Pa o2 and Mortality in Neonatal Extracorporeal Membrane Oxygenation: Retrospective Analysis of the Extracorporeal Life Support Organization Registry, 2015-2020.

OBJECTIVES: Extracorporeal life support can lead to rapid reversal of hypoxemia but the benefits and harms of different oxygenation targets in severely ill patients are unclear. Our primary objective was to investigate the association between the Pa o2 after extracorporeal membrane oxygenation (ECMO) initiation and mortality in neonates treated for respiratory failure. DESIGN: Retrospective analysis of the Extracorporeal Life Support Organization (ELSO) Registry data, 2015-2020. PATIENTS: Newborns supported by ECMO for respiratory indication were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pa o2 24 hours after ECMO initiation (H24 Pa o2 ) was reported. The primary outcome was 28-day mortality. We identified 3533 newborns (median age 1 d [interquartile range (IQR), 1-3]; median weight 3.2 kg [IQR, 2.8-3.6]) from 198 ELSO centers, who were placed on ECMO. By 28 days of life, 731 (20.7%) had died. The median H24 Pa o2 was 85 mm Hg (IQR, 60-142). We found that both hypoxia (Pa o2 < 60 mm Hg) and moderate hyperoxia (Pa o2 201-300 mm Hg) were associated with greater adjusted odds ratio (aOR [95% CI]) of 28-day mortality, respectively: aOR 1.44 (95% CI, 1.08-1.93), p = 0.016, and aOR 1.49 (95% CI, 1.01-2.19), p value equals to 0.045. CONCLUSIONS: Early hypoxia or moderate hyperoxia after ECMO initiation are each associated with greater odds of 28-day mortality among neonates requiring ECMO for respiratory failure.

Determining Optimal Mean Arterial Blood Pressure Based on Cerebral Autoregulation in Children after Cardiac Surgery.

To evaluate the feasibility of continuous determination of the optimal mean arterial blood pressure (opt-MAP) according to cerebral autoregulation and to describe the opt-MAP, the autoregulation limits, and the time spent outside these limits in children within 48 h of cardiac surgery. Cerebral autoregulation was assessed using the correlation coefficient (COx) between cerebral oxygenation and MAP in children following cardiac surgery. Plots depicting the COx according to the MAP were used to determine the opt-MAP using weighted multiple time windows. For each patient, we estimated (1) the time spent with MAP outside the autoregulation limits and (2) the burden of deviation, defined as the area between the MAP curve and the autoregulation limits when the MAP was outside these limits. Fifty-one patients with a median age of 7.1 (IQR 0.7-52.0) months old were included. The opt-MAP was calculated for 94% (IQR 90-96) of the monitored time. The opt-MAP was significantly lower in neonates < 1 month old. The patients spent 24% (18-31) of the time outside of the autoregulation limits, with no significant differences between age groups. Continuous determination of the opt-MAP is feasible in children within the first 48 h following cardiac surgery.

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

Semiautomated Regional Citrate Anticoagulation for Continuous Kidney Replacement Therapy: An Observational Study in Young Children.

OBJECTIVES: To review use of semiautomated regional citrate anticoagulation (saRCA) for continuous kidney replacement therapy (CKRT) in young children. DESIGN: Retrospective cohort study. SETTING: Three independent PICUs. PATIENTS: All consecutive children weighing less than 11 kg who received CKRT with saRCA from January 2015 to June 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-one children weighing less than 11 kg underwent CKRT with saRCA. The total duration of the CKRT was 2,014 hours, with a total of 64 CKRT sessions. Citrate intoxication occurred in four of 64 CKRT sessions (6%). Citrate intoxication was consistently observed in the few CKRT sessions where the initial lactate concentration was greater than 4 mmol/L or the ratio of replacement fluid flow to citrate flow less than 50%. The rate of unscheduled interruptions of CKRT sessions was 25% (16/64). CONCLUSIONS: We have used saRCA for CKRT in children weighing less than 11 kg. A strict protocol and intensive training are required to minimize complications.

Frequency of Extracorporeal Membrane Oxygenation Support and Outcomes After Implementation of a Structured PICU Network in Neonates and Children: A Prospective Population-Based Study in the West of France.

