Gianni Lorenzini

Effect of aliskiren treatment on endothelium-dependent vasodilation and aortic stiffness in essential hypertensive patients

AIMS Aliskiren is a new oral non-peptide renin inhibitor. Its effects on vascular function in human hypertension are unknown. We assessed whether aliskiren may improve peripheral endothelial function and arterial stiffness in essential hypertensive patients (EH), when compared with the angiotensin-converting enzyme-inhibitor ramipril. METHODS AND RESULTS Fifty EH received treatment with aliskiren (150-300 mg/daily) or ramipril (5-10 mg/daily) for 12 weeks, according to a randomized, open with blind endpoints, parallel group design. We studied the forearm blood flow (straingauge plethysmography) response to intrabrachial acetylcholine, repeated under the nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) (4 μmol/min), or the antioxidant ascorbic acid (8 mg/100 mL/min). Carotid-to-femoral pulse wave velocity (PWV), central blood pressure and augmentation index (AIx) were obtained by applanation tonometry. Brachial blood pressure was similarly normalized by aliskiren (from 149/94 to 136/86 mmHg) and ramipril (from 148/92 to 135/85 mmHg), as well as central blood pressure. Aliskiren increased (P < 0.001) the vasodilation to acetylcholine and restored the inhibitory effect of l-NMMA on acetylcholine. Ascorbic acid, which at baseline potentiated the response to acetylcholine, no longer improved endothelium-dependent relaxation after aliskiren treatment. In contrast, ramipril failed to affect the response to acetylcholine, the lacking inhibitory effect of l-NMMA, or the potentiating effect of ascorbic acid. Pulse wave velocity was significantly (P < 0.05) and similarly reduced by both drugs. Aliskiren induced a significantly (P < 0.05) greater AIx reduction than ramipril. CONCLUSION Aliskiren increased nitric oxide availability in the forearm resistance arterioles of EH, an effect probably determined by an antioxidant activity, which can also contribute to improved peripheral wave reflection.

Ghrelin restores nitric oxide availability in resistance circulation of essential hypertensive patients: role of NAD(P)H oxidase

AIMS We assessed whether acute intra-arterial infusion of exogenous ghrelin can improve endothelial dysfunction by restoring nitric oxide (NO) availability in the forearm microcirculation of essential hypertensive patients. The effect of ghrelin on endothelial dysfunction (pressurized myograph), vascular oxidative stress generation (fluorescent dihydroethidium), and phosphorylation of p47phox (western blot), an index of NAD(P)H oxidase activation, in isolated small arteries taken from essential hypertensive patients (subcutaneous biopsy) were also investigated. METHODS AND RESULTS In 18 normotensive control subjects and 18 essential hypertensive patients, we studied the forearm blood flow (strain-gauge plethysmography) response to intra-arterial acetylcholine, repeated under NO synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) or the antioxidant ascorbic acid. The protocol was repeated at the end of exogenous ghrelin intra-arterial infusion. In hypertensive patients, ghrelin normalized the blunted response to acetylcholine, restored the inhibiting effect of l-NMMA and abrogated the potentiating effect of ascorbic acid on acetylcholine. In controls, ghrelin failed to modify these vascular responses. In hypertensive patients, ghrelin decreased venous levels of malondialdehyde, lipoperoxide, and interleukin-6, and concomitantly increased endogenous antioxidant capacity. Small vessels from hypertensive patients showed an enhanced intravascular oxidative stress, which was strongly and similarly decreased by incubation with ghrelin, the NAD(P)H oxidase inhibitor gp91 ds-tat, or both. Ghrelin also normalized the overexpression of p47 phosphorylation and restored the NO availability in small vessels from hypertensive patients. CONCLUSIONS Exogenous ghrelin increases endothelial dysfunction by restoring NO availability in the forearm microcirculation of essential hypertensive patients, an effect ascribable to an antioxidant effect via inhibition of NAD(P)H oxidase activation.

