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Anaphylaxis after Administration of Heparin Flush.

Heparin is a natural product derived from porcine intestines. It works to prevent blood clots by inactivating Factor Xa (thus preventing conversion of prothrombin to thrombin) and thrombin (preventing conversion of fibrinogen to fibrin). Heparin lock flush solution (United States Pharmacopeia [USP]) is a sterile solution for injection indicated only for intravenous (IV) flushing to maintain patency of indwelling venous access devices. Each milliliter of preservative-free heparin lock flush solution contains heparin sodium 10 or 100 USP units, and sodium chloride 9 mg in water for injection. The solution also may contain sodium hydroxide and/or hydrochloric acid to achieve a pH between 5 and 7.5 (U.S. Food and Drug Administration [FDA], 2015a).

Hypersensitivity Reactions

Delayed hypersensitivity reactions to subcutaneously injected heparin are relatively common and present as eczematous plaques at injection sites (Anders & Trautmann, 2013). In contrast, anaphylactic immediate hypersensitivity reactions are rare and cause an array of systemic symptoms. These include angioedema, dyspnea, wheezing, bronchospasm, hypoxia, cough, sweating, flushing, anxiety, itching, erythema, generalized urticaria, decreased blood pressure, tachycardia, intermittent junctional escape rhythms, ventricular tachycardia, asystole, and even death (Anders & Trautmann, 2013; Santosa, Tan, & Cheng, 2013). A contaminant in heparin products, oversulfated chondroitin sulfate, caused numerous hypersensitivity reactions in 2007-2008 (FDA, 2015b). Patients presented with symptoms of hypotension, angioedema, shortness of breath, nausea, vomiting, diarrhea, and abdominal pain. Serious injuries were reported, and at least 81 people died. The affected products were recalled, new screening regimens were implemented by the FDA, and no further cases were reported.

Heparin Anaphylaxis after Heparin Flush

A search of PubMed using the terms (anaphyl* OR hypersens* OR allergic OR allergy) AND heparin was conducted, and two cases of anaphylaxis caused by heparin flushes were identified (Garajova, Nepoti, Paragona, Brandi, & Biasco, 2012; Harada et al., 1990). In those cases, as well as the case reported here, the allergy to heparin was not recognized initially; patients were re-exposed to heparin, causing a second anaphylactic reaction.

A 2012 report described the case of a 79-year-old woman who received 50 international units/5 ml IV heparin every 5-6 weeks to prevent clotting of her implantable venous access system (Garajova et al., 2012). After 52 months of treatment without problem, she experienced a reaction minutes after receiving the IV heparin solution. She developed erythema on her hands and face, as well as rhinitis, lacrimation, nausea, and vomiting. She was treated with hydrocortisone and antihistamines, and received no further heparin flushes. The patient noted she had experienced a similar, milder reaction after her previous heparin flush treatment 40 days earlier. This patient's experience was most similar to the present case, as both patients tolerated heparin flushes for several years before developing a reaction.

The other case (Harada et al., 1990) concerned a 7-year-old girl who had a catheter placed in her right radial artery in preparation for surgery to correct tetralogy of Fallot. When the catheter was flushed with heparinized saline solution, the patient's blood pressure dropped from 130/90 to 60/0 mm Hg, and swelling and redness developed on her palm, arm, and chest. The patient also had received ketamine and pancuronium bromide injection just before the heparin, making the allergy diagnosis difficult. Re-exposure to heparin flush solution 2 months later caused the same anaphylactic symptoms, along with respiratory problems requiring ventilation.

The purpose in presenting this case is to make nurses aware of this rare but serious occurrence so they can avoid dangerous re-exposures or incorrect allergy diagnoses.

Case Description

The patient was a 69-year-old White woman with a complex past medical history, including antithrombin III deficiency, hyperparathyroidism, bilateral foot drop, osteoporosis, osteoarthritis, hypertension, neuropathy of bilateral lower extremities, neurogenic bladder, inflammatory bowel syndrome, necrotizing fasciitis, sarcoidosis, heart murmur, and pulmonary embolus (with placement of a vena cava filter). Allergies were listed as adhesive tape (rash), codeine (headaches and nausea), alendronate and oral bisphosphonates (dyspepsia, neutropenia), and warfarin (anaphylaxis). See Table 1 for patient's home medications.

First Anaphylactic Reaction

The patient received heparin flushes via her port every 8 weeks for the previous 11 years with no adverse reactions. On the day of the first reaction, the patient was seen in clinic. Her weight was 100.8 kg, temperature 98.9[degrees] F, heart rate 98 beats/minute, respiratory rate 16 breaths/minute, and blood pressure 146/80 mm Hg. The patient received only saline and a heparin flush at this visit via her Port-A-Cath[R] implantable venous access system (Bard Access Systems; Salt Lake City, UT). Approximately 40 minutes later, she experienced tongue swelling, slurred speech, shortness of breath, diffuse urticaria, and a hyperemic rash on the upper body. She received 25 mg IV diphenhydramine (Benadryl[R]) followed by 100 mg of IV hydrocortisone (Solu-Cortef[R]). The reaction continued to worsen, with swelling of face and eyes, and extension of the rash.

