A comparison of the performance of contemporary, historical, and cross-lab controls in QTc assessment in conscious nonhuman primates.

Cardiovascular safety pharmacology and toxicology studies include vehicle control animals in most studies. Electrocardiogram data on common vehicles is accumulated relatively quickly. In the interests of the 3Rs principles it may be useful to use this historical information to reduce the use of animals or to refine the sensitivity of studies. We used implanted telemetry data from a large nonhuman primate (NHP) cardiovascular study (n = 48) evaluating the effect of moxifloxacin. We extracted 24 animals to conduct a n = 3/sex/group analysis. The remaining 24 animals were used to generate 1000 unique combinations of 3 male and 3 female NHP to act as control groups for the three treated groups in the n = 3/sex/group analysis. The distribution of treatment effects, median minimum detectable difference (MDD) values were gathered from the 1000 studies. These represent contemporary controls. Data were available from 42 NHP from 3 other studies in the same laboratory using the same technology. These were used to generate 1000 unique combinations of 6, 12, 18, 24 and 36 NHP to act as historical control animals for the 18 animals in the treated groups of the moxifloxacin study. Data from an additional laboratory were also available for 20 NHP. The QT, RR and QT-RR data from the three sources were comparable. However, differences in the time course of QTc effect in the vehicle data from the two laboratories meant that it was not possible to use cross-lab controls. In the case of historical controls from the same laboratory, these could be used in place of the contemporary controls in determining a treatment's effect. There appeared to be an advantage in using larger (≥18) group sizes for historical controls. These data support the opportunity of using historical controls to reduce the number of animals used in new cardiovascular studies.

Clinical Effects of Nitric Oxide Added to the Oxygenator of Children on Extracorporeal Membrane Oxygenation: Pre-Post Cohort Study.

Nitric oxide (NO) can be safely delivered through the sweep gas to the oxygenator of an extracorporeal membrane oxygenation (ECMO) circuit. It has theoretical benefits such as preventing platelet adhesion to surfaces, mitigating inflammatory response and protection against ischemia-reperfusion injury. In this uncontrolled before-after study of children on ECMO, the outcomes of those who received NO were compared with those who did not. Among 393 ECMO runs (from 337 patients), 192 of 393 (49%) received NO and 201 of 393 (51%) did not. The use of NO was associated with a 37% reduction in circuit change (adjusted risk ratio [aRR]: 0.63, 95% confidence interval [CI]: 0.42-0.93). The aRR (95% CI) for risk of neurologic injury was 0.72 (0.47-1.11). We observed potential heterogeneity of treatment effect for the risk of neurologic injury in children who had cardiac surgery: the risk with NO was lower in those who had cardiac surgery (aRR: 0.50, 95% CI: 0.26-0.96). There was no difference in survival between the study groups. In children managed with NO delivered through the ECMO circuit, we report a reduction in observed rate of circuit change and lower risk of neurologic injury in children who underwent cardiac surgery. Nitric oxide therapy on ECMO warrants prospective evaluation in children.

Comparing the sensitivity of cross-over and parallel study designs for QTc assessment: An analysis based on a single large study of moxifloxacin in 48 nonhuman primates.

