Pediatric Hematology and Oncology Patients on Extracorporeal Membrane Oxygenation: Outcomes in a Multicenter, Retrospective Cohort 2009-2021.

OBJECTIVE: To describe characteristics associated with survival for pediatric patients with an oncologic diagnosis or hematopoietic cell transplant (HCT) supported with extracorporeal membrane oxygenation (ECMO). DESIGN: Multicenter, retrospective study. SETTING: Sixteen PICUs in the United States and Israel. PATIENTS: We included patients aged younger than 19 years with an oncologic diagnosis or HCT who required ECMO support between 2009 and 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 149 patients were included in the study cohort. There were 118 patients with an oncologic diagnosis and 31 that received HCT. The indications for ECMO were respiratory failure (46%), combined respiratory and cardiac failure (28%), and cardiac failure (25%). Venovenous (V-V) ECMO was used in 45% of patients, with 53% of patients being placed on venoarterial (V-A) ECMO. For oncologic and HCT groups, survival to ECMO decannulation was 52% (62/118) and 64% (20/31), and survival to hospital discharge was 36% (43/118) and 42% (13/31), respectively. After adjusting for other factors, requiring cardiopulmonary resuscitation was associated with greater odds ratio of mortality (3.0 [95% CI, 1.2-7.7]). CONCLUSIONS: Survival to ECMO decannulation of pediatric oncologic and HCT patients in this study was 52-64%, depending upon diagnosis. However, survival to hospital discharge remains poor. Future research should prioritize understanding factors contributing to this survival gap within these patient populations.

Severe Pediatric Neurological Manifestations With SARS-CoV-2 or MIS-C Hospitalization and New Morbidity.

Importance: Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity. Objective: To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge. Design, Setting, and Participants: This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021. Exposure: Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke. Main Outcomes and Measures: The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2-related condition. Results: Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P < .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations (P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge. Conclusions and Relevance: The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery.

Flexible Bronchoscopy in Pediatric Venovenous Extracorporeal Membrane Oxygenation.

BACKGROUND: Pediatric patients with ARDS will on occasion need venovenous extracorporeal membrane oxygenation (VV-ECMO) for organ support. As these patients recover, they may benefit from lung recruitment maneuvers including flexible bronchoscopy (FB). The objective of this study was to assess the clinical course of patients who underwent FB while on VV-ECMO for ARDS. METHODS: This was a secondary analysis of a retrospective multi-center cohort at 10 United States pediatric academic quaternary care centers. Data were collected on 204 subjects age 14 d-18 y on VV-ECMO. RESULTS: 271 FBs were performed on 129 (63%) subjects. Pre-FB tidal volume was 1.8 mL/kg compared to 2.22 mL/kg following FB (P = .007). Dynamic compliance also improved from pre-FB to post-FB (2.23 vs 3.04 mL/cm H2O, P = .005). There was a low incidence of complications following FB (3.1%). Subjects in the FB group had fewer ECMO-free days (EFDs) (17.9 vs 22.1 d, P < .001), fewer ventilator-free days (VFDs) (40.0 vs 46.5 d, P = .001), and longer ICU length of stay (LOS) (18 vs 32 d, P < .001). Subjects in the early versus late FB group had more EFDs (19.4 vs 15.2 d, P = .003), more VFDs (43.0 vs 34.0 d, P = .004), and shorter ICU LOS (27.5 vs 35.5 d, P = .045). Mortality in the subjects who had at least one FB was 27.1% compared to 40% in the subjects who did not have a FB while on VV-ECMO (P = .057). CONCLUSIONS: FB can be performed on patients while anticoagulated on VV-ECMO with a low incidence of complications. FB may be beneficial especially when performed early in the course of VV-ECMO.

Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C.

BACKGROUND: Our objective was to characterize the frequency, early impact, and risk factors for neurological manifestations in hospitalized children with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or multisystem inflammatory syndrome in children (MIS-C). METHODS: Multicenter, cross-sectional study of neurological manifestations in children aged <18 years hospitalized with positive SARS-CoV-2 test or clinical diagnosis of a SARS-CoV-2-related condition between January 2020 and April 2021. Multivariable logistic regression to identify risk factors for neurological manifestations was performed. RESULTS: Of 1493 children, 1278 (86%) were diagnosed with acute SARS-CoV-2 and 215 (14%) with MIS-C. Overall, 44% of the cohort (40% acute SARS-CoV-2 and 66% MIS-C) had at least one neurological manifestation. The most common neurological findings in children with acute SARS-CoV-2 and MIS-C diagnosis were headache (16% and 47%) and acute encephalopathy (15% and 22%), both P < 0.05. Children with neurological manifestations were more likely to require intensive care unit (ICU) care (51% vs 22%), P < 0.001. In multivariable logistic regression, children with neurological manifestations were older (odds ratio [OR] 1.1 and 95% confidence interval [CI] 1.07 to 1.13) and more likely to have MIS-C versus acute SARS-CoV-2 (OR 2.16, 95% CI 1.45 to 3.24), pre-existing neurological and metabolic conditions (OR 3.48, 95% CI 2.37 to 5.15; and OR 1.65, 95% CI 1.04 to 2.66, respectively), and pharyngeal (OR 1.74, 95% CI 1.16 to 2.64) or abdominal pain (OR 1.43, 95% CI 1.03 to 2.00); all P < 0.05. CONCLUSIONS: In this multicenter study, 44% of children hospitalized with SARS-CoV-2-related conditions experienced neurological manifestations, which were associated with ICU admission and pre-existing neurological condition. Posthospital assessment for, and support of, functional impairment and neuroprotective strategies are vitally needed.

