Many patients with HIV infection need intravenous (IV) therapy at some point in the course of their treatment. IV therapy generally is provided in hospital settings, but in some circumstances it can be provided in the outpatient setting, either in the home or in an outpatient infusion center. Outpatient infusion therapy may include administration of nutrition, antibiotic therapy, and fluid and electrolyte repletion. Outpatient infusion therapy may have several benefits, including convenience for the patient, decreased exposure of immunocompromised patients to nosocomial infections, and decreased acute care costs. The administration of complex outpatient infusion therapy in AIDS patients is driven by patient needs as well as by cost demands. Unfortunately, it is difficult to obtain adequate reimbursement for home infusion and other home care services, especially for economically disadvantaged or uninsured patients. At San Francisco General Hospital (SFGH), success has been achieved in providing safe, complex outpatient infusion services to disadvantaged patients through the use of a specific HIV outpatient infusion service and though efforts to maintain adequate funding sources for services to the patient population. One significant funding source is the Ryan White Comprehensive AIDS Resources Emergency (CARE) Act, which provides funds to cities, states, and other public and private entities for providing care and support services to medically underserved individuals with HIV disease.
This chapter reviews the SFGH outpatient infusion service protocols for specific medical conditions, the types of central venous access devices (CVADs), and the advantages and disadvantages of these devices. Some of this information has been described in a review article by Gilbert et al (1) and in the Infectious Diseases Society of America (IDSA) guidelines published in 2004.(2) This discussion is not intended as a review of indications or treatment options for the clinical problems associated with outpatient infusion therapy and it should not be misconstrued as management recommendations for these problems.
| The HIV Outpatient Infusion Service at San Francisco General Hospital|
The HIV Outpatient Infusion Service at SFGH is staffed by a nurse coordinator, an inpatient and an outpatient clinical pharmacist, an infectious disease specialist, and an HIV-specialty physician. The nurse coordinator and clinical pharmacists work closely with home care nurses and home infusion suppliers to monitor patients' laboratory test results and response to therapy on a day-to-day basis. The nurse coordinator and clinical pharmacists can adjust therapy by using protocols and by consulting with the specialists, primary providers, or the attending physician of the day at the clinic.
Laboratory values, patient response, and other issues are reviewed daily or weekly as indicated by the nurse coordinator and pharmacists, and individual treatment plans are changed and updated if needed after discussion with attending physicians. For hospitalized patients who will need infusion services after discharge, the nurse coordinator and inpatient HIV clinical pharmacist work with the hospital staff to plan outpatient infusion therapy.
| Criteria for Outpatient Infusion Therapy|
Outpatient IV therapy has risks. Most notable are potential adverse effects of administered medications and the possibility of thrombosis and infection related to IV catheters. In the outpatient setting, adverse events can be difficult to monitor and manage. The suitability of individual patients for outpatient IV therapy should be carefully considered; specific criteria are listed in Table
1. Patients who do not meet these criteria probably are not good candidates for complex outpatient infusion therapy and should be considered for placement in a skilled nursing facility until IV therapy is completed or until adequate social or financial resources are available to support outpatient infusion therapy. Clinically unstable patients should not be considered for complex outpatient IV therapy. Examples include patients with Pneumocystis jiroveci pneumonia (PCP) who require more than minimal oxygen support, patients with cryptococcal meningitis or systemic bacterial infections who are febrile, and those with unstable or abnormal serum electrolytes. Additionally, patients who require more than twice-daily infusions or infusions requiring >2 hours of nursing time to complete generally are not suited for outpatient home therapy because of reimbursement limitations.
| Applications of Outpatient IV Therapy|
| Total Parenteral Nutrition Start-Up and Tapering|
Total parenteral nutrition (TPN) (3) is delivered through a CVAD. Establishing a stable TPN regimen requires close observation and monitoring to a degree usually not possible in an outpatient setting. Thus, it is important that patients are following a stable TPN regimen in the hospital prior to discharge for outpatient therapy. In addition, outpatient TPN is quite difficult to justify to insurance providers and it presents a complicated reimbursement issue (Medicare Part B requires both "permanence," necessitating at least 90 days of home parenteral nutrition, and "malabsorption of nutrients.").(4) Considerations in determining the feasibility of outpatient TPN include the availability of an appropriate IV access device, an administration schedule, nutrition prescription and preparation, and the coordination of nutrition therapy schedule with other prescribed treatments. The TPN prescription and additives must be closely scrutinized to avoid incompatibility issues as well as potential drug-nutrient interactions.
Outpatient TPN may be infused over a 24-hour period (continuous) or at 12- to 16-hour intervals (cyclic). The administration schedule is based on the patient's ability to tolerate large volumes of fluid in a given time frame as well as quality-of-life preferences. Outpatient TPN is generally a cyclic infusion that allows patients to have some freedom from the pump and to closely mimic typical eating patterns. This is considered more "physiologic" and it reduces the risks of fatty liver and hepatomegaly that are associated with long-term continuous infusion of dextrose and amino acids.
On a 12-hour infusion schedule, the patient generally receives 2 liters of solution, though this varies according to individual nutritional needs. Most patients prefer to infuse overnight, from 8 PM to 8 AM, which allows them to be ambulatory and independent during the day. The patient is instructed to set the initial pump flow rate at 180 mL/hour, thus providing 1,800 mL over a 10-hour period. At the end of 10 hours, the patient then turns the rate of infusion down to 100 mL/hour for the remaining 2 hours. This reduction in infusion rate enables the patient to taper the glucose administration and thereby decrease the propensity for hypoglycemic rebound, which may occur after complete termination of the treatment cycle. A lipid solution (ie, 500 mL of 20% lipids providing 2 calories/mL) may be given to provide additional calories and avoid essential fatty acid deficiency in long-term TPN patients. Lipids generally are not given daily with TPN; the frequency depends on the individual patient's needs.
| Peripheral Parenteral Nutrition|
Peripheral parenteral nutrition (PPN) is delivered intravenously through a peripheral vein catheter. PPN is used only as a short-term (10-14 days at most) method of nutritional intervention because it requires higher infusion volumes, and because adequate peripheral vein access is difficult to maintain. PPN may be useful when oral intake is temporarily not feasible, eg, due to cytomegalovirus (CMV) esophagitis, ulcers, or gastric obstruction. In these cases, PPN may be viewed as a way of maintaining nutritional status until therapeutic interventions allow effective oral intake. Standard PPN solution delivers about 400 kcal/L, in contrast with the approximately 1,000 kcal/L deliverable by TPN. Because of the low caloric content, PPN is infused continuously at a rate of 100-125 mL/hour to provide approximately 1,200 kcal per day. To boost the caloric intake, a 20% lipid solution (500 mL at 2 calories/mL) is given daily to provide close to 2,200 kcal per day. Because of its low glucose content, PPN can be initiated at 100-125 mL/hour and discontinued without tapering or danger of rebound hypoglycemia.
| Filters and Tubing for Parenteral Nutrition|
The U.S. Food and Drug Administration (FDA) recommends that a bacteria-retentive and air-eliminating filter should be used when infusing either central or peripheral venous solutions for parenteral nutrition, including 3-in-1 admixtures of amino acids, dextrose, and fat emulsions.(5) Standards of practice vary, but the following is suggested: a 0.22-µ filter for nonlipid-containing solutions (6) and a 1.2-µ filter for lipid-containing admixtures.(7) Reportedly, filters can be left in place for 48 hours; however, general practice is to change them daily along with the tubings. The benefits of filter use include venting to protect against air embolism, removing bacterial contamination and associated endotoxins, and removing particulate matter. The IV tubing should be "dedicated," that is, without injection ports, to guard against inadvertent medication boluses and subsequent contamination of the line. It should be used only for the parenteral nutrition solution, and should be changed daily.
| Infusion Pumps|
Parenteral nutrition is always delivered by an infusion pump so as to prevent overfeeding or clotting in the line. Numerous pumps that can be used for solution administration are available commercially. If a patient is hospitalized when parenteral nutrition is started, that patient should begin training with the same type of pump that will be used at home. Additionally, the home care agency nurses must be familiar with the pump in order to assist the patient in problem solving.