The cardiovascular safety pharmacology (SP) study conducted to satisfy ICH S7A and S7B has commonly used a cross-over study design where each animal receives all treatments. In an increasing number of cases, cross-over designs are not possible and parallel studies have to be used. These can seldom be as large as 8 animals/treatment to match an n = 8 cross-over. Animals in parallel designs receive only one treatment. Parallel studies will have a different sensitivity to detect changes. This sensitivity is a critical question in using nonclinical QTc evaluations to support an integrated proarrhythmic risk assessment under the newly released ICH E14/S7B Q&As. The current analysis used a study large enough (n = 48) to be analyzed both as a parallel and as a cross-over design to directly compare the performance of the two experimental designs coupled to different statistical models, while all other study conduct aspects were the same. A total of 48 nonhuman primates (NHP) received 2 different treatments twice: vehicle, moxifloxacin (80 mg/kg), vehicle, moxifloxacin (80 mg/kg). Post-dose QTc interval data were recorded for 48 h for each treatment. Data were analyzed using 12 animals randomly selected for each treatment in a parallel design or as an n = 48 animal cross-over study. Different statistical models were used. The primary endpoint was the residual deviation (sigma) from the models applied to hourly time intervals. The sigma was used to determine the minimal detectable difference (MDD) for the study design-statistical model combination. Two statistical models were applicable to either study design. They gave similar sigma and resulting MDD values. In cross-over designs, the individual animal identification (ID) can be used in the statistical model. This enabled the smallest MDD value. Simple statistical models for analysis were identified: Treatment + Baseline for parallel designs and Treatment + ID for cross-over designs. The statistical sensitivity of NHP parallel study designs is reasonable (MDD for n = 6 of 12.7 ms), and in combination with testing exposures higher than likely to be necessary in man could be used in an integrated risk assessment. Where sensitivity of the NHP in vivo QTc assessment is critical, the cross-over design enabled a higher sensitivity (MDD 12.2 ms for n = 4; 8 ms for n = 8).

Comparison of validity of standard nonclinical group size selection versus standard clinical group sizes for nonhuman primate QTc prolongation evaluation.

The number of animals used in a nonhuman primate (NHP) in vivo QTc assessment conducted as part of the safety pharmacology (SP) studies on a potential new drug is relatively small (4-8 subjects). The number is much smaller than the number of healthy volunteers in a conventional thorough QT (TQT) study (40-60 volunteers). How is it possible that such small studies could offer an equivalent sensitivity in an integrated nonclinical and clinical cardiac repolarization risk assessment? This study provided the opportunity to empirically demonstrate in a large number of NHPs the performance of a nonclinical evaluation at a similar size to a TQT study. By contrasting an analysis mimicking the sampling and aggregation of QTc interval data in a manner which is TQT-like with a more conventional SP-like analysis it was demonstrated that the SP-like analysis was more sensitive. In prospective power calculations 80% power at p = 0.05 can be achieved for a 5 ms QTc change with only n = 8 NHPs using the SP-like analysis and in a group of only 4 NHPs 80% power to detect 10 ms could be achieved. By contrast groups of 24 NHPs would be required to achieve 80% power to detect 5 ms using the TQT-like sampling and aggregation approach. Overall, this study has demonstrated that smaller safety pharmacology in vivo QTc assessments using all the available data in larger data aggregates can achieve sensitivity comparable to a human TQT study.

Changes in von Willebrand Factor Multimers, Concentration, and Function During Pediatric Extracorporeal Membrane Oxygenation.

OBJECTIVES: To investigate changes in von Willebrand factor (VWF) concentration, function, and multimers during pediatric extracorporeal membrane oxygenation (ECMO) and determine whether routine monitoring of VWF during ECMO would be useful in predicting bleeding. DESIGN: Prospective observational study of pediatric ECMO patients from April 2017 to May 2019. SETTING: The PICU in a large, tertiary referral pediatric ECMO center. PATIENTS: Twenty-five neonates and children (< 18 yr) supported by venoarterial ECMO. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Arterial blood samples were collected within 24 hours pre-ECMO, daily for the first 5 days of ECMO, every second day until decannulation, and 24 hours post-ECMO. The STA R Max analyzer was used to measure VWF antigen (VWF:Ag) and ristocetin cofactor (VWF:RCo) activity. VWF collagen binding (VWF:CB) was measured using an enzyme-linked immunosorbent assay. VWF multimers were measured using the semi-automated Hydragel 11 VWF Multimer assay. Corresponding clinical data for each patient was also recorded. A total of 25 venoarterial ECMO patients were recruited (median age, 73 d; interquartile range [IQR], 3 d to 1 yr). The median ECMO duration was 4 days (IQR, 3-8 d) and 15 patients had at least one major bleed during ECMO. The percentage of high molecular weight multimers (HMWM) decreased and intermediate molecular weight multimers increased while patients were on ECMO, irrespective of a bleeding status. VWF:Ag increased and the VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios decreased while patients were on ECMO compared with the baseline pre-ECMO samples and healthy children. CONCLUSIONS: Neonates and children on ECMO exhibited a loss of HMWM and lower VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag ratios compared with healthy children, irrespective of major bleeding occurring. Therefore, monitoring VWF during ECMO would not be useful in predicting bleeding in these patients and changes to other hemostatic factors should be investigated to further understand bleeding during ECMO.

