Discussion
The ICU survival rate in our cohort of critically ill children with severe SOS and MOD post HCT was 62%, despite most requiring respiratory and vasopressor support. Our mortality rate of 38% is lower than that reported in other recent post-HCT cohorts with severe SOS and MOD. In a large cohort of 71 critically ill adult patients with SOS post HCT who were treated with defibrotide, mechanical ventilation, vasopressors, and KRT were required in 59%, 52%, and 49% of patients, respectively (11). The overall ICU mortality rate was 54%; however, a higher mortality rate was observed in patients receiving IMV (84%), vasopressor support (79%), or KRT (71%), and among their 28 patients who required mechanical ventilation and renal replacement therapy, the hospital mortality rate was 93% (11). Another large cohort of 651 post-HCT patients (adults and pediatrics) pooled from 3 studies reported an estimated D100 survival rate of 38% in patients with both ventilator- and dialysis-dependence and 40% in patients with one dependence (12). Our ICU survival rate approximates the recently reported rate of 64% in a general pediatric cohort of 980 patients treated with CKRT (13).
FO is an independent risk factor for mortality in critically ill children and can prolong the course of IMV and AKI (14). In a metanalysis of 44 studies (7,505 children), each 1% increase in FO resulted in a 6% increase in odds of mortality (14). Similarly, FO adversely impacts the outcome of children post HCT. In a multicenter retrospective study of 68 critically ill children with cancer post HSCT (23 patients) who were receiving CKRT, patients with FO >10% at CKRT initiation were 6.16 times more likely to die than were those with FO ≤10% (15). Unfortunately, FO is common in children post HCT, especially in those in whom SOS develops. Capillary leak, portal hypertension-like pathophysiology leading to ascites, and refractory thrombocytopenia with subsequent need for frequent transfusions are factors that contribute to the development of FO in these patients (7). Initial management of FO includes fluid restriction and diuresis; however, CKRT should be considered when FO approaches >10%. In our cohort, FO was relatively low before starting CKRT, with FO 5% in survivors and non-survivors prior to CKRT initiation. This may have contributed to the lower mortality rate that was observed in our cohort. Following CKRT initiation, survivors in our cohort achieved less cumulative FO in the first 2 days compared to non-survivors
Urine output and the degree of AKI at the time of CKRT initiation were not associated with survival in our cohort. In fact, survivors had worse AKI before initiation of CKRT. Based on these findings, these parameters should not be used for prognosis and outcome prediction in these patients.
In our cohort, urine output was significantly higher in children who were successfully liberated from CKRT starting on the first day after CKRT. This suggests that good urine output after CKRT can serve as predictor of successful CKRT liberation. In a large pediatric cohort of 622 patients on CKRT, 54% were successfully liberated (16). Successful liberation was associated with a higher urine output prior to CKRT initiation. In our cohort, mechanical ventilation and urine output before CKRT initiation were not associated with successful liberation.
The limitations of our study include its retrospective design, small population, and absence of a control group. However, our study describes the largest pediatric cohort of post-HCT patients with severe SOS who received CKRT. This study spanned 12 years and offers valuable insight into the clinical course and outcome of these children. Prospective multi-institutional studies are required to further elucidate factors that improve these patients’ rates of survival and successful liberation from CKRT.
In summary, in this cohort of children with SOS and MOD post HCT, the ICU survival rate was 62%. Survival was higher in children who experienced less FO on the 2 days following CKRT initiation. Successful liberation from CKRT was associated with higher urine output on the 2 days following the end of the course of CKRT. Our findings suggest that CKRT has the potential to improve ICU survival for post-HCT patients with severe SOS and MOD.
6 Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
7 Author Contributions
LE contributed to planning, writing, data collection, and editing the manuscript; MH contributed to data collection, writing, and editing the manuscript; CC and EA contributed to data analysis and manuscript writing; and RE contributed to planning and editing the manuscript. All authors approved the submitted version.
8 Funding
This research was funded by the American Lebanese Syrian Associated Charities (ALSAC). Madeleine Heyn (POE student) was supported by R25CA23944 from the National Cancer Institute.
9 Acknowledgments
The authors thank Cherise Guess, PhD, ELS, for editing the manuscript.
