Late Graft Loss or Death in Pediatric Liver Transplantation: An Analysis of the SPLIT Database

Authors


* Corresponding author: G. V. Mazariegos, george.mazariegos@chp.edu

Abstract

Late graft loss (LGL) and late mortality (LM) following liver transplantation (LT) in children were analyzed from the studies of pediatric liver transplantation (SPLIT) database. Univariate and multivariate associations between pre- and postoperative factors and LGL and LM in 872 patients alive with their primary allografts 1 year after LT were reviewed. Thirty-four patients subsequently died (LM) and 35 patients underwent re-LT (LGL). Patients who survive the first posttransplant year had 5-year patient and graft survival rates of 94.2% and 89.2%, respectively. Graft loss after the first year was caused by rejection in 49% of the cases with sequelae of technical complications accounting for an additional 20% of LGL. LT for tumor, steroid resistant rejection, reoperation in the first 30 days and >5 admissions during the first posttransplant year were independently associated with LGL in multivariate analysis. Malignancy, infection, multiple system organ failure and posttransplant lymphoproliferative disease accounted for 61.8% of all late deaths after LT. LT performed for FHF and tumor were associated with LM. Patients who are at or below the mean for weight at the time of transplant were also at an increased risk of dying. Frequent readmission was also found to be associated with LM.

Introduction

Advances in surgical technique and postoperative care have allowed survival rates after pediatric liver transplantation (LT) to improve dramatically. Progress in immunosuppressive protocols has also contributed greatly to the routine survival of many children after their first postoperative year with 1-year survival rates increasing from 35% in 1982 to 86% in 2002 (1). Despite the improvement in early patient and graft-survival, a slow but continued attrition occurs after the first postoperative year, regardless of the year of transplantation. Factors that lead to improvement in long-term survival in children who survive the first year have largely been unstudied. A better understanding of the etiology of late graft loss (LGL) and late mortality (LM) could potentially result in alteration of clinical practices leading to improved long-term survival rates.

The SPLIT registry began in 1995 as a database to prospectively follow children under 18 years of age who receive liver transplants in the United States and Canada (2). The SPLIT registry currently consists of 43 transplant centers with the participating centers performing roughly 79% of all transplants in the United States. The data derived from this registry allows one to evaluate a large, multi-institutional experience in LT. The purpose of this study was to analyze the SPLIT database for the etiology and potential risk factors associated with LGL and LM in children who have survived for more than 1 year after LT.

Patients and Methods

All children from participating SPLIT centers who received their first liver transplant prior to their 18th birthday were included in this study. Research and informed consent were conducted in accord with the ethical standards of the Helsinki Declaration of 1975. Informed consent was obtained and recorded at the individual center. The data collected by individual centers was then sent to a centralized coordinating center for editing and quality control. Follow-up reports were sent at 6-month intervals for the first 2 years and then annually. The SPLIT Scientific Advisory Board (SAB) is composed of a subgroup of Principal Investigators from participating transplant centers and provides overall scientific direction to the registry and is ultimately responsible for the conduct of the registry. The Data Quality Committee (DQC), a subcommittee of the SAB, is charged with ensuring that the quality of the SPLIT database is accurate, timely and complete. Transplant centers are periodically reviewed and visited to evaluate the accuracy of the data. SPLIT also periodically compares data reported to the study with that within the UNOS database. In 2005, SPLIT centers performed 78.4% of all pediatric liver transplants in the United States. A total of 77.6% of the transplants and 83.9% of deaths were reported within 45 days of the transplant date and death date, respectively. Long-term follow-up is one of the biggest challenges to overcome in longitudinal observational studies. In 2005–06, 82.9% of the expected posttransplant follow-up forms were submitted by the centers. The data submission rate for the follow-up period of greater than 2 years was 79.4%.

