Long-term clinical outcomes in critical limb ischemia--A retrospective study of 181 patients.

OBJECTIVE: Critical limb ischemia (CLI) is the most severe manifestation of the peripheral arterial disease. To date, several prognostic factors have been identified but the data of long-term follow-up in real life setting are scarce. The aim of our study is to describe a large group of CLI patients and identify possible prognostic factors, in a long-term follow-up. PATIENTS AND METHODS: Case-control, retrospective study. 181 consecutive CLI patients with a minimum follow-up of 5 years were included in the study. RESULTS: Overall mortality was 15%, 24%, and 43% at 1, 2, and 5 years, respectively. Among known risk factors, only arterial hypertension was significantly correlated with survival rate; no differences were found between diabetics and non-diabetics. Patients treated with intravenous iloprost (46%), compared to untreated patients, showed a better (p < 0.0001) long-term outcome in terms of major amputation (6% vs. 21%), subsequent vascular surgery (4% vs. 32%) and survival rates (69% vs. 47%), at 5-year follow-up. Major amputations were significantly correlated with lower median forefoot transcutaneous values of O2 (0/3 mmHg, p < 0.001) and higher median values of CO2 (83/53 mmHg, p < 0.0001) in supine/dependent position, respectively. CONCLUSIONS: Our results confirm the poor prognosis of CLI patients in a very long-term follow-up and the severe metabolic damage caused by ischemia. A favourable role of iloprost was observed, in agreement with previous evidence in the literature.

Long-term survival of patients with critical limb ischemia treated with iloprost: response rate and predictive criteria. A retrospective analysis of 102 patients.

OBJECTIVE: Critical limb ischemia (CLI) patients have poor long-term prognosis. We showed that iloprost improves outcomes (major amputation and survival) up a 5-year follow-up, but it is not known if in this length of time the survival curves, of clinical responders and non-responders, differ. PATIENTS AND METHODS: A retrospective study enrolling 102 consecutive patients between 2004-2008, with clinical and instrumental (ultrasound, angiography, transcutaneous tensiometry of oxygen TcpO2 and carbon dioxide TcpCO2 in the affected and contralateral limbs) diagnosis of critical ischemia. All patients received the best medical therapy. Iloprost was administered (0.5-2 ng/kg/min 6 hours/day for 2-4 weeks) in all patients initially considered unsuitable for revascularization, repeating it regularly in time every six-twelve months in the case of positive response. The minimum expected follow-up was 4 years. RESULTS: 71.5% of patients were treated with iloprost and the responder rate was 71.2%. Most of the patients were regularly retreated with repeated cycles. Initial median supine TcpCO2 in symptomatic limb was higher in untreated patients than those treated (58 vs. 49 mmHg; p < 0.05) and in non-responders compared to responders (60 vs. 49 mmHg; p < 0.05). TcpCO2 directly and significantly correlated with the highest risk of mortality and seems to represent a new accurate prognostic criterion of unfavourable short and long-term response to prostanoid. In iloprost group, major amputations were significantly reduced. Revascularization was significantly higher in non-responders (57.1% vs. 11.5%; p < 0.05). There was a significantly higher prevalence of subsequent myocardial infarction in the non-iloprost group (27.6% vs. 9.6%; p < 0.05). The survival rate of non-responders was higher than untreated up until the second year (76.2% vs. 62%; p < 0.05). At 4 years we found higher survival in patients treated with iloprost (64.3% vs. 41% in untreated; p < 0.05) and in responders (75% vs. 38.1% in non-responders; p < 0.05). CONCLUSIONS: Our results confirm the favourable role of iloprost on the long-term outcome in patients with CLI. In particular, the maximum benefit is obtained in responder patients treated with multiple cycles of infusion.

Randomized, single blind, controlled trial of inhaled glutathione vs placebo in patients with cystic fibrosis.

BACKGROUND: In cystic fibrosis (CF) the defective CF transmembrane conductance regulator protein may be responsible for the impaired transport of glutathione (GSH), the first line defense of the lung against oxidative stress. The aim of this single-blind, randomized, placebo-controlled trial was to evaluate the effect of inhaled GSH in patients with CF. METHODS: 54 adult and 51 pediatric patients were randomized to receive inhaled GSH or placebo twice daily for 12 months. RESULTS: Twelve month treatment with inhaled GSH did not achieve our predetermined primary outcome measure of 15% improvement in FEV1%. Only in patients with moderate lung disease, 3, 6 and 9 months therapy with GSH resulted in a statistically significant increase of FEV1 values from the baseline. Moreover GSH therapy improved 6-minute walking test in pediatric population. GSH was well tolerated by all patients. CONCLUSIONS: Inhaled GSH has slight positive effects in CF patients with moderate lung disease warranting further study. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01450267; URL: www.clinicaltrialsgov.

