Diagnosis of acute aortic syndromes with ultrasound and d-dimer: the PROFUNDUS study.

BACKGROUND: In patients complaining common symptoms such as chest/abdominal/back pain or syncope, acute aortic syndromes (AAS) are rare underlying causes. AAS diagnosis requires urgent advanced aortic imaging (AAI), mostly computed tomography angiography. However, patient selection for AAI poses conflicting risks of misdiagnosis and overtesting. OBJECTIVES: We assessed the safety and efficiency of a diagnostic protocol integrating clinical data with point-of-care ultrasound (POCUS) and d-dimer (single/age-adjusted cutoff), to select patients for AAI. METHODS: This prospective study involved 12 Emergency Departments from 5 countries. POCUS findings were integrated with a guideline-compliant clinical score, to define the integrated pre-test probability (iPTP) of AAS. If iPTP was high, urgent AAI was requested. If iPTP was low and d-dimer was negative, AAS was ruled out. Patients were followed for 30 days, to adjudicate outcomes. RESULTS: Within 1979 enrolled patients, 176 (9 %) had an AAS. POCUS led to net reclassification improvement of 20 % (24 %/-4 % for events/non-events, P < 0.001) over clinical score alone. Median time to AAS diagnosis was 60 min if POCUS was positive vs 118 if negative (P = 0.042). Within 941 patients satisfying rule-out criteria, the 30-day incidence of AAS was 0 % (95 % CI, 0-0.41 %); without POCUS, 2 AAS were potentially missed. Protocol rule-out efficiency was 48 % (95 % CI, 46-50 %) and AAI was averted in 41 % of patients. Using age-adjusted d-dimer, rule-out efficiency was 54 % (difference 6 %, 95 % CI, 4-9 %, vs standard cutoff). CONCLUSIONS: The integrated algorithm allowed rapid triage of high-probability patients, while providing safe and efficient rule-out of AAS. Age-adjusted d-dimer maximized efficiency. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT04430400.

Management of intra-abdominal infections: recommendations by the Italian council for the optimization of antimicrobial use.

Intra-abdominal infections (IAIs) are common surgical emergencies and are an important cause of morbidity and mortality in hospital settings, particularly if poorly managed. The cornerstones of effective IAIs management include early diagnosis, adequate source control, appropriate antimicrobial therapy, and early physiologic stabilization using intravenous fluids and vasopressor agents in critically ill patients. Adequate empiric antimicrobial therapy in patients with IAIs is of paramount importance because inappropriate antimicrobial therapy is associated with poor outcomes. Optimizing antimicrobial prescriptions improves treatment effectiveness, increases patients' safety, and minimizes the risk of opportunistic infections (such as Clostridioides difficile) and antimicrobial resistance selection. The growing emergence of multi-drug resistant organisms has caused an impending crisis with alarming implications, especially regarding Gram-negative bacteria. The Multidisciplinary and Intersociety Italian Council for the Optimization of Antimicrobial Use promoted a consensus conference on the antimicrobial management of IAIs, including emergency medicine specialists, radiologists, surgeons, intensivists, infectious disease specialists, clinical pharmacologists, hospital pharmacists, microbiologists and public health specialists. Relevant clinical questions were constructed by the Organizational Committee in order to investigate the topic. The expert panel produced recommendation statements based on the best scientific evidence from PubMed and EMBASE Library and experts' opinions. The statements were planned and graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence. On November 10, 2023, the experts met in Mestre (Italy) to debate the statements. After the approval of the statements, the expert panel met via email and virtual meetings to prepare and revise the definitive document. This document represents the executive summary of the consensus conference and comprises three sections. The first section focuses on the general principles of diagnosis and treatment of IAIs. The second section provides twenty-three evidence-based recommendations for the antimicrobial therapy of IAIs. The third section presents eight clinical diagnostic-therapeutic pathways for the most common IAIs. The document has been endorsed by the Italian Society of Surgery.

Trauma Center model application in the University Hospital of Pisa: a single-center comparative study.

