Literature Review: Reducing Incidences of Central Line-Associated Blood Stream Infections

A bundle is a group of interventions related to a disease process, that when executed together, produce better outcomes than when implemented individually. Numerous studies done in the developed countries have shown that proper implementation of evidence based practices grouped together as central venous catheter bundle had brought a dramatic reduction in the incidence of CLABSI. Studies in developing countries had also shown high incidence of CLABSI and reduction in CLABSI rate albeit lesser than that of developed countries.

Studies from India have a shown a higher incidence of CLABSI and poor adherence to central line catheter bundle. Morbidity and mortality due to CLABSI is considerably high despite underreporting of such events. The development and publication of guidelines often does not lead to changes in clinical behavior and guidelines are rarely if ever, integrated into bedside practice in a timely fashion. The most effective means for achieving knowledge transfer remains an unanswered question across all medical disciplines. Our study aims to determine the compliance with CVC bundle in management of patients in medicine wards and ICU at All India Institute of Medical Sciences New Delhi and the impact of intervention in the form of periodic physician education and feedback in compliance with CVC bundle and central line catheter related complications.

Review of literature

Ever since the introduction of central venous catheters in the early 1950s, it had varied uses and later numerous studies revealed that it was associated with a varied number of complications. Although mechanical complications were common in the early years of CVC use CLABSIs quickly became recognized as a serious complication associated with their usage.

Central venous catheter

is defined as a catheter whose tip terminates in the great vessels. The great vessels are the aorta, pulmonary artery, superior vena cava,inferior vena cava, brachiocephalic veins, internal jugular veins,subclavian veins, external iliac veins, common iliac veins,femoral veins, and, in neonates, the umbilical artery/vein.

Types :

Common types of central venous catheters are Non tunneled catheters, Tunneled catheters, Implantable ports, PICC.

A peripherally inserted central catheter (PICC) is peripherally placed, but is considered a central catheter because its tip terminates in the central circulation. These venous catheters can also have single, double or triple lumens although single lumens are frequently used and are for intermediate to long term therapy for blood draws or infusions.

Complications of CVC:

Mechanical complications

(4,9)include

Pneumothorax is a common complication with subclavian and IJV cannulations without the use of ultrasound. The use of real time ultrasound reduces the number of attempts and associated with a significantly lower failure rate with internal jugular vein ( Relative risk 0.14, 95% confidence interval 0.06 to 0.33).

Limited evidence also exists for sublclavian and femoral routes in this metanalysis. Thus the chances of pneumothorax will be greatly reduced.

Pneumothorax is usually apparent immediately on Chest X rays and management may vary from simple observation to ICD placement with needle drainage needed for tension pneumothorax as emergency(11). Delayed pneumothorax is also known to occur with an incidence of 0.4%, more common with subclavian and with multiple attempts(12). Bedside ultrasonography allows diagnosis of pneumothorax to be made immediately with high sensitivity by clinician but is operator dependent(13).

Misplacement of catheters occur commonly such as tip malposition or rarely such as within artery. It is common practice to assess tip position lying above carina for right sided catheters assuming pericardial reflection below carina and below carina for left sided catheters in view of acute angulation to superior venacava(14). Management varies depending on the complication such as repositioning of tip for tip malposition lying below carina or when lying with an artery, interventional radiologist or vascular surgeon opinion is sought and removed accordingly(15).

Arterial injuries are more common with femoral and internal jugular rather than subclavian approach. A systematic review of complications of central venous catheters revealed significantly more arterial punctures (3.0% vs 0.5%) and less malpositions(5.3% vs 9.3%) with jugular access(16). It leads to hematoma in approximately 40% of patients. The best way to prevent arterial injury is by ultrasound assistance during cannulation(17). Other rarer complications are local hematomas,cerebrovascular accidents mostly seen with arterial injuries via internal jugular access, arrhythmias, perforation of the vein or right atrium, chylothorax, pseudo aneurysm, AV fistulas, cardiac tamponade, guidewire loss and catheter embolisation etc. have been reported. These complications largely depend on the site of insertion and on operator experience. Such complications can be prevented by ultrasound guidance and proper techniques.

