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Surgical Oncology 21 (2012) 207e215

Contents lists available at SciVerse ScienceDirect

Surgical Oncology
journal homepage: www.elsevier.com/locate/suronc

Review

Update on totally implantable venous access devices
Ahmad Zaghal, Mohamed Khalife, Deborah Mukherji, Nadim El Majzoub, Ali Shamseddine, Jamal Hoballah, Gabriele Marangoni, Walid Faraj*
AUB, Beirut, Lebanon

a r t i c l e i n f o
Article history: Accepted 10 February 2012 Keywords: Venous access Implantable port Complications Cancer

a b s t r a c t
The use of totally implantable venous devices (TIVAD) has changed the care and quality of life for cancer patients, these devices allow chemotherapy administration, and blood sampling without the need for repeated venipuncture. These ports are used mainly when IV access is needed only intermittently over a long period of time. We are presenting a brief overview on TIVADs, with focus on the mid and long-term complications associated with these devices with their management. Ó 2012 Elsevier Ltd. All rights reserved.

Contents Historical background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 Clinical indications, preoperative assessment, and set-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 Choice of venous access site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Surgical technique: open/percutaneous/ultrasound guidance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Initial venous access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Open approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Percutaneous approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Anatomical landmarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Ultrasound guidance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Verifying catheter tip position . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .210 Immediate complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 Pneumothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 Haemothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 Air embolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 Accidental arterial puncture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 Cardiac arrhythmia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 Pericardial tamponade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 Brachial plexus injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 Pocket hematoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 Wound dehiscence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 Late complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .212 Catheter-related blood-stream infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 Thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 Catheter dysfunction/withdrawal obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .212 Catheter rupture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 Pinch-off syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

* Corresponding author. E-mail address: wf07@aub.edu.lb (W. Faraj). 0960-7404/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.suronc.2012.02.003

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Catheter migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 Catheter embolisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 Superior vena cava erosion and perforation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 Extravasation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 Pocket infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 Difficult access of the port . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 Port inversion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 Chronic clavicular pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 Removal of TIVAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .214 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .214 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .214 Authorship statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .214 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

Historical background In 1657 Sir Christopher Wren invented the first instrument for intravenous therapy; a cannula made from the quill of a bird feather, which was used to inject drugs into the veins of dogs. The first demonstration of central venous catheterization is attributed to the German physician and physiologist Werner Forssman. In 1929, Forssman inserted a 4-French ureteric catheter a distance of 65 cm into his own antecubital vein, then walked to his X-ray department and radiographically confirmed the position of the catheter tip in his right atrium. In 1952, the French military surgeon Robert Aubaniac described the use of percutaneously placed subclavian vein catheters for rapid infusion of resuscitative fluids in military casualties. When Seldinger described a practical technique for percutaneous entry to central vessels in 1953, the stage was set for central venous cannulation to become a routine intervention. Partially implantable venous access devices were first described by Broviac [1], and modified by Hickman [2] in the 1970s, before which temporary and peripheral vein accesses were used for longterm endovenous therapies. The first placement of a TIVAD was performed in 1982 at the MD Anderson Cancer Center in Houston by John Niederhuber, using the cepahalic vein and a surgical technique [3]. In 1992 TIVAD was successfully implanted in an angiographic unit using a rdiologically guided technique [4]. Introduction The use of totally implantable venous access devices (TIVADs) has revolutionized the care and quality of life for cancer patients and patients requiring long-term intravenous therapy. These devices allow chemotherapy infusion, antibiotic administration and blood sampling without the need for repeated venepuncture [5]. This review will update healthcare professionals dealing with patients requiring long-term intravenous therapy on indications, potential complications and management of complications of TIVAD insertion and usage. Definitions TIVADs consist of a centrally inserted venous catheter (usually via external or internal jugular, or subclavian vein), whose distal tip is positioned at the junction of the superior vena cava with the right atrium. This catheter is connected proximally to a subcutaneous reservoir, usually in the anterior wall of the upper chest. As the name indicates, the device is entirely hidden under the skin and can be left in the body for years. The reservoir has a silicone covering that can be punctured with a special non-coring needle (Huber needle). TIVADs are used when intravenous access is required for

