Reminder of important clinical lesson

CASE REPORT

A midline for oxaliplatin infusion: the myth of safety devices Ben Masters,1 Tamas Hickish,2 Esther Uña Cidon2 1

Department of Medical Oncology, Poole Hospital NHS Foundation Trust, Poole, UK 2 Department of Medical Oncology, Royal Bournemouth Hospital NHS Foundation Trust, Bournemouth, UK Correspondence to Dr Esther Uña Cidon, [email protected] Accepted 16 May 2014

SUMMARY Oxaliplatin is a platinum compound mainly used in the treatment of colorectal cancer. According to its manufacturer it is not considered vesicant agent though it has been shown to cause severe tissue damage if extravasation occurs in large doses. Several cases of extravasation have been reported; most of them from incorrectly placed peripheral cannula or incorrect use of central venous access devices. To reduce these risks, peripherally inserted central catheters and midline catheters have been increasingly used and are especially helpful if poor peripheral venous access. Midlines are mainly used for patients not receiving vesicant drugs, and are generally inserted without radiological guidance. They are believed to be safe, but we present the first ever-documented oxaliplatin extravasation injury from a midline catheter.

BACKGROUND Oxaliplatin is a chemotherapy agent that is primarily used to treat colorectal cancer. It is classed as an irritant, as stated in the manufacturer’s summary of characteristics,1 although it has been reported to cause severe inflammation when extravasated, which has led to several professionals reclassifying it as a vesicant.2–4 Several cases of extravasation have previously been reported. Most of these were due to either incorrectly inserted peripheral cannula or inappropriate use of central venous access devices (CVAD).5 In current practice, peripherally inserted central catheter (PICC) lines and midlines are becoming more frequently used as active treatments and are also being used to treat cancer in older patients with often poor venous access. Unlike peripheral cannula, these devices can be used for several weeks and are more easily accessible and less invasive than CVADs. They are therefore believed to be safe and particularly useful venous access devices.6 Unfortunately, the reality is quite different and we must be just as careful and meticulous when using these devices for chemotherapy infusions.

CASE PRESENTATION

To cite: Masters B, Hickish T, Uña Cidon E. BMJ Case Rep Published online: [please include Day Month Year] doi:10.1136/bcr-2014204360

A 77-year-old woman with a history of polymyalgia rheumatica and a previous total abdominal hysterectomy presented to her general practitioner in January 2013 with right-sided abdominal discomfort. A blood test showed her to have iron deficiency anaemia and thus an urgent colonoscopy was performed which showed a suspicious neoplasm in the ascending colon. The biopsy confirmed adenocarcinoma. A staging CT scan showed

Masters B, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2014-204360

mesenteric lymphadenopathy and liver metastases. She was started on FOLFOX chemotherapy with neoadjuvant intent. Owing to poor peripheral venous access, a PICC line was inserted into her right cubital fossa and placement was confirmed radiologically. She underwent four cycles without complication. However, prior to the fifth cycle, she noticed that her right arm had swollen and erythematous at the PICC line entry site. A venous Doppler confirmed a thrombus in her distal axillary and basilica veins. Therefore, she was started on low-molecular-weight heparin and the PICC line was removed 2 weeks later. To prevent a delay in treatment, a new PICC line insertion was attempted in her left arm. Unfortunately the line was unable to pass beyond her axilla, thus a midline was inserted instead. The line was cut at 25 cm and inserted into the left ante-cubital fossa with 18 cm within the vein. Two days later she had her fifth cycle and the midline site of entry was noted to be slightly bruised and tender due to the difficulty in placing the line. The line was also difficult and sluggish to aspirate (only 1–2 mL were aspirated). However, it flushed easily and the infusion was started. Initially the patient felt a slight cold and mildly tender sensation in the upper arm on starting the infusion. After 1 h the arm became tender and was noticed to be swollen. A palpable 10×7 cm swelling was noted in her left upper arm. At this point approximately 300 mL containing 80 mg of oxaliplatin had already been infused.

TREATMENT As soon as the extravasation injury was identified the infusion was stopped. The midline was then aspirated and flushed as per protocol. Only 1 mL was aspirated, but it was flushed easily. An urgent doctor review was sought and 1500 units of hyaluronidase was injected (figures 1 and 2). The area of swelling was marked and a cold pad and 1% hydrocortisone cream were applied to the area. The patient was monitored within the department and given oral analgesia including paracetamol and codeine. The midline was then removed without further complication.