Infectious complications are most dreaded as it is associated with mortality rates upto 25% and in developing countries even up to 60% and prolong the duration of hospital stay and are largely preventable. Evidence based guidelines have been developed as the central venous catheter bundle which significantly decreases the incidence of infections as shown in below studies.CVC use in non ICU settings is associated with at least a 2 fold rise in infection rate than in ICU settings. However studies are very limited on the infection rates as well as on the preventive measures in non ICU settings.

Thrombotic complications

range from 1.2 to 3 % in subclavian veins to up to 8 to 34% in femoral cannulations. Merrer et al in a randomized control trial found significantly increased incidence of thrombotic complications(21.5% vs1.9%,p<0.001)(18).This can be avoided by judicious site selection and proper flushing techniques (9).

Every day the central venous catheters are accessed for a variety of purposes which may include frequent CVP monitoring to IV infusions. Every time the catheter is accessed it should be done in a sterile way after the port is scrubbed with antiseptics else the infection rate increases. Dressings should be changed regularly depending on the type and as indicated.

Risk factors for CLABSI :

Intrinsic factors	Extrinsic risk factors
Age – children more likely	Prolonged hospitalization before CVC insertion
Underlying diseases or conditions—hematological and immunological deficiencies, cardiovascular disease, and gastrointestinal diseases	CVC duration, with the risk increasing with CVC dwell time
Male gender	Parenteral nutrition administration
	Femoral or internal jugular access site
	Multilumen CVCs
	Lack of maximal sterile barriers
	CVC insertion in an ICU or emergency department Heavy microbial colonization at insertion site

The semi quantitative analysis of culture of

Maki

proved to be an effective and cost effective measure for the diagnosis of central venous catheter infections(19).

The study conducted by

Pronovost et al

in US which five basic measures hand washing, using full-barrier precautions during the insertion of central venous catheters, cleaning the skin with Chlorhexidine, avoiding the femoral site if possible and removal of unnecessary catheters significantly reduced the incidence of central venous line infections and served as a landmark study in the development of central venous catheter bundle(5). The study was conducted across 103 ICUs in Michigan in US and the rates of infection per 1000 catheter days were measured at 3 monthly intervals and the mean rate of infections decreased from 7.7 to 1.4 after 18 months.

After this study numerous studies were conducted which reinforced the effectiveness of the central venous catheter bundle.

Parra et al demonstrated that even a simple educational program like 15 min lecture given to ICU personnel highlighting 10 evidence based strategies can result in a reduction in CLABSI rates. In his study CLABSI rates decreased from 4.22 to 2.94 infections per 1000 catheter days(20).

WHO

conducted the

Bacteremia zero project

(21) to assess the applicability and effectiveness of the Michigan keystone ICU project in Spanish ICUs. This multifactorial nationwide intervention project was implemented between April 2008 and June 2010, with data collected at regular intervals to evaluate the progress of the project. A total of 192 ICUs (68% of all Spanish ICUs) participated in the project. The intervention was effective in reducing the incidence of CRBSI by approximately 50%in hospitals.

Burrel et al

demonstrated the benefit of having a checklist incorporating both the clinician and patient bundle(22). During this study they found that the compliance with the checklist improved significantly and the infection rate decreased by 50% when the compliance was good.

A nationwide study was conducted in US by

Furuya et al

(23) to find out the central line bundle implementation in ICU and its impact on Bloodstream infections. They found that CL bundle is associated with lower infection rates only when compliance is high. Complying with any one of three CL Bundle elements resulted in decreased CLABSI rates of 38%. This study clearly demonstrated the compliance should be very high to show a demonstrable decrease in the central line infection rate and that on-going evaluation was necessary.

Previously it was uniformly thought that femoral line insertion were associated with a greater incidence of infections .However recent studies have shown that the difference to be insignificant. A study was conducted by

Kedar S Deshpande

(24) in New York where they found that there was no stastically significant difference in the incidence of infections between the three routes in case of major infections when catheter is inserted optimally, catheter care is performed by trained by trained intensive care unit staff although there was a higher case of infections in the femoral group(0.881/1000 catheter days subclavian, 2.0/1000 catheter days internal jugular vein, 5.96/1000 catheter days femoral catheter p=0.1338)

Blood stream infections :

NNIS (National Nosocomial Infection Surveillance system) now renamed as

NHSN

(National Healthcare Safety Network) defines blood stream infections as presence of a recognized pathogen cultured from one or more blood cultures and organism cultured from blood not related to infection at another site or presence of at least one of fever, chills and hypotension with signs and symptoms and positive results not related to infection at another site and presence of at least one of the following: Common skin contaminant (e.g.diphtheroids, bacillus species, propionibacterium species, coagulase negative staphylococci or micrococci) cultured from two or more blood samples drawn on separate occasions or Common skin contaminant cultured from at least one blood culture in a sample from a patient with an intravascular catheter or Positive antigen test on blood (e.g.,

Haemophilusinfluenzae

,

Streptococcus pneumoniae

,

Neisseria meningitidis

, or group B streptococcus)(25).

