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Jan 2018 FAQs

What is alpha-gal allergy and how does it impact medication therapy?

What is the evidence for the use of high-dose intravenous vitamin C for the treatment of cancer?

What are considerations for determining whether a drug may be administered via a midline catheter?

Answers

What is alpha-gal allergy and how does it impact medication therapy?

Introduction

Food allergies are broadly defined as IgE-mediated hypersensitivity reactions to ingested food.1 Symptoms of food allergy can vary in severity, ranging from urticaria to life-threatening anaphylaxis. The most common food allergies in the United States are milk, eggs, peanuts, tree nuts, wheat, soy, fish, and shellfish. However, in the last decade, a new food allergy has been described: an allergy to mammalian meat, known as alpha-gal allergy. Unlike other food allergies, the trigger for alpha-gal allergy is not a protein: rather, it is a carbohydrate molecule found on the surface of non-primate mammalian tissue known as galactose-α-1,3-galactose, or alpha-gal. The goal of this article is to discuss the history and presentation of alpha-gal allergy, as well as its implications for medication therapy.

History and Epidemiology of Alpha-Gal Allergy

Alpha-gal allergy is a recently-described phenomenon.1 Although it is commonly known as a “red meat allergy,” allergic reactions to the alpha-gal epitope were actually first described in connection with cetuximab, a monoclonal antibody used in the treatment of cancer.2 Cetuximab was observed to cause severe hypersensitivity reactions in some individuals upon first exposure to the drug; further investigation was performed, and it was discovered that these reactions were caused by IgE antibodies targeting alpha-gal epitopes on the Fab portion of the monoclonal antibody.3-5 This hypersensitivity reaction was observed to be more common in the Southeastern United States.5 Around the same time, reports of a delayed allergic reaction to red meat were also emerging in the same geographic area. In 2009, these red meat allergies were also connected to IgE antibodies against alpha-gal.

It is thought that the increased prevalence of alpha-gal allergy in certain areas is related to the presence of certain tick species.6 The majority of patients who present with red meat allergy also present with some sort of tick bite history.5 Tick bites from Amblyomma americanum, Ixodes ricinus, Ixodes holocyclus, Haemaphysalis longicornis, and members of the Amblyomma cajennense complex have all been associated with sensitization to alpha-gal, which may subsequently lead to the development of red meat allergy.6,7 The mechanism behind this observation is still not fully understood.

While still rare, alpha-gal allergy has been reported in countries around the world, including Australia, several Western European nations, Japan, and Korea.2 Over 1000 cases of mammalian meat allergy have been reported in the United States alone.1 Patients who are frequently exposed to ticks, such as forest service employees and hunters, may be at a higher risk of developing red meat allergy.8

Clinical Presentation

The presentation of alpha-gal allergy differs slightly from that of other food allergies.5 Most commonly, alpha-gal allergy presents in adulthood, although children may also present with this allergy.9 Reactions are intermittent, and every exposure to alpha-gal may not result in symptoms.1 Common symptoms of alpha-gal allergy include nausea, diarrhea, indigestion, and urticaria after eating red meat, but reactions may be more severe, including dyspnea, hypotension, angioedema, or anaphylactic shock.4,5 Unlike other food allergies, these symptoms are usually delayed from the time of meat consumption, occurring at least 2 hours after ingestion.4 In most cases, symptoms will not occur until 3 to 6 hours after ingestion: however, certain factors may hasten the appearance of symptoms.1,4  Exercise and alcohol may shorten the time between consumption and reaction, and the tissue source of the meat can also influence the timing of the reaction. Some tissues, such as pork kidney, provide higher amounts of alpha-gal, and therefore may induce symptoms more quickly.4 The fat content of the meat and the amount of meat consumed may also play a role in whether or how quickly a reaction occurs.1 It is thought that the delayed onset of symptoms may be related to the slow absorption of orally ingested lipids.9 Ingested lipids are packaged into chylomicrons, absorbed into the lymphatic system, and eventually metabolized into low-density lipoproteins and very low-density lipoproteins. Both low-density lipoproteins and very low-density lipoproteins have alpha-gal epitopes on their surface that may react with IgE.

Meats that may induce a reaction in patients with alpha-gal allergy include beef, pork, lamb, rabbit, goat, and venison.9 Pork and beef innards contain higher amounts of alpha-gal than muscle meat from the same animals, and thus may be more likely to induce a reaction.10 Of note, alpha-gal is stable to heat, so cooking the meat does not decrease its allegenicity.11 Alpha-gal has also been detected in gelatin: most patients with red meat allergies are also sensitized to gelatin, but this may or may not cause a clinically significant allergic reaction.12 Patients continue to tolerate chicken, turkey, and fish, as these are non-mammalian meats that do not contain alpha-gal.9

