Lakshmi Raman

Pediatric Extracorporeal Life Support Organization Registry International Report 2016

The purpose of this report is to describe the international growth, outcomes, complications, and technology used in pediatric extracorporeal life support (ECLS) from 2009 to 2015 as reported by participating centers in the Extracorporeal Life Support Organization (ELSO). To date, there are 59,969 children who have received ECLS in the ELSO Registry; among those, 21,907 received ECLS since 2009 with an overall survival to hospital discharge rate of 61%. In 2009, 2,409 ECLS cases were performed at 157 centers. By 2015, that number grew to 2,992 cases in 227 centers, reflecting a 24% increase in patients and 55% growth in centers. ECLS delivered to neonates (0–28 days) for respiratory support was the largest subcategory of ECLS among children <18-years old. Overall, 48% of ECLS was delivered for respiratory support and 52% was for cardiac support or extracorporeal life support to support cardiopulmonary resuscitation (ECPR). During the study period, over half of children were supported on ECLS with centrifugal pumps (51%) and polymethylpentene oxygenators (52%). Adverse events including neurologic events were common during ECLS, a fact that underscores the opportunity and need to promote quality improvement work.

Chronic Hypoxia Impairs Murine Hippocampal Development and Depletes the Postnatal Progenitor Pool by Attenuating Mammalian Target of Rapamycin Signaling

Chronic hypoxia (CH) is a major risk factor for impaired cognitive function in various disease states, particularly in the context of cyanotic congenital heart disease. Although most brain development occurs prenatally, the dentate gyrus (DG) of the hippocampus harbors progenitor stem cells that contribute to its ongoing development postnatally. It is unclear how exposure to CH might affect postnatal hippocampal development, so we used a transgenic mouse that expresses enhanced green fluorescent protein (eGFP) within this progenitor population to determine the effect of CH on the DG. We find that exposure to 10% oxygen from postnatal d 3 to 28 results in a smaller DG with long-term impairment of hippocampal neurogenesis. Because the mammalian target of rapamycin (mTOR) pathway is a well-known regulator of cell proliferation and growth and is sensitive to hypoxia, we investigated its activation on exposure to CH and find it to be attenuated specifically in neural progenitor cells. Systemic inhibition of the mTOR pathway using rapamycin also caused impairment of hippocampal neurogenesis that mimics exposure to CH. Our findings demonstrate that CH results in long-term impairment of hippocampal neurogenesis and is mediated, in part, by attenuation of the mTOR pathway.

Year in Review 2015: Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) is a modified form of cardiopulmonary bypass. Although early trials were plagued by severe bleeding and high rates of death, subsequent experience with neonates found good survival, and ECMO became an important tool in the care of critically ill infants with respiratory failure. Since the 1980s, expansion to other groups (children, patients with cardiac disease, etc) followed as experience was obtained. Today, there is a rapid growth of ECMO, especially in the adult population. To date, >73,000 patients receiving ECMO have been reported to the international Extracorporeal Life Support Organization registry. This rapid growth in the usage of ECMO has made it possible for it to be included in the management algorithm of certain disease processes, such as ARDS, cardiopulmonary arrest, and septic shock. Significant advances in technology have made it possible to support patients on ECMO for weeks or months with success. Reduction in sedative use and experience with “awake” patients has led to ambulatory and mobile ECMO. Changes in ventilator support while on ECMO, even to the point of extubation, are also occurring. This article will review briefly some of the literature related to criteria for severity of illness before ECMO and related to ECMO care and practice. Issues relating to the use of ECMO as a resuscitative tool in cardiac arrest as well as the controversial topic of volume and outcome will also be presented.