Between 1995 and June 2004, 1611 children received a primary liver transplant at one of the SPLIT centers (Table 1). Those patients who died (174 patients) or who were retransplanted within the first posttransplant year (94 patients) were excluded from further study. Also, 471 patients had less than 1 year of follow-up at the time of analysis and were also excluded from the cohort. Those patients remaining were analyzed for mortality, graft loss and cause of death. After the first year, 872 patients were alive with their primary allografts at a median follow time of 35.9 months (range 12–98.2 months). Our study will focus on the 34 patients who died after the first postoperative year (LM) and the 35 patients who underwent retransplant during that same time period (LGL). Of the 35 patients who underwent retransplant, 8 subsequently died, but remained in the LGL endpoint as analysis of their course ceased at the time of the retransplant. This decision was made to avoid confounding variables introduced by re-retransplantation.

Table 1.  Recipient characteristics in the overall SPLIT database and in those patients who survived the first posttransplant year
 SPLIT (n = 1611) (%)>1 year f/u (n = 872) (%)
Recipient age
 0–6 months  146 (9.1)   85 (9.7)
 6–12 months  394 (24.5)  211 (24.2)
 1–5 years  510 (31.7)  261 (29.9)
 5–13 years  334 (20.7)  190 (21.8)
 >13 years  225 (13.9)  125 (14.3)
 Missing    2 (0.12)    0 (0)
Gender
 Male  741 (46.0)  392 (44.9)
 Female  869 (53.9)  470 (54.9)
 Missing    1 (0.1)    1 (0.12)
Ethnicity
 White  969 (60.1)  545 (62.5)
 Black  252 (15.6)  136 (15.6)
 Hispanic  237 (14.7)  121 (13.9)
 Asian   55 (3.4)   21 (2.4)
 American Indian   30 (1.9)   16 (1.8)
 Other   65 (4.0)   32 (3.7)
 Missing    3 (0.2)    3 (0.34)
Donor type
 Deceased whole  813 (50.5)  489 (56.0)
 Deceased split  174 (10.8)   79 (9.0)
 Deceased reduced  296 (18.4)  152 (17.4)
 Deceased missing   55 (3.4)   17 (1.95)
 Living  267 (16.6)  135 (15.5)
 Missing    6 (0.37)    0 (0)
Donor age
 0–6 months   81 (5.0)   39 (4.5)
 6–12 months   56 (3.5)   29 (3.3)
 1–18 years  813 (50.5)  483 (55.4)
 18–50 years  567 (35.2)  285 (32.7)
 >50 years   57 (3.5)   32 (3.7)
 Missing   37 (2.3)    4 (0.46)
PELD score at Tx
 <0  267 (16.6)  142 (16.3)
 0–10  305 (18.9)  182 (20.1)
 10–20  371 (23.1)  196 (22.5)
 >20  497 (30.9)  261 (29.9)
 Missing  171 (10.6)   91 (10.4)

Preoperative patient and graft characteristics examined included: recipient age, race and gender, height and weight deficit at the time of transplant, PELD score at transplant, the donor age and organ type as well as the ABO match, year of transplant and primary diagnosis of the recipient. The patient characteristics of the group surviving greater than 1 year after transplant are listed in Tables 1 and 2. For statistical purposes, patients with cholestatic liver diseases other than biliary atresia (e.g. Progressive Familial Cholestasis (PFIC), Alagille's) were grouped with patients suffering from metabolic diseases. This is justified by the relatively consistent results found after transplant in these two broad populations of patients.

