Variability in the prevalence of inappropriate medication use among older adults: A review highlighting the importance of screening methods and database types.

AIMS: The global older population is growing rapidly, and the rise in polypharmacy has increased potentially inappropriate medication (PIM) encounters. PIMs pose health risks, but detecting them automatically in large medical databases is complex. This review aimed to uncover PIM prevalence in individuals aged 65 years or older using health databases and emphasized the risk of underestimating PIM prevalence due to underutilization of detection tools. METHODS: This study conducted a broad search on the Medline database to identify articles about the prevalence of PIMs in older adults using various databases. Articles published between January 2010 and June 2023 were included, and specific criteria were applied for study selection. Two literature reviews conducted before our study period were integrated to obtain a perspective from the 1990s to the present day. The selected papers were analysed for variables including database type, screening method, adaptations and PIM prevalence. The study categorized databases and original screening tools for clarity, examined adaptations and assessed concordance among different screening methods. RESULTS: This study encompassed 48 manuscripts, covering 58 sample evaluations. The mean prevalence of PIMs within the general population aged over 65 years was 27.8%. Relevant heterogeneity emerged in both the utilized databases and the detection methods. Adaptation of original screening tools was observed in 86.2% (50/58) of cases. Half of the original screening tools used for assessing PIMs belonged to the simple category. About a third of the studies employed less than half of the original criteria after adaptation. Only three studies used over 75% of the original criteria and more than 50 criteria. CONCLUSIONS: This extensive review highlights PIM prevalence among the older adults, emphasizing method intricacies and the potential for underestimation due to data limitations and algorithm adjustments. The findings call for enhanced methodologies, transparent algorithms and a deeper understanding of intricate rules' impact on public health implications.

Effect of a multimodal training on the ability of medical students to administer the MMSE: a comparative study.

BACKGROUNDS: The Mini-Mental State Examination (MMSE) is the main screening and follow-up test for neurocognitive disorders. In France, it is often administered by medical students. Conditions allowing to administer the MMSE are strict but not well known by students, leading to mistakes in scoring. Our objectives were to assess the effect of a multimodal training on medical students' ability to administer the MMSE and to describe their previous training. METHODS: 75 medical students between the 4th and 6th year of study were included. Previous MMSE training was assessed by a standardized questionnaire. The teaching material used for our training was the article validating MMSE in French, a video explaining the steps on how to administer the MMSE test, and MMSE's scoring exercises. The ability to administer the MMSE was assessed by a Standardized practical exam (SPE). Students were self-selected and then assigned in two groups, one benefiting from all the training before SPE, and the other receiving only the article before SPE. RESULTS: 41 students were included in the training group and 34 in the control group. There was no difference between groups regarding previous training. 71% of the students had already administered a MMSE test and only 17% had received specific training. Students considered their previous training as insufficient in most cases. The overall score and scores of each subpart of the SPE were significantly higher in the training group than in the control group (overall score: median [IQR]: 71 [62-78] vs. 52 [41-57], p < 0.001). The rate of students able to complete the MMSE was higher in the training group compared to the control (85% vs. 44%, p < 0.001). Quality of the training and its usefulness were judged to be good or very good by all participants. CONCLUSIONS: A multimodal training improves the ability of medical students to administer the MMSE.

Clinical Pharmacist Intervention Reduces Potentially Inappropriate Prescriptions in a Geriatric Perioperative Care Unit Dedicated to Hip Fracture.

INTRODUCTION: Clinical pharmacist (CP) intervention improves drug prescription by identifying potentially inappropriate prescriptions (PIPs). Geriatric perioperative care units (UPOGs) provide enhanced care for patients with hip fracture, including drug prescription. However, it is not known whether adding a CP intervention in a UPOG decreases the number of PIPs. This study aimed to evaluate the effect of a CP intervention, combining an implicit and an explicit method, on the number of PIPs in a UPOG. METHODS: This single centre before-after-control-impact study recruited patients aged over 75 years admitted to a UPOG for a hip fracture. The "control group" ("before period") received usual care including two medication reconciliations, one at admission and one at discharge. The "intervention group" ("after period") received usual care and a CP intervention including two medication reconciliations, a medication review with two tools, STOPP/START and Medication Appropriateness Index, and a meeting between a CP and geriatricians. PIPs were assessed in both groups by STOPP/START and Medication Appropriateness Index and compared from hospital admission to discharge. RESULTS: A total of 209 patients were included, 150 in the control group and 59 in the intervention group (mean age: 87.2 ± 5.9 years). The number of PIPs decreased in both groups from hospital admission to discharge (p < 0.001). The number of PIPs, potentially inappropriate medications, and potential prescribing omissions decreased more in the intervention group than in the control group (adjusted intervention effect: -2.46 (95% CI: -2.63; -2.24); -1.13 (95% CI: -1.27; -0.98); and -1.35 (95% CI: -1.52; -1.18), respectively, p < 0.001 for all). DISCUSSION/CONCLUSION: A CP intervention with an explicit and implicit method improved prescriptions in a UPOG. Further randomized studies are necessary to evaluate the effect of a CP intervention on adverse drug events, health costs, and mortality.

