Risk factors for hemolysis with centrifugal pumps in pediatric extracorporeal membrane oxygenation: Is pump replacement an answer?

INTRODUCTION: Hemolysis during pediatric extracorporeal membrane oxygenation (ECMO) is associated with increased risk for renal failure and mortality. OBJECTIVES: We aim to describe risk factors for hemolysis in pediatric ECMO supported by centrifugal pumps. METHODS: We conducted an analysis of retrospective data collected at an academic children's hospital from January 2017 to December 2019. MEASUREMENTS AND RESULTS: Plasma-free hemoglobin (PFH) levels were measured daily, and hemolysis was defined as PFH>50 mg/dL. Of 46 ECMO runs over 528 ECMO days, hemolysis occurred in 23 (58%) patients over a total of 40 (8%) ECMO days. In multivariable logistic regression models, VA-ECMO (aOR=4.69, 95% CI: 1.01-21.83) and higher hemoglobin (aOR = 1.38, 95% CI: 1.06-1.81) were independently associated with hemolysis. There were also non-significant trends toward increased risk for hemolysis with higher rotational pump speed (aOR=2.39, 95% CI: 0.75-7.65), higher packed red blood cell transfusions (aOR=1.15, 95% CI: 0.99-1.34), and higher cryoprecipitate transfusions (aOR=2.01, 95% CI: 0.83-4.86). Isolated pump exchanges that were performed in 12 patients with hemolysis led to significant decreases in PFH levels within 24 h (89 vs 11 mg/dL, p<0.01). CONCLUSIONS: Hemolysis is common in pediatric ECMO using centrifugal pumps. Avoidance of high pump speeds and conservative administration of blood products may help to mitigate the risk for hemolysis. Furthermore, pump exchange may be an effective first-line treatment for hemolysis.

Venoarterial to venovenous extracorporeal life support conversion in pediatric acute respiratory distress syndrome.

In patients with pediatric acute respiratory distress syndrome (PARDS) and hemodynamic compromise who need venoarterial (VA) extracorporeal life support (ECLS), we have adopted a strategy to promote early VA-to-venovenous (VV) conversion since 2018. A single-center retrospective review was performed of all 22 patients who underwent ECLS for PARDS from 2008 to 2019. Variables were analyzed to determine factors affecting initial cannulation mode and in-hospital mortality. Outcomes were compared between before and after 2018. Of the 22 patients, 9 patients underwent initial VA-support. Small patient size and severe cardiopulmonary compromise prior to ECLS favored initial VA- over VV-support. Lactate level and vasoactive inotrope score at 24 hours post-ECLS initiation predicted in-hospital mortality. After 2018, all five patients with initial VA-support were converted to VV-support at 4.4 ± 1.3 days post-ECLS initiation without complications. In-hospital mortality decreased after 2018 (3/9) compared with before (10/13) (p = 0.041) despite longer ECLS run time (723.4 ± 384.2 vs 286.5 ± 235.1 hours, p = 0.003). The number of ECLS-related complications per ECLS 1000 run hours decreased after 2018 (7.2 ± 4.2 vs 46.9 ± 66.5, p = 0.063). Our strategy to promote early VA-to-VV conversion may be worth further evaluation in larger cohort studies.

Total synthesis and biological evaluation of the natural product (-)-cyclonerodiol, a new inhibitor of IL-4 signaling.

In a screening program of natural compounds from fungi, the known cyclopentanoid sesquiterpene (-)-cyclonerodiol was identified as a specific inhibitor of the IL-4 induced STAT6 signaling pathway (IC50 = 9.7 µM) which is required for the differentiation of naive CD4 T cells to T helper type 2 (Th2) lymphocytes. As many allergic conditions, including allergic asthma and atopic diseases, are driven by an excessive Th2 response, STAT6 is a promising target for the development of new therapeutics. The compound was synthesized in six steps from (-)-linalool using an epoxide radical cyclization as the key step.

