Mortality Risk Factors in Pediatric Onco-Critical Care Patients and Machine Learning Derived Early Onco-Critical Care Phenotypes in a Retrospective Cohort.

OBJECTIVES: To use supervised and unsupervised statistical methodology to determine risk factors associated with mortality in critically ill pediatric oncology patients to identify patient phenotypes of interest for future prospective study. DESIGN: This retrospective cohort study included nonsurgical pediatric critical care admissions from January 2017 to December 2018. We determined the prevalence of multiple organ failure (MOF), ICU mortality, and associated factors. Consensus k-means clustering analysis was performed using 35 bedside admission variables for early, onco-critical care phenotype development. SETTING: Single critical care unit in a subspeciality pediatric hospital. INTERVENTION: None. PATIENTS: There were 364 critical care admissions in 324 patients with underlying malignancy, hematopoietic cell transplant, or immunodeficiency reviewed. MEASUREMENTS: Prevalence of multiple organ failure, ICU mortality, determination of early onco-critical care phenotypes. MAIN RESULTS: ICU mortality was 5.2% and was increased in those with MOF (18.4% MOF, 1.7% single organ failure [SOF], 0.6% no organ failure; p ≤ 0.0001). Prevalence of MOF was 23.9%. Significantly increased ICU mortality risk was associated with day 1 MOF (hazards ratio [HR] 2.27; 95% CI, 1.10-6.82; p = 0.03), MOF during ICU admission (HR 4.16; 95% CI, 1.09-15.86; p = 0.037), and with invasive mechanical ventilation requirement (IMV; HR 5.12; 95% CI, 1.31-19.94; p = 0.018). Four phenotypes were derived (PedOnc1-4). PedOnc1 and 2 represented patient groups with low mortality and SOF. PedOnc3 was enriched in patients with sepsis and MOF with mortality associated with liver and renal dysfunction. PedOnc4 had the highest frequency of ICU mortality and MOF characterized by acute respiratory failure requiring invasive mechanical ventilation at admission with neurologic dysfunction and/or severe sepsis. Notably, most of the mortality in PedOnc4 was early (i.e., within 72 hr of ICU admission). CONCLUSIONS: Mortality was lower than previously reported in critically ill pediatric oncology patients and was associated with MOF and IMV. These findings were further validated and expanded by the four derived nonsynonymous computable phenotypes. Of particular interest for future prospective validation and correlative biological study was the PedOnc4 phenotype, which was composed of patients with hypoxic respiratory failure requiring IMV with sepsis and/or neurologic dysfunction at ICU admission.

Benefit of continuous kidney replacement therapy for managing tumor lysis syndrome in children with hematologic malignancies.

Introduction: Tumor lysis syndrome (TLS) is often diagnosed in children with hematological malignancies and can be life threatening due to metabolic disturbances. Continuous renal replacement therapy (CKRT) can reverse these disturbances relatively quickly when conventional medical management fails. Our objective was to investigate the benefit of CKRT in the management of TLS in children admitted to the intensive care unit with hematologic malignancies. In addition, we sought to assess risk factors for acute kidney injury (AKI) in the setting of TLS. Methods: Retrospective review of all children admitted to the intensive care unit with TLS who received CKRT from January 2012 to August 2022. Results: Among 222 children hospitalized with TLS from January 2012 to August 2022, 20 (9%) underwent CKRT to manage TLS in the intensive care unit. The patients' median age was 13 years (range 3-17 y), and most were males (18/20). T-cell acute lymphoblastic leukemia was the most common diagnosis (n=10), followed by acute myeloid leukemia (n=4), Burkitt lymphoma (n=4), and B-cell acute lymphoblastic leukemia (n=2). Five patients required mechanical ventilation, and 2 required vasopressors. The most common indication for CKRT was hyperphosphatemia, followed by, hyperuricemia, and hyperkalemia. All metabolic abnormalities corrected within 12 h of initiation of CKRT. CKRT courses were brief, with a median duration of 2 days (range 1-7 days). Having higher serum phosphorus levels 12 h preceding CKRT was significantly associated with severe acute kidney injury (AKI). The median phosphorus level was 6.4 mg/dL in children with no/mild AKI and 10.5 mg/dL in children with severe AKI (p=0.0375). Serum uric acid levels before CKRT were not associated with AKI. All children survived to hospital discharge, and the one-year survival rate was 90%. Conclusion: CKRT is safe in children with hematologic malignancies with severe TLS and reverses metabolic derangements within 6-12 h. Most patients had AKI at the initiation of CKRT but did not require long-term kidney replacement therapy. Hyperphosphatemia before initiation of CKRT is associated with higher risk of AKI.