Factors XI and XII in extracorporeal membrane oxygenation: longitudinal profile in children.

Background: Extracorporeal membrane oxygenation (ECMO) is used in children with cardiopulmonary failure. While the majority of ECMO centers use unfractionated heparin, other anticoagulants, including factor XI and factor XII inhibitors are emerging, which may prove suitable for ECMO patients. However, before these anticoagulants can be applied in these patients, baseline data of FXI and FXII changes need to be acquired. Objectives: This study aimed to describe the longitudinal profile of FXI and FXII antigenic levels and function before, during, and after ECMO in children. Methods: This is a prospective observational study in neonatal and pediatric patients with ECMO (<18 years). All patients with venoarterial ECMO and with sufficient plasma volume collected before ECMO, on day 1 and day 3, and 24 hours postdecannulation were included. Antigenic levels and functional activity of FXI and FXII were determined in these samples. Longitudinal profiles of these values were created using a linear mixed model. Results: Sixteen patients were included in this study. Mean FXI and FXII antigenic levels (U/mL) changed from 7.9 and 53.2 before ECMO to 6.0 and 34.5 on day 3 and they recovered to 8.8 and 39.4, respectively, after stopping ECMO. Function (%) of FXI and FXII decreased from 59.1 and 59.0 to 49.0 and 50.7 on day 3 and recovered to 66.0 and 54.4, respectively. Conclusion: This study provides the first insights into changes of the contact pathway in children undergoing ECMO. FXI and FXII antigen and function change during ECMO. Results from this study can be used as starting point for future contact pathway anticoagulant studies in pediatric patients with ECMO.

Platelet Phenotype and Function Changes With Increasing Duration of Extracorporeal Membrane Oxygenation.

OBJECTIVES: To investigate platelet pathophysiology associated with pediatric extracorporeal membrane oxygenation (ECMO). DESIGN: Prospective observational study of neonatal and pediatric ECMO patients from September 1, 2016, to December 31, 2019. SETTING: The PICU in a large tertiary referral pediatric ECMO center. PATIENTS: Eighty-seven neonates and children (< 18 yr) supported by ECMO. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Arterial blood samples were collected on days 1, 2, and 5 of ECMO and were analyzed by whole blood flow cytometry. Corresponding clinical data for each patient was also recorded. A total of 87 patients were recruited (median age, 65 d; interquartile range [IQR], 7 d to 4 yr). The median duration of ECMO was 5 days (IQR, 3-8 d) with a median length of stay in PICU and hospital of 18 days (IQR, 10-29 d) and 35 days (IQR, 19-75 d), respectively. Forty-two patients (48%) had at least one major bleed according to a priori determined definitions, and 12 patients (14%) had at least one thrombotic event during ECMO. Platelet fibrinogen receptor expression decreased (median fluorescence intensity [MFI], 29,256 vs 26,544; p = 0.0005), while von Willebrand Factor expression increased (MFI: 7,620 vs 8,829; p = 0.0459) from day 2 to day 5 of ECMO. Platelet response to agonist, Thrombin Receptor Activator Peptide 6, also decreased from day 2 to day 5 of ECMO, as measured by binding with anti-P-selectin, PAC-1 (binds activated GPIIb/IIIa), and anti-CD63 monoclonal antibodies (P-selectin area under the curve [AUC]: 63.46 vs 42.82, respectively, p = 0.0022; PAC-1 AUC: 93.75 vs 74.46, p = 0.0191; CD63 AUC: 55.69 vs 41.76, p = 0.0020). CONCLUSIONS: The loss of platelet response over time may contribute to bleeding during ECMO. These novel insights may be useful in understanding mechanisms of bleeding in pediatric ECMO and monitoring platelet markers clinically could allow for prediction or early detection of bleeding and thrombosis.