| Storage of Parenteral Solutions|
The reader should consult institutional policies for specific storage and solution expiration guidelines. The following recommendations are general guidelines. Parenteral solutions should be stored in a refrigerator at 4° C. It is helpful to remove the bag of solution from the refrigerator at least 30 minutes prior to infusion to avoid inducing hypothermia. Once a solution is prepared, its shelf life is up to 14 days (without added lipids) under refrigeration unless multivitamins for infusion (MVI) or insulin have been added. If lipid emulsions are infused separately from the TPN or PPN, they do not require refrigeration. If the lipid solution is in the same bag as dextrose and amino acids (3-in-1 system), the mixture should be refrigerated; its shelf life is reduced to a maximum of 7 days. The 3-in-1 system may be appropriate for decreasing the amount of supplies needed and simplifying the infusion process for the patient. When needed, MVI or insulin should be added to the parenteral nutrition solution immediately before administration. After the parenteral solution has been spiked with IV tubing, it must be used within 24 hours.
| Outpatient IV Antibiotic Therapy|
Patients with acute infections who require IV therapy, toxic patients, and patients who are clinically unstable should receive IV antibiotics in a hospital setting under close observation and monitoring. Only when they are stable and clearly improving should outpatient infusion be considered a management option.(8,9)
Commonly used aminoglycosides in the home care setting include amikacin, gentamicin, and tobramycin. These agents are primarily active against gram-negative bacteria. Current evidence suggests that once-daily administration of IV aminoglycosides may be as effective for some indications as the conventional regimens used in the inpatient setting that require multiple daily doses.(10) Because once-daily dosing is potentially less toxic compared with multiple daily dosing schedules, it is commonly used for certain indications. Once-daily dosing is not FDA approved for regimens designed to promote synergy between antibiotics or for treatment of endocarditis or meningitis.
The once-daily adult dosage of gentamicin or tobramycin is 3-5 mg/kg/day and for amikacin is 10-15 mg/kg/day. The amikacin dosage of 10-15 mg/kg/day can be divided into 2 equal doses and given at 12-hour intervals if multiple daily dosing is needed. Aminoglycosides are almost entirely excreted unchanged by the kidneys and require dosage adjustments for decreased renal function as shown in Table
Aminoglycosides should be given in normal saline (NS) or 5% dextrose in water (D5W) and infused over a 30-minute period. Gentamicin, tobramycin, and amikacin admixed for IV infusion should be stored at 2° C to 30° C. Pharmacy-prepared solutions may be frozen for up to 30 days without loss of potency.(11) Refrigeration is not required for commercially prepared sealed solutions, but the solution should be used immediately after opening and the unused portions should be discarded. Patients receiving aminoglycosides should have serum creatinine and blood urea nitrogen (BUN) checked at baseline with follow-up 2 or 3 times per week. Although once-daily IV aminoglycosides may not require monitoring of serum peak levels, serum trough levels should be checked once or twice during the course of treatment. Optimal trough levels are <2 µg/mL for gentamicin and tobramycin and <10 µg/mL for amikacin; maintaining these levels will minimize adverse effects, especially nephrotoxicity.
Ceftriaxone is a third-generation cephalosporin with activity against most gram-negative bacteria and limited activity against gram-positive bacteria. Because of its extended half-life, this drug can be used intravenously once daily, making it ideal for outpatient therapy.(12)
The usual adult dosage of ceftriaxone for treatment of most susceptible infections is 1 to 2 grams given once daily or in equally divided doses twice daily if required. The maximum adult dosage of ceftriaxone recommended by the manufacturer is 4 grams daily. Ceftriaxone is excreted through both the biliary and urinary tracts. Either renal or hepatic dysfunction alone does not require dosage adjustment; however, failure of both organs necessitates dosage adjustment.(13)
Cephalosporins sometimes can be administered safely to patients with a history of anaphylactic reactions to penicillins, provided the patients are closely monitored for serious adverse events. First-time administration should be done in a setting with adequate provisions for evaluation and treatment of anaphylaxis, and the patient should be observed closely for anaphylactic or urticarial reactions.
Ceftriaxone should be mixed in at least 50 mL of D5W or NS and administered as an IV infusion over 15-30 minutes or by IV injection over 2-4 minutes. After constitution, the solution can be exposed to light. The color of solutions may vary from light yellow to amber, depending on storage duration, diluent, and concentration. Constituted solutions with D5W or NS stored at 25° C have <10% potency loss after 3 days for 100 mL of diluent and after 24 hours for 250 mL of diluent; decreasing storage temperature to 4° C increases storage time to 10 days and 3 days, respectively.(11) The manufacturer states that solution can be frozen at -20° C for 26 weeks with no loss of stability when mixed in D5W or NS and stored in polyvinylchloride or polyolefin containers. Specific laboratory and clinical monitoring depends on the clinical syndrome being treated.
Vancomycin is commonly used in AIDS patients to treat infections due to Staphylococcus aureus and methicillin-resistant staphylococci. In the outpatient setting, once-daily dosing of IV vancomycin is preferable for cost containment and patient ease.(14) Prolonged or unnecessary use of vancomycin is discouraged in all settings because of the potential emergence of vancomycin-resistant organisms, particularly vancomycin-resistant enterococci.
For adults, vancomycin is generally given as a single loading dose of 15 mg/kg, and is typically administered at 1 gram every 12 hours regardless of the patient's renal function. In the outpatient setting, the usual dosage is 20-30 mg/kg given once daily. Dosing should be based on actual body weight. Most patients with normal renal function reach peak serum levels in the range of 30-50 µg/mL on once-daily regimens.(15) Vancomycin is primarily excreted by glomerular filtration and requires dosage adjustments for patients with decreased renal function. Dosage adjustments are shown in Table
When administered intravenously, vancomycin should be mixed in D5W or NS in concentrations no greater than 5 mg/mL. The manufacturer indicates that reconstituted solutions of vancomycin are stable under refrigeration for 14 days.(7) Rapid IV administration of vancomycin can result in a hypotensive reaction referred to as "red man's syndrome" or "red neck syndrome."(16,17) This reaction is characterized by a sudden decrease in blood pressure that can be severe and may be accompanied by flushing and/or a maculopapular or erythematous rash on the face, neck, chest, or upper extremities; the latter manifestations also may occur in the absence of hypotension. The reaction can appear during or after the completion of infusion and usually resolves spontaneously over the course of several hours, after discontinuance of the infusion. Severe reactions may necessitate the use of antihistamines, corticosteroids, or IV fluids. Pretreatment with these therapies may decrease the likelihood of this reaction. Vancomycin always should be infused over a minimum of 90 minutes. At SFGH, the infusion period is routinely extended to as long as 3 hours, depending on the dose of vancomycin and the severity of previous reactions.
Baseline renal function should be assessed prior to initiating therapy. For extended once-daily IV therapy, renal function, including urinalysis, should be monitored twice weekly. Vancomycin trough levels should be obtained 4-5 days after initiating therapy or changing dosage to ensure adequate serum concentrations. The desired vancomycin serum trough level is 5-15 µg/mL.
| Trimetrexate with Leucovorin Rescue|
Trimetrexate (TmTx), an inhibitor of dihydrofolate reductase, is an alternative therapy for PCP. It must be administered intravenously and can be given with oral dapsone to increase efficacy. Leucovorin (LCV) must be administered concurrently with TmTx to protect the patient's folic acid metabolism pathway ("LCV rescue").(18) Toxicity of TmTx includes neutropenia, thrombocytopenia, and transient elevations of liver enzymes and serum creatinine level. These toxicities are reversible with treatment interruption. TmTx should be used cautiously with agents that inhibit, block, or induce the P450 drug metabolism pathway (see Table
4). TmTx has a mean serum half-life of 11 hours.
TmTx with LCV rescue should be administered according to the parameters shown in Table
5. The oral dose of LCV should be rounded up to the next highest 25-mg increment. The recommended duration of PCP therapy is 21 days of TmTx and 24 days of LCV. The initial dose of LCV should be administered before, not after, the initial dose of TmTx and should always be continued for 72 hours after the last TmTx dose is given.
