Case Studies

J. B. (renal transplant-acute care)
B. W. (liver transplant-acute care)
J. P. (liver transplant-subacute and chronic care)
M. S. (renal transplant-subacute and chronic care)
D. D. (renal transplant-chronic care)
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Charts
Case Studies
References
Related Sites
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Vital Signs/Nursing Notes
Lab Values and Pathology Reports
Medication Profile
Physicians' Progress Notes

TRANSPLANT CERTIFICATE PROGRAM MODULE 6

IMPLEMENTING PATIENT CARE MANAGEMENT: ACUTE and CHRONIC CARE of the KIDNEY or LIVER TRANSPLANT RECIPIENT

Robert E. Dupuis, David Taber, Amy Fann


The best way to provide care for the transplant recipient is a multidisciplinary team approach, including physicians, nurses , coordinators, dieticians, physical and occupational therapists, social workers, psychologists, and pharmacists. The pharmacist plays a vital role in assuring optimal pharmaceutical care to transplant patients both in an institutional and community setting. It is the goal of this section to provide the pharmacist with the knowledge and understanding on how to provide optimal long-term pharmaceutical care to a transplant patient once they leave the hospital and return to the community. The areas that will be discussed in this section include a brief discussion of acute care issues but the main focus will be on chronic care after initial hospitalization. This will include long-term immunosuppressive strategies, infections, and complications. The long-term complications discussed will include osteoporosis, malignancy, diabetes, recurrence of disease, and chronic rejection. Although hypertension and dyslipidemias are common complications post-transplant, these areas were previously discussed in module 3 and will not be addressed here. Additionally, other considerations unique to the care of transplant patients will be mentioned. These include immunizations, potential drug interactions, non-prescription medication use, and patient medication non-adherence issues. Finally, guidance on the development of patient care plans and reimbursement strategies for pharmacists providing care to these patients will be addressed.

I. ACUTE CARE

The immediate post-operative period in abdominal organ transplantation presents multiple therapeutic challenges and potential complications. Among the most common are: graft dysfunction, electrolyte abnormalities, and infection. Assessment, prevention, and management differs somewhat between kidney and liver transplant patients as these patients undergo different surgical procedures, in addition to exhibiting different pathophysiology both before and after transplantation. Much of the immediate post transplantation care occurs in the intensive care unit (ICU) setting, particularly following orthotopic liver transplantation, but less so for kidney transplantation. Time spent in the ICU may vary from less than one day, if at all for kidney transplants to several weeks for liver transplants.

Monitoring of Graft Function Immediately Post-Transplantation

Within the hours and days immediately following liver and kidney transplantation, monitoring of graft function plays a significant role in post-operative care. Clinical laboratory tests, appearance and volume of urine and various surgical drain outputs, ultrasonography, nuclear medicine tests, and if necessary, biopsy, all aid the clinician's judgement of the new graft function.

Survival of the liver transplant patient depends upon early graft function, as currently, extracorporeal hepatic replacement devices are not standard therapy. Assessment of the liver graft function begins shortly following reperfusion. Once stabilized and in the ICU, the physical examination of a patient with a functioning liver should reveal recovery of consciousness within approximately 12 hours following surgery. Laboratory evaluation shows a characteristic elevation of liver function tests with aminotransferases in the 1000's and bilirubin concentrations also remaining elevated. Steady decline of these values should begin within 2 to 4 days. As measures of the new liver's synthetic function, prothrombin time (PT) and partial thromboplastin time (PTT) also should begin to normalize within this time period. Since a functioning liver allograft aids the body in maintaining blood glucose concentrations through gluconeogenesis, hypoglycemia in the absence of pharmacologic hypoglycemic agents, also raises concern that the liver is not functioning well. As the liver continues to improve function, electrolytes such as magnesium and phosphorus may require replacement.

Diagnosis of vascular complications from liver transplantation occurs most often through duplex ultrasonography. Ultrasound depicts blood flow in the hepatic artery, hepatic vein, and portal vein. Fluid collections surrounding the liver can also be visualized through ultrasound. Although interpretation of these tests is beyond the scope of this review, their results can influence the patient's pharmacotherapy. If the ultrasound shows decreased blood flow through these vessels, therapeutic options include pharmcotherapy, return to the operating room for restoration of blood flow, or retransplantation, in the case of primary graft nonfunction. In a hemodynamically intensity heparinization is sometimes instituted to theoretically prevent thrombosis around anastomotic sites. Also nitroglycerin and diltiazem are sometimes employed to improve blood flow. Liver edema due to volume overload could be another cause of decreased blood flow. Adequate diuresis (furosemide) and conservative fluid administration should be employed to prevent this occurrence. In addition, a number of liver transplant patients exhibit renal impairment either before, after, or before and after transplantation.

Complications related to the biliary system are reported to occur in around 10% to 12% of patients. These complications usually consist of bile leaks or biliary strictures. Bile leaks usually occur early after transplantation and involve anastomosis sites. Symptoms of a bile leak include fever and right upper quadrant pain. If a bile collection develops around the leak it can cause obstruction of the bile duct around this sight. Laboratory evidence of this includes elevation of bilirubin, GGT, and alkaline phosphatase.

In contrast to the liver transplant patient, delayed graft function is not uncommon in renal transplantation patients, necessitating reinstitution of hemodialysis. Despite the immediate necessity of hemodialysis, the patient's surgery usually results in a functioning renal allograft. Patients with a functioning graft should begin having good urine output within hours of transplantation. A urine output of fifty mililiters per hour within the first two to four hours following surgery should be expected, with some patients reaching a urine output of 1 liter per hour for the first 24 hours post-operatively. Appropriate fluid replacement is critical. With such dramatic diuresis, the patient is also at risk for electrolyte abnormalities. For this reason electrolytes (potassium, calcium, magnesium, phosphorus) must be monitored frequently. Should repletion be required, administration of potassium and magnesium should be approached in a conservative manner, as renal function is still not optimal. In a normally functioning renal allograft, serum creatinine remains elevated for the first 24 hours, then begins a constant declince to normal or near normal values. Delayed graft function occurs in 8% to 50% of cadaveric renal transplant patients, and most commonly results from the presence of acute tubular necrosis (ATN). Delayed graft function is defined as the need for dialysis in the postoperative period or the failure of serum creatinine to fall below 4 mg/dL or by 30% of the pretransplant value. Pharmacologic strategies to decrease time the renal allograft undergoes ATN include administration of calcium channel blockers, such as diltiazem, low dose dopamine (3 mcg/kg/min), and adequate hydration. Tacrolimus and cyclosporine are both associated with significant renal toxicity, therefore administration of these agents is sometimes delayed to prevent further damage to the transplanted kidney in ATN.

Stress ulcer prophylaxis is also usually indicated for most transplant patients. Two definite risk factors are mechanical ventilation and coagulopathy. Hemodialysis is another potential risk factor for stress ulcer development. At least one and likely more than one of these risk factors exist in most transplant patients. In addition, transplant patients receive large doses of corticosteroids and other medications that could precipitate or worsen gastritis. As a result of this increased risk, patients immediately post operatively should receive pharmacologic stress ulcer prophylaxis.

Within the first 48 hours of tranplantation, patients require intravenous opioids for pain control. However, as soon as the patient's pain begins to subside (within about 2 to 3 days), medication should be converted to oral dosage forms, administered on an as needed basis. The use of non steroidal antiinflammatory drugs (NSAIDS) for pain control is not recommended in this patient population. Combining NSAIDS with either cyclosporin or tacrolimus may result in synergisitic nephrotoxicity.

