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.     

Use of central venous catheters in children with haemophilia: one haemophilia treatment centre experience

Summary . We report our clinic experience with central venous catheters (CVCs) in 23 children with haemophilia, who, in total, had 35 catheters. Seventeen of the 23 children had Broviac catheters (external), 6/23 had an implantable device (Port-A-Cath) only, while four had Broviac and Port-A-Cath at different times. The age of the patients at the time of initial catheter placement ranged from 4 months to 18 years; 11 were under age 3 years. Indications for CVC placement included induction of immune tolerance, treatment of HIV-related complications, prophylactic therapy following intracranial haemorrhage, primary prophylaxis and secondary prophylaxis. Catheter-related infection was the most common complication, occurring in 84% of the external catheters. Of these infections 79% occurred in HIV-negative subjects. Staph and strep species were the most common infectious organisms isolated. Minor bleeding around the catheter occurred in 20% of cases even with adequate correction of haemophilia. Three children accidentally removed the external catheter (12%). Thrombosis of the catheter was uncommon (8%), occurring in only two patients, one of whom had a small newborn size external catheter. When presenting with line sepsis, haemophilic children who were HIV negative had transient temperature spikes approximately 1 h after catheter flushing. This presentation was different from our oncology or HIV-positive patients with CVC-related sepsis. Our experience with ports (Port-A-Cath) in haemophilic children is limited, but catheter-related infection (40%) seems to be less of a problem with the implantable device and the ports have been well accepted by our haemophilic patients and their parents.     

Complications of central venous access devices in paediatric haemophilia patients

We conducted a retrospective survey of our experience with central venous access devices (CVADs) implanted in children with haemophilia seen at the Vanderbilt Hemostasis-Thrombosis Clinic from 1986 to 2000. Following discussion with parents on the merits and risks associated with the use of CVADs for immune tolerance induction or factor prophylaxis, catheters were inserted under sterile technique in the operating room. One nurse provided demonstration and teaching about catheter care and access. Thirty central venous catheters were inserted in 22 children. Our survey revealed that the two most common complications associated with central venous catheters were bacteraemia and thrombosis. We found a sepsis rate of 0.30/1000 catheter-days or one episode of bacteraemia for every 3346 days of catheter use. The thrombosis rate of our cohort was 0.13/1000 catheter-days or one episode of thrombosis for every 7529 days of catheter use. Uncomplicated venous access is essential in children with severe haemophilia who require prophylaxis or immune tolerance induction. While infection was the most common complication observed in our series, we experienced a lower overall infection rate than several reported series. Catheter thrombosis and subsequent obstruction may occur as a result of intraluminal fibrin deposits. We conclude that the use of implantable central venous catheters is an effective method for accessing children with haemophilia. We accept that the benefits of CVADs in the treatment of paediatric haemophilia patients outweigh the previously documented risks. Future prospective studies should be designed to define all associated risks and to determine effective strategies to reduce them.     

Complications associated with central venous access device in children with haemophilia: a nationwide multicentre study in Finland

Children with haemophilia require venous access for regular infusion of coagulation factors. A central venous access device (CVAD) ensures long‐term access but associates with infectious and non‐infectious complications with proposed risk factors of young age at initial CVAD implantation and presence of an inhibitor. Our aim was to evaluate the incidence and risk factors for complications associated with CVAD usage in a retrospective nationwide multicentre study in five Finnish Paediatric Haemophilia Treatment Centers. Our study investigated 106 CVADs in 58 patients with 137 971 CVAD days. The median access survival was 1159 CVAD days, and most often a malfunction led to CVAD removal after a long survival (median of 1640 CVAD days). We detected a very low bloodstream infection rate (0.12/1000 CVAD days). The presence of neutralizing inhibitor was a significant risk factor for infection. Heparin vs. saline flushing did not influence the CVAD outcome. We detected a lower infection rate than previously reported, although 90% of the patients were very young (<2 years) at first insertion (median age = 1.02 year). Port access was frequent after initial implantation: six patients (10%) used the port daily for immune tolerance induction therapy and 74% at least twice weekly for prophylaxis. Young age did not increase the risk of infections, as 59% of the CVAD‐related infections were recorded in children over 6 years of age. Our national experience confirms the safety of prophylactic factor concentrate administration via ports even in very young children.     