Nonclinical safety assessment of epigenetic modulatory drugs: Current status and industry perspective.

Pharmaceutic products designed to perturb the function of epigenetic modulators have been approved by regulatory authorities for treatment of advanced cancer. While the predominant effort in epigenetic drug development continues to be in oncology, non-oncology indications are also garnering interest. A survey of pharmaceutical companies was conducted to assess the interest and concerns for developing small molecule direct epigenetic effectors (EEs) as medicines. Survey themes addressed (1) general levels of interest and activity with EEs as therapeutic agents, (2) potential safety concerns, and (3) possible future efforts to develop targeted strategies for nonclinical safety assessment of EEs. Thirteen companies contributed data to the survey. Overall, the survey data indicate the consensus opinion that existing ICH guidelines are effective and appropriate for nonclinical safety assessment activities with EEs. Attention in the framework of study design should, on a case by case basis, be considered for delayed or latent toxicities, carcinogenicity, reproductive toxicity, and the theoretical potential for transgenerational effects. While current guidelines have been appropriate for the nonclinical safety assessments of epigenetic targets, broader experience with a wide range of epigenetic targets will provide information to assess the potential need for new or revised risk assessment strategies for EE drugs.

Extracorporeal membrane oxygenation for neonatal collapse caused by enterovirus myocarditis.

OBJECTIVE: To describe the effect of extracorporeal membrane oxygenation (ECMO) on survival and cardiac outcome of neonates with myocardial failure secondary to severe enterovirus (EV) myocarditis. DESIGN: Retrospective case series. SETTING: A 15-bed cardiac paediatric intensive care unit (ICU). PATIENTS: We describe the clinical presentations, cardiac findings, ECMO characteristics and outcome of seven neonates with severe EV myocarditis. Additionally, 35 previously reported cases of EV myocarditis supported with ECMO are presented. INTERVENTIONS: Extracorporeal membrane oxygenation. RESULTS: Seven neonates presented with cardiovascular collapse within the first 10 days after birth and required ECMO support. Echocardiography showed left ventricular dysfunction in all and additional right ventricular dysfunction in four patients. ECG showing widespread ST changes as well as elevated troponin I indicated myocardial damage. All patients were cannulated onto ECMO shortly after ICU admission. None of the patients suffered cardiac arrest prior to ECMO initiation. Four patients survived ECMO and three survived to hospital discharge. All three survivors showed complete cardiac recovery after a median follow-up of 34 months. The survival rate in 35 previously reported cases was 34% (12/35) and including our seven cases 36% (15/42). CONCLUSIONS: In this case series, ECMO initiation prevented further deterioration and cardiac arrest in neonates with severe EV myocarditis and not responding to conventional medical therapies. Moreover, complete cardiac recovery occurred in survivors. However, these neonates may need long ECMO runs and are at increased risk for mechanical complications. Furthermore, mortality remains high due to greater disease severity.

Extracorporeal membrane oxygenation for Kawasaki disease: two case reports and the Extracorporeal Life Support Organization experience 1999-2015.

Kawasaki disease is usually a limited illness of early childhood. However, life-threatening cardiac manifestations can occur, either at acute presentation or as a consequence of coronary arterial involvement. We report the successful use of veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) for cardiac support in two children with Kawasaki disease: one with acute Kawasaki disease shock syndrome, the other with complications of coronary arteritis and subsequent surgery. We also reviewed the reported experience in the ELSO database and available literature.

