Medication Summary
The goals of pharmacotherapy are to prevent complications, to reduce morbidity, and to reduce the chances for organ rejection. Optimal therapy includes sedation, vasodilator therapy, alkalization through hyperventilation, inotropic agents with minimal pulmonary vasoconstrictive effects, and inhaled nitric oxide, when available. Sildenafil has also been used in this setting.
Vasodilators
Class Summary
These agents relax blood vessels and cause a decrease peripheral vascular resistance.
Sodium nitroprusside (Nitropress)
Sodium nitroprusside produces vasodilation and increases inotropic activity of the heart.
Nitroglycerin (Nitro-Bid, Nitro-Dur, Minitran)
Nitroglycerin causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate (cGMP) production, resulting in a decrease in blood pressure.
Amlodipine (Norvasc)
For post-transplant hypertension
Hydralazine
For post-transplant hypertension
Inotropic Agents
Class Summary
After the procedure, the patient is maintained on a combination of pressor agents while the donor heart regains energy stores. Once stabilized, the patient is rapidly weaned from the ventilator and the pressors. The chosen combination depends on the training and experience of the transplantation center.
Dopamine
Dopamine is a naturally occurring endogenous catecholamine that stimulates beta1-and alpha1-adrenergic and dopaminergic receptors in a dose-dependent fashion. It stimulates release of norepinephrine.
In low doses (2-5 μg/kg/min), dopamine acts on dopaminergic receptors in renal and splanchnic vascular beds, causing vasodilatation in these beds. In midrange doses (5-15 μg/kg/min), it acts on beta-adrenergic receptors to increase heart rate and contractility. In high doses (15-20 μg/kg/min), it acts on alpha-adrenergic receptors to increase systemic vascular resistance and raise blood pressure.
Dobutamine
Dobutamine is a sympathomimetic amine with stronger beta than alpha effects. It increases the inotropic state. Vasopressors augment the coronary and cerebral blood flow during the low-flow state associated with severe hypotension.
Dopamine and dobutamine are the drugs of choice to improve cardiac contractility, with dopamine the preferred agent in hypotensive patients. Higher dosages may cause an increase in heart rate, exacerbating myocardial ischemia.
Epinephrine (Adrenalin)
Its alpha-agonist effects include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Its beta2-agonist effects include bronchodilation, chronotropic cardiac activity, and positive inotropic effects.
Norepinephrine (Levophed)
Norepinephrine stimulates beta1- and alpha-adrenergic receptors, increasing cardiac muscle contractility and heart rate, as well as vasoconstriction; this results in systemic blood pressure and coronary blood flow increases. After obtaining a response, the rate of flow should be adjusted and maintained at a low-normal blood pressure, such as 80-100 mm Hg systolic, sufficient to perfuse vital organs.
Milrinone
Phosphodiesterase III Inhibitor, which lead to improved cardiac contractility and relaxation, along with reduction of systemic and pulmonary vascular resistances. It is used to treat post-operative low-cardiac output and ventricular dysfunction.
Pulmonary Vasodilators
Class Summary
Inhaled nitric oxide (NO) is a pulmonary vasodilator indicated for pulmonary hypertension. NO is also being studied for severe hypoxemia in acute respiratory distress syndrome (ARDS).
Nitric oxide, inhaled (INOmax)
NO is produced endogenously from the action of the enzyme NO synthetase on arginine. It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine monophosphate (cGMP), which then leads to vasodilation. When inhaled, NO decreases pulmonary vascular resistance and improves lung blood flow.
Sildenafil (Revatio)
Sildenafil promotes selective smooth muscle relaxation in lung vasculature, possibly by inhibiting PDE5. This results in a subsequent reduction of blood pressure in pulmonary arteries and an increase in cardiac output.
Immunosuppressants
Class Summary
A number of protocols exist for immunosuppression in the perioperative and postoperative period. The most appropriate initial immunosuppression protocol is not known. Every transplantation center likely has a different protocol. Clear data are difficult to obtain because of the small number of transplantations performed each year and the need for centers to standardize practice across institutions. Below are the immunosuppressants used at Loma Linda University Children’s Hospital.
Cyclosporine (Neoral, Sandimmune, GENGRAF)
Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for various organs.
For children and adults, base dosing on ideal body weight. Maintaining appropriate levels of the drug in the bloodstream is crucial to the maintenance of the allograft. Foods can alter the level of the drug and time of administration. Medication must be taken at the same time every day.
Neoral is the capsular form of cyclosporine, available in 25- and 100-mg capsules. Sandimmune is the liquid form. GENGRAF is the branded generic form, available in 25- and 100-mg capsules.
Cyclosporine is begun at 0.1 mg/kg/h IV when the donor is identified, stopped during the procedure, and restarted after transplantation; this is switched to oral dosing when possible, with a target trough cyclosporine level of 200-250 ng/mL
Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol)
Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
At Loma Linda, acute rejection is treated with IV methylprednisolone at 20 mg/kg (not to exceed a dose of 500 mg) twice daily for 8 doses. Uncomplicated rejection diagnosed on the basis of biopsy findings alone may be treated with oral prednisone at 2 mg/kg/day for 3 days, with a taper to zero over 3 weeks.
Mycophenolate mofetil (CellCept, Myfortic)
Mycophenolate mofetil, a derivative of mycophenolic acid (MPA), blocks the de novo pathway of guanosine nucleotide synthesis by inhibiting the activity of inosine monophosphate dehydrogenase and thus inhibiting de novo purine synthesis. Both T and B lymphocytes are highly dependent on the de novo pathway, whereas other cells use the purine salvage pathway of nucleotide synthesis. As a result, MPA selectively inhibits lymphocyte activity. It was approved by the FDA for prophylaxis of organ rejection in combination with other immunosuppressive drugs in children aged 3 months and older who are receiving allogeneic heart transplants.
