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.

Red Blood Cell Transfusion Requirements Before and After Implementation of a Perioperative Patient Blood Management Program in Adult Patients Undergoing Cardiac Surgery. A Before and After Observational Study.

OBJECTIVES: Anemia and transfusion are common in cardiac surgery patients, and are associated with significant morbidity and mortality. Multiple perioperative interventions have been described to reduce blood transfusion, but are rarely combined altogether. The aim of this study was to compare the incidence of red blood cell (RBC) transfusion in adult patients undergoing cardiac surgery before and after the implementation of a perioperative patient blood management (PBM) program. DESIGN: Before-and-after observational study. SETTING: Single-center French university teaching hospital. PARTICIPANTS: Adult patients scheduled for cardiac surgery. INTERVENTIONS: Perioperative patient blood management program including pre-, intra-, and postoperative interventions aimed at identifying and correcting anemia, minimizing blood loss during surgery, and optimizing coagulation. MEASUREMENTS AND MAIN RESULTS: Four hundred thirty-four patients were included in the study from January 2021 to July 2022. The incidence of perioperative RBC transfusion (intraoperatively and during the first 2 postoperative days) was significantly reduced from 43% (90/213) in the pre-PBM period to 27% (60/221) in the post-PBM period (p < 0.001). The application of a PBM program was associated with a reduction in perioperative RBC transfusion by multivariate analysis (odds ratio 0.55, 95% CI 0.36-0.85, p = 0.007), and was associated with a reduction in the median number of RBC units transfused within transfused patients (p = 0.025). These effects persisted at day 30 after surgery (p = 0.029). CONCLUSION: A perioperative PBM program in adult patients undergoing cardiac surgery was associated with a significant reduction in perioperative RBC transfusion, which persisted at day 30.

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.

Consequences of the Hsp110DE9 mutation in tumorigenesis and the 5-fluorouracil-based chemotherapy response in Msh2-deficient mice.

Heat shock proteins (HSPs) play oncogenic roles in human tumours. We reported a somatic inactivating mutation of HSP110 (HSP110DE9) in mismatch repair-deficient (dMMR) cancers displaying microsatellite instability (MSI) but did not assess its impact. We evaluated the impact of the Hsp110DE9 mutation on tumour development and the chemotherapy response in a dMMR knock-in mouse model (Hsp110DE9KIMsh2KO mice). The effect of the Hsp110DE9 mutation on tumorigenesis and survival was evaluated in Msh2KO mice that were null (Hsp110wt), heterozygous (Hsp110DE9KI/+), or homozygous (Hsp110DE9KI/KI) for the Hsp110DE9 mutation by assessing tumoral syndrome (organomegaly index, tumour staging) and survival (Kaplan-Meier curves). 5-Fluorouracil (5-FU), which is the backbone of chemotherapy regimens in gastrointestinal cancers and is commonly used in other tumour types but is not effective against dMMR cells in vivo, was administered to Hsp110DE9KI/KI, Hsp110DE9KI/+, and Hsp110wtMsh2KO mice. Hsp110, Ki67 (proliferation marker) and activated caspase-3 (apoptosis marker) expression were assessed in normal and tumour tissue samples by western blotting, immunophenotyping and cell sorting. Hsp110wt expression was drastically reduced or totally lost in tumours from Msh2KOHsp110DE9KI/+ and Msh2KOHsp110DE9KI/KI mice. The Hsp110DE9 mutation did not affect overall survival or tumoral syndrome in Msh2KOHsp110DE9KI/+ and Msh2KOHsp110DE9KI/KI mice but drastically improved the 5-FU response in all cohorts (Msh2KOHsp110DE9KI/KI: P5fu = 0.001; Msh2KOHsp110DE9KI/+: P5fu = 0.005; Msh2KOHsp110wt: P5fu = 0.335). Histopathological examination and cell sorting analyses confirmed major hypersensitization to 5-FU-induced death of both Hsp110DE9KI/KI and Hsp110DE9KI/+ dMMR cancer cells. This study highlights how dMMR tumour cells adapt to HSP110 inactivation but become hypersensitive to 5-FU, suggesting Hsp110DE9 as a predictive factor of 5-FU efficacy.

Distribution, Consequences, and Determinants of Time to Antibiotics in Children With Community-Onset Severe Bacterial Infection: A Secondary Analysis of a Prospective Population-Based Study.

