Extracorporeal Membrane Oxygenation for Neonates With Congenital Diaphragmatic Hernia: Prevalence of Seizures and Outcomes.

OBJECTIVES: We aimed to determine the prevalence of electrographic seizures and associated odds of adverse outcomes of electrographic seizures in neonates with congenital diaphragmatic hernia (CDH) receiving extracorporeal membrane oxygenation (ECMO). DESIGN: Retrospective, descriptive case series. SETTING: Neonatal ICU (NICU) in a quaternary care institution. PATIENTS: All neonates with CDH receiving ECMO undergoing continuous electroencephalographic monitoring (CEEG) and follow-up between January 2012 and December 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All eligible neonates with CDH receiving ECMO underwent CEEG (n = 75). Electrographic seizures occurred in 14 of 75 (19%): they were exclusively electrographic-only in nine of 14, both electrographic-only and electroclinical in three of 14, and electroclinical only in two of 14. Two neonates developed status epilepticus. We identified an association between presence of seizures, rather than not, and longer duration of initial session of CEEG monitoring (55.7 hr [48.2-87.3 hr] vs 48.0 hr [43.0-48.3 hr]; p = 0.001). We also found an association between presence of seizures, rather than not, and greater odds of use of a second CEEG monitoring (12/14 vs 21/61; odds ratio [OR], 11.43 [95% CI, 2.34-55.90; p = 0.0026). Most neonates with seizures (10/14), experienced their onset of seizures more than 96 hours after the start of ECMO. Overall, the presence of electrographic seizures, compared with not, was associated with lower odds of survival to NICU discharge (4/14 vs 49/61; OR 0.10 [95% CI 0.03 to 0.37], p = 0.0006). Also, the presence of seizures-rather than not-was associated with greater odds of a composite of death and all abnormal outcomes on follow-up (13/14 vs 26/61; OR, 17.5; 95% CI, 2.15-142.39; p = 0.0074). CONCLUSIONS: Nearly one in five neonates with CDH receiving ECMO developed seizures during the ECMO course. Seizures were predominantly electrographic-only and when present were associated with great odds of adverse outcomes. The current study provides evidence to support standardized CEEG in this population.

Hospital-Acquired Infection in Pediatric Subjects With Congenital Heart Disease Postcardiotomy Supported on Extracorporeal Membrane Oxygenation.

OBJECTIVE: To determine prevalence of and risk factors for infection in pediatric subjects with congenital heart disease status postcardiotomy supported on extracorporeal membrane oxygenation, as well as outcomes of these subjects. DESIGN: Retrospective cohort from the Extracorporeal Life Support Organization. SETTING: U.S. and international medical centers providing care to children with congenital heart disease status postcardiotomy. PATIENTS: Critically ill pediatric subjects less than 8 years old admitted to medical centers between January 1, 2013, and December 31, 2015, who underwent cardiac surgery for congenital heart disease and required extracorporeal membrane oxygenation support within the first 14 postoperative days. Subjects were excluded if they underwent orthotopic heart transplantation, required preoperative extracorporeal membrane oxygenation, and had more than one postoperative extracorporeal membrane oxygenation run. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 1,314 extracorporeal membrane oxygenation subject encounters in the Extracorporeal Life Support Organization registry met inclusion criteria. Neonates comprised 53% (n = 696) of the cohort, whereas infants made up 33% (n = 435). Of the 994 subjects with Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery categorizable surgery, 33% (n = 325) were in Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery category 4 and 23% (n = 231) in Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery category 5. While on extracorporeal membrane oxygenation, 229 subjects (17%) acquired one or more extracorporeal membrane oxygenation-related infections, which represents an occurrence rate of 67 infections per 1,000 extracorporeal membrane oxygenation days. Gram-negative (62%) and Gram-positive (42%) infections occurred most commonly. Forty percent had positive blood cultures. Infants and children were at higher infection risk compared with neonatal subjects; subjects undergoing less complex surgery had higher infection rates. Unadjusted survival to hospital discharge was lower in infected subjects compared with noninfected subjects (43% vs 51%; p = 0.01). After adjusting for confounders via propensity matching, we identified no significant mortality difference between infected and noninfected subjects. CONCLUSIONS: Neonatal and pediatric subjects in this study have a high rate of acquired infection. Infants and children were at higher infection risk compared with neonatal subjects. There was not, however, a significant association between extracorporeal membrane oxygenation-related infection and survival to hospital discharge after propensity matching.

Noninvasive optical measurement of microvascular cerebral hemodynamics and autoregulation in the neonatal ECMO patient.

