Reducing Heparin Concentrations in the Home Care Setting: A Case Study

Reducing Heparin Concentrations in the Home Care Setting: A Case Study By Nancy Kramer, R.N., B.S.N., C.R.N.I. T he amount of heparin flush instilled in a patient s catheter is one of those things we usually spend little time considering. We stock specific sizes, volumes, and concentrations of heparin solution or pre-filled syringes, and we use what we ve always used. However, as health care delivery evolves and outcomes are increasingly tracked and utilized in evidence-based decision making, old practices are getting a second look. One old practice in particular, the use of heparin to maintain catheter patency, is receiving closer scrutiny as provider communities are becoming more aware of the risks of heparin-induced thrombocytopenia (HIT), a possible side effect of the widely used blood thinner and flushing agent. Ordinarily, heparin prevents clotting and does not affect the platelets, components of the blood that help form blood clots. However in HIT, the immune system response to heparin can cause a decrease in the platelet count (thrombocytopenia), with potentially devastating effects. Two distinct types of HIT can occur: non-immune and immune-mediated. Non-immune HIT, which occurs most frequently, is a relatively benign condition characterized by a mild decrease in the platelet count that can resolve despite continued use of heparin. Type 1 is estimated to occur in 10 to 20 percent of patients receiving heparin therapy. The second type, immune-mediated HIT, occurs much less frequently but with potentially serious consequences, including life- and limb-threatening venous and arterial thrombosis. 1 While immune-mediated HIT causes a drop in platelets, patients who suffer from HIT are at risk for major clotting problems. In HIT, antibodies are triggered to attack the heparin in the blood, also destroying platelets to which the heparin is attached (see the box, p.22 for more information). 21

Role of the Immune System in Heparin-Induced Thrombocytopenia Heparin-induced thrombocytopenia type II (HIT) is the most frequent drug-induced, immune-mediated type of thrombocytopenia. The immune system response appears to be triggered by the immune complex that forms between the heparin and platelet factor 4 (PF4). 2 The immune system recognizes this heparin-pf4 complex as foreign, forming an antibody against it which then destroys the platelets. The drop in platelet count usually begins five to 10 days after starting heparin, although a rapid decline can occur in a patient who has antibodies from recent heparin use (within the past three months). 3 The thrombocytopenia is generally moderate with a median platelet nadir of 55 to 60 X 109/L. 4 As the platelet count falls to less than 100,000, or 50 percent of baseline, microparticles are released from the platelets that are thought to lead to prothrombotic activity. Thrombosis associated with HIT occurs in up to 50 percent of all cases, with a 20 to 30 percent risk of death. Although HIT is caused by an immune system reaction to heparin, it is not a true allergy. The PF4 antibody that causes HIT usually disappears after three months, permitting safe heparin re-exposure in selected patients (e.g., heart surgery patients) despite a history of HIT. All patients with a history of HIT should be tested for PF4 antibody before re-exposure to heparin. When heparin is re-introduced before the PF4 antibody has been eliminated from the bloodstream, a more rapid onset of HIT can be triggered. 5 Diagnosis of HIT relies on astute patient assessment and history, followed by laboratory confirmation. Symptoms of new blood clot formation are often the first indications of HIT, including pain or tenderness, sudden swelling, discoloration, visibly dilated veins, and skin that is warm to the touch. Pulmonary embolism can occur if a clot becomes dislodged in the pulmonary vasculature, and may present as shortness of breath, rapid pulse, sharp chest pain, dizziness, or feelings of anxiety and diaphoresis. Other signs of HIT can include bruising or blackening around heparin injection sites as well as the fingers and toes, which are susceptible to the small clots that can form with HIT. Laboratory assessment of the platelet count and PF4 antibody level in the blood can assist in confirming the diagnosis. Rapid diagnosis of HIT is essential to effective treatment, as the temptation to treat thrombosis with heparin would only worsen the condition. This is particularly challenging when HIT develops after heparin has already been discontinued. Delayed-onset HIT is uncommon, but has been reported up to 40 days following heparin exposure. So how likely is this problem to occur in the home setting when the only source of heparin is from IV catheter flushes? A recent study by Gettings, et al, found that 12 of 19 patients in a surgical ICU diagnosed with HIT had only been exposed to 120 to 240 units of heparin a day from catheter flushes. 6 Another study by Laster found that even a heparin-coated catheter could provide enough exposure to heparin to illicit an immune response and HIT. 7 Until recently, rates of HIT have been poorly documented, leaving clinicians with an unclear picture of just how significant and widespread the problem may be. However, recent studies in the hospital setting are demonstrating an increased incidence of HIT. They are also revealing varying levels of the condition. It is now thought that lower levels of HIT, while not life threatening on their own, can make patients susceptible to other health conditions ranging from bruising to stroke. 22