intermediate and long-term periods and are particularly usefully for intermittent therapy. Huber needle: Access to the TIVADs is performed with the percutaneous insertion of a non-coring Huber needle through the silicon port septum into the port reservoir. This needle has a hole on its side rather than at the tip. Its special shape slices rather than punctures the septum, reducing the chance of leakage through the opening, and preventing possible dislodging of silicone slivers or cores, which could lead to serious adverse events if they gain access to the circulation. Clinical indications, preoperative assessment, and set-up TIVAD is a convenient option when long-term venous access is indicated, particularly for administration of cytotoxic medications or intravenous targeted agents in cancer patients who need intermittent administration of therapy over a long period of time. TIVADs can also be used for withdrawal of blood samples when needed. One example is the use of TIVAD for patients requiring adjuvant trastuzumab therapy for breast cancer who require infusional therapy every 3 weeks for one year. TIVADs are used in long standing chronic illnesses (example: cystic fibrosis), which require repeated venous punctures for blood sampling and medication, particularly in pediatric populations. TIVADs are cosmetically more acceptable to patients compared with tunneled VADs and require far less nursing care. Careful preoperative assessment is an indispensible step before embarking on obtaining central venous access; this includes history, physical examination plus laboratory and radiological adjuncts. Medical history should focus on family and personal history of bleeding tendency, and past history of central venous cannulation, because this may have lead to a central vein thrombosis or stenosis. A full drug history including direct enquiry regarding antiplatelet agents and anticoagulants should be taken. Physical exam should focus on physical habitus of the patient, which can predict the ease or difficulty of obtaining a percutaneous central venous access. The physician should also check for evidence of dilated upper torso veins which may indicate a central vein thrombosis. Essential preoperative laboratory studies include: complete blood count, platelet count and coagulation screen. Venous duplex scan is frequently used preoperatively to map the central veins to confirm patency; it may also help in decision making as to which vein to be used. Insertion of an implantable venous access device should be performed under strict sterile conditions in the operating room under local anaesthesia, with or without sedation. General anaesthesia is required for most pediatric patients.

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Choice of venous access site The most popular implantable venous access device insertion sites are the internal, external jugular, and subclavian veins. Other potential access sites include the cephalic vein in the deltopectoral groove, axillary vein, and the gonadal vein. Lower extremity veins have been used as a last resort, when it is doomed impossible to use the upper body veins. There has been a recent increase in interest in using the cephalic vein cutdown as a central venous access site, many retrospective studies proved the safety and the feasibility for such practice, with potentially lower incidence of early complications [6]. Subclavian vein catheters are located in a cosmetically acceptable, easily accessible area; however this site has many inherent disadvantages. Because the subclavian vein constitutes the major venous drainage of the upper extremity, catheter-related venous thrombosis often results in arm swelling and pain requiring either anticoagulation/thrombolytic therapy, catheter removal, or both. The subclavian vein is also prone to stenosis when used for venous access [7]. Venepuncture of the subclavian vein is associated with the highest incidence of Pneumothorax compared with other central veins. Catheter fatigue and "pinch-off" may develop due to prolonged and repeated compression by the costoclavicular ligaments and subclavius muscle, potentially leading to catheter fracture and embolization. A large retrospective review of 774 catheters compared subclavian and internal jugular vein approaches and concluded that the internal jugular vein is the preferred site for tunnelled infusion catheter placement due to the lower incidence of symptomatic venous thrombosis [8]. A prospective trial in 2009 involving 403 patients showed that central venous access insertion site does not influence early or late occurrence of complications of venous ports connected to a standard open-ended catheter implanted in an experienced environment. The use of two dimensional ultrasound (2D-US) guidance for subclavian vein catheterization resulted in significantly fewer insertion failures compared with landmark access to the internal jugular vein or cutdown surgical access to the cephalic vein at the deltoidepectoralis groove [9]. When the superior central venous routes are not available due to thrombosis, neck radiotherapy, the most commonly technique used to obtain central venous access to the inferior vena cava is the inguinal approach via the saphenous vein, or percutaneous femoral venous access under Ultrasound guidance [10]. Surgical technique: open/percutaneous/ultrasound guidance

