Publications by authors named "Alexis Chenouard"

25 Publications

  • Page 1 of 1

Outcome analysis of a conservative approach to diaphragmatic paralysis following congenital cardiac surgery in neonates and infants: a bicentric retrospective study.

Interact Cardiovasc Thorac Surg 2021 May 17. Epub 2021 May 17.

Department of Pediatric Cardiology and Congenital Cardiac Surgery, University Hospital, Nantes, France.

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Objectives: Diaphragmatic paralysis following congenital cardiac surgery is associated with significant morbidity and mortality. Spontaneous recovery of diaphragmatic function has been described, contrasting with centres providing early diaphragmatic plication. We aimed to describe the outcomes of a conservative approach, as well as to identify factors associated with a failure of the strategy.

Methods: This is a retrospective study of patients admitted after cardiac surgery and suffering unilateral diaphragmatic paralysis within 2 French Paediatric Cardiac Surgery Centers. The conservative approach, defined by the prolonged use of ventilation until successful weaning from respiratory support, was the primary strategy adopted in both centres. In case of unsuccessful evolution, a diaphragmatic plication was scheduled. Total ventilation time included invasive and non-invasive ventilation. Diaphragm asymmetry was defined by the number of posterior rib segments counted between the 2 hemi-diaphragms on the chest X-ray after cardiac surgery.

Results: Fifty-one neonates and infants were included in the analysis. Patients' median age was 12.0 days at cardiac surgery (5.0-82.0), and median weight was 3.5 kg (2.8-4.9). The conservative approach was successful for 32/51 patients (63%), whereas 19/51 patients (37%) needed diaphragm plication. There was no difference in patients' characteristics between groups. Respiratory support prolonged for 21 days or more and diaphragm asymmetry more than 2 rib segments were independently associated with the failure of the conservative strategy [odds ratio (OR) 6.9 (1.29-37.3); P = 0.024 and OR 6.0 (1.4-24.7); P = 0.013, respectively].

Conclusions: The conservative approach was successful for 63% of the patients. We identified risk factors associated with the strategy's failure.
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http://dx.doi.org/10.1093/icvts/ivab123DOI Listing
May 2021

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.

Pediatr Crit Care Med 2021 May 7. Epub 2021 May 7.

Department of Pediatric Cardiology and Congenital Cardiac Surgery, University Hospital, Nantes, France. Department of Anesthesiology, University Hospital, Nantes, France. Department of Pediatrics, University Hospital, Rennes, France. Department of Pediatrics, Pediatric Intensive Care Unit, University Hospital, Nantes, France. Department of Pediatrics, University Hospital, Nantes, France. Inserm UMR 1153, Obstetrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Centre of Research in Epidemiology and StatisticS (CRESS), University of Paris, Paris, France. Department of Pediatrics, Neonatal Intensive Care Unit, University Hospital, Rennes, France. Neonatal and Pediatric Intensive Care Unit, University Hospital, Brest, France. Department of Pediatrics, Neonatal Intensive Care Unit, University Hospital, Nantes, France. Department of Pediatrics, Pediatric Intensive Care Unit, University Hospital, Rennes, France.

Objectives: To describe the frequency and outcomes on the use of extracorporeal membrane oxygenation 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 nonextracorporeal membrane oxygenation 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 extracorporeal membrane oxygenation support. Of these patients, 31 were first admitted to a nonextracorporeal membrane oxygenation center, where 20 were cannulated in situ (outside the regional extracorporeal membrane oxygenation center) and 11 after transfer to the extracorporeal membrane oxygenation regional center. Cardiogenic shock, highest serum lactate level, and cardiac arrest prior to first phone call with the regional extracorporeal membrane oxygenation 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 nonextracorporeal membrane oxygenation centers or not had similar 28-day post-ICU survival rates compared with those admitted in the referral extracorporeal membrane oxygenation center (58% vs 51%; p = 0.332). Preextracorporeal membrane oxygenation cardiac arrest, extracorporeal cardiopulmonary resuscitation, and lower pH at extracorporeal membrane oxygenation onset were associated with lower 28-day post-ICU survival.

Conclusions: Our local results suggest that a structured referral network for neonatal and pediatric extracorporeal membrane oxygenation 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.
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http://dx.doi.org/10.1097/PCC.0000000000002748DOI Listing
May 2021

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

Neurocrit Care 2021 Mar 9. Epub 2021 Mar 9.

