Rolf Peter Engelberger

Ultrasound-assisted thrombolysis for acute pulmonary embolism: a systematic review

Pulmonary embolism remains a common and potentially life-threatening disease. For patients with intermediate- and high-risk pulmonary embolism, catheter-based revascularization therapy has emerged as potential alternative to systemic thrombolysis or surgical embolectomy. Ultrasound-assisted catheter-directed thrombolysis is a contemporary catheter-based technique and is the focus of the present review. Ultrasound-assisted catheter-directed thrombolysis is more effective in reversing right ventricular dysfunction and dilatation in comparison with anticoagulation alone in patients at intermediate risk. However, a direct comparison of ultrasound-assisted thrombolysis with systemic thrombolysis or surgical thrombectomy is not available. Ultrasound-assisted thrombolysis with initial intrapulmonary thrombolytic bolus may also be effective in high-risk patients, but evidence from randomized trials is not available. This review summarizes current data on ultrasound-assisted thrombolysis for acute pulmonary embolism.

Fixed low-dose ultrasound-assisted catheter-directed thrombolysis for intermediate- and high-risk pulmonary embolism

AIMS No standardized local thrombolysis regimen exists for the treatment of pulmonary embolism (PE). We retrospectively investigated efficacy and safety of fixed low-dose ultrasound-assisted catheter-directed thrombolysis (USAT) for intermediate- and high-risk PE. METHODS AND RESULTS Fifty-two patients (65 ± 14 years) of whom 14 had high-risk PE (troponin positive in all) and 38 intermediate-risk PE (troponin positive in 91%) were treated with intravenous unfractionated heparin and USAT using 10 mg of recombinant tissue plasminogen activator per device over the course of 15 h. Bilateral USAT was performed in 83% of patients. During 3-month follow-up, two [3.8%; 95% confidence interval (CI) 0.5-13%] patients died (one from cardiogenic shock and one from recurrent PE). Major non-fatal bleeding occurred in two (3.8%; 95% CI, 0.5-13%) patients: one intrathoracic bleeding after cardiopulmonary resuscitation requiring transfusion, one intrapulmonary bleeding requiring lobectomy. Mean pulmonary artery pressure decreased from 37 ± 9 mmHg at baseline to 25 ± 8 mmHg at 15 h (P < 0.001) and cardiac index increased from 2.0 ± 0.7 to 2.7 ± 0.9 L/min/m(2) (P < 0.001). Echocardiographic right-to-left ventricular end-diastolic dimension ratio decreased from 1.42 ± 0.21 at baseline to 1.06 ± 0.23 at 24 h (n = 21; P < 0.001). The greatest haemodynamic benefit from USAT was found in patients with high-risk PE and in those with symptom duration < 14 days. CONCLUSION A standardized catheter intervention approach using fixed low-dose USAT for the treatment of intermediate- and high-risk PE was associated with rapid improvement in haemodynamic parameters and low rates of bleeding complications and mortality.

Catheter-Based Reperfusion Treatment of Pulmonary Embolism

Case Presentation: A 76-year-old man with a history of hemicolectomy for colon cancer 10 days previously was admitted because of syncope and severe shortness of breath. On physical examination, the patient was hemodynamically unstable, with a systolic arterial pressure of 80 mm Hg, a heart rate of 124 beats per minute, and distended jugular veins. He was agitated and unable to speak full sentences. His respiratory rate was 28 breaths per minute, and oxygen saturation was 80% on room air. Contrast-enhanced computed tomography showed a filling defect of the left main pulmonary artery, complete occlusion of the left lower lobe pulmonary artery, nonobstructive filling defects of the right lower lobe pulmonary artery, and right ventricular enlargement (right-to-left ventricular dimension ratio of 1.4) (Figure 1). The hemodynamic situation remained unchanged after initiation of treatment with oxygen, intravenous unfractionated heparin, and normal saline. Figure 1. Contrast-enhanced chest computed tomogram from the first case. Left, Complete occlusion of the left lower lobe pulmonary artery (large arrow) and nonobstructive filling defect in the right lower lobe pulmonary artery (small arrow). Right, The subannular right-to-left ventricular dimension ratio was obtained from the reconstructed 4-chamber view.1 Right (47.3 mm) and left (33.9 mm) ventricular dimensions were measured perpendicular to the interventricular septum and 1 cm above the atrioventricular annulus plane. The right-to-left ventricular dimension ratio was calculated as 1.4. Case Presentation: A 55-year-old woman suddenly developed acute shortness of breath 3 weeks after resection of a meningioma. On physical examination, the patient appeared hemodynamically stable, with a systolic arterial pressure of 100 mm Hg, a heart rate of 96 beats per minute, a respiratory rate of 18 breaths per minute, and an oxygen saturation of 89% while receiving 3 L of oxygen via face mask. A contrast-enhanced computed tomography confirmed subtotal filling defects in both main pulmonary …