Kidney Injury in Children after Hematopoietic Stem Cell Transplant.

Hematopoietic cell transplant (HCT), used for treatment of many malignant and non-malignant pediatric diseases, is associated with serious complications, limiting this therapy's benefit. Acute kidney injury (AKI), seen often after HCT, can occur at different stages of the transplant process and contributes to morbidity and mortality after HCT. The etiology of AKI is often multifactorial, including kidney hypoperfusion, nephrotoxicity from immunosuppressive and antimicrobial agents, and other transplant-related complications such as transplant-associated thrombotic microangiopathy and sinusoidal obstructive syndrome. Early recognition of AKI is crucial to prevent further AKI and associated complications. Initial management includes identifying the etiology of AKI, preventing further kidney hypoperfusion, adjusting nephrotoxic medications, and preventing fluid overload. Some patients will require further support with kidney replacement therapy to manage fluid overload and AKI. Biomarkers of AKI, such as neutrophil gelatinase-associated lipocalin can aid in detecting AKI before a rise in serum creatinine, allowing earlier intervention. Long-term kidney dysfunction is also prominent in this population. Therefore, long-term follow-up and monitoring of renal function (glomerular filtration rate, microalbuminuria) is required along with management of hypertension, which can contribute to chronic kidney disease.

Early pulmonary complications related to cancer treatment in children.

In this review, we summarize early pulmonary complications related to cancer therapy in children and highlight characteristic findings on imaging that should be familiar to a radiologist reviewing imaging from pediatric cancer patients.

Pulmonary Complications in Children Following Hematopoietic Cell Transplantation: A Case Report and Review of the Diagnostic Approach.

Pulmonary complications are common in children following hematopoietic cell transplantation (HCT) and contribute to their morbidity and mortality. Early diagnosis is essential for management and prevention of progression of lung injury and damage. In many cases, diagnosis can be challenging and may require diagnostic imaging and more invasive testing such as bronchoscopy and lung biopsy. We report the case of a 12-year-old girl who developed recurrent episodes of acute respiratory failure requiring intensive care unit admission in the post-HCT phase and describe the diagnostic and multidisciplinary approach for her management. In addition, we review the diagnostic approach of pulmonary complications post-HCT and highlight the utility and risks of bronchoscopy and lung biopsy in these children.

Continuous Renal Replacement Therapy: A Review of Use and Application in Pediatric Hematopoietic Stem Cell Transplant Recipients.

Hematopoietic stem cell transplant (HSCT) is a curative therapy for malignant and non-malignant conditions. However, complications post-HSCT contribute to significant morbidity and mortality in this population. Acute kidney injury (AKI) is common in the post-allogeneic transplant phase and contributes to morbidity in this population. Continuous renal replacement therapy (CRRT) is used often in the setting of AKI or multiorgan dysfunction in critically ill children. In addition, CRRT can be useful in many disease processes related to transplant and can potentially improve outcomes in this population. This review will focus on the use of CRRT in critically ill children in the post-HSCT setting outside the realm of acute renal failure and highlight the benefits and applications of this modality in this high-risk population.

Pulmonary Manifestations of Hematologic and Oncologic Diseases in Children.

Pulmonary complications are common in children with hematologic or oncologic diseases, and many experience long-term effects even after the primary disease has been cured. This article reviews pulmonary complications in children with cancer, after hematopoietic stem cell transplant, and caused by sickle cell disease and discusses their management.

Outcome of Acute Respiratory Failure Secondary to Engraftment in Children After Hematopoietic Stem Cell Transplant.