dissected down to the fascia overlying the deltopectoral groove, where the cephalic vein is identified. Percutaneous approach The target vein can be accessed percutaneously, either by using anatomical landmarks to determine the site and the angle of puncture, or by using the 2D-US guided technique. Anatomical landmarks Subclavian vein: The needle is inserted one to two cm below the clavicle, at the junction between the lateral one third and medial two thirds of the clavicle. Aiming the needle towards the suprasternal notch, it should be elevated approximately 30 from the frontal plane of the body. Negative pressure is kept on the plunger until venous return is observed in the syringe. Internal jugular vein: The needle is inserted at the apex of the triangle bordered by the clavicle inferiorly, the sternal head of the sternocleidomastoid muscle medially, and clavicular head of the sternocleidomastoid muscle laterally. The needle is aimed towards the ipsilateral nipple, elevated approximately 60 from the frontal plane of the body. Negative pressure is kept on the plunger until venous return is observed in the syringe. Ultrasound guidance Real time ultrasound is increasingly being recommended over traditional anatomical landmark guidance central venous catheter insertion. This enables direct visualization of needle advancement and entrance into the target vessel with reduction in complication rates [11]. After initial access, the Seldinger technique is used for inserting the introducer set (sheath, and dilator) over a guidewire; after the catheter is threaded into the introducer set, the sheath is torn into two halves and removed. Seldinger technique: named after Dr Sven-Ivar Seldinger (1921e1998), a Swedish radiologist who introduced the procedure in 1953. The target vessel is punctured with a sharp hollow needle, with ultrasound guidance if necessary, a round-tipped guidewire is then advanced through the lumen of the needle which is withdrawn; a "sheath" or a blunt cannula is then passed over the guidewire into the vessel, after which the guidewire is withdrawn [12]. In the open approach the catheter is usually inserted directly into the target vein. Verifying catheter tip position

Initial venous access This can be performed either by using the open or percutaneous approach: Open approach With the introduction of radiologically-assissted techniques in the insertion of TIVADs in 1992, percutaneous technique spread throughout the world, with a parallel increase in the incidence of early, sometimes life-threatening complication, including pneumothorax and hemothorax. Surgical cutdown tachnique is the only approach able to avoid possible immediate fatal complications. In the external or internal jugular vein approach, a small supraclavicular transverse incision is performed between the sternal and the clavicular heads of the sternocleidomastoid muscle, and the incision is deepened cautiously until the vein is identified. In cephalic vein approach: a small inferolateral incision to the clavicle into the deltopectoral region is done, subcutaneous tissue is Typically the catheter tip position is verified radiologically, either by using intraoperative fluoroscopy, or a chest X-ray postoperatively. This is important because accurate position is needed for proper functioning of the port. The desired location of the catheter tip is at the junction between the right atrium and superior vena cava. Radiologic confirmation has the advantage of being accurate, easy, and of being able to detect pneumothorax if present, however it can be time-consuming and requires radiation exposure. An alternative to radiologic confirmation is the intracavitary electrocardiogram (EKG) method, where arrhythmia is documented during the insertion of the wire. Several studies have shown that The EKG method is a satisfactory alternative to that of fluoroscopy for placement of long-term central venous catheters into the right atrium. In one study the EKG technique was described as follows: the catheter is flushed with sodium bicarbonate, a sterile left-leg ECG lead is attached to the catheter with the other

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ECG leads applied normally, on advancing the catheter through the superior vena cava, the P-wave amplitude (lead II) increases in negative deflection until greater than the QRS complex, passing the sinoatrial node, the P-wave develops an initial positive then negative deflection; the catheter is positioned so the P-wave is biphasic, representing a position midway between the sinoatrial and atrioventricular nodes [13]. Studies have also investigated the potential use of ultrasound for confirmation of central venous catheter tip location, and for detection of pneumothorax after venepuncture [14]. Port pocket creation: this is usually done after the venous access is secured and the catheter tip position verified. A separate incision (sometimes in continuity with the insertion site) is made in the anterior chest wall, 2e3 cm below the clavicle, then a subcutaneous pocket is developed using electrocautery for port positioning, the port is usually sutured to the pectoral fascia. The catheter is then tunnelled (if a separate incision was used), and connected to the port with a connecting device (catheter lock). The technique of TIVAD insertion is basically the same in pediatric age group as compared to adults, except that open approach to venous access is more used in children. Complications Immediate complications Are defined as the complications that occur during or immediately following the insertion of TIVADs, this includes the following: Pneumothorax Hemothorax Air embolism Accidental arterial puncture Cardiac arrhythmia Pericardial tamponade Brachial plexus injury