Safety of therapeutic hypothermia in children on veno-arterial extracorporeal membrane oxygenation after cardiac surgery.

OBJECTIVE: The aim of this study was to evaluate whether the use of therapeutic hypothermia in patients receiving extracorporeal membrane oxygenation after paediatric cardiac surgery is associated with increased complication rates. METHODS: We undertook a retrospective study to compare the complication rates and clinical course of children after cardiac surgery in two groups ­ extracorporeal membrane oxygenation without therapeutic hypothermia (group 1) and extracorporeal membrane oxygenation with therapeutic hypothermia (group 2). Therapeutic hypothermia was performed via the extracorporeal membrane oxygenation circuit heater-cooler device. RESULTS: A total of 96 patients were included in this study (59 in group 1 and 37 in group 2). Complications were comparable between group 1 and group 2, except that more patients with therapeutic hypothermia had hypertension while on extracorporeal membrane oxygenation. Therapeutic hypothermia was not independently associated with in-hospital mortality (adjusted odds ratio 1.16, 95% CI: 0.33-4.03; p=0.82). CONCLUSION: Therapeutic hypothermia can be safely provided to children on extracorporeal membrane oxygenation after cardiac surgery without an increase in complication rates.

Hemofiltration is not associated with increased mortality in children receiving extracorporeal membrane oxygenation.

OBJECTIVES: To investigate whether the use of continuous renal replacement therapy is independently associated with increased in-hospital mortality in children on extracorporeal membrane oxygenation. DESIGN: Retrospective, 1:1 propensity-matched cohort study. SETTING: Tertiary PICU. PATIENTS: Eighty-six children on extracorporeal membrane oxygenation, 43 of whom also received hemofiltration. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics, pre-extracorporeal membrane oxygenation hemodynamic data, fluid status, and biochemistry tests were collected, as well as duration of extracorporeal membrane oxygenation, blood product use, complications, and mortality. Forty-three children receiving extracorporeal membrane oxygenation and continuous renal replacement therapy were matched to a cohort of 43 children on extracorporeal membrane oxygenation not receiving continuous renal replacement therapy. The main indication for hemofiltration was fluid overload in 29 patients (67.4%), renal failure in nine patients (20.9%), and electrolyte abnormalities in five patients (11.6%). The median duration of hemofiltration was 108 hours (47-209 hr). Patients receiving hemofiltration had a longer duration of extracorporeal membrane oxygenation (127 hr [94-302 hr] vs 121 hr [67-182 hr]; p = 0.05) and received more platelet transfusions (0.91 mL/kg/hr [0.43-1.58 mL/kg/hr] vs 0.63 mL/kg/hr [0.30-0.79 mL/kg/hr]; p = 0.01). There were otherwise no differences in mechanical or patient-related complications between both groups. There was no difference in the proportion of patients who were successfully decannulated (81.4% vs 74.4%; p = 0.44), survived to ICU discharge (65.1% vs 55.8%; p = 0.38), or survived to hospital discharge (62.8% vs 48.8%; p = 0.19) in the controls versus the hemofiltration group. CONCLUSIONS: In-hospital mortality was similar between children on extracorporeal membrane oxygenation with and without hemofiltration although hemofiltration appeared to be associated with a slight increase in the duration of extracorporeal membrane oxygenation and more liberal platelet transfusions.

Prevalence of dysglycemia and association with outcomes in pediatric extracorporeal membrane oxygenation.