TmTx is constituted with 2 mL of D5W or sterile water for a concentration of 12.5 mg/mL that can be further diluted with D5W for a final concentration of 0.25 to 2 mg/mL. Constituted TmTx solution is stable for 24 hours with refrigeration or at room temperature but should not be frozen. Cytotoxic precautions should be observed when handling or disposing of TmTx. LCV for IV infusion can be mixed in either D5W or NS. Constituted LCV solutions should be protected from light and can be stored for up to 7 days at 4° C to 25° C. Because TmTx solution forms a precipitate on contact with the chloride ion or with LCV, it should be added only to a dextrose and water solution and infused separately from the LCV infusion. The access line should be flushed thoroughly with at least 10 mL of D5W between infusions. The oral use of LCV eliminates this problem. TmTx can be infused either peripherally or centrally over 60-90 minutes.(17)
In addition to an accurate height and weight to calculate body surface area, the following laboratory values should be obtained before starting therapy: complete blood count (CBC) with differential and platelet count, liver enzymes, serum creatinine, and BUN. Blood counts, renal panel, BUN, and liver function should be checked every 3-5 days.
Pentamidine is an alternative treatment for PCP. At SFGH, IV pentamidine is not recommended for home therapy because it is associated with a high incidence of life-threatening toxicities and requires close patient monitoring. It can be given safely, however, in an outpatient infusion center. Because life-threatening hypoglycemia can be caused by IV pentamidine, patients who live alone should not be considered for outpatient IV pentamidine therapy.(19)
The major toxicities associated with IV pentamidine therapy are nephrotoxicity, hyperkalemia, hypoglycemia, hyperglycemia, pancreatitis, hypotension, and rare cases of torsade de pointes with ventricular tachycardia.(20,21) Patients who have histories of IV drug use, concomitantly take nephrotoxic drugs, and receive large cumulative doses of pentamidine are at greater risk for developing adverse effects. Pentamidine has a long half-life, approximately 5 days. Adverse effects normally do not occur during the first 5 days of therapy, and toxicities are most prevalent after 8-12 days of therapy. Concomitant use of nephrotoxic drugs, such as nonsteroidal anti-inflammatory drugs, should be avoided, if possible. Pentamidine is absolutely contraindicated with concomitant use of foscarnet or amphotericin because of the potential for renal failure and for severe and potentially fatal calcium binding. Drugs with known pancreatic toxicity, such as didanosine, zalcitabine, and stavudine, should be avoided during therapy with pentamidine.(22) Pentamidine can be given as an intramuscular injection; however, this route is not preferred because sterile abscesses may develop at the injection site.
IV pentamidine should be given as a single 3-4 mg/kg daily dose. Actual body weight should be used for dosage calculation unless it is greater than the ideal body weight.(23) In general clinical practice, the daily dosage for IV pentamidine is 4 mg/kg for the first 7 days, then 3 mg/kg daily until therapy is completed. Generally, the dosage is decreased 20% to 30% for a serum creatinine level >1.0 mg/dL and/or blood glucose concentration <60 mg/dL. If serum amylase levels rise more than 3 times above baseline, IV pentamidine should be held. Patients with rising serum amylase levels should be evaluated to determine whether they are taking other pancreatotoxic agents; if so, these should be discontinued if possible. Additionally, if liver enzyme values rise more than 5 times above baseline, IV pentamidine should be held. Patients with rising transaminases should be evaluated to determine whether they are taking other medications with potential hepatotoxicity.
Because IV pentamidine is irritating to the venous intima, long-term peripheral infusion is not recommended. The drug may be temporarily infused peripherally until a CVAD can be placed. Pentamidine can be admixed in either D5W or NS at concentrations up to 2.5 mg/mL and is stable at room temperature for up to 48 hours.(11)
Pentamidine infusion is often associated with hypotension, though the likelihood of this reaction can be minimized if infusion time is at least 2 hours. Some patients may require longer infusion time. Hypotension can develop suddenly and may be moderate to severe (eg, systolic blood pressure <60 mm Hg). It may occur after a single dose and may be a dose-limiting adverse effect. If not contraindicated, patients should be infused with 500 mL of 5% dextrose in NS before the pentamidine infusion. Blood pressure and pulse should be assessed frequently during the infusion.
Patients receiving IV pentamidine for treatment of PCP require close monitoring for therapy response and adverse events. Accurate weight, renal panel, BUN, calcium, albumin, magnesium, amylase, and liver function test results should be checked at baseline and thereafter every 3-5 days. Blood glucose levels should be checked at baseline and before and after daily pentamidine administration. Hyperglycemia or frank diabetes may develop weeks or months after stopping IV pentamidine therapy. Laboratory values should be checked weekly for 4-6 weeks after completion of IV pentamidine therapy to monitor for development of blood sugar abnormalities. Additionally, the patient should be advised of the symptoms of hyperglycemia. Recommendations for management of pentamidine-related hypoglycemia are shown in Table
| Amphotericin B|
Amphotericin B (AmB) is used in the treatment of certain fungal infections. It is fungistatic or fungicidal, depending on obtainable body fluid concentrations and fungal susceptibility. IV AmB can be administered safely in an outpatient infusion center. At SFGH, IV AmB therapy is not recommended in the home setting unless the patient's clinical status is stable (ie, no electrolyte imbalance, abnormal renal function, or rigors) during an infusion of 2 hours or less.
Major dosage-limiting adverse events seen with AmB are myelosuppression and nephrotoxicity with severe renal electrolyte wasting (in particular, leading to hypokalemia and hypomagnesemia). Common adverse events during infusion include chills, rigors, fever, nausea, vomiting, and hypotension.(17) AmB is available in lipid formulations that, compared with the nonlipid formulation, may reduce the risk of developing renal toxicity. Allergic reactions to AmB are extremely rare.
Acutely ill patients generally are started on AmB infusion therapy in the acute care setting and may complete the course of therapy at home. Stable patients, however, may begin therapy on an outpatient basis. Because of associated nephrotoxicity, AmB should not be given with nonsteroidal anti-inflammatory drugs or aminoglycosides. Coadministration of AmB with foscarnet or IV pentamidine is absolutely contraindicated because of the high likelihood of renal failure. Dosing frequency depends on the patient's renal function and drug tolerance, particular fungal infection being treated, and need for chronic vs intermittent therapy. Therapy can be initiated at a lower dosage that is ramped up after a few doses. The lesser of either actual or ideal body weight should be used for dosage calculation. Dosages should be rounded to the nearest 5 mg.
AmB can be admixed only in D5W. Most commonly, a 500-mL volume is used. When protected from light, the solution is stable at room temperature for 24 hours and for up to 7 days at 2° C to 8° C.(11) Although the manufacturer recommends protection from light, several reports describe AmB solutions as having no appreciable loss of potency with 48 hours or less of light exposure.(11) AmB is extremely irritating to the venous intima and a CVAD is recommended for infusion.
An initial test dose of AmB may be given to check for infusion-related toxicity, but its value is controversial. A separate infusion is not necessary if a test dose is desired. After the first 2 mg of the total dose is administered over the course of approximately 20 minutes, the patient is observed closely. If minimal or no infusion-related toxicities are noted, the remainder of the dose may be administered over 2-4 hours. Subsequent infusions can be given over 2 hours or less in many patients. IV hydration and premedication can be given to minimize toxicity. Guidelines for pretreatment are shown in Table
Patients receiving AmB infusions as antifungal therapy require close monitoring. Serum creatinine, potassium, sodium, chloride, BUN, magnesium, and CBC with differential should be obtained at baseline and rechecked daily for 3 days, and 2-3 times per week thereafter. An accurate weight should be obtained before starting therapy, and then measured weekly to recalculate dosage.