Prognostic ability of four clinical grading scores in spontaneous intracerebral hemorrhage

The prognostic stratification of spontaneous intracerebral hemorrhage (ICH) is strongly recommended. The outcome of ICH is unchanged over the last 30 years due to the lack of effective therapies and high risk of severe neurological damage. Half of the deaths occur in the first 48 h from symptoms onset. Early neurological deterioration (END) represents one of the major determinants of poor outcome. Identifying which ICH patients will die or present severe functional sequels is of utmost importance for appropriate acute treatment and setting of care and post-acute services. In the latest few years, several clinical grading scores have been proposed as prognosticators of in-hospital and 30-day mortality and 90-day functional outcome. The original ICH score (oICH), the ICH grading scale (ICH-GS) and the FUNC score have been extensively validated [1–3]. The variables enclosed in these scores are age, baseline ICH volume and localization, intraventricular bleeding (IVH) and Glasgow Coma Scale (GCS). FUNC score also includes the history of cognitive impairment. In all scores, ICH volume is measured by using the ABC/2 method. In the oICH score of Hemphill (scoring range 0–6), the 30-day mortality increased from 0 % for scoring 0 to 100 % for scoring C5. In the ICH-GS (scoring range 5–13), 30-day mortality increased from less than 20 % for scoring B6 to 100 % for scoring C11 [1, 2]. The FUNC score (scoring range 0–11) is designed for predicting 90-day functional independence. Functional independence increased from 0 % for scoring B4 to 82 % for scoring 11 [3]. Much recently, a new prognostic model named EDICH score (range 0–8) has been proposed by Zis et al. [4]. This score encloses in its variables the values of international normalized ratio, but does not include age. The size of hematoma is estimated using the maximum diameter of ICH. Accordingly, Masotti et al. modified the original EDICH score (mEDICH score) by using the ABC/2 method for estimating the ICH volume instead of maximum diameter. With a better estimation of ICH volume, mEDICH showed a better predictive ability, especially as a prognosticator of the ultra-early outcomes, such as END and/or 48-h mortality [5]. The supplemental material reports the four scores and the respective calculation methods. Since literature lacks direct comparisons between these scores, we compared these four clinical grading scores in a real-life cohort of 170 ICH patients and consecutively hospitalized in a non-teaching hospital from 2006 to 2013. The GCS was first recorded on hospital admission, after resuscitation and clinical stabilization. All neuroradiological findings were determined on the initial brain CT scan. Baseline hematoma volume was measured using the ABC/ Electronic supplementary material The online version of this article (doi:10.1007/s13760-016-0609-2) contains supplementary material, which is available to authorized users.

Intracerebral hemorrhage score in patients with spontaneous intracerebral hemorrhage pretreated and not treated with antithrombotics

One of the validated prognostication models for predicting 30‐day mortality in spontaneous intracerebral hemorrhage patients is the intracerebral hemorrhage score.

Prognostic stratification of pulmonary embolism: what does it change from 2014 European Society of Cardiology guidelines?

Prognostic stratification is of utmost importance for clinical management of acute pulmonary embolism (PE). Clinical presentation, echocardiography and biomarkers represented the key points on which recommendations of European Society of Cardiology (ESC) released in 2008 were based. In fact, in 2008 the ESC prognostic model suggested to divide acute PE in high risk, heamodynamically unstable, based on presentation with shock or hypotension, and non high risk, haemodynamically stable. The non high risk PE was divided in intermediate rand low risk PE based on echocardiographic and biomarkers signs of right heart dysfunction (RHD) and myocardial damage. This approach was not an academic speculation but permitted to define the early mortality risk (>15% in high risk, 3-15% in intermediate risk, <1% in low risk) and bring the most appropriate treatment. Over the years it became clear that co-morbidity influenced the early mortality risk and may define better the low mortality risk. Practical clinical scores, such as the Pulmonary Embolism Severity Index, PESI, in its original or simplified version, demonstrated to have high prognostic power to identify high (early mortality risk over 10%) and low risk (early mortality risk ≤ 1%) patients. Furthermore, it has become clear that the combination of ESC prognostic model, based on haemodynamics, and clinical prognostic scores may improve the prognostic stratification of acute PE, especially for patients with intermediate risk in whom the range of early mortality risk is wide The latest version of ESC recommendations on management of acute PE released in August 2014 go toward this direction and suggest to divide the non high risk PE in low or intermediate risk taking in account the PESI score. In this review we describe the prognostic strategy of acute PE suggested from the latest version of ESC recommendations.