Perioperative Antibiotic Prophylaxis and Early Infectious Complications

Although surgery increases the risk of infection in many otherwise healthy individuals, infection poses even further risk for patients following organ transplantation. The need for immunosuppressives in addition to the pre-existing functional immunosuppression of end stage renal and liver disease, places these patients at high risk for life threatening infections. Infectious complications following abdominal organ transplantation have been estimated to occur in 42% to 83% of patients within 3 months of liver transplantation and from 10% to 56% in kidney transplant patients. Transplant centers report mortality from postoperative infections at rates of 4% to 23% in liver transplant patients and 5% to 30% for renal transplant patients. Although pathogens most commonly associated with infections following these procedures differ, largely because of differences surgical techniques, the high rate and severity of postoperative infectious complications solidifies the role of perioperative antibiotic prophylaxis for both liver and kidney transplantation.

Liver transplantation represents one of the most technically difficult abdominal surgeries with procedure times lasting on average of 8 to 12 hours. Liver transplantation is classified by the modified National Research Council wound classification criteria as a clean contaminated procedure. This criteria defines a clean-contaminated procedure as a procedure involving transection of gastrointestinal, oropharyngeal, GU, biliary or tracheobronchial tracts with minimal spillage or with minor breaks in technique; clean procedures performed emergently or with major breaks in technique; reoperation of clean surgery with in 7 days, or procedures following blunt trauma. Historically, liver transplant patients have received perioperative antibiotics although strong placebo comparative evidence for this practice does not exist. Despite this lack of evidence for use of perioperative antibiotics, clinicians recognize that benefits of administering antibiotics seem to outweigh the risks. Appropriate perioperative antibiotics target potential bacterial infections from pathogens commonly associated with early (< 2 weeks after procedure) infections. Coagulase negative staph., S. Aureus, Enterocci, and gram negative bacilli, such as Klebsiella, E coli, Enterbacter sp. and Citrobacter sp. These bacteria, most commonly associated with intraabdominal and wound infections, originate from the skin and intestinal lumen flora. The most commonly cited regimen consists of ampicillin plus cefotaxime. This regimen provides activity against common gram negative pathogens, some anti staphylococcal activity plus activity against enterococcus. Studies have also examined the use of ampicillin/sulbactam and other third generation cephalosporins. Evidence that 48 hours of perioperative antibiotic prophylaxis is as effective as other longer duration regimens. Selective bowel decontamination, another strategy to prevent post-transplantation infections utilizes oral gentamicin, colistin (polymyxin E), and nystatin to clear the bowel of aerobic gram negative bacilli and yeast, but is controversial. Since these agents are not well absorbed systemically, they serve to clear the gut of target organisms while avoiding systemic exposure of the drugs.

During the immediate post-transplant period while in the ICU, the liver transplant patient acquires infections similar to those nosocomial infections of other surgical ICU patients. These most commonly include ventilator-associated pneumonia, urinary tract infections, infections associated with indwelling vascular access devices, surgical wound infections, and candidal superinfections. Initial empiric antimicrobial therapy should begin with broad-spectrum antibiotics, later targeted to specific pathogens as culture and sensitivity results become available. Liver transplant patients may be more susceptible to candida infections than are other populations, due to surgical manipulation of the colonized GI tract, time in the ICU. Risk factors include elevated pretransplant serum creatinine, hemodialysis requirement, duration of ICU stay, antibiotic use (other than perioperative antibiotics) and immunosuppression. Both fluconazole and amphotericin B have been studied as candidal prophylactic agents. Several studies have shown a benefit with the use of fluconazole for antifungal prophylaxis in patients deemed to be at high risk. Amphotericin B is considered second line therapy for this indication due to its nephrotoxicity.

Infections within the first two weeks of kidney transplantation usually result from skin flora. Therefore perioperative antibiotics are targeted toward staph aureus, coagulase negative staphylococci, and streptococci. Cefazolin is the most common agent utilized for antibiotic surgical prophylaxis in this group.

The most common infectious complication immediately post renal transplantation is the occurrence of urinary tract infections. Empiric antibiotics are directed towards the most common pathogens. E coli, Staph aureus, and other gram negative rods are the most commonly cultured. First line therapy usually consists of sulfamethoxazole/trimethoprim or ciprofloxacin, as the commonly isolated organisms are usually susceptible to these two agents. Since kidney transplant patients do not usually have extended ICU stays or receive multiple antibiotic courses, they are less likely to acquire pulmonary infections and candidal superinfections.

II. SUB-ACUTE CARE

As noted in the previous section, recipients may spend a short or extended time in the ICU. After kidney transplant, most patients spend < 12 hours, if at all, whereas most liver transplants 1-3 days. Besides continued monitoring of hemodynamics, respiratory status, fluid and electrolytes other issues must be addressed.

Acute Rejection

This can occur early after transplant and its prevention is most important for long term outcome. Rejection can present as several different types after transplant. Hyperacute rejection occurs within minutes to hours after transplant and results in immediate graft loss. Fortunately this is rare and is prevented with appropriate blood matching. Accelerated rejection occurs within the first few days after transplant and is also rare and more amenable to treatment.

The most common type is acute rejection. The incidence has decreased, particularly with the new immunosuppressives and can be < 20% in kidney transplants, whereas in liver transplant it occurs in 30-50% of recipients. Although it can occur at any time, it is most likely to be seen in the first 4-7 days to first few months after transplant. Finally, the last type of rejection is chronic, which will be discussed later in this module.

Clinical signs and symptoms of acute rejection can be non-specific and sometimes non-existent in both types of transplants. These include fever, chills, myalgias, weight gain, edema, pain and tenderness around the graft site. Kidney transplants may have decreased urine output, along with hypertension. This must be distinguished from infection, calcineurin toxicity, dehydration and recurrence of disease. The most likely and often only presentation is an acute rise in serum creatinine.

In liver transplants, besides nonspecific symptoms noted above, ascites may be occur or increase and if available, a decrease in quantity and quality of bile may be present. The most likely indicators of acute rejection, are elevations of ALT, AST, AlkPhos and bilirubin. Infection and disease recurrence should be ruled out.

In the case of both kidney and liver transplant, a tissue biopsy must be done to make the diagnosis of acute rejection. This will dictate appropriate management.

A number of other events take place on the nursing ward. During this inpatient period fine tuning of immunosuppressives and other medications, addressing any pre-transplant co- mordid conditions and medications, wound care and removal of catheters and drains. Also focus is placed on the patient strengthening him or herself, maintaining appropriate dietary intake, fluid intake, ambulation, bowel function and pain control. These are important so the patient and their family can assume care outside the hospital. Another important aspect that takes place is patient education and discharge planning. Many patients are discharged within 5 days after kidney transplant and 10 days after liver transplant. Knowing their medications, how to monitor and identify any problems and document temperature, blood pressure, intake and output, weight and how to eat and exercise post transplant are extremely important for long term outcomes.

In order to make a smooth transition from inpatient to outpatient, the inpatient pharmacist should be instrumental in facilitating this process. The pharmacist should be involved in patient education, should help with identify any issues that might make discharge and chronic care problematic. The pharmacist should communicate with the transplant coordinator and make them aware of any outstanding issues and should contact the pharmacy from which the patient will obtain their medications. If the pharmacist is in an outpatient setting (clinic or community), besides interacting with the patient, he/she should be in contact with a member of the team, usually the transplant coordinator or pharmacist involved with the care and discharge of the patient.