Voriconazole is a new triazole antifungal agent. It is available in both oral and parenteral formulation. The oral formulation is preferred for outpatient therapy. If there is evidence of intolerance or malabsorption of the oral medication, the parenteral formulation may be used if the patient's clinical status is stable.(24,25)
IV voriconazole therapy must be initiated with a specific loading-dose regimen to achieve a plasma concentration on day 1 that is close to steady state. Because of high oral bioavailability, switching between IV and oral administration is appropriate when clinically indicated.(25) The loading dose is 6 mg/kg intravenously every 12 hours for 2 doses, followed by a maintenance dosage of 4 mg/kg intravenously every 12 hours. Each dose should infuse from 1-2 hours. Once the patient is able to tolerate oral medication, the tablet form of voriconazole may be utilized. Patients who weigh >40 kg should receive an oral maintenance dose of 200 mg every 12 hours; those who weigh <40 kg should receive 100 mg every 12 hours. If the patient's response is inadequate, the oral maintenance dosage may be increased to 300 mg every 12 hours (150 mg every 12 hours for patients <40 kg). If the patient is unable to tolerate treatment, the IV maintenance dosage is reduced to 3 mg/kg every 12 hours, whereas the oral maintenance dosage is decreased by 50 mg. If phenytoin is coadministered with voriconazole, the maintenance dosage of voriconazole should be increased to 5 mg/kg every 12 hours for IV formulation, and to 400 mg every 12 hours for oral formulation.
For patients with mild-to-moderate hepatic insufficiency, the standard loading dose is recommended but the maintenance dosage may be halved. Voriconazole has not been studied in patients with severe cirrhosis or in patients with chronic hepatitis B and hepatitis C disease. These patients must be monitored closely and benefits must be weighed against potential risks.
In patients with renal insufficiency, oral voriconazole clearance is not significantly affected and no dosage adjustments are needed. The IV formulation contains sulfobutyl ether beta-cyclodextrin sodium (SBECD). In patients with a creatinine clearance <50 mL/min, SBECD accumulates and can further impair renal function. In patients with renal insufficiency, oral formulation should be administered unless an assessment of the risks to the patient justifies the use of IV voriconazole.
The most common adverse effects of voriconazole are visual changes (ie, blurred vision, changes in visual acuity, and photophobia), rash, and elevated liver function tests.(24,26) Voriconazole is a substrate and inhibitor of cytochromes P2C9, 2C19, and 3A4. As such, it has the potential for numerous drug interactions.(25) Drugs that are contraindicated when administering voriconazole include long-acting barbiturates, carbamazepine, sirolimus, terfenadine, rifampin, rifabutin, astemizole, cisapride, pimozide, quinidine, and ergot alkaloids. As with any drug metabolized by the P450 cytochrome system, it is necessary to monitor each patient closely to avoid contraindicated drugs as well as to determine whether tests will be needed to monitor plasma drug concentrations or interactions. Please refer to pharmacology literature for further details.
Ganciclovir is used to treat CMV disease. Its plasma half-life is approximately 3 to 4 hours, but the intracellular half-life of ganciclovir triphosphate, which is more pertinent to efficacy than is the serum half-life of the parent drug, is >18 hours.(27) The drug is cleared by renal excretion.
Neutropenia is the most common serious adverse event associated with ganciclovir use. Ganciclovir-associated neutropenia can be treated using recombinant human granulocyte colony-stimulating factor (GCSF) to maintain the absolute neutrophil count (ANC) between 500 and 1,500 cells/µL.(20) GCSF is usually started with a loading dose of 300 µg subcutaneously and then administered at dosages of 150-300 µg subcutaneously 3 times a week. The patient's nadir ANC (drawn just before giving a GCSF dose) should be monitored and the GCSF dose should be titrated to maintain the patient's neutrophil count in target range.
Thrombocytopenia is a dose-limiting adverse event. Ganciclovir should be stopped for platelet counts <20,000 cells/µL. If coadministration of myelosuppressive drugs (eg, zidovudine, myelotoxic chemotherapy) cannot be avoided, it is important to monitor blood counts closely during therapy. Less frequent adverse events are gastrointestinal effects, rash, and neurotoxicity. The effects of ganciclovir on human reproductive organs are unknown, but the drug can cause permanent sterility in other mammalian species. Patients should be advised about this possible risk before starting therapy.
The IV dosage of ganciclovir ranges from 5 to 15 mg/kg/day given either once daily or divided into twice-daily doses. Ganciclovir dosages should be decreased for renal insufficiency according to the manufacturer's package insert.
Ganciclovir is initially constituted with 10 mL of sterile water (bacteriostatic water containing parabens should not be used because of potential precipitation) and is stable for 12 hours at room temperature. The initial solution is further diluted in D5W or NS and admixtures are stable for up to 35 days when stored at 4° C to 8° C.(7) Cytotoxic precautions should be observed when handling or disposing of ganciclovir. IV ganciclovir irritates the venous intima and should not be given peripherally for extended periods.
An accurate measure of the patient's weight, CBC with differential and platelet count, and serum creatinine should be obtained when starting therapy. Subsequent blood counts should be checked 2-3 times per week during induction, then once weekly during maintenance therapy. Serum creatinine and weight should be rechecked every 2-4 weeks.
Foscarnet is used to treat CMV disease and acyclovir-resistant herpes simplex and zoster disease. The plasma half-life is approximately 3-4 hours.(28) As with ganciclovir, the intracellular half-life of foscarnet is more pertinent to drug efficacy than is its plasma half-life. Whereas the intracellular half-life of foscarnet is not known, it probably does not exceed plasma half-life to the extent observed with ganciclovir, and daily dosing is necessary.(27) The drug is cleared renally.
Foscarnet's most common serious adverse event is reversible nephrotoxicity.(29) The second most common serious adverse event is infusion-related decreased ionized serum calcium levels, which may explain the nausea, extremity and circumoral paresthesias, occasional arrhythmias, seizures, and mental status changes temporally related to foscarnet administration. Foscarnet also can cause renal losses of total body calcium, phosphate, magnesium, and potassium. Foscarnet should not be given concomitantly with IV pentamidine because of the potential for severe and potentially fatal hypocalcemia. Additionally, foscarnet may cause anemia.
The dosage of foscarnet ranges from 40 to 120 mg/kg either given as a once-daily infusion or split into twice-daily infusions. Precise dosage adjustments of foscarnet, even for small changes in renal function, are necessary to minimize risk of nephrotoxicity. The manufacturer's package insert contains a detailed nomogram outlining dosing adjustment for renal function.
Foscarnet is supplied as a premixed solution in glass bottles at a concentration of 24 mg/mL. To minimize rapid decreases in serum ionized calcium levels, foscarnet must be administered over a period of 2-3 hours via an IV pump.(30)
Foscarnet can precipitate in the presence of calcium, magnesium, and phosphorus, and these agents should not be given concurrently. To reduce the risk of nephrotoxicity, patients should receive a concomitant infusion of 500 to 1000 mL NS. IV foscarnet irritates the venous intima and should not be given peripherally. If it must be administered peripherally, foscarnet should be diluted with NS to a concentration of 12 mg/mL or less.
Before foscarnet therapy is initiated, the following measurements should be obtained: accurate patient weight, CBC with differential and platelet count, and renal panel, as well as BUN, calcium, phosphorus, magnesium, and albumin levels. Albumin levels should be used to calculate corrected serum calcium levels. Renal function and serum electrolytes should be checked 2-3 times per week during induction, then once weekly during maintenance therapy. Blood counts and weight should be rechecked every 2-4 weeks.
Cidofovir is a nucleotide analogue with potent activity against a broad spectrum of herpes viruses. The active intracellular metabolite of cidofovir, cidofovir diphosphate, has a half-life of 17-30 hours. Cidofovir's long intracellular half-life allows for long dosing intervals and makes it a good agent for outpatient treatment of CMV.
Dose-limiting nephrotoxicity is the major adverse event seen with cidofovir.(31,32) Proteinuria is a highly sensitive sign of incipient nephrotoxicity. To reduce the risk of nephrotoxicity, concomitant administration of probenecid is necessary. Probenecid inhibits tubular reabsorption of cidifovir and therefore increases cidofovir urinary excretion and decreases the risk of nephrotoxicity. Because high doses of probenecid are required for this effect, probenecid-associated adverse events such as hypersensitivity, nausea, vomiting, fever, and myalgia may be common. Probenecid is a sulfa drug; hypersensitivity may be compounded in AIDS patients, as HIV infection is associated with higher incidence of sulfa allergy. Adequate hydration and sodium loading appear to be useful in reducing nephrotoxicity.