Pharmacological inhibition of the mTOR pathway impairs hippocampal development in mice

Brain injury is an important cause of morbidity in infants at risk for exposure to chronic hypoxia. Using a transgenic mouse that expresses green fluorescent protein (GFP) within this progenitor population we have previously shown that exposure to chronic hypoxia significantly decreases the progenitor stem cell pool in the dentate gyrus of the hippocampus that is in part mediated by inhibition of the mammalian target of rapamycin (mTOR) pathway. Hence we hypothesized that pharmacological inhibition of the mTOR pathway using rapamycin will alter the progenitor stem cell pool and impair the development of the dentate gyrus. We find that prolonged inhibition of the mTOR pathway causes a decrease in the early progenitor stem cell pool, demonstrated by decreased GFP-expressing progenitors, which persists long term. However there is a significant increase in proliferating progenitor cell pool, as seen by increased BrdU that is coupled with increased apoptosis thereby leading to fewer Neu N-expressing mature neurons. Further inhibition of the mTOR pathway leads to depletion of the astrocyte and microglial pool in the dentate gyrus as well. Overall our findings demonstrate that pharmacological inhibition of the mTOR pathway leads to impaired development of the DG, raising the concern that in young children could impair cognitive development.

Perinatal chronic hypoxia induces cortical inflammation, hypomyelination, and peripheral myelin-specific T cell autoreactivity

pCH is an important risk factor for brain injury and long‐term morbidity in children, occurring during the developmental stages of neurogenesis, neuronal migration, and myelination. We show that a rodent model of pCH results in an early decrease in mature myelin. Although pCH does increase progenitor oligodendrocytes in the developing brain, BrdU labeling revealed a loss in dividing progenitor oligodendrocytes, indicating a defect in mature cell replacement and myelinogenesis. Mice continued to exhibited hypomyelination, concomitant with long‐term impairment of motor function, weeks after cessation of pCH. The implication of a novel neuroimmunologic interplay, pCH also induced a significant egress of infiltrating CD4 T cells into the developing brain. This pCH‐mediated neuroinflammation included oligodendrocyte‐directed autoimmunity, with an increase in peripheral myelin‐specific CD4 T cells. Thus, both the loss of available, mature, myelin‐producing glial cells and an active increase in autoreactive, myelin‐specific CD4 T cell infiltration into pCH brains may contribute to early pCH‐induced hypomyelination in the developing CNS. The elucidation of potential mechanisms of hypoxia‐driven autoimmunity will expand our understanding of the neuroimmune axis during perinatal CNS disease states that may contribute to long‐term functional disability.

Erythropoietin-mediated neuroprotection in a pediatric mouse model of chronic hypoxia

Chronic hypoxia (CH), a disease state that accounts for significant morbidity and mortality in pediatrics, occurs in many children during critical periods of hippocampal development and cortical myelination. Hippocampal neurogenesis occurs throughout postnatal life and is important for normal development, thus impairment results in long-term cognitive deficits. Erythropoietin (EPO), a drug commonly known for its role in erythrogenesis, has recently been evaluated in neuroprotection in neonatal injury models and preterm brain injury. However, the effects of EPO therapy on hippocampal neurogenesis and myelination in pediatric CH are unknown. We show that CH decreases hippocampal neurogenesis in a pediatric mouse model. This decrease in early and late progenitors, and actively dividing cells is rescued with EPO treatment. Furthermore, we show that CH during this critical time decreases oligodendrocyte progenitor (OPC) populations in the cortex, leading to defective myelination. However, EPO therapy is only able to rescue the OPC but not the loss of mature myelin. Overall, our findings demonstrate that CH in developing mice has significant effects on hippocampal neurogenesis and OPCs, which can be rescued with EPO treatment. Future studies should confirm the role of this FDA-approved therapy in neuroprotection in at-risk pediatric populations.

Coagulation Profile Is Not a Predictor of Acute Cerebrovascular Events in Pediatric Extracorporeal Membrane Oxygenation Patients

We performed a retrospective matched case–control study evaluating whether the traditional coagulation profile predicts cerebrovascular events in children on extracorporeal membrane oxygenation (ECMO) in a 71 bed intensive care unit at a tertiary children’s hospital. Between 2009 and 2014, 241 neonates and children were initiated on ECMO. The cumulative 5 year incidence of intracranial hemorrhage and infarct was 9.2% and 7.9%, respectively. Thirty-six cases were individually matched 1:1 with control subjects based on age, primary diagnosis, ECMO type, cannulation site, and the presence of pre-ECMO coagulopathy. In-hospital mortality was higher among the cases compared with control subjects (78 vs. 22%, p < 0.01). The median laboratory values that assisted with heparin anticoagulation monitoring (activated clotting time, partial thromboplastin time, and antifactor Xa) and the laboratory data that assisted with blood product administration (platelet count, prothrombin time, fibrinogen, and d-dimer) during the 24 and 72 hour periods before the cerebrovascular event did not show any significant difference between the hemorrhage group and their controls or between the infarct group and their controls. The traditional coagulation profile did not predict acute cerebrovascular events in our cohort. Other markers of neurologic injury on ECMO are yet to be elucidated. Prospective studies to determine better predictors of cerebrovascular complications in pediatric ECMO patients are required.