OBJECTIVES: To describe the frequency and outcomes on the use of extracorporeal membrane oxygenation (ECMO) among critically ill neonates and children within a structured pediatric critical care network in the West of France. To assess the optimality of decision-making process for patients primarily admitted in non-ECMO centers. DESIGN: Observational prospective population-based study from January 2015 to December 2019. PATIENTS: Neonates over 34 weeks of gestational age, weighing more than 2,000 g and children under 15 years and 3 months old admitted in one of the 10 units belonging to a Regional Pediatric Critical Care Network. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eight-thousand one hundred eighty-nine children and 3,947 newborns were admitted within one of the 10 units of the network over the study period. Sixty-five children (8.1% [95% CI, 6.2-10‰]) and 35 newborns (9.4% [95% CI, 6.4-12%]) required ECMO support. Of these patients, 31 were first admitted to a non-ECMO center, where 20 were cannulated in situ (outside the regional ECMO center) and 11 after transfer to the ECMO regional center. Cardiogenic shock, highest serum lactate level, and cardiac arrest prior to first phone call with the regional ECMO center were associated with higher rate of in situ cannulation. During the study period, most of the patients were cannulated for underlying cardiac issue (42/100), postoperative cardiac surgery instability (38/100), and pediatric (10/100) and neonatal (10/100) respiratory distress syndrome. Patients primarily admitted in non-ECMO centers or not had similar 28-day post-ICU survival rates compared with those admitted in the referral ECMO center (58% vs 51%; p = 0.332). Pre-ECMO cardiac arrest, ECMO, and lower pH at ECMO onset were associated with lower 28-day post-ICU survival. CONCLUSIONS: Our local results suggest that a structured referral network for neonatal and pediatric ECMO in the region of Western France facilitated escalation of care with noninferior (or similar) early mortality outcome. Our data support establishing referral networks in other equivalent regions.

Impact of Arterial Carbon Dioxide and Oxygen Content on Cerebral Autoregulation Monitoring Among Children Supported by ECMO.

BACKGROUND: Cerebral autoregulation (CA) impairment is associated with neurological complications among children supported by extracorporeal membrane oxygenation (ECMO). Severe variations of arterial CO2 (PaCO2) and O2 (PaO2) tension after ECMO onset are common and associate with mortality and poor neurological outcome. The impact of gas exchange on CA among critically ill patients is poorly studied. METHODS: Retrospective analysis of data collected prospectively from 30 children treated with veno-arterial or veno-venous ECMO in the PICU of Nantes University Hospital, France. A correlation coefficient between the variations of regional cerebral oxygen saturation (rSO2) and the variations of mean arterial blood pressure (MAP) was calculated as an index of CA (cerebral oxygenation reactivity index, COx). Cox-MAP plots were investigated allowing determining lower limit of autoregulation (LLA) and upper limit of autoregulation (ULA) limits of autoregulation. Age-based normal blood pressure was used to adjust the MAP, LLA, and ULA data from each patient and then reported as percentage (nMAP, nLLA, and nULA, respectively). RSO2, COx, nMAP, nLLA, and nULA values were averaged over one hour before each arterial blood gas (ABG) sample during ECMO run. RESULTS: Thirty children (median age 4.8 months [Interquartile range (IQR) 0.7-39.1], median weight 5 kg [IQR 4-15]) experiencing 31 ECMO runs were included in the study. Three hundred and ninety ABGs were analyzed. The highest values of COx were observed on day 1 (D1) of ECMO. The relationship between COx and PaCO2 was nonlinear, but COx values tended to be lower in case of hypercapnia compared to normocapnia. During the whole ECMO run, a weak but significant correlation between PaCO2 and nULA was observed (R = 0.432, p = 0.02). On D1 of ECMO, this correlation was stronger (R = 0.85, p = 0.03) and a positive correlation between nLLA and PaCO2 was also found (R = 0.726, p < 0.001). A very weak negative correlation between PaO2 and nULA was observed within the whole ECMO run and on D1 of ECMO (R = -0.07 p = 0.04 and R = -0.135 p = <0.001, respectively). The difference between nULA and nLLA representing the span of the autoregulation plateau was positively correlated with PaCO2 and negatively correlated with PaO2 (R = 0.224, p = 0.01 and R = -0.051, p = 0.004, respectively). CONCLUSIONS: We observed a complex relationship between PaCO2 and CA, influenced by the level of blood pressure. Hypercapnia seems to be globally protective in normotensive or hypertensive condition, while, in case of very low MAP, hypercapnia may disturb CA as it increases LLA. These data add additional arguments for very cautiously lower PaCO2, especially after ECMO start.