Besides having a good understanding of their care, the patient should leave the hospital with names and contact information of individuals responsible for their care, a list of current medications and a diary of important monitoring parameters that they can carry with them and is accessible to any health care provider involved in their care.

III. CHRONIC CARE

Although the most crucial time for a transplant patient is during their initial hospital stay, there are a large number of potential complications a transplant patient may experience upon discharge from the hospital. As we continually improve immunosuppressive regimens and prevent graft loss, particularly due to acute rejection, it will be increasingly important to identify, prevent, and treat immunologic and nonimmunologic long-term complications in transplant patients. As drug therapy experts, we have an important role to help prevent and manage these complications.

LONG-TERM IMMUNOSUPPRESSIVE STRATEGIES

Despite excellent short term results, long-term graft failure and patient death are still a major problem in kidney and liver transplantation. Graft failure in kidney transplant patients is usually a function of cardiovascular disease or chronic rejection; whereas, in liver transplant patients, graft loss and patient death is often related to recurrence of primary disease, renal failure, infections and cardiovascular disease. For these reasons, long-term immunosuppressive strategies in kidney versus liver transplant patients are very different. In general, liver transplant recipients usually can tolerate a more rapid and pronounced withdrawal of immunosuppression. This may include withdrawal of corticosteroids within 3 to 6 months post-transplant and withdrawal of antimetabolites within 6 to 12 months post-transplant. Long-term, liver transplant recipients often are receiving a calcineurin inhibitor as their sole immunosuppressant. Kidney transplant recipients, on the other hand, usually require a longer taper of their immunosuppression. Often, they must be maintained on a 2 or 3 drug regimen. Each transplant center usually develops protocols which give guidelines on specific immunosuppressive use and withdrawal strategies. The pharmacist should know these protocols. Table 1 gives some general guidelines concerning long-term monitoring, adverse effects and strategies for specific immunosuppressives.

Scheduled monitoring of transplant patients is a very important part of their care. Table 2 gives an example of a specific monitoring schedule for transplant patients. Some patients require more frequent and intense monitoring if they develop complications such as rejection, infection, or adverse drug events. For more information about specific immunosuppressant monitoring criteria please refer to Table 1 and Module 5. It is also important to insure that transplant patients are aware of the importance of self-monitoring. Patients are usually educated on how to monitor their blood pressures, weights, intakes and outputs, temperatures, calorie intake and blood glucoses when necessary. This information is recorded in a patient diary for clinicians to review during routine clinic visits. It is important for transplant patients to understand what signs and symptoms might suggest a problem that needs further investigation, such as fevers, nausea, vomitting, diarrhea, pain, decreased urinary output, rapid weight gain or loss, uncontrolled blood pressures or uncontrolled blood glucoses.

INFECTIONS

Infection is one of the most common life-threatening complications of long-term immunosuppressive therapy. A patient's risk of developing infection is based upon two factors; the degree of exposure to given pathogens and the overall level of immunosuppression. Once a patient leaves the hospital, their exposure to virulent pathogens is decreased and therefore they are at lower risk of developing infections. However, a number of pathogens are ubiquitous in nature, and are therefore, more apt to cause infections in immunosuppressed patients. These include bacteria, viruses, and fungus.

Transplant patients are at highest risk for developing certain types of infections based upon time from their transplant. In the first month post-transplant (usually while in the hospital and shortly thereafter), the most common occurring infections include nosocomial bacterial and fungal infections of the surgical wound, lungs, urinary tract, and vascular access devices. These infections are not unlike the ones seen in nonimmunosuppressed surgical patients.

During the period between 1 month and 6 months post-transplant, immunomodulating viruses such as cytomegalovirus (CMV), epstein-barr virus (EBV), herpes simplex virus (HSV), hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) commonly recur in pre-exposed patients. CMV is a common and potentially devastating viral infection in transplant recipients and will be discussed in further detail. Opportunistic infections caused by pathogens such as pneumocystis carinii, asperigillus, and listeria become more prevalent. It is during this period that prophylactic antimicrobial use is critical to prevent these potentially fatal infections. Table 3 presents information on specific types of infections, the causative pathogens, most common symptoms seen, suggested prophylactic regimens for prevention, and treatment options.

Once a patient is greater than six months from their transplant, infections can be divided into one of three categories to determine their infection risks. Most patients (>80%) have good graft function and are being maintained on minimal amounts of immunosuppression. This group of patients has similar infection problems to those of the general public. These include intestinal and respiratory viruses as well as community bacterial pneumonias. Opportunistic infections are rare in this group unless the transplant patient has been exposed to a particularly virulent pathogen. The second group of transplant patients (10%) goes on to develop chronic infections with certain viruses, such as CMV, EBV, HBV, HCV. These viruses can cause significant morbidity including end-organ damage. Chronic long-term antiviral therapy is often employed in this setting. The remaining group of patients develops recurrent acute rejections or chronic rejection, which results in the patients being exposed to larger amounts of immunosupprression. These are the patients that often develop chronic viral infections and are at an increased risk for developing chronic opportunistic infections from pneumocystic carinii, listeria, nocardia, cryptococcus, and asperigillus. Often, this group of patients requires lifelong antibiotic and/or antifungal prophylaxis.

CMV is the most common and most important post-transplant infection. The disease usually presents within 1 to 6 months after transplantation. It is a ubiquitous virus belonging to the herpes family. The virus can potentiate the risk for developing both bacterial and fungal infections. CMV is also associated with chronic injury to the transplanted organ( chronic arteriopathy of the kidney, vanishing bile ducts of the liver). CMV infection in transplant recipients usually originates from an antibody seropositive donor organ, reactivation of latent viruses due to immunosuppression, or blood products from seropositive donors. Transmission of CMV from an antibody positive donor to an antibody negative recipient leads to an 80% to 100% infection rate and a 40% to 50% clinical disease rate; a positive donor to a positive recipient leads to a 40% to 60% reactivation rate and a 20% to 30% disease rate; a negative donor to a negative recipient leads to a 0% to 5% infection rate. Transplant patients at highest risk for developing the disease are ones who have or are:

  • Serologically donor +/recipient – at the time of transplant
  • Elderly
  • Received large amounts of perioperative blood transfusions
  • Received antilymphocyte antibodies (OKT3, Thymoglobulin, or Atgam),
  • Received a retransplant due to acute rejection
  • Receiving larger amounts of immunosuppression.

Diagnosis of CMV is based upon both clinical and laboratory findings. Serological diagnosis is based upon positive antibody seroconversion from a previously seronegative person or a greater than, or equal to, fourfold increase in antibody titers in a previously seropositive person. CMV may be detected by culturing body fluids, such as bronchoalveolar lavage, urine, blood, and tissue biopsy. CMV is contained within the host's white blood cells, which appear to have large intranuclear inclusion bodies. However, identification of virus in the blood (antigenemia) or positive antibody seroconversion is not diagnostic for active disease without clinical signs and symptoms. Table 3 contains the most common signs and symptoms seen with CMV disease.

Intravenous ganciclovir is the first-line agent used for the treatment of CMV disease in solid organ transplant patients. Foscarnet is considered a second-line agent due to the severe toxicities that may develop with its use. Additionally, CMV hyperimmune globulin, nonspecific immunoglobulins and have been utilized in combination with antivirals for refractory cases.