OBJECTIVES: To describe the distribution, consequences and potential determinants of time to antibiotics administration in children with community-onset severe bacterial infections (COSBIs). DESIGN: Secondary analysis of the available data from a prospective population-based study from 2009 to 2014. SETTING: An administrative area in western France accounting for 13% of the national pediatric population. PATIENTS: All children from 1 month to 16 years old admitted to a PICU or who died before admission and had a COSBI. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The time to antibiotics was divided into patient interval (from first signs of COSBI to the first medical consultation) and medical interval (from the first consultation to appropriate antibiotics administration). The association between the medical interval and child outcome was studied by a multinomial logistic regression model and the potential determinants of the patient and medical intervals were by a Cox proportional-hazards model. Of the 227 children included (median age 2.1 yr), 22 died (9.7%), and 21 (9.3%) had severe sequelae at PICU discharge. Median patient and medical intervals were 7.0 hours (interquartile range [IQR], 2.0-16.5 hr) and 3.3 hours (IQR, 1.1-12.2 hr), respectively. The last quartile of medical interval was not associated with death (adjusted odds ratio [aOR], 3.7; 95% CI, 0.8-17.5) or survival with severe sequelae (aOR, 1.3; 95% CI, 0.4-4.0) versus survival without severe sequelae. Patient interval was shorter in younger children (adjusted hazard ratio [aHR], 0.95; 95% CI, 0.92-0.99), and medical interval was reduced when the first consultation was conducted in a hospital (aHR, 1.5; 95% CI, 1.1-2.0) versus outpatient medicine. CONCLUSIONS: For children with COSBI, we found no significant association between medical interval and mortality or severe sequelae. An initial hospital referral could help reduce the time to antibiotics in COSBIs.

Performance of Next-Generation Sequencing for the Detection of Microsatellite Instability in Colorectal Cancer With Deficient DNA Mismatch Repair.

BACKGROUND & AIMS: Next-generation sequencing (NGS) was recently approved by the United States Food and Drug Administration to detect microsatellite instability (MSI) arising from defective mismatch repair (dMMR) in patients with metastatic colorectal cancer (mCRC) before treatment with immune checkpoint inhibitors (ICI). In this study, we aimed to evaluate and improve the performance of NGS to identify MSI in CRC, especially dMMR mCRC treated with ICI. METHODS: CRC samples used in this post hoc study were reassessed centrally for MSI and dMMR status using the reference methods of pentaplex polymerase chain reaction and immunohistochemistry. Whole-exome sequencing (WES) was used to evaluate MSISensor, the Food and Drug Administration-approved and NGS-based method for assessment of MSI. This was performed in (1) a prospective, multicenter cohort of 102 patients with mCRC (C1; 25 dMMR/MSI, 24 treated with ICI) from clinical trials NCT02840604 and NCT033501260, (2) an independent retrospective, multicenter cohort of 113 patients (C2; 25 mCRC, 88 non-mCRC, all dMMR/MSI untreated with ICI), and (3) a publicly available series of 118 patients with CRC from The Cancer Genome Atlas (C3; 51 dMMR/MSI). A new NGS-based algorithm, namely MSICare, was developed. Its performance for assessment of MSI was compared with MSISensor in C1, C2, and C3 at the exome level or after downsampling sequencing data to the MSK-IMPACT gene panel. MSICare was validated in an additional retrospective, multicenter cohort (C4) of 152 patients with new CRC (137 dMMR/MSI) enriched in tumors deficient in MSH6 (n = 35) and PMS2 (n = 9) after targeted sequencing of samples with an optimized set of microsatellite markers (MSIDIAG). RESULTS: At the exome level, MSISensor was highly specific but failed to diagnose MSI in 16% of MSI/dMMR mCRC from C1 (4 of 25; sensitivity, 84%; 95% confidence interval [CI], 63.9%-95.5%), 32% of mCRC (8 of 25; sensitivity, 68%; 95% CI, 46.5%-85.1%), and 9.1% of non-mCRC from C2 (8 of 88; sensitivity, 90.9%; 95% CI, 82.9%-96%), and 9.8% of CRC from C3 (5 of 51; sensitivity, 90.2%; 95% CI, 78.6%-96.7%). Misdiagnosis included 4 mCRCs treated with ICI, of which 3 showed an overall response rate without progression at this date. At the exome level, reevaluation of the MSI genomic signal using MSICare detected 100% of cases with true MSI status among C1 and C2. Further validation of MSICare was obtained in CRC tumors from C3, with 96.1% concordance for MSI status. Whereas misdiagnosis with MSISensor even increased when analyzing downsampled WES data from C1 and C2 with microsatellite markers restricted to the MSK-IMPACT gene panel (sensitivity, 72.5%; 95% CI, 64.2%-79.7%), particularly in the MSH6-deficient setting, MSICare sensitivity and specificity remained optimal (100%). Similar results were obtained with MSICare after targeted NGS of tumors from C4 with the optimized microsatellite panel MSIDIAG (sensitivity, 99.3%; 95% CI, 96%-100%; specificity, 100%). CONCLUSIONS: In contrast to MSISensor, the new MSICare test we propose performs at least as efficiently as the reference method, MSI polymerase chain reaction, to detect MSI in CRC regardless of the defective MMR protein under both WES and targeted NGS conditions. We suggest MSICare may rapidly become a reference method for NGS-based testing of MSI in CRC, especially in mCRC, where accurate MSI status is required before the prescription of ICI.

