Cyclosporine in systemic sclerosis. results of a forty-eight–week open safety study in ten patients

Objective. To evaluate safety and efficacy of cyclosporin A (CSA) treatment in systemic sclerosis (SSc). Methods. Ten patients with ⩽60 months of SSc were entered into a 48-week open study of CSA. Patients with hypertension or azotemia were excluded. Concurrent use of nonsteroidal antiinflammatory agents or diuretics was not permitted. The extent of cutaneous and visceral involvement at 48 weeks and at study entry were compared. Results. Adverse reactions (especially nephrotoxicity) were frequent, usually transient, often dose-limiting, and usually associated with CSA doses ⩾3–4 mg/kg/day. Skin thickening decreased significantly (P <0.001), while pulmonary and cardiac involvement remained unchanged. Conclusion. CSA should undergo blinded controlled study in patients with SSc.     

Treatment of pulmonary hypertension with the continuous infusion of a prostacyclin analogue, iloprost

Objective—To compare prostacyclin with an analogue, iloprost, in treatment of severe pulmonary hypertension.
Patients—Eight patients with severe pulmonary hypertension: primary in five, thromboembolic pulmonary hypertension in three.
Methods—All patients underwent right heart catheterisation. Mean (SEM) right atrial pressure was 9.9 (2.2) mm Hg, mean pulmonary artery pressure 67.4 (3.0) mm Hg, cardiac index 1.75 (0.13) l/min/m² and mixed venous oxygen saturation 59.1(3.1)%. Continuous intravenous epoprostenol (prostacyclin, PGI₂) or iloprost was given for phase I (three to six weeks); the patients were then crossed over to receive the alternate drug in an equivalent phase II.
Main outcome measures—Exercise tolerance was measured at baseline and at the end of phase I and II with a 12 minute walk; distance covered, rest period, percentage drop in arterial oxygen saturation (ΔSaO₂%) and percentage rise in heart rate (ΔHR%).
Results—Walking distance covered rose from (mean (SEM)) 407.5 (73) to 591 (46) m with PGI₂ (p = 0.004) and to 602.5 (60) m while on iloprost (p = 0.008). Rest period decreased from 192 (73) seconds at baseline to 16 (16) seconds with PGI₂ (p = 0.01) and to 58 (34) seconds with iloprost (p = 0.008). ΔHR% was 37.5(6)% at baseline, 35(3)% on PGI₂, and 24(6)% on iloprost (p = 0.04).
Conclusions—Both intravenous PGI₂ and iloprost caused significant improvement in exercise tolerance. Iloprost offers an alternative to PGI₂ treatment of severe pulmonary hypertension.

Keywords: prostacyclin;  vasodilatation;  iloprost;  pulmonary hypertension     

Improved endothelial function after endothelin receptor blockade in patients with systemic sclerosis

Objective

Impaired endothelium‐dependent vasodilator function may contribute to vascular damage in patients with systemic sclerosis (SSc). This study was undertaken to investigate whether increased activity of the endothelin 1 (ET‐1) system plays a role in the occurrence of endothelial dysfunction in patients with SSc.

Methods

In 12 patients with SSc (6 with diffuse cutaneous SSc [dcSSc] and 6 with limited cutaneous SSc [lcSSc]), forearm blood flow responses to graded doses of acetylcholine (ACh) and sodium nitroprusside (SNP) given intraarterially were assessed by plethysmography, during infusion of saline and following selective blockade of ET_A receptors with BQ‐123 (10 nmoles/minute).

Results

During saline infusion, the vasodilator response to ACh was blunted in patients with SSc as compared with that in healthy controls (P < 0.001), whereas the response to SNP was not different between groups (P = 0.27). The vasodilator effect of ET_A receptor antagonism was higher in patients than in controls (P < 0.001), indicating enhanced ET‐1–mediated vasoconstriction in SSc. In patients, ET_A receptor blockade resulted in a potentiation of the vasodilator response to ACh (P < 0.001 versus saline), but did not affect the response to SNP (P = 0.31). Notably, both the vasodilator effect of ET_A receptor antagonism and the improvement in the responsiveness to ACh following BQ‐123 infusion were higher in patients with dcSSc than in those with lcSSc (P < 0.01).