Treatment

The treatment for alpha-gal allergy is similar to that of other food allergies: avoidance of triggers (ie, red meat), and carrying an epinephrine auto-injector.9 Some patients with alpha-gal allergy may be able to tolerate small quantities of meat, but others may not. Some patients may also require avoidance of gelatin and/or dairy for complete cessation of symptoms. If avoidance is not possible, desensitization may be an option. One patient with alpha-gal allergy was successfully desensitized to cetuximab, and 2 patients with alpha-gal allergy have been successfully desensitized to beef.13,14

Implications for Medication Therapy

As mentioned above, alpha-gal allergy was first described in patients with first-dose anaphylactic reactions to cetuximab. However, other medications have been shown to cause reactions in patients with alpha-gal allergy as well. Table 1 provides a summary of medications or ingredients that have been reported to provoke allergic reactions in patients with alpha-gal allergy. It is important, however, to be aware that this list may not be all-inclusive, as our knowledge of this allergy is still limited. There are 3 situations that may result in the presence of alpha-gal in a medication: the drug itself may contain alpha-gal epitopes, the drug may be derived from a mammalian source, or the drug may contain inactive ingredients derived from mammalian sources. Each of these situations will be discussed in more detail below.

Medications with alpha-gal epitopes

Hypersensitivity to cetuximab has been linked to the presence of IgE antibodies that attack alpha-gal epitopes on the monoclonal antibody itself.15 In addition to cetuximab, certain other medications have been shown to contain alpha-gal epitopes as well. Some monoclonal antibodies have glycosylation that is similar to that of cetuximab, and although it is rare, these monoclonal antibodies have the potential to provoke hypersensitivity reactions in patients with alpha-gal allergy. In the case of 1 patient, first-dose anaphylaxis to infliximab was found to be mediated by IgE to alpha-gal.16 Antivenoms have similarly been found to provoke allergic reactions in patients with alpha-gal allergy. One published case report describes an alpha-gal mediated hypersensitivity reaction to the purified ovine antibody Crotalidae polyvalent immune Fab antivenom (CroFab).17 This patient had no prior history of alpha-gal allergy, but experienced diffuse hives soon after administration of CroFab began. She was subsequently found to have significant titers of IgE antibodies to alpha-gal, and it was suspected that alpha-gal allergy was the cause of her reaction. In a small experimental study, a variety of equine antivenoms were found to contain alpha-gal epitopes and provoke skin reactions upon skin prick testing in patients with alpha-gal sensitization.18 This may indicate a potential for increased risk of first-dose hypersensitivity reactions among patients with alpha-gal allergy.

Medications that may contain alpha-gal due to sourcing methods

Heparin has been noted as a theoretical risk to patients with alpha-gal allergy, because the product is sourced from mammalian tissues (bovine lung and porcine intestinal mucosa).19 Although alpha-gal epitopes are not present on heparin molecules, there may be contamination with alpha-gal during the manufacturing process. The amount of contamination may vary from lot to lot. One case series found that a prophylactic three-drug regimen (hydrocortisone, diphenhydramine, and famotidine) appears to allow for the safe use of heparin in patients with mammalian meat allergy undergoing cardiac surgery. One patient who received only two drugs as prophylaxis (dexamethasone and diphenhydramine) experienced a life-threatening reaction at the end of his cardiac procedure; however, of the 2 patients who received the three-drug prophylactic regimen, 1 had only a mild rash postoperatively, and 1 experienced no symptoms. Alternatives to heparin such as bivalirudin and argatroban may also be viable options for these patients.

Inactive ingredients with alpha-gal epitopes

Animal byproducts such as gelatin and magnesium stearate have been reported to cause reactions in patients with alpha-gal allergy. One case report describes a woman with documented mammalian meat allergy who experienced a severe systemic hypersensitivity reaction after using a vaginal capsule made from porcine gelatin.20 Other allergic reactions have been reported in relation to gelatin in vaccines; these case reports are discussed in the section below. Magnesium stearate, an excipient used for lubrication during the tablet manufacturing process, may be synthesized from bovine or vegetable organic fatty acids.21 One case report describes a patient with alpha-gal allergy who developed symptoms after taking a number of different oral medications. This patient experienced diarrhea and chest tightness after taking acetaminophen and naproxen in gelatin capsules, hives after using hydrocodone-acetaminophen and clonidine tablets, and laryngeal edema, abdominal cramping, nausea, and diarrhea after taking lisinopril. The only inactive ingredient these medications had in common was magnesium stearate, so it was determined that the patient was likely reacting to this ingredient.

Vaccinations and alpha-gal allergy

Vaccines may provoke a reaction in patients with alpha-gal allergy if animal products are used at any point in the manufacturing process. Several vaccines contain gelatin, which may provoke a reaction in some patients with alpha-gal allergy.22 In particular, herpes zoster is known to have a relatively high gelatin content, but there are many other vaccines that contain gelatin as well, including measles, mumps, rubella (MMR), rabies, varicella, yellow fever, oral typhoid, and some influenza vaccines (trivalent Fluzone, FluMist, and Fluenz Tetra).23 Additionally, contamination with alpha-gal may arise from the vaccine production methods: for example, the measles, mumps, rubella (MMR) and herpes zoster vaccines use bovine calf serum during production, which may serve as an additional source of alpha-gal antigen.22 The herpes zoster vaccination has been reported to cause severe allergic reactions in patients with alpha-gal allergy.22,24 However, there is also one published case report of a patient with alpha-gal allergy receiving the herpes zoster vaccine without reaction.25 This patient also did not exhibit gelatin-specific IgE on skin or serum testing. This case highlights the potential for variability among patients with alpha-gal allergy: some patients will react to gelatin in vaccines, while others may not.