Continuous Monitoring of Cerebral Autoregulation in Children Supported by Extracorporeal Membrane Oxygenation: A Pilot Study.

OBJECTIVE: Cerebral autoregulation (CA) impairment may pose a risk factor for neurological complications among children supported by extracorporeal membrane oxygenation (ECMO). Our first objective was to investigate the feasibility of CA continuous monitoring during ECMO treatment and to describe its evolution over time. The second objective was to analyze the association between CA impairment and neurological outcome. DESIGN: Observational prospective study. PATIENTS AND SETTING: Twenty-nine children treated with veno-arterial or veno-venous ECMO in the PICU of Nantes University Hospital, France, and the PICU of the IRCCS Giannina Gaslini Institute in Genoa, Italy. MEASUREMENTS: A correlation coefficient between the variations of regional cerebral oxygen saturation and the variations of mean arterial blood pressure (MAP) was calculated as an index of CA (cerebral oxygenation reactivity index, COx). A COx > 0.3 was considered as indicative of autoregulation impairment. COx-MAP plots were investigated allowing determining optimal MAP (MAPopt) and limits of autoregulation: lower (LLA) and upper (ULA). Neurological outcome was assessed by the onset of an acute neurological event (ANE) after ECMO start. RESULTS: We included 29 children (median age 84 days, weight 4.8 kg). MAPopt, LLA, and ULA were detected in 90.8% (84.3-93.3) of monitoring time. Mean COx was significantly higher during day 1 of ECMO compared to day 2 [0.1 (0.02-0.15) vs. 0.01 (- 0.05 to 0.1), p = 0.002]. Twelve children experienced ANE (34.5%). The mean COx and the percentage of time spent with a COx > 0.3 were significantly higher among ANE+ compared to ANE- patients [0.09 (0.01-0.23) vs. 0.04 (- 0.02 to 0.06), p = 0.04 and 33.3% (24.8-62.1) vs. 20.8% (17.3-23.7) p = 0.001]. ANE+ patients spent significantly more time with MAP below LLA [17.2% (6.5-32.9) vs. 5.6% (3.6-9.9), p = 0.02] and above ULA [13% (5.3-38.4) vs. 4.2% (2.7-7.4), p = 0.004], respectively. CONCLUSION: CA assessment is feasible in pediatric ECMO. The first 24 h following ECMO represents the most critical period regarding CA. Impaired autoregulation is significantly more severe among patients who experience ANE.

Right watershed cerebral infarction following neck cannulation for veno-arterial extracorporeal membrane oxygenation in pediatric septic shock: a case series.

Children supported by extracorporeal membrane oxygenation present a high risk of neurological complications. Although carotid cannulation is known to be associated with neurologic injury, conflicting data exist with regard to the predominance of right- or left-sided lesions. We describe here two infants requiring veno-arterial extracorporeal membrane oxygenation for septic shock who encountered right watershed infarction ipsilateral to carotid artery cannulation. Hemodynamic failure seems to be the most probable underlying mechanism. The asymmetry of transcranial Doppler metrics in one case and the low right regional cerebral oxygen saturation value observed soon after right cannulation in both cases suggest an insufficient cerebral collateral flow compensation. The risk of ipsilateral watershed injury should be considered before cervical cannulation, notably in the context of sepsis and an evaluation of the cerebral collateral blood flow before and just after cannulation may be interesting in order to identify infants with higher risk of ipsilateral ischemic lesions.

The Prognostic Value of Early Amplitude-Integrated Electroencephalography Monitoring After Pediatric Cardiac Arrest.