Introduction: Respiratory complications due to engraftment syndrome (ES) in the post-hematopoietic stem cell transplant (HSCT) setting can lead to acute respiratory failure (ARF). Outcomes of children developing ARF due to engraftment are unknown. Methods: We conducted a retrospective analysis of 1,527 pediatric HSCT recipients and identified children who developed ARF due to ES over a 17-year period. Thirty patients that developed ARF and required invasive mechanical ventilation (IMV) due to ES were included in this study. Results: The survival rate for our cohort was 80% [alive at intensive care unit (ICU) discharge]. The most common underlying primary disease was hematologic malignancy, and 67% of children underwent allogeneic HSCT. Further, 73% required vasopressor drips and 23% underwent dialysis. Survivors had a shorter median ICU length of stay than did non-survivors (15 vs. 40 days, respectively, p = 0.01). Survivors had a significantly lower median cumulative fluid overload % on days 4 and 5 after initiation of IMV than did non-survivors (2.8 vs. 14.0 ml/kg, p = 0.038 on day 4, and 1.8 vs. 14.9 ml/kg, p = 0.044 on day 5, respectively). Conclusion: Our results suggest that children who develop ARF during engraftment have better ICU survival rates than do those with other etiologies of ARF post-HSCT. Furthermore, fluid overload contributes to mortality in these children; therefore, strategies to prevent and address fluid overload should be considered.

Use of recombinant activated factor VII for uncontrolled bleeding in a haematology/oncology paediatric ICU cohort.

: Bleeding among critically ill paediatric haematology/oncology (CIPHO) patients leads to significant morbidity and mortality. Recombinant activated factor VII (rFVIIa) has shown some benefits in previous reported off-label use when conventional therapies have failed. However, data in CIPHO are lacking. We retrospectively studied (2006-2014) the efficacy and outcomes in CIPHO patients younger than 21 years who received at least one rFVIIa dose for bleeding in the ICU. Of 39 patients, the majority had leukaemia (59%), bone marrow transplantation (77%) and a life-threatening bleed (80%) with most common site being pulmonary haemorrhage (44%). Most needed invasive mechanical ventilation (87%) or vasopressor support (59%). After rFVIIa administration, 56% had cessation or decreased bleeding. Packed red blood cell transfusion requirements decreased significantly 48-72 h after rFVIIa administration. Lower baseline prothrombin time and more rFVIIa doses were related to bleeding control. A favourable response was associated with higher survival (55% in responders versus 18% in nonresponders, P = 0.019). Overall, bleeding-related mortality was 37.5%, highest in pulmonary haemorrhage. Two patients had thromboembolic events. Use of rFVIIa for CIPHO patients appears to be well tolerated with low adverse events. Despite half of the patients having a favourable response of cessation or decrease in bleeding after rFVIIa administration, mortality was high. These findings highlight the need for prospective studies to evaluate interventions to improve outcomes in this population.

Efficacy and Safety of Recombinant Activated Factor VII Off-label Use in a Pediatric Hematology/Oncology Cohort.

BACKGROUND: Recombinant activated factor VII (rFVIIa) has been used off-label to treat or prevent severe bleeding in patients for whom conventional treatments are unsuccessful. However, studies in children remain limited. PROCEDURE: To examine the efficacy and safety of rFVIIa, we performed a retrospective analysis of rFVIIa off-label use in a pediatric hematology/oncology cohort at a single center from 2006 to 2014. RESULTS: Of 58 patients identified, 46 (79.3%) received rFVIIa to treat bleeding and 12 (20.7%) to prevent bleeding. Thirty-three (71.7%) patients had life-threatening bleeding. In the treatment group, 63.0% patients were responders (ie, bleeding decreased or stopped) and 37.0% were nonresponders (ie, bleeding did not change). Blood products usage was similar between responders and nonresponders. After rFVIIa administration, prothrombin time, partial thromboplastin time and lactate were significantly lower, but fibrinogen was significantly higher in responders than nonresponders. Venous thromboembolism developed in 5.2% (3/58) patients, but its relation to rFVIIa remains unclear. Responders had significantly lower mortality than nonresponders (17.2% vs. 82.4%, P<0.0001). CONCLUSIONS: rFVIIa controlled most bleeding events in this cohort, despite predominance of life-threatening bleeding, suggesting good efficacy. Venous thromboembolism rate was low. Further studies are warranted to identify predictors of favorable response to rFVIIa in similar patients.