Table 1. Medications and ingredients reported as potential reaction triggers in alpha-gal-allergic patients.15-22

Medications with alpha-gal epitopes

Inactive ingredients with alpha-gal epitopes

Medications with mammalian sources and potential for contamination with alpha-gal

Cetuximab

Gelatin

Heparin

Crotalidae antivenom (CroFab)

Magnesium stearate

Vaccines produced with mammalian tissues

Equine antivenoms

Infliximab

Conclusion

Alpha-gal allergy is a recently-described IgE-mediated hypersensitivity to mammalian meat. Although it primarily presents as a food allergy, it can significantly impact a patient’s medication therapy as well. Some drug molecules contain alpha-gal epitopes, and animal byproducts such as gelatin and magnesium stearate are frequently used in the production and formulation of many medications. Unfortunately, manufacturers do not routinely test for alpha-gal content in their products: therefore, it is important for pharmacists to be aware of this issue and conscious of inactive medication ingredients.2,21 In order to successfully manage patients with alpha-gal allergy, pharmacists must recognize drugs and ingredients that may provoke a reaction, contact manufacturers for detailed information about animal byproduct content/use when necessary, and weigh the benefits and risks of medication administration for each individual patient.21

References

1.         Iweala OI, Burks AW. Food allergy: our evolving understanding of its pathogenesis, prevention, and treatment. Curr Allergy Asthma Rep. 2016;16(5):37.

2.         van Nunen S. Tick-induced allergies: mammalian meat allergy, tick anaphylaxis and their significance. Asia Pac Allergy. 2015;5(1):3-16.

3.         Commins SP, Jerath MR, Cox K, Erickson LD, Platts-Mills T. Delayed anaphylaxis to alpha-gal, an oligosaccharide in mammalian meat. Allergol Int. 2016;65(1):16-20.

4.         Platts-Mills TA, Schuyler AJ, Hoyt AE, Commins SP. Delayed anaphylaxis involving IgE to galactose-alpha-1,3-galactose. Curr Allergy Asthma Rep. 2015;15(4):512.

5.         Saleh H, Embry S, Nauli A, Atyia S, Krishnaswamy G. Anaphylactic reactions to oligosaccharides in red meat: a syndrome in evolution. Clin Mol Allergy. 2012;10(1):5.

6.         Wilson JM, Schuyler AJ, Schroeder N, Platts-Mills TA. Galactose-alpha-1,3-galactose: atypical food allergen or model IgE hypersensitivity? Curr Allergy Asthma Rep. 2017;17(1):8.

7.         Chinuki Y, Ishiwata K, Yamaji K, Takahashi H, Morita E. Haemaphysalis longicornis tick bites are a possible cause of red meat allergy in Japan. Allergy. 2016;71(3):421-425.

8.         Fischer J, Lupberger E, Hebsaker J, et al. Prevalence of type I sensitization to alpha-gal in forest service employees and hunters. Allergy. 2017;72(10):1540-1547.

9.         Stewart PH, McMullan KL, LeBlanc SB. Delayed red meat allergy: clinical ramifications of galactose-alpha-1,3-galactose sensitization. Ann Allergy Asthma Immunol. 2015;115(4):260-264.

10.       Jappe U, Minge S, Kreft B, et al. Meat allergy associated with galactosyl-alpha-(1,3)-galactose (alpha-Gal)-Closing diagnostic gaps by anti-alpha-Gal IgE immune profiling. Allergy. 2017.

11.       Apostolovic D, Tran TA, Hamsten C, Starkhammar M, Cirkovic Velickovic T, van Hage M. Immunoproteomics of processed beef proteins reveal novel galactose-alpha-1,3-galactose-containing allergens. Allergy. 2014;69(10):1308-1315.

12.       Mullins RJ, James H, Platts-Mills TA, Commins S. Relationship between red meat allergy and sensitization to gelatin and galactose-alpha-1,3-galactose. J Allergy Clin Immunol. 2012;129(5):1334-1342.e1331.

13.       Unal D, Coskun R, Demir S, Gelincik A, Colakoglu B, Buyukozturk S. Successful beef desensitization in 2 adult patients with a delayed-type reaction to red meat. J Allergy Clin Immunol Pract. 2017;5(2):502-503.

14.       Garcia-Menaya J, Cordobes-Duran C, Gomez-Ulla J, et al. Successful desensitization to cetuximab in a patient with a positive skin test to cetuximab and specific IgE to alpha-gal. J Investig Allergol Clin Immunol. 2016;26(2):132-134.