Extracorporeal Membrane Oxygenation Candidacy in Pediatric Patients Treated With Hematopoietic Stem Cell Transplant and Chimeric Antigen Receptor T-Cell Therapy: An International Survey.

INTRODUCTION: Pediatric patients who undergo hematopoietic cell transplant (HCT) or chimeric antigen receptor T-cell (CAR-T) therapy are at high risk for complications leading to organ failure and the need for critical care resources. Extracorporeal membrane oxygenation (ECMO) is a supportive modality that is used for cardiac and respiratory failure refractory to conventional therapies. While the use of ECMO is increasing for patients who receive HCT, candidacy for these patients remains controversial. We therefore surveyed pediatric critical care and HCT providers across North America and Europe to evaluate current provider opinions and decision-making and institutional practices regarding ECMO use for patients treated with HCT or CAR-T. METHODS: An electronic twenty-eight question survey was distributed to pediatric critical care and HCT providers practicing in North America (United States and Canada) and Europe through the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network and individual emails. Responses to the survey were recorded in a REDCap® database. RESULTS: Two-hundred and ten participants completed the survey. Of these, 159 (76%) identified themselves as pediatric critical care physicians and 47 (22%) as pediatric HCT physicians or oncologists. The majority (99.5%) of survey respondents stated that they would consider patients treated with HCT or CAR-T therapy as candidates for ECMO support. However, pediatric critical care physicians identified more absolute and relative contraindications for ECMO than non-pediatric critical care physicians. While only 0.5% of respondents reported that they consider HCT as an absolute contraindication for ECMO, 6% of respondents stated that ECMO is contraindicated in HCT patients within their institution and only 23% have an institutional protocol or policy to guide the evaluation for ECMO candidacy of these patients. Almost half (49.1%) of respondents would accept a survival to hospital discharge of 20-30% for pediatric HCT patients requiring ECMO as adequate. CONCLUSIONS: ECMO use for pediatric patients treated with HCT and CAR-T therapy is generally acceptable amongst physicians. However, there are differences in the evaluation and decision-making regarding ECMO candidacy amongst providers across medical specialties and institutions. Therefore, multidisciplinary collaboration is an essential component in establishing practice guidelines and advancing ECMO outcomes for these patients.

Tracheostomy and long-term mechanical ventilation in children after veno-venous extracorporeal membrane oxygenation.

OBJECTIVE: Our objective is to characterize the incidence of tracheostomy placement and of new requirement for long-term mechanical ventilation after extracorporeal membrane oxygenation (ECMO) among children with acute respiratory failure. We examine whether an association exists between demographics, pre-ECMO and ECMO clinical factors, and the placement of a tracheostomy or need for long-term mechanical ventilation. METHODS: A retrospective multicenter cohort study was conducted at 10 quaternary care pediatric academic centers, including children supported with veno-venous (V-V) ECMO from 2011 to 2016. RESULTS: Among 202 patients, 136 (67%) survived to ICU discharge. All tracheostomies were placed after ECMO decannulation, in 22 patients, with 19 of those surviving to ICU discharge (14% of survivors). Twelve patients (9% of survivors) were discharged on long-term mechanical ventilation. Tracheostomy placement and discharge on home ventilation were not associated with pre-ECMO severity of illness or pre-existing chronic illness. Patients who received a tracheostomy were older and weighed more than patients who did not receive a tracheostomy, although this association did not exist among patients discharged on home ventilation. ECMO duration was longer in those who received a tracheostomy compared with those who did not, as well as for those discharged on home ventilation, compared to those who were not. CONCLUSION: The 14% rate for tracheostomy placement and 9% rate for discharge on long-term mechanical ventilation after V-V ECMO are important patient-centered findings. This study informs anticipatory guidance provided to families of patients requiring prolonged respiratory ECMO support, and lays the foundation for future research.

Veno-Venous Extracorporeal Membrane Oxygenation for Children With Cancer or Hematopoietic Cell Transplant: A Ten Center Cohort.