Table 2.  Primary diagnosis of patients who were alive with their first allograft 1 year after LT
Primary Diagnosisn%
EHBA37342.8
Metabolic & other cholestatic24227.8
FHF10011.5
Cirrhosis 82 9.4
Tumor 40 4.6
Other 34 3.9
Missing  1 0.1

The postoperative factors examined included: presence and number of reoperations within the first 30 days, sepsis within the first 30 days, hepatic artery or portal vein thrombosis within the first year, the development of biliary leaks or strictures (intrahepatic or anastamotic), occurrence of cytomegalovirus (CMV) or Epstein Barr Virus (EBV) infection (symptomatic or asymptomatic), the primary immunosuppression, the presence and number of acute rejections in the first year, the occurrence of steroid resistant rejection (defined as acute cellular rejections requiring antibody therapy as part of their treatment), the incidence of chronic rejection, the year of transplant, the length of primary hospitalization and the number of readmissions in the first year.

Statistical analysis

Data are presented as percentage, mean ± standard deviation or median. The Kaplan–Meier method was used for estimating probability of patient and graft-survival following the first year of transplant. The Cox proportional hazards model was used to test univariate and multivariate associations, and factors found to be significant at the 0.20 level in the univariate model were further examined in the multivariate model. All statistical analyses were performed using the SAS system for Windows (SAS Institute Inc, Cary, NC).

Results

We defined late events as those occurring after the first posttransplant year. This time point was chosen to avoid the effects of early factors on transplant outcome. As several other papers have examined variables surrounding early graft and patient-survival, the 1-year mark allows a clear separation from the early losses already well delineated in these prior studies. Although there is clearly a bias toward survival in these patients, it is this population that requires further analysis if true life-time survival is to be expected after LT. This time-point has also been well established in the literature (3–5).

As expected, patients who survive the first posttransplant year enjoy a better 5-year survival when compared to patients from the entire SPLIT registry (Figure 1). The 5-year patient and graft-survival rates of those who survive the first year with their LT are 94.2% and 89.2%, respectively, with the overall SPLIT database survival of 82% and 72% (1).

Figure 1.

Kaplan–Meier probability curve for survival in patients who survived the first year after pediatric liver transplantation.

Late graft loss

Graft loss after the first year was caused by rejection (acute or chronic) in 48.5% of the cases with the sequelae of hepatic artery thrombosis (HAT) and biliary strictures accounting for an additional 20% of graft losses (Table 3). Recurrence of disease and hepatitis C infection, common causes of LGL in the adult LT population, accounted for very few graft losses in this series. Of note, the primary cause of three cases of LGL was not recorded in the database.

Table 3.  Etiology of late graft loss after LT (n = 35)*
 n%
Chronic rejection13 37.1
Other514.3
 Venoocclusive disease1 
 Parenteral nutrition1 
 Regenerative nodular hyperplasia1 
 Fulminant liver failure1 
 Chronic cholangitis1 
Acute rejection411.4
HAT411.4
Biliary3 8.6
Missing3 8.6
HCV1 2.9
Recurrent disease1 2.9
Stopped immunosupression1 2.9

Among the pre- and postoperative variables analyzed; LT for tumor compared to biliary atresia (p = 0.002), the occurrence of steroid resistant rejection (p = 0.0001) and greater than 5 admissions over the first posttransplant year compared to none (p = 0.0001) were associated with LGL by univariate analysis (Table 4). Variables found to have any association with LGL were then scrutinized by multivariate analysis.

Table 4.  Factors associated with late graft loss by univariate analysis
 HR95% CIp-Value
Hepatic artery thrombosis2.070.89–4.820.084
CMV infection1.710.92–3.160.087
>1 episode of ACR1.860.99–3.40.054
Reop in 1st 30 days1.590.95–2.650.073
Transplant for tumor3.76 1.6–8.830.002
Steroid resistant ACR3.461.81–6.440.0001
>5 admissions in 1st year5.372.28–12.70.0001

Although HAT, >1 episode of ACR in the first year, CMV and EBV infection/PTLD were not found to be independently associated with LGL; LT for tumor (p = 0.0007), occurrence of steroid resistant rejection (p = 0.0013), reoperation in the first 30 days (p = 0.048) and >5 admissions during the first posttransplant year (p = 0.0007) were all independently associated with LGL in multivariate analysis (Table 5).