15.       Chung C, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-α-1,3-galactose. N Engl J Med. 2008;358(11):1109-1117.

16.       Chitnavis M, Stein DJ, Commins S, Schuyler AJ, Behm B. First-dose anaphylaxis to infliximab: a case of mammalian meat allergy. J Allergy Clin Immunol Pract. 2017;5(5):1425-1426.

17.       Rizer J, Brill K, Charlton N, King J. Acute hypersensitivity reaction to Crotalidae polyvalent immune Fab (CroFab) as initial presentation of galactose-alpha-1,3-galactose (alpha-gal) allergy. Clin Toxicol (Phila). 2017;55(7):668-669.

18.       Fischer J, Eberlein B, Hilger C, et al. Alpha-gal is a possible target of IgE-mediated reactivity to antivenom. Allergy. 2017;72(5):764-771.

19.       Kleiman AM, Littlewood KE, Groves DS. Delayed anaphylaxis to mammalian meat following tick exposure and its impact on anesthetic management for cardiac surgery: a case report. A A Case Rep. 2017;8(7):175-177.

20.       Vidal C, Mendez-Brea P, Lopez-Freire S, Gonzalez-Vidal T. Vaginal capsules: an unsuspected probable source of exposure to alpha-gal. J Investig Allergol Clin Immunol. 2016;26(6):388-389.

21.       Muglia C, Kar I, Gong M, Hermes-DeSantis ER, Monteleone C. Anaphylaxis to medications containing meat byproducts in an alpha-gal sensitized individual. J Allergy Clin Immunol Pract. 2015;3(5):796-797.

22.       Stone CA, Jr., Hemler JA, Commins SP, et al. Anaphylaxis after zoster vaccine: Implicating alpha-gal allergy as a possible mechanism. J Allergy Clin Immunol. 2017;139(5):1710-1713.e1712.

23.       Dreskin SC, Halsey NA, Kelso JM, et al. International Consensus (ICON): allergic reactions to vaccines. World Allergy Organ J. 2016;9(1):32.

24.       Akella K, Patel H, Wai J, Roppelt H, Capone D. Alpha gal-induced anaphylaxis to herpes zoster vaccination. Chest. 2017;152(4)(suppl):A6.

25.       Pinson ML, Waibel KH. Safe administration of a gelatin-containing vaccine in an adult with galactose-alpha-1,3-galactose allergy. Vaccine. 2015;33(10):1231-1232.

January 2018

The information presented is current as of December 12, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What is the evidence for the use of high-dose intravenous vitamin C for the treatment of cancer?

Introduction

Vitamin C is an antioxidant and a cofactor in various enzyme pathways.1-3 It also plays a role in collagen synthesis and the inhibition of hyaluronidase.  Vitamin C exists in 2 states, ascorbic acid, the reduced form, and dehydroascorbic acid (DHA), the oxidized form, that enters the cell via sodium-dependent vitamin C transporters (SVCTs) and glucose transporters (GLUTs), respectively.1 Vitamin C deficiency occurs when the blood plasma concentration is <11.4 uM.

The role of vitamin C in cancer

Cancerous cells have decreased oxygen content, which produces reactive oxygen species.1 Intravenous administration of vitamin C bypasses the first past effect. This allows vitamin C, a prodrug, to reach cancer cells to deliver very high amounts of ascorbate radicals and hydrogen peroxide leading to cancer regression, although the exact mechanism is unknown.4,5 Another mechanism by which vitamin C may stop cancer growth is by inhibiting hyaluronidase and preventing the breakdown of extracellular matrix to prevent metastases.2 Initial animal studies that evaluated the use of intravenous vitamin C showed that it played a role in inhibiting the growth of cancer cells.6

Intravenous vitamin C has been used with chemotherapy drugs (eg, paclitaxel, carboplatin) for synergy.4 Vitamin C is different from chemotherapeutic agents because it does not kill healthy cells. In the 1980s, 2 randomized, double-blind studies were conducted at the Mayo Clinic with 10 grams of oral vitamin C per day compared to placebo.2 Neither study showed an improvement in symptoms or survival. The purpose for the recent interest in re-evaluating the use of high-dose vitamin C for the treatment of cancer is that these 2 studies used oral vitamin C, which was found to have a lower bioavailability than intravenously administered vitamin C.2,4 Thus the oral dosage form is thought to be responsible for sub-therapeutic doses and the lack of effect observed in these trials.

Literature Review

A literature search was conducted to identify studies evaluating the use of high dose intravenous vitamin C in patients with cancer.

A systematic review evaluated data from 6 studies on oral ascorbate (n=3694), 16 studies on intravenous ascorbate (n=489), and 13 studies on oral and intravenous ascorbate (n=4380) that were mainly observational studies, case series and reports, and randomized controlled trials. The authors concluded that, overall, the evidence for the use of intravenous vitamin C in patients with cancer was unclear based on the literature available.7  Most of the studies on intravenous ascorbate (11 of 16 studies) included patients with any advanced metastatic cancer, whereas the remainder of the studies did not clearly state the extent of the disease. The dose of intravenous vitamin C ranged from 500 mg daily to 100 grams administered 3 times a week.