We performed a multicenter retrospective cohort study of children with 14 days to 18 years of age in the United States from 2011 to 2016 with cancer or hematopoietic cell transplant (HCT) who were supported with veno-venous extracorporeal membrane oxygenation (V-V ECMO). We compared the outcomes of children with oncological diagnoses or HCT supported with V-V ECMO to other children who have received V-V ECMO support. In this cohort of 204 patients supported with V-V ECMO, 30 (15%) had a diagnosis of cancer or a history of HCT. There were 21 patients who had oncological diagnoses without HCT and 9 children were post-HCT. The oncology/HCT group had a higher overall ICU mortality (67% vs. 28%, P < 0.001), mortality on ECMO (43% vs. 21%, P < 0.01), and ICU mortality among ECMO survivors (35% vs. 8%, P < 0.01). The oncology/HCT group had a higher rate of conversion to veno-arterial (V-A) ECMO (23% vs. 9%, P = 0.02) (RR, 2.5; 95% CI, 1.1-5.6). Children with cancer or HCT were older (6.6 vs. 2.9 years, P = 0.02) and had higher creatinine levels (0.65 vs. 0.4 mg/dL, P = 0.04) but were similar to the rest of the cohort for other pre-ECMO variables. For post-HCT patients, survival was significantly worse for those whose indication for HCT was cancer or immunodeficiency (0/6) as compared to other nonmalignant indications (3/3) (P = 0.01).

Extracorporeal Life Support Organization (ELSO): 2020 Pediatric Respiratory ELSO Guideline.

DISCLAIMER: This guideline describes prolonged extracorporeal life support (ECLS) and extracorporeal membrane oxygenation (ECMO), applicable to Pediatric respiratory failure. These guidelines describe useful and safe practice, prepared by ELSO and based on extensive experience and are considered consensus guidelines. These guidelines are not intended to define standard of care and are revised at regular intervals as new information, devices, medications, and techniques become available.

Mechanical Ventilation in Children on Venovenous ECMO.

BACKGROUND: Venovenous extracorporeal membrane oxygenation (VV-ECMO) is used when mechanical ventilation can no longer support oxygenation or ventilation, or if the risk of ventilator-induced lung injury is considered excessive. The optimum mechanical ventilation strategy once on ECMO is unknown. We sought to describe the practice of mechanical ventilation in children on VV-ECMO and to determine whether mechanical ventilation practices are associated with clinical outcomes. METHODS: We conducted a multicenter retrospective cohort study in 10 pediatric academic centers in the United States. Children age 14 d through 18 y on VV-ECMO from 2011 to 2016 were included. Exclusion criteria were preexisting chronic respiratory failure, primary diagnosis of asthma, cyanotic heart disease, or ECMO as a bridge to lung transplant. RESULTS: Conventional mechanical ventilation was used in about 75% of children on VV-ECMO; the remaining subjects were managed with a variety of approaches. With the exception of PEEP, there was large variation in ventilator settings. Ventilator mode and pressure settings were not associated with survival. Mean ventilator FIO2 on days 1-3 was higher in nonsurvivors than in survivors (0.5 vs 0.4, P = .009). In univariate analysis, other risk factors for mortality were female gender, higher Pediatric Risk Estimate Score for Children Using Extracorporeal Respiratory Support (Ped-RESCUERS), diagnosis of cancer or stem cell transplant, and number of days intubated prior to initiation of ECMO (all P < .05). In multivariate analysis, ventilator FIO2 was significantly associated with mortality (odds ratio 1.38 for each 0.1 increase in FIO2 , 95% CI 1.09-1.75). Mortality was higher in subjects on high ventilator FIO2 (≥ 0.5) compared to low ventilator FIO2 (> 0.5) (46% vs 22%, P = .001). CONCLUSIONS: Ventilator mode and some settings vary in practice. The only ventilator setting associated with mortality was FIO2 , even after adjustment for disease severity. Ventilator FIO2 is a modifiable setting that may contribute to mortality in children on VV-ECMO.

Alveolar Macrophage Chemokine Secretion Mediates Neutrophilic Lung Injury in Nox2-Deficient Mice.

