Not just a small adult

In this issue of TRANSFUSION, Couban et al.1 present the results of one of but a handful of randomized transfusion trials that involve children. More specifically, the authors initiated a prospective, blinded, randomized, crossover study of unmodified whole blood-derived platelets, apheresis platelets, or plasma-depleted platelets with a primary end point of protocol-defined acute, febrile, nonhemolytic reaction (FNHTR) in children age 3-17 years. The study was terminated early due to the institution in Canada of universal WBC reduction and was replaced with a prospective audit of FNHTR. The importance of this study lies not so much in its findings as in its unique focus on pediatric transfusion recipients. Thorough search of the transfusion and pediatric hematology-oncology literature reveals a paucity of studies in children. Often the studies are from a single institution and/or have only a small number of patients in each study arm, which results in low statistical power. Accrual of patients may take so long that new scientific data or practice guidelines negate the impact of the study before it can be completed. The establishment of networks of investigators working collaboratively with a data management and statistical coordinating center provide large patient populations and unique patient cohorts and sophisticated data management, randomization, and statistical analyses. Two examples of successful pediatric networks are the U.S. Neonatal Research Network and the Canadian Registry of Pediatric Thrombosis. In 1986, the NIH instituted the Neonatal Research Network, a cooperative multi-institutional group of between 14 and 16 clinical centers that collect epidemiologic data and utilize common protocols in well-designed clinical trials aimed at evaluating interventions related to the management of infants in neonatal intensive care units. During the third funding period, 1996 through 2001, clinical trials were initiated on prevention or treatment of intraventricular hemorrhage, retinopathy of prematurity, and pulmonary hypertension and on the use of erythropoietin2 and inhaled nitric oxide. Several registries have also been established that provide outcome measures, particularly on neurodevelopmental outcome in extremely low-birth-weight infants. Unfortunately, to date, careful studies of transfusion criteria or selected components did not reach high enough priority for the steering committee of the Neonatal Research Network to warrant study. A new funding period is about to begin, however, with new protocols in development. Under the guidance of the late Maureen Andrew, several regional and multi-institutional Canadian studies successfully quantified a 20- to 30-percent incidence of thrombocytopenia in the newborn nursery3 and studied the usefulness of prophylactic platelet transfusion in selected newborns.4 These studies served as the basis for the many cooperative Canadian studies including the Canadian Thrombosis Registry. These collaborators have published widely on neonatal and childhood stroke prevention and therapy,5 treatment of immune thrombocytopenia,6 and recently on the rate of FNHTRs in hematology-oncology patients.7 The now-frequent administration of indomethacin and nitric oxide, both known to induce platelet dysfunction, and the increasingly frequent use of standard heparin, low-molecular-weight heparin, and tissue plasminogen activator in infants with catheter-related thrombosis, where the risk of clinical bleeding is significantly higher in the presence of thrombocytopenia, demands additional high-quality clinical trials such as those performed by the Neonatal Research Network and the Canadian groups. The best studied thrombocytopenic disorder of childhood is a neonatal disease—neonatal alloimmune thrombocytopenia. While management remains controversial,8,9 multi-institutional, multinational studies are underway to compare antenatal maternal IVIG therapy, with or without steroids, fetal platelet transfusions, or a combined approach and to optimize postnatal treatment of the previously undiagnosed infant.10 The principal goals of platelet transfusion in the neonate and child do not differ from those in adults—prevention of significant thrombocytopenia or a thrombocytopathy that might result in life-threatening or clinically significant hemorrhage—yet, controversies abound. Past attempts to examine the use of prophylactic platelet transfusions were fraught with methodologic difficulties and differing ideological views. Key among the controversies is whether to transfuse platelets to maintain an established baseline platelet count or when frank bleeding occurs (J. Bussell, oral communication, December 2001).11 The platelet transfusion trigger is also debated,12 although recent studies suggest the safety of a count of 10,000 platelets per μL in adults with acute myelogenous leukemia.13 Concomitant infection and downward trending likely need to be assessed,14 but no studies have yet attempted to study these phenomena in association with dose and minimum effective platelet count. In children with solid tumors for whom no transfusionstudies have been published, the predisposition to hemorrhage from local tumor invasion, especially in children with brain tumors, must be considered. In addition to the indications for platelet transfusion and the platelet transfusion trigger, platelet dosing has not been studied in children since the study by Roy et al.15 in 1973. Based on post-transfusion recovery and the life span of transfused platelets, a dose of 0.5 × 1011 platelets per 10 kg has been a recommended since 1960 and this dose recommendation is often found in transfusion medicine textbooks. Norol et al.16 questioned the correctness of that approach by performing a dose-escalation study using apheresis platelets that had been WBC reduced before storage in 13 evaluable children (and 69 adults) with acute myelogenous leukemia or who received conditioning for allogeneic bone marrow transplant. They were able to demonstrate higher platelet increments, longer intervals between transfusions (increasing from 2.5 to 4.4 days), and a more marked dose-effect relationship in the children as compared to the adults in the study.17 The platelet component used in this study was maximized for quality, which raises questions as to the applicability of their findings to routine practice. Nevertheless, the findings are intriguing and could be used as the basis for studies comparing platelet components. The CCI and the percent platelet recovery are measures often used to evaluate the response to platelet transfusions. The CCI uses body surface area and the percent platelet recovery uses blood volume, estimated at 75 mL per kg. Analysis of data from the Trail to Reduce Alloimmunization to Platelets (TRAP study) brought into question the validity of these measures. It has been suggested that regression analysis of post-transfusion platelet count increments rather than the CCI or the percent platelet recovery, both of which are calculated as ratios of the platelet increment and the number of platelets transfused, may be more informative to assess the efficacy of platelet transfusions. However, the definition of efficacy needs to take into account the fact that post-transfusion platelet response may be due to modification of either platelet number or platelet quality or both.17 Future studies that measure the efficacy of platelet transfusions in children must also take into account differences in body surface area measurement18 and the marked differences in blood volume among infants and children.19 The NIH and the FDA now recognize the importance of inclusion of women and children in all aspects of research including clinical trials and drug studies. In 1993, the NIH Revitalization Act (Section 492B of Public Law 103-43) established that women and minorities needed to be included in studies unless such inclusions are inappropriate based on compelling support. That law was further refined so that since 1998, any research that involves human subjects must include children unless there are scientific and ethical reasons to not include them. In 1997, the FDA Modernization Act was passed to provide exclusivity extension of patent to both new and soon-to-be marketed drugs. This act encourages studies in pediatric patients when it is determined that information from these studies produce health benefits. Guidance documents provide an outline of critical issues in pediatric drug development and approaches to study these drugs in pediatric populations utilizing sound statistical approaches and with an emphasis on ethical conduct (http://www.ctda.gov/cber/guidelines.htm). Age classifications have been defined and recommendations for pharmakokinetic measurements take into account surface area differences. As the National Heart, Lung, and Blood Institutes Transfusion and Hemostasis Clinical Research Network moves forward in establishing topics for investigation, it should utilize the concepts inherent in the FDA Modernization Act and the knowledge gained from the Neonatal Research Network and other cooperative trails to investigate blood transfusion efficacy and dosing. In particular, platelet transfusion should be studied to fill an ever-widening gap in our knowledge of component selection, dosing, and adverse reactions. In the course of progression of a disease, we must always be cognizant that neither the course of disease nor therapy is always similar enough to allow extrapolation to children of efficacy from adult studies. Routes of administration, volume of distribution, physiology of metabolism and excretion, study endpoints, and adverse events may be vastly different in a newborn, a toddler, or an older child as compared to an adult.

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