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.

Epidemiology of Community-Onset Severe Bacterial Infections in Children and Its Evolution: A Population-Based Study in France.

OBJECTIVES: To describe the epidemiology of community-onset severe bacterial infections in children and its recent evolution. DESIGN: Prospective, observational, population-based study from 2009 to 2014. SETTING: An administrative area accounting for 13% of the French pediatric population. PATIENTS: All children 1 month to 16 years old who died before admission or were admitted to a PICU for a community-onset severe bacterial infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The incidence and mortality rate of community-onset severe bacterial infections were compared with data from a reference population-based study conducted between 2000 and 2006, that is, before national recommendations for antimeningococcal C and antipneumococcal generalized vaccinations. Among the 261 children included (median age 25 mo), 28 (10.7%) died. The main diagnoses were meningitis (n = 85; 32%) and purpura fulminans (n = 59; 22%). The most common isolated bacteria were Neisseria meningitidis (n = 75; 29%), including 47 (63%) cases of serogroup B and 15 (20%) serogroup C, Streptococcus pneumoniae (n = 49, 19%), and Staphylococcus aureus (n = 15; 6%). The incidence of community-onset severe bacterial infections was three per 100,000 person-years (95% CI, 2.6-3.3) and had decreased by 53% from the reference period. Mortality rate was 0.3 per 100,000 person-years (95% CI, 0.2-0.4) and had decreased by 73% from the reference period. The incidence of community-onset severe bacterial infections caused by N. meningitidis and S. pneumoniae was 0.8 and 0.5 per 100,000 person-years and had decreased by 70% and 67% from the reference period. The incidence of community-onset severe bacterial infections-related to Staphylococcus aureus was 0.16 per 100,000 person-years and had increased by 220% from the reference period. CONCLUSIONS: The incidence and mortality rate of community-onset severe bacterial infections, except for S. aureus infection, have decreased in France. N. meningitidis and S. pneumoniae continue to account for many infections, which indicates the need for better vaccination coverage and spectrum.

Continuous cerebral and myocardial selective perfusion in neonatal aortic arch surgery.

BACKGROUND: To assess the feasibility and early outcome of continuous cerebral and myocardial selective perfusion (CCMSP) during aortic arch surgery in neonates. METHODS: We performed a single-center retrospective study between 2008 and 2019 on neonates who underwent aortic arch surgery with or without associated heart lesion repair. CCMSP with moderate hypothermia levels (28°C) was achieved using selective brachiocephalic artery and ascending aorta cannulation. Target rates of cerebral and myocardial perfusion were 25 to 35 mL/kg/min and 150 ml/m2/min. Cardiopulmonary bypass (CPB) variables and clinical outcomes were analyzed. RESULTS: Overall, 69 neonates underwent either isolated aortic arch repair (n = 31) or aortic arch repair with ventricular septal defect (VSD) closure (n = 38). Age and weight medians were 8 [6 to 15] days and 3.4 [2.9-3.5] kg, respectively. Mean CPB and aortic clamping times were 134 ± 47 and 26 ± 5 minutes for isolated aortic arch repair, and 159 ± 47 and 75 ± 30 minutes for aortoplasty accompanied by VSD closure. Mean CCMSP time was 52 ± 21 minutes with cerebral rate of 32.6 ± 10 mL·kg-1 ·min-1 . Overall in hospital survival was 98.5% (68/69). Major complications were: postoperative cardiac failure requiring mechanical support followed by stroke (n = 1; 1.44%) and transient renal failure requiring dialysis (n = 2; 2.89%). Neither myocardial nor digestive complication occurred. CONCLUSION: CCMSP is a safe and reproducible strategy for cerebral, myocardial and visceral protection in neonatal aortic arch repair, with or without VSD closure, resulting in low complication and mortality.

Vaccine-preventable severe morbidity and mortality caused by meningococcus and pneumococcus: A population-based study in France.

