sirolimus and Critical-Illness

Critical limb ischemia, the most severe form of peripheral arterial disease, results in extremity amputation if left untreated. Endovascular recanalization of stenotic or occluded infrapopliteal arteries has recently emerged as an effective form of therapy, although the duration of patency is typically limited by restenosis. Recently, it has been suggested that drug-eluting stents originally developed for the coronary arteries might also be effective in preventing restenosis in the infrapopliteal arteries. This prospective, randomized, controlled clinical trial tested the hypothesis that treatment of infrapopliteal arterial occlusive lesions with an everolimus-eluting stent (Xience V) would provide superior patency to treatment with a bare-metal stent (Multi-Link Vision).. A sample size of 140 patients was planned to be enrolled at five European investigative sites. The primary end point was arterial patency at 12 months, defined as the absence of ≥50% restenosis based on quantitative analysis of contrast angiography.. Between March of 2008 and September of 2009, 74 patients were treated with Xience V and 66 patients were treated with Vision. After 12 months, the primary patency rate after treatment with Xience V was 85% compared with 54% after treatment with Vision (P = .0001). Treatment with Xience V significantly reduced mean in-stent diameter stenosis (21% ± 21% vs 47% ± 27%; P < .0001) and mean in-stent late lumen loss (0.78 ± 0.63 vs 1.41 ± 0.89 mm; P = .001). There were no differences in the percentage of patients receiving a designation of Rutherford class 0 or 1 at the 12-month follow-up visit (56% for Vision, vs 60% for Xience V; P = .68). Major extremity amputations were rare in both groups (two for Vision and one for Xience V). The use of the Xience V stent significantly reduced the need for repeat intervention: freedom from target lesion revascularization was 91% for Xience V vs 66% for Vision (P = .001).. Treatment of the infrapopliteal occlusive lesions of critical limb ischemia with everolimus-eluting stents reduces restenosis and the need for reintervention compared with bare metal stents.

Topics: Aged; Aged, 80 and over; Amputation, Surgical; Angioplasty; Arterial Occlusive Diseases; Cardiovascular Agents; Constriction, Pathologic; Critical Illness; Drug-Eluting Stents; Europe; Everolimus; Female; Humans; Ischemia; Kaplan-Meier Estimate; Limb Salvage; Male; Metals; Middle Aged; Popliteal Artery; Prospective Studies; Prosthesis Design; Radiography; Recurrence; Risk Assessment; Risk Factors; Sirolimus; Stents; Time Factors; Treatment Outcome; Vascular Patency

Chylothorax can be a presenting symptom of complex lymphatic anomaly in children and is associated with significant respiratory morbidity. Historically, the traditional pharmacological treatment has been octreotide. There are several treatments that have been utilized in the past few years including sirolimus; however, data regarding their efficacy and outcomes is limited. Furthermore, sirolimus has proven efficacy in complex vascular malformations, and hence, its utility/efficacy in infantile primary chylous effusions warrants further investigation.. In this retrospective study at Texas Children's Hospital, data were extracted for all infants with chylothorax who were treated with sirolimus between 2009 and 2020. Details regarding underlying diagnosis, comorbidities, and number of days from sirolimus initiation to resolution of effusion were collected.. Initially a total of 12 infants were identified. Among them, seven patients had complete data and were included in the study. Reasons for chylous effusions include presumed complex lymphatic anomaly, generalized lymphatic anomaly, and complex congenital lymphatic anomaly. The mean duration of sirolimus treatment needed for chest tube removal was 16 days, with a median of 19 days and range of 7-22 days. No patients had progression of effusions while on sirolimus.. With close monitoring, sirolimus appears to be an effective therapy for pediatric lymphatic effusions even in critically ill infants. The study also demonstrates shorter duration of chest tube requirement after initiation of sirolimus compared to previous studies. Larger multi-institutional studies are needed to further support our findings.

Topics: Child; Chylothorax; Critical Illness; Humans; Infant; Lymphatic Abnormalities; Octreotide; Pleural Effusion; Retrospective Studies; Sirolimus

A 59-year-old man with critical claudication underwent left femoro-anterior bypass grafting, which was uneventful. The graft was tunneled medially across the knee, then anterior to the tibia. His symptoms recurred 1 year later and he was found to have critical stenosis of the vein graft just proximal to the anterior tibial arterial anastomosis. This was treated with scaffolded balloon angioplasty and implantation of a coronary, zotarolimus-eluting balloon-expandable stent, which was also uneventful. However, his claudication again recurred 1 year later. Diagnostic angiography revealed crush, deformation and restenosis of the balloon-expandable stent requiring surgical revision of the bypass graft.