Conclusion

ET‐1–dependent vasoconstrictor tone is increased predominantly in the subgroup of SSc patients with dcSSc, in whom acute blockade of ET_A receptors was able to improve impaired endothelium‐dependent vasodilator function. Our results suggest novel vasculoprotective effects of ET_A receptor antagonism and support further exploration of strategies that target the ET‐1 pathway in SSc.

     

Comprehensive noninvasive assessment of cardiac involvement in limited systemic sclerosis

Objective. To assess cardiovascular abnormalities in patients with limited systemic sclerosis (SSc), using noninvasive cardiac techniques. Methods. Sixty-three patients with limited SSc were prospectively evaluated with Doppler echocardiography and thallium-201 perfusion scintigraphy after a cold-stress test and radionuclide ventriculography. Results. In the patients with limited SSc, there was a significantly high prevalence of abnormal left- and right-diastolic function parameters (P = 0.001 and P = 0.0002, respectively), thickening of papillary muscles (46%; P = 0.003), and mild mitral regurgitation (49%; P < 0.0001), compared with controls. Systolic pulmonary arterial hypertension was detected in 9 patients (14%), and pericardial effusion in 11 patients (18%). In 64% of patients with limited SSc, an ischemic response was detected on the thallium cold-stress scan; similarly, an ischemic response was detected in 57% of patients with primary Raynaud's phenomenon (P < 0.0001 versus controls). Conclusion. Although the frequency of cardiovascular symptoms was low in patients with limited SSc, a significant rate of cardiovascular abnormalities was found by noninvasive cardiac techniques.     

Isolated diffusing capacity reduction in systemic sclerosis

Objective. To determine the long-term outcome of patients with systemic sclerosis (SSc) and an isolated reduction in the diffusing capacity for carbon monoxide (DLco) at the time of initial evaluation. Methods. Patients with an isolated reduction in DLco (i.e., normal forced vital capacity [FVC] and normal ratio of the forced expiratory volume in one second [FEV₁] to the FVC) on initial evaluation were identified from among 815 patients with SSc who were carefully followed up throughout their illness. We requested that patients have repeat pulmonary function testing (PFT), and the outcomes of these tests, as well as cardiopulmonary and survival outcomes, were determined. Results. An isolated reduction in DLco, with a normal FVC was detected in 152 (19%) of the 815 patients. A subset of those with an isolated reduction in DLco (11%) developed isolated pulmonary hypertension and had severely reduced survival rates. Pulmonary hypertension was strongly associated with an initial DLco of < 55% of predicted normal and a FVC (% predicted)/DLco (% predicted) ratio of > 1.4. Among all patients in whom this ratio was > 1.4, 22% developed isolated pulmonary hypertension, compared with only 2% of those whose ratio was <1.4 (P < 0.01). Of the 152 patients with isolated DLco reduction, 73 (48%) underwent PFTs a mean of 5.4 years (range 2.0–13.2) after the initial PFT. Only 6 (8%) of these 73 patients ever had serious pulmonary disease: 5 had isolated pulmonary hypertension, and 1 had severe pulmonary fibrosis. Half of the patients with a low initial DLco demonstrated a significant improvement (>20%) at followup testing that could not be explained by the demographic, clinical, or laboratory findings at the first visit. Conclusion. Isolated reduction in DLco is a frequent abnormality in SSc. Overall, it is associated with a good prognosis for survival and for pulmonary morbidity. A small subset of patients (11%) who have a very low DLco (<55% of predicted) have developed isolated pulmonary hypertension, all of whom had limited scleroderma.     

Systemic sclerosis therapy with iloprost: a prospective observational study of 30 patients treated for a median of 3 years

