Biomarkers of Inflammation and Lung Recovery in Extracorporeal Membrane Oxygenation Patients With Persistent Pulmonary Hypertension of the Newborn: A Feasibility Study.

OBJECTIVES: Extracorporeal membrane oxygenation is a treatment for Persistent Pulmonary Hypertension of the Newborn with high mortality. HYPOTHESIS: the extracorporeal membrane oxygenation circuit results in inflammatory responses that mitigate against successful weaning. DESIGN: Single-center prospective observational feasibility study. SETTING: PICU. PATIENTS: Twenty-four neonates requiring extracorporeal membrane oxygenation support for Persistent Pulmonary Hypertension of the Newborn. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The reference outcome was death or more than 7 days of extracorporeal membrane oxygenation support. Other outcomes included serial measures of plasma-free hemoglobin and markers of its metabolism, leucocyte, platelet and endothelial activation, and biomarkers of inflammation. Of 24 participants recruited between February 2016 and June 2017, 10 died or required prolonged extracorporeal membrane oxygenation support. These patients were sicker at baseline with higher levels of plasma-free hemoglobin within 12 hours of cannulation (geometric mean ratio, 1.92; 95% CIs, 1.00-3.67; p = 0.050) but not thereafter, versus those requiring less than 7 days extracorporeal membrane oxygenation. Serum haptoglobin concentrations were significantly elevated in both groups. Patients who died or required prolonged extracorporeal membrane oxygenation support demonstrated elevated levels of platelet-leucocyte aggregation, but decreased concentrations of mediators of the inflammatory response: interleukin-8, C-reactive protein, and tumor necrosis factor α. CONCLUSIONS: Clinical status at baseline and not levels of plasma-free hemoglobin or the systemic inflammatory response may determine the requirement for prolonged extracorporeal membrane oxygenation support in neonates.

An Observational Cohort Feasibility Study to Identify Microvesicle and Micro-RNA Biomarkers of Acute Kidney Injury Following Pediatric Cardiac Surgery.

OBJECTIVES: Micro-RNA, small noncoding RNA fragments involved in gene regulation, and microvesicles, membrane-bound particles less than 1 µm known to regulate cellular processes including responses to injury, may serve as disease-specific biomarkers of acute kidney injury. We evaluated the feasibility of measuring these signals as well as other known acute kidney injury biomarkers in a mixed pediatric cardiac surgery population. DESIGN: Single center prospective cohort feasibility study. SETTING: PICU. PATIENTS: Twenty-four children (≤ 17 yr) undergoing cardiac surgery with cardiopulmonary bypass without preexisting inflammatory state, acute kidney injury, or extracorporeal life support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Acute kidney injury was defined according to modified Kidney Diseases Improving Global Outcomes criteria. Blood and urine samples were collected preoperatively and at 6-12 and 24 hours. Microvesicles derivation was assessed using flow cytometry and NanoSight analysis. Micro-RNAs were isolated from plasma and analyzed by microarray and quantitative real-time polymerase chain reaction. Data completeness for the primary outcomes was 100%. Patients with acute kidney injury (n = 14/24) were younger, underwent longer cardiopulmonary bypass, and required greater inotrope support. Acute kidney injury subjects had different fractional content of platelets and endothelial-derived microvesicles before surgery. Platelets and endothelial microvesicles levels were higher in acute kidney injury patients. A number of micro-RNA species were differentially expressed in acute kidney injury patients. Pathway analysis of candidate target genes in the kidney suggested that the most often affected pathways were phosphatase and tensin homolog and signal transducer and activator of transcription 3 signaling. CONCLUSIONS: Microvesicles and micro-RNAs expression patterns in pediatric cardiac surgery patients can be measured in children and potentially serve as tools for stratification of patients at risk of acute kidney injury.

Renal Replacement Therapy in the Critically Ill Child.

