved by the evening dosing of H 2-receptor antagonists and of asthma by the evening dosing of special drug delivery forms of theophylline and morning methylprednisolone administration has proven to be beneficial. Controlled-onset extended-release verapamil constitutes the first chronotherapy of essential hypertension and ischemic heart disease; once-a-day bedtime dosing results in a high drug concentration in the morning and afternoon and a reduced one overnight. Studies demonstrate effective 24-hour control of blood pressure, including the attenuation of its rapid rise in the morning, without induction of nighttime hypotension. Moreover, this formulation effectively controls angina, especially in the morning when the risk of ischemia is greatest. Determination of the role of verapamil chronotherapy in the primary prevention of cardiovascular morbidity and mortality awaits the results of the CONVINCE trial now in progress.