CLABSI vs CRBSI :

Further 2 distinct terminologies are used in relation to central line infections these are used interchangeably usually though they are different.

A

CLABS

I ( central line associated blood stream infections) is defined as BSI if a CVC was present at the time of or within 48 hrs before the defining blood culture was obtained. There is no requirement to identify the organism on the catheter. This definition was developed for surveillance, not for diagnosis.

In contrast, a

CRBSI

(catheter related blood stream infection) requires that the CVC be in place at the time the positive blood culture was obtained and a positive quantitative or semi quantitative culture of the same organism from the catheter or time to positivity.

The CLABSI definition is more practical than the CRBSI definition for surveillance. However, it may overestimate the true rate of CVC–related infections, as it can sometimes be difficult to determine infections related to the central line rather than remote unrecognized infections (for example, urinary tract infections, pneumonia, intra-abdominal abscess). Interobserver variability and a lack of standardization in CLABSI surveillance are other important limitations(26).

Usually the organism grown on culture is likely to be significant only when atleast 15 CFU or 10 *3 colonies are isolated of the same organism.

Catheter infection and colonization:

Catheter infection and colonization can occur by 3 routes –

• Extra luminal from organisms migrating along the catheter surface,
• Intraluminal through the ports or through contaminated fluids rarely,
• Hematogenous from a source of infection elsewhere in the body.

Terminologies commonly used with regard to catheter infection and colonization are defined as follows (24)

1. Catheter infection

A. 15 CFU on catheter tip with the same bacteria and sensitivities (one different sensitivity included) in one or more blood cultures.

B. Resolution of clinical signs and symptoms of infection in 24–48 hrs after catheter removal regardless of bacterial growth either in blood or on catheter tip.

C. 15 CFU on catheter tip with local signs of infection regardless of blood culture bacterial growth.

2. Catheter colonization

A. Catheter tip with 15 CFU without growth in blood cultures and another source of infection found.

B. Catheter tip with 15 CFU and bacteria in peripheral blood cultures from another source of infection.

3. Contamination: <

15 CFU on catheter tip without bacterial growth in blood cultures or bacteria in blood cultures from another source of infection.

Till date most of the studies have emphasized in catheter related infections as proposed by NHSN but as of date due to the aggressive use of broad spectrum antibiotics culture negativity is more common. So to remove this confounding factor any fever in a patient with central line which has no proven focus of infection elsewhere and resolves within 2 days after removal of central line can be taken as CLRI. This is based on the fact that catheter infection is “cured” only with removal or a prolonged course of intravenous antibiotics; the relatively short courses of antibiotics used for ICU infections could not truly affect the catheter infection end point. However antibiotic use can result in negative cultures results even in the presence of catheter infection.

This definition was implemented in a study by

Kedar S Deshpande et al

(24)in New York where they found that the overall incidence of central line infection is low whatever the route may be and there was no stastically significant increase in infections in the femoral route provided proper strict aseptic insertion and maintenance techniques are followed. Thus the dangerous mechanical complications of pneumothorax can be avoided.

Developing countries scenario:

Rosenthal et al

(27)showed that the neonatal blood stream infections to be 5 times higher in developing countries than the developed countries. INICC conducted a surveillance study in 36 countries involving 422 ICUs and found a overall increased incidence of HAI. CLABSI rates were found to be 3 times higher when compared with USA (6.8 per 1000 CL days vs 2 per 1000 CL days). There was increased resistance to multiple gram negative organisms and MRSA was also more frequent in developing countries(28). Unadjusted crude excess mortality rate was also higher in developing countries both for CLABSI and VAP in the range of 7.3% to 15.2%

Reasons for the differences in the degree of burden of HAIs in developing countries include the following: Limited knowledge and training in basic infection prevention and control , Limited awareness of the dangers associated with HAIs , Inadequate infrastructure and limited resources, Poor adherence to routine hand hygiene, Reuse of equipment (for example, needles, gloves) , Poor environmental hygiene and overcrowding, Understaffing, Inappropriate and prolonged use of antimicrobials and invasive devices , Limited local and national policies and guidelines, Variable adherence to official regulations or legal frameworks, where they exist and Insufficient administrative support.

