Monthly recombinant tissue plasminogen activator administration to implantable central venous access devices decreases infections in children with haemophilia

Summary.  Central venous access devices (CVAD) have been effectively used in the care of haemophilia patients. This is particularly true in children, who often have difficult venous access. CVAD complications (infection and thrombosis), risk factors, and complication rates, have been well-documented. However, effective interventions which decrease complication rates have not been identified. In this study, we review our experience with the use of monthly recombinant tissue plasminogen activator (rtPA) administration in haemophilia patients with fully implanted CVADs. Data on 19 haemophilia patients with 24 CVADs were available for analysis, with a total of 24 520 CVAD days. An infection rate of 0.04 infections per 1000 CVAD days and a thrombosis rate of 0.04 thrombi per 1000 CVAD days was observed. The observed infectious complication rate is at least one logarithm lower than many published CVAD infection rates in haemophilia patients who have not received rtPA administration. No bleeding complications were noted. Monthly rtPA is safe and appears to be effective in decreasing CVAD infection rates. Larger, randomized controlled studies are indicated to validate this finding.     

Tissue plasminogen activator to prevent central venous access device infections: a systematic review of central venous access catheter thrombosis, infection and thromboprophylaxis

Summary.  The recent unequivocal demonstration that prophylaxis, three to four weekly factor infusions, is effective in preventing joint disease in children with haemophilia, has provided impetus to initiate prophylaxis early in such children. Yet, nearly a quarter (22%) of the 83% who required central venous access devices for factor infusion developed central venous access catheter (CVAD)-related infection. This limitation of CVAD use prevents many families from initiating prophylaxis. The frequent occurrence of local thrombosis accompanying CVAD-related infection in surgical patients and autopsy cases, the thrombogenic plastic CVAD surfaces, and local clot formation at the insertion site, suggest the potential role of thrombolytic agents in preventing these infections. Yet, correlation between CVAD-related infection and local thrombosis in children with haemophilia are lacking, and thromboprophylaxis to prevent CVAD-related infection is controversial. Tissue plasminogen activator (t-PA), a recombinant serine protease glycoprotein that lyses plasmin-bound fibrin and is safe and effective in the treatment of occluded catheters, has not been evaluated in the prevention of these infections. We performed a literature review of CVAD-related infection, CVAD-related thrombosis, and thromboprophylaxis studies to evaluate the role of t-PA in the prevention of these infections in children with haemophilia. Metanalysis of published thromboprophylaxis trials demonstrate current prophylaxis regimens do not prevent CVAD infection, and further, that thrombosis and infection do not necessarily occur simultaneously. Pilot data demonstrate CVAD infection reduction in haemophilic children by monthly t-PA in 18 haemophilic children, suggesting the potential role of t-PA in CVAD infection prevention. Clinical trials to evaluate t-PA in CVAD infection prevention are justified.     

Air Travel and Venous Thromboembolism: A Systematic Review

CONTEXT: Despite multiple attempts to document and quantify the danger of venous thromboembolism (VTE) following prolonged travel, there is still uncertainty about the magnitude of risk and what can be done to lower it. OBJECTIVES: To review the methodologic strength of the literature, estimate the risk of travel-related VTE, evaluate the efficacy of preventive treatments, and develop evidence-based recommendations for practice. DATA SOURCES: Studies identified from MEDLINE from 1966 through December 2005, supplemented by a review of the Cochrane Central Registry of Controlled Trials, the Database of Abstracts of Reviews of Effects, and relevant bibliographies. STUDY SELECTION: We included all clinical studies that either reported primary data concerning travel as a risk factor for VTE or tested preventive measures for travel-related VTE. DATA EXTRACTION AND ANALYSIS: Two reviewers reviewed each study independently to assess inclusion criteria, classify research design, and rate methodologic features. The effect of methodologic differences, VTE risk, and travel duration on VTE rate was evaluated using a logistic regression model. DATA SYNTHESIS: Twenty-four published reports, totaling 25 studies, met inclusion criteria (6 case-control studies, 10 cohort studies, and 9 randomized controlled trials). Method of screening for VTE [screening ultrasound compared to usual clinical care, odds ratio (OR) 390], outcome measure [all VTE compared to pulmonary embolism (PE) only, OR 21], duration of travel (<6 hours compared to 6-8 hours, OR 0.011), and clinical risk ("higher" risk travelers compared to "lower," OR 3.6) were significantly related to VTE rate. Clinical VTE after prolonged travel is rare [27 PE per million flights diagnosed through usual clinical care, 0.05% symptomatic deep venous thrombosis (DVT) diagnosed through screening ultrasounds], but asymptomatic thrombi of uncertain clinical significance are more common. Graduated compression stockings prevented travel-related VTE (P < 0.05 in 4 of 6 studies), aspirin did not, and low-molecular-weight heparin (LMWH) showed a trend toward efficacy in one study. CONCLUSIONS: All travelers, regardless of VTE risk, should avoid dehydration and frequently exercise leg muscles. Travelers on a flight of less than 6 hours and those with no known risk factors for VTE, regardless of the duration of the flight, do not need DVT prophylaxis. Travelers with 1 or more risk factors for VTE should consider graduated compression stockings and/or LMWH for flights longer than 6 hours.     

