Cathodal iontophoresis of treprostinil induces a sustained increase in cutaneous blood flux in healthy volunteers.

OBJECTIVE: Prostacyclin analogues are the most effective drugs to treat sclerodermic digital ulcers, but their systemic use is limited by their frequent side effects. The authors tested whether the prostacyclin analogues treprostinil and iloprost, delivered by cutaneous iontophoresis, induce sustained vasodilatation. METHODS: Twenty healthy volunteers received treprostinil by cathodal iontophoresis on the forearm. Skin blood flux was quantified using laser Doppler imaging. RESULTS: Treprostinil 250 µM induced an increase in cutaneous vascular conductance AUC(80) (min) (31 897 ± 24 390 %BL·min) compared with NaCl 0.9% (P < .005), treprostinil 2.5 µM (P < .005), and treprostinil 25 µM (P < .005). This was confirmed when flux was recorded for up to 10 hours. Systemic and skin tolerance of treprostinil were good. Iloprost was stopped early because of local toxicity. CONCLUSION: Treprostinil cathodal iontophoresis induces a sustained increase in cutaneous blood flow with good local tolerance. This could be investigated as a new local therapy for digital ulcers in scleroderma.

Involvement of cytochrome epoxygenase metabolites in cutaneous postocclusive hyperemia in humans.

Several mediators contribute to postocclusive reactive hyperemia (PORH) of the skin, including sensory nerves and endothelium-derived hyperpolarizing factors. The main objective of our study was to investigate the specific contribution of epoxyeicosatrienoic acids in human skin PORH. Eight healthy volunteers were enrolled in two placebo-controlled experiments. In the first experiment we studied the separate and combined effects of 6.5 mM fluconazole, infused through microdialysis fibers, and lidocaine/prilocaine cream on skin PORH following 5 min arterial occlusion. In the second experiment we studied the separate and combined effects of 6.5 mM fluconazole and 10 mM N(G)-monomethyl-l-arginine (l-NMMA). Skin blood flux was recorded using two-dimensional laser speckle contrast imaging. Maximal cutaneous vascular conductance (CVC(max)) was obtained following 29 mM sodium nitroprusside perfusion. The PORH peak at the placebo site averaged 66 ± 11%CVC(max). Compared with the placebo site, the peak was significantly lower at the fluconazole (47 ± 10%CVC(max); P < 0.001), lidocaine (29 ± 10%CVC(max); P < 0.001), and fluconazole + lidocaine (30 ± 10%CVC(max); P < 0.001) sites. The effect of fluconazole on the area under the curve was more pronounced. In the second experiment, the PORH peak was significantly lower at the fluconazole site, but not at the l-NMMA or combination site, compared with the placebo site. In addition to sensory nerves cytochrome epoxygenase metabolites, putatively epoxyeicosatrienoic acids, play a major role in healthy skin PORH, their role being more important in the time course rather than the peak.

Iontophoresis of endothelin receptor antagonists in rats and men.

INTRODUCTION: The treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA) bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis. METHODS: Cathodal and anodal iontophoresis of bosentan and sitaxentan were performed on anaesthetized rat hindquarters without and during endothelin-1 infusion. Skin blood flow was quantified using laser-Doppler imaging and cutaneous tolerability was assessed. Iontophoresis of sitaxentan (20 min, 20 or 100 µA) was subsequently performed on the forearm skin of healthy men (n = 5). RESULTS: In rats neither bosentan nor sitaxentan increased skin blood flux compared to NaCl. When simultaneously infusing endothelin-1, cathodal iontophoresis of sitaxentan increased skin blood flux compared to NaCl (AUC(0-20) were 44032.2 ± 12277 and 14957.5 ± 23818.8 %BL.s, respectively; P = 0.01). In humans, sitaxentan did not significantly increase skin blood flux as compared to NaCl. Iontophoresis of ERAs was well tolerated both in animals and humans. CONCLUSIONS: This study shows that cathodal iontophoresis of sitaxentan but not bosentan partially reverses endothelin-induced skin vasoconstriction in rats, suggesting that sitaxentan diffuses into the dermis. However, sitaxentan does not influence basal skin microvascular tone in rats or in humans.