Prevention of CMV using antiviral prophylaxis is desirable. The ideal prophylactic regimen has not been determined. Most transplant centers have protocols specifying which patients should receive prophylaxis and which agent to use. Commonly used regimens include the use of oral and intravenous ganciclovir, oral acyclovir, and intravenous CMV hyperimmune globulin. Prophylaxis is usually continued for the first 3 to 4 months post-transplant. Table 3 contains more specific information regarding the dosing and monitoring of these agents.

Because prophylactic therapy is not always effective and expensive, preemptive therapy has been used to try and prevent CMV disease. The technique involves withholding prophylactic therapy and monitoring laboratory tests to identify presymptomatic CMV viremia. CMV antigenemia may be the best predictor of clinical CMV disease when compared to polymerase chain reaction (PCR), serology, and shell viral assay. Once a patient develops viremia, they will usually receive treatment with intravenous ganciclovir. There is a lack of uniformity on who should receive this therapy and when treatment should be initiated.

OSTEOPOROSIS

Osteoporosis is a long-term complication associated with organ transplantation. The most critical period of bone loss appears to be the first 6 months post-transplant. A transplant patient's risks for developing osteoporosis can be separated into two categories. The first being the risk factors seen in the general population, such as menopause (women), family history, small frame, smoking, alcohol and caffeine consumption, sedentary lifestyle, and lack of calcium intake. The second category includes the risk factors that are unique to transplant patients, which are their pre-transplant underlying disease states (such as end-stage kidney and liver disease) and immunosuppressants.

Glucocorticoids inhibit calcium absorption from the GI tract, induce urinary calcium loss, inhibit bone formation and accelerate bone resorption. Cyclosporine and tacrolimus increase bone resorption, leading to bone loss. When a calcineurin inhibitor is used in combination with glucocorticoids, the effects on bone are more pronounced then when either agent is used alone. These effects are dose and duration dependent. Therefore, early and rapid taper of the immunosuppression is an important strategy to help minimize bone loss during the first 3 to 6 months post-transplant.

Preexisting osteomalacia is almost always present in patients undergoing kidney and liver transplantation. In renal disease, this is usually a function of this kidney's inability to produce 1,25-dihydroxyvitamin D3. This, in turn, leads to hyperparathyroidism and bone loss. In liver disease, the bone loss is usually more pronounced and due to factors such as altered vitamin D metabolism, malabsorption of calcium, alcoholism, poor nutrition, and hypogonadism.

All transplant patients should receive a thorough pre-transplant evaluation to determine their risk of developing osteoporosis. This should include a complete history to assess and minimize modifiable risk factors, dual-energy x-ray absorptiometry (DEXA) to assess bone density, and blood and urine laboratory tests to identify and correct metabolic and secondary causes of bone loss. In addition, these tests should be maintained post-transplant (every 6 months for the first 18 months post-transplant, then once yearly).

Preventive therapy should be considered in every transplant patient. Similar to the general population, once a transplant patient develops osteoporosis, effective treatment approaches are difficult to determine. This is due to the lack of well conducted, prospective controlled trials in the transplant population. Current treatment options include, but are not limited to the use of calcitonin, bisphosphonates and hormonal replacement. Alendronate and risedronate are indicated for corticosteroid induced osteoporosis. The use of agents such as raloxifene and fluoride are controversial. Calcium and vitamin D supplementation is recommended in all patients receiving corticosteroids and osteopenic and osteoporotic transplant patients. Table 4 lists more specific information about the prevention and management of osteoporosis in transplantation.

DIABETES

Post-transplant diabetes mellitus (PTDM) is another complication. There is a growing body of evidence that links hyperinsulinemia and hyperglycemia with an increased risk of developing atherosclerosis and cardiovascular disease. Cardiovascular disease, especially in kidney transplant patients, is now the leading cause of death among long-term transplant recipients. It is therefore extremely important to identify and effectively treat PTDM.

Currently, there is no consensus on the definition of PTDM. Some clinicians recommend looking solely at fasting blood sugars (FBS's) on 3 separate occasions, while others advocate the use of oral glucose tolerance tests (OGTT) in addition to FBS's, while still others suggest the additional use of serial HbA1C concentrations. One recently proposed definition is a blood glucose of >400 mg/dl at any one point, or >200 mg/dl for more than 2 weeks, or the need for insulin treatment for at least 2 weeks. This, along with the use of serial measurements of HbA1C, should form the basis for diagnosing PTDM. Based on the varying methods of defining and identifying PTDM, the incidence has been reported to be between 4% and 20%.

Recognition, prevention, and treatment of PTDM is a very important aspect of a transplant patient's long-term care. It is important to insure that every transplant patient is pre-screened for potential risk factors for developing PTDM. Risk factors that have been identified include impaired OGTT, impaired C-peptide secretion, and African-American or Saudi Arabian ethnicity. Additionally, any patients that have risk factors for developing type II diabetes mellitus are at higher risk for developing PTDM. Some of the immunosuppressives utilized in transplantation are a major factor in developing PTDM. Genetic predisposition may also be important. Corticosteroids likely decrease the number and affinity of insulin receptors, impair glucose uptake in the musculature, impair insulin production, and impede the activation of the glucose/FFA cycle. Corticosteroids also induce insulin resistance. Cyclosporine and tacrolimus are postulated to cause the inhibition of specific cellular proteins, resulting in the decreased production of insulin from beta cells in the pancreas. This effect appears to be dose dependent. Although initially this may be reversible, long-term use of cyclosporine or tacrolimus may cause irreversible damage to the beta cells. There is a controversy over which agent is more diabetogenic, cyclosporine or tacrolimus. It appears from clinical trials that the increased potency of tacrolimus may induce a more pronounced impairment of insulin production and secretion when compared to cyclosporine. However, this may be offset by steroid sparing effects of tacrolimus based immunosuppressant regimens. Sirolimus or mycophenolate mofetil are not associated with PTDM.

Since calcineurin inhibitor and corticosteroid dose and duration are significant factors associated with PTDM, most strategies center around reducing or altering immunosuppressant regimens in patients identified to be at risk for developing this complication. Commonly, rapid tapering of corticosteroids is suggested. The ultimate goal in this strategy is early discontinuation of the corticosteroid. Unfortunately, this may not be possible in patients who have or are at high risk for having acute cellular rejection. By utilizing one of the newer immunosuppressants, such as mycophenolate mofetil or sirolimus, it may be feasible to remove or reduce the dose of the diabetogenic immunosuppressants. Regardless, if a patient is known to have, or is at high risk for developing PTDM, close monitoring of blood glucose and HbA1C is warranted. Additionally, it is especially important in this population to educate and attempt to reduce other known cardiovascular risk factors, such as hypertension, smoking, dyslipidemia, and obesity.

The treatment of PTDM is similar to the treatment of type II diabetes mellitus, with certain exceptions. Although some patients can be controlled on oral sulfonylureas, most patients will require exogenous insulin. In theory, agents such as metformin, rosiglitazone, and pioglitazone would be beneficial in this population due to their postulated mechanisms of action. However, extreme caution should be used when initiating any of these agents based upon their relative contraindications (renal dysfunction) and potential side effects (hepatotoxicity). A PTDM patient should be educated on the same issues as a DM patient, including proper hyper and hypoglycemic monitoring, diet, foot and eye care, and cardiovascular risk reductions. Be aware that it may be possible to discontinue antihyperglycemic therapy once a patient's immunosuppressive regimen is altered or reduced.