Silent Pulmonary Embolism in Patients with Deep Venous Thrombosis: A Systematic Review

Purpose

To determine, by systematic review of the literature, the prevalence of silent pulmonary embolism in patients with deep venous thrombosis.

Methods

Twenty-eight included published investigations were identified through PubMed. Studies were selected if methods of diagnosis of pulmonary embolism were described; if pulmonary embolism was stated to be asymptomatic; and if raw data were presented. Studies were stratified according to whether silent pulmonary embolism was diagnosed by a high-probability ventilation-perfusion lung scan using criteria from the Prospective Investigation of Pulmonary Embolism Diagnosis, computed tomography pulmonary angiography, or conventional pulmonary angiography (Tier 1), or by lung scans based on non-Prospective Investigation of Pulmonary Embolism Diagnosis criteria (Tier 2).

Results

Silent pulmonary embolism was diagnosed in 1665 of 5233 patients (32%) with deep venous thrombosis. This is a conservative estimate because many of the investigations used stringent criteria for the diagnosis of pulmonary embolism. The incidence of silent pulmonary embolism was higher with proximal deep venous thrombosis than with distal deep venous thrombosis. Silent pulmonary embolism seemed to increase the risk of recurrent pulmonary embolism: 25 of 488 (5.1%) with silent pulmonary embolism versus 7 of 1093 (0.6%) without silent pulmonary embolism.

Conclusion

Silent pulmonary embolism sometimes involved central pulmonary arteries. Because approximately one third of patients with deep venous thrombosis have silent pulmonary embolism, routine screening for pulmonary embolism may be advantageous.     

Clinical Utility of Central Venous Saturation for the Calculation of Cardiac Index in Cardiac Patients

BackgroundMixed venous saturation (MVS) obtained from the distal pulmonary artery (PA) during Swan-Ganz catheterization is the criterion standard for calculating cardiac output (CO) and cardiac index (CI) with the use of the Fick method. We think that calculating CI with the use of central venous saturation (CVS) instead of PA-MVS is both feasible and accurate. Earlier studies were small, enrolled heterogeneous patient populations, and resulted in inconsistent findings.MethodsAll patients undergoing right heart catheterization from January 2011 to January 2012 in our catheterization lab with simultaneous measurements of MVS obtained from the distal PA and CVS obtained from the superior vena cava (SVC) or right atrium (RA) were included. Out of the 902 patients enrolled, we excluded patients (n = 50) who had known cardiac shunt or dialysis fistula, had duplicate medical records, or were septic. We calculated the CI with the use of the assumed Fick method using both MVS (criterion standard) and CVS (SVC or RA saturations) in the remaining 852 patients. We measured the correlation and the agreement between the 2 methods with the use of the Pearson correlation coefficient and Bland-Altman analysis.ResultsTotals of 112 patients with simultaneous PA and RA saturation measurements (group I) and 740 patients with simultaneous PA and SVC saturation measurements (group II) were included. We found an excellent linear correlation between SVC and PA saturation (r = 0.928) and between RA and PA saturation (r = 0.95). There was also an excellent correlation between CI calculated with the use of PA saturation and CI calculated with the use of SVC (r = 0.87) or RA (r = 0.93) saturation. The mean bias of CVS-derived CI compared with MVS-derived CI (criterion standard) was −0.1 (95% limits of agreement [LOA] −1 to +0.77) in the SVC group and −0.006 (LOA −0.68 to +0.69) in the RA group. Patients with low CI had stronger correlation and smaller bias between the 2 methods compared with those with normal or high CI. The presence of baseline hypoxemia, valvular heart disease, or acute coronary syndrome had no significant effect on the correlation or the bias between the 2 methods.ConclusionsIn cardiac patients, CVS can be used as a surrogate to true MVS in the calculation of CI. This method is readily available in patients who have central venous access, and may aid in early goal-directed treatment when cardiogenic shock is suspected.     