The Trauma Center, Hub, is a highly specialized hospital indicated for complex major trauma management after stabilization at a 1st level hospital, Spoke. Although in the United States this organization demonstrated its effectiveness in mortality, in the Italian context, data available are limited. On 30 September 2018, the University Hospital of Pisa formalized the introduction of the Trauma Center, optimizing Emergency Department (ED) organization to guarantee the highest standard of care. The aim of this study was to demonstrate that the new model led better outcomes. We conducted a comparative retrospective study on 1154 major traumas over 24 months: the first 12 months (576 patients) correspond to the period before Trauma Center introduction, and the following 12 (457 patients) to the subsequent period. Results showed increase in greater dynamics and primary centralization by helicopter (p < 0.001, p 0.006). A systematic assessment with ABCDE algorithm was performed in a higher number of patients in the most recent period, from 38.4% to 80.3% (p < 0.001). Focused Assessment with Sonography for Trauma (FAST) performed by the emergency doctor increased after Trauma Center introduction, p value < 0.001. The data show an increase of ATLS certification among staff from 51.9 to 71.4% and a reduction in early and late mortality after the Trauma Center introduction (p value 0.05 and < 0.01). Fewer patients required intensive and surgical treatments, with a shorter hospital stay. The results demonstrate the advantage in terms of outcomes in the organization of the Trauma Center in the Italian context.

Multi-centric study for development and validation of a CT head rule for mild traumatic brain injury in direct oral anticoagulants: the HERO-M nomogram.

BACKGROUND: Nomograms are easy-to-handle clinical tools which can help in estimating the risk of adverse outcome in certain population. This multi-center study aims to create and validate a simple and usable clinical prediction nomogram for individual risk of post-traumatic Intracranial Hemorrhage (ICH) after Mild Traumatic Brain Injury (MTBI) in patients treated with Direct Oral Anticoagulants (DOACs). METHODS: From January 1, 2016 to December 31, 2019, all patients on DOACs evaluated for an MTBI in five Italian Emergency Departments were enrolled. A training set to develop the nomogram and a test set for validation were identified. The predictive ability of the nomogram was assessed using AUROC, calibration plot, and decision curve analysis. RESULTS: Of the 1425 patients in DOACs in the study cohort, 934 (65.5%) were included in the training set and 491 (34.5%) in the test set. Overall, the rate of post-traumatic ICH was 6.9% (7.0% training and 6.9% test set). In a multivariate analysis, major trauma dynamic (OR: 2.73, p = 0.016), post-traumatic loss of consciousness (OR: 3.78, p = 0.001), post-traumatic amnesia (OR: 4.15, p < 0.001), GCS < 15 (OR: 3.00, p < 0.001), visible trauma above the clavicles (OR: 3. 44, p < 0.001), a post-traumatic headache (OR: 2.71, p = 0.032), a previous history of neurosurgery (OR: 7.40, p < 0.001), and post-traumatic vomiting (OR: 3.94, p = 0.008) were independent risk factors for ICH. The nomogram demonstrated a good ability to predict the risk of ICH (AUROC: 0.803; CI95% 0.721-0.884), and its clinical application showed a net clinical benefit always superior to performing CT on all patients. CONCLUSION: The Hemorrhage Estimate Risk in Oral anticoagulation for Mild head trauma (HERO-M) nomogram was able to predict post-traumatic ICH and can be easily applied in the Emergency Department (ED).

Comparison between Arterial Blood Gases and Oxygen Reserve Index™ in a SCUBA Diver: A Case Report.

Hypoxia and hyperoxia are both worrisome issues potentially affecting SCUBA divers, but validated methods to monitor these two conditions underwater are still lacking. In this experiment, a volunteer SCUBA diver was equipped with a pulse oximeter to detect peripheral oxygen saturation (SpO2) and a device to monitor the oxygen reserve index (ORi™). ORi™ values were compared with arterial blood oxygen saturation (SaO2) and the partial pressure of oxygen (PaO2) obtained from the cannulated right radial artery at three steps: at rest out of water; at -15 m underwater after pedaling on a submerged bike; after resurfacing. SpO2 and ORi™ mirrored the changes in SaO2 and PaO2, confirming the expected hyperoxia at depth. To confirm the potential usefulness of an integrated SpO2 and ORi™ device, further studies are needed on a broader sample with different underwater conditions and diving techniques.

Minimal is not minor also in patients with mild traumatic brain injury on oral direct anticoagulant therapy.