OBJECTIVES: To evaluate the relationship between glucose derangement, insulin administration, and mortality among children on extracorporeal membrane oxygenation. DESIGN: Retrospective cohort. SETTING: Tertiary PICU. PATIENTS: Two hundred nine children receiving extracorporeal membrane oxygenation, including 97 neonates. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hyperglycemia and severe hyperglycemia were defined as a single blood glucose level greater than 15 mmol/L (270 mg/dL) and greater than 20 mmol/L (360 mg/dL), respectively. Hypoglycemia and severe hypoglycemia were defined as any single glucose level less than 3.3 mmol/L (60 mg/dL) and less than 2.2 mmol/L (40 mg/dL), respectively. A total of 15,912 glucose values were recorded. The median number of glucose values was 59 per patient, corresponding to a mean 0.53 ± 0.12 tests per hour. Sixty-nine patients (33.0%) without dysglycemia and who received no insulin were defined as the control group. Eighty-nine (42.6%) and 26 (12.4%) patients developed hyperglycemia and severe hyperglycemia, respectively. Sixty-three (30.1%) and 17 (8.1%) patients developed hypoglycemia and severe hypoglycemia, respectively. Sixty-one patients (29.2%) received IV insulin during extracorporeal membrane oxygenation. Both hyperglycemia and hypoglycemia were associated with increased mortality on extracorporeal membrane oxygenation (46% and 48%, respectively, vs 29% of controls; p = 0.03). However, after adjusting for severity of illness and extracorporeal membrane oxygenation complications, abnormal glucose levels were not independently related to mortality. CONCLUSIONS: Dysglycemia in children on extracorporeal membrane oxygenation was common but not independently associated with increased mortality. The optimal glucose range for this high-risk population requires further investigation.

Elective decompression of the left ventricle in pediatric patients may reduce the duration of venoarterial extracorporeal membrane oxygenation.

We aimed to determine the effect of elective left heart decompression at the time of initiation of central venoarterial extracorporeal membrane oxygenation (VA ECMO) on VA ECMO duration and clinical outcomes in children in a single tertiary ECMO referral center with a large pediatric population from a national referral center for pediatric cardiac surgery. We studied 51 episodes of VA ECMO in a historical cohort of 49 pediatric patients treated between the years 1990 and 2013 in the Paediatric Intensive Care Unit (PICU) of the Royal Children's Hospital, Melbourne. The cases had a variety of diagnoses including congenital cardiac abnormalities, sepsis, myocarditis, and cardiomyopathy. Left heart decompression as an elective treatment or an emergency intervention for left heart distension was effectively achieved by a number of methods, including left atrial venting, blade atrial septostomy, and left ventricular cannulation. Elective left heart decompression was associated with a reduction in time on ECMO (128 h) when compared with emergency decompression (236 h) (P = 0.013). Subgroup analysis showed that ECMO duration was greatest in noncardiac patients (elective 138 h, emergency 295 h; P = 0.02) and in patients who died despite both emergency decompression and ECMO (elective 133 h, emergency 354 h; P = 0.002). As the emergency cases had a lower pH, a higher PaCO2 , and a lower oxygenation index and were treated with a higher mean airway pressure, positive end-expiratory pressure, and respiratory rate prior to receiving VA ECMO, we undertook multivariate linear regression modeling to show that only PaCO2 and the timing of left heart decompression were associated with ECMO duration. However, elective left heart decompression was not associated with a reduction in length of PICU stay, duration of mechanical ventilation, or duration of oxygen therapy. Elective left heart decompression was not associated with improved ECMO survival or survival to PICU discharge. Elective left heart decompression may reduce ECMO duration and has therefore the potential to reduce ECMO-related complications. A prospective, randomized controlled trial is indicated to study this intervention further.

Delayed extracorporeal membrane oxygenation in children after cardiac surgery: two-institution experience.