ventilation, where patients may even present with a tension Pneumothorax [15]. Treatment of post-central catheter iatrogenic pneumothorax ranges from simple observation, to thoracostomy tube insertion, depending on size and emergence of signs or symptoms (dyspnea, tracheal shift, i.e. tension pneumothorax). Haemothorax Haemothorax is arbitrarily defined as sufficient bleeding into the pleural space to raise the pleural fluid haematocrit to 50% of that of the peripheral blood. Iatrogenic haemothoraces occur most often after an intrathoracic artery or vein has been perforated during placement of a central venous catheter [16]. During subclavian vein cannulation, subclavian artery, the pulmonary artery and other adjacent vessels such as the intercostal artery and the internal mammary artery may be punctured [17]; similarly carotid artery, and brachiocephalic vein [18], may be punctured during internal jugular vein cannulation, resulting in haemothorax. Haemothorax after central venous catheters insertion can be prevented by avoiding multiple cannulation attempts by using ultrasound guidance, where the target vein can be punctured under direct vision. Tube thoracostomy with a large-bore chest tube to drain pleural blood is the mainstay of therapy for haemothroax. Chest tubes are used to remove blood, monitor bleeding, and re-expand the lung. Thoracotomy is reserved for patients with massive haemothorax. Air embolism This is an uncommon but potentially fatal complication which occurs as a consequence of air entry into the vasculature which then travels to the right ventricle and/or pulmonary circulation. Catheter-related venous air embolism may be caused by mechanical problems (fracture or detachment of catheter connections, inadequate function of introducer sheaths), failure to occlude the insertion needle or the catheter opening during introduction [19] or persistence of a subcutaneous tract after catheter removal [20]. The risk of venous air embolism is increased by conditions that decrease central venous pressure, such as hypovolaemia, deep inspiration or the patient being in the upright position during instrumentation [21]. Patients may present with altered level of consciousness, tachycardia, chest pain, shortness of breath, irregular breathing, cyanosis, or cardiovascular collapse. In cases of massive air embolism a characteristic sound may be heard over the precordium, known as "bruit derouet" or "bruit de moulin" an analogy to the sound produced by a waterwheel [25]. Diagnosis is confirmed by echocardiography. During central venous cannulation, air embolism can usually be prevented by appropriate positioning of the patient (Trendelenberg position: head below the level of the right atrium). Treatment of air embolism involves nitrogen washout; highflow supplemental oxygen increases the partial pressure of oxygen and decreases the partial pressure of nitrogen in blood [22]; this produces a positive pressure gradient for the diffusion of nitrogen from the air bubbles to the blood, accelerating bubble resorption. In contrast, nitrous oxide, when given during general anesthesia, can diffuse from blood to air emboli, causing clinical deterioration as gas bubbles enlarge [23], thus nitrous oxide should be discontinued at the first suspicion of an air embolism. The patient is placed in the Trendelenberg position, and rolled to the left side (left lateral decubitus position), this positioning helps to trap air in the apex of the ventricle and prevent it from reaching

Immediate complication Pneumothorax Hemothorax

Incidence

1e4% 1e11% for small needle injuries 0.1e0.8% for large-bore needles Air embolism Rare Accidental arterial puncture 0e15% Cardiac arrhythmia 23e25% for ventricular arrhythimas 6e40% for atrial arrhythmias 0.9% serious arrhythmias requiring cardioversion Pericardial tamponade Up to 10% Brachial plexus injury Rare Isidoro Di Carlo, Roberto Biffi. Totally implantable venous access devices management in mid- and long-term clinical setting. 2011. Springer. E-ISBN: 978-88-470-2373-4

Pneumothorax Pneumothorax is the most common complication after central venous catheterization, due to inadvertent pleural puncture at the time of inserting the needle into the target vein. Its incidence is approximately 1e4%, largely dependent on the experience of the operator, and the site of venepuncture. It is thought to be higher with subclavian vein catheterization. In catheterization of the internal jugular vein, the risk of pneumothorax can be minimized by the use of ultrasound guidance. The diagnosis of pneumothorax may be delayed for hours or days in some instances due to minimal clinical symptoms or radiographic signs on initial evaluation. Late presentation may also be precipitated by positive pressure