Inhibition of TGF-ß signaling by the fungal lactones (S)-curvularin, dehydrocurvularin, oxacyclododecindione and galiellalactone.

TGF-ß is a multifunctional cytokine that regulates cell proliferation, differentiation, apoptosis and extracellular matrix production. Deregulation of TGF-ß production or signaling plays a pivotal role in a variety of pathological processes such as cancer, metastasis, angiogenesis and fibrosis. Therefore, TGF-ß inhibitors should be promising therapeutic agents for the suppression of cancer progression and metastasis as well as fibrotic disorders. In a screening program of natural compounds from fungi inhibiting the TGF-ß dependent expression of a reporter gene in HepG2 cells, we found that the fungal lactones (S)-curvularin, dehydrocurvularin, oxacyclododecindione and galiellalactone inhibited the binding of the activated Smad2/3 transcription factors to the DNA and antagonized the cellular effects of TGF-ß including reporter gene activation and expression of TGF-ß induced genes in HepG2 and MDA-MB-231 cells. The most active compound oxacyclododecindione inhibited TGF-ß dependent reporter activity with IC50-values of 190-217 nM. In an in vitro angiogenesis assay, the fungal lactones strongly decreased the formation of capillary-like tubules of MDA-MB-231 cells on Matrigel.

Inhibition of TGF-ß signaling, vasculogenic mimicry and proinflammatory gene expression by isoxanthohumol.

TGF-ß is a multifunctional cytokine that regulates cell proliferation, differentiation, apoptosis and extracellular matrix production. Deregulation of TGF-ß production or signaling has been associated with a variety of pathological processes such as cancer, metastasis, angiogenesis and fibrosis. Therefore, TGF-ß signaling has emerged as an attractive target for the development of new cancer therapeutics. In a screening program of natural compounds from fungi inhibiting the TGF-ß dependent expression of a reporter gene in HepG2 cells, we found that the flavone isoxanthohumol inhibited the binding of the activated Smad2/3 transcription factors to the DNA and antagonized the cellular effects of TGF-ß including reporter gene activation and expression of TGF-ß induced genes in HepG2 and MDA-MB-231 cells. In an in vitro angiogenesis assay, isoxanthohumol (56 µM) strongly decreased the formation of capillary-like tubules of MDA-MB-231 cells on Matrigel. In addition, we found that isoxanthohumol blocked IFN-γ, IL-4 and IL-6 dependent Jak/Stat signaling and strongly inhibited the induction of pro-inflammatory genes in MonoMac6 cells at the transcriptional level after LPS/TPA treatment.

Maintaining Mobility in a Patient Who Is Pregnant and Has COVID-19 Requiring Extracorporeal Membrane Oxygenation: A Case Report.

OBJECTIVE: Mobilization while receiving life support interventions, including mechanical ventilation and extracorporeal membrane oxygenation (ECMO), is a recommended intensive care unit (ICU) intervention to maintain physical function. The purpose of this case report is to describe a novel approach to implementing early mobility interventions for a patient who was pregnant and receiving ECMO while continuing necessary infectious disease precautions because of diagnosed coronavirus disease-19 (COVID-19). METHODS: A 27-year-old woman who was pregnant was admitted to the ICU with COVID-19 and rapidly developed acute respiratory failure requiring 9 days of ECMO support. After a physical therapist consultation, the patient was standing at the bedside by hospital day 5 and ambulating by hospital day 9. RESULTS: The patient safely participated in physical therapy during ICU admission and was discharged to home with outpatient physical therapy follow-up after 14 days of hospitalization. CONCLUSION: Early mobility is feasible during ECMO with COVID-19, and active participation in physical therapy, including in-room ambulation, may facilitate discharge to home. Innovative strategies to facilitate routine activity in a patient who is critically ill with COVID-19 require an established and highly trained team with a focus on maintaining function. IMPACT: Early mobility while intubated, on ECMO, and infected with COVID-19 is feasible while adhering to infectious disease precautions when it is performed by an experienced interdisciplinary team.