OBJECTIVE: There are limited data on the outcomes of children receiving delayed (≥7 days) extracorporeal membrane oxygenation after cardiac surgery. The primary aim of this project is to identify the aetiology and outcomes of extracorporeal membrane oxygenation in children receiving delayed (≥7 days) extracorporeal membrane oxygenation after cardiac surgery. PATIENTS AND METHODS: We conducted a retrospective review of all children ≤18 years supported with delayed extracorporeal membrane oxygenation after cardiac surgery between the period January, 2001 and March, 2012 at the Arkansas Children's Hospital, United States of America, and Royal Children's Hospital, Australia. The data collected in our study included patient demographic information, diagnoses, extracorporeal membrane oxygenation indication, extracorporeal membrane oxygenation support details, medical and surgical history, laboratory, microbiological, and radiographic data, information on organ dysfunction, complications, and patient outcomes. The outcome variables evaluated in this report included: survival to hospital discharge and current survival with emphasis on neurological, renal, pulmonary, and other end-organ function. RESULTS: During the study period, 423 patients undergoing cardiac surgery were supported with extracorporeal membrane oxygenation at two institutions, with a survival of 232 patients (55%). Of these, 371 patients received extracorporeal membrane oxygenation <7 days after cardiac surgery, with a survival of 205 (55%) patients, and 52 patients received extracorporeal membrane oxygenation ≥7 days after cardiac surgery, with a survival of 27 (52%) patients. The median duration of extracorporeal membrane oxygenation run for the study cohort was 5 days (interquartile range: 3, 10). In all, 14 patients (25%) received extracorporeal membrane oxygenation during active cardiopulmonary resuscitation with chest compressions. There were 24 patients (44%) who received dialysis while being on extracorporeal membrane oxygenation. There were eight patients (15%) who had positive blood cultures and four patients (7%) who had positive urine cultures while being on extracorporeal membrane oxygenation. There were nine patients (16%) who had bleeding complications associated with extracorporeal membrane oxygenation runs. There were 10 patients (18%) who had cerebrovascular thromboembolic events associated with extracorporeal membrane oxygenation runs. Of these, 19 patients are still alive with significant comorbidities. CONCLUSIONS: This study demonstrates that mortality outcomes are comparable among children receiving extracorporeal membrane oxygenation ≥7 days and <7 days after cardiac surgery. The proportion of patients receiving extracorporeal membrane oxygenation ≥7 days is small and the aetiology diverse.

Hemolysis in pediatric patients receiving centrifugal-pump extracorporeal membrane oxygenation: prevalence, risk factors, and outcomes.

OBJECTIVES: To explore the prevalence and risk factors for hemolysis in children receiving extracorporeal membrane oxygenation and examine the relationship between hemolysis and adverse outcomes. DESIGN: Retrospective, single-center study. SETTING: Tertiary PICU. PATIENTS: Two hundred seven children receiving extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma-free hemoglobin was tested daily and hemolysis was diagnosed based on peak plasma-free hemoglobin as mild (< 0.5 g/L), moderate (0.5-1.0 g/L), or severe (> 1.0 g/L). Gender, age, weight, diagnosis, oxygenator type, cannulation site, mean venous inlet pressure, mean pump speed, mean flow, and visible clots in the extracorporeal membrane oxygenation circuit were entered into the ordered logistic regression model to identify risk factors of hemolysis. Complications and clinical outcomes were compared across four hemolysis groups. Of the 207 patients, 69 patients (33.3%; 95% CI, 27.0-40.2%) did not have hemolysis, 98 patients (47.3%; 95% CI, 40.4-54.4%) had mild hemolysis, 26 patients (12.5%; 95% CI, 8.4-17.9%) had moderate hemolysis, and 14 patients (6.8%; 95% CI, 3.7-11.1%) had severe hemolysis with a median peak plasma-free hemoglobin of 1.51 g/L (1.18-2.05 g/L). The independent risk factors for hemolysis during extracorporeal membrane oxygenation were use of Quadrox D (odds ratio, 7.25; 95% CI, 3.10-16.95; p < 0.001) or Lilliput (odds ratio, 37.32; 95% CI, 8.95-155.56; p < 0.001) oxygenators, mean venous inlet pressure (odds ratio, 0.95; 95% CI, 0.91-0.98; p = 0.002), and mean pump speed (odds ratio, 2.89; 95% CI, 1.36-6.14; p = 0.006). Patients with hemolysis were more likely to experience a longer extracorporeal membrane oxygenation run and require more blood products. After controlling for age, weight, pediatric index of mortality 2, and diagnosis, patients with severe hemolysis were more likely to die in the ICU (odds ratio, 5.93; 95% CI, 1.64-21.43; p = 0.007) and in hospital (odds ratio, 6.34; 95% CI, 1.71-23.54; p = 0.006). CONCLUSIONS: Hemolysis during extracorporeal membrane oxygenation with centrifugal pumps was common and associated with a number of adverse outcomes. Risk factors for hemolysis included oxygenator types, mean venous inlet pressure, and mean pump speed. Further studies are warranted comparing pump types while controlling both physical and nonphysical confounders.