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the pulmonary circulation [24],air can then be aspirated with central line or pulmonary artery catheter to right atrium/right ventricle. Accidental arterial puncture Unintended arterial puncture occurs in 2%e4.5% of central venous catheterizations, resulting in arterial injury in 0.1%e0.5% of patients [26]. Usually this results in localized haematoma formation, however the haematoma may enlarge rapidly if the patient is coagulopathic, or if a large puncture wound is produced by the introduction of the sheath itself into the artery. Pseudoaneurysm, arteriovenous fistula, and airway compromise may occur particularly with carotid artery puncture during attempting internal jugular vein venepuncture. In the presence of occlusive (atheromatous) carotid disease, inadvertent puncture may carry the risk of precipitating a cerebrovascular accident [27]. In cases of inadvertent carotid artery puncture, (incidence:2e8% [30]), if the patient is judged to be at low risk of complications (high risk: coagulopathic, heparinized, elderly), remove the cannula and apply firm pressure for 10 min, monitor the neurological, haemodynamic and airway state during this time and be prepared for emergency intubation. Consult a vascular surgeon if required to determine if surgical exploration or repair (open, or endovascular) is warranted. Indications for exploration may include an enlarging haematoma, airway compression, pre-existing carotid artery disease, a neurological event or cardiovascular instability. During subclavian venous catheterization, arterial punctures occur in 6e8% of the time [27,28], for pediatric patients the rate is 10% [29]. The subclavian artery, the pulmonary artery and other adjacent vessels such as the intercostal artery and the internal mammary artery may be punctured, resulting in haemothorax [17]. Such hemorrhages can be difficult to detect due to blood tracking into the pleural cavity, this is in addition to the fact that the subclavian artery is in an anatomically non-compressible location, which means that local pressure is ineffective. If the sheath has been inadvertently introduced into the subclavian artery, the sheath should be kept I place and an urgent vascular surgical opinion obtained for possible endovascular or open repair of the arterial defect. Cardiac arrhythmia Mechanical stimulation from the catheter can result in many types of atrial and ventricular arrhythmias. Cardiac arrhythmias during central venous catheter insertion (induced by the guidewire) are typically transient events with no haemodynamic consequences. Atrial fibrillation has been reported in patients with central venous catheter embolization [5]. Positional arrhythmias (atrial fibrillation, ventricular tachycardia) have been reported in patients with peripherally inserted central venous catheters [31]. There is a positive correlation with the height of the patient and the right subclavian position, where ventricular ectopy is significantly more common in shorter patients, and when the catheter is inserted through right subclavian vein [32]. This complication can be prevented by careful confirmation of the catheter tip position. Pericardial tamponade

The signs and symptoms of cardiac tamponade may appear a few minutes [34] to 5 months [35] after insertion of the catheter, in 36% of the patients they developed in the first 24 h and in 82% during the first week. The signs and symptoms of pericardial tamponade include pain or discomfort in the chest or epigastrium, nausea, dyspnea, tachycardia, engorgement of neck veins, pulsus paradoxus, hypotension, low-voltage electrocardiography and enlargement of the area of cardiac dullness. This complication can be avoided by adherence to proper technique in the placement of these catheters, ensuring that the catheter tip lies proximal to the cardiac silhouette, optimally in the superior vena cava, 2 cm proximal to the pericardial reflection [33]. The “Right Main Bronchus Criterion‟ by Rutherford and colleagues states that that the tip should lie proximal to the angle formed between the right main bronchus and the trachea [36]. This anatomical landmark represents the upper limit of the pericardial reflection over the lower superior vena cava. This complication should be managed on an emergency basis; all infusions through the line should be stopped, followed by aspiration from the catheter as a primary tool for evacuation of the tamponade. While resuscitating the patient, if this does not work, pericardiocentesis should be performed, and the catheter should be removed. If feasible a pericardial window may be performed, cardiothoracic surgery consultation should be obtained early for possible thoracotomy.

Brachial plexus injury Brachial plexus injury during central venous catheter insertion, although uncommon, has been described in the literature. The brachial plexus, stellate ganglion, vagus, accessory, hypoglossal and phrenic nerves are all closely associated with the internal jugular vein, any of these structures may be injured during cannulation attempts. More commonly, local anaesthetic injected at the time of cannulation may transiently block these nerves [37]. Early complications: this include the following Hemoptysis Pocket hematoma Wound dehiscence

Early complication

Incidence

Hemoptysis 0.03% Pocket hematoma 0e4.5% Wound dehiscence 3% Isidoro Di Carlo, Roberto Biffi. Totally implantable venous access devices management in mid- and long-term clinical setting. 2011. Springer. E-ISBN: 978-88-470-2373-4

Pocket hematoma Pocket hematoma can occur as an early complication after insertion of TIVADs, particularly in patients who are using anticoagulant or antiplatelet therapy. Poor surgical technique has been associated with a higher incidence of pocket hematoma development [38]. Usually this is treated conservatively, and the use of the port should be delayed until resorption in order to avoid the risk of infection [10].