Table 5.  Factors associated with late graft loss by multivariate analysis
 HR95% CIp-Value
Transplant for tumor4.581.89–11.070.0007
Reop in 1st 30 days1.71 1.0–2.920.048 
>5 admissions in 1st year4.871.96–12.20.007 
Steroid resistant ACR2.971.53–5.760.001 

Late mortality

The causes of late mortality after LT are listed with their relative frequencies in Table 6. Malignancy, infection, MSOF and PTLD accounted for 61.8% of all late deaths. Of note, chronic rejection accounted for a mere 2.9% of all deaths in patients who survived the first posttransplant year.

Table 6.  Etiology of late mortality after LT (n = 34)
 n%
Malignancy720.6
 Recurrence/metastasis6 
 Denovo malignancy1 
Sepsis/infection514.7
MSOF514.7
PTLD414.7
Other3 8.8
 Cardiomyopathy1 
 Cystic fibrosis1 
 Aplastic anemia1 
Cardiopulmonary3 8.8
Cerebral edema/infarct3 8.8
Portal vein thrombosis1 2.9
Pancreatitis1 2.9
Liver failure1 2.9
Chronic rejection1 2.9

Univariate analysis revealed that transplantation for tumor (p < 0.0001) or for FHF (p = 0.068) compared to biliary atresia and those performed in patients weighing between zero and two standard deviations (SD) below the mean (p = 0.034) is associated with an increased risk of late mortality. LT complicated by HAT (p = 0.008) and >5 readmissions in the first posttransplant year (p = 0.008) were also associated with late death after transplant (Table 7).

Table 7.  Factors associated with late mortality by univariate analysis
 HR95% CIp-Value
Transplant for FHF2.62  0.93–7.360.068
Transplant for tumor8.47  2.99–23.97 <0.0001 
Wt deficit (vs above mean)2.85  1.08–7.540.034
Hepatic artery thrombosis3.34  1.29–8.660.008
>5 admissions in 1st year4.05  1.44–11.40.008

Multivariate analysis confirmed that LT performed for FHF (p = 0.026) and tumor (p < 0.0001) is independently associated with late mortality in patients who survived the first year after transplant (Table 8). Patients zero to two SD below the mean for weight at the time of transplant were also at an increased risk of dying after the first posttransplant year when compared to those over the mean. Patients who were greater than two SD below the mean did not have an increased risk of late mortality after the first year (data not shown). Frequent readmission during the first posttransplant year was found to be independently associated with late mortality by multivariate analysis. EBV and CMV related complications were not found to be associated with late mortality.

Table 8.  Factors associated with late mortality by multivariate analysis
 HR95% CIp-Value
Transplant for FHF 3.441.16–10.22  0.026
Transplant for tumor10.263.57–29.46<0.0001
Wt deficit 3.781.38–10.38  0.010
Hepatic artery thrombosis 2.660.96–7.36  0.059
>5 admissions in 1st year 4.781.54–14.8  0.007

Discussion

Although single-center reports regarding LGL and mortality have been published in the past, these studies were focused on mixed adult and pediatric patient populations and were limited by the relatively small number of patients experiencing LGL or LM (3–8). The size and homogeneity of data in the SPLIT database overcomes these limitations. The database also allows for a more comprehensive and current look at late mortality and graft loss using data acquired from multiple centers. Several studies have utilized the 1-year time point to define “late” events (3–5). The majority of graft losses after LT occur early in the postoperative period, usually in the first few months. Graft failure in this time is mostly due to primary nonfunction and thrombosis with early mortality due to infection, PTLD and bleeding (10). In clinical practice, most of these complications are resolved by the first posttransplant year. In attempting to better understand late events after LT and the complex interaction between factors associated with late outcomes after LT, analysis is best accomplished looking at LGL and LM separately.