Risk factors for poor outcome in older patients admitted in a surgical intensive care unit.

BACKGROUND: The benefit of a stay in an intensive care unit (ICU) is not certain for older patients, particularly in the surgical context. AIMS: The objective of this study was to identify the factors associated with an unfavourable outcome in this population. DESIGN: Prospective, descriptive, monocentric study conducted in the surgical ICU of a French university hospital. METHODS: Patients aged ≥75 years admitted in the surgical ICU for a predicted length of stay ≥48 hours were included. Patients received an initial and a 6-months nutritional and functional assessment performed by physicians and nurses. The outcome was considered as favourable if the Katz Activities of Daily Living (ADL) variation (ADL delta = 6-months ADL - ICU admission ADL) was between 0 and -0.5 point 6 months after ICU discharge and unfavourable if the ADL delta decreased by more than 0.5 points or if the patient had died 6 months after ICU discharge. RESULTS: Fifty-six patients-32 (57%) male-aged 79 [77; 83] y were included. ICU mortality was 19%; 6-month mortality was 22%. Median ADL delta was -0.5 [-0.5-0] points. A low ADL score (P = .0438) and a low albumin level (P = .0213) at admission were the two independent factors associated with an unfavourable outcome. CONCLUSION: Mortality and loss of independence were high in this elderly population during and after their surgical ICU stay. The benefit of a systematic collaboration between intensive care specialists, ICU nurses, and geriatricians, to assess and manage nutritional and functional problems and to prevent a pejorative outcome in patients over 75 years old admitted in surgical ICU needs to be studied. RELEVANCE TO CLINICAL PRACTICE: There should be systematic screening for objective markers of undernutrition and frailty on ICU admission of older patients as they are associated with a poor prognosis.

[Deliberate intoxication with Datura Stramonium, a rare cause of confusion]. / L'intoxication volontaire à Datura Stramonium, une cause rare de confusion.

Many drugs can be responsible for this syndrome. Although it remains rare, poisoning by Datura Stramonium should be considered in the event of anticholinergic syndrome in the elderly, particularly in the event of anticholinergic manifestations.

[The proper use of carboxymaltose iron and its economic impact in the geriatric wards of a French university hospital]. / Bon usage du fer carboxymaltose et impact économique dans les services gériatriques d'un CHU.

The proper use and economic impact of carboxymaltose iron were evaluated for patients hospitalized in the geriatric wards of a French university hospital from November 2019 to April 2020. Martial supplementation was recommended for 75.7% of the 173 patients who received carboxymaltose iron: 43.4% had a real indication for carboxymaltose iron, while 14.4% could have received sucrose iron and 17.9% could have received per os iron. Compliance with the recommendations would have generated savings of 10,345.80 euros (32.1%).

Association between orthostatic blood pressure dysregulation and geriatric syndromes: a cross-sectional study.

BACKGROUND: Orthostatic blood pressure dysregulation, including orthostatic hypotension (OH) and orthostatic hypertension (OHT), is common in the elderly. The association between OH and, to a lesser extent, OHT with geriatric syndromes is controversial and little investigated. Our objective was to assess the association between orthostatic blood pressure dysregulation and geriatric syndromes in an ambulatory outpatient population. METHODS: This observational study included all outpatients for whom a one-visit comprehensive geriatric assessment was performed during a year. OH was defined as a decrease of at least 20 mmHg in systolic blood pressure (SBP) and/or 10 mmHg in diastolic blood pressure (DBP) after 1 or 3 min of standing. OHT was defined as an increase of more than 20 mmHg in SBP after 1 or 3 min of standing. Comorbidities, drugs regimen, a history of previous falls, nutritional, frailty, functional and cognitive status were compared between patients with OHT or OH and controls (NOR). RESULTS: Five hundred thirty patients (mean age: 82.9 ± 5.1 years) were included. 19.6% had an OH and 22.3% an OHT. OHT patients were more frequently female, had more diabetes and a lower resting SBP than patients with NOR. OH patients had a higher resting SBP than NOR. After adjusting for age, sex, resting SBP and diabetes, OHT was associated with a low walking speed (OR = 1.332[1.009-1.758]; p = 0.043) and severe cognitive impairment at MMSe score (OR = 1.629[1.070-1.956]; p = 0.016) compared to NOR. Conversely, OH was associated with a lower grip strength (p = 0.016) than NOR. CONCLUSION: OHT and OH are common in elderly but associated with different geriatric phenotypes.