A quasi experimental study was conducted by Apisarnthanarak et al in Thailand where he found improved adherence to central line bundle particularly hand hygiene improved significantly after intervention from 8% to 54% and CA-BSI decreased significantly from 14 per 1000 catheter days to 1.4 per 1000 catheter days(29) .

Indian scenario:

Indian studies have shown that the incidence if central venous catheter infections are 3 to 4 times higher in our settings and that gram negative bacteria and fungi are more common in our settings compared to gram positive infections in western settings(30)(31), The Study conducted by

Pawar et al

in Escort hospital revealed that gram negative bacilli had a higher prevalence ( 71% ) as against western settings where gram positive organisms account for 70 % . They also found that the duration of catheterization, coexistent infections and increased temperature were the important predictors of CLABSI.

A study was conducted in 12 Indian ICUs by

INICC

which revealed a higher incidence in our settings and a overall poor adoption of the catheter bundle practices and the incidence gradually and progressively decreased after proper practices (6,18). Prospective surveillance in Indian ICUs yielded a central venous catheter-related bloodstream infection (CVC-BSI) rate of 7.92 per 1000 catheter-days(18). The incidence of central venous catheter infections then decreased subsequently after the adoption of proper practices. The study also revealed that proper education; performance feedback and outcome and process surveillance of CLABSI rates significantly improved infection control practices and brought a 54% decline in CLABSI incidence(6)

.

INICC

conducted a prospective before and after cohort study in eight Indian cities where they found implementation of six components of INICC simultaneously resulted in a significant reduction in CLABSI from 6.4 CLABSIs per 1000 central line days to 3.9 CLABSIs per 1000 central line days resulting in 53% CLABSI rate reduction which was highly significant(31).

Some studies had shown that empowering the nurses with the central venous bundle and to interfere if the proper practices are not followed will go a long way in the further reduction of CLABSIs. However in spite much of the reported successes in ICU population the non ICU population are still at a significant risk of infection. In developing countries empowering the nurses is still a long way to go as understaffing and proper techniques are still not adopted(15,6). Still application of inexpensive and practical infection prevention efforts, such as improved hand hygiene and removal of CVCs when they are no longer needed, can have a major impact on CLABSI rates.

IHI central venous catheter bundle was implemented as a project in 5 million lives campaign(32). Essential features are

Hand Hygiene

:

The cornerstone of WHO’s “

Clean Care Is Safer Care

” campaign, the “

My 5 Moments for Hand Hygiene

” approach, has resulted in the development of resources, including localized country-specific tools, to facilitate adherence to hand hygiene guidelines(33).

To minimize the risk of CLABSI associated with direct contact of the hands of health care personnel, the 2011 USCDC guideline recommends that hand hygiene be performed at the following times: before and after palpating the site of catheter insertion, before and after inserting the catheter, before and after accessing, replacing, repairing, or dressing the catheter. In addition, after the antiseptic has been applied to the site, further palpation of the insertion site should be avoided, unless aseptic technique is maintained (34).

Adherence to hand hygiene is generally suboptimal with rates under 40 % in multiple studies. Improving hand hygiene can be achieved through multiple educational interventions.

Maximum sterile barrier precautions

:

Raad et al

conducted a prospective randomized control study to determine the effectiveness of the maximum sterile precautions .they found that the control group had 6 times higher infection rates and the infections occurred early and mostly were caused by skin microorganisms(35).