A small single-center phase II study in 23 patients with adenocarcinoma of the prostate found that none of the patients achieved the primary outcome of a ≥50% reduction in prostate-specific antigen (PSA) at 12 weeks with an initial 5 gram intravenous dose of vitamin C followed by a final dose of 60 grams on week 3 to week 12 plus an oral 500 mg dose vitamin C for 26 weeks.8

A case series of 9 patients with different cancer types received 25 to 100 grams of intravenous vitamin C for 21 days based on vitamin C blood concentration.9

Patients with active cancer further received infusions every 2 to 3 days weekly and patients on maintenance treatment received weekly infusions supplemented with oral vitamin C. Overall, the authors observed an improvement in the quality of life, noting that intravenous vitamin C may have anticancer activity and may be used with conventional therapy without a concern for drug interactions.

A case report of a 5-year old child who was previously treated with chemotherapy for neurofibromatosis described reduction and stabilization of tumors, with the disappearance of a mass after treatment with intravenous vitamin C initiated at 7 grams and titrated to 15 grams per week for a total of 100 treatment infusions.10 The level of vitamin C blood concentration was 190 mg/dL to 210 mg/dL. Another case report of a 74-year-old woman with hepatocellular cancer and multiple pulmonary metastases was treated with 20 grams vitamin C intravenously twice weekly resulting in regression of pulmonary metastases and regression of hepatic mass with vitamin C and transarterial chemoembolization.11

Administration and Stability

Intravenous vitamin C is not available as an FDA-approved product. However, a study by Monti et al. was conducted to determine the chemical stability of intravenous vitamin C.12 The preparation contained sterile water, magnesium chloride, calcium gluconate, and ascorbic acid as a 75 gram and 100 gram dose. The product was stable up to 6 hours after preparation.

Oral administration of vitamin C results in sub-therapeutic concentrations of vitamin C levels unlike intravenous route which produces a higher blood concentration of vitamin C that may have antitumor activity.7,13 The pro-oxidative effects of intravenous vitamin C were seen at doses resulting in a blood concentration of >100 uM.1 Intravenous vitamin C has an elimination half-life of ~2 hours, therefore an adequate schedule needs to be maintained to achieve desirable blood concentrations.14  Factors such as the relationship between dose, plasma concentration and time as well as volume of distribution and saturation all play an important role in the determination of an appropriate regimen.15

Unfortunately, the appropriate regimen for the use of intravenous vitamin C in patients with cancer is unknown.15 In a protocol by Cameron et al. it was suggested to administer 10 days of intravenous vitamin C followed by oral supplementation and booster doses.16 Riordan et al. detailed a protocol involving a 4-week titration period for intravenous vitamin C starting at 15 grams per day 2 to 3 times a week on week 1 and 100-grams per day 2 to 3 times a week on week 4.17 A daily 5-gram supplement was recommended for days the patient did not receive intravenous vitamin C to maintain blood concentration levels.

Safety   

Although vitamin C is relatively safe, there still is a concern for adverse effects associated with the use of high doses (eg, gastrointestinal disturbances).18 There is also a concern about potential aluminum toxicity, especially with high-doses, prolonged use, or renal dysfunction, since parenteral products may contain aluminum. Studies have shown that intravenous vitamin C administration can cause nausea, dry mouth, dry skin, and minor edema.19 Two phase I studies have shown that doses up to 1.5 g/kg have resulted in good tolerance and safety profiles. However, the excessive use of vitamin C may increase cardiovascular morbidity and mortality, and the risk of thrombosis.

Vitamin C can lead to a ‘rebound effect’ or a drastic decrease in vitamin C levels, which is caused by the induction of hepatic enzymes involved in the metabolism of ascorbate at high doses.20 Vitamin C is involved in hydrogen peroxide production, which at high concentrations can cause hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. Oxalate nephropathy can occur with the use of vitamin C since a metabolite of ascorbic acid is oxalic acid.3,21 Even though intravenous vitamin C therapy is safe, toxicities such as cardiac arrest, renal toxicity, and metabolic abnormalities have been reported in phase I and phase II studies.7 One patient has also experienced the Jarisch-Herxheimer reaction, which causes acne outbreaks and strong odorous perspiration.9 Typically, this reaction is seen in patients with a microbial infection. 

Conclusion

Oncology is a rapidly evolving therapeutic field. Although there are multiple therapeutic options available, some patients ultimately may not benefit or achieve remission or cure. Intravenous vitamin C is an interesting treatment option since it does not seem to cause detrimental adverse effects seen with some other conventional chemotherapeutic agents. The use of intravenous vitamin C still remains controversial. Many of the studies look at a wide range of cancer types so effectiveness in one type of cancer cannot be extrapolated to another.9 More high-quality studies are needed to determine the effectiveness of intravenous vitamin C monotherapy and when used with other chemotherapeutic agents.22 However, the available evidence provides practical information for patients who have no alternative treatment options left.23 

References:

1. Gillberg L, Orskov AD, Liu M, et al. Vitamin C – a new player in regulation of the cancer epigenome. [Published ahead of print November 2, 2017]. Semin Cancer Biol. doi: 10.1016/j.semcancer.2017.11.001.