Iloprost is useful in the short-term treatment of severe Raynaud’s phenomenon and ischaemic ulcers in patients with systemic sclerosis (SSc), but its long-term effects are largely unknown. The aim of this study was to report long-term outcome (median follow-up 36 months) in a prospective observational study of a cohort of 30 consecutive patients with SSc who received iloprost therapy with maintenance infusions every 3 weeks after an initial cycle of 5 consecutive days. At the end of the observation, compared to the pretreatment point, we observed complete healing of digital ulcers in 19/21 patients (90%), a decrease of the Raynaud’s phenomenon visual analogue score from 10/10 (25th–75th percentile 7–10) to 5/10 (4–6.75) (P <0.001) and, in patients with diffuse cutaneous involvement, of the modified Rodnan skin thickness score from 25.5 (16.5–31.5) to 16 (13.5–20) (P= 0.02), minimal improvement of the Health Assessment Questionnaire from 0.87 (0.68–1.37) to 0.75 (0.62–1.25), which was neither statistically nor clinically significant. The forced vital capacity was not significantly changed, but the diffusion capacity corrected for the alveolar volume decreased from 71% (54–76.7) of the expected value to 62% (51.5–71) (P= 0.02). In one patient with limited SSc a positive effect on pulmonary hypertension was observed. Six patients, after a median of 25 months of treatment and healing of digital ulcers, discontinued the therapy; after a median of 10 months ulcers did not recur in five of these six. Other reasons for discontinuation were: tolerability (1), disease progression (normotensive renal crisis: 1), and death due to intracranial haemorrhage (1). This same patient had previously suffered a central retinal vein thrombosis. In conclusion, long-term therapy with iloprost in patients with SSc has a durable effectiveness on ischaemic ulcers and Raynaud’s phenomenon, but it is not possible to conclude that the natural history of the disease was modified. Received: 23 August 2001 / Accepted: 22 November 2001     

Long term inhalation of iloprost in a child with primary pulmonary hypertension: an alternative to continuous infusion

Primary pulmonary hypertension is a rare disease in childhood associated with a poor prognosis. However, during the past 10 years, pulmonary vasodilator treatment has somewhat improved its prognosis. Long term continuous infusion of prostacyclin (epoprostenol) has been shown to improve physical capacity and to reduce mortality in primary and secondary pulmonary hypertension. It has been reported in adults that daily repetitive inhalation of iloprost, a prostacyclin analogue, seems also suitable for long term therapy of pulmonary hypertension. Repetitive inhalation of iloprost was administered to a 5 year old boy with severe primary pulmonary hypertension. He showed continuous clinical improvement without any side effects over the three years of treatment. This treatment may offer an alternative to continuous intravenous prostacyclin infusion and obviates the need for a permanent central venous catheter.


Keywords: iloprost; inhalation; prostacyclin; pulmonary hypertension     

Aerosolized iloprost for pulmonary vasoreactivity testing in children with long‐standing pulmonary hypertension related to congenital heart disease

Background: In congenital heart disease with increased pulmonary blood flow and pressure, progressive changes in the vascular structure can lead to irreversible pulmonary hypertension (PH). Pulmonary hemodynamic parameters are used to determine whether surgical correction is no longer indicated. In this study, aerosolized iloprost was used to assess pulmonary vasoreactivity in children with long‐standing PH related to congenital heart disease. Methods: Children with long‐standing and severe PH secondary to congenital heart disease were included in this study. Various hemodynamic parameters were measured before and after iloprost inhalation (0.5 μg/kg), and vascular resistance was determined. Responders to the iloprost test were defined as those with a decrease in both pulmonary vascular resistance (PVR) and pulmonary‐to‐systemic vascular resistance ratio (R_p/R_s) of >10%. Results: Eighteen children aged between 7 months and 13 years with long‐standing and severe PH secondary to congenital heart disease were studied. Thirteen children had a positive response, resulting in a mean (± SD) decrease of PVR from 9.3 ± 4.6 to 4.6 ± 2.7 Wood U · m² (P < 0.001), and a mean decrease of R_p/R_s from 0.54 ± 0.37 to 0.24 ± 0.14 (P = 0.005). Conclusions: Iloprost‐induced pulmonary vasodilator responses vary among children with PH related to congenital heart disease. The use of inhale iloprost in the cardiac catheterization laboratory results in pulmonary vasoreactivity for some of these children particularly a reduction in PVR and the pulmonary‐to‐systemic vascular resistance ratio. © 2008 Wiley‐Liss, Inc.     