BACKGROUND: In a context of suboptimal vaccination coverage and increasing vaccine hesitancy, we aimed to study morbidity and mortality in children related to missing or incomplete meningococcal C and pneumococcal conjugate vaccines. METHODS: We conducted a prospective, observational, population-based study from 2009 to 2014 in a French administrative area that included all children from age 1 month to 16 years who died before admission or were admitted to an intensive care unit for a community-onset bacterial infection. Vaccine-preventable infection was defined as an infection with an identified serotype included in the national vaccine schedule at the time of infection and occurring in a non- or incompletely vaccinated child. Death and severe sequelae were studied at hospital discharge. Frequencies of vaccine-preventable morbidity and mortality caused by meningococcus and pneumococcus were calculated. RESULTS: Among the 124 children with serotyped meningococcal (n = 75) or pneumococcal (n = 49) severe infections included (median age 26 months), 20 (16%) died and 12 (10%) had severe sequelae. Vaccine-preventable infections accounted for 18/124 infections (15%, 95% CI 9, 22), 5/20 deaths (25%, 95% CI 9, 49), and 3/12 severe sequelae cases (25%, 95% CI 0, 54). The vaccine schedule for meningococcal C and pneumococcal conjugate vaccinations was incomplete for 71/116 (61%) children targeted by at least one of these two vaccination programs. CONCLUSIONS: Mortality and morbidity rates related to vaccine-preventable meningococcal or pneumococcal infection could be reduced by one quarter with better implementation of immunisation programs. Such information could help enhance the perception of vaccine benefits and fight vaccine hesitancy.

Strong antineoplastic effects of metformin in preclinical models of liver carcinogenesis.

Studies suggest that metformin, widely used for treating Type 2 diabetes, possesses innate antineoplastic properties. For metabolic syndrome patients with hepatocellular carcinoma (HCC), metformin may provide antitumoral effects. We evaluated the impact of metformin on tumour growth and visceral fat composition using relevant preclinical models of metabolic syndrome. Studies were performed in three hepatoma cell lines, in HepG2 xenograft mice fed with standard chow (SC) diet, 60% high-fat diet (HFD) or 30% fructose diet (FR), and an ex vivo model of human cultured HCC slices. Visceral fatty acid composition was analysed by magnetic resonance imaging (MRI). Metformin had a dose-dependent inhibitory effect on cell proliferation and apoptosis in vitro through the deregulation of mTOR/AMPK, AKT and extracellular signal regulated kinase (ERK) signalling pathways. Tumour engraftment rates were higher in HFD mice than SC mice (hepatic: 79% compared with 25%, P=0.02) and FR mice (subcutaneous: 86% compared with 50%, P=0.04). Subcutaneous tumour volume was increased in HFD mice (+64% compared with FR and SC, P=0.03). Metformin significantly decreased subcutaneous tumour growth via cell-cycle block and mammalian target of rapamycin (mTOR) pathway inhibition, and also induced hypoxia and decreased angiogenesis. In ex vivo tumour slices, metformin treatment led to increased necrosis, decreased cyclin D1 and increased carbonic anhydrase-9 (CA-9). Metformin caused qualitative changes in visceral fat composition of HFD mice, with decreased proportions of polyunsaturated fatty acids (14.6% ± 2.3% compared with 17.9% ± 3.0%, P=0.04). The potent antitumoral effects of metformin in multiple preclinical models implicating several molecular mechanisms provide a strong rationale for clinical trials including combination studies in HCC patients.

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.

Noninvasive Estimation of Arterial CO2 From End-Tidal CO2 in Mechanically Ventilated Children: The GRAeDIENT Pilot Study.

OBJECTIVES: The aim of our pilot study was to develop a model to better predict Paco2 in mechanically ventilated children using noninvasive parameters including volumetric capnography. DESIGN: Prospective clinical pilot study. SETTING: Level III PICU. PATIENTS: Sixty-five mechanically ventilated children. INTERVENTIONS: None. MATERIALS AND METHODS: We conducted a prospective clinical pilot study that included all children admitted to the PICU (< 18 yr; weight, > 3 kg; mechanically ventilated, > 6 hr; with an arterial line). A predictive model for PaCO2 was developed using linear multivariable regression. Among the data collected in PICU patients, candidate predictors of PaCO2 were defined by a panel of experts and included end-tidal partial pressure of carbon dioxide, ventilation parameters, and data resulting from the analysis of volumetric capnogram recorded 5 minutes before an arterial blood gas. Children with tidal volume less than 30 mL were excluded because of technical limits. RESULTS: A total of 65 children (43 boys, 65%) (65 [21-150] mo old) were analyzed. By linear multivariable regression, the best model included the mean airway pressure, end-tidal partial pressure of carbon dioxide, FIO2, and the capnographic index with an R equal to 0.90, p value less than 0.001. After correction, 95% (n = 62) of children had an estimated PaCO2 at ± 5 mm Hg. CONCLUSION: Our model developed provides an accurate estimation of the PaCO2 using end-tidal CO2 and noninvasive variables. Studies are needed to validate the equation in PICUs.