OBJECTIVES: Although renal replacement therapy is widely used in critically ill children, there have been few comprehensive population-based studies of its use. This article describes renal replacement therapy use, and associated outcomes, in critically ill children across the United Kingdom in the largest cohort study of this patient group. DESIGN: A retrospective observational study using prospectively collected data. SETTING: Data from the Pediatric Intensive Care Audit Network database which collects data on all children admitted to U.K. PICUs. PATIENTS: Children (< 16 yr) in PICU who received renal replacement therapy between January 1, 2005, and December 31, 2012, were identified. INTERVENTIONS: Individual-level data including age, underlying diagnosis, modality (peritoneal dialysis and continuous extracorporeal techniques [continuous renal replacement therapy]), duration of renal replacement therapy, PICU length of stay, and survival were extracted. MEASUREMENTS AND MAIN RESULTS: Three-thousand eight-hundred twenty-five of 129,809 PICU admissions (2.9%) received renal replacement therapy in 30 of 33 centers. Volumes of renal replacement therapy varied considerably from 0% to 8.6% of PICU admissions per unit, but volume was not associated with patient survival. Overall survival to PICU discharge (73.8%) was higher than previous reports. Mortality risk was related to age, with lower risk in older children compared with neonates (odds ratio, 0.6; 95% CI, 0.5-0.8) although mortality did not increase over the age of 1 year; mode of renal replacement therapy, with lower risk in peritoneal dialysis than continuous renal replacement therapy methodologies (odds ratio, 0.7; 0.5-0.9); duration of renal replacement therapy (odds ratio, 1.02/d; 95% CI, 1.01-1.04); and primary diagnosis, with the lowest survival in liver disease patients (53.9%). CONCLUSIONS: This study describes current renal replacement therapy use across the United Kingdom and associated outcomes. We describe a number of factors associated with outcome, including age, underlying diagnosis, and renal replacement therapy modality which will need to be factored into future trial design.

The use of extracorporeal membrane oxygenation in neonates with severe congenital diaphragmatic hernia: a 26-year experience from a tertiary centre.

OBJECTIVES: Neonates with severe congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation (ECMO) have a high rate of mortality. There is controversy regarding optimal time of surgical intervention. We present our data over a 26-year period. METHODS: We analysed data from our Extracorporeal Life Support Organization registry forms between 1989 and 2015, in order to determine the factors affecting survival outcome for repair of congenital diaphragmatic hernia with ECMO as a bridge to surgery and/or recovery. RESULTS: Ninety-eight neonates with congenital diaphragmatic hernia requiring ECMO were identified. In-hospital mortality was 32%. The overall mortality (47.9%) in our study was seen up to 7 months, after this point there was no mortality. There was no difference in survival in patients repaired using pre-, intra- or postoperative ECMO (P = 0.65). Requiring haemofiltration at any point was significantly associated with reduced survival [hazard ratio 2.7 (95% confidence interval 1.5-4.9); P = 0.01] as was the presence of neurological complications [hazard ratio 3.7 (95% confidence interval 1.6-8.5); P = 0.003]. Age, Apgar score, mode of delivery, side, associated cardiac comorbidities, pH, partial pressure of carbon dioxide, partial pressure of oxygen, oxygen saturations, bicarbonate, high-frequency oscillatory ventilation, mode of ECMO, inhaled nitric oxide, pulmonary complications and bleeding were not associated with any survival difference. CONCLUSIONS: We believe that all neonates with severe diaphragmatic hernia should be given the option of ECMO if clinically indicated. Provided these patients survive the initial postoperative period, they go on to have a sustained survival benefit. Long-term cost analysis and morbidity need to be taken into account to determine the true effect of ECMO on congenital diaphragmatic hernia.

Experience of Circuit Survival in Extracorporeal Continuous Renal Replacement Therapy Using Small-Calibre Venous Cannulae.

