Comprehensive Prognostication in Critically Ill Pediatric Hematopoietic Cell Transplant Patients: Results from Merging the Center for International Blood and Marrow Transplant Research (CIBMTR) and Virtual Pediatric Systems (VPS) Registries

Abstract

Critically ill pediatric allogeneic hematopoietic cell transplant (HCT) patients may benefit from early and aggressive interventions aimed at reversing the progression of multiorgan dysfunction. Therefore, we evaluated 25 early risk factors for pediatric intensive care unit (PICU) mortality to improve mortality prognostication. We merged the Virtual Pediatric Systems and Center for International Blood and Marrow Transplant Research databases and analyzed 936 critically ill patients ≤21 years of age who had undergone allogeneic HCT and subsequently required PICU admission between January 1, 2009, and December 31, 2014. Of 1532 PICU admissions, the overall PICU mortality rate was 17.4% (95% confidence interval [CI], 15.6% to 19.4%) but was significantly higher for patients requiring mechanical ventilation (44.0%), renal replacement therapy (56.1%), or extracorporeal life support (77.8%). Mortality estimates increased significantly the longer that patients remained in the PICU. Of 25 HCT- and PICU-specific characteristics available at or near the time of PICU admission, moderate/severe pre-HCT renal injury, pre-HCT recipient cytomegalovirus seropositivity, <100-day interval between HCT and PICU admission, HCT for underlying acute myeloid leukemia, and greater admission organ dysfunction as approximated by the Pediatric Risk of Mortality 3 score were each independently associated with PICU mortality. A multivariable model using these components identified that patients in the top quartile of risk had 3 times greater mortality than other patients (35.1% versus 11.5%, P < .001, classification accuracy 75.2%; 95% CI, 73.0% to 77.4%). These data improve our working knowledge of the factors influencing the progression of critical illness in pediatric allogeneic HCT patients. Future investigation aimed at mitigating the effect of these risk factors is warranted.

Keywords: Hematopoietic stem cell transplantation; Intensive care units; Organ dysfunction scores; Pediatric; Prognosis; Survival analysis.

Figure 1.. Inclusion / Exclusion Criteria

The VPS and CIBMTR databases were queried and merged to produce the final study population of n=936 patients. 1,071 allogeneic HCT patients from VPS were successfully merged with CIBMTR records. Of these, 135 were excluded due to relapsed malignancy after HCT and prior to PICU admission. The final study population included 936 patients age <21 years admitted to a PICU between 1/1/2009–12/31/2014 each underwent a first allogeneic HCT in the USA/Canada between 1/1/2008–12/31/2014 and had not relapsed from primary disease at the time of PICU admission. These 936 patients accounted for 1,532 PICU admissions during the study interval.

Figure 2.. PICU Mortality Increases with Increasing Length of Stay

Patients have increasing mortality risk the longer they are unable to be discharged from the PICU. Many patients are discharged from the PICU within the first week of PICU stay. Mortality point estimates with 95% confidence intervals for patients still requiring the PICU after 1 week are 17.4% (14.7–20.1), 20.5% (16.2–24.8), and 23.6% (17.0–30.3) for 1^st, 2^nd, and 3^rd PICU admissions, respectively. Mortality estimates for patients still requiring the PICU after 2 weeks increase to 32.0% (26.8–37.2), 37.9% (30.1–45.8), and 47.8% (35.6–60.0) for 1^st, 2^nd, and 3^rd PICU admissions, respectively. Mortality estimates for patients still requiring the PICU after 4 weeks increase to 45.0% (35.9–54.1), 54.6% (41.1–68.0), and 66.7% (50.3–83.1) for 1^st, 2^nd, and 3^rd PICU admissions, respectively. These estimates pertain to each independent PICU admission, not to cumulative days in the PICU over the study interval.

Figure 3.. PICU Mortality Stratified by Multivariate Risk Group

A multivariable model using 5 clinical variables accurately cumulative incidence of PICU mortality over time. Cumulative incidence of mortality for patients in the 1^st, 2^nd, 3^rd, and 4^th quartiles of risk according to the multivariable model are plotted across PICU length of stay. Patients who were discharged alive are censored at the time of PICU discharge. Comparison of cumulative incidence curves using Gray’s test demonstrated significant differences in curves (p<0.001).