Respiratory Care Considerations in the Childhood Cancer Patient.

This article reviews the common pulmonary complications seen in the pediatric oncology population and our approach to diagnosis, management, and therapy considerations in this specialized population, including patients receiving chemotherapy, radiation, and hematopoietic stem cell transplantation. Although infections cause the most significant complications in this population, non-infectious complications, including acute lung injury from chemotherapy or radiation, idiopathic interstitial pneumonia, diffuse alveolar hemorrhage, bronchiolitis obliterans, and cryptogenic organizing pneumonia, also occur commonly. With improvements in survival of childhood cancer, there are now a growing number of adults who are childhood cancer survivors who may be encountered by therapists in adult hospitals. We also review the growing literature on the emerging late pulmonary findings in these adult childhood cancer survivors.

Safety and Benefits of Bronchoalveolar Lavage and Lung Biopsy in the Management of Pulmonary Infiltrates in Children With Leukemia.

BACKGROUND: Children with leukemia are at risk of developing life-threatening opportunistic pulmonary infections. The role of bronchoalveolar lavage (BAL) and lung biopsy (BX) in the management of these patients is controversial. In this study, we evaluate the yield and safety of BAL and BX in children with leukemia. PROCEDURE: We reviewed the records of all children with leukemia who underwent either BAL or BX between 1997 and 2007 at the St Jude Children's Research Hospital. RESULTS: A total of 64 patients were included, of whom 35 (55%) had BX and 29 (45%) had BAL. Positive results were obtained in 69% of BAL cohort and in 46% of BX cohort. Both procedures resulted in change in antimicrobial coverage (77% in BX, 83% in BAL). Pulmonary hemorrhage occurred in 2 patients, and transient hypoxia was the most frequent complication. All resolved without negatively impacting the clinical course. CONCLUSIONS: Both BAL and BX are safe and useful in the management of children with leukemia and pulmonary disease.

A Critical Care and Transplantation-Based Approach to Acute Respiratory Failure after Hematopoietic Stem Cell Transplantation in Children.

Acute respiratory failure contributes significantly to nonrelapse mortality after allogeneic hematopoietic stem cell transplantation. Although there is a trend of improved survival over time, mortality remains unacceptably high. An understanding of the pathophysiology of early respiratory failure, opportunities for targeted therapy, assessment of the patient at risk, optimal use of noninvasive positive pressure ventilation, strategies to improve alveolar recruitment, appropriate fluid management, care of the patient with chronic lung disease, and importantly, a team approach between critical care and transplantation services may improve outcomes.

Continuous renal replacement therapy in children post-hematopoietic stem cell transplantation: the present and the future.

Allogeneic hematopoietic stem cell transplantation (HSCT) use has expanded markedly to treat different disorders like hematologic malignancies, immunodeficiency, and inborn errors of metabolism. However, it is commonly associated with complications that limit the benefit of this therapy. Acute renal failure occurs commonly after HSCT and results in increased risk of mortality. In many instances, children post-HSCT develop acute renal insufficiency in the context of other organ failure, necessitating intensive care unit admission for management. Recently, continuous renal replacement therapy (CRRT) has emerged as the favored modality of renal replacement therapy in the care of critically ill children who are hemodynamically unstable. Currently, CRRT is being utilized more often in the care of critically ill post- HSCT children to treat renal failure or to prevent fluid overload (FO). FO > 20% has been shown in many studies to be an independent risk of mortality in critically ill children and therefore, many clinicians will initiate this therapy due to FO even without overt renal failure. CRRT may be beneficial in disease processes as acute lung injury due to removal of fluid. CRRT results in improved oxygenation in post-HSCT children with acute lung injury and this improvement is sustained for at least 48 hours after initiation of this therapy. Survival in post-HSCT children requiring this therapy ranges from 17% to 45%, however, long term survival is still poor. This review will discuss current practice of CRRT in children post-HSCT, as well as future directions.

Association of IL-1ß -511 polymorphism with severe veno-occlusive disease in pediatric-matched allogeneic hematopoietic stem cell transplantation.