A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH study group

OBJECTIVE: We sought to compare the acute hemodynamic effects of inhaled nitric oxide (NO) and aerosolized iloprost in primary pulmonary hypertension (PPH). BACKGROUND: Inhalation of the stable prostacyclin analogue iloprost has recently been described as a novel therapeutic strategy for PPH and may offer an alternative to continuous intravenous infusion of prostacyclin or inhalation of NO. METHODS: During right heart catheterization, 35 patients with PPH sequentially inhaled 40 ppm of NO and 14 to 17 microg of iloprost, and the effects on hemodynamics and blood gases were monitored. RESULTS: Both NO and iloprost caused significant increases in cardiac output, mixed-venous oxygen saturation and stroke volume as well as significant decreases in pulmonary artery pressure and pulmonary vascular resistance, whereas only inhaled iloprost significantly increased the arterial PO2 (p = 0.01). Compared with inhaled NO, aerosolized iloprost was more effective in reducing pulmonary artery pressure (-8.3 +/- 7.5 mm Hg vs. -4.3 +/- 8.8 mm Hg; p = 0.0001) and the pulmonary vascular resistance (-447 +/- 340 dynes x s x cm(-5) vs. -183 +/- 305 dyne x s x cm(-5); p < 0.0001). Furthermore, aerosolized iloprost caused a significantly greater increase of the cardiac output compared with NO (+0.7 +/- 0.6 liter/min vs. +0.3 +/- 0.4 liter/min; p = 0.0002) and had a more pronounced effect on the mixed-venous oxygen saturation (p = 0.003). CONCLUSIONS: During acute drug testing, aerosolized iloprost was more potent than inhaled NO as a pulmonary vasodilator in PPH at the doses used in this study.     

Brief Report: Effect of ambrisentan treatment on exercise‐induced pulmonary hypertension in systemic sclerosis: A prospective single‐center,open‐label pilot study

Objective

Exercise‐induced pulmonary hypertension (ePH) may represent an early, clinically relevant phase in the spectrum of pulmonary vascular disease. The purpose of this pilot study was to describe the changes in hemodynamics and exercise capacity in patients with systemic sclerosis (SSc) spectrum–associated ePH treated with open‐label daily ambrisentan.

Methods

Patients were treated with ambrisentan, 5 mg or 10 mg once daily, for 24 weeks. At baseline and 24 weeks, patients with SSc spectrum disorders exercised in a supine position, on a lower extremity cycle ergometer. All patients had normal hemodynamics at rest. We defined baseline ePH as a mean pulmonary artery pressure of >30 mm Hg with maximum exercise and a transpulmonary gradient (TPG) of >15 mm Hg. The primary end point was change in pulmonary vascular resistance (PVR) with exercise. Secondary end points included an improvement from baseline in 6‐minute walking distance, health‐related quality of life assessments, and cardiopulmonary hemodynamics.

Results

Of the 12 enrolled patients, 11 completed the study. At 24 weeks there were improvements in mean exercise PVR (85.8 dynes × second/cm⁵; P = 0.003) and mean distance covered during 6‐minute walk (44.5 meters; P = 0.0007). Improvements were also observed in mean exercise cardiac output (1.4 liters/minute; P = 0.006), mean pulmonary artery pressure (−4.1 mm Hg; P = 0.02), and total pulmonary resistance (−93.0 dynes × seconds/cm⁵; P = 0.0008). Three patients developed resting pulmonary arterial hypertension during the 24 weeks.

Conclusion

Exercise hemodynamics and exercise capacity in patients with SSc spectrum–associated ePH improved over 24 weeks with exposure to ambrisentan. Placebo‐controlled studies are needed to confirm whether this is a drug‐related effect and to determine optimal therapeutic regimens for patients with ePH.

     

Pulmonary dysfunction and hepatopulmonary syndrome in cirrhosis and portal hypertension

Background: Pulmonary dysfunction including the hepatopulmonary syndrome (HPS) is an important complication to cirrhosis and portal hypertension. However, the precise relation to liver dysfunction and the prevalence of HPS are unclear. Aims: We therefore aimed to assess (i) the prevalence of HPS in consecutive alcoholic cirrhotic patients, (ii) the degree of pulmonary dysfunction in relation to liver function and (iii) the response of a 100% oxygen test on cardiopulmonary and peripheral oxygenation. Methods: Fifty patients with cirrhosis and 12 matched healthy controls were entered in this study. All underwent haemodynamic and pulmonary investigations [lung diffusing capacity for carbon monoxide (DLCO), contrast‐enhanced echocardiography and detection of extrapulmonary shunt fraction]. A 100% oxygen test was performed with the assessment of arterial oxygen tension (PaO₂), the alveolar‐arterial oxygen gradient (AaPO₂) and peripheral transcutaneous oxygen tension (tcPO₂). Results: The prevalence of HPS was 10%. PaO₂ and DLCO were reduced in 32 and 72% and AaPO₂, was increased in 60% of the patients respectively. DLCO correlated with indicators of liver dysfunction (galactose elimination capacity, P<0.01, indocyanine green clearance, P<0.001), portal hypertension (post‐sinusoidal resistance, P<0.01) and central hypovolaemia (central and arterial blood volume, P<0.01). After 100% oxygen inhalation, the changes in PaO₂, AaPO₂, tcPO₂ and heart rate were abnormal in the patients compared with controls (P<0.02). Conclusions: Pulmonary dysfunction in alcoholic cirrhosis is common and relates to different aspects of liver dysfunction, whereas the prevalence of HPS is low. The haemodynamic response to oxygen inhalation is clearly impaired and HPS and pulmonary dysfunction seem to be caused by different pathophysiological mechanisms.     