Other adverse effects associated with cidofovir therapy are neutropenia (which may require support with GCSF), alopecia, ocular hypotony, iritis, and uveitis. Patients receiving cidofovir should be monitored closely by an ophthalmologist. Concomitant HIV protease inhibitor drug therapy is a relative contraindication to cidofovir administration because it is associated with an increased risk of vision-impairing ocular hypotony or uveitis. Cidofovir has shown mutagenic properties in female and male rats. The effects on human embryogenesis are unknown but patients should be advised about possible effects before starting therapy.
Because of possible hypersensitivity reactions to probenecid and severe and potentially irreversible nephrotoxicity to cidofovir, standard practice at SFGH is to give outpatient cidofovir therapy only in an infusion center. Renal function, routine urinalysis, CBC with differential and platelets, and liver enzymes should be checked within 72 hours before each administration. Patients with a baseline serum creatinine >1.5 mg/dL, estimated creatinine clearance <55 mL/min, or proteinuria >2+ should not begin cidofovir therapy. Additionally, the dosage of cidofovir therapy should be reduced or held if proteinuria rises to >3+ or if serum creatinine increases >0.5 mg/dL above baseline.
Cidofovir can be given through peripheral IV access, with a dosage range of 3-5 mg/kg mixed in 100 mL of NS as a single infusion over a period of 1 hour per week for 2 weeks during induction therapy and every other week as maintenance therapy. The recommended protocol for administration of cidofovir is shown in Table
8. Admixed solutions should be used within 24 hours and should not be refrigerated or frozen to extend storage time. There is no experience at this time to support the concurrent infusion of other drugs with cidofovir or the addition of other drugs to admixture solutions. Cytotoxic precautions should be observed when handling or disposing of cidofovir.
| Hydration and Electrolyte Repletion|
Fluid and electrolyte deficits in HIV-infected patients may arise from prolonged periods of vomiting, diarrhea, or night sweats. Additionally, various medications such as IV AmB and foscarnet frequently cause the loss of electrolytes.
Potassium and magnesium may be combined in IV solution at various concentrations. Phosphorous and calcium are compatible only in large volumes of IV fluid, with 1 liter of solution containing a maximum of 20 millimoles of phosphorus and 9 milliequivalents of calcium without precipitation. Generally, it is best to infuse phosphorous and calcium in separate solutions. None of the above electrolyte solutions are compatible with AmB infusion solutions.
| The Use of CVADs in the Outpatient Setting|
CVADs are catheters whose tips are placed in the superior vena cava (SVC). They have cutaneous access ports suitable for intermittent connection to IV tubings that can be used either to infuse solutions or to withdraw blood specimens. Except for use in very short courses of IV hydration or antibiotic therapy, CVADs are preferable to peripheral IV devices in the outpatient setting because tip placement in the SVC allows for rapid hemodilution of the infusate and causes less venous irritation. All CVADs are associated with a risk of thrombotic and infectious complications. However, with proper care and strict sterile technique, these devices often can be used for long periods of time without complications.
Not all types of CVAD are appropriate in the outpatient setting. Appropriate outpatient devices include peripherally inserted central catheters (PICCs), tunneled central venous catheters such as the Hickman and Groshong devices, and subcutaneous implanted ports such as MediPort and Port-A-Cath. Devices that are inappropriate for outpatient use include jugular vein catheters, percutaneously placed subclavian vein catheters, and femorally placed catheters. In AIDS patients receiving foscarnet or ganciclovir for CMV disease, it has been reported that percutaneously placed central catheters have higher rates of infection than do tunneled catheters.(33) Additionally, anecdotal clinical experience at SFGH Medical Center suggests that subcutaneous implanted chest ports have high rates of infections; these often have resulted in delayed replacement of CVADs and increased patient morbidity. Therefore, implanted chest ports probably are not optimal for therapies requiring frequent device access. All outpatient IV devices should be single lumen, if possible, to decrease risk of infection.(34) If a multilumen catheter is used to administer parenteral nutrition, a port for hyperalimentation should be designated and labeled. The designated hyperalimentation port should not be used for other purposes, such as administration of fluids, medications, blood, and blood products.(35)
| Types of CVADs|
| PICC Lines|
Inserted in a peripheral vein in the antecubital fossa (usually the cephalic or basilic vein) and threaded into the SVC, PICC lines can be used for all therapies and for blood collection. (Catheters that are advanced only to peripheral vasculature are considered peripheral or midline catheters.) PICC lines are best suited for patients who require daily infusion therapies for up to 6 months. No recommended maximum dwell time has been established; some patients have used a PICC for a year or more without problems.(36) Patients with traumatized antecubital spaces or a history of multiple failed cannulation attempts are not suitable for using PICC lines.(37) Because of the risk of dislodgement or limitation of upper extremity movement, a PICC may not be the best choice of device in active patients. Disadvantages of PICC lines include restricted flow rate from small lumen size, the need for intact venous anatomy in the arms for placement, an increased risk of venous thrombosis in the extremity used, and the need for sutures to prevent accidental dislodgement.(38,39)
PICC lines can be inserted by certified nurses or physicians in various settings, including a radiology suite, physician's office, and patient's home. An X ray is required to verify the tip placement in the SVC before initiating IV therapy. PICC catheters are thin-walled, thus high flow rates or excessive pressure when flushing can result in bursting of the catheter.(37,40) The vacuum blood-collection system should be avoided because it generates extremely high pressure and can rupture the catheters. Instead, a 10-mL syringe should be used to collect blood specimens from PICC lines.(36) Patients often have phlebitis within the first 10 days of insertion, with tenderness and erythema extending from the insertion site to several inches above it.(38,41) Treatment involves keeping the arm elevated and applying warm compresses. Additionally, the site should be periodically observed for any signs of cellulitis.
In addition to the general CVAD care guidelines given below, the external catheter should be assessed for leakage and the hub connection should be assessed for any signs of cracking. Administration sets, including secondary sets and add-on devices such as caps and access hubs, should be replaced no more frequently than every 72 hours unless clinically indicated. If blood, blood products, hyperalimentation, or lipid emulsions are administered, tubing and add-on devices should be replaced within 24 hours of initiating the infusion.(42) Repair of any external catheter damage should follow the manufacturer's guidelines. Suture placement should be checked when changing the dressing. If sutures are missing, the device should be held in place with steristrips until the sutures can be replaced. Monofilament nylon, rather than silk, should be used to replace missing sutures as a method of decreasing the risk of infection. One study suggested that sutureless securement devices reduced the catheter-related bloodstream infections rates when compared with suture securement. However, the Centers for Disease Control and Prevention (CDC) will have no recommendation for securement devices until further studies are done.(43)
With each dressing change, the external length of the catheter should be measured and documented. If a segment of a PICC extrudes from the exit site, it should not be readvanced because of the risk of infection, and an X ray should be obtained to check the position of the catheter tip.(36) The risk of catheter thrombosis and occlusion can be minimized with careful attention to flushing the device according to specific manufacturer or institutional guidelines for care.(44) General guidelines for flushing open-ended catheters are to use 3 mL of 100 units/mL heparin solution. For flushing close-ended catheters, manufacturer guidelines should be followed. At each use, the catheter should be flushed according to the protocol abbreviated as SASH (saline-administer drug-saline-heparin), an acronym well known to infusion nurses and easily taught to patients and caregivers.(45) After withdrawal or infusion of blood products, the catheters should be flushed with 10-20 mL of NS, followed by heparin. Recommendations for frequency of flushing idle PICC lines vary from every 8 hours to weekly.(34,39,46)
| Tunneled Central Venous Catheters|
Central venous catheters can be tunneled or nontunneled. At SFGH, tunneled catheters are recommended for the outpatient setting. Tunneled lines are long-term external catheters made of durable, medical-grade silicone that are "tunneled" subcutaneously between the vein insertion site and the skin exit site.(39,44) Usually, the tip of the catheter is advanced into the SVC. A Dacron cuff is attached proximal to the exiting end of the catheter and placed within the tunnel under the skin. Within 7-10 days of catheter insertion, scar tissue grows onto the cuff, anchoring the catheter and preventing microorganisms from migrating up the tunnel. The cuff can be impregnated with antimicrobial compounds for increased short-term protection against infection.