Wound dehiscence Pericardial tamponade caused by central venous catheter perforation of the heart, or great vessels is an uncommon but a potentially deadly complication with catastrophic consequences. This complication has an estimated incidence of 3%. It results from either poor surgical technique or from impaired wound

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healing. Wound dehiscence has been associated with bevacizumab (monoclonal antibody to VEGF) therapy; Patients receiving bevacizumab within 10 days of port placement had a higher incidence of wound dehiscence [39]. Wound dehiscence mandates immediate cessation of the administration of therapeutic agents via the device, and initiation of local wound care [10].

Thrombosis Catheter-related thrombosis remains the most common complication leading to irreversible dysfunction, its incidence is underestimated because it is usually asymptomatic. Thrombosis may occur both in the TIVAD and its dwelling vein. Sleeve thrombosis is the most common type and it tends to occur earlier. The catheter sleeve becomes covered with an adherent coating of fibrin and collagen which envelopes the outer surface of the catheter and extends along the entire length of the catheter from the point of insertion in the vein to the tip. This can interfere with catheter function, is prone to developing local infection and sepsis, and may progress to a less common mural veno-occlusive thrombosis [10]. Percutaneous stripping of totally implantable venous access devices (TIVAD) in case of catheter-related sleeve has been recently proved to be technically feasible and safe, with an overall success rate of 91.9% [42]. Thrombosis may occur in four distinct locations (right atrium/ central vein) or the catheter (intralumen/fibrin sheath) [43]. Right atrial thrombus is a rare but life-threatening complication possibly leading to pulmonary embolism and cardiac arrest. Prompt surgical thrombectomy is recommended, while medical treatments may be attempted for pediatric patients with small to moderate sized thrombi. Central vein thrombosis is usually unnoticeable but, when left untreated, may progress to extensive obstruction of the superior vena cava. An antithrombotic agent, such as unfractionated or lowmolecular-weight heparin, is the first choice, while surgical intervention is not recommended due to lack of benefits. Intraluminal thrombotic occlusion (2e3%) and fibrin sheath formation (42e100%) are common etiologies associated with device malfunction. A compressed flush can cause catheter disconnection or migration as well as venous thrombo-embolism. Both conditions are minor and can be readily resolved by fibrinolytic agents, surgical removal of the device should only be considered after fibrinolytic agents have failed or therapy has been terminated because of its minor severity and high success rate of medical treatment [43]. This complication can be prevented by following maintenance guidelines for the TIVADs, namely saline and heparin flushing of the ports, Prophylactic urokinase has been studied in the management of long-term venous access devices in children, and it was found that Urokinase administration every 2 weeks significantly affects the rate of occlusive events in ports and tunneled catheters and of infectious events in external catheters as compared to heparin administration [44]. Catheter dysfunction/withdrawal obstruction Resistance to withdrawal from TIVADs can be due to catheter thrombosis (more common) or due to non-thrombotic occlusion due to drug crystallization, catheter kinking, or pinch-off syndrome. Adding a solution that returns the pH of the crystallized medication back into the normal range may dissolve the precipitate. Lipid occlusions also may occur and are more prevalent with silicone catheters because lipid emulsions adhere to silicone, Ethyl alcohol at a 70% solution may be used to dissolve lipid occlusions [47]. Sodium hydroxide solution can also be used to dissolve a combination of lipids and fibrin after administration of TPN through the device. Administration of compatible medications and fluids and appropriate and adequate VAD flushing prevent non-thrombotic occlusions from occurring [48].

Late complications This includes the following: Catheter-related bloodstream infection Thrombosis Catheter dysfunction Catheter rupture Pinch-off syndrome Catheter migration Catheter embolisation Superior vena cava erosion and perforation Extravasation Pocket infection Difficult access of the port (port inversion)

Late complication

Incidence

Catheter-related bloodstream infection 2.4e16% Thrombosis 1e56% Catheter dysfunction 0.8e9% Catheter rupture 0.1e2.1% Catheter migration 0.2e1.7% Catheter embolisation 0e3.1% Superior vena cava erosion and perforation 0.4e1% Extravasation 0.5e6% Pocket infection 2.5% Difficult access of the port (port inversion) 0e1% Isidoro Di Carlo, Roberto Biffi. totally implantable venous access devices management in mid- and long-term clinical setting. 2011. Springer. E-ISBN: 978-88-470-2373-4