Management of Deep Vein Thrombosis of the Upper Extremity

Case 1: A 34-year-old previously healthy male office manager was admitted with acute onset of heaviness, pain, and functional impairment of his right arm. The arm was cyanotic and massively swollen (Figure 1). For the past weeks, he reported transient paresthesia of his right arm during overhead activities and was unable to perform repetitive or strenuous arm exercise. He had a fracture of the right clavicle after a ski accident 5 years previously. The fracture was managed conservatively. There was no personal or family history of thrombosis. Conventional phlebography confirmed axillary and subclavian vein thrombosis (Figure 2, top), and treatment with intravenous unfractionated heparin was started. Figure 1. Clinical presentation of case 1 with massive swelling and cyanosis of the right arm (left). One day after pharmacomechanical thrombolysis, signs of thrombosis have markedly improved (right). Figure 2. Baseline digital subtraction venogram from case 1 with extensive filling defects in the axillary subclavian veins (top). Control venogram after 15 hours of pharmacomechanical thrombectomy confirmed resolution of filling defects and restored venous flow (middle). Positional venography obtained during abduction of the right arm confirmed the venous thoracic outlet syndrome with residual stenosis of the subclavian vein at the costoclavicular junction (white arrow, bottom). Case 2: A 55-year-old man with lung cancer presented with swelling, heaviness, and pain in his left arm 1 week after completion of chemotherapy administered via a left-sided indwelling central venous catheter. Axillary and subclavian vein thrombosis was confirmed by ultrasonography. Low-molecular-weight heparin (LMWH) was initiated, and the catheter was removed 3 days later because it was no longer functional. At 1 week, pain and functional impairment had not improved, and the circumference of the left upper arm had increased by 2 cm. Case 3: A 65-year-old woman with metastatic ovarian cancer presented with swelling of the face and both arms, headache, …

Fixed low-dose ultrasound-assisted catheter-directed thrombolysis followed by routine stenting of residual stenosis for acute ilio-femoral deep-vein thrombosis

Patients with ilio-femoral deep-vein thrombosis (DVT) are at high risk of developing the post-thrombotic syndrome (PTS). In comparison to anticoagulation therapy alone, extended venography-guided catheter-directed thrombolysis without routine stenting of venous stenosis in patients with ilio-femoral DVT is associated with an increased risk of bleeding and a moderate reduction of PTS. We performed a prospective single-centre study to investigate safety, patency and incidence of PTS in patients with acute ilio-femoral DVT treated with fixed-dose ultrasound-assisted catheter-directed thrombolysis (USAT; 20 mg rt-PA during 15 hours) followed by routing stenting of venous stenosis, defined as residual luminal narrowing >50%, absent antegrade flow, or presence of collateral flow at the site of suspected stenosis. A total of 87 patients (age 46 ± 21 years, 60% women) were included. At 15 hours, thrombolysis success ≥50% was achieved in 67 (77%) patients. Venous stenting (mean 1.9 ± 1.3 stents) was performed in 70 (80%) patients, with the common iliac vein as the most frequent stenting site (83%). One major (1%; 95% CI, 0-6%) and 6 minor bleedings (7%; 95%CI, 3-14%) occurred. Primary and secondary patency rates at 1 year were 87% (95% CI, 74-94%) and 96% (95% CI, 88-99%), respectively. At three months, 88% (95% CI, 78-94%) of patients were free from PTS according to the Villalta scale, with a similar rate at one year (94%, 95% CI, 81-99%). In conclusion, a fixed-dose USAT regimen followed by routine stenting of underlying venous stenosis in patients with ilio-femoral DVT was associated with a low bleeding rate, high patency rates, and a low incidence of PTS.