OUTCOME AND FOLLOW-UP The regional plastic surgery service was also contacted and they advised for the arm to be reviewed daily. The patient was allowed to go home with a cold pack and analgesia including oral morphine. The following day, the upper arm swelling had reduced in size; however, the erythema and redness had worsened and spread distally into the forearm. 1

Reminder of important clinical lesson

Figure 1 Acute extravasation in upper left arm after removing the midline and having applied local hyaluronidase. Figure 3 Consequently, she was started on anti-inflammatory medication and an urgent review by the Plastic’s team was organised for the following day. They were concerned about the ongoing distal spread of the injury and provided the patient with a sling to keep the forearm elevated. Over the following few days the erythema turned to a dark purple, with the patient’s pain worsening, but the swelling had halted. Her pain was localised to the dorsal aspect of her upper arm, and she was advised to take regular paracetamol, codeine and ibuprofen with oral morphine as required. A repeat CT staging was organised at this point to assess progress and it showed good partial response of the primary tumour and metastases, and chemotherapy was therefore discontinued. She underwent a right-sided hemicolectomy without complication and a liver hepatectomy the following month. She has been followed up since and has not shown any evidence of recurrence. Moreover the area of extravasation is completely healed without sequalae (figures 3 and 4).

Left arm 2 months after the acute episode of extravasation.

Oxaliplatin has been shown to be effective in advanced colorectal cancer.5 When combined with oral capecitabine, peripheral cannulae are often used for oxaliplatin administration. However, when used in combination with infusional 5-fluorouracil, it is administered through a CVAD, often a port-a-cath. Although port-a-caths aim at reducing the risk of phlebitis and soft tissue injury, they are not free of complications, and some of the oxaliplatin extravasation injuries have occurred due to incorrect identification of the subcutaneous device within the chest wall.2 This has resulted in several cases

of high-dose extravasation causing long-lasting toxicity.5 To overcome this problem, Hickman lines and PICC lines have been recommended as they have visible ports. There are also several cases of oxaliplatin extravasation from peripheral cannula reported in the literature.5 Although these tend to be smaller in volume as peridevice swelling becomes more evident at an earlier stage. The inflammation from peripheral limb extravasation injury can not only cause direct damage to subcutaneous tissues (with subsequent pain and swelling), but can also cause a compartment syndromelike effect on the peripheral tissues which can lead to severe pain and tissue necrosis, and therefore close monitoring is essential.7 Patients should be followed closely while receiving the infusion and be taught to detect and relate any potential complication to the team promptly to avoid further damage. Once the extravasation has been detected, all supportive and therapeutic measures must be started as explained below. Although appearing similar in design and function to PICC lines, midlines are actually peripheral access devices.6 They are inserted peripherally without radiological guidance, and are consequently prone to the same complications as peripheral cannula. In this case, the tissue damage caused by accidental extravasation was made potentially more serious by the use of a midline. The reason for this is that they increase the risk of more proximal extravasation injuries in the upper arm. The soft tissue in this part of the arm tends to be less dense than in the forearm, which is particularly evident in the elderly. This allows larger volumes to extravasate before being recognised by the

Figure 2 Closer picture after acute extravasation.

Figure 4

DISCUSSION

2

Closer picture 2 months after the acute extravasation. Masters B, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2014-204360