The slide rule: a new method for the assessment of acid-base equilibrium disorders.

AIM: Maps and nomograms are routinely used to evaluate acid-base equilibrium (ABE), but often require previous skilled practice and time to be used in the clinical setting; moreover, some definite alterations may be missed. The aim of this study was to evaluate the new slide rule (patented by Authors) for the rapid, precise and complete assessment and diagnosis of altered blood gas analysis (ABG) parameters and compare it to traditional methods. METHODS: Once pH, bicarbonate and PaCO(2) values are known by arterial blood gas analysis (ABG), the slide rule can calculate, show and instantly diagnose the related alteration, including possible mixed partial compensated ones. In this regard, 330 patients coming from 6 (4 national and 2 foreign) clinics were studied; each patient underwent evaluation of ABG alterations using traditional methods and the slide rule immediately thereafter. RESULTS: The results of consecutive evaluations on involved patients made by specialists in all clinics were in agreement; nonetheless, the slide rule was far more user friendly, rapid and complete in the ABE alterations' diagnostic range, in comparison with traditional methods. CONCLUSION: All involved specialists confirmed that the new slide rule was able to rapidly diagnose ABE alterations, including mixed or partially compensated ones that may be missed by traditional methods.

Is transcutaneous oxygen and carbon dioxide monitoring indispensable in short- and long-term therapeutic management of non-reconstructable lower critical limb ischemia?

AIM: The aim of this study was to evaluate the capacity of transcutaneous partial pressure of O(2) (TCpO(2)) and CO(2) (TCpCO(2)) to predict clinical response to pharmacological treatment in short- and long-term follow-up of unreconstructable critical limb ischemia (CLI) treated with prostanoids; to suggest a diagnostic and therapeutic algorithm able to define the possibility of prostanoid therapy in unreconstructable CLI at high risk of limb loss. METHODS: Twenty-six consecutive patients with CLI (21 with distal trophic lesions, 31 symptomatic limbs) considered unreconstructable after peripheral angiography and with a history of type 2 diabetes mellitus underwent daily parenteral Iloprost treatment for 2-3 weeks. RESULTS: Transcutaneous gas-analytic monitoring (TGM) in non-reconstructable CLI treated with Iloprost divided patients into 2 groups: early responders (ER) with increased TcpO(2) and normalization of TcpCO2, and non responders (NR) with unchanged TcpO(2) and TcpCO(2) parameters. In the NR who underwent a second cycle of Iloprost within a few months of the first, TGM further divided the patients into another subgroup of late responders (LR) with TcpO(2) and TcpCO(2) similar to the ER group and a subgroup of NR, who, after pharmacological treatment failure, should undergo eventual surgical re-timing and/or spinal cord stimulation in a final attempt to save the limb. CONCLUSIONS: In the short-term follow-up of CLI, a marked reduction in supine/dependent TcpO(2) and a marked increase in supine TcpCO(2) at the symptomatic forefoot proved to be significant predictors of major amputation risk. In the long-term follow-up period, TGM showed that, in ER and in LR, the favourable effect of pharmacological therapy observed in the first 6 months will disappear over the next 6 months, suggesting an algorithm of 2- to 3-week cycles of prostanoid therapy repeated every year. In NR treated with surgical and/or alternative therapies who did not undergo major amputations, prolonged instrumental TGM will provide a constant evaluation of metabolic parameters, thus providing the possibility to save the limb with additional pharmacological therapy.

A review of microvascular measurements in wound healing.

The microcirculatory evaluation in patients affected by arteriopathic or venous ulcers is usually carried out using laser Doppler flowmetry, transcutaneous oxygen (transcutaneous pressure of oxygen, TcPO(2)), and carbon dioxide (transcutaneous pressure of carbon dioxide, TcPCO(2)) measurements and capillaroscopy. These techniques provide significant pathophysiologic and prognostic information. TcPO(2) and TcPCO(2) diagnose and classify the extent of arterial disease in the leg ulcers caused by arterial disease; the prognostic value is recognized, though doubts about its prognostic potential exist in the case of leg ulcer. Laser Doppler flowmetry is able to identify the first functional impairment in the early stages of the arterial disease and in the complicated venous insufficiency. Capillaroscopy gives us morphological and quantitative parameters of the capillary bed that is damaged in arteriopathic and venous ulcers; nevertheless, it does not provide us with definite prognostic indexes. Combining the 3 methods may contribute to yield objective measures in the clinical management of lower extremity ulcers.