Single nucleotide polymorphisms (SNPs) of the interleukin 1 (IL-1) family have been implicated in acute graft-versus-host disease and mortality postallogeneic hematopoietic stem cell transplantation (HSCT) in adults. Hepatic veno-occlusive disease (VOD) is a well-known complication of HSCT and can result in an increased risk of mortality. In this study, we sought to investigate the association of both patient and donor genotypes at the IL-1ß -511 cytidine/thymidine (C/T) polymorphic site with hepatic VOD and mortality in an exclusive pediatric cohort undergoing matched myeloablative allogeneic HSCT. Donor TT genotype was associated with higher cumulative incidence of grade III-IV hepatic VOD at 3 months after transplantation relative to donor CT and CC genotypes (25±13.1% in TT, 2.9±2.9% in CT, and 3.6±3.6% in CC; P=0.024). Neither recipient nor donor IL-1ß -511 single nucleotide polymorphisms genotypes were associated with mortality or relapse. Our findings suggest that donor, rather than host, genotype at the IL-1ß -511 polymorphic site may associate with higher risk for severe VOD after matched allogeneic HSCT. Our findings challenge the assumption that host factors are exclusively responsible for VOD and suggest a novel role for the donor inflammasome pathway in inducing injury and microvascular disease after HSCT, which merits further study in a larger cohort analysis.

Impact of neutrophil recovery on oxygenation in pediatric oncology patients with acute hypoxemic respiratory failure.

Neutrophil recovery has been implicated in deterioration of oxygenation and exacerbation of lung injury in pediatric oncology patients. Our objectives were to determine the impact of neutrophil recovery on oxygenation in pediatric oncology patients with acute hypoxemic respiratory failure (AHRF) and to identify risk factors that result in oxygenation worsening. A cohort of 24 neutropenic pediatric oncology patients with AHRF in whom neutrophil recovery occurred during a course of mechanical ventilation was evaluated. Oxygenation index (OI) and PaO(2)/FiO(2) ratio showed a trend of improvement after neutrophil recovery. Mean PaO(2)/FiO(2) pre-recovery was 205±48.67 versus 225±72.24 postrecovery (P=0.08), whereas mean pre-recovery OI was 9.39±0.96 compared with 8.31±1.1 postrecovery (P=0.078). Seven episodes (24% of the total episodes) of recovery were characterized by worsening of oxygenation. Tripling absolute neutrophil count on Day+2 compared with Day+1 postrecovery was associated with 28-fold increase in risk of oxygenation worsening. In conclusion, resolution of neutropenia lead to significant deterioration of oxygenation in 24% of episodes of neutrophil recovery in a pediatric oncology cohort with AHRF. Our findings suggest that a faster ANC increment in the 2 days after recovery is associated with an increased risk of oxygenation worsening.

Severe H1N1-associated acute respiratory failure in immunocompromised children.

BACKGROUND: Severe pandemic influenza A (H1N1) infection can lead to acute respiratory failure (ARF) with associated high mortality. Children with malignancy may be at higher risk of H1N1-associated ARF because of underlying primary disease or immunosuppression associated with chemotherapy. PROCEDURE: We describe the clinical course and outcome of critically ill pediatric oncology/hematology patients with H1N1-associated ARF. RESULTS: Five patients were admitted to the St. Jude Children's Research Hospital (SJCRH) ICU with H1N1 infection during the 2009-2010 influenza season. Underlying diagnoses included 2 patients with acute lymphoblastic leukemia and one each with neuroblastoma, brainstem glioma, and hemolytic anemia secondary to pyruvate kinase deficiency. All patients were mechanically ventilated secondary to ARF following unsuccessful trials of non-invasive ventilatory support. The majority of patients (4/5) required inotropic support, and none required dialysis. Further measures to support their ARF included high frequency oscillatory ventilation in 2 patients, nitric oxide in 3 patients, and surfactant in 1 patient. Three patients had bronchopleural air leak. All patients received oseltamivir; however, 2 were switched to intravenous zanamivir once resistance to oseltamivir was documented. Mean duration of mechanical ventilation was 24 ± 6.8 days and mean duration of ICU admission was 37 ± 12 days. All patients survived to hospital discharge. CONCLUSION: Our series suggests an overall favorable outcome in immunocompromised children with H1N1-related ARF. Our experience underscores the value of aggressive support during H1N1-related ARF, and early detection and management of oseltamivir-resistant H1N1 infection in this high-risk population.