BACKGROUND: Extra-corporeal membrane oxygenation (ECMO) is a life-saving intervention for severe respiratory and cardiac diseases. However, 50% of survivors have abnormal neurologic exams. Current ECMO management is guided by systemic metrics, which may poorly predict cerebral perfusion. Continuous optical monitoring of cerebral hemodynamics during ECMO holds potential to detect risk factors of brain injury such as impaired cerebrovascular autoregulation (CA). METHODS: We conducted daily measurements of microvascular cerebral blood flow (CBF), oxygen saturation, and total hemoglobin concentration using diffuse correlation spectroscopy (DCS) and frequency-domain diffuse optical spectroscopy in nine neonates. We characterize CA utilizing the correlation coefficient (DCSx) between CBF and mean arterial blood pressure (MAP) during ECMO pump flow changes. RESULTS: Average MAP and pump flow levels were weakly correlated with CBF and were not correlated with cerebral oxygen saturation. CA integrity varied between individuals and with time. Systemic measurements of MAP, pulse pressure, and left cardiac dysfunction were not predictive of impaired CA. CONCLUSIONS: Our pilot results suggest that systemic measures alone cannot distinguish impaired CA from intact CA during ECMO. Furthermore, optical neuromonitoring could help determine patient-specific ECMO pump flows for optimal CA integrity, thereby reducing risk of secondary brain injury. IMPACT: Cerebral blood flow and oxygenation are not well predicted by systemic proxies such as ECMO pump flow or blood pressure. Continuous, quantitative, bedside monitoring of cerebral blood flow and oxygenation with optical tools enables new insight into the adequacy of cerebral perfusion during ECMO. A demonstration of hybrid diffuse optical and correlation spectroscopies to continuously measure cerebral blood oxygen saturation and flow in patients on ECMO, enabling assessment of cerebral autoregulation. An observation of poor correlation of cerebral blood flow and oxygenation with systemic mean arterial pressure and ECMO pump flow, suggesting that clinical decision making guided by target values for these surrogates may not be neuroprotective. ~50% of ECMO survivors have long-term neurological deficiencies; continuous monitoring of brain health throughout therapy may reduce these tragically common sequelae through brain-focused adjustment of ECMO parameters.

Pumpless arteriovenous extracorporeal membrane oxygenation: A novel mode of respiratory support in a lamb model of congenital diaphragmatic hernia.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is commonly required in neonates with congenital diaphragmatic hernia (CDH) complicated by pulmonary hypertension (PH). ECMO carries significant risk, and is contraindicated in the setting of extreme prematurity or intracranial hemorrhage. Pumpless arteriovenous ECMO (P-ECMO) may represent an alternative for respiratory support. The present study summarizes our initial experience with P-ECMO in a lamb model of CDH. STUDY DESIGN: Surgical creation of CDH was performed at 65-75days' gestation. At term (135-145days), lambs were delivered into the P-ECMO circuit. Three animals were maintained on a low-heparin infusion protocol (target ACT 160-180) and three animals were maintained with no systemic heparinization. RESULTS: Animals were supported by the circuit for 380.7 +/- 145.6h (range, 102-504h). Circuit flow rates ranged from 97 to 208ml/kg/min, with adequacy of organ perfusion demonstrated by stable serum lactate levels (3.0 +/- 1.7) and pH (7.4 +/- 0.3). Necropsy demonstrated no evidence of thrombogenic complications. CONCLUSION: Pumpless extracorporeal membrane oxygenation achieved support of CDH model lambs for up to three weeks. This therapy has the potential to bridge neonates with decompensated respiratory failure to CDH repair with no requirement for systemic anticoagulation, and may be applicable to patients currently precluded from conventional ECMO support.

Umbilical cannulation optimizes circuit flows in premature lambs supported by the EXTra-uterine Environment for Neonatal Development (EXTEND).