Difficult airway management of a child impaled through the neck.

We report the difficult airway management of a child impaled through the neck by a wooden plant support. The various options are discussed and the involvement of experienced personnel together with a clear preformulated plan of action is stressed.

Amlodipine, enalapril, and dependent leg edema in essential hypertension.

Calcium channel blockers (CCBs) blunt postural skin vasoconstriction, an autoregulatory mechanism that minimizes gravitational increases in capillary pressure and avoids fluid extravasation when standing. To evaluate the dose-response relation between this pharmacological interference and dependent edema, a frequent side effect of CCBs during antihypertensive treatment, skin blood flow (laser Doppler flowmetry) at the dorsum of the foot, both supine and with the limb passively placed 50 cm below the heart level, and leg weight (Archimedes principle) were measured at baseline, during increasing doses of the dihydropyridine amlodipine (5 and 10 mg UID each for 2 weeks), and after drug withdrawal in 10 hypertensive men. Because angiotensin-converting enzyme inhibitors may attenuate ankle swelling by CCBs, those parameters were evaluated according to a similar design during amlodipine (10 mg UID) and enalapril (20 mg UID) combined (n=10). As a control, the effect of enalapril monotherapy (10 and 20 mg UID for 2 weeks each) was evaluated in a third series of patients (n=8). Amlodipine (5 mg UID) increased leg weight without modifying postural vasoconstriction (the percent skin blood flow decrease from horizontal to dependent position), which indicates that extravascular fluid shift was independent of postural skin vasoconstriction. At 10 mg UID, however, amlodipine blunted postural vasoconstriction and increased leg weight further, which suggests that skin blood flow autoregulation limited additional fluid transfer. Both parameters normalized after drug withdrawal. Enalapril per se did not affect cutaneous vasomotion or leg weight but reduced the amount of dependent fluid extravasation by the CCB despite a persistent antagonism for postural vasoconstrictor responses.

Eosinophilic inflammation in stable chronic obstructive pulmonary disease. Relationship with neutrophils and airway function.

The number and significance of airway eosinophils in stable COPD is controversial. Aims of this study were to evaluate airway inflammation in patients with stable COPD compared with other groups, and to examine the correlations between inflammatory markers and functional indices of airway obstruction. Cellular analysis and evaluation of eosinophil cationic protein (ECP) levels in induced sputum were made in 46 subjects (10 patients with clinically stable COPD, 15 patients with asthma, 11 asymptomatic smokers, and 10 healthy control subjects). As expected, eosinophils were significantly (p < 0.01) higher in patients with asthma (22.2%) than in other groups (COPD, 0.7%; smokers, 0.2%; control subjects, 0.2%), and neutrophils were significantly (p < 0.01) higher in patients with COPD (77.5%) than in the other groups (asthma, 26.7%; smokers, 33.1%; control subjects, 35.9%). However, eosinophils were also increased in patients with COPD, as compared with healthy controls (p < 0.05). Sputum ECP levels were significantly and similarly higher in both asthma and COPD groups than in the other two groups (p < 0.01). In patients with COPD and asymptomatic smokers, considered as a whole, good correlations were found between eosinophils and ECP, on the one hand, and between FEV(1) and the FEV(1)/FVC ratio, on the other. Our data suggest that eosinophils may be involved in the airway inflammation of COPD.

Acetylcholine-mediated vasodilatation and tissue-type plasminogen activator release in normal and hypertensive men.