Impact of continuous renal replacement therapy on oxygenation in children with acute lung injury after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Acute lung injury (ALI) continues to carry a high mortality rate in children after allogeneic hematopoietic stem cell transplant (HSCT). Continuous renal replacement therapy (CRRT) is often used for these patients for various indications including renal failure and fluid overload, and may have a beneficial effect on oxygenation and survival. Therefore, we sought to determine the effect of CRRT on oxygenation in mechanically ventilated pediatric allogeneic HSCT patients with ALI, and to document survival to intensive care unit discharge in this at-risk population receiving both mechanical ventilation and CRRT. PROCEDURE: Retrospective analysis of a pediatric allogeneic HSCT cohort admitted to intensive care unit of a single pediatric oncology center from 1994 to 2006 who received CRRT during a course of mechanical ventilation for ALI. RESULTS: Thirty post-HSCT mechanically ventilated children with ALI who underwent CRRT were included. There was a significant improvement in PaO(2)/FiO(2) with median increase of 31 and 43 in the 24 and 48 hr intervals after initiation of CRRT compared with the 24 hr interval before CRRT (P = 0.0008 and 0.0062, respectively). This improvement in PaO(2)/FiO(2) correlated significantly with reduction of fluid balance achieved after initiation of CRRT (P = 0.0001). There was a trend not reaching statistical significance in improvement in mean airway pressure 48 hr after CRRT in survivors compared to non-survivors. CONCLUSIONS: CRRT improved oxygenation in mechanically ventilated pediatric allogeneic HSCT patients with ALI.

Outcomes of hematopoietic stem cell transplant patients who received continuous renal replacement therapy in a pediatric oncology intensive care unit.

OBJECTIVES: To assess the long-term benefits of continuous renal replacement therapy (CRRT) in this patient population and to analyze factors associated with survival. Hematopoietic stem cell transplantation is being utilized as curative therapy for a variety of disorders. However, organ dysfunction is commonly associated with this therapy. Continuous renal replacement therapy (CRRT) is increasingly being used in the treatment of this multiorgan dysfunction. DESIGN: Retrospective cohort study. SETTING: A free-standing, tertiary care, pediatric oncology hospital. PATIENTS: Twenty-nine allogeneic hematopoietic stem cell transplantation patients who underwent 33 courses of CRRT in the intensive care unit between January 2003 and December 2007. INTERVENTIONS: Cox proportional hazards regressions models were used to examine the relationship between demographic and clinical variables and length of survival. MEASUREMENTS AND MAIN RESULTS: The median length of survival post CRRT initiation was 31 days; only one patient survived >6 mos. Factors associated with increased risk of death included: higher bilirubin and blood urea nitrogen levels before and at 48 hrs into CRRT, lower Pao2/Fio2 ratios at 48 hrs of CRRT, and higher C-reactive protein levels, as well as lower absolute neutrophil counts at CRRT end. CONCLUSION: In this single-center study, CRRT was not associated with long-term survival in pediatric allogeneic hematopoietic stem cell transplantation patients. Clinical data exist, both before and during CRRT, that may be associated with length of survival. Lower C-reactive protein levels at CRRT end were associated with longer survival, suggesting that the ability to attenuate inflammation during CRRT may afford a survival advantage. These findings require confirmation in a prospective study.

Successful use of a rapid response team in the pediatric oncology outpatient setting.

In a clinic setting, the RRT, in conjunction with the ICU intensivist, succesfully treated a septic patient with fluid resuscitation and a vasoactive medication, and subsequently facilitated a quick transport to a higher level of care. St. Jude Children's Research Hospital's successful use of the RRT in the clinic setting suggests that RRTs can be used to improve patient outcomes across the spectrum of inpatient as well as outpatient hospital settings. Our experience suggests that RRTs can be beneficial in filling a gap in patient safety in outpatient clinics.