Treatment of systemic sclerosis with recombinant interferon-γ. A phase I/II clinical trial

Objective. A phase I/II trial to examine the safety and efficacy of interferon-γ (IFN_γ) therapy for patients with systemic sclerosis (SSc). Methods. An 18-week open-label study was performed. Eighteen patients with rapidly progressive SSc were enrolled, 14 of whom completed at least 16 weeks of the study. These 14 patients had a mean age of 40 years and had been diagnosed as having SSc an average of 10.1 months prior to study entry. Recombinant IFN_γ was injected intramuscularly 3 times weekly for 18 weeks. Six patients received a 0.1 mg/m² dose, while 8 patients received a 0.5 mg/² dose. Patients who completed the 18-week trial were offered maintenance therapy at a dose of up to 0.5 mg/m². The effects of IFN_γ on skin involvement were assessed by 2 methods: 1) evaluation of skin thickness, by scoring 15 zones according to a 0 (normal skin) to 3 (hidebound skin) scale; and 2) determination of the total body surface area involved, by using 2-dimensional body diagrams to indicate areas affected, and then having a second, “blinded,” assessor calculate the area score with a planimeter. Results. The mean skin thickness score decreased from a baseline of 25.9 to 19.1 (P < 0.03), and the mean area scores declined from 33.1 to 19.6 (P < 0.02) after 18 weeks of IFN_γ treatment. Ten patients had a >25% decrease in area score. Five patients had a ⩾70% decrease in area score, and 3 of them have not experienced disease recurrence for 6 to 17 months after discontinuation of IFN_γ. Five patients withdrew before the study ended. Three of these patients developed renal crisis, which may reflect the severity of the SSc in the study group, although an adverse effect of IFN_γ in SSc cannot be excluded. Conclusion. IFN_γ was associated with a beneficial effect on the skin involvement in most of this series of patients with rapidly progressive SSc. A placebo-controlled study will be necessary to confirm these results.     

Clinical significance of serum growth differentiation factor-15 levels in systemic sclerosis: association with disease severity

Abstract

Objective To determine serum growth differentiation factor-15 (GDF-15) levels and their clinical associations in patients with systemic sclerosis (SSc).

Methods Serum GDF-15 levels were examined by enzyme-linked immunosorbent assay in 61 patients with SSc and 24 healthy individuals. In a retrospective longitudinal study, sera from 14 patients with SSc were analyzed (duration of follow-up 1.2–7.2 years).

Results Serum GDF-15 levels were significantly elevated in SSc patients (1340 ± 910 pg/ml) compared with healthy individuals (213 ± 79 pg/ml; P < 0.001). Among SSc patients, patients with diffuse cutaneous SSc (n = 31) had higher levels of serum GDF-15 (1609 ± 1069 pg/ml) than those with limited cutaneous SSc (n = 30; 1142 ± 646 pg/ml; P < 0.05). SSc patients with high GDF-15 levels (≥1000 pg/ml) had pulmonary fibrosis, decreased vital capacity, and decreased diffusion capacity for carbon monoxide more often than those with low GDF-15 levels (<1000 pg/ml). GDF-15 levels correlated positively with the extent of skin sclerosis and inversely with percentage vital capacity and diffusion capacity for carbon monoxide in patients with SSc. In a longitudinal study, serum GDF-15 levels were generally decreased during the follow-up.

Conclusion Serum GDF-15 levels were increased in patients with SSc and associated with the extent of skin sclerosis and the severity of pulmonary fibrosis. These results suggest that GDF-15 may play a role in the development of cutaneous and pulmonary fibrosis in SSc. Measurement of serum GDF-15 may be useful for risk stratification in early disease stage.     