2. Cieslak JA, Cullen. Treatment of pancreatic cancer with pharmacological ascorbate. Curr Pharm Biotechnol. 2015;16(9):759-770.

3. Padayatty SJ, Levine M. Reevaluation of ascorbate in cancer treatment: Emerging evidence, open minds and serendipity. J Am Coll Nutr. 2000;19(4):423-425.

4. Ma Y, Chapman J, Levine M, et al. High-dose parenteral ascorbate enhanced chemotherapy of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med. 2014 Feb 5;6(222):1-10.

5. Du J, Cullen JJ, Buettner GR. Ascorbic acid: Chemistry, biology, and the treatment of cancer. Biochem Biophys Acta. 2012;1826(2):443-457.

6. Wilson MK, Baguley BC, Wall C, et al. Review of high-dose intravenous vitamin C as an anticancer agent. Asia Pac J Clin Oncol. 2014;10(1):22-37.

7. Jacobs C, Hutton B, Ng T, et al. Is there a role for oral or intravenous ascorbate (vitamin C) in treating patients with cancer? A systematic review. Oncologist. 2015;20(2):210-223.

8. Nielsen TKHøjgaard MAndersen JT, et al. Weekly ascorbic acid infusion in castration-resistant prostate cancer patients: A single-arm phase II trial. Transl Androl Urol. 6(3):517-528.

9. Raymond YC, Glenda CS, Meng LK. Effects of high doses of vitamin C on cancer patients in Singapore: Nine cases. Integr Cancer Ther. 15(2):197-204.

10. Mikirova N, Hunnunghake R, Scimeca RC, et al. High-dose intravenous vitamin C treatment of a child with neurofibromatosis type 1 and optic pathway glioma: A case report. Am J Case Rep. 17:774-781.

11. Seo M, Kim J, Shim J. High-dose vitamin C promotes regression of multiple pulmonary metastases originating from hepatocellular carcinoma. Yonsei Med J. 2015;56(5):1449-1452.

12. Monti DA, Bazzan AJ, Zabrecky G, et al. Brief report: Stability and chemical characteristics of injectable ascorbic acid for patients with cancer. [Published online ahead of print October 2, 2017] Altern Ther Health Med. pii: AT5681

13. Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: Implications for oral and intravenous use. Ann Intern Med. 2004;140(7):533-537.

14. Nielsen TKHøjgaard MAndersen JT, et al. Elimination of ascorbic acid after high-dose infusion in prostate cancer patients: a pharmacokinetic evaluation. Basic Clin Pharmacol Toxicol. 2015;116(4):343-348.

15. Gonzalez MJ, Miranda JR, Duconge J, et al. Schedule dependence in cancer therapy: Intravenous vitamin C and the systemic saturation hypothesis. J Orthomol Med. 2012;27(1):9-12.

16. Cameron E. Protocol for the use of vitamin C in the treatment of cancer. Med Hypotheses. 1991 Nov;36(3):190-194.

17. Riordan HD, Hunninghake RB, Riordan NH, et al. Intravenous ascorbic acid: Protocol for its application and use.  P R Health Sci J. 2003;22(3):287-290.

18. Lexicomp [database online]. Hudson, OH: Wolters Kluwer Health, Inc; 2017. Accessed December 25, 2017.

19. Kim K, Bae O, Koh S, et al. High dose vitamin C injection to cancer patients may promote thrombosis through procoagulant activations of erythrocytes. Toxicol Sci. 2015 Oct;147(2):350-359

20. Frei B, Lawson S. Vitamin C and cancer revisited. Proc Natl Acad USA. 2008;105(32):11037-11038. 

21. Verrax J, Calderon B. The controversial place of vitamin C in cancer treatment. Biochem Pharmacol. 2008;76(12)1644-1652.

22. Parrow NL, Leshin JA, Levine M. Parenteral ascorbate as a cancer therapeutic: A reassessment based on pharmacokinetics. Antioxid Redox Signal. 2013;19(17):2141-2156.

23. Hoffer LJ, Robitaille L, Zakarian R, et al. High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: A phase I-II clinical trial. PLoS One. 2015;10(4):e0120228.

January 2018

The information presented is current as of December 25, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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What are considerations for determining whether a drug may be administered via a midline catheter?

Introduction

Midline catheters represent a unique vascular access device (VAD) for patients requiring intravenous (IV) administration of drugs or other infusates.1,2 After their introduction in the 1950s, hypersensitivity and phlebitis reactions to the manufacturing materials led to a temporary decline in the use of midline catheters through the 1990s; however, a redesign of these products in recent years has led to their renewed adoption. Midline catheters have properties that differ from those of traditional peripheral IV catheters and central venous catheters (CVCs). Therefore, questions often arise regarding the appropriateness of administering specific drugs via midline catheter. This review provides an overview of midline catheters and a summary of properties that influence the determination of whether a drug is appropriate for administration via midline catheter.