Acute endotoxemia inhibits microvascular nitric oxide-dependent vasodilation in humans.

Nitric oxide (NO) is crucial for the microvascular homeostasis, but its role played in the microvascular alterations during sepsis remains controversial. We investigated NO-dependent vasodilation in the skin microcirculation and plasma levels of asymmetric dimethylarginine (ADMA), a potent endogenous inhibitor of the NO synthases, in a human model of sepsis. In this double-blind, randomized, crossover study, microvascular NO-dependent (local thermal hyperemia) and NO-independent vasodilation (post-occlusive reactive hyperemia) assessed by laser Doppler imaging, plasma levels of ADMA, and l-arginine were measured in seven healthy obese volunteers, immediately before and 4 h after either a i.v. bolus injection of Escherichia coli endotoxin (LPS; 2 ng/kg) or normal saline (placebo) on two different visits at least 2 weeks apart. LPS caused the expected systemic effects, including increases in heart rate (+43%, P < 0.001), cardiac output (+16%, P < 0.01), and rectal temperature (+1.4°C, P < 0.001), without change in arterial blood pressure. LPS affected neither baseline skin blood flow nor post-occlusive reactive hyperemia but decreased the NO-dependent local thermal hyperemia response, l-arginine, and, to a lesser extent, ADMA plasma levels. The changes in NO-dependent vasodilation were not correlated with the corresponding changes in the plasma levels of ADMA, l-arginine, or the l-arginine/ADMA ratio. Our results show for the first time that experimental endotoxemia in humans causes a specific decrease in endothelial NO-dependent vasodilation in the microcirculation, which cannot be explained by a change in ADMA levels. Microvascular NO deficiency might be responsible for the heterogeneity of tissue perfusion observed in sepsis and could be a therapeutic target.

Predictors of in-hospital mortality in elderly patients with acute venous thrombo-embolism: the SWIss Venous ThromboEmbolism Registry (SWIVTER)

AIMS Although acute venous thrombo-embolism (VTE) often afflicts patients with advanced age, the predictors of in-hospital mortality for elderly VTE patients are unknown. METHODS AND RESULTS Among 1247 consecutive patients with acute VTE from the prospective SWIss Venous ThromboEmbolism Registry (SWIVTER), 644 (52%) were elderly (≥65 years of age). In comparison to younger patients, the elderly more often had pulmonary embolism (PE) (60 vs. 42%; P< 0.001), cancer (30 vs. 20%; P< 0.001), chronic lung disease (14 vs. 8%; P= 0.001), and congestive heart failure (12 vs. 2%; P< 0.001). Elderly VTE patients were more often hospitalized (75 vs. 52%; P< 0.001), and there was no difference in the use of thrombolysis, catheter intervention, or surgical embolectomy between the elderly and younger PE patients (5 vs. 6%; P= 0.54), despite a trend towards a higher rate of massive PE in the elderly (8 vs. 4%; P= 0.07). The overall in-hospital mortality rate was 6.6% in the elderly vs. 3.2% in the younger VTE patients (P= 0.033). Cancer was associated with in-hospital death both in the elderly [hazard ratio (HR) 4.91, 95% confidence interval (CI) 2.32-10.38; P< 0.001] and in the younger patients (HR 4.90, 95% CI 1.37-17.59; P= 0.015); massive PE was a predictor of in-hospital death in the elderly only (HR 3.77, 95% CI 1.63-8.74; P= 0.002). CONCLUSION Elderly patients had more serious VTE than younger patients, and massive PE was particularly life-threatening in the elderly.

The vasodilatory response of skin microcirculation to local heating is subject to desensitization.