OBJECTIVES: To describe an experience of circuit survival in extracorporeal continuous renal replacement therapy using small-calibre (< 7 French gauge [F]) venous cannulae. DESIGN: An observational study. SETTING: A multidisciplinary, university-affiliated PICU. SUBJECTS: Case note review of all continuous renal replacement therapy episodes (1998-2010), which used vascular access cannulae of an external diameter less than 7F, was performed. MEASUREMENTS AND MAIN RESULTS: Forty-nine patients underwent continuous renal replacement therapy treatment during which circuit blood flow was delivered using either 5F or 6.5F double-lumen cannulae. One hundred thirty-nine circuits were employed (median per patient, 2; interquartile range, 1-3) in providing 4,903 hours of therapy (median duration of therapy, 43 hr; interquartile range, 22-86 hr); allowing for censoring, the median circuit survival time was 40 hours (95% CI, 28-66). Eighty-one circuits (58%) failed because of clotting/technical problems, equating to a circuit failure rate of 16.5 (95% CI, 13.3-20.5) per 1,000 hours of continuous renal replacement therapy. The probability of a circuit surviving 40 hours or greater was 50% with 43% (95% CI, 34-53%) expected to survive 60 hours or more. No significant relationship between circuit survival and the calibre of the cannula deployed was identified; however, placement of venous access in an internal jugular vein was associated with improved circuit survival. CONCLUSIONS: Contrary to previous reports, vascular access cannulae of a caliber less than 7F can support sufficiently prolonged continuous renal replacement therapy to make them a useful means of delivering renal support in neonates and small infants.

Pump controlled retrograde trial off from VA-ECMO.

We describe our novel technique of Pump Controlled Retrograde Trial Off that relies on the retrograde flow to maintain circuit integrity and allow a longer trial off from venoarterial extracorporeal membrane oxygenation support without circuit clot formation or significant patient hemodynamic compromise. This technique avoids the insertion of an arteriovenous bridge and the need to clamp the circuit. We present data on five neonatal patients who were trialled off using this method.

Is levosimendan effective in paediatric heart failure and post-cardiac surgeries?

A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was 'do children with heart failure post-cardiac surgery undergoing treatment with levosimendan have an acceptable haemodynamic improvement?' The use of levosimendan as a vasoactive drug is an accepted intervention for patients with altered haemodynamics post-cardiac surgeries. However, the role of levosimendan and its efficacy have been debated. Eleven relevant papers were identified, which represented the best evidence to answer the question. The author, journal, date, country of publication and relevant outcomes are tabulated. The 11 studies comprised 3 randomized trials, 2 of which compared levosimendan and milrinone. A single-centre randomized study that included 40 infants showed that cardiac output (CO) and cardiac index (CI) increased overtime in the levosimendan group compared with the milrinone group. The significant interaction for CO (P = 0.005) and CI (P = 0.007) indicated different time courses in the two groups. A similar, European randomized study undertaken on neonates (n = 63) showed better lactate levels [P = 0.015 (intensive care admission); P = 0.048 (after 6 h) with low inotropic scores in the levosimendan group. Although the length of mechanical ventilation and mortality were less, this was statistically insignificant. A retrospective cohort analysis (n = 13) in children reported a reduced use of dobutamine and improvement in the ejection fraction from 29.8 to 40.5% (P = 0.015) with the use of levosimendan. In a questionnaire-based study from Finland, 61.1% of respondents felt that it had saved the lives of some children when the other treatments had failed. No study reported any adverse effect attributable to use of levosimendan. In conclusion, the above studies were in favour of levosimendan as a safe and feasible drug providing potential clinical benefit in low cardiac output syndrome (LCOS) and post-cardiac surgeries when other vasoactive drugs were insufficient to maintain stable haemodynamics. A small sample size was indeed a limitation in all the above studies. Furthermore, it is best used as a rescue drug on a named-patient basis. A small sample size was indeed a limitation in all the above studies. Larger, well-designed trials are required to further evaluate the efficacy and feasibility of levosimendan in paediatric heart failure and post-cardiac surgeries.

Extracorporeal membrane oxygenation and severe acute respiratory distress secondary to Legionella: 10 year experience.