Late graft loss

The SPLIT database demonstrated that the majority of LGLs were caused by acute and chronic rejection (48.5% of all LGL) and by the chronic effects of hepatic arterial thrombosis (11.4% of LGL) and biliary strictures (8.6% of LGL).

In a review from Belgium, Wallot et al. described the etiology and risk factors for graft loss occurring after the third postoperative month (8). Although the study included children transplanted across all eras of transplant and with varied immunosuppressive regimens, a striking number of graft losses were found to be due to immunosuppression reduction associated with PTLD. Similar to our study, biliary and arterial complications as well as chronic rejection (17%) remain a significant contributor to LGL. The concerning impact of chronic rejection on LGL seen in this study is confirmed by our findings. Although small in absolute numbers, there is clearly a subset of patients who suffer LGL due to chronic rejection, contrasting published accounts of an almost insignificant incidence of this complication (9,10).

Those patients who experience more than one episode of acute cellular rejection were found to have an almost two-fold increase in LGL, a finding that reaffirms recent studies that demonstrate an association between chronic rejection and recurrent acute cellular rejections (8,11). Similar to other studies, steroid-resistant rejection was also found to be associated with LGL (8). Although tacrolimus has been shown to dramatically decrease the rate of chronic rejection in pediatric liver-transplant recipients (9–12), analysis of the SPLIT data did not show any difference in LGL in those children receiving cyclosporine versus tacrolimus (data not shown). Our data also demonstrated that the incidence of LGL was similar in patients transplanted before 2002 when compared to those receiving LT after 2002.

Our analysis also shows that patients who required multiple operations and those requiring frequent readmission during the first posttransplant year have an increased incidence of LGL, suggesting that early technical complications and infections arising from the initial transplant procedure significantly impair long-term graft-survival. It is also important to note that unlike earlier studies, technical variant grafts (living or deceased donor) had similar rates of LGL when compared to whole allografts (1,6,8,10).

The solitary graft loss in patients transplanted for tumor was due to chronic rejection. Although multivariate analysis demonstrated an association between transplant for tumor and LGL, small sample size makes interpretation of these results difficult.

Late mortality

Death in children who survive their first posttransplant year is caused by sepsis, multisystem organ failure and posttransplant lymphoproliferative disease. In contrast to the adult transplant population (13,14), recurrent disease and cardiopulmonary diseases are not common findings after pediatric LT. Approximately 30% of the SPLIT patients who died after their first posttransplant year succumbed due to infection, sepsis or MSOF. Although the data is limited by the relative lack of details surrounding these deaths, mortality due to sepsis is much more common after LT compared to the general population. A recent single center review found 60% of LM occurring due to septic complications and PTLD with the remainder of deaths caused by recurrent malignancy (3).

Similar to the findings in LGL analysis, frequent readmission in the first year is associated with late mortality. Although HAT and biliary complications contribute to LM, only three patients had significant liver dysfunction as the primary cause of LM. The large majority of late deaths in this study were thus due to malignancy and primary infections not associated with technical issues.

Children who were 0–2 SD below the mean for weight were also more likely to suffer from LM when compared to those above the mean. The effect of malnutrition on pre- and posttransplant outcomes has been clearly demonstrated in the past, with dramatically reduced posttransplant survival if transplanted with Z scores for weight of <1.0 (15). The reason for this remains unclear, though severe preoperative malnutrition associated with liver disease may play a role in the recipient's ability to overcome the metabolic stresses associated with liver transplantation.

In our study, the majority of the 34 children who died had weight z scores at transplant below the mean as compared to 252/838 (31%) children with weight z scores above the mean who survived. A total of 113 children had significant weight deficit at transplant that continued to year 1. Seven of these patients subsequently died from sepsis (n = 1), PTLD (n = 2), multiple organ failure (n = 1), cardiopulmonary causes (n = 2) and metastatic liver malignancy in one child. Interestingly, patients who were greater than 2 SD below the mean in weight at the time of transplant did not have an increased risk of LM. Although one can only speculate about the reasons behind this finding, it is possible that the weight in some of these patients is artificially elevated due to ascites or that a larger proportion of patients transplanted with this weight deficit experienced mortality early in the course of LT. This issue could be resolved by a more specific examination of the impact of perioperative nutrition and height and weight at the time of transplant in the SPLIT population.