A novel system for teaching the in-plane vascular access technique: A simulation study

The long-axis in-plane approach is amenable to ultrasound-guided central venous catheterization. However, the long-axis in-plane approach is considered difficult to learn because the needle should remain visible in the ultrasound beam during the procedure. We developed a novel competency-based modular system to acquire the skills for the long-axis in-plane approach. The purpose of this study is to evaluate the efficacy of this system.The study was approved by the local ethics committee. Participants performed ultrasound guided venous catheterization (pre-test), attended a 2-hour hands-on session with the teaching system and were then evaluated again (posttest). The teaching system is a simulator device consisting of an ultrasound probe, a simulated vessel, a needle, and an endoscope connected to a computer to visualize the image inside the simulated vessel. The success rate, visualization of the needle tip, and puncture accuracy were measured before and after training. The puncture accuracy was determined by evaluating the distance of the needle tip and needle shaft from the center of a simulated vessel. Primary outcomes were the success rate and the puncture accuracy. The secondary outcome was needle tip visualization. McNemar test was used to analyze success rate and needle tip visualization. Tukey test was used to analyze puncture accuracy. A P value <.05 was considered statistically significant.Forty-seven participants were enrolled in this study. The success rate was significantly increased (pre-test 79%, posttest 94%, P = .04). Ultrasound images from 42 participants were analyzed for puncture accuracy. Puncture accuracy significantly increased for needle tip distance (P = .03), but not shaft distance (P = .1). The needle tip visualization was significantly improved (P = .02).A novel competency-based teaching system was constructed in a step-by-step manner, which improved needle tip visualization and puncture accuracy, with a higher success rate.     

Central venous access devices for paediatric patients with haemophilia: a single-institution experience

Summary.  Use of a central venous access device (CVAD) can facilitate early introduction of home-based infusion of factor concentrate for long-term prophylaxis or immune tolerance therapy in children with bleeding disorders. The aim was t o review outcomes associated with use of CVAD. Retrospective review of paediatric patients with bleeding disorders was observed at the Mayo Clinic Comprehensive Hemophilia Center. Thirty-seven CVAD were placed in 18 patients (haemophilia A [ n  = 15], type 3 von Willebrand disease [ n  = 2] and haemophilia B [ n  = 1]). Follow-up was for 45 952 CVAD days, and median time that CVAD remained in place was 1361 days per device. Factor VIII (FVIII) inhibitors were present in 4 of the 15 patients. Ten CVAD-related infections occurred (median, 672 days; range, 72–1941 days), of which six were in one patient with FVIII inhibitors. Overall infection rate was 0.22 (95% confidence interval [CI], 0.10–0.40) per 1000 CVAD days, with 0.11 infections in patients without FVIII inhibitors compared with a pooled incidence of 0.66 (95% CI, 0.44–0.97) reported in the literature. Indications for removal of 27 CVAD were blockage, change to peripheral venous access, catheter displacement, infection, leak in the port septum, short catheter and skin erosion. No clinically apparent thrombosis or sequelae of thrombosis were observed. Infection is the most common complication associated with CVAD use and is increased in patients who have inhibitors. The low rate of clinically apparent thrombosis reflects our practice of not screening for thrombosis. The low infection rate reflects our practice of using and reinforcing the aseptic technique.     