Acute lung injury (ALI), developing as a component of the systemic inflammatory response syndrome (SIRS), leads to significant morbidity and mortality. Reactive oxygen species (ROS), produced in part by the neutrophil NADPH oxidase 2 (Nox2), have been implicated in the pathogenesis of ALI. Previous studies in our laboratory demonstrated the development of pulmonary inflammation in Nox2-deficient (gp91phox-/y) mice that was absent in WT mice in a murine model of SIRS. Given this finding, we hypothesized that Nox2 in a resident cell in the lung, specifically the alveolar macrophage, has an essential anti-inflammatory role. Using a murine model of SIRS, we examined whole-lung digests and bronchoalveolar lavage fluid (BALf) from WT and gp91phox-/y mice. Both genotypes demonstrated neutrophil sequestration in the lung during SIRS, but neutrophil migration into the alveolar space was only present in the gp91phox-/y mice. Macrophage inflammatory protein (MIP)-1α gene expression and protein secretion were higher in whole-lung digest from uninjected gp91phox-/y mice compared to the WT mice. Gene expression of MIP-1α, MCP-1, and MIP-2 was upregulated in alveolar macrophages obtained from gp91phox-/y mice at baseline compared with WT mice. Further, ex vivo analysis of alveolar macrophages, but not bone marrow-derived macrophages or peritoneal macrophages, demonstrated higher gene expression of MIP-1α and MIP-2. Moreover, isolated lung polymorphonuclear neutrophils migrate to BALf obtained from gp91phox-/y mice, further providing evidence of a cell-specific anti-inflammatory role for Nox2 in alveolar macrophages. We speculate that Nox2 represses the development of inflammatory lung injury by modulating chemokine expression by the alveolar macrophage.

Nox2 Regulates Platelet Activation and NET Formation in the Lung.

The mortality rate of patients with critical illness has decreased significantly over the past two decades, but the rate of decline has slowed recently, with organ dysfunction as a major driver of morbidity and mortality. Among patients with the systemic inflammatory response syndrome (SIRS), acute lung injury is a common component with serious morbidity. Previous studies in our laboratory using a murine model of SIRS demonstrated a key role for NADPH oxidase 2 (Nox2)-derived reactive oxygen species in the resolution of inflammation. Nox2-deficient (gp91phox-/y) mice develop profound lung injury secondary to SIRS and fail to resolve inflammation. Alveolar macrophages from gp91phox-/y mice express greater levels of chemotactic and pro-inflammatory factors at baseline providing evidence that Nox2 in alveolar macrophages is critical for homeostasis. Based on the lung pathology with increased thrombosis in gp91phox-/y mice, and the known role of platelets in the inflammatory process, we hypothesized that Nox2 represses platelet activation. In the mouse model, we found that platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) and CXCL7 were increased in the bronchoalveolar fluid of gp91phox-/y mice at baseline and 24 h post intraperitoneal zymosan-induced SIRS consistent with platelet activation. Activated platelets interact with leukocytes via P-selectin glycoprotein ligand 1 (PSGL-1). Within 2 h of SIRS induction, alveolar neutrophil PSGL-1 expression was higher in gp91phox-/y mice. Platelet-neutrophil interactions were decreased in the peripheral blood of gp91phox-/y mice consistent with movement of activated platelets to the lung of mice lacking Nox2. Based on the severe lung pathology and the role of platelets in the formation of neutrophil extracellular traps (NETs), we evaluated NET production. In contrast to previous studies demonstrating Nox2-dependent NET formation, staining of lung sections from mice 24 h post zymosan injection revealed a large number of citrullinated histone 3 (H3CIT) and myeloperoxidase positive cells consistent with NET formation in gp91phox-/y mice that was virtually absent in WT mice. In addition, H3CIT protein expression and PAD4 activity were higher in the lung of gp91phox-/y mice post SIRS induction. These results suggest that Nox2 plays a critical role in maintaining homeostasis by regulating platelet activation and NET formation in the lung.

Neutrophil azurophilic granule exocytosis is primed by TNF-α and partially regulated by NADPH oxidase.

Neutrophil (polymorphonuclear leukocyte) activation with release of granule contents plays an important role in the pathogenesis of acute lung injury, prompting clinical trials of inhibitors of neutrophil elastase. Despite mounting evidence for neutrophil-mediated host tissue damage in a variety of disease processes, mechanisms regulating azurophilic granule exocytosis at the plasma membrane, and thus release of elastase and other proteases, are poorly characterized. We hypothesized that azurophilic granule exocytosis would be enhanced under priming conditions similar to those seen during acute inflammatory events and during chronic inflammatory disease, and selected the cytokine TNF-α to model this in vitro. Neutrophils stimulated with TNF-α alone elicited intracellular reactive oxygen species (ROS) generation and mobilization of secretory vesicles, specific, and gelatinase granules. p38 and ERK1/2 MAPK were involved in these components of priming. TNF-α priming alone did not mobilize azurophilic granules to the cell surface, but did markedly increase elastase release into the extracellular space in response to secondary stimulation with N-formyl-Met-Leu-Phe (fMLF). Priming of fMLF-stimulated elastase release was further augmented in the absence of NADPH oxidase-derived ROS. Our findings provide a mechanism for host tissue damage during neutrophil-mediated inflammation and suggest a novel anti-inflammatory role for the NADPH oxidase.