OBJECTIVES: To assess the ability of amplitude-integrated electroencephalography monitoring within 24 hours of the return of spontaneous circulation to prognosticate neurologic outcomes in children following cardiac arrest DESIGN:: Retrospective review of prospectively recorded data. An amplitude-integrated electroencephalography background score was calculated according to background activity during the first 24 hours after return of spontaneous circulation, a higher score correlating with more impaired background activity. The primary endpoint was the neurologic outcome as defined by the Pediatric Cerebral Performance Category at PICU discharge (Pediatric Cerebral Performance Category 1-3: a good neurologic outcome; Pediatric Cerebral Performance Category 4-6: a poor neurologic outcome). SETTING: A referral PICU. PATIENTS: Thirty children with a median age of 10 months (2-38 mo) and a male/female sex ratio of 1.3 were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighteen patients were assigned to the favorable outcome group and 12 to the unfavorable outcome group. The median time between return of spontaneous circulation and amplitude-integrated electroencephalography initiation was 4 hours (3-9 hr). The amplitude-integrated electroencephalography score within 24 hours after return of spontaneous circulation was significantly higher in the children with poor outcomes compared with those with good outcomes (12 ± 4 vs 25 ± 8; p < 0.001). Background activity during amplitude-integrated electroencephalography monitoring was able to predict poor neurologic outcomes at PICU discharge, with an area under the receiver operating characteristic curve of 0.91 (95% CI, 0.81-1.00). CONCLUSIONS: Early amplitude-integrated electroencephalography monitoring may help predict poor neurologic outcomes in children within 24 hours following cardiac arrest.

Implementation of a Nurse-Driven Sedation Protocol in a PICU Decreases Daily Doses of Midazolam.

OBJECTIVES: To evaluate the impact of a nurse-driven sedation protocol on the length of mechanical ventilation, total daily doses of sedatives, and complications of sedation. DESIGN: A single-center prospective before and after study was conducted from October 2010 to December 2013. SETTING: Twelve-bed surgical and medical PICU of the university-affiliated hospital in Nantes, France. PATIENTS: A total of 235 patients, between 28 days and 18 years old, requiring mechanical ventilation for at least 24 hours were included in the study; data from 194 patients were analyzed. INTERVENTIONS: During the first study phase, no protocol was used. During the second phase, patients were sedated according to a nurse-driven protocol. MEASUREMENTS AND MAIN RESULTS: In the whole population, the length of mechanical ventilation did not differ between protocol and control groups (protocol, 4 [3-8] vs control, 5 [3-7.5]; p = 0.44). Analyzing age subgroups, the length of mechanical ventilation was significantly shorter in the protocol group than in the control group in children older than 12 months (4 [3-8] vs 5 [2.75-11.25] d; p = 0.04). Daily dose of midazolam decreased during the protocol phase compared with the control phase (1 [0.56-1.8] and 1.2 [0.85-2.4] mg/kg/d, respectively; p = 0.02). No differences were shown regarding other daily dose of drugs. In the control group, 68% of children had more than 20% of COMFORT-behavior scale assessment under the target (oversedation) versus 59% in the protocol group (p = 0.139). CONCLUSIONS: Implementation of a nurse-driven sedation protocol in a PICU is feasible and safe, allowed a decrease in daily dose of benzodiazepines, and decreased the duration of mechanical ventilation in older patients.

Physiological effects of invasive ventilation with neurally adjusted ventilatory assist (NAVA) in a crossover study.

BACKGROUND: Neurally Adjusted Ventilatory Assist (NAVA) is a mode of assisted mechanical ventilation that delivers inspiratory pressure proportionally to the electrical activity of the diaphragm. To date, no pediatric study has focused on the effects of NAVA on hemodynamic parameters. This physiologic study with a randomized cross-over design compared hemodynamic parameters when NAVA or conventional ventilation (CV) was applied. METHODS: After a baseline period, infants received NAVA and CV in a randomized order during two consecutive 30-min periods. During the last 10 min of each period, respiratory and hemodynamic parameters were collected. No changes in PEEP, FiO2, sedation or inotropic doses were allowed during these two periods. The challenge was to keep minute volumes constant, with no changes in blood CO2 levels and in pH that may affect the results. RESULTS: Six infants who had undergone cardiac surgery (mean age 7.8 ± 4.1 months) were studied after parental consent. Four of them had low central venous oxygen saturation (ScvO2 < 65 %). The ventilatory settings resulted in similar minute volumes (1.7 ± 0.4 vs. 1.6 ± 0.6 ml/kg, P = 0.67) and in similar tidal volumes respectively with NAVA and with CV. There were no statistically significant differences on blood pH levels between the two modes of ventilation (7.32 ± 0.02 vs. 7.32 ± 0.04, P = 0.34). Ventilation with NAVA delivered lower peak inspiratory pressures than with CV: -32.7 % (95 % CI: -48.2 to -17.1 %, P = 0.04). With regard to hemodynamics, systolic arterial pressures were higher using NAVA: +8.4 % (95 % CI: +3.3 to +13.6 %, P = 0.03). There were no statistically significant differences on cardiac index between the two modes of ventilation. However, all children with a low baseline ScvO2 (<65 %) tended to increase their cardiac index with NAVA compared to CV: 2.03 ± 0.30 vs. 1.91 ± 0.39 L/min.m2 (median ± interquartile, P = 0.07). CONCLUSIONS: This pilot study raises the hypothesis that NAVA could have beneficial effects on hemodynamics in children when compared to a conventional ventilatory mode that delivered identical PEEP and similar minute volumes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01490710 . Date of registration: December 7, 2011.