Hypofibrinolysis: A common,major cause of osteonecrosis

In 30 patients with osteonecrosis of the hip (12 idiopathic, 18 secondary), we assessed the role of hypofibrinolysis mediated by high levels of piasminogen activator inhibitor (PAI). We evaluated hypofibrinoiysis as a common, potentially reversible, pathophysiologic cause of idiopathic osteonecrosis. In all 18 patients with secondary osteonecrosis. PAI was normal, as was the ability to activate fibrinoiysis. Nine of the 12 patients with idiopathic osteonecrosis had exceptionally high PA1 levels and could not normally elevate tissue piasminogen activator (tPA-Fx), the major stimulator of fibrinolysis, after 10 min of venous occlusion at 100 mm Hg. The group of 12 patients with idiopathic osteonecrosis, compared to the 18 with secondary osteonecrosis, had low mean stimulated tPA-Fx (1.92 vs. 7.6 IU/mi, P .001) and very high stimulated PAI-Fx (70 vs. 7.6 U/mi, P ? .01). Three of the 12 patients with idiopathic osteonecrosis had both normal PAI and normal Stimulated tPA-Fx. These three patients and 14 of the 18 with secondary osteonecrosis had high lipoprotein (a) [Lp(a)] (>20 mg/dI). Mean Lp(a) was much higher (60 mg/dI) in the patients with secondary osteonecrosis than Lp(a) (16 mg/dI, P ? .001) in the 12 patients with idiopathic osteonecrosis. These findings suggest that hypofibrinoiysis mediated by high PAI is a common cause of idiopathic osteonecrosis, whereas high Lp(a) may play an etiologic role in secondary osteonecrosis. Prospective studies of patients with high PA1 and/or high Lp(a) should be carried out to assess further their apparently causal roles in osteonecrosis. © 1994 Wiley-Liss, Inc.     

Clinical safety and outcome of recombinant tissue plasminogen activator in patients with stroke attributable to small artery occlusion: A protocol for systematic review and meta-analysis

Background:Recent observations raised concern that the intravenous recombinant tissue plasminogen activator (rt-PA) may result in damage to stroke patients caused by small artery occlusion (SAO). Thus, we perform a protocol for meta-analysis to investigate the efficacy and safety of intravenous thrombolysis with rt-PA in SAO-patients.Methods:The search-style electronic libraries, including Pubmed, Embase, the Cochrane Library, Web of Science, Wanfang Data, VIP Chinese Journals, and China Biomedical Literature Service System are used for document retrieval in June 2021 with no restrictions on language. The risk of bias in include articles will be assessed using the Cochrane Risk of Bias Tool. We perform the meta-analysis by Stata version 10.0 software and calculated the statistics using the inverse variance statistical method. Binary outcomes are presented as Mantel-Haenszel-style risk ratios with 95% confidence interval. Continuous outcomes are reported as mean differences.Results:The results of the article will be shown in a peer-reviewed journal.Conclusion:Intravenous rt-PA may be effective and safe in SAO-patients.     

Risk of Venous Thromboembolism Following Peripherally Inserted Central Catheter Exchange: An Analysis of 23,000 Hospitalized Patients

Background

Catheter exchange over a guidewire is frequently performed for malfunctioning peripherally inserted central catheters (PICCs). Whether such exchanges are associated with venous thromboembolism is not known.

How to achieve full prophylaxis in young boys with severe haemophilia A: different regimens and their effect on early bleeding and venous access

To facilitate early prophylaxis, step‐up regimens starting prophylaxis with infusions 1× week^?1 were introduced. Choice of initial regimen may affect outcome. This study aims to classify initial prophylactic regimens and compare them on short‐term outcome. From the ‘European Paediatric Network for Haemophilia Management' (PedNet) registry, patients with severe haemophilia A without inhibitors, born 2000–2012, receiving prophylaxis were included. Treatment centres were classified according to the initial frequency of prophylactic infusions and the age at reaching infusions ≥3× week^?1. Bleeding, and central venous access device (CVAD) use were compared at age 4 years. In 21 centres with 363 patients, three regimens were identified: (i) start prophylaxis with ≥3× week^?1 infusions before age three (full: 19% of centres, 18% of patients); (ii) start 1–2× week^?1, increasing frequency as soon as possible (asap), reaching ≥3× week^?1 before age three (43% of centres, 36% of patients); (iii) start 1–2× week^?1, increasing frequency according to bleeding (phenotype), reaching ≥3× week^?1 after age three (38% of centres, 46% of patients). Prophylaxis was started at median 1.2 years on the full and asap regimen vs 1.8 years on the phenotype regimen. Complete prevention of joint bleeds was most effective on the full regimen (32% full vs. 27% asap and 8% phenotype), though at the cost of using most CVADs (88% full vs. 34% asap and 22% phenotype). The three prophylaxis regimens identified had different effects on early bleeding and CVAD use. This classification provides the first step towards establishing the optimum prophylactic regimen.     

