teaser
Successful paediatric lung transplantation relies on the coordinated efforts of a multidisciplinary team. The clinical pharmacist’s input is essential in managing the complex drug therapy required
Anna Carollo*
Silvana Bavetta*
Piera Polidori*
*Clinical pharmacist, ISMETT, Palermo, Italy
Special thanks to:
F Venuti*, R Di Stefano*
A Provenzani*, MG Sidoti*, V Zampardi*
C Patella*, I Casucci*
*Clinical pharmacist, ISMETT, Palermo, Italy
In 1983 Cooper performed the first ever single lung transplant on a patient affected by pulmonary fibrosis; in 1990 the first ever bilateral transplant was attempted, with a much better prognosis of survival than single lung transplantation.[1] To date, although the techniques have improved greatly, the proper therapeutic management of lung recipients through a multidisciplinary approach is just as important.
Lung transplant recipients have a wide variety and increasing number of underlying disorders, but in paediatric recipients, cystic fibrosis and primary pulmonary hypertension remain the two most common disorders for which lung transplantation is performed.[2]
The expectation of a poor outcome for medical reasons is the major contraindication to listing for lung transplant. Although some contraindications are relative and not absolute, some are clearly absolute such as HIV and Hepatitis B infection and active mycobacterium (M) tuberculosis.
Furthermore, these patients experience other complications while waiting for organ availability including respiratory failure, bronchiectases, infections, Malnutrition/malabsorption.
It is necessary to adopt a multidisciplinary approach enabling the direct intervention of the pharmacist during every phase of transplant, given that these patients are more at risk of transplant failure due to their age and ongoing pathologies.
There are three phases in which the pharmacist performs his/her unique function: pre-transplant, transplant and post-transplant.
[[HPE51.60]]
Pre-transplant phase
The patient is referred to the outpatient clinic of a pneumology or paediatric operative unit for assessment in order to ascertain the:
- Mandatory prerequisites for lung transplant.
- Possible contraindications – through a screening process based on laboratory tests and physical measurements.
This phase also includes clinical observation of the patient enrolled on the waiting list as per standard protocols. During this phase, accurate control of patient’s home treatment and a good assessment of the patient’s nutritional status and diet are both important.
The diet must be high in calories, very rich in salts, and high in key vitamins such as A, D, E and K. In the presence of cystic fibrosis, it is necessary to administer pancreatic enzymes. If possible, one third of these enzymes should be administered before meals, one third during the meal and one third at the end of the meal. As regards breastfeeding infants, the capsules should be opened and the granules mixed with the milk: they must not be pulverised as they are gastro-protected and, if crushed, do not work properly.[3]
In order to obtain a good lung transplant outcome in patients with end-stage diseases, they need to be in the ‘transplant window’, ie, the time in which the disease process is advanced but the patient is stable and well enough to survive the waiting time and the transplant procedure. This will vary according to the disease process and the individual patient.
All cystic fibrosis patients have chronic respiratory tract colonisation, and are at high risk of chronic lung infections.
Infections are a common issue related to respiratory tract colonisation, and pan-resistant organisms have become an increasing problem with greater antibiotic exposure.
Antibiotic therapy is mainly administered intravenously; oral and aerosol administrations are available as well. Antibiotic dosages for paediatric patients are generally higher than normal dosages, particularly for patients with cystic fibrosis, and the therapy must last at least 14 days for it to be effective. Antibiotics must be used in patients with symptoms of infection with pathogenic bacteria in the respiratory tract, supported by cultures and antibiograms. Penicillinase-resistant agents (ie, cloxacillin, oxacillin, minocycline) or cephalosporins are the drugs of choice against Staphylococcus aureus. Erythromycin, amoxicillin-clavulanate, ampicillin, tetracyclines, trimetoprim-sulphametoxazole or, at times, chloramphenicol may be used alone or combined for the prolonged treatment (administered in an outpatient regimen) of respiratory diseases caused by different microorganisms. Ciprofloxacin is effective against sensitive strains of pseudomonas. For severe pulmonary relapses, especially as regards patients colonised with pseudomonas, the parenteral administration of the antibiotic therapy is recommended; this often requires hospitalisation, but the therapy may also be administered at home to a group of carefully selected patients. An aminoglycoside (tobramycin, gentamicin) is generally given together with intravenous anti-pseudomonal penicillin. Intravenous administration of cephalosporins and monobactam antibiotics with anti-pseudomonal activity may also be useful. The pharmacist monitors the blood concentration of aminoglycosides and modifies dosages with the physician in order to achieve adequate blood levels.[4]
Aerosol therapy[5] is much used to reduce the side effects of systemic drugs and to deliver drugs in high concentrations directly to the lungs; furthermore, the inhalation route offers other benefits as it facilitates the management of home therapy hence improving the patients’ quality of life (see Box 2).
[[HPE51.61]]
Transplant phase
This phase starts when a potential donor becomes available and the most suitable patient among those on the waiting list is contacted; the phase encompasses the surgical intervention, and ends with post-op intensive care.
During this phase, the pharmacist is present before and during the overall surgical procedure.
The pharmacist verifies the appropriateness of medical drug prescriptions and their compliance with current protocols and, should they not, alerts the physician. The pharmacist also verifies drug or food allergies, if any, and makes sure there are no interactions.
Recipients receive perioperative antibiotics, which – in the case of patients with cystic fibrosis – is appropriate for their specific microbiologic profile.
Patients with pulmonary hypertension who are on prostaglandin I2 (PGI2) prior to transplant stay on this medication in the post transplant phase instead of changing to PGE1, and are then weaned off PGI2 over several days.