Evaluation of the relationship between plasma transfusion and nosocomial infection after cardiac surgery in children younger than 1 year.

OBJECTIVES: Recent data have suggested a link between plasma transfusion and the development of nosocomial infections in critically ill children. However, to our knowledge, no study has specifically focused on this association among children undergoing cardiac surgery. Thus, the main objective of this study was to analyze the relationship between plasma transfusion after cardiac surgery and the risk of nosocomial infections, including bloodstream infections, mediastinitis, and ventilator-associated pneumonia, in children younger than 1 year. DESIGN: Observational single-center study. SETTING: A 12-bed tertiary PICU in a university hospital in France. PATIENTS: Children less than 1 year admitted after cardiac surgery under cardiopulmonary bypass between November 2007 and December 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data from 233 children were analyzed, of which 94 children (40%) had been transfused with plasma during their PICU stay. Fifty-six episodes of nosocomial infections (51 children) were reported, yielding a nosocomial infection ratio of 24%. The unadjusted odds ratio for developing nosocomial infections associated with plasma transfusion was 4.1 (95% CI, 2.1-7.9; p < 0.001). After adjusting for a propensity score, there was no difference between the two groups (adjusted odds ratio, 1.5; 95% CI, 0.5-4.0; p = 0.5). CONCLUSION: Plasma transfusion following cardiac surgery under cardiopulmonary bypass was not independently associated with the development of nosocomial infections in children (< 1 yr old) after adjustment for a propensity score.

Regional citrate anticoagulation for pediatric CRRT using integrated citrate software and physiological sodium concentration solutions.

BACKGROUND: In continuous renal replacement therapy (CRRT), regional citrate anticoagulation offers an attractive alternative to heparinization, especially for children with a high bleeding risk. METHODS: We report on a new management approach to CRRT using integrated citrate software and physiological sodium concentration solutions. Convective filtration was performed with pre-filter citrate anticoagulation using an 18 mmol/L citrate solution and a post-filter replacement fluid. The citrate flow rate was automatically adjusted to the blood flow rate by means of integrated citrate software. Similarly, calcium was automatically infused into children to maintain their blood calcium levels within normal range. RESULTS: Eleven CRRT sessions were performed (330 h) in seven critically ill children aged 3-15 years (extreme values 15-66 kg). Disease categories included sepsis with multiorgan dysfunction (n = 2) and hemolytic uremic syndrome (n = 5). Median effluent dose was 2.1 (extreme values 1.7-3.3) L/h/1.73 m2. No session had to be stopped because of metabolic complications. Calcium levels, both in the circuits and in the circulating blood of the children, remained stable and secure. CONCLUSIONS: Regional citrate anticoagulation can be used in children with a body weight of >15 kg using integrated citrate software and commercially available solutions with physiological sodium concentrations in a safe, effective and convenient procedure.

High-dose intravenous immunoglobulin versus albumin 4% in paediatric toxic shock syndrome: a randomised controlled feasibility study.