Currently, all patients, regardless of the type of head injury, should undergo a head computerized tomography (CT) if on oral anticoagulant therapy. The aim of the study was to assess the different incidences of intracranial hemorrhage (ICH) between patients with minor head injury (mHI) and patients with mild traumatic brain injury (MTBI) and whether there were differences in the risk of death at 30 days as a result of trauma or neurosurgery. A retrospective multicenter observational study was conducted from January 1, 2016, to February 1, 2020. All patients on DOACs therapy who suffered head trauma and underwent a head CT were extracted from the computerized databases. Patients were divided into two groups MTBI vs mHI all in DOACs treatment. Whether a difference in the incidence of post-traumatic ICH was present was investigated, and pre- and post-traumatic risk factors were compared between the two groups to assess the possible association with ICH risk by propensity score matching. 1425 with an MTBI in DOACs were enrolled. Of these, 80.1% (1141/1425) had an mHI and 19.9% (284/1425) had an MTBI. Of these, 16.5% (47/284) patients with MTBI and 3.3% (38/1141) with mHI reported post-traumatic ICH. After propensity score matching, ICH was consistently found to be more associated with patients with MTBI than with mHI (12.5% vs 5.4%, p = 0.027). Risk factors associated with immediate ICH in mHI patients were high energy impact, previous neurosurgery, trauma above the clavicles, post-traumatic vomiting and headache. Patients on MTBI (5.4%) were found to be more associated with ICH than those with mHI (0.0%, p = 0.002). also when the need for neurosurgery or death within 30 days were considered. Patients on DOACs with mHI have a lower risk of presenting with post-traumatic ICH than patients with MTBI. Furthermore, patients with mHI have a lower risk of death or neurosurgery than patients with MTBI, despite the presence of ICH.

"Decision tree analysis for assessing the risk of post-traumatic haemorrhage after mild traumatic brain injury in patients on oral anticoagulant therapy".

BACKGROUND: The presence of oral anticoagulant therapy (OAT) alone, regardless of patient condition, is an indication for CT imaging in patients with mild traumatic brain injury (MTBI). Currently, no specific clinical decision rules are available for OAT patients. The aim of the study was to identify which clinical risk factors easily identifiable at first ED evaluation may be associated with an increased risk of post-traumatic intracranial haemorrhage (ICH) in OAT patients who suffered an MTBI. METHODS: Three thousand fifty-four patients in OAT with MTBI from four Italian centers were retrospectively considered. A decision tree analysis using the classification and regression tree (CART) method was conducted to evaluate both the pre- and post-traumatic clinical risk factors most associated with the presence of post-traumatic ICH after MTBI and their possible role in determining the patient's risk. The decision tree analysis used all clinical risk factors identified at the first ED evaluation as input predictor variables. RESULTS: ICH following MTBI was present in 9.5% of patients (290/3054). The CART model created a decision tree using 5 risk factors, post-traumatic amnesia, post-traumatic transitory loss of consciousness, greater trauma dynamic, GCS less than 15, evidence of trauma above the clavicles, capable of stratifying patients into different increasing levels of ICH risk (from 2.5 to 61.4%). The absence of concussion and neurological alteration at admission appears to significantly reduce the possible presence of ICH. CONCLUSIONS: The machine-learning-based CART model identified distinct prognostic groups of patients with distinct outcomes according to on clinical risk factors. Decision trees can be useful as guidance in patient selection and risk stratification of patients in OAT with MTBI.

Risk of delayed intracranial haemorrhage after an initial negative CT in patients on DOACs with mild traumatic brain injury.