Legionella-associated respiratory failure has a high mortality, despite modern ventilation modalities. Extracorporeal membrane oxygenation (ECMO) is used to achieve gas exchange independent of pulmonary function in patients with severe respiratory failure. This was a retrospective review of the management and outcome of patients with Legionella-associated respiratory failure treated with ECMO support in a large ECMO center over the past 10 years. A retrospective review of patients with confirmed Legionella-associated severe respiratory failure managed with ECMO support at a single center. Between 2000 and 2010, 19 patients with severe respiratory failure caused by Legionella were managed with ECMO after failure to respond to conventional intensive care management. Median PaO2/FiO2 ratio was 66 and median pCO2 was 60 torr. Sixteen patients (84%) survived to hospital discharge. Extracorporeal membrane oxygenation should be considered in patients with Legionella-associated respiratory failure, who have failed conventional ventilation.

Fixed dilated pupils and tacrolimus toxicity in paediatric liver transplant patients.

We report a case series of four children who developed fixed dilated pupils associated with high tacrolimus levels (>30 nanograms/millilitre [ng/mL]) in the immediate post-operative period following isolated liver or liver and small bowel transplantation.

Continuous hemofiltration in the control of neonatal hyperammonemia: a 10-year experience.

In a 10-year review of the utilization of continuous veno-venous hemofiltration (CVVH) for the treatment of neonatal hyperammonemia, 14 patients were identified with hyperammonemia due to either a urea cycle defect or an organic acidemia. Intensive care survival was 64%. The pretreatment level of serum ammonia and the rapidity of ammonia clearance did not differ between survivors and non-survivors (p = 0.16 and p = 0.93, respectively). Likewise, the duration of CVVH therapy did not differ between survivors and non-survivors (p = 0.1). Indicators of pretreatment physiological stress showed either a correlation with non-survival [Pediatric Risk of Mortality (PRISM) score, p = 0.006, cardioactive drug requirement, p = 0.003], or demonstrated a trend to such a correlation (serum lactate, p = 0.06). Complications associated with the CVVH technique were infrequent. Hypotension was seen in seven patients, but in only one patient did it arise de novo following the initiation of CVVH. In conclusion, neither the severity of the hyperammonemic state nor the efficacy of ammonia removal correlated with patient outcome. The pre-CVVH PRISM score and requirement for cardio-active medication were significantly greater in those patients who did not survive their acute illness. The pre-CVVH physiological condition of the neonates in this cohort was the main determinant of outcome.

A case of acute papillary muscle rupture in a child with campylobacter enteritis and citrullinaemia.

We report a case of acute papillary muscle rupture associated with intercurrent Campylobacter jejuni gastroenteritis in a child with a diagnosis of citrullinaemia, requiring urgent mitral valve replacement.

Performance of polymethyl pentene oxygenators for neonatal extracorporeal membrane oxygenation: a comparison with silicone membrane oxygenators.

OBJECTIVE: To review the performance of polymethyl pentene versus silicone oxygenators in terms of efficiency in priming and oxygenation, oxygenator resistance, requirements for coagulation proteins and consumption of blood products, for neonatal extracorporeal membrane oxygenation (ECMO) patients. STUDY DESIGN: Forty consecutive neonates were selected retrospectively pre- and post-introduction of the new polymethyl pentene (PMP) oxygenators. They formed two equal groups. After calculation of the sample size, data were collected from ELSO registry forms and patient records. Results were analysed using parametric and non-parametric tests. RESULTS: Neonatal PMP (N-PMP) oxygenators were smaller, faster and easier to prime. They were less efficient than silicone oxygenators, especially in carbon dioxide elimination, and, therefore, required higher sweeps. The preservation of coagulation proteins was significantly better, but there was no reduction in the consumption of blood products, despite having less than half the surface area and significantly lower blood path resistance. CONCLUSION: Small PMP oxygenators (Medos Hilite 800 LT) provide adequate gas exchange and offer technical advantages in terms of more efficient priming, reduced haemodynamic resistance and better control and preservation of coagulation proteins than silicone oxygenators.