Properties of midline catheters

Midline catheters differ from other VADs with regard to their insertion and termination sites.1,3  Midline catheters are inserted peripherally into the antecubital fossa or upper arm via the basilic, cephalic, or brachial vein, and extend from 8 to 20 cm centrally, where the catheter tip terminates at or below the axillary vein. Because this termination site is distal to those of CVCs and peripherally inserted central catheters (PICCs), midline catheters are not considered to dwell in the central circulation.1 Whereas the central termination site of CVCs and PICCs provide the ability to administer a wider range of infusates (eg, vesicants), this is not recommended with VADs terminating distal to the central circulation. Another distinction includes that central VADs may also be more appropriate in patients needing longer-term therapy (eg, ≥4 weeks).3 Also, compared with central VADs, some reports indicate midline catheters are associated with lower risks of thrombosis (<2% with midline vs 1% to 38.5% with PICC) and catheter-related bloodstream infection (CRBSI; between 0 and 0.2 per 1,000 catheter days with midline vs 2.1 to 2.3 and 2.4 to 2.7 per 1,000 catheter days with PICCs and CVCs, respectively). 1

Compared with midline catheters, peripheral IV catheters are inserted more distally, and most often utilize veins of the dorsum of the hand for cannulation.4 Peripheral IV catheters have high first-attempt failure rates (26% in adults, 54% in children) and often require recannulation in larger more proximal sites.1,2 Therefore, midline catheters may reduce the need for recannulation and thereby afford a longer dwell time. Additionally, patient mobility is greater with midline catheters because of the location of their insertion site.2  Lastly, compared with drug administration via peripheral IV catheter, the risk of phlebitis may be reduced with administration via midline catheter because of its termination in an area with a higher rate of blood flow.2 The rates of CRBSI have also been reported to be lower with midline vs peripheral catheters (0 to 0.2 vs 0.5 per 1,000 catheter days). 1

Overall, the properties of midline catheters may make them preferable in patients requiring durations of IV treatment between those commonly reserved for peripheral and central catheters. Compared with peripheral catheters, midline placement may be preferred in patients who are candidates for early discharge and who require continuation at home of intermediate-term (eg, 1 to 4 weeks) IV therapy. 3 Likewise, midline catheters may be preferred to CVCs or PICCs in patients who require intermediate rather than longer durations of IV therapy. The CDC recommends consideration of midline catheters when the duration of IV therapy is likely to exceed 6 days.1,5

Considerations for drugs administered via midline catheter

The main consideration in determining whether a drug is appropriate for administration via midline catheter is its ability to cause phlebitis.2 Phlebitis is inflammation of a vein caused by damage to the tunica intima, which may be accompanied by erythema, swelling, pain, heat, and a palpable cord if thrombosis is present.  If chemical phlebitis occurs, the midline catheter should be removed and an alternative VAD should be placed in the opposite arm.3

Chemical phlebitis may be caused by drugs that irritate the vasculature, usually because of extremes of pH or osmolarity.3 Infusates that are generally accepted as appropriate to administer via midline catheter include infusates with a pH between 5 and 9 and with osmolarity <600 mOsm/L.1,3 The 2016 Infusion Nurses Society (INS) Standards of Practice document recommends against the use of midline catheters for continuous administration of vesicant therapy, parenteral nutrition, or other infusates with an osmolarity >900 mOsm/L.3  If vesicants are administered intermittently, INS recommends caution be exercised to avoid undetected extravasation. Lastly, the standards recommend midline catheters be avoided in patients with a history of thrombosis, hypercoagulability, venous stasis, or with a need to preserve vein integrity, such as in patients with end-stage renal disease.

There is no comprehensive list of drugs that are appropriate for administration via midline catheter. Clinicians considering drug administration via this VAD should review the chemical properties of the drug under consideration from reputable resources (eg, prescribing information) to compare them with the guidances above. Nonetheless, a review of literature of known vesicants and drugs reported to cause vascular injury or extravasation indicates some drugs that may present higher risk when administered via midline catheter. For example, many cytotoxic agents (ie, chemotherapy) are considered vesicants and should not be administered via midline catheters according to INS standards.6,7 Additionally, in 2017, the INS assigned a Vesicant Task Force to publish a list of noncytotoxic vesicant medications and solutions.7 The Table below, while not exhaustive, details drugs from this list, as well as drugs that have extremes of pH or osmolarity that have been associated with vascular injury or extravasation.8

 

Table. Noncytotoxic vesicants and drugs with extremes of pH or osmolarity reported to cause vascular injury or extravasation.3,7,8

Noncytotoxic vesicants

Hyperosmolar agents

Acidic and alkaline agents

Drug

Risk levela

Drug

Osmolarity

(mOsm/L)