Figure 1. Timeline of clinical course of children with SOS post HCT, * denotes non-survivors
Figure 2 . Laboratory values and survival
Figure 3 . FO and survival
Figure 4. Urine output and successful liberation from CKRT. D-1 represents the day before CKRT initiation and D+1 represents the day after CKRT discontinuation
References
1. Bonifazi F, Barbato F, Ravaioli F, Sessa M, Defrancesco I, Arpinati M, et al. Diagnosis and Treatment of VOD/SOS After Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol. 2020;11:489.2. Cairo MS, Cooke KR, Lazarus HM, Chao N. Modified diagnostic criteria, grading classification and newly elucidated pathophysiology of hepatic SOS/VOD after haematopoietic cell transplantation. Br J Haematol. 2020;190(6):822-36.3. Elbahlawan L, Bissler J, Morrison RR. Continuous Renal Replacement Therapy: A Review of Use and Application in Pediatric Hematopoietic Stem Cell Transplant Recipients. Front Oncol. 2021;11:632263.4. Huang B, Shan J, Yi L, Xin Y, Zhong Z, Xu H. Risk factors for acute kidney injury in pediatric patients after hematopoietic stem cell transplantation: a systematic review and meta-analysis. Pediatr Nephrol. 2024;39(2):397-408.5. James V, Angelo J, Elbahlawan L. Kidney Injury in Children after Hematopoietic Stem Cell Transplant. Curr Oncol. 2023;30(3):3329-43.6. Richardson PG, Smith AR, Kernan NA, Lehmann L, Soiffer RJ, Ryan RJ, et al. Pooled analysis of Day 100 survival for defibrotide-treated patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome and ventilator or dialysis dependence following haematopoietic cell transplantation. Br J Haematol. 2020.7. Mahadeo KM, McArthur J, Adams RH, Radhi M, Angelo J, Jeyapalan A, et al. Consensus Report by the Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplant Consortium Joint Working Committees on Supportive Care Guidelines for Management of Veno-Occlusive Disease in Children and Adolescents: Part 2-Focus on Ascites, Fluid and Electrolytes, Renal, and Transfusion Issues. Biol Blood Marrow Transplant. 2017;23(12):2023-33.8. Corbacioglu S, Carreras E, Ansari M, Balduzzi A, Cesaro S, Dalle JH, et al. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation. Bone Marrow Transplantation. 2018;53(2):138-45.9. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):c179-84.10. Goldstein SL, Currier H, Graf C, Cosio CC, Brewer ED, Sachdeva R. Outcome in children receiving continuous venovenous hemofiltration. Pediatrics. 2001;107(6):1309-12.11. Debureaux PE, Darmon M, Bige N, Moreau AS, Mokart D, Morel G, et al. Sinusoidal Obstruction Syndrome in Critically Ill Patients in the Era of Defibrotide: A Retrospective Multicenter Study. Transplant Cell Ther. 2021;27(4):338.e1-.e7.12. Richardson PG, Smith AR, Kernan NA, Lehmann L, Soiffer RJ, Ryan RJ, et al. Pooled analysis of Day 100 survival for defibrotide-treated patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome and ventilator or dialysis dependence following haematopoietic cell transplantation. Br J Haematol. 2020;190(4):583-7.13. Starr MC, Gist KM, Zang H, Ollberding NJ, Balani S, Cappoli A, et al. Continuous Kidney Replacement Therapy and Survival in Children and Young Adults: Findings From the Multinational WE-ROCK Collaborative. Am J Kidney Dis. 2024.14. Alobaidi R, Morgan C, Basu RK, Stenson E, Featherstone R, Majumdar SR, et al. Association Between Fluid Balance and Outcomes in Critically Ill Children: A Systematic Review and Meta-analysis. JAMA Pediatr. 2018;172(3):257-68.15. Raymakers-Janssen P, Lilien MR, Tibboel D, Kneyber MCJ, Dijkstra S, van Woensel JBM, et al. Epidemiology and Outcome of Critically Ill Pediatric Cancer and Hematopoietic Stem Cell Transplant Patients Requiring Continuous Renal Replacement Therapy: A Retrospective Nationwide Cohort Study. Crit Care Med. 2019;47(11):e893-e901.16. Stenson EK, Alhamoud I, Alobaidi R, Bottari G, Fernandez S, Fuhrman DY, et al. Factors associated with successful liberation from continuous renal replacement therapy in children and young adults: analysis of the worldwide exploration of renal replacement outcomes collaborative in Kidney Disease Registry. Intensive Care Med. 2024.
Table 1. Characteristics of survivors and non-survivors