Buccofacial Apraxia, Oropharyngeal Dysphagia, and Dementia Severity in Community-Dwelling Elderly Patients.

Apraxia occurs frequently in patients with dementia. Buccofacial apraxia (BFA) characteristics have been less investigated than limb or speech apraxia. An association between BFA and oropharyngeal dysphagia (OD) in old patients with dementia has not yet been explored. We aimed to assess the prevalence of BFA in patients with dementia and evaluate the relationship between BFA, OD, and dementia. We have prospectively included 117 outpatients with dementia referred to a geriatric consultation. Oropharyngeal dysphagia was diagnosed using the volume viscosity swallowing test (V-VST). Buccofacial apraxia was evaluated by miming 7 meaningless gestures. A complementary geriatric assessment of 6-domains completed the evaluation. Buccofacial apraxia was present in 54 (48.6%) patients. Proxies reported OD more frequently in the group of patients with BFA compared to the group without (P = .04). Prevalence of OD assessed with the V-VST was similar between patients with and without apraxia (P = .9). Patients with BFA had a significant lower Mini-Mental State Examination suggesting a more severe cognitive decline (18.1 ± 4.5 vs 15.8 ± 5, P = .01), a lower activities of daily living relative to disabilities (5 ± 0.8 vs 4.3 ± 1.3, P = .001), and had a lower gait speed that indicated frailty (P = .03).In conclusion, our results indicate a relationship between BFA and severity of dementia, disability, and frailty with no significant association between BFA and OD.

[A rare but increasing aetiology of febrile dyspnea in the elderly]. / Une dyspnée fébrile chez un patient âgé.

Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infectious disease well described in patients living with HIV (PLHIV) but that can occur in other immunosuppressed patients. Currently, its incidence decreases in PLHIV but increases in non-HIV immunosuppressed patients, particularly in case of hematological diseases. Thus, in elderly, the diagnosis of PJP should be evoked in case of subacute pneumonia rapidly evolving to an acute respiratory distress, with or without interstitial pneumonia at chest radiography, and a context of immunosuppression.

Benefits of a Pre-Treatment Comprehensive Geriatric Assessment in a Rare Case of Gemella Haemolysans Endocarditis in an 86-Year-Old Patient and a Review of the Literature.

Infective endocarditis is a serious condition, which is associated with high mortality in elderly patients. Gemella haemolysans (GH) is a microorganism from the Streptococcus family, rarely involved in infective endocarditis. Here, we present a case of Gemella haemolysans endocarditis in an 86-year-old patient, successfully treated by antibiotics and surgery following a pre-treatment comprehensive geriatric assessment (CGA). This case is discussed in the context of a review of all published cases of Gemella haemolysans endocarditis. We illustrate the benefit of a systematic pre-treatment comprehensive geriatric assessment in elderly patients with infective endocarditis.

Acute cardiac failure secondary to senile systemic amyloidosis.

Hereditary or senile transthyretin (TTR) cardiac amyloidosis is a rare and underestimated cause of heart failure in old patients. New diagnostic methods, particularly cardiac MRI and proteomic analysis, have been recently developed that enable both earlier identification and development of specific treatments.We report a case of cardiac amyloidosis revealed through late-onset heart failure.

[Minimal geriatric assessment by an advanced practice nurse]. / Évaluation gériatrique minimale par une infirmière en pratique avancée.

The prevalence of haematological malignancies increases in elderly patients. The complexity of therapeutic management makes it necessary to evaluate them using a global approach, namely bio-psycho-environmental. Identifying and assessing their weaknesses are part of the roles of advanced practice nurse (APN). Various tools are used to do this, including the G8 questionnaire, which directs patients towards a comprehensive geriatric assessment, or the Geriatric core dataset, designed to be used during clinical trials and which is more detailed and faster. Could an APN use the latter?