Skin preparation:

Reducing colonization at the insertion site is a crucial part of CLABSI prevention. It can be done with aqueous povidone iodine, aqueous chlorhexidine, alcoholic chlorhexidine or alcoholic povidone iodine. A recent meta analysis revealed that the 2 %chlorhexidine is associated with a 50% decrease in the CLABSI rates compared to povidone iodine(36). However, a recent study by

Furuya et al

(23) identified the importance of allowing chlorhexidine to dry fully before CVC insertion in order to optimize the use of this agent. An economic analysis suggested that using chlorhexidine rather than povidone iodine would result in a 1.6% decrease in CLABSIs and a 0.23% decrease in mortality, as well as save $113 per catheter used(37). The proposed mechanism is believed to be prolonged antimicrobial effect, its lack of inactivation to blood and serum and synergistic effect with alcohol. However whether chlorhexidine alcohol combination is superior to alcoholic povidone iodine is still unresolved. The role of alcohol as antiseptic agent is often forgotten while describing chlorhexidine(38). CDC recommends >0.5% chlorhexidine alcohol to be used in case of central line insertion. However a recent Indian study conducted in 2013 by Kulkarni et al found that both povidone iodine and chlorhexidine had zero colony counts in skin preparation(39).

Maintenance:

Catheter site dressings can be done by transparent to semitransparent dressings or gauze dressings. The advantage with sterile dressings is that visual inspection can be done daily and they need to be changed once in 7 days unless gauze dressings which needs to be changed every 2 days. However if patient is in DIC or there is bleeding at the site of insertion gauze dressings are preferred(40).

The current recommendations are to assess the continued need for the catheter every day, perform catheter site care with Chlorhexidine at dressing changes, replace administration sets and add-on devices no more frequently than every 72 hours, unless contamination occurs, replace tubing used to administer blood, blood products, or lipids within 24 hours of start of infusion, change caps no more often than 72 hours or according to manufacturer’s recommendations and whenever the administration set is changed(41).

Shapey et al conducted a prospective audit in a university teaching hospital and found that several breaches were there in CVC post insertion care with a failure rate of 44.8% mostly in caps, dressings and proposed that focus should be shifted to best practice implementation rather than further teaching(42)

The significance of catheter maintenance or post insertion bundle was demonstrated by Guerin et al who showed that implementation of a post insertion bundle in hospitals with good compliance to insertion bundle resulted in decrease in CLABSIs from 5.7 to 1.1 CLABSIs per catheter days. He emphasized that insertion bundle by itself was not sufficient. The interventions done were assessing the catheter site daily, changing dressings if necessary, application of chlorhexidine sponge at the catheter site, assessing the need for catheter daily, performing hand hygiene and alcohol scrub before accessing hub each time(43).

Using closed container systems than open container infusion systems had significantly reduced the incidence of CLABSI in many studies. This was demonstrated by Maki et al who conducted a study in 4 countries and found that switching to closed infusion containers decreased CLABSIs from 10.1 to 3.3 per 1000 catheter days RR 0.33 p<0.001(44).

Prompt removal of catheters:

Zingg et al

in his study found that in several site visits, neither the nurse nor the treating physician knew why the patient had a CVC particularly in non ICU settings. They also showed that catheters in non ICU settings had a longer dwell time and lesser utilization(45) .

Trick et al

in his study found that 4.6% of catheter-days were not justified. Both of these research groups also found differences in CVC use between ICU and non-ICU settings: unjustified CVC–days were more common in the non-ICU settings. The median duration of CVC days were more common for catheters that were unjustified rather than justified. They also proposed as to consider removal of CVC if needed when patient is getting transferred out of ICU (46).

Von Willebrand disease (VWD) is the most common inherited bleeding disorder in humans (Williams & Patel, 2015). The condition is characterised by prolonged mucous membrane and skin bleeds (Green, 2018) and, in more severe forms, by bleeding of the joints (Swedish Council on Health Technology, 2011). These bleeds occur due to inadequate levels or dysfunction of von Willebrand factor (VWF; Swedish Council on Health Technology, 2011), which plays a significant role in platelet adhesion and aggregation during haemostasis (Peyvandi, Garagiola, & Baronciani, 2011). There are three main classifications of VWD: Type 1, Type 2 and Type 3, all of which are based on the quantity and quality of VWF (Green, 2018). The inheritance pattern for most patient types of VWD is autosomal dominant (Green, 2018), affecting both men and women equally (Cameron, Jelinek, Kelly, Brown, & Little, 2015). There are, however, rare cases of Acquired von Willebrand syndrome (AVWS) that can also occur (Nichols et al., 2008). Diagnosis of VWD can be complex (Williams & Patel, 2015), requiring detailed personal and familial history of bleeding symptoms in addition to screening tests and diagnostic tests to confirm diagnosis (Lee, Berntorp, & Hoots, 2014). Several treatments exist for the management of VWD, tailored to the type and severity of the condition (Green, 2018).