EBV-related disease remains an important cause of LM after LT. Fortunately, most large centers have adopted monitoring and preemptive therapy protocols similar to those published by UCLA and Pittsburgh (16,17). Notably, both series enjoyed dramatic decreases in the incidence and mortality of PTLD since instituting monitoring and preemptive therapy strategies based on serial measurements of quantitative EBV DNA by PCR (3,18). These strategies have also been successful in decreasing the incidence of severe perioperative CMV infections. The prevention of EBV-related tumors and the introduction of successful treatments for PTLD likely account for the lack of any correlation between symptomatic CMV and EBV infections, PTLD and either LGL or LM in this study. The fact that the development of these complications was not associated with either late outcome in our study suggests that EBV-related complications are being successfully treated without causing LGL due to acute or chronic rejection. This represents an important advance, which is likely due to the development of specific therapies for PTLD and highlights the importance of immune monitoring in this unique group of patients.

Recurrent malignancy remains the Achilles' heel of transplantation for nonresectable childhood hepatic tumors. Patients receiving LT for cancer suffered from a near ten-fold risk of late mortality when compared to a standard group transplanted for biliary atresia. These results differ from those of earlier analyses in which pretransplant diagnosis was not associated with late outcome. Of note, preoperative variables, such as tumor size, type and stage were not investigated in this study and we thus suggest caution in the selection of patients receiving a LT for tumor. In addition, patients transplanted for tumor often receive perioperative cytotoxic chemotherapy, which may ultimately increase their risk of serious infections and the development of other denovo malignancies. Two-thirds of LM in this study group was due to recurrence and metastases of the tumor, with the remaining mortality due to cardiomyopathy, likely a complication of chemotherapy. These results also support the establishment of registry efforts to document all transplant variables in pediatric patients undergoing transplant for liver tumors and to develop prospective analysis of outcomes and optimal timing of transplantation.

Fulminant hepatic failure is one of the most challenging clinical situations in pediatric transplantation. As these children do not suffer from chronic illness, one would expect excellent long-term results with survival past the perioperative period. However, this has not proven to be the case. Early mortality in patients transplanted for FHF is higher than that after LT for other conditions (19,20). Our study is the first to demonstrate that even a year after successful LT, patients who suffered from FHF have a markedly increased risk of dying. Thirty percent of the LM observed in the patients transplanted for FHF in this study was due to multi-organ failure and sepsis. Although the exact etiology of all LM in this population has not been examined fully, a recent review of the SPLIT experience with FHF does suggest increased infectious and neurologic complications after LT for FHF (19). One explanation may be that patients who suffer from FHF have a dysregulation of the natural killer cell lineage, which results in a deranged response to self and other antigens. This dysregulation may also lead to an increased susceptibility to infectious complications after transplantation, which is an important etiology of late death after LT (21).

In summary, LGL in this large multicenter series is related to immunologic factors, rejection and delayed sequelae of technical complications. Despite the traditional perception of the tolerogenicity of the liver and the reported low incidence of chronic rejection currently in liver transplantation, our data suggests that improvement in long-term immunosuppression remains to be achieved. Furthermore, septic complications and malignancy, two factors traditionally associated with over immunosuppression continue to account for the majority of late mortalities.

Although this report is constrained by the natural limitations of database registries, it is the first to examine LGL and mortality in a large multi-center pediatric patient population. Further subgroup analysis is needed to further maximize the impact of these findings to individual patients in unique clinical scenarios. This report underscores the urgent need for individualized patient specific immunosuppression and monitoring that can guide optimal immunosuppression over the long term.