Muscarinic agents release tissue plasminogen activator (t-PA) in the forearm circulation of normal subjects, but no information exists about their effect in those hypertensive patients in whom the response to endothelial-mediated vasodilators is blunted. Acetylcholine, an endothelium-dependent vasodilator and a muscarinic agonist that releases t-PA from in-vitro systems, and sodium nitroprusside, an endothelium-independent vasodilator, were infused into the brachial artery at rates calculated to cause a similar degree of vasodilatation. The study was performed in five elderly, smoking hypertensive patients in whom the clustering of detrimental factors for endothelial function permitted prediction of defective endothelial-mediated vasorelaxation, and five young, normotensive, nonsmoking male volunteers. Forearm blood flow was assessed by venous plethysmography; t-PA and plasminogen activator inhibitor 1 (PAI-1) antigen values were expressed as flow-dependent (net release, the product of venoarterial concentration gradient and forearm blood flow) or independent (absolute and fractional concentration gradients) indices. In patients, acetylcholine did not change flow and net release and concentration gradients of t-PA, suggesting that vasodilatation as such, possibly by increasing fluid shear stress, may induce t-PA release in human forearm. In normal subjects, acetylcholine and sodium nitroprusside increased t-PA antigen net release at the highest infusion rate, an effect attributable to forearm hyperperfusion, since absolute and fractional gradients did not change significantly. PAI-1 antigen did not change during either infusion in both controls and patients, indicating the absence of an endothelial pool to be mobilized acutely.

Fibrinogen and mortality in chronic critical limb ischaemia.

OBJECTIVE: Plasma fibrinogen predicts cardiovascular events in patients with stable peripheral arterial occlusive disease, but its predictive value in patients with chronic critical limb ischaemia, a condition associated with a high risk of death, is unknown. DESIGN: A prospective cohort study. SETTING: Determination of fibrinogen and other potential predictors during clinic-based work-up of patients admitted for diagnostic and therapeutic evaluation. SUBJECTS: A total of 108 patients (72 +/- 10 years, 78 males) with atherosclerotic occlusive disease and critical limb ischaemia (pain at rest and/or trophic lesions) followed up for a median period of 1.6 years). (range: 8 days-5.5 years; 218 patient-years). MAIN OUTCOME MEASURES: Total mortality. RESULTS: Forty-five deaths (71% cardiovascular) occurred during the follow-up. Baseline fibrinogen was higher in those who died in the early follow-up period (first 6 months), as were white cell count and serum creatinine, while haematocrit was lower. Plasma fibrinogen values correlated positively with white cell count, and negatively with haematocrit; other cardiovascular prognostic factors did not differ. Only plasma fibrinogen predicted survival independently in multivariate age-corrected Cox regression analysis. Relative risk of death doubled for each standard deviation above the mean and increased with each tertile increase in fibrinogen. CONCLUSIONS: Fibrinogen predicted death in these elderly arteriopaths with critical limb ischaemia, particularly those who died in the first months following critical ischaemia. Inflammatory stimuli secondary to severely defective tissue oxygenation and possibly sepsis and necrosis, might have stimulated fibrinogen, an acute-phase reactant, thereby compromising organ perfusion through increased blood viscosity and/or promoting thrombosis.

Ultrasonic nebulization of hypertonic solution: a new method for obtaining specimens from nasal mucosa for morphologic and biochemical analysis in allergic rhinitis.

Various techniques are used to collect specimens from the nasal mucosa for morphologic and biochemical analysis. The purpose of this study was to devise a method that overcomes some of the disadvantages (e.g., invasive procedure, samples not suitable for cytologic and biochemical analysis, lack of standardization, and poor reproducibility) of these techniques. The new method requires subjects, with neck extended, to inhale an ultrasonic nebulization of a hypertonic (3% NaCl) solution (UNHS) for 5 min. They then blow their nose into a Petri dish, one nostril at a time with the other one blocked. The secretions are dispersed with 0.1% dithiothreitol in phosphate buffer solution for 20 min. Total cell count (TCC) is evaluated, and the cellular suspension is divided into two aliquots: one is centrifuged and the supernatants are collected for eosinophil cationic protein (ECP) measurements; the other is cytocentrifuged and the slides, stained with Diff-Quik, are used for differential cell count. The results obtained with the UNHS and nasal lavage (NL) methods were compared. Eleven nonatopic healthy subjects and 19 allergic rhinitic patients were studied. Total cell count (x10(5)) was significantly higher with UNHS than with NL (13.0+/-12.3 vs 1.9+/-1.6; P<0.01) The differential cell count was similar with the two procedures. ECP levels (microg/l) were higher with UNHS than with NL (39.1+/-38.2 vs 16.7+/-41.2; P<0.01). For evaluation of reproducibility, four healthy and six rhinitic subjects underwent UNHS on two occasions within 5 days, and the results of two samples (sample 1 vs sample 2) were analyzed. Reproducibility was good as to TCC, differential cell count, and ECP.