Pathophysiology

VWD is a bleeding disorder that causes prolonged mucosal bleeding following vascular injury and is attributable to dysfunction or deficiency of the plasma protein VWF, inhibiting the formation of haemostatic plugs (Green, 2018). VWF is an essential component of haemostasis (Williams & Patel, 2015), with two distinct functions responsible for binding and stabilisation of blood coagulating factor VIII (FVIII) and platelet adhesion to sites of vascular damage (Hassan, Saxena, & Ahmad, 2012). It is synthesised in endothelial cells and megakaryocytes (Lee et al., 2014) and can be found throughout the body in blood plasma and platelets in varying multimeric sizes (Hassan et al., 2012). The larger sizes have been noted to be more effective in the process of haemostasis (Hassan et al., 2012).  VWF carries out its primary functions secondary to vascular injury (Williams & Patel, 2015). This injury leaves subendothelial collagen cells exposed which stimulates release of VWF by several triggers such as histamine, thrombin, fibrin and estrogen (Peyvandi et al., 2011). VWF then goes on to facilitate binding of FVIII and platelets to collagen cells via glycoprotein 1b (GPIb) receptors which are located on the platelet surface (Hassan et al., 2012). Following this adhesion, platelet activation occurs via intracellular signalling (Reininger, 2008). Once activated, platelets undergo a conformational change leading to the activation of platelet glycoprotein 2b3a (GPIIbIIIa) receptor allowing mediation of platelet aggregation via fibrinogen binding and eventual thrombus formation thus completing primary haemostasis (Federici, 2011).

Patients with VWD who possess insufficient VWF to carry out normal haemostasis may present clinically with characteristic symptoms such as contusions, epistaxis, menorrhagia, prolonged bleeds from minor wounds, post tooth extractions, surgery, child birth, and gastrointestinal bleeds (Federici, 2011). Severe symptoms such as musculoskeletal bleeding are more likely to occur in severe classifications (Federici, 2011). Within the 3 types of VWD, an additional four subcategories falling within Type 2, all of which have unique clinical features and significance with regard to diagnosis and treatment (Sadler et al., 2006). Type 1 is the most commonly encountered form of VWD and is defined by decreased VWF activity associated with reduced synthesis, intracellular retention or due to increased clearance (Green, 2018). Type 2 patients are further categorised into four subtypes, Type 2A presents with reduced synthesis or higher than normal proteolysis of high-molecular-weight VWF multimers, Type 2B shows increased affinity of VWF to GPIb platelet receptors and Type 2M show normal measurements of multimers with an inability to bind to collagen or platelet GPIb receptors, while binding site mutations for FVIII characterise Type 2N patients (Green, 2018). Type 3 is rare among patients and presents with complete or near absence of VWF attributed to significant gene deletions that affect synthesis and secretion of VWF (Green, 2018). Acquired von Willebrand syndrome is a rare haemorrhagic condition and presents with symptoms similar to inherited VWD (Mital, 2016). Characteristically, AVWS does not present with previous personal and familial bleeding symptoms and occurs more often in older age groups (Mital, 2016). Development normally occurs as a result of other conditions such as lymphoproliferative, myeloproliferative, cardiovascular and autoimmune disorders but may also present with some non-haematological conditions as well as in the use of some prescription drugs (Mital, 2016). Due to complexity, the pathology of AVWS is not fully understood (Mital, 2016). Deficiency of functioning VWF is thought to occur in the presence of specific antibodies against VWF, its absorption onto surfaces of neoplastic cells, mechanic injury or frequency of clearance (Mital, 2016).

Epidemiology/Prevalence

Prevalence of VWD is often cited as approximately 1% of the general population (Williams & Patel, 2015), however, variances of diagnostic criteria and differences between standardised clinical laboratory methodologies may influence reported incidence rates differently (Federici, 2011). Prevalence of the six VWD types can also vary from study to study (Lee et al., 2014). Summary of data collected from a series of studies places prevalence of Type 1 VWD to occur in approximately 70% of cases, Type 2 in 17% and Type 3 in 13% (Lee et al., 2014). Though VWD affects both men and women equally, women are often higher represented due to tendency to present with menorrhagia, which develops in >80% of women with VWD (Lee et al., 2014). Prevalence of Acquired von Willebrand syndrome is difficult to ascertain due to low rates of detection and common misdiagnoses (Mital, 2016).