Tunneled central venous catheters may be inserted in a surgical suite or an interventional radiologic suite; use of an interventional radiologic suite can decrease cost. After placement, the exit site must be protected with sterile gauze or transparent dressings until it has healed.(34,46) The external catheter should be securely taped to the chest wall to prevent dislodgement, especially during the first 2-4 weeks after insertion until connective tissue has grown onto the cuff.(41) After this period, if a dressing is not used on the exit site, the catheter should be secured to the chest with paper tape or an adhesive bandage to prevent entanglement and pulling on the cuff.(46) Patients or caregivers can palpate the site daily for signs of infection and wash the catheter exit site with soap and water unless contraindicated by clinical condition.
In addition to the general care guidelines just described, the external catheter should be assessed for leakage and the hub connection should be assessed for signs of cracking. The administration sets and add-on devices such as caps and access hubs should be replaced no more frequently than every 72 hours unless clinically indicated. The administration sets and add-on devices should be replaced within 24 hours of initiating an infusion of blood, blood products, hyperalimentation, or lipid emulsions.(42) Repair of any external catheter damage should follow the manufacturer's guidelines. The risk of catheter thrombosis and occlusion can be minimized with careful attention to flushing the device according to specific manufacturer or institutional guidelines.(44) General guidelines for flushing are to use 3-5 mL of 100 units/mL heparin solution, applying the SASH protocol. Some facilities use 10 units/mL of heparin as research shows it is equally effective.(36) After withdrawal or infusion of blood products, the catheters should be flushed with 10-20 mL of NS, followed by heparin. The manufacturer of the Groshong catheter recommends flushing with saline only and at less frequent intervals because the device has an internal valve designed to prevent blood reflux into the catheter. The recommended frequency of flushing tunneled catheters when not in use varies from every 8 hours to weekly.(34,39,46)
| Implanted Ports|
Implantable IV ports are usually made of a compressed self-sealing silicon septum encased in titanium or plastic housing that is attached to a silicone catheter. The ports are totally implanted beneath the skin without visible external parts. They are best suited for cyclic therapies and for patients who do not like to have external parts when the CVAD is not in use. To access the port, a special angled noncoring Huber needle is inserted into the skin. A traditional needle would lacerate the port septum and result in blood leakage and contact with air.(36) Ports are usually designed to sustain 500-2,000 punctures (34) and are routinely placed in a subcutaneous pocket either in the chest (chest port) or in the arm (PASport). In cancer patients, ports have been reported as having lower infection rates compared with externally placed CVADs.(38,47,48) Because implanted ports require less frequent flushing and are protected by the skin when not in use, they are ideal for intermittent IV therapies, such as chemotherapy. Their utility in continuous (eg, daily) IV therapy is less clear and frequent accessing can result in skin breakdown over the port septum. Experience with AIDS patients at SFGH has demonstrated that daily accessing of the ports causes skin excoriation, which increases the risks for port infection. Because surgical intervention is generally required to remove and inspect the infected implanted ports, particularly chest ports, infections tend to be more costly and difficult to treat compared with infections associated with external catheters.
Slight edema and tenderness usually develop at the port site for the first few days after placement, making access difficult. The needle used during the placement procedure may be left in place postoperatively to allow for immediate use so as to avoid accessing the device through the skin until the site has healed. Additionally, within the first 10 days of inserting a PASport, phlebitis is common and may manifest as tenderness and erythema extending from the insertion site to several inches above it.(49) Elevation of the arm and application of warm compresses can treat this problem successfully. The site should be observed periodically for signs of cellulitis.
Ports should be accessed only with Huber or noncoring needles. PASports should not be used with needles larger than 19 gauge, to prevent damage to their small septums.(37) Once placed in the port, the needle should be securely anchored with a dressing to prevent dislodgment during infusions. Correct needle placement should be confirmed before infusion by aspiration of blood and slow injection of 5 mL saline.(41) Ports should never be forcibly flushed if resistance is felt because of the risk of thrombus dislodgment or catheter rupture. Malposition of the catheter tip should be suspected when difficulty in blood aspiration is resolved with a patient's cough, Valsalva maneuver, or change in body position such as turning the head or reclining. Persistent inability to obtain blood return may be an indication of poor catheter tip placement, catheter migration, or thrombus formation.(45)
Access needles usually are removed after every IV infusion. The port should not be accessed for more than 7 days without changing the needle.(34) If the access needle is left in place, the device site should be covered with a sterile dressing. When the port is used for continuous infusion, the site should be checked frequently for needle dislodgment.(38) The skin over implanted ports should be routinely assessed for tissue breakdown associated with frequent, multiple needle punctures. Unused ports should be flushed with heparin at least monthly according to the manufacturer's specific recommendations. With each use, the standard practice is to flush the port with 5 mL of 100 units/mL heparin solution using the SASH protocol. After each blood collection or blood product transfusion, the port should be flushed with 10-20 mL of saline followed by heparin. Because of the walls of these devices are thin, IV pumps should be used at low infusion rates.
| CVAD Selection for the Outpatient Setting|
Selecting the correct device depends on both the purpose and the impact on the patient's quality of life.(39,44) Patient preference should always be central to making this choice. Repeated needlesticks to access an implanted port may be unappealing to some patients. Other patients may want an implanted device so that they can swim or bathe when the device is not being accessed. Some patients may not have the visual acuity or motor skills needed to access a port. Additionally, the patient's venous access must be considered. Patients with a history of IV drug use, traumatized antecubital areas, or a history of multiple failed cannulation attempts generally do not have adequate peripheral venous access and are limited to tunneled lines or chest ports.(37) An overview of different types of devices and their uses is provided in Table
| General Care of CVADs in the Outpatient Setting|
Proper care of CVADs seems to be the single most important factor in reducing the risk of complications.(34,41) One study in AIDS patients suggested that the most significant factor associated with risk of CVAD infections is nonadherence to recommended device care.(50) Possible reasons cited include not understanding proper CVAD care; changes in the patients' mental status because of infection, dementia, or depression; fatigue from disease progression; failing eyesight or poor manual dexterity; placement of the device in an anatomic location that is difficult to access; not having proper supplies or equipment; and a change of home care providers. This finding suggests that AIDS patients and home care providers who use these devices need frequent assessment of both CVAD care technique and CVAD care supplies.
The medical literature does not reflect a consensus on standardized care for CVADs,(34,37,46) and the practitioner should refer to institutional policies and manufacturer recommendations for care of specific devices. To reduce infectious complications, care guidelines for all central devices include using strict aseptic technique when accessing the device; minimizing catheter manipulation during entry into the system; prompt dressing changes if dressings become wet, loose, or soiled; routine flushing of the line when not in use; and removal of catheters when they are no longer essential.(34,37,41,46)
The literature also reflects a lack of consensus on recommendations for catheter exit-site care and type of central line dressings.(37,46) Skin cleansing and preparation procedures usually include the use of alcohol followed by povidone/iodine or chlorhexidine gluconate. One study has shown that skin preparations using a 2% aqueous chlorhexidine gluconate lowered bloodstream infection rates in comparison with preparations using 10% povidone/iodine or 70% alcohol.(51) In July 2000, the FDA approved a 2% tincture of chlorhexidine preparation for skin antisepsis. Other preparations of chlorhexidine might not be as effective.(43) Use of antibiotic ointment at the catheter site has been examined and remains controversial. Clinical studies demonstrate that common triple-antibiotic ointments, or any antibiotic ointments that have no fungicidal activity, are associated with increased fungal colonization. Iodophor ointment also does not decrease infection rates.(34,39,44,46) Recent CDC guidelines suggest that any ointment that is to be applied to the catheter insertion site should be checked against the catheter and ointment manufacturers' recommendations regarding compatibility in order to avoid compromising the integrity of the catheter.(43)
The use of occlusive dressings is also controversial. In some studies, clear, semipermeable plastic dressings have been associated with increased colonization of exit sites and catheter-related infections.(52,53) In contrast, other studies did not find a difference between the incidences of infection associated with transparent dressings and gauze dressings.(54) If used, transparent dressings should have high water permeability in order to keep the catheter site dry. Compromised skin integrity and sweating can be problematic when maintaining dressings. Patients may develop sensitivity to the dressing material, cleansing agent, or tape. Dressing material and technique should be adapted to specific patient needs and should not be restricted unnecessarily by institutional protocol or market forces. The CDC has no recommendation for types of dressing but indicates that gauze dressing might be preferred if blood or drainage is oozing from the catheter insertion site.(43) During dressing changes and catheter removal, the insertion site should be inspected for signs of infection such as redness, swelling or fluctuance, tenderness, and drainage.