While research in the inpatient setting continues, data from the home care setting specifically in home infusion is scant at best. Significant challenges to data collection exist, including cost and the relatively short time that patients are on service compared to the trajectory of HIT. The fact is although we may not see a case of HIT develop in a patient, we don t know if patient exposure to heparin while on home infusion service doesn t contribute to a problem later in the continuum of care. For this reason, even in the absence of data, an increasing number of practitioners are asserting that patient exposure to heparin should be reduced as a precautionary measure. In the home and alternatesite infusion practice, this can be accomplished by using lower concentrations of heparin in routine catheter flushing. Some in our industry may question the value of adopting this as a policy and procedure largely because of fears that catheter occlusions rates could increase. In the following case study, one infusion provider organization lowered heparin concentrations while maintaining catheter patency rates. Their story demonstrates that it is possible to lower patient exposure to heparin, and thus reduce the risk of HIT, without the detrimental effect of increased occlusions. Nancy Kramer, R.N., B.S.N., CRNI, is NHIA s Vice President of Clinical Affairs. She can be reached at (513) 515-9440 or nancy.kramer@nhia.org. University of Iowa Community HomeCare: A Retrospective Data Review By Kelli Krutsinger, R.N., B.S.N., C.R.N.I. Prior to November 2006, the University of Iowa Community HomeCare s practice was to flush before and after administration of all therapies using the SASH (saline, antibiotic, saline, heparin) technique. In addition, un-used lumens were flushed once a day. PICCs and tunneled catheters were flushed with 3cc, and implanted ports with 5cc. Using heparin concentrated at 100U/mL meant that a patient with a double lumen PICC line receiving a once-a-day antibiotic was receiving 400U of heparin per day. While at the Infusion Nurses Society (INS) 2007 fall conference in Washington, D.C, I attended a lecture on HIT. The speaker indicated that flushing a central venous catheter (CVC) with only 400U of heparin a day was enough to cause heparin-induced thrombocytopenia. 6 Based on this new information, I decided that our organization should re-evaluate its procedures with the idea of reducing overall patient exposure to heparin. We had two patients that had been taken off of heparin due to suspected HIT and we did not want to put any of our patients at an increased risk. I began reviewing the literature to determine a safe and effective heparin concentration. The first reference I checked was the 2006 INS Standards of Practice, which note that flushing vascular access devices with a heparin solution will ensure patency. 8 However, the standard on flushing notes the possibility of HIT and suggests using the lowest possible concentration of heparin. I continued searching the literature looking for recommendations for heparin concentration for CVC flushes. While I wasn t able to find specific recommendations for the home setting, one article showed that HIT occurred in patients with as little as 120U/day of heparin. 6 Taking all this information into account, our organization decided to change its heparin flush protocol. In February 2006, we made the switch from a heparin concentration of 100U/mL to 10U/mL. We continued to use 3cc flushes on PICCs and tunneled catheters, and 5cc flushes on implanted ports. The ports only receive 100U/mL of heparin when they are deaccessed. We continued to use the same injection cap we were using for a year prior to the introduction of the new heparin flush protocol. The transition has gone very smoothly, and, most importantly, we have maintained our catheter out- 23

Exhibit 1 Occlusion Rates Before and After New Heparin Flush Protocols Time Period PICC Lines Occlusions Occlusion Rate Before (2/19/2006 2/18/2007) 277 9 3.25% After (2/19/2007 2/18/2008) 329 8 2.43% Source: University of Iowa Community HomeCare Data collection is key to understanding the outcome of a change in clinical procedures, and sharing this information contributes to the body of home infusion clinical knowledge comes throughout and following the heparin concentration change. We were encouraged by the fact that we had no increase in occlusion rates of CVCs following the transition, which we defined as a line that will not aspirate or flush (see Exhibit 1). In addition, we have not received any reports of patients diagnosed with HIT since we made the change. We will continue to use the 10U/mL heparin, as we evaluate the feasibility of a change to saline-only flushes. Conclusion The concentration of heparin used to routinely flush vascular access devices must be carefully evaluated in light of the risk for heparin-induced thrombocytopenia in susceptible patients. In the absence of home infusion based clinical research, providers are encouraged to examine their internal patient outcomes in the application of evidence-based research from the hospital setting. Data collection is key to understanding the outcome of a change in clinical procedures, and sharing this information contributes to the body of home infusion clinical knowledge. Kelli Krutsinger, R.N., B.S.N., C.R.N.I., is the Nurse Manager at University of Iowa Community HomeCare. She can be reached by phone at (319) 337-8522 or by e-mail at krutsingerk@healthcare.uiowa.edu. References 1. Franchini, Massimo. Heparin-induced thrombocytopenia: An update. Thrombosis Journal. 2005;(14). 2. McNulty I, Eliezer K, Kim K. Thombocytopenia following heparin flush. Progress in Cardiovascular Nursing. 2007; 20(4): 143-147. 3. Swanson, Joseph. Heparin-Induced Thrombocytopenia. Journal of Infusion Nursing. 2007; 30(4): 232-240. 4. Warkentin TE. Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia. Arch Pathol Lab Med. 2002; 126: 1415-1423. 5. Baroletti SA, Goldhaber SZ. Heparin-induced thrombocytopenia. Circulation. 2006; 114:e355- e356. 6. Gettings E, Brush K, VanCott E, Hurford W. Outcome of postoperative critically ill patients with heparin-induced thrombocytopenia: An observational retrospective case-control study. Crit Care. 2006; 10(6): R161. 7. Laster JL, Nichols WK, Silver D. Thrombocytopenia associated with heparin-coated catheters in patients with heparin-associated anti-platelet antibodies. Arch Internal Med. 1989; 149:2285-2287. 8. Infusion Nurses Society (INS). Infusion Nursing Standards of Practice. 2006; 29; S56. 24