Cardiovascular effects of octreotide in patients with hepatic cirrhosis

Octreotide is thought to reduce splanchnic and variceal blood flow with minimal effects on the systemic circulation in cirrhotic patients with portal hypertension. However, we noticed significant bradycardia in some patients immediately after administration of bolus doses of octreotide. Therefore, we investigated the effect of intravenous octreotide on systemic hemodynamics in 59 patients with cirrhosis. In two double-blind, placebo-controlled protocols, 32 patients received a 25-μg bolus and 20 patients received an infusion of 50-μg/hr of octreotide/placebo. Immediately after the bolus dose of octreotide was administered, there were significant reductions in pulse rate (77 ± 3 vs. 65 ± 3 beats per minute, P < .01) and cardiac output (9.2 ± 0.8 vs. 7.9 ± 0.8 L/min; P < .01) and significant increases in mean arterial pressure (81 ± 3 vs. 87 ± 3 mm Hg; P < .05), mean pulmonary artery pressure (9.1 ± 1.0 vs. 16.6 ± 1.5 mm Hg; P < .01), right atrial pressure (3.8 ± 0.8 vs. 6.6 ± 1.0 mm Hg; P < .01), right ventricular pressure (7.1 ± 0.6 vs. 12.5 ± 1.3 mm Hg; P < .01), pulmonary capillary wedge pressure (4.8 ± 0.8 vs. 11.2 ± 1.4 mm Hg; P < .01), systemic vascular resistance, and pulmonary vascular resistance. Thirty minutes after the start of the infusion, there were significant increases in mean right atrial pressure, right ventricular pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure. This study suggests that intravenous octreotide has significant effects on the systemic circulation in patients with cirrhosis and that these effects appear to be more marked after administration of bolus doses.     

Assessment of the vasodilator response in primary pulmonary hypertension. Comparing prostacyclin and iloprost administered by either infusion or inhalation.

AIMS: To directly compare the differential effects of oxygen, prostacyclin and iloprost (aerosolized and intravenous) in primary pulmonary hypertension. METHODS AND RESULTS: Twenty-one patients with severe primary pulmonary hypertension underwent right heart catheterization following oxygen inhalation, inhalation of aerosolized iloprost, intravenous prostacyclin or intravenous iloprost. The stability of the iloprost solution was tested for up to 4 weeks. Oxygen slightly decreased pulmonary vascular resistance. Intravenous prostacyclin (7.2+/-3.4 ng kg(-1) min(-1)) reduced pulmonary (1772+/-844 vs 1325+/-615 dyn s cm(-5), P<0.001) and systemic vascular resistance, and arterial and right atrial pressure, while cardiac output increased. Iloprost inhalation diminished pulmonary (1813+/-827 vs 1323+/-614 dyn s cm(-5), P<0.001) and systemic vascular resistance, and pulmonary artery (58+/-12 vs 50+/-12 mmHg,P<0.001) and right atrial pressure, while cardiac output increased. With intravenous iloprost (1.2+/-0.5 ng kg(-1) min(-1), n=8) a decrease in pulmonary (2202+/-529 vs 1515+/-356 dyn s cm(-5), P<0.05) and systemic vascular resistance and right a trial pressure occurred while cardiac output increased. Iloprost solution remained stable for 33 days while losing <10% (4 degrees C) of its active drug concentration.Conclusions Intravenous iloprost and prostacyclin have very similar haemodynamic profiles. In contrast, only inhaled iloprost exerted selective pulmonary vasodilation, reducing pulmonary vascular resistance and pulmonary artery pressure without systemic vasodilation. The longer half-life and extended stability despite lower costs render iloprost an attractive alternative to chronic prostacyclin treatment in primary pulmonary hypertension.     