Biomaterials and Adipose-Derived Mesenchymal Stem Cells for Regenerative Medicine: A Systematic Review

The use of biological templates for the suitable growth of adipose-derived mesenchymal stem cells (AD-MSC) and “neo-tissue” construction has exponentially increased over the last years. The bioengineered scaffolds still have a prominent and biocompatible framework playing a role in tissue regeneration. In order to supply AD-MSCs, biomaterials, as the stem cell niche, are more often supplemented by or stimulate molecular signals that allow differentiation events into several strains, besides their secretion of cytokines and effects of immunomodulation. This systematic review aims to highlight the details of the integration of several types of biomaterials used in association with AD-MSCs, collecting notorious and basic data of in vitro and in vivo assays, taking into account the relevance of the interference of the cell lineage origin and handling cell line protocols for both the replacement and repairing of damaged tissues or organs in clinical application. Our group analyzed the quality and results of the 98 articles selected from PubMed, Scopus and Web of Science. A total of 97% of the articles retrieved demonstrated the potential in clinical applications. The synthetic polymers were the most used biomaterials associated with AD-MSCs and almost half of the selected articles were applied on bone regeneration.     

Effects of tissue plasminogen activator on medium-term functional independence: A propensity score-matched analysis

This study revealed the effects of tissue plasminogen activator (tPA) on medium-term functional independence in patients with stroke. We retrospectively examined 240 patients from April 2016 to March 2019 and selected 68 who met our criteria. After adjusting the functional status at the onset by propensity score matching, the functional independence measure (FIM) on admission to and discharge from the convalescent rehabilitation wards was compared between the groups classified by the presence or absence of tPA. Twelve pairs were derived by propensity score matching. Upon admission to the convalescent rehabilitation ward, the median score of the FIM was significantly higher in the tPA group than in the non-tPA group (P = .028). Patients in the tPA group had higher median FIM scores at discharge than those in the non-tPA group (P = .060). The difference in the independence level of activities of daily living (ADL) between the groups with and without tPA may gradually decrease with continuous inpatient rehabilitation. However, the tPA group tended to have high levels of independence in ADL at the time of discharge.     

Sixty-Minute Alteplase Protocol: A New Accelerated Recombinant Tissue-Type Plasminogen Activator Regimen for Thrombolysis in Acute Myocardial Infarction

Objectives. Our aim was to design and evaluate a new and easily administered recombinant tissue-type plasminogen activator (rt-PA) regimen for thrombolysis in acute myocardial infarction (AMI) based on established pharmacokinetic data that improve the reperfusion success rate.

Background. Rapid restoration of Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow is a primary predictor of mortality after thrombolysis in AMI. However, TIMI grade 3 patency rates 90 min into thrombolysis of only 50% to 60% indicate an obvious need for improved thrombolytic regimens.

Methods. Pharmacokinetic simulations were performed to design a new rt-PA regimen. We aimed for a plateau tissue-type plasminogen activator (t-PA) plasma level similar to that of the first plateau of the Neuhaus regimen. These aims were achieved with a 20-mg rt-PA intravenous (i.v.) bolus followed by an 80-mg i.v. infusion over 60 min (regimen A). This regimen was tested in a consecutive comparative trial in 80 patients versus 2.25 10⁶ IU of streptokinase/60 min (B), and 70 mg (C) or 100 mg (D) of rt-PA over 90 min. Subsequently, a confirmation trial of regimen A in 254 consecutive patients was performed with angiographic assessment by independent investigators of patency at 90 min.

Results. The comparative phase of the trial yielded, respectively, TIMI grade 3 and total patency (TIMI grades 2 and 3) of 80% and 85% (regimen A), 35% and 50% (B), 50% and 55% (C) and 60% and 70% (D). In the confirmation phase of the trial, regimen A yielded 81.1% TIMI grade 3 and 87.0% total patency. At follow-up angiography 7 (4.1%) of 169 vessels had reoccluded. In-hospital mortality rate was 1.2%. Nadir levels of fibrinogen, plasminogen and alpha₂-antiplasmin were 3.6 ± 0.8 mg/ml, 60 ± 21% and 42 ± 16%, respectively (mean ± SD). Fifty-seven patients (22.4%) suffered from bleeding; 3.5% needed blood transfusions.

Conclusions. The 60-min alteplase thrombolysis in AMI protocol achieved a TIMI grade 3 patency rate of 81.1% at 90 min with no indication of an increased bleeding hazard; it was associated with a 1.2% overall mortality rate. These results are substantially better than those reported from all currently utilized regimens. Head to head comparison with established thrombolytic regimens in a large-scale randomized trial is warranted.