Brain Physics Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Background: Cerebral autoregulation (CA) impairment is associated with neurological complications among children supported by extracorporeal membrane oxygenation (ECMO). Severe variations of arterial CO (PaCO) and O (PaO) 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 (rSO) 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). RSO, 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 PaCO 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 PaCO 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 PaCO was also found (R = 0.726, p < 0.001). A very weak negative correlation between PaO 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 PaCO and negatively correlated with PaO (R = 0.224, p = 0.01 and R =  -0.051, p = 0.004, respectively).

Conclusions: We observed a complex relationship between PaCO 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 PaCO, especially after ECMO start.
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http://dx.doi.org/10.1007/s12028-021-01201-8DOI Listing
March 2021

The Use of Intraoperative Peripheral Extracorporeal Membrane Oxygenation in High-Risk Airways Tumor Removal Procedures in Neonates and Children: A Single-Center Case Series.

ASAIO J 2021 Jan 28. Epub 2021 Jan 28.

From the Department of Pediatric Anesthesiology, University Hospital, Nantes, France Pediatric Intensive Care Unit, University Hospital, Nantes, France Department of ENT surgery, University Hospital, Nantes, France Department of Pediatric Surgery, University Hospital, Nantes, France Congenital Cardiac Surgery, University Hospital, Nantes, France Department of Pediatric Anesthesiology, Pediatric Intensive Care Unit, University Hospital, Nantes, France.

Airway surgery involving trachea or main stem bronchi in neonates and children is challenging. The use of extracorporeal support for such unusual indications is poorly described. Here, we report on three patients receiving peripheral extracorporeal membrane oxygenation (ECMO) to maintain adequate ventilation while improving surgical site exposure. Case 1 is a 9-year-old boy diagnosed with proximal left stem bronchus endoluminal tumor; cases 2 and 3 are a neonate and a young infant diagnosed with a subcarinal bronchogenic cyst. Planned ECMO use consisted in peripheral venoarterial cannulation through jugular and carotid access. There was no bleeding complication during and after surgical care. Hemodynamic and respiratory supports were optimized in all cases. Children were successfully weaned off ECMO immediately after surgery. Planned peripheral ECMO cannulation offers optimal conditions for high-risk airway surgery in neonates and children.
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http://dx.doi.org/10.1097/MAT.0000000000001360DOI Listing
January 2021

Amplitude-integrated electroencephalography after pediatric extracorporeal cardiopulmonary resuscitation: A pragmatic illustration of its relevance at the bedside for intensivists.

Artif Organs 2021 Mar 17;45(3):318-319. Epub 2020 Nov 17.

Pediatric Intensive Care Unit, University Hospital, Nantes, France.

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http://dx.doi.org/10.1111/aor.13831DOI Listing
March 2021

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

Neurocrit Care 2021 Jun 8;34(3):935-945. Epub 2020 Oct 8.

Brain Physics Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

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.
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http://dx.doi.org/10.1007/s12028-020-01111-1DOI Listing
June 2021

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

Perfusion 2021 Apr 5;36(3):293-298. Epub 2020 Aug 5.

Pediatric Intensive Care Unit, University Hospital, Nantes, France.

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.
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http://dx.doi.org/10.1177/0267659120946724DOI Listing
April 2021

Monocytic Human Leukocyte Antigen DR Expression in Young Infants Undergoing Cardiopulmonary Bypass.

Ann Thorac Surg 2021 05 8;111(5):1636-1642. Epub 2020 Jul 8.

CHU Nantes, Pôle Anesthésie Réanimations, Service d'Anesthésie Réanimation Chirurgicale, Hôtel Dieu, Nantes, France.

Background: Monocytic human leukocyte antigen DR (mHLA-DR) expression levels have been reported to be a marker of immunosuppression and a predictor of sepsis and mortality. There are, however, scant data regarding mHLA-DR monitoring in young infants after cardiopulmonary bypass. Our objectives were to investigate the kinetics of mHLA-DR expression and to determine whether mHLA-DR levels are associated with healthcare-associated infection (HAI) after cardiopulmonary bypass in young infants.

Methods: mHLA-DR levels were analyzed by flow cytometry using a standardized method in 49 infants (<3 months old) with congenital heart disease before and after cardiopulmonary bypass. Results are expressed as the number of anti-HLA-DR antibodies per cell (AB/c).

