Clinical controversies in anticoagulation monitoring and antithrombin supplementation for ECMO.

During extracorporeal membrane oxygenation (ECMO), a delicate balance is required to titrate systemic anticoagulation to prevent thrombotic complications within the circuit and prevent bleeding in the patient. Despite focused efforts to achieve this balance, the frequency of both thrombotic and bleeding events remains high. Anticoagulation is complicated to manage in this population due to the complexities of the hemostatic system that are compounded by age-related developmental hemostatic changes, variable effects of the etiology of critical illness on hemostasis, and blood-circuit interaction. Lack of high-quality data to guide anticoagulation management in ECMO patients results in marked practice variability among centers. One aspect of anticoagulation therapy that is particularly challenging is the use of antithrombin (AT) supplementation for heparin resistance. This is especially controversial in the neonatal and pediatric population due to the baseline higher risk of bleeding in this cohort. The indication for AT supplementation is further compounded by the potential inaccuracy of the diagnosis of heparin resistance based on the standard laboratory parameters used to assess heparin effect. With concerns regarding the adverse impact of bleeding and thrombosis, clinicians and institutions are faced with making difficult, real-time decisions aimed at optimizing anticoagulation in this setting. In this clinically focused review, the authors discuss the complexities of anticoagulation monitoring and therapeutic intervention for patients on ECMO and examine the challenges surrounding AT supplementation given both the historical and current perspectives summarized in the literature on these topics.

Ischemia-induced autophagy contributes to neurodegeneration in cerebellar Purkinje cells in the developing rat brain and in primary cortical neurons in vitro.

Increased autophagy/mitophagy is thought to contribute to cerebellar dysfunction in Purkinje cell degeneration mice. Intriguingly, cerebellar Purkinje cells are highly vulnerable to hypoxia-ischemia (HI), related at least in part to their high metabolic activity. Whether or not excessive or supraphysiologic autophagy plays a role in Purkinje cell susceptibility to HI is unknown. Accordingly, we evaluated the role of autophagy in the cerebellum after global ischemia produced by asphyxial cardiac arrest in postnatal day (PND) 16-18 rats, using siRNA-targeted inhibition of Atg7, necessary for microtubule-associated protein light chain 3-II (LC3-II) and Atg12-Atg5 complex formation. Two days before a 9min asphyxial cardiac arrest or sham surgery, Atg7 or control siRNA was injected intracisternally to target the cerebellum. Treatment with Atg7 siRNA: 1) reduced Atg7 protein expression in the cerebellum by 56%; 2) prevented the typical ischemia-induced formation of LC3-II in the cerebellum 24h after asphyxial cardiac arrest; 3) improved performance on the beam-balance apparatus on days 1-5; and 4) increased calbindin-labeled Purkinje cell survival assessed on day 14. Improved Purkinje cell survival was more consistent in female vs. male rats, and improved beam-balance performance was only seen in female rats. Similar responses to Atg7 siRNA i.e. reduced autophagy and neurodegeneration vs. control siRNA were seen when exposing sex-segregated green fluorescent protein-LC3 tagged mouse primary cortical neurons to oxygen glucose deprivation in vitro. Thus, inhibition of autophagy after global ischemia in PND 16-18 rats leads to increased survival of Purkinje cells and improved motor performance in a sex-dependent manner.

Context-Responsive Anticoagulation Reduces Complications in Pediatric Extracorporeal Membrane Oxygenation.

Purpose: We sought to determine the impact of a comprehensive, context-responsive anticoagulation and transfusion guideline on bleeding and thrombotic complication rates and blood product utilization during extracorporeal membrane oxygenation (ECMO). Design: Single-center, observational pre- and post-implementation cohort study. Setting: Academic pediatric hospital. Patients: Patients in the PICU, CICU, and NICU receiving ECMO support. Interventions: Program-wide implementation of a context-responsive anticoagulation and transfusion guideline. Measurements: Pre-implementation subjects consisted of all patients receiving ECMO between January 1 and December 31, 2012, and underwent retrospective chart review. Post-implementation subjects consisted of all ECMO patients between September 1, 2013, and December 31, 2014, and underwent prospective data collection. Data collection included standard demographic and admission data, ECMO technical specifications, non-ECMO therapies, coagulation parameters, and blood product administration. A novel grading scale was used to define hemorrhagic complications (major, intermediate, and minor) and major thromboembolic complications. Main Results: Seventy-six ECMO patients were identified: 31 during the pre-implementation period and 45 in the post-implementation period. The overall observed mortality was 33% with no difference between groups. Compared to pre-implementation, the post-implementation group experienced fewer major hemorrhagic and major thrombotic complications and less severe hemorrhagic complications and received less RBC transfusion volume per kg. Conclusions: Use of a context-responsive anticoagulation and transfusion guideline was associated with a reduction in hemorrhagic and thrombotic complications and reduced RBC transfusion requirements. Further evaluation of guideline content, compliance, performance, and sustainability is needed.

Neurological sequelae of 2009 influenza A (H1N1) in children: a case series observed during a pandemic.

OBJECTIVE: To outline a series of cases demonstrating neurologic complications in children with Influenza infection. The ongoing 2009 influenza A (H1N1) presents significant challenges to the field of pediatric critical care and requires increased awareness of new presentations and sequelae of infection. Since World Health Organization declared a H1N1 pandemic, much attention has been focused on its respiratory manifestations of the illness, but limited information regarding neurologic complications has been reported. DESIGN: Case series. SETTING: Pediatric intensive care unit of a tertiary care medical facility. PATIENTS: Four children admitted to the pediatric intensive care unit between March and November 2009 at the Children's Hospital of Pittsburgh with altered mental status and influenza infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The clinical course was extracted by chart review and is summarized. All children demonstrated a coryzal prodrome, fever, and altered level of consciousness at admission, and one child presented with clinical seizures. Diagnostic studies performed to establish a diagnosis are summarized. All children had abnormal electroencephalograms early in their intensive care unit course and 50% had abnormal imaging studies. All children survived but 50% had neurologic deficits at hospital discharge. CONCLUSION: We conclude that 2009 influenza A (H1N1) can cause significant acute and residual neurologic sequelae. Clinicians should consider Influenza within a comprehensive differential diagnosis in children with unexplained mental status changes during periods of pandemic influenza.