KEY POINTS: Bronchopulmonary dysplasia is a disease of extreme prematurity that occurs when the immature lung is exposed to gas ventilation. We designed a novel 'artificial womb' system for supporting extreme premature lambs (called EXTEND) that obviates gas ventilation by providing oxygen via a pumpless arteriovenous circuit with the lamb submerged in sterile artificial amniotic fluid. In the present study, we compare different arteriovenous cannulation strategies on EXTEND, including carotid artery/jugular vein (CA/JV), carotid artery/umbilical vein (CA/UV) and umbilical artery/umbilical vein (UA/UV). Compared to CA/JV and CA/UV cannulation, UA/UV cannulation provided significantly higher, physiological blood flows to the oxygenator, minimized flow interruptions and supported significantly longer circuit runs (up to 4 weeks). Physiological circuit blood flow in UA/UV lambs made possible normal levels of oxygen delivery, which is a critical step toward the clinical application of artificial womb technology. ABSTRACT: EXTEND (EXTra-uterine Environment for Neonatal Development) is a novel system that promotes physiological development by maintaining the premature lamb in a sterile fluid environment and providing gas exchange via a pumpless arteriovenous oxygenator circuit. During the development of EXTEND, different cannulation strategies evolved with the aim of improving circuit flow. The present study examines how different cannulation strategies affect EXTEND circuit haemodynamics in extreme premature lambs. Seventeen premature lambs were cannulated at gestational ages 105-117 days (term 145-150 days) and supported on EXTEND for up to 4 weeks. Experimental groups were distinguished by cannulation strategy: carotid artery outflow and jugular vein inflow (CA/JV; n = 4), carotid artery outflow and umbilical vein inflow (CA/UV; n = 5) and double umbilical artery outflow and umbilical vein inflow (UA/UV; n = 8). Circuit flows and pressures were measured continuously. As we transitioned from CA/JV to CA/UV to UA/UV cannulation, mean duration of circuit run and weight-adjusted circuit flows increased (P < 0.001) and the frequency of flow interruptions declined (P < 0.05). Umbilical vessels generally accommodated larger-bore cannulas, and cannula calibre was directly correlated with circuit pressures and indirectly correlated with flow:pressure ratio (a measure of post-membrane resistance). We conclude that UA/UV cannulation in fetal lambs on EXTEND optimizes circuit flow dynamics and flow stability and also supports circuit flows that closely approximate normal placental flow.

Short-Term Neurodevelopmental Outcome in Congenital Diaphragmatic Hernia: The Impact of Extracorporeal Membrane Oxygenation and Timing of Repair.

OBJECTIVES: The purpose of this study was to assess the need and timing of extracorporeal membrane oxygenation in relation to congenital diaphragmatic hernia repair as modifiers of short-term neurodevelopmental outcomes. DESIGN: Retrospective study. SETTING: A specialized tertiary care center. PATIENTS: Between June 2004 and February 2016, a total of 212 congenital diaphragmatic hernia survivors enrolled in our follow-up program. Neurodevelopmental outcome was assessed at a median age of 22 months (range, 5-37) using the Bayley Scales of Infant Development, third edition. Fifty patients (24%) required extracorporeal membrane oxygenation support. Four patients (8%) were repaired prior to cannulation, 25 (50%) were repaired on extracorporeal membrane oxygenation, and 21 (42%) were repaired after decannulation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children with congenital diaphragmatic hernia, who required extracorporeal membrane oxygenation scored on average 4.6 points lower on cognitive composite (p = 0.031) and 9.2 points lower on the motor composite (p < 0.001). Language scores were similar between groups. Mean scores for children with congenital diaphragmatic hernia repaired on extracorporeal membrane oxygenation were significantly lower for cognition (p = 0.021) and motor (p = 0.0005) outcome. Language scores were also lower, but did not reach significance. A total of 40% of children repaired on extracorporeal membrane oxygenation scored below average in all composites, whereas only 9% of the non-extracorporeal membrane oxygenation, 4% of the repaired post-extracorporeal membrane oxygenation, and 25% of the repaired pre-extracorporeal membrane oxygenation patients scored below average across all domains. Only 20% of congenital diaphragmatic hernia survivors repaired on extracorporeal membrane oxygenation support scored within the average range for all composite domains. Duration of extracorporeal membrane oxygenation support was not associated with a higher likelihood of adverse cognitive (p = 0.641), language (p = 0.147), or motor (p = 0.720) outcome. CONCLUSIONS: Need for extracorporeal membrane oxygenation in congenital diaphragmatic hernia survivors is associated with worse neurocognitive and neuromotor outcome. Need for congenital diaphragmatic hernia repair while on extracorporeal membrane oxygenation is associated with deficits in multiple domains. Overall time on extracorporeal membrane oxygenation did not impact neurodevelopmental outcome.

Corrigendum: An extra-uterine system to physiologically support the extreme premature lamb.

This corrects the article DOI: 10.1038/ncomms15112.

An extra-uterine system to physiologically support the extreme premature lamb.

