Barriers to primary prophylaxis in haemophilic children: the issue of the venous access

Abstract

Modern treatment for hemophilic children is based on prophylaxis and immune tolerance induction (ITI). Both treatment regimens are based on frequent infusions at early ages, therefore an adequate venous access is essential. Peripheral veins represent the best option, however, different solutions, as central venous access devices (CVADs) and arteriovenous fistulae (AVFs), can be adopted if needed. CVADs have been used in hemophiliacs, however their survival is affected by infectious complications. Among CVADs, fully implantable devices are usually preferred to external lines due to a lower infectious risk. The limited survival of CVADs may have a relevant impact on treatment outcome, especially in case of ITI where treatment interruptions are counterproductive. To overcome such drawbacks, internal AVF has been considered as an alternative option owing to a lower rate of infectious complications. Moreover, AVF is easy to use in the home setting and well accepted by children. Possible complications not preventing AVF use are postoperative hematoma and transient symptoms of distal ischemia; one case of symptomatic thrombosis has been reported so far. Long-term complications include loss of patency, aneurysmatic dilatation and, rarely, limb dysmetria and a regular follow-up is mandatory to allow early remedial intervention. Surgical dismantlement of AVF is recommended as soon as transition to peripheral veins is possible.

Introduction

Modern treatment for children with severe haemophilia is based on early prophylaxis, which is able to prevent recurrent bleeding and joint damage^1–4, and, in the case of inhibitor development, on immune tolerance induction (ITI), in order to eradicate the antibodies and restore the efficacy of replacement therapy⁵.

Both treatment regimens involve frequent infusions and are usually started at an early age as home treatment administered by parents or caregivers, thus requiring an adequate and stable venous access. To overcome the difficulties of regular venipuncture in children lacking suitable peripheral veins, central venous access devices (CVADs) have been used in haemophiliacs although infectious and thrombotic complications greatly affect their duration⁶.

More recently, the creation of an arteriovenous fistula (AVF) has been increasingly used because of the lower complication rate associated with this strategy^7–9.

Peripheral veins

Peripheral veins remain the preferred option if large enough to bear frequent accesses, considering that the factor concentrates can be delivered through small needles (23–25 gauge) and the infusion time required is short. The main issue in this setting is the training for parents/caregivers, which should be individualised and carried out in a Haemophilia Centre. Parents/caregivers should be trained in standard venipuncture techniques and informed about the need to change the site of injection frequently to avoid scar formation on the skin and in the vessel walls. Local anaesthetic creams may be used to abolish pain and to allow children to adapt gradually to the practice of regular infusions. Moreover, the tailored and incremental dosing schedules recently proposed for the initiation of early prophylaxis^10,11 may further facilitate this approach.

In the absence of suitable peripheral veins, particularly when demanding infusion regimens are required, the insertion of a CVAD or creation of an AVF may be valid alternatives.

Central venous access devices

CVADs can be distinguished into three groups: external non-tunnelled, external tunnelled and fully implantable devices. Catheters of the first type are rarely used in haemophilic children because of their brief duration and the risk of accidental removal; the other two types have been more extensively adopted. Fully implantable catheters (referred to as ports) are usually preferred to external lines because of their lower rate of infectious complications⁶. CVADs are implanted under aseptic conditions and general anaesthesia. Broad-spectrum antibiotic prophylaxis is given before and 6 hours after the insertion. The external/internal jugular vein or the subclavian vein is exposed by a cervical incision and the catheter tip is placed in the superior vena cava. In the case of port placement the device is placed in a pocket created in the subcutaneous tissue beneath the clavicle and the catheter passes through a subcutaneous tunnel from the pocket to the cervical incision. External catheters can be used immediately after insertion, while it is preferable to access ports after suture removal in order to avoid port-site haematomas. The use of CVAD requires meticulous adherence to sterile techniques, flushing with saline/heparin solution and periodic monitoring of the caregiver’s ability in these procedures. CVADs can be used for blood sampling, although this practice should be performed carefully because of the risk of clotting and infection in the catheter lumen due to residual blood. Although a needle is required, causing some discomfort, ports offer many advantages compared to external lines because they generally last longer, cannot be accidentally displaced by pulling, require less day-to-day care and do not need protective dressings during bathing. On the other hand, the insertion and removal procedures for external catheters are easier and they do not require a needle stick.

In the last decade, CVADs have been increasingly used in haemophilic children to give regular prophylaxis and ITI^12–19, however the occurrence of complications limits the duration of CVAD to the point that up to five catheters per patient maybe required^20–24. In a meta-analysis of 48 studies including haemophiliacs using different types of CVAD⁶, the pooled incidence of infection was 0.66 per 1000 catheter days and, in a multivariate model, three factors were associated with an increased risk of infection: presence of inhibitors, use of external catheters and age between 2 and 6 years at the time of placement of the CVAD. The same study reported a CVAD removal rate because of infection and thrombosis of 70% and 4%, respectively. These findings were confirmed by the results from a prospectively studied cohort in which the need for venous access was greater in children with inhibitors who, compared with children without inhibitors, were younger at the time of port insertion, had a higher rate of early infections of the port and earlier removal because of infection²⁵. However, in this study the age at port insertion was not independently associated with infectious complications but rather with the early development of inhibitors and the subsequent indication for ITI.. Moreover, daily port use (as during ITI) was associated with a higher rate of earlier infections compared with less frequent port use²⁵. Preliminary data from the International ITI Study (I-ITI Study, www.itistudy.com,²¹) have shown lower success rates, higher failure rates and slower ITI responses in patients with CVAD infections than in patients with uninfected CVAD, suggesting that catheter-related infections may have an impact on ITI outcome. CVAD infections are classified as local (exit site), regional (tunnel or pocket), or systemic (sepsis) with an increasing grade of severity. It has been suggested that bleeding occurring around the port or exit site may favour microbial growth and subsequent catheter infection, particularly in children with inhibitors^17,25.