BACKGROUND: Repeat head CT in patients on direct oral anticoagulant therapy (DOACs) with minor traumatic brain injury (MTBI) after an initial CT scan without injury on arrival in the Emergency Department (ED) is a common clinical practice but is not based on clear evidence. AIM: To assess the incidence of delayed intracranial haemorrhage (ICH) in patients taking DOACs after an initial negative CT and the association of clinical and risk factors presented on patient arrival in the ED. METHODS: This retrospective multicentre observational study considered patients taking DOACs undergoing repeat CT after a first CT free of injury for the exclusion of delayed ICH after MTBI. Timing between trauma and first CT in the ED and pre- or post-trauma risk factors were analysed to assess a possible association with the risk of delayed ICH. RESULTS: A total of 1426 patients taking DOACs were evaluated in the ED for an MTBI. Of these, 68.3% (916/1426) underwent a repeat CT after an initial negative CT and 24 h of observation, with a rate of delayed ICH of 1.5% (14/916). Risk factors associated with the presence of a delayed ICH were post-traumatic loss of consciousness, post-traumatic amnesia and the presence of a risk factor when the patient presented to the ED within 8 h of the trauma. None of the patients with delayed ICH at 24-h repeat CT required neurosurgery or died within 30 days. CONCLUSIONS: Delayed ICH is an uncommon event at the 24-h control CT and does not affect patient outcome. Studying the timing and characteristics of the trauma may indicate patients who may benefit from more in-depth management.

Predictors of post-traumatic complication of mild brain injury in anticoagulated patients: DOACs are safer than VKAs.

Although mild traumatic brain injury (MTBI) in people on oral anticoagulant treatment (OAT) is a frequent challenge for Emergency Department (ED), strong guidelines recommendations are lacking. In the attempt to assess the safety profile of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs), we have recruited 473 patients with a MTBI on OAT (43.6% males; age 81.8 ± 8.7 years), admitted to the Pisa's University Hospital ED (Jan 2016-Oct 2018). All patients underwent a head CT scan with those with no sign of acute bleedings remaining under clinical observation for the ensuing 24 h. Fifty patients (10.6%, 95% CI: 8.1-13.7%) had immediate intracranial hemorrhage (ICH), with a prevalence of patient-important outcomes due to immediate ICH of 1.1% (95% CI 0.4-2.4%); 3 patients died (0.6%, 95% CI 0.2-1.8) and 2 required neurosurgical intervention. Immediate ICHs were more frequent in VKA-treated than in DOAC-treated patients (15.9 vs. 6.4%. RR 2.5. 95%CI 1.4-4.4. p < 0.05). Multivariate analysis identified that post-traumatic amnesia, evidence of trauma above clavicles, high blood glucose, high blood pressure (BP) at arrival, and low prothrombin activity were predictors of immediate ICH. The prevalence of delayed ICH was 1.0% (95%CI 0.4-2.5%) without differences between DOACs and VKAs. Despite ICH being a frequent complication of MTBI in patients on OAT, immediate and delayed patient-important outcomes are rare. DOACs have a better safety profile than VKAs. Simple clinical parameters such as blood pressure at arrival or blood glucose might provide useful predictors of immediate ICH.Trial registration number: 11924_CIPRIANO. Local ethics committee approval number 33096.

Ophthalmological emergencies and the SARS-CoV-2 outbreak.

Since the end of 2019, an outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), originating in the Chinese city of Wuhan has spread rapidly worldwide causing thousands of deaths. Coronavirus disease (COVID-19) is supported by SARS-CoV-2 and represents the causative agent of a potentially fatal disease that is of great global public health concern. Italy has been the first European country recording an elevated number of infected forcing the Italian Government to call for total lockdown. The lockdown had the aim to limit the spread of infection through social distancing. The purpose of this study is to analyze how the pandemic has affected the patient's accesses to the Ophthalmological Emergency Department of a tertiary referral center in central-northern Italy, during the lockdown period. The charts of all patients that came to the Emergency Department during the lockdown period (March 10 -May 4, 2020) have been retrospectively collected and compared with those in the same period of 2019 and the period from 15 January- 9 March 2020. A significant reduction of visits during the lockdown has been observed, compared with those of pre-lockdown period (reduction of 65.4%) and with those of the same period of 2019 (reduction of 74.3%). Particularly, during the lockdown, minor and not urgency visits decreased whereas the undeferrable urgency ones increased. These pieces of evidence could be explained by the fear of patients to be infected; but also revealed patients misuse of emergency services.

Safe chest tube placement in a patient with tension pneumothorax receiving rivaroxaban therapy for non-valvular atrial fibrillation.