Malignancy

Although malignancies following transplantation are rare, compared to the general population, a transplant patient is 20 to 50 times more likely to develop a malignancy. The most common types of cancers that develop in this population include squamous cell carcinomas of the skin, non-Hodgkin's lymphomas, Kaposi's sarcoma, in situ carcinomas of the uterine cervix, carcinomas of the vulva and perineum, hepatobiliary carcinomas, and a variety of sarcomas. The overall incidence of cancer is approximately 6% in this population, with the average age of these patients being fairly young, at 42 years. The two most common types of tumors in transplant patients are cancers of the skin and lips and non-Hodgkin's lymphoma. The scope of this discussion will be limited to these two cancers.

Skin and lip cancers account for roughly 37% of all cancers seen in transplant patients. There is a 7 to 21-fold increase in incidence when compared to the general population, depending on the amount of sun exposure. This risk increases with time after transplant, and is as high as a 54% incidence at 20 years post-transplant. Unfortunately, when these cancers do develop in transplant patients, they are usually more aggressive and metastasize earlier. This is why it is extremely important to counsel transplant patients on the avoidance of sun exposure and the copious use of sunscreens or protective clothing (brimmed hats or sun visors). This is especially the case in individuals who may be at higher risk due to their characteristical traits (blond or red hair, fair skin, and blue eyes). All transplant patients should be examined on a regular basis for identification and removal of any premalignant skin lesions. Treatment options for skin cancers include surgical excision, topical 5-fluorouracil, cryosurgery, or radiotherapy. For patients with malignancy, withdrawal or lowering the level of immunosuppression is important.

The second most common cancer experienced by transplant recipients is non-Hodgkin's lymphoma (NHL), also referred to as post-transplant lymphoproliferative disease (PTLD). The incidence varies greatly, but has been reported to be as high as 5%. There is a 28 to 49-fold increase in developing this cancer in transplant patients compared to the general population. NHL is a morphologically diverse cancer. Timing of the disease can occur anywhere from 1 to greater than 10 years post-transplant. Polyclonal hyperplasia usually appears within the first year of transplantation. Patients may present with fever, pharyngitis and adenopathy. PTLD that presents early post-transplant (within the first year) usually is a less aggressive disease and responds well to reductions in immunosuppression. Conversely, late presenting PTLD often is difficult to treat and does not usually respond well to reductions in immunosuppression. The major risk factor for developing PTLD is the degree of immunosuppression. Additionally, there is a substantially higher incidence of PTLD in pediatric patients who are epstein-barr virus (EBV) antibody negative at the time of transplantation. There is a close association between the development of PTLD and EBV. The development of PTLD from EBV infection follows a stepwise process. This process starts with a primary infection of B-cells by EBV. This progresses into a latent infection. Reactivation of EBV occurs in transplant patients receiving long-term immunosuppression. This eventually leads to malignant B-cells developing by mechanisms that are not fully understood. Management of PTLD is often very difficult, and is complicated by the fact that disease is often diagnosed late and the patients often have poor performance statuses at the time of diagnosis. Initially, reduction in the degree of immunosuppression is attempted. This often produces a good response in patients with less aggressive forms of PTLD. PTLD almost universally responds poorly to chemotherapy. Radiotherapy may increase survival rates in patients with localized disease. Monoclonal antibodies, such as Rituximab, have shown promising results. Currently, it is believed that acyclovir and ganciclovir probably plays a minimal role as a therapeutic option in the treatment or prevention of PTLD. Because treatment options are limited with PTLD, focus should be made on preventing this disease. The rational use of immunosuppressive regimens is an important part of prevention.

CHRONIC REJECTION

Kidney

Although there have been significant reductions in the incidence of acute rejection episodes in the past decade, the incidence of chronic rejection has remained largely unchanged. The definition of chronic rejection is not universal. Most classifications are based on tissue biopsy results, which include interstitial fibrosis and tubular atrophy, while others require the presence of artheriosclerosis in the renal vasculature. Currently, chronic rejection accounts for approximately 15% to 20% of all graft failures. The time it takes to develop chronic rejection is highly variable. Chronic rejection can occur as early as 1 year post-transplant, but is more likely to occur 5 to 10 years post-transplant. Clinical manifestations of chronic rejection include a steady progressive worsening of renal function indicated by increasing serum creatinine concentrations, proteinuria, and arterial hypertension. Urinary protein excretion of 1 to 2 grams per day is highly suggestive of chronic rejection. Early diagnosis is a key to prevention. Diagnosis based on tissue biopsy also helps differentiate between chronic rejection and other problems that may present with the same clinical and laboratory findings, such as acute cellular rejection or calcineurin nephrotoxicity. Many immunologic and nonimmunologic factors have been implicated in increasing the likelihood of developing chronic rejection. Nonimmunologic factors include race, gender, size and match, hypertension, hyperlipidemia, and infection. African-Americans have a higher incidence of graft failure due to chronic rejection. It has also been noted that recipients of organs from non-white male donors have inferior graft survival rates. Hyperlipidemia has been correlated to proteinuria, hypoalbuminemia, and chronic rejection. The fact that certain immunosuppressive agents cause dyslipidemias increases the importance of the recognition and proper treatment of this disorder. Please see Module 3 for more information. Infection with CMV also has been associated with the development of chronic rejection. The most important immunologic factor implicated in the development of chronic rejection is the number of episodes and severity of acute cellular rejection. Therefore, the monitoring and treating of acute rejection is an important preventive measure to reduce the incidence of chronic rejection. Histoincombatibility, insufficient immunosuppression, and the presence of HLA antibodies also have been implicated with chronic rejection.

Pharmacological management and prevention of chronic rejection has been largely unsuccessful. Strategies that have been attempted include the use of induction therapy with anti-lymphocyte antibodies, different and varying degrees of immunosuppressant regimens utilizing cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus, and leflunomide, control of blood pressure and lipids, and dietary supplementation with fish oils. Use of ACE inhibitors or angiotensin receptor blockers may be of some benefit to prevent chronic rejection when used to control blood pressure. The use of statins to control lipids have gained much recognition recently and also may be of some use to prevent chronic rejection. Currently, chronic rejection remains a major problem in renal transplantation.

Liver

Chronic rejection in liver transplantation occurs in less than 5% of recipients. The reasons for this are largely unclear, but a number of hypotheses include the fact that the liver has a large parenchymal cell mass, a large number of passenger leukocytes, express low number of MHC class I and II cells, and has a regenerative capability. Because the liver is basically an immunologic organ capable of producing its own leukocytes, it is theorized that this may cause a mild self-limiting graft-versus-host response, inducing tolerance between the transplanted liver and the host's immune system. Studies have shown that complete removal of immunosuppression can be tolerated in a small number of liver transplant recipients without detrimental consequences. Chronic rejection in liver transplantation can occur early (3 to 6 months post-transplant), or more commonly later (>12 months). Clinically, it usually presents as a moderately slow progressive increase in liver function tests (transaminases and bilirubin) coupled with a decline in the liver's synthetic function capabilities. This can manifest into coagulopathies, portal hypertension, and ascites. Late-stages of chronic rejection may lead to arterial thrombosis.

If chronic rejection does occur, however, it needs to be diagnosed in similar fashion to renal transplant patients. A transplant liver tissue biopsy must be performed for definitive diagnosis. On the tissue biopsy, chronic rejection is diagnosed by the absence of bile ducts in the portal triad. Several studies have shown that conversion from cyclosporine to tacrolimus might be of some benefit in reversing or halting the progression of chronic liver rejection.