Reminder of important clinical lesson patient or by the health professional responsible for the infusion. This is the most likely reason for our patient receiving such a high volume and dose of oxaliplatin into her upper arm before becoming symptomatic. However, within 1–2 h of finishing the infusion the arm had become tender, painful, swollen and bruised. To complicate this, inflammation in the upper arm tends to spread distally, putting the patient at risk of compartment syndrome and therefore end-organ damage. Fortunately, in our case, simple measures such as using a sling slowed this progress. In our case, almost immediately postrecognition of the extravasation injury, cold compression and analgesics were administered. However, there is still currently some debate as to whether cold compression or hot pads should be used acutely to either reduce swelling or increase drug breakdown, respectively.8 In this case, cold compression was preferentially used to reduce pain and swelling. de Lemos and Walisser8 have suggested that cold compression may also cause local vasoconstriction and reduce cellular injury, although it is thought that it may precipitate or worsen peripheral neuropathy. Alternatively, warm compresses are thought to aid drug removal by local vasodilation and reduce the risk of peripheral neuropathy. However, they may also increase cellular uptake, hence causing greater tissue damage. Therefore the debate is still ongoing and further research into this area is needed. Unfortunately, there is currently no known antidote for oxaliplatin extravasation. In this case hyaluronidase was injected, as it is used in vinca alkaloids extravasation to prevent subcutaneous tissue damage. This enzyme will degrade hyaluronic acid, which is a constituent of the normal interstitial barrier. Thus, it increases the distribution and absorption of locally injected substances. It has been tested in animals and humans with good results, preventing skin necrosis.9 10 During the week following the oxaliplatin extravasation injury our patient’s arm continued to be painful and swollen despite non-steroidal anti-inflammatories. The swelling and inflammation did not remain localised to the upper arm and slowly spread into the forearm. Owing to her worsening symptoms and potential risk of developing compartment syndrome she was referred to the plastic surgeons. They advised a cuff and collar sling to prevent neurovascular compromise. This simple measure proved to be very effective by elevating the arm to prevent further distal spread, and to ease the pain by reducing excessive movement and use of the arm. This case highlights the very serious potential complications of extravasation injuries even from chemotherapy agents that are classed as irritants. It also reveals that although midlines have been given the image of being safe devices to use (as there are fewer documented complications in comparison to peripheral cannulae and port-a-caths), they can still be the cause of significant extravasation injuries. It also highlights how they may allow larger extravasation injuries to occur prior to recognition, therefore causing greater pain and potential complications to the patient. In view of this, PICC lines and Hickman lines should be considered to be the safest devices for chemotherapy agents including oxaliplatin,3 as although it is classed as an irritant, oxaliplatin extravasation can cause severe pain and swelling. Most importantly, all infusions of potentially toxic

Masters B, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2014-204360

chemotherapy agents should be carefully monitored by both the patient and at regular intervals by a trained nurse throughout the infusion. Early signs and symptoms of extravasation can therefore be recognised and promptly treated as per local guidelines, resulting in less-severe injury.

Learning points ▸ Midlines should not be used for the administration of drugs, which are vesicants and avoided in those that are potentially vesicant in nature such as oxaliplatin. ▸ To detect early signs of extravasation midline catheters should be closely monitored throughout the infusion by the patient and at regular intervals by a trained nurse. ▸ Although midlines are thought to be safe peripheral access devices, they may in fact allow more severe extravasation injuries to occur. ▸ Although not clear recommendations, in opinion of these authors, extravasation injuries require daily review for the first few days until symptoms and signs are settled; then weekly or fortnightly until the healing process is finished. ▸ Simple slings can be useful in affected limbs to prevent distal inflammatory spread, thus reducing the risk of compartment syndrome. Plastic surgical review may also be necessary. ▸ The benefits of applying cold packs or hot pads immediately after oxaliplatin extravasation injury is still debated and requires further research.

Contributors BM and EUC have written the case report. BM, TH and EUC have written the discussion and references and abstract. BM has taken pictures and TH has taken the consent form. BM, TH and EUC have read and approved the manuscript. Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed.

REFERENCES 1 2 3 4 5 6 7 8 9 10

Eloxatin, summary of product characteristics. http://www.sanofi-aventis.co.uk/ products/Eloxatin_SPC.pdf Ener RA, Meglathery SB, Styler M. Extravasation of systemic hemato-oncological therapies. Ann Oncol 2004;15:858–62. Foo KF, Michael M, Toner G, et al. A case report of oxaliplatin extravasation. Ann Oncol 2003;14:961–2. Baur M, Kienzer HR, Rath T, et al. Extravasation of oxaliplatin (Eloxatin®)—clinical course. Onkologie 2000;23:468–71. Kretzschmar A, Pink D, Thuss-Patience P, et al. Extravasations of oxaliplatin. J Clin Oncol 2003;21:4068–9. Cheung E, Baerlocher M, Asch M, et al. Venous access: a practical review for 2009. Can Fam Physician 2009;55:494–6. Theman TA, Hartzell TL, Sinha I, et al. J Clin Oncol 2009;27:198–200. de Lemos ML, Walisser S. Management of extravasation of oxaliplatin. J Onco Pharm Pract 2005;11:159–62. Raszka WV Jr, Kueser TK, Smith FR, et al. The use of hyaluronidase in the treatment of intravenous extravasation injuries. J Perinatol 1990;10:146–9. Bertelli G, Dini D, Forno GB, et al. Hyaluronidase as an antidote to extravasation of Vinca alkaloids: clinical results. J Cancer Res Clin Oncol 1994;120:505–6.

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Reminder of important clinical lesson

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Masters B, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2014-204360

A midline for oxaliplatin infusion: the myth of safety devices.

Oxaliplatin is a platinum compound mainly used in the treatment of colorectal cancer. According to its manufacturer it is not considered vesicant agen...
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