Experience with mobile inhaled nitric oxide during transport of neonates and children with respiratory insufficiency to an extracorporeal membrane oxygenation center.

OBJECTIVE: To share our experience with the use of inhaled nitric oxide (iNO) during the transport of ventilated neonates and children to an extracorporeal membrane oxygenation (ECMO) center and to discuss the efficacy and safety of iNO use in this situation. DATA SOURCES: Case note review of 55 consecutive patients transported while receiving iNO to Glenfield Hospital, Leicester, UK, for consideration of ECMO. STUDY SELECTION: Retrospective case note review. DATA EXTRACTION: The clinical condition of each patient recorded at arrival of the transport team at the referring hospital, during transport, and at arrival at Glenfield Hospital. Preclinical and postclinical conditions were compared using the paired Student's t-test. DATA SYNTHESIS: Overall data showed a significant improvement in transcutaneous oximetry measurements (Spo(2): 84.8% preclinical, 90.6% postclinical; p = .006) and Pao(2) (59 torr [7.87 kPa] preclinical, 84 torr [11.23 kPa] postclinical; p = .001) during transport in our patient group. Based on limited safety data, no untoward events or toxic metabolites were observed with iNO therapy during transport. CONCLUSIONS: iNO does appear to improve oxygenation during transfer of patients for ECMO in our series. Based on limited safety data, iNO appears safe to use in transport.

Venovenous extracorporeal membrane oxygenation for respiratory failure in inotrope dependent neonates.

It is often stated that venovenous extracorporeal membrane oxygenation (VV ECMO) should not be used in inotrope dependent patients. It is our practice to use VV ECMO in most patients with respiratory failure even though many of these patients are receiving significant doses of inotropes. Our objective was to review the mode of ECMO in relation to precannulation doses of inotropes administered to neonates treated with ECMO for respiratory failure. Forty-three consecutive case notes were reviewed. Data were collected for basic demographic and ECMO parameters. Inotropic doses were converted to a single score for ease of comparison, with one point equivalent to 1 microg/kg/min dopamine. Forty-three neonates were studied; 37(86%) were treated with VV ECMO and 6 (14%) were treated with VA ECMO. Significant pre-ECMO inotropic support (score > 10) was present in 30 (70%) of the 43 cases. Of these patients, 26 were treated via VV ECMO with a survival rate of 84%, while 4 were treated with VA ECMO with a survival of 75%. Inotrope scores fell to nonsignificant levels (< 10) within 24 hours, regardless of ECMO mode. Mean arterial blood pressure remained above precannulation levels in both groups. VV ECMO allows safe treatment of neonatal respiratory failure in the presence of significant inotropic support. We recommend VV ECMO for neonatal respiratory failure in all cases except where double lumen cannulation is impossible or when septic shock is refractory to inotropic support (i.e., mean blood pressure < 35 mm Hg despite inotrope score of > 100).

Extracorporeal life support in pertussis.

Severe B. pertussis infection in infants is characterized by severe respiratory failure, pulmonary hypertension, leukocytosis, and death. This retrospective case analysis highlights the course and outcome of severe B. pertussis infection treated with extracorporeal membrane oxygenation (ECMO) at a single center. Over the last decade, out of a total caseload of nearly 800 infants and children, 12 infants with severe B. pertussis have been referred for ECMO therapy to our center. All infants with pertussis infection who received ECMO therapy were less than 3 months of age at presentation and unvaccinated. There was a high mortality rate (7 of 12 infants died), which was associated with an elevated neutrophil count at presentation and multiorgan dysfunction characterized by intractable pulmonary hypertension, persistent systemic hypotension, renal insufficiency, and fits. ECMO should be offered to children with pertussis infection and respiratory failure refractory to mechanical ventilation. However, further research is required to determine the optimal management for infants receiving ECMO therapy with this disease.