Outcomes in children with refractory pneumonia supported with extracorporeal membrane oxygenation.

PURPOSE: To review the use of extracorporeal membrane oxygenation (ECMO) in severe paediatric pneumonia and evaluate factors that may affect efficacy of this treatment. METHODS: Retrospective study of the ECMO database of a tertiary paediatric intensive care unit and chart review of all patients who were managed with ECMO during their treatment for severe pneumonia over a 23-year period. The main outcome measures were survival to hospital discharge, and ICU and hospital length of stay. We compared the groups of culture-positive versus culture-negative pneumonia, venoarterial (VA) versus venovenous (VV) ECMO, community- versus hospital-acquired cases, and cases before and after 2005. RESULTS: Fifty patients had 52 cases of pneumonia managed with ECMO. Community-acquired cases were sicker with higher oxygenation index (41.5 ± 20.5 versus 26.8 ± 17.8; p = 0.031) and higher inotrope score [20 (5-37.5) versus 7.5 (0-18.8); p = 0.07]. Use of VA compared with VV ECMO was associated with higher inotrope scores [20 (10-50) versus 5 (0-20); p = 0.012]. There was a trend towards improved survival in the VV ECMO group (82.4 versus 62.9 %; p = 0.15). Since 2005, patients have been older [4.7 (1-8) versus 1.25 (0.15-2.8) years; p = 0.008] and survival has improved (88.2 versus 60.0 %; p = 0.039). CONCLUSIONS: Survival in children with pneumonia requiring ECMO has improved over time and is now 90 % in the modern era. Risk factors for death include performing a circuit change [odds ratio (OR) 5.0; 95 % confidence interval (CI) 1.02-24.41; p = 0.047] and use of continuous renal replacement therapy (OR 4.2; 95 % CI 1.13-15.59; p = 0.032).

Outcomes of second-run extracorporeal life support in children: a single-institution experience.

BACKGROUND: After weaning from mechanical circulatory support with extracorporeal membrane oxygenation or ventricular assist devices, patients may recurrently deteriorate and require reinstitution of support. Potential benefits of this desperate strategy are not well documented. METHODS: We reviewed the hospital records of all patients in whom second-run mechanical circulatory support was instituted from May 1988 to August 2010. RESULTS: Second-run support was instigated in 26 (4.6%) of 567 patients who underwent short-term mechanical circulatory support. Underlying pathologies requiring support were cardiac in 20 patients (76.9%) and noncardiac in 6 patients (23.1%).The majority of patients were younger than 1 year old (73.1%, n=19). Fifteen patients (57.7%) survived second-run support, but only 7 patients (26.9%) survived to discharge from the hospital. After a median follow-up of 42.5 months (range, 16 to 66 months), 4 patients (15.4%) were alive, but 3 of them had various degrees of developmental delay. CONCLUSIONS: Selection of patients who can benefit from second-run support is a complex process with unpredictable results. Survival after second-run mechanical circulatory support in children is worse compared with single-run patients. Long-term prospects for survivors are so grim that this strategy should probably not be recommended.