Topics: Angioplasty, Balloon; Cardiovascular Agents; Computed Tomography Angiography; Critical Illness; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Intermittent Claudication; Male; Middle Aged; Peripheral Arterial Disease; Prosthesis Design; Prosthesis Failure; Recurrence; Reoperation; Saphenous Vein; Sirolimus; Time Factors; Treatment Outcome; Ultrasonography, Doppler, Duplex; Vascular Grafting; Vascular Patency

Topics: Administration, Oral; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Hemorrhage; Humans; Infant; Klippel-Trenaunay-Weber Syndrome; Male; Sirolimus; Skin Diseases; Treatment Outcome

Increasing evidence implicates mitochondrial dysfunction as an early, important event in the pathogenesis of critical illness-induced multiple organ failure. We previously demonstrated that prevention of hyperglycemia limits damage to mitochondria in vital organs, thereby reducing morbidity and mortality. We now hypothesize that inadequate activation of mitochondrial repair processes (clearance of damaged mitochondria by autophagy, mitochondrial fusion/fission, and biogenesis) may contribute to accumulation of mitochondrial damage, persistence of organ failure, and adverse outcome of critical illness.. Prospective, randomized studies in a critically ill rabbit model.. University laboratory.. Three-month-old male rabbits.. We studied whether vital organ mitochondrial repair pathways are differentially affected in surviving and nonsurviving hyperglycemic critically ill animals in relation to mitochondrial and organ damage. Next, we investigated the impact of preventing hyperglycemia over time and of administering rapamycin as an autophagy activator.. In both liver and kidney of hyperglycemic critically ill rabbits, we observed signs of insufficient autophagy, including accumulation of p62 and a concomitant decrease in the microtubule-associated protein light-chain-3-II/microtubule-associated protein light-chain-3-I ratio. The phenotype of insufficient autophagy was more pronounced in nonsurviving than in surviving animals. Molecular markers of insufficient autophagy correlated with impaired mitochondrial function and more severe organ damage. In contrast, key players in mitochondrial fusion/fission or biogenesis were not significantly different regarding survival status. Therefore, we focused on autophagy to study the impact of preventing hyperglycemia. Both after 3 and 7 days of illness, autophagy was better preserved in normoglycemic than in hyperglycemic rabbits, which correlated with improved mitochondrial function and less organ damage. Stimulation of autophagy in kidney with rapamycin correlated with protection of renal function.. Our findings put forward insufficient autophagy as a potentially important contributor to mitochondrial and organ damage in critical illness and open perspectives for therapies that activate autophagy during critical illness.

Topics: Animals; Autophagy; Biomarkers; Critical Illness; Hyperglycemia; Immunosuppressive Agents; Kidney; Male; Microtubule-Associated Proteins; Mitochondria, Liver; Mitochondrial Diseases; Mitochondrial Dynamics; Mitophagy; Multiple Organ Failure; Prospective Studies; Rabbits; Random Allocation; Sirolimus; Survival Analysis

To report the long-term outcomes of a single-center prospective study investigating primary placement of everolimus-eluting metal stents for recanalization of long infrapopliteal lesions compared to a matched historical control group treated with plain balloon angioplasty and provisional placement of bare metal stents in a bailout manner.. The study included 81 patients (63 men; mean age 71 years, range 45-85) suffering from critical limb ischemia (CLI) and angiographically proven long-segment (at least 1 lesion >4.5 cm) de novo infrapopliteal artery disease who underwent below-the-knee revascularization with either primary placement of everolimus-eluting stents (n = 47, 51 limbs, 102 lesions) or angioplasty and bailout bare metal stenting (n = 34, 36 limbs, 72 lesions). Clinical and angiographic follow-up was collected at regular time intervals. Primary clinical and angiographic endpoints included patient survival, major amputation-free survival, angiographic primary patency, angiographic binary restenosis (>50%), and overall event-free survival. Results were stratified according to endovascular treatment received. Multivariable Cox proportional hazards regression analysis was applied to adjust for confounding factors of heterogeneity.. Baseline demographics were well matched. No significant differences were identified between the 2 groups with regard to overall 3-year patient survival (82.2% versus 65.7%; p = 0.90) and amputation-free survival (77.1% versus 86.9%; p = 0.20). Up to 3 years, lesions fully covered with everolimus-eluting stents were associated with significantly higher primary patency [hazard ratio (HR) 7.98, 95% CI 3.69 to 17.25, p < 0.0001], reduced binary restenosis (HR 2.94, 95% CI 1.74 to 4.99, p < 0.0001), and improved overall event-free survival (HR 2.19, 95% CI 1.16 to 4.13, p = 0.015) versus the matched historical control group.. Primary infrapopliteal everolimus-eluting stenting for CLI treatment significantly inhibits restenosis and improves long-term angiographic patency and overall patient event-free survival compared to balloon angioplasty and bailout bare metal stenting.