Contrast venography in young Haemophiliacs with implantable central venous access devices

To assess the risk of deep vein thrombosis in Haemophiliacs with long-term central venous catheters, we studied Haemophiliacs followed at our centre with implantable venous access devices (ports) in place for > 6 months. Medical records were reviewed for a history of catheter-related complications. Each patient was examined for physical stigmata of thrombosis. Patency of the vessels was evaluated by contrast venography. Of 21 males with ports, 19 had factor VIII deficiency and two factor IX deficiency. Nineteen ports were evaluable (i.e. were in place for > 6 months). Seventeen patients have their original ports in place; two ports were replaced for mechanical dysfunction (1) and recurrent infection (1). Difficulty withdrawing or infusing occurred with three ports, two of which were cleared with urokinase. Physical examination was normal on all 19 patients. Venograms were performed in 13 of 19 patients. Parents of the remaining six patients refused venography because of the need for peripheral venipuncture. One patient had a small nonocclusive thrombus on the same side as his functioning catheter, and another had minimal narrowing of the subclavian vein at the site of a prior catheter. The overall prevalence of clinically relevant upper venous system thrombosis identifiable by contrast venography was zero (95% CI, 0–23%). We conclude that Haemophiliacs do not have as high a risk of thrombosis as other populations of patients with central venous catheters. The theoretical risk of thrombosis should not preclude use of central venous catheters in patients with Haemophilia.     

MRI after removal of central venous access device reveals a high number of asymptomatic thromboses in children with haemophilia

Central venous access devices (CVADs) are often required in children with haemophilia to secure venous access for prophylactic treatment or immune tolerance therapy. Complications of CVADs include infections, thrombosis and mechanical problems. This study sought to determine the outcome of the vessels by magnetic resonance imaging (MRI) in children with haemophilia and to assess risk factors for development of catheter-related deep venous thrombosis (DVT). After the removal of CVAD an MRI of the chest and neck was performed to 20 boys with haemophilia who each had 1-3 (total number 27) CVADs placed. MRI revealed DVT in five children (25%). As their CVADs were functional at the time of the removal, the DVTs were clinically silent. However, there had been suspicion of DVT leading to replacement of the CVAD in one case. All the children with DVT had their CVADs inserted initially below the age of 1 year. The clinical signs of mild post-thrombotic syndrome (PTS) were common: dilated chest wall veins were observed in 11 (55%) children and were associated with DVT in three cases. Arm circumference discrepancy was observed in one child with DVT. No correlation between the duration or number of CVADs and DVT was detected. None of the patients had subjective symptoms of PTS. Silent DVT is a common complication of CVAD. Catheter insertion at a young age seems to predispose to thrombosis. The long-term consequences of the DVTs remain unknown.     

Surveillance of infectious complications associated with central venous access devices in children with haemophilia

PURPOSE: To analyse the risk factors for infection associated with central venous access device (CVAD) use in children with haemophilia. METHODS: Risk factors for CVAD infection among patients with congenital haemophilia who had had a CVAD implanted at a single institution were evaluated utilizing the following variables: age at CVAD placement, age at end of study, number of days with a CVAD, percentage of lifetime with a CVAD, and history of inhibitor. RESULTS: Fifty-nine patients had a total of 97,936 (median 1768 days per patient) CVAD days in the study period. The median age at CVAD placement was 2.7 years (range 0-14.0). Twenty-six (44%) patients reported CVAD infections during the study period from January 1993 to October 2000. Twenty-four patients had their CVAD replaced, 17 (71%) of whom reported having infections and seven (29%) of whom had a history of inhibitor. The strongest predictor for having any infections was inhibitor status (P=0.16), although none of the risk factors had statistically significant effects. Among the 26 patients reporting infections, 42% had more than one CVAD-related infection. Seven patients had multiple infections involving the same organism. The mean rate of infection was 0.45 per 1000 catheter days, with a 95% confidence interval of 0.33-0.60. Those with a history of inhibitor had an infection rate of 0.66 compared with 0.38 per 1000 catheter days (P=0.09) for those without a history of inhibitor. Patients who were older (greater than the median age of 2.7) at CVAD placement had a lower rate of infection (0.29 vs. 0.65, P<0.01) compared with those < or =2.7 years. Adjustment for inhibitor status had little impact on these results. For the group as a whole, the median time to first infection was 1977 days from CVAD placement. Patients who were older at CVAD placement or study exit had lower relative hazards of infection (P=0.05 and P=0.09 respectively), while those who had inhibitors had a higher but not statistically significant relative hazard of 1.88 (P=0.13). CONCLUSIONS: These data reveal that while considerable numbers of patients develop CVAD-related infection, the interval between catheter placement and infection can be quite long. In addition, the earlier in life a CVAD is placed, the higher the risk of infectious complications, as evidenced by the tendency towards a higher infection rate. Measures to prevent CVAD-related infection might be focused on very young patients who appear to be at higher risk.     