The number of patients treated with direct oral anticoagulants is increasing worldwide. Although bleeding complications associated with direct oral anticoagulants are lower than those associated with vitamin K antagonists, the increased number of patients treated with these anticoagulants suggests that a higher absolute number of patients are at risk. Tube thoracostomy is an invasive procedure with a high risk of bleeding. To date, among direct oral anticoagulants, only dabigatran has a well-studied antidote to reverse its effects during emergency procedure or surgery. This report describes a case in which emergency placement of a tube thoracostomy, in a patient with type 2 respiratory failure due to left tension pneumothorax and receiving the anticoagulant rivaroxaban, in the pharmacokinetics phase with greater anticoagulant effect, did not result in bleeding greater than that typically encountered during such interventions. The procedure ended successfully with no acute complications.

Spontaneous bleeding of the inferior pancreatic-duodenal artery in median arcuate ligament syndrome: do not miss the diagnosis.

Median arcuate ligament syndrome (MALS) is a rare condition in which the median arcuate ligament (MAL) causes compression of the coeliac trunk. The chronic compression leads to coeliac trunk luminal narrowing and reduced blood supply to the abdominal splanchnic organs with possible local complications such as pseudo-aneurysms and spontaneous bleeding. Its incidence is probably underestimated due to the poor availability of color Doppler ultrasonography (CD-US), especially in an Emergency Department (ED) setting. A 44-year old woman presented to Pisa University Hospital ED with acute abdominal pain. An abdominal ultrasonography scan (US scan) was performed showing the presence of free liquid in the Douglas pouch. The abdominal computed tomography scan (CT scan) highlighted the presence of a large mesenteric hematoma. A CD-US revealed a significant stenosis of the coeliac artery. A selective angiography confirmed the diagnosis of MALS with a pseudo-aneurysm of the inferior pancreatic-duodenal artery, which was successfully embolized.

Nutritional status of Ugandan school-children: The effect of age imprecision.

OBJECTIVES: To analyze the nutritional status of Ugandan school-children in a cross-sectional and longitudinal perspective, considering the effect of age imprecision. MATERIALS AND METHODS: Anthropometric measurements of 831 school-children (381 males and 450 females) were analyzed. A subsample of 246 children was measured in July 2014 and 2015. Stunting (based on height-for-age Z-scores), underweight (weight-for-age), and thinness (body mass index-for-age) prevalence were calculated. Three different ages were used: declared (from schools registers), attributed (based on multiple information sources), and bootstrap (from 10,000 replicates). Significant differences among malnutrition prevalence calculated with different ages and in different groups were assessed by means of bootstrap analysis. Longitudinal analysis was conducted using a paired t test. RESULTS: The mean prevalence of malnutrition calculated with declared, attributed, or bootstrap ages were very similar: stunting (11.9-12.7); underweight (5.4-5.9); thinness (3.3-3.7); and obesity (0.7). Undernutrition was more prevalent among older children, while obesity was mostly associated with young age. Obesity was equally distributed among sexes, while undernutrition was more prevalent among females of up to 10 years of age and males above 10 years. The longitudinal analysis indicated a reduction in underweight and thinness, and an increase in stunting, especially among older children. DISCUSSION: Age imprecision did not significantly affect malnutrition estimates. Despite the decline in the prevalence of thinness and underweight observed over a 1-year period, undernutrition persists, with an observed rise in stunting. On the other hand, obesity is starting to appear. Public health efforts are required to eliminate stunting and address the emerging burden of obesity.

Intracranial hemorrhage in anticoagulated patients with mild traumatic brain injury: significant differences between direct oral anticoagulants and vitamin K antagonists.

Prognosis after mild traumatic brain injury (MTBI) on oral anticoagulant therapy (OAT) is uncertain. We evaluated the rate of immediate and delayed traumatic intracranial hemorrhage (ICH) comparing vitamin K antagonists (VKAs) to direct oral anticoagulants (DOACs) and the safety of a clinical management protocol. In this single-center prospective observational study, we enrolled 220 patients on OAT with MTBI. After a first negative CT scan, asymptomatic patients underwent a close neurological observation; if neurologically stable, they were discharged without a second CT scan and followed up for 1 month. Out of the 220 patients, 206 met the inclusion criteria. 23 of them (11.2%) had a positive first CT scan for ICH. Only 1 (0.5%, 95% CI 0.0-1.4%) died because of ICH; no one required neurosurgical intervention. The observed prevalence rate of immediate ICH resulted statistically higher in VKAs-treated patients compared to those treated with DOACs (15.7 vs. 4.7%, RR 3.34, 95% CI 1.18-9.46, P < 0.05). In the 1-month follow-up, 5 out of the 183 patients with a negative CT scan were lost. Out of the remaining 178 patients, only 3 showed a delayed ICH (1.7%, 95% CI 0.0-3.6%), 1 of them died (0.6%, 95% CI 0.5-1.7%) and the others did not require neurosurgical intervention. DOACs resulted safer than VKAs also in the setting of MTBI. In our observation, the rate of delayed hemorrhage was relatively low. Patients presenting with a negative first CT scan and without neurological deterioration could be safely discharged after a short period of in-ward observation with a low rate of complications and without a second CT scan.