In the developed world, extreme prematurity is the leading cause of neonatal mortality and morbidity due to a combination of organ immaturity and iatrogenic injury. Until now, efforts to extend gestation using extracorporeal systems have achieved limited success. Here we report the development of a system that incorporates a pumpless oxygenator circuit connected to the fetus of a lamb via an umbilical cord interface that is maintained within a closed 'amniotic fluid' circuit that closely reproduces the environment of the womb. We show that fetal lambs that are developmentally equivalent to the extreme premature human infant can be physiologically supported in this extra-uterine device for up to 4 weeks. Lambs on support maintain stable haemodynamics, have normal blood gas and oxygenation parameters and maintain patency of the fetal circulation. With appropriate nutritional support, lambs on the system demonstrate normal somatic growth, lung maturation and brain growth and myelination.

Venoarterial Extracorporeal Life Support for Neonatal Respiratory Failure: Indications and Impact on Mortality.

Venoarterial (VA) extracorporeal life support (ECLS) for neonatal respiratory failure is associated with increased mortality compared with venovenous (VV) ECLS. It is unclear whether this is a causal relationship or reflects differences in baseline disease severity between infants managed with these two strategies. Our objective was to identify clinical variables associated with the preferential selection of VA over VV ECLS, as these may confound the association between VA ECLS and increased mortality. We identified documented indications for preferential VA selection through chart review. We then assessed how the presence of common indications impacted mortality. Thirty-nine cases met eligibility. Severity of hypotension/degree of inotropic support and ventricular dysfunction on echocardiogram before cannulation were the most common specific indications for preferential VA ECLS. Mortality was 12.5% when neither high inotropic support nor ventricular dysfunction was present. Mortality rose to 20% with high inotropic support and 25% with ventricular dysfunction present alone and to 50% when both were present. We conclude that severe hypotension and ventricular dysfunction before ECLS cannulation are common indications for VA ECLS that likely influence survival. Research assessing the impact of ECLS cannulation mode on survival should adjust for baseline differences between groups for these important variables.

A single center's conversion from roller pump to centrifugal pump technology in extracorporeal membrane oxygenation.

OVERVIEW:: Recent advances in blood pump technology have led to an increased use of centrifugal pumps for prolonged extracorporeal membrane oxygenation (ECMO). Data from the Extracorporeal Life Support Organization confirms that many institutions have converted to centrifugal pumps after prior experience with roller pump technology. Centrifugal pump technology is more compact and may generate less heat and hemolysis than a conventional roller pump. Based on the potential advantages of centrifugal pumps, a decision was made institution-wide to convert to centrifugal pump technology in pediatric implementation of ECMO. Based on limited prior experience with centrifugal pumps, a multidisciplinary approach was used to implement this new technology. The new centrifugal pump (Sorin Revolution, Arvada, CO) was intended for ECMO support in the cardiac intensive care unit (CICU), the pediatric intensive care unit (PICU) and the neonatal intensive care unit (NICU). DESCRIPTION:: The perfusion team used their knowledge and expertise with centrifugal pumps to create the necessary teaching tools and interactive training sessions for the technical specialists who consisted primarily of registered nurses and respiratory therapists. The first phase consisted of educating all personnel involved in the care of the ECMO patient, followed by patient implementation in the CICU, followed by the PICU and NICU. CONCLUSION:: The institution-wide conversion took several months to complete and was well received among all disciplines in the CICU and PICU. The NICU personnel did use the centrifugal pump circuit, but decided to revert back to using the roller pump technology. A systematic transition from roller pump to centrifugal pump technology with a multidisciplinary team can ensure a safe and successful implementation.

High-frequency percussive ventilation and bronchoscopy during extracorporeal life support in children.

Variables affecting duration of pediatric extracorporeal life support (ECLS) are poorly defined. Prior analyses suggested increased mortality risk with prolonged ECLS. Lung recruitment strategies with improved secretion mobilization may shorten ECLS duration. High frequency percussive ventilation (HFPV) has been used, predominantly in inhalational injury, as a mode of ventilation to improve secretion clearance. We describe the application of HFPV and therapeutic bronchoscopies in pediatric ECLS and evaluate outcomes with a same-center historical control population. After May 2011, all children (n = 14) on ECLS were managed with HFPV during extracorporeal support (HFPV cohort). This group's demographics and outcomes were compared with ECLS patients in our unit immediately before the utilization of HFPV (pre-HFPV cohort, n = 22). The HFPV and pre-HFPV cohorts had similar demographics and utilization of venoarterial ECLS. In univariate analysis, the HFPV group underwent more bronchoscopies and experienced more ECLS-free days (days alive and off ECLS) at 30 and 60 days. In multivariate analysis, use of HFPV was independently associated with ECLS-free days. We conclude that use of HFPV and bronchoscopies during ECLS for respiratory failure was associated with an increase in ECLS-free days and that this association should be prospectively evaluated.