Guillain-Barré syndrome: rehabilitation outcome and recent developments.

Guillain-Barré syndrome is the most common polyneuropathy causing major disability and respiratory failure. Respiratory complications are the main cause of death. Improved respiratory care and new treatment strategies such as plasmaphoresis and immunoglobulin have been shown to improve outcome. We studied the course and outcome of 37 patients with Guillain-Barré syndrome who were admitted to a rehabilitation and respiratory care facility over a 10-year period. There were 21 males and 16 females with a mean age of 62+/-3 years. Fourteen patients developed respiratory failure requiring endotracheal intubation and mechanical ventilation. The mean duration of mechanical ventilation was 38+/-10 days. All patients were successfully liberated from the ventilator. However, 83 percent of the patients were moderately to severely disabled at the time of discharge. Thirteen out of 37 (35 percent) developed long-term disability. None of the patients died over the period of follow-up. These results indicate that early recognition and treatment of respiratory complications in Guillain-Barré syndrome could reduce the morbidity and mortality of this condition.

Calcium channel blockers blunt postural cutaneous vasoconstriction in hypertensive patients.

The aim of this work was to test whether calcium channel blockers interfere with skin vasoconstrictor reflexes that minimize postural increases in capillary pressure and avoid fluid extravasation and eventually subcutaneous edema. Studies were conducted in 23 untreated mild to moderate essential hypertensives; drugs, either calcium channel blockers or not, were given for 2 weeks according to a crossover, sequence-randomized design. Skin blood flow was measured by laser Doppler flowmetry in two skin areas: (1) the dorsum of the foot, where arteriovenous anastomoses are poorly represented, and (2) the plantar surface of the great toe, where those anastomoses are predominant. Determinations were obtained both with the foot at heart level and with it placed passively 50 cm below the heart level; percent flow changes from the horizontal to the dependent position were the measure of postural vasoconstriction. Two dihydropyridine derivatives, amlodipine (10 mg UID) and nifedipine (60 mg UID), and verapamil (240 mg BID), a chemically unrelated compound, diminished to similar extents the postural fall in skin blood flow at the dorsum of the foot. Blockade of alpha1-adrenergic and AT-1 subtype angiotensin II receptors by doxazosin (4 mg UID) and losartan (50 mg UID), respectively, exerted no effect. Postural skin blood flow responses at the plantar surface of the great toe were unmodified during the pharmacological trials. Thus, calcium channel blockers of different chemical origins antagonized postural skin vasoconstriction at the dorsum of the foot. The data indicate altered postural capillary blood flow regulation, since arteriovenous anastomoses are anatomically absent at this site; the effect was independent of either alpha1-adrenoceptor or angiotensin II receptor antagonism. Interference with skin postural vasoconstrictor mechanisms may result in net filtration of fluid to the extravascular compartment. This mechanism might explain the as yet unknown pathogenesis of ankle edema during treatment with calcium antagonists.

Drugs by inhalatory route: an overview and upcoming clinical perspectives.

The physical properties of aerosols are reviewed. The physiological basis of inhalation therapy is then briefly reviewed together with the aerosol devices currently available and the therapeutic uses of inhaled drugs, focusing on the treatment of parenchymal lung diseases and extra respiratory disorders. Finally, new perspectives for inhalation therapy are examined.

Congestive heart failure in elderly patients: controlled study of delapril versus captopril.

In this controlled trial, 30 elderly patients with congestive heart failure, New York Heart Association (NYHA) classes II and III, were randomly assigned to treatment with captopril 25 mg three times daily or delapril 15 mg twice daily. At the end of an 8-week treatment period, clinical symptoms of heart failure were significantly relieved by both drugs, with a consistent and statistically significant improvement in patients' quality of life evaluated using a symptoms/activity scale (p < 0.001). None of the patients was judged NYHA class III at the end of the trial and 40% were assigned to class I (p < 0.01). There was a relevant, but not statistically significant, increase in exercise duration in both treatment groups (10% captopril group, 14% delapril group), but the number of patients discontinuing the exercise test for dyspnea was 50% less in the delapril group. Neither drug had evident effects on echocardiographic left ventricular parameters. Two patients treated with captopril and 3 with delapril complained of mild-to-moderate adverse reactions. The safety of both drugs was confirmed by laboratory tests.