Diagnosis

In the diagnosis of VWD, personal and familial history in conjunction with several diagnostic and screening tools are utilised (Lee et al., 2014). Screening tools, though often imprecise, are useful to general practitioners in guiding referral of patients to specialists (Lee et al., 2014). Initial laboratory testing consists of complete blood count, partial thromboplastin time, bleeding time and platelet function analysis (Lee et al., 2014). Definitive diagnosis of VWD relies on diagnostic testing of VWF function in conjunction with consistent clinical history (Lee et al., 2014).

Treatment Aims

Von Willebrand Disease is a lifelong condition with no cure (Castaman, Goodeve & Eikenboom, 2013). Management will therefore continue throughout a patient’s life. Treatment of VWD aims to prevent or stop bleeding episodes (Heijdra, Cnossen & Leebeek, 2017). This is achieved by increasing plasma concentration levels of von Willebrand factor (VWF) and Factor VIII (FVIII) to adequate haemostatic levels (Sadler et al., 2006) (Rodeghiero, 2013). For women, treatment is usually heavily focused on controlling heavy menstrual bleeding and pregnancy related haemorrhage.

Most patients suffering VWD will only require treatment if the patient has experienced trauma, or is having major or minor surgical procedures or dental procedures (Castaman, Goodeve & Eikenboom, 2013). However, more severe forms may require ongoing treatment to maintain Factor levels (Sadler et al., 2006). Treatment options also vary dependent on the type and severity of disease, and patient response to previous treatments (Heijdra, Cnossen & Leebeek, 2017). A variety of therapeutic approaches are used to achieve normal haemostasis, including Desmopressin, Infusion of plasma-concentrates, Anti-fibrinolytic agents, and for women, hormonal contraceptive therapies (Federici et al., 2002). The use of these treatment options are discussed below.

Treatment Options

Desmopressin (DDAVP):

DDAVP is a synthetic hormone which binds to the receptors targeted by vasopressin (Federici et al., 2002). These receptors, when activated, stimulate the release of VWF and FVIII from endogenous stores in the endothelium (James, 2017) (Schneppenheim, 2011) (Schneppenheim, 2011). Factor levels are rapidly increased; often 3-5 fold original levels (Schneppenheim, 2011). DDAVP is the most widely used treatment and is effective for most patients with Type 1 VWD (Heijdra, Cnossen & Leebeek, 2017). Responses of patients with type 2 VWD are difficult to predict. Subtype 2/B are contraindicated against DDAVP due to the risk of severe thrombocytopenia. Type 3 VWD patients are unresponsive to DDAVP as they do not produce any VWF and therefore have no stores to release when receptors are activated (Schneppenheim, 2011).  Patient responses to DDAVP are varied but individual responses are consistent over time (Heijdra, Cnossen & Leebeek, 2017). Therefore a DDAVP test is used establish an individual’s response to the drug, prior to clinical need (Schneppenheim, 2011) (Heijdra, Cnossen & Leebeek, 2017). Response to DDAVP is deemed adequate if levels of plasma VWF increase 3 fold (Schneppenheim, 2011). If the response is deemed adequate, DDAVP is the first choice of management. Mild Side effects of the drug include flushing, transient headache and hypotension (Tiede, 2012). DDAVP is administered intravenously, subcutaneously and intranasal (Heijdra, Cnossen & Leebeek, 2017). Intranasal sprays are often used as home treatments in case of bleeding, but are not as effective at increasing factor levels (Heijdra, Cnossen & Leebeek, 2017). Use of DDAVP is recommended for minor surgeries.