Catheter-related blood-stream infection Catheter-related bloodstream infections are defined as bacteremia/fungemia in a patient with an intravascular catheter with at least one positive blood culture obtained from a peripheral vein, clinical manifestations of infection (i.e., fever, chills, and/or hypotension), and no apparent source for the bloodstream infection except the catheter. Bloodstream infections are considered to be associated with a central line if the line was in use during the 48-h period before the development of the bloodstream infection [40]. Infection can complicate TIVADs in up to 4.8% of the cases, with gram positive cocci being the most prevalent organisms [41]. Catheter-related infections can be prevented by strictly following the universal precautions of asepsis, strict adherence to hand washing and aseptic technique is crucial for reducing CVC related infections. It is of utmost importance to educate the patient regarding the potential risks of CVC infection, and inform them that the device should only be accessed by trained and qualified personnel using strict aseptic technique. Once diagnosed, the TIVAD will usually need to be removed, and empirical broad spectrum antibiotics commenced. The choice of antibiotics will depend on local policies and the immunocompetence of the patient.

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Mechanical occlusion that occurs when a catheter tip lies against the vessel wall can be prevented by proper positioning of the tip of the catheter, and may be managed by catheter exchange and placement of a longer catheter. This complication often occurs with shorter catheters with tips high in the superior vena cava [50]. Catheter rupture In 1997 Biffi et al. [49] reported three cases of port catheter rupture in 178 ports, the incidence of port rupture was estimated to be 1.68% (0.09/1000 port days). Rupture occurred 66 days after the placement, during a pause between subsequent chemotherapy cycles. In this series, symptoms consisted of palpitations and chest discomfort in two patients while the third patient remained asymptomatic [49]. Etiology remains elusive, however incorrect placement has been advocated as the most important cause, in case of such an event the patient should be managed by an experienced vascular surgeon and interventional radiologist, as in most cases the ruptured catheter can be retrieved by non operative interventional measures [5,50]. Pinch-off syndrome This term refers to the compression of a central VAD catheter between the clavicle and first rib. Signs of catheter compression include difficulty withdrawing blood from the device and resistance to infusion of fluids [52]. A “pinch-off sign‟ of catheter indentation as it passes beneath the clavicle may be present on chest x-ray. In a 2008 review of 112 cases, the mean time from catheter to insertion to detection of “pinch-off‟ was 5.3 months [53]. Repeated compressions (caused by shoulder and arm movement) can cause a mechanical obstruction of the catheter and, in some cases, weaken the catheter in that area. The weakened catheter may begin to leak and could potentially transect and embolize to the heart [54], pulmonary artery [55] or coronary sinus [56]. Percutaneous retrieval using a transvenous snare is usually successful [50] [5],. Catheter pinch-off can be prevented by inserting central VADs using a lateral internal jugular vein, rather than a subclavian vein, approach [52]. Catheter migration Catheter tip migration is a late complication that also has been called ““secondary malposition‟‟ [50]. The risk of catheter tip migration is increased when catheters are ““short‟‟ and have their tips in the subclavian vein or upper third of the superior vena cava. Arm and shoulder movement, increased intrathoracic pressure caused by coughing or vomiting, congestive heart failure, and forceful flushing can result in catheter movement. The catheter can loop, kink, coil, and curl, catheters that loop at acute angles are at risk for fracture [48]. The catheter tip can migrate to locations such as the internal jugular vein in the neck or contralateral brachiocephalic vein [51]. Catheter tips that migrate to the internal jugular vein may cause pain or unusual sensations in the neck, ear, or shoulder areas and patients may report that they hear an odd sound when their catheters are flushed [52]. Catheter embolisation

Common sites for embolization of the distal fragment are the central veins, right atrium, right ventricle [54], and pulmonary arteries [55]. Catheter embolization may present with signs or symptoms as serious as cardiac arrhythmia [5,57], or as an incidental finding on routine chest imaging, surprisingly, most patients are asymptomatic. The most common symptom is pain or pressure during an attempt to use the damaged catheter [58], other common symptoms are cough, palpitations, and swelling around the port site caused by fluid extravasation, sustained ventricular tachycardia, although rare, may also occur [57]. It is imperative to remove the embolized segment when this complication is recognized. Retrieval of the distal fragment is commonly via a percutaneous vascular route [5] [50], in some cases, open thoracotomy or even electing to leave the fragment in place may be preferable [59].