[Practical review of driving in older patient: from theory to practice]. / La conduite chez la personne âgée, de la théorie à la pratique.

As the French population is ageing, the number of older people on the road is increasing all the time. For many older adults, this everyday activity remains an important way of maintaining their independence. Putting this right into question on the sole basis of age can be seen as a particularly stigmatising measure. However, this population is particularly vulnerable on the road. While behavioural factors are frequently involved in young adults, driving errors seem to be more frequently the main mechanism in older people. Driving is a succession of complex tasks that can be affected by ageing and the presence of pathologies (cognitive decline, sensory deficiencies or cardiovascular conditions that have not stabilised, etc.). As these medical conditions increase with age, it is important that healthcare professionals identify high-risk situations. When it is required, the professionals should assist patients to stop driving and find alternatives. Maintaining the mobility and ensure safety for older adults on the road remain challenging for the community. In this article, we discuss the issues surrounding the maintenance of driving in older adults. We also discuss the appropriate way to help patients stop driving when necessary.

Changes in carotid arterial wall viscosity and carotid arterial stiffness in type 2 diabetes patients.

BACKGROUND AND AIMS: Changes in arterial wall viscosity (AWW) and stiffness during type 2 diabetes (T2D) have been little investigated. We explored changes in carotid AWV considering change in arterial stiffness and loading conditions, in patients with T2D. METHODS: This cross-sectional, monocentric study compared 19 middle-aged patients with T2D to 30 non-diabetic (ND) controls. The absolute viscosity (WV) was determined as the area of the pressure-lumen cross-sectional area (P-LCSA) loop obtained by carotid tonometry and contralateral echo-tracking. The relative viscosity was determined as the ratio between WV and the elastic energy stored within the arterial wall (WV/WE). Carotid geometry, midwall stress, distensibility and elastic modulus were also compared between groups. RESULTS: T2D patients were older and more frequently had hypertension. Internal diameter, mean central and pulse blood pressure were higher in T2D patients but midwall stress was similar compared to ND controls. WV and WV/WE were higher in T2D patients when compared with ND controls (23 [16-41] vs. 11 [7-18] mm Hg.mm2, p=0.007 and 21% [17-25] vs. 12% [8-17], p < 0.001 respectively) even after adjustment on confounding factors. Carotid arterial stiffness was higher in T2D patients, but after adjustment this difference was only observed for the highest levels of midwall stress. CONCLUSIONS: Carotid AWV and stiffness are increased in T2D patients but only AWV is significantly increased after considering loading conditions. Whether this increase in energy dissipation within the arterial wall contributes to alter cardiovascular coupling in T2D remains to be established.

Adaptation of Arterial Wall Viscosity to the Short-Term Reduction of Heart Rate: Impact of Aging.

Background Changes in arterial wall viscosity, which dissipates the energy stored within the arterial wall, may contribute to the beneficial effect of heart rate (HR) reduction on arterial stiffness and cardiovascular coupling. However, it has never been assessed in humans and could be altered by aging. We evaluated the effect of a selective HR-lowering agent on carotid arterial wall viscosity and the impact of aging on this effect. Methods and Results This randomized, placebo-controlled, double-blind, crossover study performed in 19 healthy volunteers evaluated the effects of ivabradine (5 mg BID, 1-week) on carotid arterial wall viscosity, mechanics, hemodynamics, and cardiovascular coupling. Arterial wall viscosity was evaluated by the area of the hysteresis loop of the pressure-lumen cross-sectional area relationship, representing the energy dissipated (WV), and by the relative viscosity (WV/WE), with WE representing the elastic energy stored. HR reduction by ivabradine increased WV and WE whereas WV/WE remained stable. In middle-aged subjects (n=11), baseline arterial stiffness and cardiovascular coupling were less favorable, and WE was similar but WV and therefore WV/WE were lower than in youth (n=8). HR reduction increased WV/WE in middle-aged but not in young subjects, owing to a larger increase in WV than WE. These results were supported by the age-related linear increase in WV/WE after HR reduction (P=0.009), explained by a linear increase in WV. Conclusion HR reduction increases arterial wall energy dissipation proportionally to the increase in WE, suggesting an adaptive process to bradycardia. This mechanism is altered during aging resulting in a larger than expected energy dissipation, the impact of which should be assessed. Registration URL: https://www.clinicaltrials.gov; Unique identifier: 2015/077/HP. URL: https://www. eudract.ema.europa.eu; Unique identifier: 2015-002060-17.