Results: Postoperative mHLA-DR expression was reduced in all infants. Eleven patients (22%) developed HAI, and 4 patients (8%) died during the 30-day follow-up. mHLA-DR expression was significantly lower on postoperative day 4 in the HAI group compared with those who without HAI (3768 AB/c [range, 1938-6144] vs 13,230 AB/c [range, 6152-19,130], P = .014). Although mHLA-DR expression was associated with postoperative severity, mHLA-DR ≤4500 AB/c in the first 72 hours among patients with higher postoperative severity (extracorporeal membrane oxygenation and/or corticoids and/or delayed closure of sternum) was associated with occurrence of HAI in the univariate analysis (odds ratio, 6.3; 95% confidence interval, 1.0-38.7; P = .037).

Conclusions: Cardiopulmonary bypass induces a profound decrease in mHLA-DR expression in young infants. Among patients with higher postoperative severity, low level of mHLA-DR in the early postoperative period is associated with the development of HAI.
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http://dx.doi.org/10.1016/j.athoracsur.2020.05.071DOI Listing
May 2021

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

Pediatr Crit Care Med 2020 03;21(3):248-255

Pediatric Intensive Care Unit, University Hospital, Nantes, France.

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.
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http://dx.doi.org/10.1097/PCC.0000000000002171DOI Listing
March 2020

Interrater Agreement Between Critical Care Providers for Background Classification and Seizure Detection After Implementation of Amplitude-Integrated Electroencephalography in Neonates, Infants, and Children.

J Clin Neurophysiol 2020 May;37(3):259-262

Pediatric Intensive Care Unit, University Hospital, Nantes, France.

Purposes: Amplitude-integrated EEG (aEEG) has been widely developed in neonatal intensive care unit, but few studies focused on pediatric intensive care unit. Furthermore, reliability of aEEG under real-life conditions is unknown.

Methods: Participants were nurses from a 12-bed pediatric intensive care unit in a referral university hospital in France. Amplitude EEG was implemented after standardized training, including e-learning course, individual feedback and bedside teaching concerning monitoring installation, background classification patterns recognition, artefact analysis, and seizure detection. The primary judgment criterion was the agreement (Cohen Kappa) between nurses and aEEG experts for the detection of abnormal aEEG traces (moderately or severely altered background pattern according to Hellström-Westas classification and/or seizure activity).

Results: During the study period, 196 consecutives traces from 79 patients were analyzed by 51 nurses. According to expert's classification, 53% of traces were abnormal, including 17.5% of severely abnormal traces (severely altered traces and/or seizure activity) and 14% exhibiting seizure activity. Moderate agreement between experts and nurses was found for detection of any abnormal trace (k = 0.53; 95% confidence interval [CI]: 0.39-0.67). Substantial agreement was found for severely altered traces (k = 0.71; 95% CI: 0.57-0.85). Finally, fair agreement was found for seizure detection (irrespective of background classification, k = 0.40; 95% CI: 0.25-0.54).

Conclusions: These results suggest that aEEG monitoring may be implemented in routine nursing care in pediatric intensive care unit. Further training courses are needed to enhance nurses' skill in detecting seizures activity at the bedside.
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http://dx.doi.org/10.1097/WNP.0000000000000634DOI Listing
May 2020

Immunophenotype of a Rat Model of Duchenne's Disease and Demonstration of Improved Muscle Strength After Anti-CD45RC Antibody Treatment.

Front Immunol 2019 9;10:2131. Epub 2019 Sep 9.

Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France.

Corticosteroids (CS) are standard therapy for the treatment of Duchenne's muscular dystrophy (DMD). Even though they decrease inflammation, they have limited efficacy and are associated with significant side effects. There is therefore the need for new protolerogenic treatments to replace CS. Dystrophin-deficient rats ( ) closely resemble the pathological phenotype of DMD patients. We performed the first Immunophenotyping of rats and showed leukocyte infiltration in skeletal and cardiac muscles, which consisted mostly of macrophages and T cells including CD45RC T cells. Muscles of DMD patients also contain elevated CD45RC T cells. We treated rats with an anti-CD45RC MAb used in previous studies to deplete CD45RC T cells and induce immune tolerance in models of organ transplantation. Treatment of young rats with anti-CD45RC MAb corrected skeletal muscle strength and was associated with depletion of CD45RC T cells with no side effects. Treatment of young rats with prednisolone resulted in increase in skeletal muscle strength but also severe growth retardation. In conclusion, anti-CD45RC MAb treatment has potential in the treatment of DMD and might eventually result in reduction or elimination of CS use.
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http://dx.doi.org/10.3389/fimmu.2019.02131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746111PMC
November 2020

CXCR5PD1ICOS Circulating T Follicular Helpers Are Associated With Donor-Specific Antibodies After Renal Transplantation.