PURPOSE: Toxic shock syndrome (TSS) is a rare disease responsible for significant morbidity and mortality. Intravenous immunoglobulin (IG) therapy in paediatric TSS could improve shock and organ failure, but more consistent efficacy and safety data are needed. Our objective was to determine whether a randomised clinical trial (RCT) assessing intravenous IG in TSS in children is feasible. METHODS: We performed a multicentre, feasibility, double-blind RCT assessing efficacy of high-dose intravenous IG versus albumin 4% (control group) within the first 12 hours of shock onset. Included patients were aged above 1 month and below 18 years with suspected TSS and septic shock. Feasibility was assessed by measuring inclusion rate, protocol compliance and missing data regarding death and the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) Score. Other secondary clinical outcomes were evaluated during hospital stay, at 60 day and 1 year. RESULTS: 28 patients, admitted in 6 paediatric intensive care units during 36 consecutive months and followed for 1 year, received the allocated treatment: 13 in intravenous IG group, 15 in control group. The median age was 10.6 years and the sex ratio was 1. Inclusion rate was above 50%, protocol deviations were below 30% and missing data regarding death and PELOD-2 Score below 10%. No difference concerning secondary clinical outcomes between groups was observed, and more adverse events were reported in the control group. CONCLUSION: It seems to be feasible to conduct an RCT assessing intravenous IG efficacy and safety in paediatric TSS but must be realised internationally, with choice of a clinically relevant endpoint and a specific design in order to be realistic. TRIAL REGISTRATION NUMBER: NCT02219165.

Effectiveness of intraoperative use of dexmedetomidine in reducing the incidence of tachyarrhythmia after congenital cardiac surgery in neonates and infants: a doubly robust method estimation analysis.

OBJECTIVES: The antiarrhythmic effects of dexmedetomidine (DEX) have been suggested, but there are controversial reports on the effectiveness of intraoperative use of DEX to reduce the incidence of postoperative tachyarrhythmia (POT). METHODS: From a local European Congenital Heart Surgery Association database, we included patients operated for congenital heart diseases under cardiopulmonary bypass within a 5-year period (2017-2021), during which intraoperative use of high dose of DEX (1-1.4 µg/kg/h) was implemented. A doubly robust matching estimation of the causal effect of DEX on the incidence of POT was conducted. We combined a multimodal estimation model in patients not exposed to DEX (disease risk score) as well as a regression analysis in a matched cohort for patients exposured to DEX. RESULTS: From a cohort of 593 surgeries (514 patients) occurring during the study period, doubly matched analysis consisted of the analysis of 426 surgeries conducted under DEX or not (213 per group). The probability of developing POT in patients exposed to DEX was 6.6% (95% confidence interval 0.032-0.099) vs 14.5% (95% confidence interval 0.098-0.193) in the group of patients not exposed to DEX. The doubly robust matched estimation method showed a mean reduction of 8.8% (95% confidence interval -0.137 to -0.023) of POT when DEX is used for intraoperative anaesthesia. CONCLUSIONS: The use of high doses of DEX during anaesthesia for congenital heart surgery in neonates and infants is associated with a moderate but significant reduction of POT.

Evolution of Carboxyhemoglobin in Children Supported by Extracorporeal Membrane Oxygenation: An Observational Single-Center Study.

Carboxyhemoglobin (COHb) is potentially a novel marker of hemolysis on extracorporeal membrane oxygenation (ECMO) and may be useful as an indicator for circuit-related complication in adults, but little is known about COHb levels in children. An observational single-center study was performed between January 2018 and December 2021. Fifty-eight children were included and COHb levels were obtained along with routine blood gas analysis before, during, and after ECMO support. From the 6th hour of ECMO support, the COHb level increased relative to the pre-ECMO level, with an adjusted mean difference of 0.44 (95% confidence interval [CI], 0.26-0.62; p < 0.001) and remained higher during ECMO run and within 6 hours after weaning ( p < 0.001). Among the 18 children (31%) who experienced at least one circuit-related complication leading to a circuit change, we observed a significant decrease in COHb levels within 24 hours after the circuit change, compared with the 24 hours before (adjusted mean difference, 0.54%; 95% CI, 0.27-0.80; p < 0.001). The maximal daily COHb level was able to predict circuit-related complications within 24 hours following COHb measurement with an area under the receiver operating characteristic (ROC) curve of 0.85 (95% CI, 0.77-0.92; p < 0.001).