Descriptive analysis of emergency department oxygen use in acute exacerbation of chronic obstructive pulmonary disease

Background: Inconsistencies in oxygen therapy recommendations in acute exacerbation of chronic obstructive pulmonary disease (COPD) may result in variability in emergency department (ED) oxygen management of patients with COPD. The aim of this study was to describe oxygen management in the first 4 h of ED care for patients with exacerbation of COPD. Methods: A retrospective medical record audit was conducted at four public and one private ED in Melbourne, Australia. Participants were 273 adult ED patients with COPD presenting with a primary complaint of shortness of breath from July 2006 to July 2007. Outcome measures were physiological data, including oxygen saturation (SpO₂), oxygen delivery devices and flow rates on ED arrival, 1 and 4 h. Results: Oxygen was used in 82.0% of patients. Patients who required oxygen had higher incidence of ambulance transport (P < 0.001), triage category 2 (P= 0.006), home oxygen use (P < 0.001), and increased work of breathing on ED arrival (P < 0.001), and higher median respiratory rate (P < 0.001) and heart rate (P= 0.001). SpO₂ > 90% occurred in the majority of patients (87.5%; 96.4%; 95.6%); however, a considerable number of patients with SpO₂ < 90% were not given oxygen (61.8%; 30%; 45.5%). Conclusions: A number of patients with documented hypoxaemia were not given oxygen and there may be variables other than oxygen saturation that may influence oxygen use. Future research should focus on increasing the evidence‐based supporting oxygen use and better understanding of clinicians' oxygen decision‐making in patients with COPD.     

Ventricular Arrhythmias and Autonomic Profile in Patients with Primary Pulmonary Hypertension

The aim of our study was to assess the arrhythmic profile in patients with primary pulmonary hypertension (PPH) and its correlation with autonomic features, echocardiographic indexes and pulmonary function. We studied 9 subjects with a mean age of 42 ± 11 years. All underwent echocardiography, 24-hour Holter monitoring, and cardiopulmonary exercise testing. Left ventricle ejection fraction was normal (65 ± 6%). The right ventricle end diastolic volume was increased (108 ± 32 ml/m²) with a slight reduction of ejection fraction (49 ± 5%). Right ventricle systolic pressure was increased (91 ± 25 mmHg). Heart rate variability analysis showed evidence of a reduced standard deviation of all NN intervals (SDNN) compared with the control group (102.8 ± 32 versus 156.1 ± 32, p < 0.005). Patients with significant ventricular arrhythmias had a lower SDNN, and lower baseline and effort PO₂ (SDNN: 87.0 ± 15 versus 115.4 ± 38; baseline PO₂: 63.2 ± 12% versus 78.8 ± 7%; effort PO₂: 50.7 ± 13% versus 68.7 ± 19%). The patients with SDNN lower than 90 ms were characterized by a higher right ventricle systolic pressure (115.0 ± 22.9 mmHg versus 79.2 ± 17.8 mmHg, p = 0.035). The patients who experienced syncope had higher SDNN (131.7 ± 36 versus 88.4 ± 20, p < 0.05), higher effort PO₂ (77.5 ± 14 mmHg versus 52.3 ± 14 mmHg, p < 0.03). The patients with PPH evidenced an increased sympathetic activity. Premature ventricular beats were more frequent in those subjects with higher adrenergic drive and lower oxygen saturation. Patients with episodes of syncope seem to have a relatively higher vagal activity, and effective mechanisms of adjustment in blood oxygenation during effort.     

Osteoprotegrin interacts with biomarkers and cytokines that have roles in osteoporosis,skin fibrosis,and vasculopathy in systemic sclerosis: A potential multifaceted relationship between OPG/RANKL/TRAIL and Wnt inhibitors

Abstract

Objectives: We explored the interactions of osteoprotegerin (OPG) with biomarkers of bone turnover and cytokines, including soluble receptor activator for nuclear factor kappa beta ligand (sRANKL), tumor necrosis factor-related apoptosis-induced ligand (TRAIL), and Wnt inhibitors in osteoporosis, vasculopathy and fibrosis related to systemic sclerosis (SSc).

Methods: The study included 46 SSc patients and 30 healthy controls. Skin thickness, pulmonary fibrosis and/or hypertension, digital ulcers, and calcinosis cutis of SSc patients were assessed. We determined bone mineral density (BMD), and OPG, sRANKL, TRAIL, secreted frizzled-related protein 1 (sFRP-1), Dickkopf-related protein 1 (DKK-1), sclerostin in the serum of both patients and controls.