[Intraoperative hypotension and delirium in patients with hip fracture]. / Hypotension per-opératoire et syndrome confusionnel chez les patients présentant une fracture de l'extrémité supérieure du fémur.

Postoperative delirium is common after hip fracture surgery in elderly patients and is associated with poor outcome (higher risk of mortality, institutionalization and length of stay). The relationship between modifiable intra-operative risk factors, such as intra-operative hypotension, and postoperative delirium is unclear. The main objective of this study was to evaluate the association between intra-operative hypotension and the development of a postoperative delirium in older patients with hip fracture. A secondary aim was to assess the impact of other pre- and intra-operative predisposing factors (anaesthetic approaches or specific anaesthetic drugs, surgery duration, timing of surgery, type of implants used as primary treatment, intra-operative blood loss) on developing postoperative delirium in this elderly population. This retrospective monocentric study included 100 consecutive hip fracture patients, aged 75 years and older, admitted to a dedicated ortho-geriatric unit. All patients were screened for post-operative delirium using the confusion assessment method performed by a geriatrician. Intra-operative hypotension was defined as a decrease of more than 30% below the preoperative baseline for systolic blood pressure or a decrease in mean arterial pressure (MAP) below 60 mmHg. Post-operative delirium (n = 37; 37.8%) and intra-operative hypotension (n = 80; 81.6%) are both common in old patients but we did not demonstrate a significant association regardless of the chosen definition. The following risk factors were significantly associated with postoperative delirium: surgical delay (OR 1.47[1.01-2.02]; p = 0.02), institutionalisation (OR 2.25[1.33-3.8]; p = 0.02) and postoperative acute kidney injury (OR 2.34[1.32-4.15]; p = 0.02). Postoperative delirium is common in old patients with hip fracture and is associated with postoperative complications, institutionalisation and surgical delay but not with intra-operative risk factors.

Chronic neurological disorders and related comorbidities: Role of age-associated physiological changes.

Current knowledge indicates that the physiological aging process starts with subclinical changes at the molecular and cellular level, which affect nearly all physiological systems. For example, the age-associated remodeling of the immune system (i.e., immunosenescence) and vascular aging per se can contribute to frailty and vulnerability among older adults. They are also described as being implicated in the pathophysiology of some major chronic comorbid conditions such as age-associated diseases of the central (e.g., stroke, Parkinson's disease, Alzheimer's disease, and related disorders) and peripheral (e.g., polyneuropathy) nervous systems. These neurologic disorders are also among the greatest contributors to geriatric syndromes, which refer to highly prevalent and chronic conditions among aged people of multifactorial origin, such as delirium, falls, incontinence, and frailty. Neurologic disorders can also occur in patients with one or more geriatric syndromes and thus further interfere with the quality of life, physical function, morbidity, and mortality. This chapter presents and discusses in three sections the complex interrelationships between the main determinants of aging with a specific focus on vascular aging, chronic neurologic disorders, and the specific clinical presentation of geriatric syndromes in older people.

Endothelium-dependent adaptation of arterial wall viscosity during blood flow increase is impaired in essential hypertension.

BACKGROUND AND AIMS: Arterial wall viscosity (AWV) is regulated by endothelium-derived NO and epoxyeicosatrienoic acids (EETs) under baseline physiological conditions. Whether these factors regulate AWV during blood flow increase and whether this mechanism is affected in essential hypertensive patients (HT) remain unknown. METHODS: The evolution of radial artery diameter, wall thickness and arterial pressure in response to an increase in flow induced by hand skin heating were measured in 18 untreated HT and 14 normotensive controls (NT) during local infusion of saline and the respective pharmacological inhibitors of NO-synthase and EETs synthesis by cytochrome P450, L-NMMA and/or fluconazole. AWV was estimated by the ratio of the viscous energy dissipated (WV) to the elastic energy stored (WE) obtained from the pressure-diameter relationship. Concomitant changes in operating conditions, which influence the AWV, were taken into account by calculating the midwall stress. RESULTS: Baseline WV and WE were higher in HT than in NT but WV/WE was similar. In saline condition, WV/WE increased in HT during heating but not in NT. In the presence of L-NMMA and/or fluconazole, WV/WE increased during heating in NT. In contrast, these inhibitors did not modify the increase in WV/WE during heating in HT compared to saline. In all conditions, a larger increase in WV than WE was responsible for the increase in WV/WE. CONCLUSIONS: The release of NO and EETs maintains a stable AWV during flow increase and this endothelial adaptive regulation is lost during essential hypertension, which may promote excessive viscous energy dissipation and cardiovascular uncoupling. Restoration of EETs availability with inhibitors of soluble epoxide hydrolase could thus constitute a promising pharmacological approach to restore the endothelial adaptive regulation of AWV.