Hemolysis-Associated Nitric Oxide Dysregulation during Extracorporeal Membrane Oxygenation.

Acute intravascular hemolysis during extracorporeal membrane oxygenation (ECMO) leads to increased levels of cell-free hemoglobin (FHb). Our aim was to investigate whether FHb levels are associated with nitric oxide (NO) consumption and clinical outcomes. A prospective observational study was performed involving pediatric patients on ECMO. Blood samples were collected before, during, and after the ECMO run, and plasma was evaluated for FHb, oxyhemoglobin, and NO consumption. Clinical data were collected including baseline patient characteristics, indications for ECMO, circuit changes, and mortality. Correlations between laboratory measures and associations between laboratory measures and clinical observations were evaluated. Twenty-three patients (11 male, 17 neonates) were enrolled with a median weight of 3.1 kg (interquartile range, 2.8-14.0 kg) and median ECMO run of 12 days (interquartile range, 5-19 day). There was a significant increase in FHb over time on ECMO (p = .007), and significant correlations were present between NO consumption and both FHb (r = .41, p = .01) and oxyhemoglobin levels (r = .98, p < .0001). Patients on ECMO for sepsis (n = 6) had lower average levels of oxyhemoglobin (mean [standard deviation {SD}] 14.5 [4.4] versus 19.0 [5.0] µM, p = .07) and NO consumption (mean [SD] 15.8 [4.1] versus 19.8 [3.7] µM, p = .04) during ECMO than patients with other indications. In the 3 days leading up to a circuit change, there were increases in mean total cell-free hemoglobin levels (24%/day, p = .08), oxyhemoglobin (37%/day, p = .005), and NO consumption (40%/day, p = .006) (n = 5). There were no significant associations identified between peak or average plasma measures of hemolysis and type of ECMO (venovenous versus venoarterial) or mortality. For children on ECMO, we observed a strong correlation between increased levels of plasma FHb and elevations in oxyhemoglobin and NO consumption; however, these changes were not associated with increased mortality. Increased hemolysis before circuit changes may be both a marker and a contributor to circuit failure.

Challenges at the Bedside With ECMO and VAD.

Patients on circulatory support can be the source of multiple challenges including optimizing the circuit for specific congenital heart lesions, troubleshooting circuit failures, transporting patients on the circuit, anticoagulation and bleeding, transitioning to more mobile ventricular assist device, listing for thoracic organ transplantation, weaning from the circuit, and educating the patient and family about mechanical support. These challenges ideally require a specialized multidisciplinary team, which includes anesthesiologists, child life specialists, extracorporeal membrane oxygenation (ECMO) specialists, intensivists, nurses, nutritionists, perfusionists, pharmacists, respiratory therapists, social workers, and surgeons.

Risk factors for mortality in 137 pediatric cardiac intensive care unit patients managed with extracorporeal membrane oxygenation.

OBJECTIVE: To identify factors associated with mortality in children with heart disease managed with extracorporeal membrane oxygenation (ECMO). DESIGN: Retrospective chart review. SETTING: Tertiary care university-affiliated children's hospital. PATIENTS: All pediatric cardiac intensive care unit patients managed with ECMO between January 1, 1995, and June 30, 2001. INTERVENTIONS: None. RESULTS: During the study period, 137 patients were managed with ECMO in the pediatric cardiac intensive care unit. Of the 137 patients, 80 (58%) survived > or =24 hrs after decannulation, and 53 (39%) survived to hospital discharge. Patients managed with ECMO following cardiac surgery were analyzed separately from patients not in the postoperative period. Factors associated with an increased probability of mortality in the postoperative patients were age <1 month, male gender, longer duration of mechanical ventilation before ECMO, and development of renal or hepatic dysfunction while on ECMO. Single ventricle physiology and failure to separate from cardiopulmonary bypass were not associated with an increased risk of mortality. Cardiac physiology and indication for ECMO were not associated with mortality rate. Although longer duration of ECMO was not associated with increased mortality risk, patients with longer duration of ECMO were less likely to survive without heart transplantation. CONCLUSIONS: In a series of 137 patients managed with ECMO in a pediatric cardiac intensive care unit, survival to hospital discharge was 39%. In postoperative patients only, mortality risk was increased in males, patients <1 month old, patients with a longer duration of mechanical ventilation before initiation of ECMO, and patients who developed renal or hepatic failure while on ECMO.