The patient was transferred to the emergency department (ED), where her vital signs on arrival were as follows: temperature 97.8[degrees] F, heart rate 99 beats/minute, respiratory rate 18 breaths/minute, blood pressure 142/73 mm Hg, and oxygen saturation 90% on room air. The patient was treated with 2 liters of oxygen via nasal cannula and 0.3 mg intramuscular (IM) epinephrine, 125 mg IV methylprednisolone (Solu-Medrol[R]), 20 mg IV famotidine (Pepcid[R]), and 25 mg IV diphenhydramine. She remained alert and oriented throughout the episode. The patient was discharged with a prescription for 40 mg oral prednisone daily for 4 days, as well as a 0.3 mg epinephrine auto-injector kit for use at the first sign of another allergic reaction. The reaction was reported to the pharmacy with the lot number, expiration date, and manufacturer of the heparin flush product. The patient did not receive allergy testing because the reaction was presumed to be due to a contaminated lot of heparin.

Second Anaphylactic Reaction

Approximately 7 months later, the patient experienced another allergic reaction in response to a heparin flush given in clinic. She had been treated over the intervening 7 months at a different facility, which had different port-flushing protocols. She had received only saline flushes during that time, with no exposure to heparin. The patient was having her port accessed to obtain blood for laboratory work. Her vital signs included heart rate of 75 beats/minute, respiratory rate of 16 breaths/minute, and blood pressure of 130/70 mm Hg. Her Port-A-Cath was flushed with normal saline and then with heparin. Within 60 seconds of the heparin flush, the patient asked to sit up. Intense itching began in her left axilla and spread throughout her body. The patient reported difficulty focusing along with some loss of self-control. She had burning and intense heat from head to groin, as well as diaphoresis. A diffuse red rash developed, accompanied by eyelid swelling and shortness of breath. The patient received 0.3 mg IM epinephrine, 50 mg IV diphenhydramine, and a 0.9% saline IV infusion. Her reaction then started to resolve and she was transferred to the ED for evaluation and further treatment.

Vital signs on arrival to the ED included temperature of 97.2[degrees] F, heart rate 94 beats/minute, respiratory rate 24 breaths/minute, blood pressure 91/78 mm Hg, and oxygen saturation 98% on room air. She was treated with 20 mg IV famotidine and 125 mg IV methylprednisolone; the saline infusion was continued. At discharge, the patient was prescribed 40 mg prednisone by mouth daily and was instructed to use over-the-counter famotidine, both for the next 4 days. An allergy to heparin was documented in the patient's medical record. Saline flushes replaced heparin flushes from that point forward.


The Naranjo algorithm was used to determine the likelihood that the heparin flush solution caused the patient's reaction (Naranjo et al., 1981). The total score of 6 suggested the heparin flush solution as the probable cause (see Table 2). However, the case has some limitations. The exact heparin product used, along with ingredients, manufacturer, and lot number, could not be confirmed. Authors retrieved the National Drug Code numbers of heparin flush products purchased by the clinic around the time of these reactions. These numbers were for preservative-free, porcine heparin lock flush 100 units/mL intravenous solution, containing heparin, sodium chloride, and hydrochloric acid or sodium hydroxide as needed for pH. It thus seems unlikely the patient's reaction was due to a preservative. However, this cannot be determined absolutely, as the patient could have received preserved heparin from a multi-use vial if the usual heparin flush products were unavailable.

Contamination of the heparin also was an unlikely cause for the reaction, as no other patients at this clinic experienced anaphylactic reactions to heparin flushes around the time of these episodes. Additionally, a PubMed search was conducted for reports of contaminated heparin during this time; none were identified. While heparin allergy may be a likely cause of the reaction, the patient was not advised to undergo allergy testing. No conclusive evidence therefore exists about this patient's heparin allergy or which anticoagulant may be safe for her to receive in the future.

Nursing Implications

Because these reactions are so rare, they may be overlooked by nurses and other healthcare professionals or attributed to other causes, as was the case for the few patients in whom this has been described. This has led to dangerous re-expo sures. Furthermore, it also could lead to an incorrect allergy diagnosis if a heparin flush is administered directly after another medication and the reaction is attributed incorrectly to the other drug. Therefore, nurses and other healthcare professionals must be alert to the potential for sensitization due to prolonged exposure to heparin.

To facilitate understanding by healthcare professionals and promote a safe environment for patients, each institution should have a heparin flush administration policy and procedure. Institutional central venous access device flush policies typically identify the routine flush product, amount, frequency of flushing when the port is not in use, and the timing of flush before and after medication administration and blood draws through the IV line. Authors of this article recommend the policy also require nurses to assess the patient before administering any heparin flush, including identification of any signs or symptoms during the last administration that could represent sensitization. If sensitization signs and/or symptoms were present, the heparin dose should be withheld and the provider contacted for discussion. Any potential patient reaction should be documented thoroughly in the patient's medical record. In addition, each unit or clinic in which heparin flushes are administered should have available emergency medications for possible anaphylaxis.