RECURRENCE OF DISEASE

Due to the increase in graft and patient survival accomplished in recent years, the recurrence of pre-transplant diseases is a major concern. This includes diseases seen in both renal and liver transplantation. As such, it is very important to develop strategies for early diagnosis and prevention of these recurrences. Recurrence of disease in renal transplant recipients include metabolic disorders, such as glomerulonephritis, diabetes, amyloidosis, oxalosis, cystinosis, Fabry's disease, and sickle cell anemia. Recurrence of diseases in liver transplant recipients is also a major long-term complication. This is especially the case in patients who were transplanted with end-stage liver disease secondary to viral hepatitis. Liver failure due to viral hepatitis is now the leading reason for transplantation. Recurrence of HBV has been substantially reduced (from nearly 100% to 30 - 50%) by use of antiviral agents, such as lamivudine, used in combination with long-term passive immunization with hepatitis B immune globulin. Recurrence of HCV in post-transplant patients is universal. These patients often are receiving lower amounts of immunosuppression in order to attempt to prevent unchecked viral replication. Additionally, studies are currently underway looking at the utility of interferon, ribavirin, and pegylated interferon in the post-transplant hepatitis C positive patient. Nonetheless, currently, HCV recurrence, and subsequent end-stage liver failure and death is a major complication. Other diseases that have been seen to recur in liver transplantation include autoimmune hepatitis, diseases of the biliary tree, and hepatocellular carcinoma.

Immunizations

Although immunization is an important part of infectious disease prevention in the general population, its role in transplant patients has not been well studied. Certainly, all patients awaiting transplant should have their immunizations brought up to date. These include diptheria, tetanus, pertussis, and MMR. Infants should receive H. influenza b vaccination. Additionally, the use of the hepatitis B, pneumoccocal, and influenza vaccinations is generally recommended in patients awaiting transplantation. The use of varicella zoster virus vaccination in pre-transplant pediatric patients is controversial and is not universally recommended.

Most clinicians still recommend using immunizations post-transplant as long as the vaccine does not contain live viruses. A few small studies have shown the effectiveness of diptheria, tetanus, H. influenza, and inactive polio vaccines in post-transplant patients. Influenza also appears to be effective in the post-transplant patient, although response rates are less compared to immunocompetent people. Hepatitis B vaccine produces lower rates of antibody response in transplant patients, so pre-transplant administration of this vaccine series should be stressed. Pneumococcal infections are fairly common post-transplant, so booster vaccinations are recommended. To date, no vaccination study conducted in transplant patients has shown an increase in rejection rates or any other serious side effects, so use of preventative vaccination in the post-transplant population should be advocated.

DRUG INTERACTIONS

As a pharmacist, one of the most important roles in providing pharmaceutical care to transplant recipients is the recognition and prevention of potential serious drug interactions. Three of the major immunosuppressants currently prescribed, cyclosporine, tacrolimus, and sirolimus, are primarily metabolized and eliminated via the cytochrome P450 IIIA4 enzyme system. This means that the transplant patient is at high-risk for being exposed to numerous drug interactions. Before any new drug is prescribed in these patients, it should be scrutinized to determine its potential in effecting the drug metabolism of the immunosuppressants or any other agents the transplant patient is receiving. Use of drugs that inhibit or induce the cytochrome P450 IIIA4 system are not absolutely contraindicated, as this would eliminate a large number of important therapeutic options in these patients. One must be diligent in monitoring for organ function and adverse effects when adding or discontinuing one of these interacting agents. Table 5 lists some of the most commonly encountered drug interactions that may effect transplant patients.

NON-PERSCRIPTION MEDICATIONS

Potential severe consequences may arise with the use of certain over-the-counter (OTC) medications in transplant patients. It is important to educate and monitor these patients closely for non-prescription medication use. In addition to potential drug interactions through the cytochrome P450 IIIA4 enzyme system, non-prescription medication use can often combine with the immunosuppressants to increase the likelihood of developing severe adverse drug reactions, such as nephrotoxicity. This includes the use of very common classes of OTC's, such as NSAIDS, cough and cold products, herbal products, and vitamins. Table 6 lists some of the more common reasons why people seek OTC medications, the non-prescription medications that should be avoided, and recommended alternatives for transplant patients.

With the recent explosion in the use of herbal products has come the increased identification of significant herb-drug interactions. This is a difficult problem to address for a number of reasons. First and most importantly, the experimental data concerning drug-herb interactions is sparse. There is a lack of clinical trials, case reports, and case series reviews. To compound this issue, herbs are unregulated products that can be obtained from a plethora of sources. Additionally, patients often see herbal products not as drugs, eliciting a pharmaceutical response, but rather as a supplement similar to vitamins. This leads to the under reporting of herbal use during patient medication histories. It is therefore our responsibility to review each patient's medication profile to potentially identify and prevent drug-herb interactions. These interactions can be of a pharmacokinetic or pharmacodynamic nature.

St. John's Wort has recently been identified to induce hepatic enzymes, and transplant patients taking this herb have had significant reductions in cyclosporine concentrations, resulting in rejection. The immunostimulating effects of Echinacea, Astragalus, licorice, alfalfa sprouts, and zinc may offset the immunosuppressive effects of the calciineurin inhibitors, antimetabolites, and corticosteroids. Feverfew, garlic, ginger, and Ginkgo all increase the risk of bleeding. Additionally, ginseng should be avoided, as it may increase bleeding and augment the effects of corticosteroids. Guar gum may inhibit or slow the absorption of many agents, including the immunosuppressants. Saiboku-to may increase corticosteroid effects, while sho-salko (both Asian herb mixtures) may have the reverse effect. The use of chili pepper may increase the likelihood of developing ulcers in this population.

In general, herbs should be avoided in this population. If a transplant patient is adamant about taking herbal products, close therapeutic monitoring is required in order to ensure rapid identification and correction of potential drug-herb interactions.

MEDICATION NON-ADHERENCE

Another potential dangerous complication that should not be overlooked in these patients is medication non-adherence. Identifying transplant patients with medication non-adherence difficulties is an important part of their long-term management. Once a transplant patient is identified as being non-compliant with prescribed regimens, it is important to identify and alleviate the secondary causes. Commonly encountered problems include medication cost, complexity of regimen, undesirable side effects, lack of proper education, and patient apathy or psychological difficulties. All of these problems can and must be overcome to help prevent patients from developing major complications from non-adherence, including graft loss and death. For more information about how to educate and alleviate these problems, please refer to Module 7.

DEVELOPMENT OF A PATIENT CARE PLAN

In order for a pharmacist to provide optimal and efficient pharmaceutical care to transplant patients, the development of a well designed care plan is crucial. A formalized pharmaceutical care plan should provide a logical, consistent framework that identifies transplant patient's drug-related problems, develops interventions to resolve or prevent the problems, documents the findings, and measures progress toward desired pharmacotherapeutic outcomes. Although the basic purpose of the pharmaceutical care plan is universal, the specific development of a patient care plan should be based upon the most commonly encountered drug-related problems seen in that particular population. Each pharmacist must develop an outline for their care plan they feel comfortable using. In order to provide optimal pharmaceutical care, the pharmacist should be in close contact with the other health providers caring for transplant patients. The transplant coordinator is usually responsible for maintaining close contact with the patient, and most of the important therapeutic decisions should ultimately be routed through them. This section provides demonstrates how to develop a care plan and utilize it in a efficient manner to expose, correct, document, and bill drug-related transplant issues. It is up to you, as a practicing clinician, to develop and utilize your own care plan specific for your patients and setting.