Front Immunol 2019 10;10:2071. Epub 2019 Sep 10.

Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.

Donor-specific anti-HLA antibodies (DSAs) are a major risk factor associated with renal allograft outcomes. As a trigger of B cell antibody production, T follicular helper cells (Tfhs) promote DSA appearance. Herein, we evaluated whether circulating Tfhs (cTfhs) are associated with the genesis of antibody-mediated rejection. We measured cTfh levels on the day of transplantation and 1 year after transplantation in blood from a prospective cohort of 237 renal transplantation patients without DSA during the first year post-transplantation. Total cTfhs were characterized as CD4CD45RACXCR5, and the three following subsets of activated cTfh were analyzed: CXCR5PD1, CXCR5PD1ICOS, an CXCR5PD1CXCR3. Immunizing events (previous blood transfusion and/or pregnancy) and the presence of class II anti-HLA antibodies were associated with increased frequencies of activated CXCR5PD1, CXCR5PD1ICOS, and CXCR5PD1CXCR3 cTfh subsets. In addition, ATG-depleting induction and calcineurin inhibitor treatments were associated with a relative increase of activated cTfh subsets frequencies at 1 year post-transplantation. In multivariate survival analysis, we reported that a decrease in activated CXCR5PD1ICOS at 1 year after transplantation in the blood of DSA-free patients was significantly associated with the risk of developing DSA after the first year ( = 0.018, HR = 0.39), independently of HLA mismatches ( = 0.003, HR = 3.79). These results highlight the importance of monitoring activated Tfhs in patients early after transplantation and show that current treatments cannot provide early, efficient prevention of Tfh activation and migration. These findings indicate the need to develop innovative treatments to specifically target Tfhs to prevent DSA appearance in renal transplantation.
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http://dx.doi.org/10.3389/fimmu.2019.02071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746839PMC
October 2020

Virus or Bacteria: Is It the Only Cause of Sepsis-Induced Rhabdomyolysis?

Pediatr Crit Care Med 2018 07;19(7):694

Pediatric Intensive Care Unit, Nantes University Hospital, Nantes, France Neurometabolism department, Nantes University Hospital, Nantes, France Reference Centre of Inherited Metabolic Diseases, Hospital Necker Enfants Malades, APHP, Institute Imagine, University Paris Descartes, Paris, France Pediatric Intensive Care Unit, Nantes University Hospital, Nantes, France.

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http://dx.doi.org/10.1097/PCC.0000000000001550DOI Listing
July 2018

HLA-DR expression in neonates after cardiac surgery under cardiopulmonary bypass: a pilot study.

Intensive Care Med Exp 2018 Jan 11;6(1). Epub 2018 Jan 11.

CHU Nantes, Pôle anesthésie réanimations, Service d'anesthésie réanimation chirurgicale, Hôtel Dieu, Nantes, France.

Monocyte HLA-DR expression has been reported as a marker of immunosuppression and a predictor of sepsis development. However, to date, there is no report on monocyte HLA-DR monitoring exclusively in neonates (< 28 days of life) who underwent cardiac surgery under cardiopulmonary bypass (CPB), which have a high risk of nosocomial infection. In this pilot study, we studied nine neonates with a diagnosis of congenital heart disease requiring surgery under CPB. There was a significant reduction in monocyte HLA-DR expression for the first two postoperative days, as compared to preoperatively (p = 0.004). Moreover, neonates who displayed an episode of NI had a dramatically lower HLA-DR expression at day 4, as compared to neonates without NI (4257 AB/c [2220-5895] vs 14,947 AB/c [9858-16,960]; p = 0.04). Our preliminary results could indicate that HLA-DR expression may be a useful biomarker of immunosuppression-induced secondary infection after CPB in neonates.
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http://dx.doi.org/10.1186/s40635-017-0166-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764905PMC
January 2018

Maternal consumption of quinine-containing sodas may induce G6PD crises in breastfed children.

Eur J Pediatr 2017 Oct 21;176(10):1415-1418. Epub 2017 Aug 21.