Nurses and providers should be reminded of anaphylaxis as a possible reaction to heparin, even in response to a low-dose heparin flush product and even if a patient has tolerated such treatments in the past. They should be able to identify these occurrences to prevent dangerous re-exposures or incorrect designation of allergy diagnoses in patients receiving other medications with a heparin flush. Policies and procedures should require nurses to assess a patient for signs and symptoms of potential sensitization, and contain an algorithm identifying when administration of heparin flushes can be resumed. IMS


Anders, D., & Trautmann, A. (2013). Allergic anaphylaxis due to subcutaneously injected heparin. Allergy, Asthma & Clinical Immunology, 9(1), 1. doi:10. 1186/1710-1492-9-1

Garajova, I., Nepoti, G., Paragona, M., Brandi, G., & Biasco, G. (2012). Port-a-Cath-related complications in 252 patients with solid tissue tumours and the first report of heparin-induced delayed hypersensitivity after Port-a-Cath heparinisation. European Journal of Cancer Care, 22(1), 125-132. doi:10.1111/ecc.12008

Harada, A., Tatsuno, K., Kikuchi, T., Takahashi, Y, Sai, S., Murakami, Y, & Takada, K. (1990). Use of bovine lung heparin to obviate anaphylactic shock caused by porcine gut heparin. The Annals of Thoracic Surgery, 49(5), 826-827. doi:10.1016/0003-4975(90)90037-7

Naranjo, C.A., Busto, U., Sellers, E.M., Sandor, P, Ruiz, I., Roberts, E.A., ... Greenblatt, D.J. (1981). A method for estimating the probability of adverse drug reactions. Clinical Pharmacology & Therapeutics, 30(2), 239-245.

Santosa, A., Tan, S., & Cheng, Y (2013). Recurrent intradialytic heparin induced anaphylaxis: Workup and management. Asia Pacific Allergy, 3(4), 285.

U.S. Food and Drug Administration (DA). (2015a). Heparin flush solution, USP. Retrieved from http://www.accessdata. 037s158lbl.pdf

U.S. Food and Drug Administration (FDA). (2015b). Information on heparin. Retrieved from safety/postmarketdrugsafetyinformation forpatientsandproviders/ucm112597.htm

Gabrielle Ruggiero, Lisa M. Holle, Nancy Baccaro, Ellen Oliver

Gabrielle Ruggiero, PharmD, is a consultant pharmacist in Connecticut.

Lisa M. Holle, PharmD, BCOP, FHOPA, is Associate Clinical Professor, School of Pharmacy, University of Connecticut, Storrs, CT, and practices at Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut, Farmington, CT.

Nancy Baccaro, APRN, ANP-BC, MS, AOCN, ACHPN, is Oncology Nurse Practitioner, Surgical Oncology, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut, Farmington, CT.

Ellen Oliver, BSN, RN, is retired, but was Surgical Oncology RN, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut, Farmington, CT.

Patient's Home Medications

Albuterol (Ventolin[R]) as needed
Aspirin 325 mg two tablets three times daily
Carisoprodol (Soma[R]) 350 mg three times daily
Cinacalcet (Sensipar[R]) 30 mg Monday, Wednesday, and Friday
Dicyclomine (Bentyl[R]) 10 mg two capsules every 4 hours as needed
Docusate (Colace[R]) 200 mg three times daily
Folic acid 1 mg daily
Fluticasone/salmeterol (Advair[R]) inhaler 250/50 one puff
  twice daily
Magnesium 800 mg daily
Multivitamin 1 tablet daily
Oxycodone controlled release (Oxycontin[R]) 30 mg three times daily
Oxycodone immediate release 5 mg three tablets every 3
  hours as needed
Senna 1 tablet three times daily as needed
Valsartan (Diovan[R]) 160 mg daily
Vitamin D 100 international units Monday to Friday
Zoledronic acid (Reclast[R]) infusion yearly


Naranjo Adverse Drug Reaction Scale for This Reaction

Question                                Answer    Score

1. Are there previous conclusive         Yes        1
  reports on this reaction?
2. Did the adverse event occur           Yes        2
  after the suspected drug was
3. Did the adverse reaction              Yes        1
  improve when the drug was
  discontinued or a specific
  antagonist was administered?
4. Did the adverse reaction              Yes        2
  reappear when the drug was
5. Are there alternative causes          Yes       -1
  (other than the drug) that could
  have caused the reaction?
6. Did the reaction reappear when      Not done     0
  a placebo was given?
7. Was the drug detected in the        Not done     0
  blood (or other fluids) in
  concentrations known to be toxic?
8. Was the reaction more severe        Not done     0
  when the dose was increased or
  less severe when the dose was
9. Did the patient have a similar         No        0
  reaction to the same or similar
  drugs in any previous exposure?
10. Was the adverse event confirmed      Yes        1
  by any objective evidence?            Total       6

Source: Naranjo et al., 1981
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Title Annotation:Case Study
Author:Ruggiero, Gabrielle; Holle, Lisa M.; Baccaro, Nancy; Oliver, Ellen
Publication:MedSurg Nursing
Date:Nov 1, 2017
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