Nitric oxide supplementation influences vascular permeability and endothelial cell-leukocyte interactions, improves the matching of ventilation and shortens the duration of lung perfusion of postoperative mechanical ventilation.[6] The pharmacist manages the nitric oxide and verifies the completeness of the documentation relating to the consumption of the drug. The pharmacist is responsible for the sterile preparation of the drugs required for transplant including immunosuppressants, antibiotics, vasopressors, and emergency preparations in syringes.
Compared to other solid organs, lung transplant appears to have a higher propensity for graft rejection, so the levels of immunosuppressive agents are generally kept relatively high. The first-line regimen consists of a triple immunosuppressive therapy with tacrolimus, mycophenolate mofetil and steroids.
Routine haematologic, biochemical and drug level analyses are performed and medication adjustments are made accordingly.
Based on medical orders, the pharmacist attends to aggressive nutritional support by TPN formulations, and recommends enteral nutrition as necessary.
Post-transplant phase
This phase encompasses ICU and post-ICU care as well as long-term post-discharge care.
Post-lung transplant complications can be immediate, early and late (see Box 3).[7]
[[HPE51.62]]
An important consideration in children with end-stage pulmonary disease is growth inhibition, which is one of the side effects of the combination of immunosuppressive drugs, particularly steroids, administered after lung transplantation.
During the patient’s hospital stay, the clinical pharmacist must particularly monitor the pharmacological therapies related to:
- Antiviral, antibiotics and antifungal drugs.
- Inhalation therapies (antibiotics, antisecretory drugs).
- Immunosuppression.
- Control of fluid intake (drug concentration).
- (Enteral and parenteral) nutrition and vitamin absorption.
- Pancrelipase enzymes.
- Evacuant enemas.
Antibiotic therapies must be specific to the organisms isolated in bronchial secretions; therefore it is necessary to perform a rapid culture by collecting the secretions with a pharyngeal swab or through direct aspiration.
Infection plays a significant role throughout the post-transplant course.
The most significant infections seen in the first several weeks following transplant include cytomegalovirus (CMV), especially in recipients who were CMV-negative and received lungs from a CMV-positive recipient, and bacterial lower respiratory tract infection. The approach to prophylaxis and treatment of CMV is with intravenous ganciclovir for four to six weeks following transplant. The ganciclovir injection is prepared by the pharmacist under the vertical hood, and labelled properly.[8]
The antibiotic therapy is mainly administered intravenously; oral and aerosol administrations are available as well, as already described in the pre-transplant phase.
Oral corticosteroids are indicated for breastfeeding children affected by extended forms of bronchiolitis, and for patients with refractory bronchospasm, allergic bronchopulmonary aspergillosis, and inflammatory complications (ie, arthritis and vasculitis). The long-term adoption of a corticosteroid therapy administered every other day may slow down the deterioration of pulmonary functions; however, due to complications associated with the use of steroids, it is not recommended as a routine therapy. Patients receiving corticosteroids must be carefully monitored for possible alterations of the glucose metabolism and growth inhibition.[9]
Tacrolimus, ciclosporin, sirolimus, and mycophenolate immunosuppression therapies are administered to children in liquid oral formulations, prepared in individual doses by the pharmacy service.
As regards patients with cystic fibrosis, the inhalation formulation is being evaluated as in other countries of the European Community.[10]
It is very important to educate parents on the proper management of their children’s post-transplant therapies; for this reason, patients are sent home with a manual on the management of transplant recipients. The manual also includes specific sections on how to attend to the cleanliness of the patients and their surgical wounds, and on nutrition, physical activity, check-ups and pharmacological therapies. Additionally, the pharmacist participates in educating the patients’ parents through counselling on various topics and aspects of drug therapy in order to increase therapy adherence. This is particularly important for immunosuppressants, nutrition, pancreatic enzymes, and antibiotic and inhalation therapies.
Conclusion
The successful prevention and treatment of lung graft dysfunction is the direct result of joint efforts by the patient, family and multidisciplinary transplant team (surgeon, pneumologist, pharmacist, respiratory therapist, dietitian and nurse). Long-term survival of lung transplant recipients depends upon open communication and interaction between the members of the team. New therapies, in the hands of the transplant team at an experienced transplant centre will allow lung transplantation to continue to improve as a therapeutic option for children with lung disease. Cooperation and education among the specialists on the team ensure optimal care for these high-risk and medically complex children. It is important to note that the pharmacist contributes to the care processes at all stages.
References
1. Amir H Tejani, William E Harmon, et al. Pediatric solid organ transplantation Munksgaard. Copenhagen; 2000.
2. Eithne F MacLaughlin. Pediatric solid organ transplantation Munksgaard. Copenhagen; 2000.
3. Jeanette M Hasse, Linda S Blue. American Dietetic Association: Chicago, Illinois; 2002.
4. Audrey Wells et al. Resp and Crit Care Med Vol.27; Num 5, 2006.
5. Marlyn S Woo. Paed Resp Rev (2004) 5,249–254.
6. Eric N Mendeloff. Pediatric solid organ transplantation Munksgaard. Copenhagen; 2000.
7. Stuart C Sweet. Pediatric solid organ transplantation Munksgaard. Copenhagen; 2000.
8. Marylin SWoo. Pediatric solid organ transplantation Munksgaard. Copenhagen; 2000.
9. GB Mallory et al. Eur Respir J 2004;24:839–845.
10. Aldo T Iacono et al. New Engl J Med 2006;354:141–50.