Although consensus regarding line flushing protocols is lacking,(22,37,47) all CVADs require routine flushing while not in use in order to maintain patency and minimize thrombotic complications. Flushing frequency varies with the type of devices used, and flushing guidelines generally recommend heparinized saline or NS as flushing solutions. The concentration of heparin depends on the device used and the patient's condition. As a general rule, however, the lowest effective concentration of heparin should be used and the volume of heparinized saline should be roughly twice the volume of the cannula.(34) Flushing with NS alone is controversial and is not currently a common practice.(34) Some CVADs have a 2-way valve on their distal ends that allows both blood drawing and IV infusion while preventing blood from entering the catheter when not in use. Valved catheters are sometime referred to by the brand name Groshong. Because of the valved design, these devices are usually flushed weekly with NS alone instead of the heparinized saline used in nonvalved catheters. In 1 pilot study, however, the use of heparinized saline decreased the likelihood of intraluminal clot formation and catheter occlusion in Groshong catheters.(55) While flushing, a "stop/start" flushing method and a positive-end pressure technique are recommended. This pulsatile flow technique, rather than even syringe pressure, creates turbulent flow and theoretically decreases the buildup of residue on the internal lumen of the CVAD.(56) A positive-end pressure technique (clamping the CVAD while maintaining syringe pressure) minimizes blood reflux and prevents catheter thrombosis. One study has shown that the use of positive displacement devices is effective in preventing catheter occlusions.(57) Positive displacement devices are attached to the end of central venous catheters and used as access ports with leur-lock and other needleless systems. These devices create positive pressure when ports are deaccessed and prevent backflow of blood into the catheter; this is useful in preventing intraluminal or extraluminal thrombus formation.
Because heparin may not be compatible with some infused agents, the SASH protocol should be used. If multiple medications are administered at the same time, the catheter should be flushed with saline between medications and with heparin at the end. Because the flushing solution may interfere with laboratory test results on blood drawn through the device, 5-10 mL of blood should be discarded before obtaining laboratory samples.(34) Additionally, specimens for some laboratory tests such as coagulation studies should be obtained only by peripheral venipuncture and not from a CVAD.(58) After blood withdrawal or blood infusion, the device should be flushed with 10-20 mL of NS to remove residual blood cells before heparinization.
| CVAD Complications|
Central device complications include events that occur during or after insertion and adverse events related to the device itself. Periprocedural complications that have been reported are pneumothorax, hematoma, air embolism, cardiac arrhythmia, arterial puncture, plexus irritation, and perforation of heart and great vessels. Postinsertion complications include phlebitis, infection, septicemia, SVC syndrome, venous thrombosis, pulmonary embolism, and skin necrosis. Device-related complications include fibrin sheath formation, catheter thrombosis, catheter migration or torsion of the port reservoir, catheter fracture or embolism, and pinch-off syndrome for tunneled catheters.(57,59) Infection and catheter occlusion or thrombosis are the 2 most common complications seen in CVADs.(60) Catheter migration occurs infrequently and catheters usually can be salvaged using interventional radiology techniques. Symptoms of catheter fracture include chest wall swelling at the pocket or insertion site, pain in the shoulder or port area without swelling, resistance to injection or withdrawal of fluids, and sudden onset of chest pain or cough.(61) Many of the device-related complications are found at the time of contrast-enhanced evaluation for device malfunction. Intermittent CVAD flow difficulties may be caused by a pinching off of the tunneled catheter between the clavicle and first rib.(46,61) Pinched-off catheters can be identified by chest radiograph and should be repositioned before use. External catheter tubing and hubs may wear from repeated use or damage during access procedures with needles. Repair kits for replacing broken hubs and external catheter tubing are available to help avoid total replacement of the device.
It is not clear whether there are differences in CVAD-associated complication rates between general and HIV-infected populations. Some authors have found significant differences in infection rates,(62,63) whereas others have not.(64-66) Infection is a major CVAD complication and is of particular concern for patients with compromised immune systems. In 1 study involving HIV-infected patients, the presence of an IV catheter was the single most important risk factor for Staphylococcus aureus bacteremia in patients who use non-IV drugs.(67) Other studies have shown that CVADs are the second most common source of bacteremia in AIDS patients.(68,69) These studies most commonly identify S aureus, followed by Staphylococcus epidermis, Staphylococcus pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterobacteriaceae, and Candida species as causative organisms.
Appropriate care of CVADs appears to be the single most important factor in reducing the risks of complications in AIDS patients.(67) Consequently, the clinician must provide the best care possible for these devices, especially in the outpatient setting.
| Evaluation and Management of Catheter-Related Thrombosis|
Catheter-related thrombosis may occur despite rigorous adherence to flushing and heparin protocols, especially in hypercoagulable patients.(44,48) Causes include platelet deposition on foreign substances introduced into the vascular system, fibrin deposition that can occur anywhere from the catheter tip to the exit site, fibrin sheaths that can form within 5 to 7 days of placement, and catheter tip placement causing occlusion or thrombus, provoking inflammation.(34,70) Other risk factors include venous irritation from some types of chemotherapy or high osmolarity solutions, drug precipitation within the catheter, and venous stasis from tumor compression.
Early recognition of catheter tip occlusion usually improves the chances of successful treatment of thrombotic complications.(44) The first sign of occlusion is difficulty aspirating blood from the device. This difficulty usually stems from a thrombus, a fibrin sheath that can act as a 1-way valve, or a catheter tip that is lodged against the vein wall.(34,46,48,71) Other possibilities include lipid deposits or precipitates, catheter malposition, and mechanical failure.(34) Port devices should always be checked for needle dislodgement from the septum. Changing the position of the patient's arm or head or having the patient perform the Valsalva maneuver, cough, or take deep breaths may change the position of the catheter tip.(34,46) Untreated catheter tip occlusion can result in progressive thrombosis associated with increasing resistance to infusion, catheter occlusion, and septic thrombosis. Patients with catheters that have either persistent partial or sudden complete withdrawal occlusion should be seen by an interventional radiologist for contrast-enhanced studies and evaluation of catheter tip placement.