Plasma-Concentrates:

Infusions of prepared doses of concentrated VWF and FVIII are used to increase plasma levels and are the treatment of choice when excessive bleeding needs to be prevented (such as major surgery) or when response to DDAVP is inadequate (Schneppenheim, 2011). Infusion therapies can be used for all disease types, but are most commonly used for patients with Type 3 VWD, Type 2/B VWD (due to Contraindication to DDAVP), and patients who are unresponsive to DDAVP (Schneppenheim, 2011) (Heijdra, Cnossen & Leebeek, 2017). Concentrates are most commonly used during surgery or after trauma, but may also be used as prophylaxis for severe forms of the disease (Federici et al., 2002) (Tiede, 2012). Patients with severe forms are usually Type 3 and suffer recurrent spontaneous bleeds, including joint bleeds and Gastrointestinal bleeds in the elderly (Heijdra, Cnossen & Leebeek, 2017). No adverse effects are experienced and the majority of surgical cases are resolved with a single administration (Federici et al., 2002).

Anti-fibrinolytic agents:

These agents inhibit the interaction of plasminogen with fibrin, preventing the degradation of formed fibrin clots (Heijdra, Cnossen & Leebeek, 2017) (Tiede, 2012). Examples include Tranexamic acid and Aminocaproic acid. The drugs are low cost with few side effects and are able to be administered orally or intravenously (Heijdra, Cnossen & Leebeek, 2017). Anti-fibrinolytic medications are often prescribed before and after surgical or dental procedures for patients with bleeding disorders.

Management Strategies for Women

Management strategies for women with VWD are more complex than for men due to the challenges or controlling haemostatic bleeding due to menstruation and child-birth (James, 2017). Women will often experience menorrhagia, a menstrual period with abnormally heavy or prolonged bleeding. If not properly managed, menorrhagia often leads to iron deficiencies, which, if severe, may require blood transfusions (Heijdra, Cnossen & Leebeek, 2017). DDAVP intranasal spray is often used at the beginning of the menstrual cycle to control excessive bleeding (Rodeghiero, 2013) Contraceptives also control heavy bleeding during menstrual periods. Estrogen present in birth control boosts plasma levels of VWF and FVIII activity. Oral contraceptives are recommended for women not wishing to fall pregnant but wanting to maintain fertility (Rodeghiero, 2013) (Heijdra, Cnossen & Leebeek, 2017). Often a combination of hormonal contraceptives and anti-fibrinolytic agents are used during menstruation (Schneppenheim, 2011) (Heijdra, Cnossen & Leebeek, 2017). For Women who do not wish to preserve fertility, Hysterectomies may greatly improve quality of life, though Surgical Complications due to VWD must be considered (James, 2017). VWD in women will also increase the risk of post-partum haemorrhage .Plasma concentrations of VWF rise during pregnancy, but will fall below acceptable levels post-partum (Heijdra, Cnossen & Leebeek, 2017). Anti-fibrinolytic agents and DDAVP are given in combination for at least 7 days post-partum to reduce the risks (Heijdra, Cnossen & Leebeek, 2017).

Outcomes

Although VWD has no cure and will affect the patient for life, it is a disease that is well understood and in most cases easily managed (Sadler et al., 2006). Treatments are highly effective and most patients will only require treatment when undergoing surgery or after experiencing trauma (Sadler et al., 2006). Modern technologies have allowed treatments to become more individually tailored. Plasma-concentrates can be tailored to patients and their individual levels of required VWF and FVIII (Heijdra, Cnossen & Leebeek, 2017) (Heijdra, Cnossen & Leebeek, 2017). Patients with mild presentations of the disease may only require counselling and advice about the use of anti-fibrinolytics for use pre and post invasive procedures (Rodeghiero, 2013).

Paramedic Relevance

VWD is the most common inherited bleeding disorder world-wide (James, 2017). It affects all racial backgrounds, and occurs in both males and females. In Australia the estimated number of cases is over 200 000. Paramedics may therefore encounter cases of VWD, although it is unlikely to be the main presenting issue of the patient. Knowledge of the disease would therefore benefit paramedics, and allow them to recognise the potential complications that a patient with VWD may face. Symptoms that may be present in patients with VWD include muco-cutaneous bleeding, hematomas, excessive bleeding after trauma or surgery, bleeding from minor wounds, oral cavity bleeding, joint and muscle bleeding (rare), and for women post-partum haemorrhage and menorrhagia (Rodeghiero, 2013) (James, 2017) (Schneppenheim, 2011). Medical alert bracelets or cards, a family history of VWD, and the use of medications such as anti-fibrinolytics including Amicar, Cyklokapron, Lysteda and Intra nasal desmopressin, may also alert paramedics to the patients condition.

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