Thrombosis is another well-recognised complication of CVAD use even in haemophiliacs^26–30. Thrombosis on or around the catheter is usually asymptomatic, while mural thrombi on the vessel wall have the potential to progress to symptomatic venous thrombosis. Moreover, any thrombus may serve as a nidus for infection. Risk factors for catheter-related thrombosis have not been clearly identified, although an increased thrombotic risk was reported in children with CVADs inserted percutaneously in the subclavian vein on the left side of the body³¹.

Arteriovenous fistulae

To avoid the high rate of infectious complications which severely affects the duration of catheter use and treatment feasibility, internal AVF have been considered an alternative option for vascular access in haemophilic children since 1999⁷. Skilled vascular surgeons are needed to identify the suitable vascular site by examining arterial pulses, vein calibres and elasticity of vessels walls. Usually the non-dominant upper limb is preferred. AVF are normally created proximally to the elbow crease, with the construction of an arteriovenous anastomosis between the brachial artery and a nearby vein using an end-to-side or side-to-side technique. The blood flow through the AVF is evaluated by physical examination and Doppler ultrasound, which is performed regularly until maturation of the AVF and during the long-term follow-up. Successful maturation of the anastomosis is defined as a dilatation and arterialisation of the vein sufficient to allow regular concentrate infusion. There are published data on the creation of 40 and 9 AVF in 35 and 8 haemophilic children from Italy and the USA, respectively^7–9. In the Italian series, which involves a larger number of patients followed-up for a longer period, almost 50% of children had inhibitors at the time of the creation of the AVF. The median time to AVF maturation was 1 month and successful maturation was obtained in 82% of cases. Complications not preventing AVF use were postoperative haematoma (in 19%, all with inhibitors), early and transient symptoms referable to distal ischemia in 9% and thrombosis of a venous branch downstream of the anastomosis in one case. Other later complications included loss of patency (1 patient), limb hypertrophy (1 patient), and aneurysmatic dilatation (1 patient)⁹. In this series AVF were used for a median of 5 years (range: 1–7) and allowed regular infusions for both prophylaxis and ITI. On this basis, the low rate of complications supports the use of AVF in haemophilic children who need a stable venous access for long-term intensive regimens. An AVF is easy to use in the home setting and parents/caregivers are trained on standard venipuncture techniques as for peripheral vein access. In the USA study an informal assessment of patients and caregivers indicated a high grade of acceptance and satisfaction with AVF⁸.

In order to prevent any shunt-related complication, AVF should be surgically remodelled in case of excessive enlargement or totally dismantled if no longer needed, encouraging the transition to the use of peripheral veins as soon as possible.

Table I summarises the main pros and cons of the different types of venous access in haemophilic children.

Table I.

Pros and cons of different types of venous access in haemophilic children

Type	Pros	Cons
Peripheral veins	- No external devices inserted - No anatomical changes - No surgery required - No special care required	- Low likelihood of successful access at first attempt - Possible haematoma at site of injection
External tunnelled CVAD	- Percutaneous insertion - No needles required - Immediate use - Low risk of leakage	- High risk of infections - Limited duration (≤ 1 year) - Rigorous training needed - Frequent care - Risk of thrombosis - Limits some physical activities - Scarce acceptability - Risk of displacement
Fully implantable CVAD	- Longer duration (> 1 year) - Less frequent care - No limitation of physical activities - Aesthetically acceptable	- Risk of infections - Rigorous training needed - Surgical insertion - Proper needle required - Possible skin erosion after prolonged use - Risk of thrombosis
AVF	- No infections - Long duration (years) - No special care required - Standard venipuncture technique - No limitation in physical activities - Aesthetically acceptable	- Delayed use (after 1–3 months) - Surgical procedure by skilled surgeon - Risk of thrombosis - Risk of shunt-related complications - Risk of upper limb dysmetria (rare)

CVAD: central venous access device

AVF: arteriovenous fistula

Conclusions

The availability of an adequate venous access is an integral part of the modern management of haemophilia in children, since it is crucial in order to deliver treatment regimens correctly. Although peripheral veins represent the best option, different solutions, such as CVADs and AVF, can be adopted in cases of difficult access. Several factors guiding a tailored choice include the child’s age, the patient’s/caregiver’s compliance and the frequency of infusions. It must be realised that the maturation of AVF can be delayed in very young children with veins of small calibre and that CVADs are associated with an increased risk of infection if sterile techniques are not strictly applied and/or frequent infusions are required. To date, the ideal venous access for children lacking suitable peripheral veins has not been unequivocally identified and each option has advantages and drawbacks which may have a different individual relevance. On this basis, every effort must be made to optimise and individualise treatment regimens because this has the potential to improve treatment feasibility reducing the need for alternative venous accesses.