Acknowledgments

The Studies of Pediatric Liver Transplantation (SPLIT) is funded by a grant from National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (U01-DK061693-01A1). Additional support is provided by Astellas Pharma US, Inc. and Roche Laboratories.

SPLIT Research Group

Stephen Dunn, MD, Jerome Manendez, MSN, RN, Louise Flynn, MSN, RN, Alfred I Dupont Hospital for Children, Wilmington, DE; Maureen Jonas, MD, Laura Krawczuk, CPNP, Marielle Christoff, Boston Children's Hospital, Boston, MA; Robert Kane, MD, Harvey Solomon, MD, Erin Phillips, Laurie Ferrer, Cardinal Glennon Children's Hospital, St. Louis University, St. Louis, MO; Thomas Heffron, MD, Jill DePaolo, Todd Pillen, Laurel Davis, RN, Children's Healthcare of Atlanta, Atlanta, GA; John Bucuvalas, MD, Fred Ryckman, MD, Andre Hawkins, Gajra Arya, Children's Hospital, Cincinnati, Cincinnati, OH; Michael R. Narkewicz, MD, Ronald J. Sokol, MD, Frederick Karrer, MD, Cara Mark, MD, Kathy Orban-Eller, RN, MS, Children's Hospital Denver, University of Colorado School of Medicine, Denver, CO; Abhi Humar, MD, Brenda Durand, RN, Leslie Studenski, MPH, University of Minnesota, Minneapolis, MN; Elizabeth Rand, MD, Kathleen Anderer, CRNP, Children's Hospital of Philadelphia, Philadelphia, PA; George Mazariegos, MD, Nydia Chien, RN, MSN, Lynn Seward, RN, Children's Hospital of Pittsburgh, Thomas E Starzl Transplantation Institute, Pittsburgh, PA; Paul Atkison, MD, PhD, Children's Hospital Western Ontario, London, Ontario, Canada; Jay Roden, MD, Naveen Mittal, MD, Lisa Cutright, RN, CPNP, Children's Medical Center of Dallas, Dallas, TX; Grzegorz Telega, MD, Stacee Lerret, CPNP, Children's Hospital of Wisconsin, Milwaukee, WI; Estelle M. Alonso, MD, Joan Lokar, APN/NP, Susan Kelly, RN, BSN, Katie Neighbors, MPH, Children's Memorial Medical Center, Transplant Center of Excellence, Chicago, IL; Walter S. Andrews, MD, James Daniel, MD, Vicki Fioravanti, RN, CCTC, Angela Tendick, RN, BSN, Children's Mercy Hospital, Kansas City, MO; Anne S. Lindblad, PhD, Ravinder Anand, PhD, Changhong Song, PhD, Karen Martz, MS, Jeff Mitchell, Gladys Fraser, Nicole Hornbeak, Nirali Patel, Jianghang He, The EMMES Corporation, Rockville, MD; Annie Fecteau, MD, Vicky Lee Ng, MD, Maria De Angelis, NP, Andreanne Benidir, Hospital for Sick Children, Toronto, Toronto, Ontario, Canada; Kathleen Schwarz, MD, Paul Colombani, MD, May Kay Alford, MSN, CPNP, Michelle Felix, MSN, CPNP, Robert Jurao, Johns Hopkins Hospital, Baltimore, MD; James Eason, MD, John Eshun, MD, Sandra L. Powell, RN, MSN, Le Bonheur Children's Medical Center, Memphis, TN; Deborah Freese, MD, Jody Weckwerth, RN, Jean Greseth, RN, Lori Young, RN, Mayo Medical School, Rochester, MN; Robert Fisher, MD, Michael Akyeampong, RN, Medical College of Virginia, Richmond, VA; Samuel So, MD, William Berquist, MD, Marcia Castillo, RN, Annalie