Superior vena cava erosion and perforation This is a rare, but potentially life-threatening late complication of TIVADs, it usually has unspecific symptoms (chest pain, dyspnea, unilateral pleural effusion, hemodynamic collapse), and patients with left-sided, large-bore catheters are at a relatively higher risk [45]. Improvements in catheter composition and construction have greatly decreased the incidence of vascular erosion. Catheters are now softer and more flexible than they were in the past. Central VADs with tips that abut the superior vena cava wall within 45 degrees of perpendicular have been attributed to cause most cases of reported vascular erosion [46]. Extravasation Even with the best surgical techniques and devices, accidental extravasation still occurs. There are four primary causes of extravasation from ports: incomplete needle placement and needle dislodgment, thrombus or fibrin sheath formation, perforation of the superior vena cava, and catheter fracture [60]. This condition can be asymptomatic (involving non-vesicants), or may present as shoulder pain in cases of chest wall infiltration, or as substernal chest pain in cases of mediastinal leakage [61], or it may present as devastating tissue necrosis (involving vesicants). If cytotoxic extravasation occurs, the action depends on the drug combination. In extravasation of vesicant drugs (primarily anthracyclines e.g., doxorubicin and epirubicin), progressive tissue necrosis occurs. It is important to aspirate as much as possible of the cytostatic agent immediately and to avoid further drug instillation by using the catheter to inject potential antidotes. Furthermore, immediate surgical intervention to resect all necrotic tissue is recommended [62]. It has been demonstrated that Savene (Totect, dexrazoxane) is an effective antidote for patients who have suffered anthracycline extravasations [63]. Topical dimethyl sulfoxide (DMSO) can be effective and well tolerated in managing anthracycline extravasation. Hayaluronidase should be injected within 1 h of extravasation, ideally through the intravenous device delivering the enzyme to the same tisse for extravasation of vinca alkaloids and taxanes [64]. Pocket infection

Catheter embolisation can occur after catheter rupture, for example in cases of pinch-off syndrome, or after catheter disconnection or separation [5].

Pocket infection usually presents as erythema or induration of the skin overlying the implantable port.

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This can be prevented by following strict aseptic technique during insertion of these devices, as well as during accessing them. This may require removal of the device. Difficult access of the port Difficulty in accessing a port may be caused by patient’s obesity with increased subcutaneous fat deposition over the reservoir, or more commonly due to port inversion. Port inversion The reservoir of the TIVAD can flip over so that they are partially or completely inverted, risk is increased when ports are not sutured in the fascia during implantation, or when only one suture is placed to anchor the portal body. Shoulder movement and large amounts of breast tissue increase the risk that a portal body can rotate or flip over. Patients who manipulate their portal bodies have been termed ‘’port fiddlers‟ or labeled as having ‘’Twiddler‟s Syndrome‟. When portal bodies rotate or flip, the septum of the port is generally not accessible, and if an attempt is made to insert a Huber needle, a blood return will not be obtainable. The risk of inversion is reduced when portal bodies are adequately sutured to the fascia, preferably with non-absorbable sutures [48]. Chronic clavicular pain This is an underreported late complication of TIVAD insertion, which may be related to nerve-damage during creation of the subcutaneous pocket, persistent neck pain and discomfort can be associated with catheter thrombosis. Removal of TIVAD Removal of the TIVAD is indicated when therapy via the device is no longer needed, or if complications develop, such as infection, catheter migration, etc. Removal of implantable ports is a surgical procedure which should be carried out using strict aseptic technique. An incision should be made into the fibrous tissue which forms around the port, the anchoring sutures should then be cut and the port can be removed, ensuring that the entire catheter length is pulled from the venous system [65]. The tip of the withdrawn catheter should always be inspected to make sure that it is intact, the subcutaneous incision can then be sutured and dressings applied. This is usually a simple procedure, however it can be difficult if the catheter adheres to the wall of the central vein after long-term use [66]. If a forced retrieval maneuver is used to withdraw the catheter, these “stuck” catheters can fragment. A catheter that adheres firmly to a vessel wall can usually be left in situ because it is not likely to migrate to the heart or lungs [66]. Conclusion The use of totally implantable venous access devices (TIVADs) has revolutionized the care and quality of life for cancer patients and patients requiring long-term intravenous therapy. Reduction of complication rates is possible through the combined efforts of medical oncologists, surgeons, and nursing staff. Conflict of interest The authors have no conflicts of interest of any sort to declare in relation with this article.

Authorship statement Guarantor of the integrity of the study: Walid Faraj Study concepts: Ahmad Zaghal Study design: Deborah Mukherji Definition of intellectual content: Ali Shamseddine Literature research: Nadim El Majzoub Manuscript preparation: Walid Faraj Manuscript editing: Mohamed Khalife Manuscript review: Jamal Hoballah

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