Results: OPG, sclerostin, and sFRP-1 levels were similar between patients and controls (P?>?0.05). Femoral neck and lumbar spine BMD and vitamin D levels were lower, and the OC, NTX, sRANKL, DKK1 and TRAIL levels were significantly higher, in patients than in controls (p?<?0.05). In subgroup analysis, patients with higher modified Rodnan skin score (mRodnan) had higher DKK-1, sclerostin, and TRAIL levels (p?<?0.05); those with diffuse SSc subtype had lower BMD values than those with limited SSc (p?<?0.05). Skin and pulmonary fibrosis linked negatively with BMD measures.

Conclusion: we showed that sRANKL levels were higher and correlated with bone turnover markers. It may be related to osteoporosis in SSc. The OPG level was unaltered in SSc patients. Higher TRAIL levels associated with skin thickness may indicate vascular dysfunction or injury. Higher DKK-1 and sclerostin levels may be related to a reactive increase in cells and be prominently linked to fibrosis in SSc.     

Borderline Mean Pulmonary Artery Pressure in Patients With Systemic Sclerosis: Transpulmonary Gradient Predicts Risk of Developing Pulmonary Hypertension

Objective

To determine whether patients with systemic sclerosis (SSc) and borderline mean pulmonary artery pressure (PAP) at cardiac catheterization are more likely to develop pulmonary hypertension (PH) than those in whom pulmonary pressure is normal.

Methods

Patients with SSc in whom PH and significant interstitial lung disease had been excluded at baseline were enrolled in our prospective cohort. Analysis of followup data identified patients who met prespecified criteria prompting repeat catheterization to reassess for possible PH. Using Kaplan‐Meier, receiver operating characteristic, and Cox regression methods, we studied the development of PH and death.

Results

Of 228 patients in this study, 86 had borderline mean PAP (21–24 mm Hg) at baseline. Following prespecified criteria, 76 patients underwent repeat catheterization, and 29 of these developed PH. Two cases were related to disease of the left side of the heart. The average mean PAP increased from baseline (20.2 mm Hg) to followup (24.3 mm Hg) (P < 0.05 by Student's t‐test). Patients with borderline mean PAP were more likely to develop PH than patients with mean PAP ≤20 mm Hg (P < 0.001 by log rank test, hazard ratio [HR] 3.7). A transpulmonary gradient (TPG) ≥11 mm Hg at baseline also predicted PH (P < 0.001 by log rank test, HR 7.9). Incident development of pulmonary arterial hypertension (PAH) was not benign, with a mortality of 18% within 3 years.

Conclusion

Our findings indicate that borderline mean PAP and an elevated TPG in patients with SSc predict progression to PH. These patients should be monitored closely for the development of PH. Our findings indicate that catheterization data are useful in patients considered at risk of PAH.

     

Capillary dimension measured by computer-based digitalized image correlated with plasma endothelin-1 levels in patients with systemic sclerosis

Endothelial and vascular damage are main leading disability in systemic sclerosis (SSc). Raynaud’s phenomenon is the early symptom that presents vascular damage. Nailfold capillaroscopy (NFC) is an easily accessible diagnostic tool in secondary Raynaud’s phenomenon. Considering the endothelial damage, clinical manifestations, and plasma cytokines was compared with traditionally used NFC parameter for, which to observe the number of capillaries, deletions in 3 mm, apical limb width and the capillary width itself. We hypothesize that a computer-based NFC system can generate a new powerful parameter which predicts the capillary dimension. We investigated the relationship among the plasma endothelin-1 (ET-1), clinical manifestations and quantitative analysis of computerized NFC, and to assess the optimal method in SSc. The level of ET-1 in 60 SSc patients, 30 healthy, and 23 disease controls were measured by enzyme-linked immunosorbent assay (ELISA) kit. We present a significant difference in all parameters of NFC between SSc patients and control groups. ET-1 level was increased in patients with SSc. In SSc group, capillary dimension and loss of capillaries were strongly associated with digital ulceration (p < 0.01) and pulmonary hypertension (p < 0.05). Capillary dimension and ET-1 level was in correlation with skin-hardening grade, and was higher in SSc patients with pulmonary hypertension or digital ulcer. Capillary dimension showed strong correlation with the endothelin-1 in SSc, healthy and disease control groups. (Rs = 0.31/p < 0.05, Rs = 0.82/p < 0.001, Rs = 0.83/p < 0.001). The results suggest that computer-based microscopic analysis of NFC is a useful method that potentially provides information on organ involvement and plasma ET-1. Capillary dimension maybe a powerful parameter possibly applicable in outpatient clinic for assessing SSc patients.