Bula, Stanford University Med Center, Palo Alto, CA; Sukru Emre, MD, Benjamin Shneider, MD, Nanda Kerkar, MD, Salvador Cuellar, CRC, Mount Sinai Medical Center, New York, NY; Saul Karpen, MD, PhD, Jaymee Mayo, RN, BSN, John Goss, MD, Douglas Fishman, MD, Val McLin, MD, Beth Carter, MD, Christine O'Mahony, MD, Thomas Aloia, MD, Donna Garner, PNP, Texas Children's Hospital, Houston, TX; Susan Gilmour, MD, MSc, FRCPC, Bernadette Dodd, RN, BScN, Norman Kneteman, MD, MSc, FRCSC, University of Alberta, Edmonton; Sue McDiarmid, MD, Susan Fiest, RN, BSN, CCRC, UCLA Medical Center, Los Angeles, CA; Steven Lobritto, MD, Lesley Smith, MD, Patricia Harren, NP, Kristin Maseda, New York Presbyterian Hospital, New York, NY; Fernando Alvarez, MD, Steven Martin, MD, Carol Viau, RN, Sainte-Justine Hospital, Montreal, Quebec, Canada; Ross Shepherd, MD, Jeffrey Lowell, MD, Michelle Nadler, RN, St. Louis Children's Hospital, St. Louis, MO; Joel Lavine, MD, Ajai Khanna, MD, Rosemarie Clawson, RN, University of California, San Diego Med Center, San Diego, CA; James Lopez, MD, PhD, John Magee, MD, Vicky Shieck, RN, BSN, CCTN, University of Michigan, Ann Arbor, MI; Jeffrey Fair, Steven Lichtman, Ken Andreoni, Joanne Prinzhorn, Valorie Buchholz, University of North Carolina, Chapel Hill, Chapel Hill, NC; Simon Horslen, Melissa Young, University of Washington, Seattle, WA; Glenn Halff, MD, Stacey Wallace, University of Texas, HSC San Antonia, San Antonio, TX; Joseph Tector, MD, Joel Lim, MD, Jean Molleston, MD, Jean Pearson, Indiana University Medical Center, Indianápolis, IN; Humberto Soriano, MD, Kathleen Falkenstein, PhD, PNP, St Christopher's, Philadelphia, PA Andreas Tzakis, MD, Tomoaki Kato, MD, Debbie Weppler, RN, MSN, Lisa Cooper, RN, Monica Gonzalez, RN, BSN, Alma Santiago, University of Miami/Jackson Memorial, Miami, FL; Munci Kalayoglu, MD, Anthony D'Alessandro, MD, Nissa Erickson (CI), Robert Judo, Stuart Knechtle, MD, Elizabeth Spaith, RN, University of Wisconsin, Madison, WI; Regino Gonzalez-Peralta, MD, Marcia Hodik, RN, Stacia McCracken, ARNP, University of Florida – Shands, Gainesville, FL, Philip Rosenthal, MD, Danusia Filipowski, MD, University of California, San Francisco, San Francisco, CA; Linda Book, MD, Molly O'Gorman, MD, Cynthia K. Kawai, MS, APRN, Lacey Bruschke, BSN, RN, Jennifer Kraus, RN, Primary Children's Medical Center, Salt Lake City, UT; Alan Langnas, DO, Dean Antonson, MD, Jean Botha, MB, Bch, Wendy Grant, MD, Debra Sudan, MD, Debb Andersen, RN, Beverly Fleckten, BS, CCRC, Kris Seipel, BS, University of Nebraska Medical Center, Omaha, NB; J. Michael Millis, MD, Patricia Boone, RN, MSN, University of Chicago, Chicago, IL; Dev M. Desai, MD, Sherri Javis, RN, Duke University Medical Center, Durham, NC; Peter Abt, MD, Tomi Shisler, FNP, Cindy Mack, RN, University of Rochester Medical Center, Rochester, NY.

Ancillary