Aging is associated with a diminished axon reflex response to local heating on the gaiter skin area.

OBJECTIVES: Elderly patients are susceptible to skin ulcerations on the supramedial malleolar area of the leg. Our aim was, using local thermal hyperemia, to study microvascular function on the gaiter skin area of elderly, but otherwise healthy volunteers, because abnormal microvascular reactivity could contribute to ulcerations in this region. METHODS: Two groups of healthy volunteers were enrolled according to age, including 20 subjects aged from 18 to 30 years (young group) and 42 subjects aged from 60 to 86 years (older group). Local thermal hyperemia to 43°C was performed for 1 h using heating circular probes and skin blood flow was recorded using Laser Doppler Imaging, with or without 2 h lidocaine/prilocaine cream application. Sodium nitroprusside iontophoresis was also performed. RESULTS: The initial local thermal hyperemia peak was lower in the older group (14.7 mV/mmHg±6.9) compared to the young group (19.9±7.2, P=0.009). Lidocaine/prilocaine cream decreased the initial local thermal hyperemia peak and the late plateau for all groups. The local thermal hyperemia plateau and sodium nitroprusside iontophoresis corrected for skin resistance did not differ between older and younger subjects. CONCLUSIONS: Physiological aging is associated with an altered initial axon reflex response to local heating in the supramedial malleolar skin. Further work is required to determine whether these changes are more pronounced in frail and dependent groups and whether they could explain the higher incidence of skin ulcerations in the supramedial malleolar skin associated with venous insufficiency and neuropathy.

Impaired transient vasodilation and increased vasoconstriction to digital local cooling in primary Raynaud's phenomenon.

Raynaud's phenomenon (RP) is defined as episodic ischemia of the extremities in response to cold. Although the structure of skin capillaries is normal in primary RP, some data suggest impairment of microvascular function. We aimed at testing whether digital skin blood flow was lower in RP than in controls while cooling locally. We further evaluated the contribution of sensory nerves in the response. We recruited 21 patients with primary RP and 20 healthy volunteers matched on age and gender. After a 10-min baseline at 33°C, skin temperature was cooled at 15 or 24°C during 30 min on the forearm and the finger while monitoring perfusion with a custom-design laser Doppler flowmetry probe. Perfusion was also assessed after topical anesthesia. Blood flow was expressed as cutaneous vascular conductance (CVC). Data were subsequently expressed as area above the curve (AAC(0-30)) of the percentage decrease from baseline CVC (%BL). CVC on the dorsum of the finger was lower in RP patients compared with controls at 15°C (AAC(0-30) were 106,237.2 and 69,544.3%BL·s, respectively; P = 0.02) and at 24°C (AAC(0-30) were 86,915 and 57,598%BL·s, respectively; P = 0.04) whereas we observed no significant difference on the finger pad and the forearm. Topical anesthesia increased CVC in patients with RP (P = 0.05), whereas it did not affect reactivity in controls (P = 0.86). Our study shows exaggerated skin microvascular vasoconstriction to local cooling on the dorsum of the finger in primary RP compared with controls. Part of this abnormal response in primary RP depends on sensitive nerves.

Effect of oral sildenafil on skin postocclusive reactive hyperemia in healthy volunteers.

OBJECTIVE: Sildenafil is a type 5 phosphodiesterase inhibitor that has a theoretical ability to increase hyperemia following a short bout of ischemia. We tested if oral sildenafil increases skin PORH in healthy volunteers. METHODS: We assessed forearm skin PORH (occlusion of blood flow for five minutes) in ten healthy volunteers 120minutes following the oral administration of 50 or 100mg of sildenafil. Cutaneous blood flow on the forearm was monitored using LDF. RESULTS: The PORH peak, expressed as a percentage of baseline, was clearly increased with 100mg sildenafil: 746% (95% CI 447-1044) versus 484% (95% CI 354-613) with 50mg sildenafil, and 468% (95% CI 347-588) without sildenafil (p=0.03 for 100mg versus 50mg and control). Oral sildenafil at 50mg increased the AUC of PORH on the forearm compared with control: 4568PU.sec (95% CI: 2252-6883) with 50mg sildenafil versus 1030 PU.sec (95% CI 737-1322) without sildenafil (p=0.006). Likewise, 100mg sildenafil increased the AUC (5271PU.sec (95% CI -81-10,623), albeit bordering on significance (p=0.07). Neither dose increased maximal LTH. CONCLUSIONS: Acute sildenafil administration at 50 and 100mg enhances skin hyperemia following a short bout of ischemia.