Venous thrombosis around the catheter can occur without compromise of catheter function, and most patients do not exhibit early clinical signs of deep-vein thrombosis. Symptoms of venous obstruction include complaints of shoulder or arm pain; unilateral swelling of the arm, neck, or face; cyanosis; venous distention or palpable venous cord; prominent superficial venous collaterals; and, rarely, SVC syndrome or pulmonary embolus.(34,70) Patient complaints of pain or swelling distal to the insertion site of a CVAD should arouse suspicion of thrombus formation. Diagnosis can be confirmed with venographic contrast studies, Doppler sonography, or computed tomography scanning.(72) Catheter-related thrombosis sometimes can be treated without removing the device by using local or systemic infusion of thrombolytic therapy in combination with guide wire manipulation.(34,44) In the past, urokinase was the fibrinolytic agent of choice for catheter-related thrombosis. However, the FDA halted the use of urokinase in 1999 because of the possible increased risk of transmitting infectious agents. In September 2001, the FDA approved low-dose t-PA (tissue-type plasminogen activator), brand name CathFlo Activase, for catheter clearance; t-PA is currently the only thrombolytic agent approved by the FDA for this purpose. The manufacturer's recommendations and institutional guidelines should be followed when CathFlo Activase is used. Generally, 1 or 2 doses of 2 mg of CathFlo Activase will restore catheter function. Using a stopcock method, the t-PA should be left in the occluded catheter for 30 minutes, then 4-5 mL of blood should be aspirated gently; this should remove CathFlo Activase and the residual clot. The catheter should be flushed with 20-30 mL of saline, then heparinized. If the catheter remains occluded, the process can be repeated with a second dose of CathFlo Activase with longer (up to 120 minutes) dwelling time.(56) For thrombotic catheter occlusions that do not respond to thrombolytic therapy, objective diagnosis with radiologic techniques is advisable. In cancer patients with subclavian vein central lines or implanted ports, daily use of low-dose warfarin or low-molecular-weight heparin has been found to prevent catheter occlusion and thrombotic events.(34,57,73)
Another complication is extravasation of chemotherapy because of needle dislodgment from implanted ports, damage to or separation of the catheter, and fibrin and thrombus formation, causing occlusion, increased back pressure, and subsequent leakage at the venous entry site.(61,71) Practitioners should consider very carefully whether to administer chemotherapy through a CVAD with partial occlusion. Catheter function always should be assessed completely before administering chemotherapy vesicants and the site should be examined for signs of previous extravasation. Additionally, the patient should be questioned about any discomfort during or after treatment and when flushing the device at home. Redness, swelling, and tenderness can signify either extravasation or infection and should receive prompt evaluation.(61,71)
| Evaluation of CVAD-Related Infections|
Infection is probably the most common complication of CVAD use in the outpatient setting. Catheter-related infections can occur at any time the device is in place. Pathogenic organisms can enter and infect intravascular devices by contamination of the infusate, contamination at junctions in IV tubing, contamination at the insertion site, and systemic seeding from a distant source.(52,53,70,74) Specific recommendations for the diagnosis and management of catheter-related infections are listed in the IDSA guidelines published in 2001.(75)
CVAD-related infections are classified as either local or systemic. Local infections include insertion- or exit-site infections, port or reservoir infections, and tunnel infections, which occur along the subcutaneous tunnel or tract of the catheter.(33,70,74) Insertion- or exit-site infections usually present with inflammation with or without purulent discharge from the catheter insertion or exit site. Localized pain, erythema, induration, and tenderness within 2 cm of the catheter insertion or exit site may be present, although signs in immunosuppressed patients can be subtle.(76) Strict hand washing, aseptic techniques, and proper skin preparation (such as using 2% chlorhexidine to disinfect the site) can effectively prevent insertion-site infections. Port or reservoir infections present with induration, erythema, or tenderness involving the skin over the access port, and there may be a purulent exudate in the subcutaneous pocket around or within the reservoir. Tunnel infections are defined by the presence of tenderness, erythema, or induration that extends along the subcutaneous tunnel tract for more than 2 cm from the exit site. Signs of exit-site inflammation or infection may not be present.(75,76,77) Systemic catheter-related infections include bacteremia or septicemia, suppurative thrombophlebitis, and distant complications such as endocarditis or metastatic abscesses.(76) Although systemic catheter-related infection is rare, it can be life threatening once it occurs, especially in immunocompromised patients. Patients with CVADs that present with fever, chills accompanied by hypotension, hyperventilation, altered mental status, or nonspecific gastrointestinal complaints such as nausea or abdominal pain should be evaluated immediately and receive appropriate therapy.
Confirmed diagnosis of catheter-related bacteremia is complicated by conflicting information on the best methodology for identifying microorganisms. CVAD-related bacteremia is usually confirmed when the same pathogen can be isolated from peripheral blood culture and catheter culture, or when there is no clinical evidence of another source of infection.(70) Reports on the diagnostic value of catheter tip culture at time of device removal have been variable, probably because positive tip cultures may result from colonization of the site and not necessarily from systemic infection.(53,70) Definitive diagnosis of CVAD-related bacteremia usually requires isolation of the same organism from exudate at the catheter insertion or exit site and from the circulating blood, antibiotic-refractory septicemia that resolves with device removal, and differential quantitative blood cultures growing >10 colonies of the same organism from both the CVAD and circulation.(70,74) A more pragmatic criterion for CVAD-related bacteremia is isolation of a known bacterial pathogen (eg, S aureus, E coli, and Staphylococcus pyogenes) from a blood culture, or isolation of a possible pathogen (eg, S epidermidis) from 2 separate blood cultures. The diagnosis also can be made empirically if signs of bacteremia resolve with catheter removal with or without a course of antibiotic therapy. The utility of drawing blood cultures through the CVAD has been questioned because specimens easily may become contaminated.(52,74)
| Evaluation of Suspected Catheter-Associated Infection|
Early recognition of superficial infection at the skin insertion or exit site may help prevent systemic infection and save the device. Complaints of erythema, pain, fever, or exudate should be evaluated immediately. In neutropenic or immunocompromised patients, these signs may be minimal or absent.(44,70) Bacteremic AIDS patients may not present with fever.(68) More than 50% of patients presenting with CVAD-related bacteremia and sepsis have no inflammation at the catheter site.(52,53,74) This situation is more likely to occur in immunocompromised patients. Any exudate from the insertion site should be cultured, and 2 bacterial cultures and 1 fungal blood culture should be obtained from separate IV sites. Patients with complaints of fevers, chills, diaphoresis, malaise, muscle aches, weakness, tachycardia, mental status changes, or pain associated with the device also should have 2 blood cultures from separate sites and 1 fungal blood culture drawn. Patients with minimal or no objective findings but with mild subjective discomfort should have, at least, close follow-up to rule out evolving infection.
| Treating CVAD-Related Infections|
Management of confirmed CVAD-related infections depends on the causative organism, whether the infection is local or systemic, the type of CVAD used, and the physical condition of the patient.(70) Many CVAD-related infections can be treated without catheter removal.(48)
Insertion- and exit-site infections are generally easier to treat and less likely to require device removal than are tunnel, tract, or pocket infections, septic thrombus, or septicemia. Uncomplicated insertion- and exit-site infections in clinically stable patients can be treated with frequent site care and a 10- to 14-day course of appropriate oral or IV antibiotics. Implanted ports that are already accessed can have the needle left in place for antibiotic infusion and blood sampling. Implanted ports with skin-site infections should not be accessed because that could increase the risk of flushing microorganisms into the circulation.(61) Peripheral access should be used until the overlying skin has healed.
Tunnel, tract, or pocket infections are more difficult to treat with antibiotics and usually require device removal, especially in pseudomonal infections.(44,46,52,70) One group of investigators reported that treatment of exit or tunnel infections in AIDS patients inevitably required catheter removal.(63) In this study, it appeared that successful treatment of bacteremia without CVAD removal was more likely in the absence of skin infection or necrosis. Confirmed tunnel catheter pocket infections or port abscesses require immediate removal of catheter and 7-10 days of appropriate antibiotic therapy. Reinsertion of a tunneled intravascular catheter in a stable patient ideally should be done after a systemic antibiotic course of therapy is completed and repeat blood samples drawn 5-10 days later yield negative cultures.(75)
The need for removal of a catheter depends on whether or not the device can be adequately sterilized with antibiotic therapy. It is often possible to treat catheter-related infections without removing the device, particularly when they are caused by gram-positive, coagulase-negative staphylococci.(52) On the other hand, eradication of Candida or S aureus infection with antibiotic therapy alone is rare and usually necessitates removal of the device.(48) An infected device must be removed in case of persistently positive blood cultures or failure of the patient to improve clinically despite appropriate antibiotic therapy. If there is persistent bacteremia or fungemia, or a lack of clinical improvement after removal of a colonized catheter associated with a bloodstream infection (especially 13 days after catheter withdrawal and initiation of appropriate antimicrobial therapy), aggressive evaluation for septic thrombosis, infective endocarditis, and other metastatic infections should be undertaken.(75) Patients, especially IV drug users, with confirmed catheter-related S aureus bloodstream infections should undergo transesophageal echocardiography to rule out vegetations and infective endocarditis.
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