Cross-sectional and longitudinal analysis of nutritional status of school-children from Bumbire Island (United Republic of Tanzania).

OBJECTIVE: To analyze the nutritional status of schoolchildren from Bumbire Island (Tanzania) from cross-sectional and longitudinal perspectives. METHODS: During 2014 and 2015, we collected anthropometric measurements in a sample of 437 schoolchildren (226 males, 211 females; 5-16 years). A sub-sample of 126 children were measured in both surveys. Socio-demographic data have been taken and dietary habits investigated. The accuracy of age data was checked. Malnutrition prevalence was calculated according to the WHO references and the z-score criteria. RESULTS: The prevalence of undernutrition was high (stunting: 30.7%; underweight: 12.9%; thinness: 4.5%), while overweight was rare (2.4%). The prevalence of stunting was higher in males and in older children. The one-year longitudinal analysis indicated that stunting prevalence increased. CONCLUSIONS: Undernutrition is affecting Bumbire Island children, likely due to micronutrient deficiencies. The effects of linear growth deficit continue to accumulate throughout childhood and adolescent years.

[Marcato aumento delle concentrazioni di procalcitonina dopo idroclorotiazide-edema polmonare indotta.]

INTRODUCTION: In the Medline database there are approximately 60 cases reporting toxic pulmonary edema, a life-threatening event, induced after consumption of hydrochlorothiazide, one of the most common antihypertensive drugs. Moreover, increased procalcitonin concentrations have been reported after cardiogenic pulmonary edema. We report the rare case of a hydrochlorothiazide-induced pulmonary edema, which was followed by a marked increase of the procalcitonin concentrations. CLINICAL CASE: A middle-aged woman was admitted to the Emergency Department for severe dyspnea and chills. Such symptoms began 30 minutes after consumption of hydrochlorothiazide. Her physical examination and chest-X-ray were compatible with pulmonary edema, however her brain natriuretic peptide levels and echocardiogram were almost normal. Interestingly she had extremely elevated procalcitonin concentrations with normal white blood cells count and C-reactive protein levels only mildly increased. We hypothesized toxic pulmonary edema and started treatment with non-invasive mechanical ventilation, with the patient presenting rapid clinical improvement. CONCLUSIONS: Even if extremely rare, hydrochlorothiazide may induce pulmonary edema; significant increase of procalcitonin concentrations may occur in this condition and perhaps in other cases of toxic pulmonary edema. Practitioners should be aware of this condition in order to spare expensive and useless, in this case, investigations such as blood cultures and treatments (antibiotics) if other signs of infection are absent.

Nitric oxide modulates tissue plasminogen activator release in normotensive subjects and hypertensive patients.

We evaluated the possible role of NO in modulating tissue plasminogen activator (t-PA) release in the forearm microcirculation of normotensive subjects and hypertensive patients. Essential hypertensive patients are characterized by endothelial dysfunction because of a reduced NO availability and also show an impaired t-PA release. In healthy volunteers and essential hypertensive patients, we studied local t-PA release and forearm blood flow changes (strain-gauge plethysmography) induced by intrabrachial administration of acetylcholine (0.45 and 1.5 microg/100 mL/min) and of sodium nitroprusside (0.5 and 1.0 microg/100 mL/min), an endothelium-dependent and -independent agonist, respectively. Acetylcholine was also repeated in the presence of intra-arterial infusion of the NO synthase inhibitor N(G)-monomethyl-l-arginine (100 microg/100 mL/min). In normotensive subjects, vasodilation to acetylcholine was blunted by N(G)-monomethyl-l-arginine. In these subjects, acetylcholine infusion induced a significant, dose-dependent increase in net forearm t-PA release. N(G)-monomethyl-l-arginine significantly reduced basal t-PA release, as well as acetylcholine-induced t-PA release. In essential hypertensive patients, vasodilation to acetylcholine was reduced as compared with controls and resistant to N(G)-monomethyl-l-arginine. In contrast to what was observed in healthy control subjects, in hypertensive patients, acetylcholine had no effect on t-PA release. Similarly, N(G)-monomethyl-l-arginine failed to modify either the tonic or the agonist-induced t-PA release. Both tonic and agonist-induced release of NO are directly involved in t-PA release by endothelial cells. Essential hypertension, characterized by a reduction in tonic and stimulated NO availability, is also associated with impaired capacity of t-PA release, suggesting a major role of impaired NO availability in worsening both vasodilation and t-PA release.