Long‐term follow‐up of children with haemophilia – low incidence of infections with central venous access devices

This study reports on 15 years of experience, in a single haemophilia care centre in France, with central venous access devices (VADs) in children with haemophilia. Following the insertion of a central VAD, patients were requested to return to the hospital on a quarterly basis for a multidisciplinary appointment which included clinical examination, chest X‐ray, cardiac and major vessels ultrasound and preventive fibrinolysis. The family was urged to return to the Haemophilia Care Centre if complications or problems occurred. The follow‐up comprised 50 patients. Data were collected prospectively. The total number of days with a VAD was 86 461 days and the total number of times the VAD was used was 41 192 (approximately every other day). Mean duration of VAD placement was 1269 days (range 113–2794 days). There were 25 complications, of which 9 haematomas and 5 systemic infections. Two VADs, infected with Staphylococcus aureus, had to be replaced. The infection rate was calculated as 0.0578 infections/1000 catheter days. There were no cases of thrombosis. This study concluded that most VAD infections in children can be avoided, even in patients requiring intense, prolonged treatment. The very low infection rate was achieved through the efforts of a multidisciplinary team, combined with extensive training for all individuals involved, adherence to written protocols and specific monitoring measures.     

Consensus recommendations for use of central venous access devices in haemophilia

Venous access is essential for delivery of haemophilia factor concentrate. Wherever possible, peripheral veins remain the route of choice, and the use of central venous access devices (CVADs) should be limited to cases of clear need in patients with caregivers able to exercise diligence in CVAD care and should continue no longer than necessary. CVADs are of recognized value for repeated administration of coagulation factors in haemophilia, particularly for prophylaxis and immune tolerance therapy and in young children. Evidence to guide best practices has been fragmentary, and standardized methods for CVAD usage have yet to be established. We have developed management recommendations based upon available published evidence as well as extensive clinical experience. These recommendations address patient and CVAD selection; CVAD placement, care and removal; caregiver/patient guidance; and complications, including infection and thrombosis. In the absence of inhibitors, ports are recommended, primarily because of fewer associated infections than with external catheters. For patients with inhibitors, ports also appear to be associated with fewer infections. Infection is the most frequent complication, and recommendations to prevent and treat infections are supported by extensive clinical data and experience. Strict adherence to handwashing and aseptic technique are essential elements of catheter care. Evidence-based data regarding the detection and treatment of CVAD-related thrombotic complications are limited. Caregiver education is an integral part of CVAD use and the procedural practices of users should be regularly re-assessed. These recommendations provide a basis for sound current CVAD practice and are expected to undergo further refinements as new evidence is compiled and clinical experience is gained.     

Overview of the use of implantable venous access devices in the management of children with inherited bleeding disorders

Summary.  Frequent infusion of factor concentrates may be challenging in young boys with haemophilia, especially if their disease is complicated by inhibitors. A central venous access device (CVAD) is often placed in young patients in need of repeated infusions for prophylaxis or immune tolerance induction. Although user friendly and capable of providing reliable venous access, these devices are associated with a high complication rate over time. In the haemophilia population, major complications include CVAD-associated infections and deep venous thrombosis, which is most often silent. Established risk factors for catheter-related infection include age less than 6 years at the time of CVAD placement and use of an external CVAD when compared with a totally implantable device such as a port. Avoidance of CVAD-related infections is facilitated by strict adherence to aseptic technique. The risk of deep venous thrombosis appears related to the duration for which the catheter is in place, with the risk increasing beyond 4 years. The promotion of a strict clinic policy in which CVADs are left in place for as short a time as possible should decrease the risk of complications. In rare cases where a totally implantable CVAD cannot be placed for technical reasons, an arteriovenous fistula may provide reliable venous access. In all cases, however, venous access via peripheral veins is preferred over CVADs.     