Background: In humans, local heating increases skin perfusion by mechanisms dependent on nitric oxide (NO). Because the vascular effects of NO may be subject to desensitization, we examined whether a first local thermal stimulus would attenuate the hyperemic response to a second one applied later. Methods: Twelve healthy young men were studied. Skin blood flow (SkBF) was measured on forearm skin with laser Doppler imaging. Local thermal stimuli (temperature step from 34 to 41°C maintained for 30 minutes) were applied with temperature‐controlled chambers. We also tested the influence of prior local heating on the vasodilation induced by sodium nitroprusside (SNP), a donor of NO. Results: On reheating the same spot after two hours, the response of SkBF (i.e., plateau SkBF at 30 minutes minus SkBF at 34°C) was lower than during the first stimulation (mean±SD 404±212 perfusion units [PU] vs. 635±100 PU; P<0.001). There was no such difference when reheating after four hours (654±153 vs. 645±103 PU; P=NS). Two, but not four, hours after local heating, the response of SkBF to SNP was reduced. Conclusion: The NO‐dependent hyperemic response induced by local heating in human skin is subject to desensitization. At least one part of the mechanism implicated consists of a desensitization to the effects of NO itself.

Comparison of the diagnostic performance of the original and modified Wells score in inpatients and outpatients with suspected deep vein thrombosis

INTRODUCTION The original and modified Wells score are widely used prediction rules for pre-test probability assessment of deep vein thrombosis (DVT). The objective of this study was to compare the predictive performance of both Wells scores in unselected patients with clinical suspicion of DVT. METHODS Consecutive inpatients and outpatients with a clinical suspicion of DVT were prospectively enrolled. Pre-test DVT probability (low/intermediate/high) was determined using both scores. Patients with a non-high probability based on the original Wells score underwent D-dimers measurement. Patients with D-dimers < 500 μg/L did not undergo further testing, and treatment was withheld. All others underwent complete lower limb compression ultrasound, and those diagnosed with DVT were anticoagulated. The primary study outcome was objectively confirmed symptomatic venous thromboembolism within 3 months of enrollment. RESULTS 298 patients with suspected DVT were included. Of these, 82 (27.5%) had DVT, and 46 of them were proximal. Compared to the modified score, the original Wells score classified a higher proportion of patients as low-risk (53 vs 48%; p < 0.01) and a lower proportion as high-risk (17 vs 15%; p = 0.02); the prevalence of proximal DVT in each category was similar with both scores (7-8% low, 16-19% intermediate, 36-37% high). The area under the receiver operating characteristic curve regarding proximal DVT detection was similar for both scores, but they both performed poorly in predicting isolated distal DVT and DVT in inpatients. CONCLUSION The study demonstrates that both Wells scores perform equally well in proximal DVT pre-test probability prediction. Neither score appears to be particularly useful in hospitalized patients and those with isolated distal DVT.

Haemodialysis acutely reduces the plasma levels of ADMA without reversing impaired NO-dependent vasodilation.

End-stage renal disease patients have endothelial dysfunction and high plasma levels of ADMA (asymmetric omega-NG,NG-dimethylarginine), an endogenous inhibitor of NOS (NO synthase). The actual link between these abnormalities is controversial. Therefore, in the present study, we investigated whether HD (haemodialysis) has an acute impact on NO-dependent vasodilation and plasma ADMA in these patients. A total of 24 patients undergoing maintenance HD (HD group) and 24 age- and gender-matched healthy controls (Control group) were enrolled. The increase in forearm SkBF (skin blood flow) caused by local heating to 41 degrees C (SkBF41), known to depend on endothelial NO production, was determined with laser Doppler imaging. SkBF41 was expressed as a percentage of the vasodilatory reserve obtained from the maximal SkBF induced by local heating to 43 degrees C (independent of NO). In HD patients, SkBF41 was assessed on two successive HD sessions, once immediately before and once immediately after HD. Plasma ADMA was assayed simultaneously with MS/MS (tandem MS). In the Control group, SkBF41 was determined twice, on two different days, and plasma ADMA was assayed once. In HD patients, SkBF41 was identical before (82.2+/-13.1%) and after (82.7+/-12.4%) HD, but was lower than in controls (day 1, 89.6+/-6.1; day 2, 89.2+/-6.9%; P<0.01 compared with the HD group). In contrast, plasma ADMA was higher before (0.98+/-0.17 micromol/l) than after (0.58+/-0.10 micromol/l; P<0.01) HD. ADMA levels after HD did not differ from those obtained in controls (0.56+/-0.11 micromol/l). These findings show that HD patients have impaired NO-dependent vasodilation in forearm skin, an abnormality not acutely reversed by HD and not explained by ADMA accumulation.