What's new in emergencies, trauma, and shock? Heparin in severe traumatic brain injury: Beyond venous thromboembolism prevention?

Journal of Emergencies, Trauma, and Shock I 7:3 I Jul Sept 2014 cytokines or chemokines, which specifi cally drive the accumulation of parenchymal and peripheral immune cells in the injured brain region. Such mechanisms have been demonstrated in animal models, mostly in rodents, as well as in human brain.[1-4] The complex interaction of cytokines and cell types installs a network of events, which subsequently intersect with adjacent pathological cascades including oxidative stress, excitotoxicity, or reparative events including angiogenesis, scarring, and neurogenesis. It is well-accepted that neuroinflammation is responsible for benefi cial and detrimental effects, contributing to secondary brain damage but also facilitating neurorepair.[5] In clinical studies some groups reported a proportional cytokine production in either the cerebrospinal fl uid or intraparenchymal tissue with initial brain damage, mortality, or poor outcome scores.[6-8] However, except for corticosteroids, no anti-infl ammatory agents have been tested in STBI, and the negative results with these may have been fl awed by their multiple side effects.[9] Furthermore, the balance between VTE prevention and bleeding occurrence, hematoma enlargement or rebleeding represents the key point for the choice of pharmacological prevention in patients with STBI or intracranial hemorrhage (ICH), both spontaneous and traumatic, especially in the fi rst 72 h from event onset. STBI has long been associated with abnormal coagulation parameters, but the exact mechanisms underlying this phenomenon are poorly understood.[10] Coagulopathy after STBI includes hypercoagulable and hypocoagulable states that can lead to secondary injury by either the induction of thrombosis or the progression of hemorrhagic brain lesions. The rationale for pharmacological prophylaxis is based on high burden of VTE in patients suffering for intracranial bleedings, both for incidence and related-mortality. The intracranial bleeding is considered an absolute or at least a relative contraindication to antithrombotic treatment which makes physicians reluctant to use. Otherwise the occurrence of a VTE episode during the acute phase of STBI or ICH represents a much more worrying problem for the use of parenteral and/or oral anticoagulant therapy. Vena caval fi lters could be an option but, unfortunately, are weighted from potential serious side-effects. Literature evidence on VTE In this issue of JETS, the authors of the article entitled “Early Initiation of Prophylactic Heparin in Severe Traumatic Brain Injury is Associated with Accelerated Improvement on Brain Imaging” showed that the early administration of heparin within 72 h from event onset in patients with severe traumatic brain injury (STBI) seems to improve patients’ outcomes, beyond their direct effect of venous thromboembolism (VTE) prevention suggesting that neurological improvement could be ascribed to the pleyotropic anti-infl ammatory properties of heparin. Although this article represents only a generating hypothesis study with several methodological problems, such as retrospective nature, selection bias, absence of infl ammatory and coagulopathy biomarker assays, and limited sample size; the hypothesis raised by the study is enchanting.

Bilateral Thalamic Infarct in Two Unresponsive Octogenarians

Bilateral thalamic infarct (BTI) represents an uncommon stroke presentation. Pathophysiology recognizes the occlusion of an anatomic variant of the thalamic blood supply from perforating branche s of posterior cerebral arteries. Presentation could be nonspecific and dramatic in the same time, being coma or stupor the possible clinical scenario encountered. Diagnosis is performed by neuroradiological imaging showing the typical bilateral paramedian thalamic infarcts. Literature lacks of evidence in very old patients, therefore we describe two cases of BTI occurred in octogenarians presenting unresponsive.BTI in very old patients presenting comatose should be taken in account as diagnostic possibili ty.

Menorrhagia, Tranexamic Acid and False Negative D-Dimer in Patients with Venous Thromboembolism Case Report and Systematic Literature Review

A 56 years-old woman came to our attention for abrupt onset of shortness of breath. Pulmonary embolism was firstly ru led out due to negative D -Dimer and unlikely probability. On second day, the patient presented with heavy menorrhagia and treated with tranexamic acid (TA). She informed that similar episode happened some months ago, so she had been treated with cycles of