Drug

pH

Acyclovir

Yellow

Arginine

950

Acyclovir

11

Amiodarone

Yellow

Calcium chloride 10%

2040

Amiodarone

3.5-4.5

Arginine

Yellow

Calcium gluconate

669

Conivaptan

3.4-3.8

Calcium chloride

Red

Contrast media

Variesb

Doxycycline

1.8-3.3

Calcium gluconate

Red

Dextrose 10%-50%

504-2520

Phenytoin

10-12

Contrast media, nonionic

Red

Hypertonic saline

Varies by concentration

Promethazine

4.0-5.5

Dextrose ≥10%-12.5%

Yellow

Mannitol 20%

1369

Sodium thiopental

10-11

Dextrose ≥12.5%

Red

Phenytoin

700

Vancomycin

4

Dobutamine

Red

Potassium ≥60 mEq/L

≥763

Dopamine

Red

Sodium bicarbonate 8.4%

2000

Epinephrine

Red

TPN

Commonly >900

Mannitol ≥20%

Yellow

Nafcillin sodium

Yellow

Norepinephrine

Red

Pentamidine isethionate

Yellow

Pentobarbital sodium

Yellow

Phenobarbital sodium

Yellow

Phenylephrine

Red

Phenytoin

Red

Potassium ≥60 mEq/L

Yellow

Promethazine

Red

Sodium bicarbonate

Red

Sodium chloride ≥3%

Red

TPN >900 mOsm

Red

Vancomycin

Yellow

Vasopressin

Red

aRisk level was assigned based on literature reports of peripheral administration. Risk level of red indicates higher risk and greater literature documenting tissue damage upon extravasation. Risk level of yellow indicates intermediate risk and less literature documenting tissue damage upon extravasation.

bOsmolarity varies. For further information, see American College of Radiology guideline.9

Abbreviations: TPN=total parenteral nutrition.

 

One drug that has generated controversy regarding its appropriateness for administration via midline catheter is vancomycin.3 Based on the range of pH values generally considered appropriate for midline administration, vancomycin would be excluded because of its pH of 4. However, the INS Task Force identified limited literature describing extravasation of vancomycin. Furthermore, in vitro evidence suggested that vancomycin-associated endothelial damage is caused by factors other than pH. Additionally, the risk of cytotoxicity is reduced by intermittent compared with continuous infusion, as well as by dilution of vancomycin to concentrations of 2 to 5 mg/mL. One randomized controlled trial found that the incidence of total complications, phlebitis, and thrombosis did not significantly differ when vancomycin was administered for less than 6 days via midline catheter vs PICC.3,10

Conclusion

Midline catheters have properties unique from those of peripheral and central VADs. Determinations regarding the administration of drugs via midline catheter should consider properties of each drug individually because no definitive guidance is available to list the appropriateness of all drugs. Generally, drugs that are vesicants or have extremes of pH or osmolarity should not be administered via midline catheters.

References

1.         Adams DZ, Little A, Vinsant C, Khandelwal S. The midline catheter: a clinical review. J Emerg Med. 2016;51(3):252-258.

2.         Griffiths V. Midline catheters: indications, complications and maintenance. Nurs Stand. 2007;22(11):48-57; quiz 58.

3.         Gorski L, Hadaway L, Hagle ME, McGoldrick M, Orr M, Doellman D. Infusion therapy standards of practice. Journal of Infusion Nursing. 2016;39(1S):S1-159.

4.         Frank RL. Peripheral venous access in adults. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate; 2017. https://www.uptodate.com/contents/peripheral-venous-access-in-adults?source=search_result&search=peripheral%20catheter%20insertion&selectedTitle=2~150. Accessed December 12, 2017.

5.         Centers for Disease Control and Prevention. Intravascular catheter-related infection (BSI). Centers for Disease Control and Prevention website. https://www.cdc.gov/infectioncontrol/guidelines/BSI/index.html. Updated November 5, 2015. Accessed December 11, 2017.

6.         Boulanger J, Ducharme A, Dufour A, et al. Management of the extravasation of anti-neoplastic agents. Support Care Cancer. 2015;23(5):1459-1471.

7.         Gorski LA, Stranz M, Cook LS, et al. Development of an evidence-based list of noncytotoxic vesicant medications and solutions. J Infus Nurs. 2017;40:26-40.

8.         Reynolds PM, MacLaren R, Mueller SW, Fish DN, Kiser TH. Management of extravasation injuries: a focused evaluation of noncytotoxic medications. Pharmacotherapy. 2014;34(6):617-632.

9.         Davenport MS, Asch D, Cavallo J, et al. ACR manual on contrast media version 10.3. American College of Radiology website. https://www.acr.org/-/media/ACR/Files/Clinical-Resources/Contrast_Media.pdf. Updated May 31, 2017. Accessed December 12, 2017.

10.       Caparas JV, Hu JP. Safe administration of vancomycin through a novel midline catheter: a randomized, prospective clinical trial. J Vasc Access. 2014;15(4):251-256.

January 2018

The information presented is current as of December 12, 2017.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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