STEP ONE: DATA COLLECTION

Data collection is a vital part of the patient care plan and provides the information from which the drug-related problems are exposed and corrected. Early post-transplant, patients have frequent and intense monitoring of their vital signs and laboratory values. Much of the therapeutic decision making is based upon accurate collection and assessment of these monitoring parameters. As such, before any drug-related issues are addressed, it is important not only to closely review that particular day's monitoring parameters, but to review past values as well. This will help identify trends in values that may give a better picture of what drug-related problems exist. Any form that is used to collect data should have the ability to contain enough information to identify trends in vital signs and laboratory values.

Forms 1 and 2 provide examples of monitoring sheets that can be used to collect data in a transplant patient. Looking at Form 1, you can see that this is divided into two sections. The top third of the form contains the demographic and pre-transplant information. This information is important to identify pre-transplant conditions and medications that need attention post-transplant. In this example patient, we can see that his past medical history is significant for retinopathy, chronic gastritis, insulin-dependent diabetes mellitus (IDDM), hypertension, and hypothyroidism. These medical conditions must be closely monitored post-transplant because a number of them (specifically retinopathy, hypertension IDDM, and gastritis) may worsen post-transplant due to the long-term side effects of the immunosuppressants.

The bottom third of the form contains tables that can be used to monitor the long-term complications in a transplant patient. By recording each complication in the given table, pharmacists can use this data to expose and correct drug-related issues. For example, by documenting the patient's acute rejection episodes, we will be able to identify patients at risk for the long-term consequences of multiple acute rejections, such as chronic rejection and chronic opportunistic infections. This will allow us to recommend appropriate preventive therapy, such as adjustments in the patient's immunosuppressant regimen and continuation of antibiotic prophylaxis. Another example, would be documentation and treatment of UTI on 9/4/00. Form 2 provides an instrument to collect and review data containing vital signs, laboratory values, immunosuppressant regimens, and cultures. Each time a patient is seen by a pharmacist, they should thoroughly review all of this data. This will allow us to identify trends in these values, and make the appropriate interventions. The data on this form represents a kidney transplant patient who was transplanted on 8/28/00 (see Form 1). Today (9/18/00), you are seeing this patient on his second clinic visit for a standard follow-up appointment. We can see that there has been a downward trend in his white blood cells (WBC) and platelets. Notice if we only reviewed this day’s (9/18/00) values, the WBC and platelets appear to be within normal limits. Only by reviewing the values over the past several visits can we expose this trend. This information will be important when developing our problem list.

Each time a pharmacist sees a patient, they should obtain a detailed medication list. Form 3 provides a sheet that can be used by the pharmacist for each patient encounter. At the top of the form, there is a section to record any subjective data obtained during the patient interview. Referring back to the example patient, on his first clinic visit (9/12/00), he complains of tremors. On his second visit(9/18/00) we can see that he is complaining of cramping, bloating, and diarrhea. This information would be important when assessing the patient's problem list. The pharmacist should obtain an accurate and detailed list of current medications, including drug, dose, frequency, route and refills. It is important not only to review this with the patient, but also to review past appointment drug lists as well. This will expose any changes that were made since the last visit and may additionally identify any inconsistencies between what the patient is listed as taking and what the patient is actually taking. In transplant patients, this is not an uncommon phenomena due to the relative complexity of their drug regimens. Often, simple interventions and corrections of drug regimens can prevent future severe adverse drug reactions.

STEP TWO: DEVELOPMENT OF A DRUG-RELATED PROBLEM LIST

Once you have completed all of the data collection accurately, development of a drug-related problem list is required. This is similar to the differential list of problems a physician may develop, but is specific to drug-related issues. Often it is difficult to simply focus only on drug-related problems in the transplant population because certain diseases may actually cause similar effects as drugs. A problem list should consist of the observations made while reviewing trends in monitoring parameters and should focus on drug-related problems. In our kidney transplant example patient, we discovered and documented several problems (see middle section of form 3). We will use the problem list to develop our recommendations for changes in current therapies, which will be documented in the assessment and plan section on the form.

It is important to address all of the drug-related concerns in your problem list and not to focus in only on the immunosuppression. Often, transplant pharmacists makes important interventions on drugs that may be overlooked because they are not immunosuppressants or transplant related. For instance, if we return to our case, we see that the patient is receiving levothyroxine 100 mcg po qd. On his first visit (9/12/00), he was out of refills, synthroid was renewed and a TSH level was recommended and ordered. On his next clinic visit (9/18/00) his TSH comes back high and further questioning determines that he has not been taking his Synthroid. In addition to this, on 9/12/00 he had an increase in his total cholesterol and HDL for which simvistatin was started.

STEP 3: ASSESSMENT AND PLAN

The assessment and plan is based on the accurate interpretation of the data collection, medications, and the problem list. Although using monitoring sheets can help in efficient and complete data collection, the analysis of this data by the pharmacist is based upon their therapeutic knowledge base and experience. This is something that cannot be conveyed in one or even several modules, but must be learned from practical hands-on experience and guidance. It is important to develop your knowledge base from the evidence based medical literature and through practical experiences over time. When developing your assessments, you should not only list what you believe to be the assessment, but also why you determined this to be the case. This will not only help convey your thoughts to your colleagues, but also help when reviewing your previous notes.

If we return to our example case, we see that on 9/18/00 his WBC and platelet counts have fallen over the past week. This may be a side effect of a number of transplant related medications, most commonly mycophenolate mofetil and ganciclovir. It also may be a symptom of CMV infection or disease. In order to decide which is the most likely cause, the use of other information becomes very important. We can see from the patient's vital signs (see form 2) that he has been afebrile, and from his subjective reports (see top section of form 3), without complaints of malaise and fatigue. This would suggest CMV as the likely cause. Additionally, the patient subjectively complains of nausea and diarrhea (see top section of form 3), two frequently reported side effects of mycophenolate mofetil. However, CMV infection of the gastrointestinal tract may also produce these symptoms. Often, it is difficult to determine the true cause of a given number of symptoms. For this patient, we've recommended decreasing the dose of mycophenolate mofetil (see middle section of form 3).

Your plan should contain the recommended medication changes and future monitoring parameters to ensure appropriate pharmaceutical care. It should be as specific as possible, including new drugs, doses, frequencies, and routes. Monitoring recommendations should include which specific parameters are needed, such as laboratory values, frequency of desired monitoring, and any adjustments that may be necessary based upon the results of the recommended monitoring parameters. The plan should focus on the best way to resolve or prevent any identified drug-related problems that were mentioned in the assessment. New problems should not be addressed here without first being mentioned in the assessment. In our case example, we've recommended decreasing his mycophenolate dose to 500 mg PO bid based upon both subjective and objective data indicating that he is having an adverse drug reaction (see bottom section form 3). In the plan, we have recommended monitoring parameters to insure that our intervention helps alleviate his complaints. Follow-up is a very important part of the development of a patient specific plan.

Please see Form 3 for additional examples of how to address drug-related problems in the assessment and plan.

STEP 4: FOLLOW UP and DOCUMENTATION OF OUTCOMES

As the health care system continues to strive for efficient, cost-containing medical care, it is important, as health care providers, to demonstrate our ability to significantly contribute to developing better outcomes at reduced costs. This is achieved through documentation and appropriate follow-up to drug interventions that were previously addressed and corrected. This can be accomplished by the use of complete pharmaceutical care plans and well maintained notes. Any interventions that were made on previous visits should be addressed at the present patient visit for possible documentation of outcome. For instance, if we again return to our example case, we see a section on the bottom of Form 3 for previous interventions and outcomes. On this patient's first visit (9/12/00), we recommended reducing his tacrolimus dose based upon an increased blood concentration, an increased serum potassium and creatinine, and a subjective complaint of mild tremor indicative of tacrolimus toxicity. On this visit, the patient is no longer complaining of tremor, and his serum potassium and creatinine concentrations have decreased. It is important to document the outcomes of your interventions for several reasons, including the ability to use outcomes for efficient and accurate billing to third party payers.