Population Pharmacokinetics of Levosimendan and its Metabolites in Critically Ill Neonates and Children Supported or Not by Extracorporeal Membrane Oxygenation.

BACKGROUND: Levosimendan (LVSMD) is a calcium-sensitizer inotropic and vasodilator agent whose use might have a beneficial effect on the weaning of venoarterial extracorporeal membrane oxygenation (VA-ECMO). In light of LVSMD pharmacological characteristics, we hypothesized that ECMO may induce major pharmacokinetic (PK) modifications for LVSMD and its metabolites. OBJECTIVE: The aim of this study was to investigate the PK of LVSMD and its metabolites, and to assess the effects of ECMO on PK parameters. METHODS: We conducted a multicentric, prospective study (NCT03681379). Twenty-seven infusions of LVSMD were performed, allowing for the collection of 255 blood samples. Non-linear mixed-effects modeling software (MONOLIX®) was used to develop a parent-metabolite PK model of LVSMD and its metabolites. RESULTS: Most patients received a 0.2 µg/kg/min infusion of LVSMD over 24 h. After elimination of non-reliable samples or concentrations below the limit of quantification, 166, 101 and 85 samples were considered for LVSMD, OR-1855 and OR-1896, respectively, of which 81, 53 and 41, respectively, were drawn under ECMO conditions. Parent-metabolite PK modeling revealed that a two-compartment model with first-order elimination best described LVSMD PK. Use of a transit compartment allowed for an explanation of the delayed appearance of circulating OR-1855 and OR-1896, with the latter following a first-order elimination. Patient weight influenced the central volume of distribution and elimination of LVSMD. ECMO support increased the elimination rate of LVSMD by 78%, and ECMO also slowed down the metabolite formation rate by 85% for OR-1855, which in turn is converted to the active metabolite OR-1896, 14% slower than without ECMO. Simulated data revealed that standard dosing may not be appropriate for patients under ECMO, with a decrease in the steady-state concentration of LVSMD and lower exposure to the active metabolite OR-1896. CONCLUSIONS: ECMO altered PK parameters for LVSMD and its metabolites. An infusion of LVSMD over 48 h, instead of 24 h, with a slightly higher dose may promote synthesis of the active metabolite OR-1896, which is responsible for the long-term efficacy of LVSMD. Further trials evaluating ECMO effects using a PK/pharmacodynamic approach may be of interest. REGISTRATION: ClinicalTrials.gov identifier number NCT03681379.

Continuous Amplitude-Integrated Electroencephalography During Neonatal and Pediatric Extracorporeal Membrane Oxygenation.

PURPOSE: Early prognostication of neurologic outcome in neonates and children supported with extra-corporeal membrane oxygenation (ECMO) is challenging. Amplitude-integrated EEG (aEEG) offers the advantages of continuous monitoring and 24-hours availability at the bedside for intensive care unit providers. The objective of this study was to describe the early electrophysiological background patterns of neonates and children undergoing ECMO and their association with neurologic outcomes. METHODS: This was a retrospective review of neonates and children undergoing ECMO and monitored with aEEG. Amplitude-integrated EEG was summarized as an aEEG background score determined within the first 24 hours of ECMO and divided in 3-hour periods. Screening for electrical seizures was performed throughout the full ECMO duration. Neurologic outcome was defined by the Pediatric Cerebral Performance Category score at hospital discharge. RESULTS: Seventy-three patients (median age 79 days [8-660], median weight 4.78 kg [3.24-10.02]) were included in the analysis. Thirty-two patients had a favorable neurologic outcome and 41 had an unfavorable neurologic outcome group at hospital discharge. A 24-hour aEEG background score >17 was associated with an unfavorable outcome with a sensitivity of 44%, a specificity of 97%, a positive predictive value of 95%, and a negative predictive value of 57%. In multivariate analysis, 24-hour aEEG background score was associated with unfavorable outcome (hazard ratio, 6.1; p = 0.001; 95% confidence interval, 2.31-16.24). The presence of seizures was not associated with neurologic outcome at hospital discharge. CONCLUSIONS: Continuous aEEG provides accurate neurologic prognostication in neonates and children supported with ECMO. Early aEEG monitoring may help intensive care unit providers to guide clinical care and family counseling.