Feasibility and Determinants of Orthostatic Hypotension Self-measurement at Home in an Elderly Community-Dwelling Population.

BACKGROUND: Orthostatic hypotension (OH) measurement reproducibility is poor. Our objectives were to assess feasibility of self-detection home-measured OH (HOH) and HOH determinants. METHODS: Subjects older than 65 years, attending a geriatric outpatient clinic, able to understand the HOH protocol: 3 blood pressure (BP) measures after 5 minutes of seating and BP measures after 1 and 3 minutes of standing, each morning and evening for 3 consecutive days were lent a validated digital automatic sphygmomanometer. Reports containing at least 4 correct measurements were deemed a success. Factors associated with HOH were studied. RESULTS: HOH feasibility was 82.8% (241 subjects) with no difference between participants who failed or succeeded. Among the 241 subjects (mean age (SD) = 78.0 (8.3) years old; 62.1% of women), 139 were free of HOH, 70 had 1 HOH episode and 32 had 2 or more HOH episodes. Hypertension, dementia, atrial fibrillation, diabetes, and heart failure were found in 70.0%, 10.4%, 9.4%, 8.8%, and 3.4% of cases, respectively. Subjects were treated with antihypertensive, benzodiazepine, statin medication in 47.3%, 9.3%, 7.4% of cases, respectively, and 42.4% experienced polypharmacy. HOH episodes were associated with dementia (P = 0.01), presence of OH during the geriatric outpatient clinic assessment (P = 0.0002), statin therapy (P = 0.04), and polypharmacy (P = 0.0002). In multivariate analysis, benzodiazepine (OR (95% CI) = 2.59 (1.10-6.08) and statin medication (OR (95% CI) = 1.92 (1.10-3.33)) remained significantly associated with HOH. CONCLUSIONS: HOH had a good feasibility and relevant determinants. A study to address the predictive value of HOH will be conducted.

Evidence for a Role of Vascular Endothelium in the Control of Arterial Wall Viscosity in Humans.

Arterial wall viscosity (AWV) is a major cause of energy dissipation along the arterial tree. Its determinants remain controversial but an active endothelial regulation has been suggested. Our objective was to assess in humans the physiological role of endothelium-derived nitric oxide (NO), epoxyeicosatrienoic acids and the effect of modulating smooth muscle tone in the regulation of AWV. We simultaneously measured radial artery diameter, wall thickness, and arterial pressure in healthy volunteers during the local infusion of inhibitors of NO-synthase (NG-monomethyl-l-arginine), epoxyeicosatrienoic acids synthesis by cytochrome P450 (fluconazole), the epoxyeicosatrienoic acids cellular targets calcium-activated potassium channels (tetraethylammonium), alone and in combination. AWV was estimated from the relative viscosity expressed as the ratio of the area of the hysteresis loop of the pressure-diameter relationship to the area under the loading phase. Arterial tone was assessed by measuring change in wall stiffness and midwall stress. NG-monomethyl-l-arginine paradoxically reduced relative viscosity (34.9±8.9%-28.9±8.6%). Conversely, relative viscosity was not modified by fluconazole (33.5±15.5%-32.0±13.6%) but increased by tetraethylammonium (31.7±6.6%-35.7±8.0%). This increase was more marked with NG-monomethyl-l-arginine+fluconazole (31.1±10.7%-43.3±13.2%) and NG-monomethyl-l-arginine+tetraethylammonium (29.5±2.3%-41.5±11.1%) compared with inhibitors alone. Sodium nitroprusside decreased AWV (35.4±2.9%-28.7±2.0%). These effects were associated with parallel change in tone but of different magnitude for similar variations in viscosity, suggesting tone-dependent and independent mechanisms. In conclusion, this is the first demonstration that the endothelial factors, NO and epoxyeicosatrienoic acids, regulate AWV in humans and support the role of arterial tone in this regulation. CLINICAL TRIAL REGISTRATION: URL: https://eudract.ema.europa.eu. Unique identifier: RCB2007-A001-10-53.