Topics: Aged; Aged, 80 and over; Amputation, Surgical; Angioplasty, Balloon; Arterial Occlusive Diseases; Cardiovascular Agents; Constriction, Pathologic; Critical Illness; Disease-Free Survival; Drug-Eluting Stents; Everolimus; Female; Greece; Humans; Ischemia; Kaplan-Meier Estimate; Lower Extremity; Male; Metals; Middle Aged; Popliteal Artery; Proportional Hazards Models; Prospective Studies; Radiography; Risk Assessment; Risk Factors; Sirolimus; Stents; Time Factors; Treatment Outcome; Vascular Patency

Midterm technical and clinical evaluation of stent angioplasty with drug-eluting stents in infrapopliteal lesions in patients with critical limb ischemia (CLI).. Percutaneous stent angioplasty was performed in 128 limbs in 114 patients presenting with 320 vascular lesions. Lesions with up to 6 cm in length and at least one patent vessel below the obstruction were treated; 341 drug-eluting Cypher(R) stents (diameter of 2.5-3.5 mm; length of 18-33 mm) were implanted. Follow-up examinations were performed up to 18 months postinterventionally using clinical examination, ankle-brachial index (ABI) calculation, and color coded Duplex sonography. Patency rates were calculated on the basis of the Kaplan-Meier life-table analysis.. Technical success was achieved in 99.06%. Minor complications (hematoma, distal emboli, and vessel dissection) were documented in 8.77% of the patients. The 6, 12, and 18 months primary patency rate as controlled by Duplex sonography was 89.8, 84.2 and 83.3%, respectively; 77.6% of the lesions healed postinterventionally. The cumulative limb salvage rate was 95.6%.. Drug-eluting stent (DES) angioplasty in infrapopliteal arteries is a safe and effective technique for the treatment of patients with CLI. The use of a DES results in favorable technical and clinical outcome in the midterm follow-up.

Topics: Adult; Aged; Aged, 80 and over; Angioplasty, Balloon; Ankle Brachial Index; Arterial Occlusive Diseases; Cardiovascular Agents; Critical Illness; Drug-Eluting Stents; Female; Germany; Humans; Ischemia; Kaplan-Meier Estimate; Limb Salvage; Lower Extremity; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Sirolimus; Time Factors; Treatment Outcome; Ultrasonography, Doppler, Color; Vascular Patency

Patients who present with myocardial infarction (MI) and unprotected left main coronary artery (ULMCA) disease represent an extremely high-risk subset of patients. ULMCA percutaneous coronary intervention (PCI) with drug-eluting stents (DES) in MI patients has not been extensively studied.. In this retrospective multicenter international registry, we evaluated the clinical outcomes of 62 consecutive patients with MI who underwent ULMCA PCI with DES (23 ST-elevation MI [STEMI] and 39 non-ST-elevation MI [NSTEMI]) from 2002 to 2006.. The mean age was 70 +/- 12 years. Cardiogenic shock was present in 24%. The mean EuroSCORE was 10 +/- 8. Angiographic success was achieved in all patients. Overall in-hospital major adverse cardiac event (MACE) rate was 10%, mortality was 8%, all due to cardiac deaths from cardiogenic shock, and one patient suffered a periprocedural MI. At 586 +/- 431 days, 18 patients (29%) experienced MACE, 12 patients (19%) died (the mortality rate was 47% in patients with cardiogenic shock), and target vessel revascularization was performed in four patients, all of whom had distal bifurcation involvement (two patients underwent repeat PCI and two patients underwent bypass surgery). There was no additional MI. Two patients had probable stent thrombosis and one had possible stent thrombosis. Diabetes [hazard ratio (HR) 4.22, 95% confidence interval (CI) (1.07-17.36), P = 0.04), left ventricular ejection fraction [HR 0.94, 95% CI (0.90-0.98), P = 0.005), and intubation [HR 7.00, 95% CI (1.62-30.21), P = 0.009) were significantly associated with increased mortality.. Patients with MI and ULMCA disease represent a very high-risk subgroup of patients who are critically ill. PCI with DES appears to be technically feasible, associated with acceptable long-term outcomes, and a reasonable alternative to surgical revascularization for MI patients with ULMCA disease. Randomized trials are needed to determine the ideal revascularization strategy for these patients.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; California; Cardiovascular Agents; Cardiovascular Diseases; Coronary Angiography; Coronary Artery Disease; Critical Illness; Drug-Eluting Stents; Feasibility Studies; Female; Hospital Mortality; Humans; Italy; Kaplan-Meier Estimate; Male; Myocardial Infarction; Paclitaxel; Proportional Hazards Models; Registries; Retrospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Sirolimus; Time Factors; Treatment Outcome

Topics: Angioplasty, Balloon, Coronary; Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Bypass; Coronary Artery Disease; Critical Illness; Drug-Eluting Stents; Hospital Mortality; Humans; Myocardial Infarction; Paclitaxel; Research Design; Risk Assessment; Risk Factors; Severity of Illness Index; Sirolimus; Time Factors; Treatment Outcome