Central venous access devices in haemophilia

Central venous access devices (CVADs) can facilitate repeated and/or urgent administration of coagulation factors in haemophilic patients. We conducted a systematic review and meta-analysis of complication rates and risk factors for poor outcome. Forty-eight studies with a total of 2704 patients and 2973 CVADs were included. The primary indications for CVADs were immune tolerance therapy (34.9% of patients), difficult venous access (31.8%) and prophylaxis (29.1%). Fully implanted CVADs were employed in 77.4% of cases and external CVADs in 22.6%. A total of 1190 infections were reported, and the pooled incidence of infection was 0.66 per 1000 CVAD days [confidence interval (CI), 0.44-0.97 per 1000 CVAD days]. Among patients developing infection, the pooled time to first infection was 295 days (CI, 181-479 days). Presence of inhibitors was an independent risk factor for infection with an incidence rate ratio (IRR) of 1.67 (CI, 1.15-2.43). Infection was less likely in patients >6 years of age (IRR, 0.46; CI, 0.27-0.79) and recipients of fully implanted CVADs (IRR, 0.31; CI, 0.12-0.86). Available information on thrombosis was limited, with only 55 cases being reported. Eventually, 31.3% of CVADs were removed, and infection was the reason for removal in 69.9% of cases and thrombosis in 4.1%. The pooled time period CVADs remained indwelling prior to removal or the expiration of the study observation period was 578 days per CVAD (CI, 456-733 days per CVAD). CVADs can confer major benefits in patients with haemophilia requiring long-term venous access, and serious complications are rare.     

Complications of central venous catheters in patients with haemophilia and inhibitors

We report our clinical experience with central venous catheters (CVCs) in 15 patients with haemophilia who, in total, had 34 catheters inserted. Eighteen devices were Hickman, six were Port-A-Cath and 10 were nontunnelled catheters (one Quinton, seven antecubital, one jugular and one subclavian vein access). All patients had factor VIII/IX inhibitors at the time of insertion. The mean age at operation was 8.8 years (range 16 months-39 years). Eight of the 15 patients (26/34 implanted catheters, 76%) presented some kind of complication. Pericatheter bleeding during the postoperative period affected a total of seven CVCs (7/34, 20%) in six patients, which required substitutive treatment for several days. Infection was reported in 15 of the CVCs (15/34, 44%), and four of these (4/15, 26%) had more than one episode, with a mean of 1.4 infection episodes per catheter (21/15). The infection rate was 0.2 infections per 1000 patient days or 0.1 per 1000 catheter days. Despite the usefulness of CVCs in haemophilic patients, the high incidence of complications requires careful assessment of the type of device as well as continuous surveillance.     

A prospective clinical trial of implantable central venous access in children with haemophilia

To assess the risks associated with the use of central venous ports in children with haemophilia, 15 HIV-negative patients were prospectively evaluated. Port insertion was required for immune tolerance in two inhibitor patients and continuous prophylaxis in 13 patients with severe factor VIII deficiency, for whom surgery was covered with recombinant factor VIII (rFVIII), then given daily at home until day 6. One inhibitor patient (titre 7 BU/ml) received high-dose rFVIII by continuous infusion until day 3, followed by an immune tolerance treatment scheme; the other (titre 12 BU/ml) was given recombinant activated factor VII by continuous infusion until day 7. After training on the use of the port, all patients continued their infusion programme at home. All ports remained in place for a median period of 413 d (range 125–509). The median number of entries into the port was 184 (range 53–567). Port-site haematoma and infection occurred in one patient on day 7 when an inhibitor became detectable (titre 12 BU/ml). An infectious complication occurred in another patient after 310 d. The port infection rate was 0.42 per 1000 patient-days (0.33 per 1000 entries into the port). This protocol for port placement with short hospitalization appears feasible and safe.     