Therapeutic implications of recent megatrials: in favor of old drugs.

Data from controlled clinical studies comparing active drugs versus placebo or comparing different classes of drugs and their meta-analysis seem to indicate that although more subtle differences in the effects of various antihypertensive drugs cannot be ruled out, the protective effects against cardiovascular morbidity and mortality of all classes of drugs, including conventional therapy based on diuretics and beta-blockers and their combination, are largely explained by the extent of blood pressure (BP) reduction. Therefore BP control is still the main target of antihypertensive therapy. The benefits of diuretics have been well documented, particularly when these drugs are used at appropriate and/or optimal doses to achieve the optimal antihypertensive effect with the least occurrence of side effects, including negative metabolic effects. Therefore they must still be included among first line antihypertensive drugs. By contrast, beta-blockers seem recently to have lost their previously favored status as initial therapy for hypertension owing to their lower preventive effects against cardiovascular events as compared with diuretics in elderly hypertensive patients and against stroke as compared with other treatments, and to their negative metabolic effects. However, although evidence-based data must be taken into account, the choice of antihypertensive therapy aimed at BP control in individual patients must be made according to clinical characteristics. We believe that a wide range of choices among various antihypertensive drugs, above all diuretics and also beta-blockers, offers an appropriate possibility of selecting the right drug and the right combinations according to the clinical profile of the individual patient.

Identification of a cytochrome P450 2C9-derived endothelium-derived hyperpolarizing factor in essential hypertensive patients.

OBJECTIVES: We assessed the role of cytochrome P450 2C9 (CYP 2C9)-derived endothelium-derived hyperpolarizing factor (EDHF) in the forearm microcirculation of essential hypertensive patients (EH) by utilizing sulfaphenazole (SUL), a selective CYP 2C9 inhibitor. BACKGROUND: In EH patients, EDHF acts as a compensatory pathway when nitric oxide (NO) availability is reduced. Cytochrome P450 2C9 is a possible source of EDHF. METHODS: In 36 healthy subjects (normotensive [NT]) and 32 hypertensive patients (HT), we studied forearm blood flow (strain-gauge plethysmography) changes induced by intraarterial acetylcholine (ACH) and bradykinin (BDK), repeated during N(G)-monomethyl-L-arginine (L-NMMA) (100 mug/100 ml/min) or SUL (0.03 mg/100 ml/min). In HT, the effect of SUL on ACH and BDK was repeated during vitamin C (8 mg/100 ml/min). Sodium nitroprusside (SNP) was utilized as control. RESULTS: In NT, vasodilation to ACH and BDK was blunted by L-NMMA and not changed by SUL. In contrast, in HT responses to ACH and BDK, reduced compared with NT, were resistant to L-NMMA. In these patients, SUL blunted vasodilation to ACH and to a greater extent the response to BDK. When retested with vitamin C, SUL was no longer effective on both endothelial agonists. In 2 final groups of normotensive control subjects, vasodilation to ACH or BDK residual to cyclooxygenase and L-NMMA blockade was further inhibited by simultaneous SUL infusion. Response to SNP, similar between NT and HT, was unaffected by SUL. CONCLUSIONS: Cytochrome P450 epoxygenase-derived EDHF acts as a partial compensatory mechanism to sustain endothelium-dependent vasodilation in HT, particularly the BDK-mediated response, when NO activity is impaired because of oxidative stress.