Dosage regimens vary by institutional protocol. At Loma Linda, mycophenolate mofetil is given as part of the primary immunosuppression regimen. Dosing begins at 300 mg/m2/day or 40 mg/kg/day divided into 2 doses and is increased as tolerated to maintain a mycophenolic acid level of 2-5 µg/mL
Mycophenolate mofetil is administered IV or orally at 500 mg/m2 or 20 mg/kg twice daily; dosing is adjusted as necessary to maintain a mycophenolate mofetil level of 2-5 µg/mL and a white blood cell (WBC) count of at least 4 × 109/L
Prednisone
Prednisone is an immunosuppressant used for treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It is an oral steroid with approximately 5 times the potency of endogenous steroids. Minimal to no oral prednisone should be given for the first 21 days after transplantation unless rejection occurs.
Programs that use steroids typically start with oral prednisone at a dosage of 2 mg/kg/day and then wean over the first 3 months to a maintenance regimen of 0.1-0.3 mg/kg once daily or once every other day.
Tacrolimus (Prograf)
Tacrolimus suppresses humoral immunity (T-cell activity). It is a calcineurin inhibitor with 2-3 times the potency of cyclosporine. Tacrolimus can be used at lower doses than cyclosporine, but it has severe adverse effects, including renal dysfunction, diabetes, and pancreatitis. Levels are adjusted according to renal function, hepatic function, and adverse effects.
In children, tacrolimus bioavailability is about 31%, though whole-blood concentrations in a study of 31 children younger than 12 years indicate that children require higher doses than adults to achieve similar trough concentrations. A high-fat meal reduces the mean area under the curve (AUC) by 37%, whereas a high-carbohydrate meal decreases the mean AUC by 28%. Peak concentrations are also reduced by 77% and 65%, respectively.
Tacrolimus is not commercially available as a liquid preparation; the solution must be compounded in a local pharmacy.
Azathioprine (Imuran, Azasan)
Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease the proliferation of immune cells, which results in lower autoimmune activity. Antimetabolites are used to block the uptake of vital nutrients needed by the cells. As implied, these drugs affect not only the cells of the immune system but also other cells of the body. The potency of therapy is dose dependent. Azathioprine is not effective treatment for acute rejection episodes but remains an economical choice for long-term immunosuppression.
Among the antiproliferative agents, azathioprine has been the therapeutic mainstay. According to the ISHLT, however, mycophenolate mofetil is now used in approximately 60% of pediatric patients who receive a heart transplant. Again, no prospective studies are available.
Sirolimus (Rapamune)
Sirolimus, also known as rapamycin, is a macrocyclic lactone produced by Streptomyces hygroscopicus. It is a potent immunosuppressant that inhibits T-cell activation and proliferation by a mechanism that is distinct from that of all other immunosuppressants. This inhibition suppresses cytokine-driven T-cell proliferation by inhibiting progression from the G1 phase to the S phase in the cell cycle.
Sirolimus is a newer agent that works synergistically with calcineurin inhibitors. There is little published experience with this agent in pediatric heart transplantation, but what is available seems to indicate some usefulness in the management of rejection, renal dysfunction, and calcineurin adverse effects.
Everolimus (Afinitor, Afinitor Disperz, Zortress)
Everolimus is an mTOR inhibitor, which inhibits the mammalian target of Rapa. Transition to an mTORi has been shown to reduce allograft vasculopathy and renal dysfunction, but has not yet been studied in children.
An initial dose of 0.25 - 1.5 mg is given twice daily and titrate to target a trough level of 5-8 ng/mL in the first year post-transplant and 3-5 ng/mL after the first post-transplant year.
Lymphocyte immune globulin, equine (Atgam)
This agent inhibits the cell-mediated immune response by altering T-cell function or by eliminating antigen-reactive cells.
There is little prospective, randomized data to suggest a single schedule that is superior, but experience suggests that a short infusion is best tolerated.
At Loma Linda, antithymocyte globulin 1.5 mg/kg/day is administered by slow IV administration over 6 hours. This dosage is continued for 7-10 days. A lymphocyte profile should be obtained on day 3, with a target absolute CD3 count of less than 200 cells/mL. The use of high-dose IV immunoglobulin in the treatment of graft rejection may be beneficial.
Immune Globulins
Class Summary
Intravenous immunoglobulin (IVIG) is the usual choice. It is derived from human plasma and is composed of all 4 immunoglobulin G (IgG) subclasses.
Intravenous immunoglobulin (IVIG; Carimune Gammagard S/D, Gamunex-C, Octagam)
IVIG uses anti-idiotypic antibodies to neutralize circulating myelin antibodies. IVIG down-regulates proinflammatory cytokines, including interferon-gamma. It blocks Fc receptors on macrophages, suppresses inducer T cells and B cells, and augments suppressor T cells. In addition, IVIG blocks the complement cascade, promotes remyelination, and may increase cerebrospinal fluid (CSF) IgG (10%).
Antifungals, Topical
Nystatin topical (Mycostatin topical, Pediaderm AF, PediDri)
To prevent post-transplant candidiasis.
Antivirals, CMV
Valganciclovir (Valcyte)
For prevention and treatment of post-transplant CMV and EBV infection.
Antibiotic
Antiplatelet Agents, Cardiovascular
Alkalinizing Agents
Electrolytes
Magnesium oxide (Mag-Caps, Mag-Ox 400, Uro-Mag)
Magnesium hydroxide (Milk of Magnesia)
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View of the recipient's chest after the heart is removed, with the patient on cardiopulmonary bypass.