Regulation of tissue plasminogen activator in sickle cell anemia

Evidence of activation of the clotting system in individuals with sickle cell anemia (SCA) has been observed by several investigators. It has been suggested that the clotting and fibrinolytic systems may play a role in the pathophysiology of vaso-occlusion in SCA. We reported previously evidence of abnormal fibrinolytic activity as reflected in decreased releasable tissue plasminogen activator (t-PA) using a functional assay. We have examined the mechanism of the decreased functional releasable t-PA in individuals with SCA. We studied 12 patients with respect to releasable t-PA, fast acting inhibitor to t-PA (or PAI-1), and immunoreactive or antigenic t-PA. These SCA individuals were at their baseline states and not taking medications known to interfere with the fibrinolytic or clotting systems. We found that the mean releasable t-PA for the SCA individuals was 0.01 IU/ml of plasma with a standard error of mean (SEM) of 0.01. The mean releasable t-PA of 118 healthy normal controls was 0.70 IU/ml with SEM 0.10 (P less than .001). The mean level of fast-acting inhibitor to t-PA in unoccluded circulation of the SCA patients' plasma was 16.5 IU/ml with SEM of 3.54. The mean plasma levels of fast-acting inhibitor to t-PA in 56 healthy controls was 2.56 IU/ml with SEM of 0.29 (P less than .0001). The SCA patients had a mean baseline t-PA antigen level of 5.98 ng/ml with SEM of 1.72. The mean level of t-PA antigen of 78 healthy controls using the same technique was 4.3 ng/ml with SEM of 2.7 (not significant). The mean baseline functional t-PA for SCA individuals was 0.15 IU/ml with SEM 0.01 and the mean baseline functional t-PA for 118 controls was 0.17 IU/ml with SEM 0.10. These data suggest that the mechanism of decreased releasable t-PA in sickle cell anemia is related to an elevation of fast-acting inhibitor to t-PA and that antigenically t-PA is present in normal quantities in the baseline plasma in this population.     

重组组织型纤溶酶原激活剂联合尿激酶治疗急性脑梗死的临床观察

目的观察低剂量重组组织型纤溶酶原激活剂(rt-PA)联合尿激酶静脉溶栓治疗急性脑梗死的远期疗效和安全性。方法选择急性脑梗死患者161例,分为4组:联合溶栓组44例,给予静脉rt-PA尿激酶;rt-PA组37例,尿激酶组32例,对照组48例。观察治疗前及治疗后90 d美国国立卫生研究所卒中量表(NIHSS)评分,同时观察再梗死率、脑出血率及病死率。结果与治疗前比较,4组治疗后90 d NIHSS评分差异均有统计学意义(P<0.01)。3个溶栓组与对照组在90 d有效率及疗效满意率差异均有统计学意义(P<0.01);3个溶栓组90 d有效率及疗效满意率差异无统计学意义(P>0.05)。联合溶栓组与rt-PA组和尿激酶组脑出血率比较差异均有统计学意义(2.3%υs 18.9%υs 18.7%,P<0.05)。结论 rt-PA联合尿激酶治疗急性脑梗死远期疗效和单用rt-PA、单用尿激酶相当,但脑出血率降低,因此该治疗方法是安全有效的,值得推广应用。     

One-year follow-up after recombinant tissue plasminogen activator administered to patients with acute myocardial infarction

Of 106 patients seen within 4 h of chest pain with 107 episodes of acute myocardial infarction, nine died before or during hospitalization mainly from cardiogenic shock, and four died during the next year, three were sudden deaths. The 93 survivors were reviewed at a mean of 53 (range 49-70) weeks after infarction. Of these 93, 18 had had attempted angioplasty (successful in 12) and 15 had had coronary artery bypass grafting (including one patient who had coronary artery bypass grafting performed after unsuccessful angioplasty). The remaining 61 patients continued on medical therapy only. During the one-year follow-up two patients suffered reinfarction and a further 22 had one or more cardiac admissions, mostly for chest pain. At review, 22 patients had angina (16 New York Heart Association Grade I or II) and five dyspnoea (all NYHA Grade II). Forty-three patients were taking oral nitrates, 53 were receiving calcium antagonists, 54 were using betablocking agents and 73 used anti-platelet agents. However, many of these patients continued on anti-anginal therapy prophylactically after their myocardial infarction, without continuing chest pain. Thus after recombinant tissue plasminogen activator therapy and following hospital discharge the mortality rate for patients with acute myocardial infarction was four out of 97 (4.1%) and reinfarction rate among survivors was two out of 93 (2.2%). Although the incidence of cardiac symptoms was low this may be partly due to the high incidence of angioplasty and coronary artery grafting, together with the use of anti-anginal agents.