REIMBURSEMENT

Pharmacists continue to be recognized as important providers of health care. This recognition has occurred primarily on the state and local level with Medicare and some third party payors. This recognition has occurred in the form of changes in pharmacy practice acts in many states, recruitment of and contracting with pharmacists into physician practice groups, Medicare and Medicaid programs which include pharmacists in the care of patients with conditions such as diabetes, asthma, receiving multiple medications, need for immunization to name a few. Despite this progress, there are still a number of payors or other participants in health care delivery system ( physicians and patients) who are unaware of the services that pharmacists can provide. Even on the national level, pharmacists are not officially recognized as "providers". A number of national organizations are attempting to change this problem. Therefore, the pharmacist who seeks reimbursement must have specific plans and goals that can be communicated to payors, healthcare providers and patients and result in improved patient outcomes.

This next section will discuss important issues and provide a template for obtaining reimbursement for pharmaceutical care services for transplant recipients. The attached algorithm ( FIGURE) illustrates what a pharmacist needs to consider in order to navigate the reimbursement process.

The first step would be to obtain a provider number. This is a number that identifies the specific healthcare provider and allows for claims processing. This number must be obtained from each payor that the pharmacist is planning to submit a request for reimbursement. The pharmacist may have to meet certain requirements in order to obtain this number, depending on the payor. These could include type of degree, years of experience, special certification. This information, along with an application should be requested from each payor.

In a hospital setting, the pharmacist would also have to be recognized as a provider. Usually this consist of applying for credentialing and hospital priviledges. The pharmacist would have to submit the appropriate application form, evidence of licensure and liability insurance, a physician letter of support and a list of specific activities and location of where services will be provided (eg. outpatient clinic, inpatient consults).

Another important step, is to develop a data collection and documentation system as illustrated in the previous section. This should include reason for patient encounter and intervention (subjective and objective information), intensity of evaluation (assessment), services provided (plan, followup and outcome) and patient contact time..

Included in this documentation is a record of the patient's insurance information , along with permission (signed) from patient to provide these services. In addition, any services provided should have either a request from the patient's physician or statement indicating that this service is medically neccesary. This must have a physician's signature on either a prescription or order or form letter depending on setting. Once the patient is seen by the pharmacist and a plan is outlined, the pharmacist should provide the physician and patient with a summary of this interaction.

It is important that the pharmacist determine what the overall goals and specific activities will be in attempting to provide services to transplant recipients. Will they focus on patient education regarding drug therapy and/or disease management as well as how often they will see patient. One example would be to spend scheduled time with the patient every 1-3 months depending on outlined plan. The number of reimbursed interactions may be dictated by the third party payor and/or agreed upon with physician or patient. These should be discussed with the patient and their primary healthcare providers( transplant team or primary care physician or specialist).

Once the above steps have been taken, then the process of coding and billing for services should be implemented. The type and amount of reimbursement is dependent on the practice setting, and its relationship to physician care. Medicare is the primary payor for health care in transplant recipients and there are several private payors who administer the Medicare program at the local level. Reimbursement for healthcare providers falls under Medicare part B. In order to submit a claim is it necessary to complete and submit a HCFA 1500 claim( see attached). Another form, called the Pharmacist Care Claim Form(PCCF) should also be completed(see attached). The PCCF was developed by the National Community Pharmacists Association(formerly NARD) and incorporates the coding system developed by the National Council for Prescription Drug Programs. This form is more easily understandable language. Which forms are required depends on the payor. For Medicare claims, the HCFA 1500 is required. For other payors, it may be necessary to complete both forms.

The PCCF is divided in several sections, which use a number of codes. These sections include reasons for services, professional services, recommendations and result of services, the level of service, a section to write a brief and specific interaction and billing codes and fees.

The HCFA 1500 claim form requires a much more involved consideration of diagnosis, type of patient (new or established), where services are provided (office or pharmacy, clinic, hospital, nursing home, etc), the presence or absence of a physician ("incident to"), what level (degree of complexity) of services are provided. One need to be aware of Medicare rules and regulations in order to correctly completes this form. Diagnostic codes are found in the International Classification of Diseases, 9th Revision, and Clinical Modification (ICD-9-CM) code book. This is available from a number of medical publishers and the American Medical Association. Keep in mind that only a physician can make a diagnosis. A diagnosis code is required, but it must be the same diagnosis code used by physician and must be as specific and as closely related to the reason for encounter as possible. Since there is no room on this form for much narrative description of encounter the medical necessity document and/or patient encounter form should be submitted with claim.

Another key step is determining the level of service provided and the appropriate code. This information is specifically defined and found in the Physician's Current Procedural Terminology (CPT) code manual. This can also be obtained from the American Medical Association. This coding is determined by several components, which are referred to as Evaluation/Management (E/M) services. One is the type of patient. Most patient encounters fall under either new or established. Second, is the presence or absence of the physician during the encounter. Third, the history (H) and physical exam (PE). The H & PE are further divided into problem-focused, expanded problem-focused, detailed, and comprehensive. These are based on specific criteria which include history of present illness (HPI), review of systems (ROS) and elements of past history (PMH) each of these categories. Most pharmacist encounters, would generally include a brief HPI, ROS and PMH. (See table for specific codes) in an established patient without a physician.

Another component that must be utilizied is the level of medical decision making. This can range from minimal, straight forward, low complexity, moderate complexity and high complexity. These are based on the number of possible diagnosis and/or management options, amount and/or complexity of data to be reviewed, risk of complications and/or morbidity or mortality. Currently, most pharmacists bill and are reimbursed at either the minimal or straightforward level.

Another component that must be utilizied is the level of medical decision making. This can range from minimal, straight forward, low complexity, moderate complexity and high complexity. These are based on the number of possible diagnosis and/or management options, amount and/or complexity of data to be reviewed, risk of complications and/or morbidity or mortality. Currently, most pharmacists bill and are reimbursed at either the minimal or straightforward level.

Once all documents are submitted for reimbursement, it take several weeks before any claim is paid. These are usually submitted to the medical benefits department, rather than the pharmacy benefits. Follow-up to determine the status of the claim may be necessary. If claim is rejected, then the pharmacist should determine why and how this can be corrected. Keep in mind that not all payor may compensate pharmacists, at least initially. This could be because of its never been done before or lack of understanding of the value of pharmacist services. Materials from a number of organizations( ASHP, AACP, NCPA, NIPCO) may be useful in promoting the value of these services.

In summary, reimbursement for pharmacy services is possible, but requires an understanding of rules and regulations governing provision and documentation of these services. Keep in mind that these can change and can be interpreted differently by local administrators for each payor. The pharmacist should contact the appropriate payors, particulary Medicare, and determine what is needed to become a provider, what are procedures for submitting a claim and under what circumstances and setting( hospital vs freestanding pharmacy or clinic), can they submit claims and what types of claims can be submitted. The success which a pharmacist achieves with this process is not how much compensation is received, generally it is not much, but rather the improvement in patient outcomes and the recognition that pharmacists play a vital role in the care of these patients.