A clear solution Immune globulin intravenous (human) 5% solvent/detergent treated If you re thinking about IGIV treatment, now s the time to consider octagam. With a proven record of safety, tolerability and efficacy 1,octagam comes ready to use and can be stored at room temperature for 24 months. If you think octagam could be the right solution for you and your patients please call us toll free on 866-766-4860 or visit us during the Baltimore conference at booth #420. IMPORTANT SAFETY INFORMATION octagam is contraindicated in individuals with intolerance to immunoglobulins, especially in immunoglobulin A (IgA) deficiency, when the patient has IgE mediated antibodies to IgA. Immune Globulin intravenous (Human) (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Other possible side effects with octagam include: aseptic meningitis, hemolysis, transfusion-related acute lung disease (TRALI) and thrombotic events. Immune Globulin Intravenous (Human) products have been reported to be associated with various minor reactions, such as headache, chills, backache, chest pain, fever, allergic reactions, arthralgia, dizziness, changes in blood pressure, cutaneous reactions and/or nausea and vomiting. Cases of reversible aseptic meningitis and migraine and isolated cases of reversible hemolytic anemia and reversible increases in liver function tests have been observed with octagam. Immediate anaphylactic and hypersensitivity reactions are a remote possibility. As with all medicines made from human plasma, the risk of spreading infectious agents, including viruses, cannot be completely eliminated. Some types of blood glucose testing systems falsely interpret the maltose contained in octagam as glucose. This has resulted in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin, resulting in life-threatening hypoglycemia. See brief summary of PI on facing page. 1 Ochs HD, Pinciaro PJ and the octagam Study Group. octagam 5%, an Intravenous IgG Product, is Efficacious and Well Tolerated in Subjects with Primary Immunodeficiency Diseases. J. Clin Immunol 2004,24;3:309-314

octagam Immune Globulin Intravenous (Human) 5% Solvent/Detergent Treated Brief Summary Please consult Package Insert for full prescribing information octagam is indicated for the treatment of primary immune deficient diseases, such as: congenital agammaglobulinemia and hypogammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome and severe combined immunodeficiencies. CONTRAINDICATIONS Intolerance to homologous immunoglobulins, especially in very rare cases of immunoglobulin A (IgA) deficiency, when the patient has IgE mediated antibodies to IgA. WARNINGS Immune Globulin intravenous (Human) (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as stabilizer accounted for a disproportionate share of the total number. octagam does not contain sucrose. See PRECAUTIONS and DOSAGE AND ADMINISTRA- TION sections for important information intended to reduce the risk of acute renal failure. octagam, should only be administered intravenously. Other routes of administration have not been evaluated. octagam should be given at the infusion rate under DOSAGE AND ADMINISTRATION at least until the physician has had adequate experience with a given patient. Immediate anaphylactic and hypersensitivity reactions are a rare possibility. Epinephrine should be available for treatment of any acute anaphylactoid reactions. octagam contains only trace amounts of IgA (<0.2 mg/ml in a 5% solution). Nonetheless, it should not be given to patients with IgE mediated antibodies to IgA or selective IgA deficiencies. octagam is made from human plasma of US origin. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Octapharma (Tel. no. 866 766 4860). The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering it to the patient. Blood Glucose Testing Some types of blood glucose testing systems (for example, those based on the glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase methods) falsely interpret the maltose contained in octagam as glucose. This has resulted in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin, resulting in life-threatening hypoglycemia. Also, cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings. Accordingly, when administering octagam or other parenteral maltose-containing products, the measurement of blood glucose must be done with a glucose-specific method. The product information of the blood glucose testing system, including that of the test strips, should be carefully reviewed to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose- containing parenteral products. PRECAUTIONS Aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to two days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cu.mm., predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dl. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. It appears that patients with a history of migraine may be more susceptible. Periodic monitoring of renal function tests and urine output is particularly important in patients judged to have a potential increased risk of developing acute renal failure. Renal function, including a measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed prior to the initial infusion of octagam, and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. For patients judged to be at risk for developing renal dysfunction, it may be prudent to reduce the amount of product infused per unit time by infusing octagam at a maximum rate less than 0.07 ml/kg (3.3 mg/kg)/minute (200 mg/kg/hour). Assure that patients are not volume depleted prior to the initiation of the infusion of octagam. Hemolysis IGIV products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis. Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration [see Adverse Reactions]. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis. Transfusion-Related Acute Lung Injury (TRALI) There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1-6 hrs after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support. IGIV recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum. Thrombotic Events Thrombotic events have been reported in association with IGIV [see ADVERSE REACTIONS]. Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. The potential risks and benefits of IGIV should be weighed against those of alternative therapies for all patients for whom IGIV administration is being considered. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. Drug/Laboratory Test Interactions If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done [see PRECAUTIONS]. If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum [see PRECAUTIONS]. Because of the potentially increased risk of thrombosis, baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies [see PRECAUTIONS]. octagam 5% contains maltose which can be misinterpreted as glucose by certain types of blood glucose testing systems (for example, by systems based on GDH-PQQ or glucose-dyeoxidoreductase methods). Due to the potential for falsely elevated glucose readings, only testing systems that are glucosespecific, should be used to test or monitor blood glucose levels in patients receiving maltose-containing parenteral products, including octagam. The product information of the blood glucose testing system, including that of the test strips, should be carefully reviewed to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose-containing parenteral products [see WARNINGS]. Drug Interactions Antibodies in octagam may interfere with the response to live viral vaccines, such as measles, mumps, and rubella. Physicians should be informed of recent therapy with IGIVs, so that administration of live viral vaccines, if indicated, can be appropriately delayed 3 or more months from the time of IGIV administration. Admixtures of octagam with other drugs and intravenous solutions have not been evaluated. It is recommended that octagam be administered separately from other drugs or medications which the patient may be receiving. The product should not be mixed with IGIVs from other manufacturers. The infusion line may be flushed before and after administration of octagam with either normal saline or 5% dextrose in water. Various passively transferred antibodies in immunoglobulin preparations can confound the results of serological testing. See DOSAGE AND ADMINISTRATION SECTION. Pregnancy Category C Animal reproduction studies have not been performed with octagam. It is also not known whether octagam can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. octagam should be given to a pregnant woman only if clearly needed. ADVERSE REACTIONS General Reported adverse reactions to octagam in patients with either congenital or acquired immunodeficiencies are similar in kind and frequency to other IGIV products. Various minor reactions, such as headache, chills, backache, chest pain, fever, allergic reactions, arthralgia, dizziness, changes in blood pressure, cutaneous reactions and/or nausea and vomiting may occasionally occur. Reactions to intravenous immunoglobulins tend to be related to the rate of infusion. Cases of reversible aseptic meningitis and migraine and isolated cases of reversible hemolytic anemia and reversible increases in liver function tests have been observed with octagam. Immediate anaphylactic and hypersensitivity reactions are a remote possibility. Epinephrine should be available for treatment of any acute anaphylactoid reaction. [See WARNINGS]. Postmarketing The following adverse reactions have been identified and reported during the post-approval use of IGIV products: Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion Associated Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm cardiac arrest, thromboembolism, vascular collapse, hypotension, coma loss of consciousness, seizures, tremor, Steven-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis, pancytopenia, leukopenia, hemolysis positive direct antiglobulin (Coombs) test, pyrexia, rigors, back pain, hepatic dysfunction, abdominal pain Because postmarketing reporting of these reactions is voluntary and the at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction, or establish a causal relationship to exposure to the product. Such is also the case with literature reports authored independently. Primary lmmunodeficiency Diseases The subset of drug related adverse events in trial OCTA-06 reported by at least 3% of subjects during the 12-month treatment is given in the table below. Table 6: Subjects with At Least One Drug Related Adverse Event (Study OCTA-06) octagam 5% Number of subjects: 46 Number Percentage of subjects of all subjects Headache NOS 7 15% Nausea 3 7% Back pain 2 Chest pain NEC 2 Injection site reaction NOS 2 Rigors 2 Manufactured by: OCTAPHARMA Pharmazeutika Produktionsges.m.b.H Oberlaaer Strasse 235 A-1100 Vienna, Austria OCTAPHARMA AB Elersvagen 40 SE 112 75, Sweden Distributed by: Octapharma USA, Inc. 121 River Street, Suite 1201 Hoboken, New Jersey 07030 866 766 4860 2009 Octapharma USA Inc. All rights reserved. 12/2008