TEG Platelet Mapping and Impedance Aggregometry to Predict Platelet Transfusion During Cardiopulmonary Bypass in Pediatric Patients.

Background: Cardiopulmonary bypass-related platelet dysfunction can increase the risk of intra- and post-operative bleeding in children undergoing cardiac surgery. More accurate laboratory tests that identify acquired platelet abnormalities could allow for rapid identification of patients at risk of bleeding and provide therapies that could reduce bleeding and platelet transfusions. We hypothesized that thromboelastography with platelet mapping (TEG-PM) and multiple electrode impedance aggregometry (MEIA) as functional measures of platelet function would predict who will require platelet transfusion. Our secondary hypothesis was that platelet aggregation at both arachidonic acid (AA) and adenosine diphosphate (ADP) receptors would correlate between TEG-PM and MEIA results. Methods: In this prospective study from August 2013 to December 2015, children from newborn to 5 years of age with congenital heart disease undergoing cardiopulmonary bypass had blood samples collected and analyzed at four time points: pre-bypass, post-bypass, post-operatively on arrival to the Cardiac Intensive Care Unit, and 24 h after arrival. Results: Of the 44 patients analyzed, the 10 patients who received peri-operative platelet transfusion were significantly younger (p = 0.05), had higher STAT (Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery) Mortality Categories (p < 0.002) and longer cardiopulmonary bypass times (p = 0.02). In univariate analysis, four variables were associated with peri-operative platelet transfusion: pre-operative age [OR 0.95 (0.93, 0.98), p = 0.03], cardiopulmonary bypass time [1.5 (1.31, 1.68), p = 0.008], STAT Mortality Category [3.64 (3.40, 3.87), p < 0.001], and TEG-PM ADP [0.79 (0.65, 0.93), p = 0.04]. ROC analysis demonstrated moderate predictive value of TEG-PM ADP with AUC of 0.745 (0.59, 0.91). A TEG-PM ADP value of less than or equal to 21 had 85% sensitivity and 70% specificity for platelet transfusion. In the multivariate analysis, only STAT Mortality Category predicted platelet transfusion. TEG-PM and MEIA results correlated for the AA receptor at all 4 time points, but the same tests at the ADP receptors did not correlate. Conclusions: TEG-PM ADP may provide more clinically relevant information regarding platelet function compared to the MEIA at the ADP receptor in children requiring cardiopulmonary bypass. There was limited correlation between TEG-PM and MEIA results which raises a concern about the accuracy of these tests at the ADP receptor. Lower pre-operative TEG-PM ADP MA may predict intra-operative platelet transfusions; however, larger studies are needed to determine the utility of TEG-PM and MEIA in guiding platelet transfusions in this population.

A Novel Surgical Approach to Mechanical Circulatory Support in Univentricular Infants.

BACKGROUND: Historically, the options for mechanical circulatory support in infants, particularly those with single-ventricle physiology, have been limited and outcomes have generally been poor. We report a new approach implemented for long-term support in a series of such patients. METHODS: This study is a single-center case series of 7 patients with single-ventricle physiology after stage 1 palliation supported with mechanical circulatory support using a novel technique, between May 2014 and September 2015. Our technique included modification and implantation of commercially available pediatric cannulae into the common atrium and the ascending aorta or reconstructed neoaorta and utilization of a centrifugal extracorporeal pump. RESULTS: Median circulatory support duration was 64 days (range, 35 to 99). One adverse neurologic event was observed in 1 patient, and bleeding requiring reoperation in 2 patients. Support to recovery, decision, or heart transplantation was accomplished in all cases. Of all patients, 43% were successfully discharged home. CONCLUSIONS: Our experience shows that long-term extracorporeal mechanical circulatory support of patients with underlying single-ventricle physiology after stage 1 palliation is feasible utilizing our technique. This approach overcomes several major challenges encountered in these patients, such as high flow requirement and stability of the cannulae, and allows extubation, rehabilitation, and at times, myocardial recovery.

Continuous Flow Device Support in Children Using the HeartWare HVAD: 1,000 Days of Lessons Learned From a Single Center Experience.

The purpose of this study is to provide a single center experience with a continuous flow device in adolescents with end-stage heart failure. A retrospective single center analysis of patients aged 18 years or younger implanted with HVAD (HeartWare Inc, Framingham, MA) between October 2012 and March 2014 was performed. Demographics, preimplant and postimplant clinical data, survival, and adverse events (AEs) were recorded. A matched group of adults based on diagnosis, body surface area (BSA), and time period were used for outcome comparisons. Six adolescents with dilated cardiomyopathy were implanted with the HVAD. Median age and BSA were 13.4 years and 1.45 m2, respectively. All were Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile-1 or profile-2. Median days on device were 108 with total patient-days on device of 1,017. Four adolescents were discharged home on device all in New York Heart Association 1. Five underwent transplantation with 100% survival. There were 18 AEs with one AE per 170 days on device. Compared with the adult cohort (n = 5), there was no difference in 1 year survival (p = 0.32). HVAD support in adolescents is highly successful as a bridge to transplantation. It provides early rehabilitation and improvement in quality of life. Morbidity is not negligible but appears comparable with that seen in adults.