Cardiovascular mortality and C-reactive protein in elderly patients beginning dialysis: reverse epidemiology?

BACKGROUND AND AIMS: Cardiovascular disease is a major cause of mortality in end-stage renal disease patients (ESRD). The rate of elderly and polypathologic patients in ESRD is increasing. Elevated levels of C-reactive protein (CRP) have been shown to be associated with increased mortality in ESRD patients. The aim of this study was to examine whether, in elderly ESRD patients, the conventional relationship between elevated CRP and cardiovascular mortality is maintained. METHODS: This prospective European cohort study included 150 ESRD patients. Data obtained at baseline included demographics, comorbidity, late referral to a nephrologist, high-sensitivity CRP, and serum albumin and hemoglobin levels. Cardiovascular events were analysed as a combined end-point. RESULTS: The mean age of the cohort was 61 years (22-90), with 33.3% of patients over 70 years (75 yrs, 70-83 yrs). Forty-two patients (28.2%) experienced at least one cardiovascular event. Interaction between age over 70 years and CRP exceeding 3 mg/L was a protective factor. Patients over 70 years beginning dialysis with a CRP value <3 mg/L had a higher cardiovascular risk than those with a CRP value >3 mg/L. Multivariate analysis showed that the independent risk factors for cardiovascular events were, in the whole cohort, age over 70 years, previous cardiovascular comorbidity, and interaction between age and CRP. CONCLUSIONS: This trial shows a reverse relation between cardiovascular risk in dialysis patients over 70 and CRP level. This may be a useful element in evaluating older patients before long-term dialysis.

[Predictors of functional decline of older persons after an hospitalisation in an acute care for elder unit: importance of recent functional evolution]. / Facteurs prédictifs du déclin fonctionnel de la personne âgée après une hospitalisation en court séjour gériatrique: importance de l'évolution fonctionnelle récente.

OBJECTIVES: To identify the predictors of functional decline of older persons after hospitalization in an Acute Care for Elder unit (ACE). METHODS: Retrospective observational study based on a population hospitalised in ACE unit in Grenoble University Hospital. Dead patients within hospitalisation and patient fully disable or already hospitalized 15 days before hospitalisation were excluded. The primary outcome was the functional decline defined by a loss in activity daily life (ADL) between discharge and 15 days before hospitalisation. The predictive factors included socio-demographic data, geriatric assessment and the admission pathway. RESULTS: 184 patients were included (mean 86.4±6.2 years, 64.1% women). The admission by emergency department was predominant (77.2%). The mean length of stay was 16.0±9.5 days. A functional decline as present for 31.0% des patients; for 95% of these patients, the functional decline occurred before admission to ACE. Factors associated with functional decline at discharge were: recent functional decline, ADL level at admission, pressure sore, denutrition and admission via the emergency room (ER) (p<0.05). In the multivariate analysis, recent functional decline was strongly associated with functional decline at discharge (OR=58.8, p<0.01). Outside this factor, ADL level at admission (OR=3.2, p<0.01), hypoalbuminemaia (OR=2.6, p=0.01) and an admission via the ER (OR=2.6, p=0.05) were independently associated with functional decline at discharge. CONCLUSION: Better management of hospitalised older persons, according to the ACE model, has diminished the negative functional effects of hospitalization. Identification of recent functional decline rather than other usually identified predictors would be useful for detection of older patients who might benefit from a geriatric program. Detecting and correcting early malnutrition and developing direct admissions mechanisms may improve functional prognosis of hospitalised older patients.