The use of extracorporeal life support in adolescent amlodipine overdose

Calcium channel blocker (CCB) toxicity is associated with refractory hypotension and can be fatal. A 13 year old young woman presented to the emergency department(ED) six hours after an intentional overdose of amlodipine, barbiturates, and alcohol. She remained extremely hypotensive despite the administration of normal saline and calcium chloride and despite infusions of norepinephrine, epinephrine, insulin, and dextrose. Due to increasing evidence of end organ dysfunction, Extracorporeal Life Support (ECLS) was initiated 9 hours after presentation to the ED. The patients blood pressure and end organ function immediately improved after cannulation. She was successfully decannulated after 57 hours of ECLS and was neurologically intact. Patients with calcium channel blocker overdose who are resistant to medical interventions may respond favorably to early ECLS.

Regional cerebral abnormalities measured by frequency-domain near-infrared spectroscopy in pediatric patients during extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is a form of advanced cardiorespiratory support provided to critically ill patients with severe respiratory or cardiovascular failure. While children undergoing ECMO therapy have significant risk for neurological morbidity, currently there is a lack of reliable bedside tool to detect the neurologic events for patients on ECMO. This study assessed the feasibility of frequency-domain near-infrared spectroscopy (NIRS) for detection of intracranial complications during ECMO therapy. The frequency-domain NIRS device measured the absorption coefficient (µa) and reduced scattering coefficient (µs′) at six cranial positions from seven pediatric patients (0–16 years) during ECMO support and five healthy controls (2–14 years). Regional abnormalities in both absorption and scattering were identified among ECMO patients. A main finding in this study is that the abnormalities in scattering appear to be associated with lower-than-normal µs′ values in regional areas of the brain. Because light scattering originates from the intracellular structures (such as nuclei and mitochondria), a reduction in scattering primarily reflects loss or decreased density of the brain matter. The results from this study indicate a potential to use the frequency-domain NIRS as a safe and complementary technology for detection of intracranial complications during ECMO therapy.

An International Survey on Ventilator Practices Among Extracorporeal Membrane Oxygenation Centers.

Although the optimal ventilation strategy is unknown for patients placed on extracorporeal support, there are increasing reports of extubation being used. Our objective was to describe the change in ventilation strategies and use of tracheostomy and bronchoscopy practices among extracorporeal membrane oxygenation (ECMO) centers across the world. A descriptive, cross-sectional 22 item survey of neonatal, pediatric, and adult ECMO centers was used to evaluate ventilator strategies, extubation, bronchoscopy, and tracheostomy practices. Extubation practices are increasing among all types of ECMO centers, representing 27% of all patients in pediatric centers, 41% of all patients in mixed centers, and 52% of all patients in adult centers. The most common mode of ventilation during ECMO is pressure control. There is a trend toward increased use of bilevel ventilation particularly for lung recruitment. Additionally, there is a trend toward increase in performance of bronchoscopy (pediatrics: 69%, mixed centers: 81%, adults: 76%) and tracheostomy. Among the centers performing tracheostomies, 45% reported the percutaneous method (pediatric: 31%, mixed: 46%, adult: 57%), 19% reported the open method (pediatric: 9%, mixed: 27%, adult: 24%), and 10% reported using both types of tracheostomies (pediatric: 2%, mixed: 8%, adult: 16%). Our study shows that ECMO centers are extubating their patients, performing tracheostomies and bronchoscopies on their patients more than in the previous years. There remains significant variation in ECMO ventilator strategies and management internationally. Future studies are needed to correlate these changes in practices to outcome benefits.