Department of Pediatric Intensive Care, Nantes University Hospital, Nantes, France.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect often presenting with neonatal jaundice and/or hemolytic anemia. G6PD hemolytic events are linked with exposure to a pro-oxidant agent. We here report three cases of initial G6PD crises in breastfed children secondary to maternal consumption of a tonic drink which contains quinine. Quinine was found in breast milk of one of the mothers after she consumed tonic water.

Conclusion: The amount of quinine that is transmitted through breast milk appears to be sufficient to induce G6PD crises in breastfed children. We hence recommend that consumption of quinine-containing sodas during breastfeeding should be avoided in populations with a high prevalence of G6PD deficiency. What is Known: • G6PD hemolytic events are linked with exposure to a pro-oxidant agent. • Ingestion of fava beans by a mother who was breastfeeding has been reported to induce a neonatal G6PD crisis. What is New: • Maternal consumption of tonic drink which contains quinine appears to be sufficient to induce G6PD crises in breastfed children. • Maternal consumption of quinine-containing sodas during breastfeeding should be avoided in populations with a high prevalence of G6PD deficiency.
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http://dx.doi.org/10.1007/s00431-017-2998-5DOI Listing
October 2017

Regional Citrate Anticoagulation: Beware of Recirculation Phenomenon.

Ther Apher Dial 2017 04 13;21(2):206-207. Epub 2017 Feb 13.

Pediatric Intensive Care Unit, Nantes University Hospital, Nantes, France.

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http://dx.doi.org/10.1111/1744-9987.12505DOI Listing
April 2017

Anti-CD28 Antibody and Belatacept Exert Differential Effects on Mechanisms of Renal Allograft Rejection.

J Am Soc Nephrol 2016 Dec 9;27(12):3577-3588. Epub 2016 May 9.

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1064, Nantes, France;

Belatacept is a biologic that targets CD80/86 and prevents its interaction with CD28 and its alternative ligand, cytotoxic T lymphocyte antigen 4 (CTLA-4). Clinical experience in kidney transplantation has revealed a high incidence of rejection with belatacept, especially with intensive regimens, suggesting that blocking CTLA-4 is deleterious. We performed a head to head assessment of FR104 (n=5), a selective pegylated Fab' antibody fragment antagonist of CD28 that does not block the CTLA-4 pathway, and belatacept (n=5) in kidney allotransplantation in baboons. The biologics were supplemented with an initial 1-month treatment with low-dose tacrolimus. In cases of acute rejection, animals also received steroids. In the belatacept group, four of five recipients developed severe, steroid-resistant acute cellular rejection, whereas FR104-treated animals did not. Assessment of regulatory T cell-specific demethylated region methylation status in 1-month biopsy samples revealed a nonsignificant trend for higher regulatory T cell frequencies in FR104-treated animals. Transcriptional analysis did not reveal significant differences in Th17 cytokines but did reveal higher levels of IL-21, the main cytokine secreted by CD4 T follicular helper (Tfh) cells, in belatacept-treated animals. In vitro, FR104 controlled the proliferative response of human preexisting Tfh cells more efficiently than belatacept. In mice, selective CD28 blockade also controlled Tfh memory cell responses to KLH stimulation more efficiently than CD80/86 blockade. Our data reveal that selective CD28 blockade and belatacept exert different effects on mechanisms of renal allograft rejection, particularly at the level of Tfh cell stimulation.
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http://dx.doi.org/10.1681/ASN.2015070774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118475PMC
December 2016

Phenotype and functions of B cells in patients with acute brain injuries.

Mol Immunol 2015 Dec 9;68(2 Pt A):350-6. Epub 2015 Sep 9.

Intensive Care Unit, Anesthesia and Critical Care Department, Nantes University Hospital, Nantes, France; Thérapeutiques Cliniques et Expérimentales des Infections, EA 3826 Nantes, France. Electronic address:

Background: Brain injuries (BI) induce a state of systemic immunosuppression, leading to a high risk of pneumonia. In this pilot study, we investigated the status of B cell compartment in BI patients.

Methods: A prospective observational study was performed in 2 intensive care units in a university hospital. Blood samples were collected in 14 patients at day 1 and day 7 after acute BI. The phenotype and the ability of B cells to secrete IL-10 were compared to 11 healthy volunteers (HV).

Results: Among the circulating lymphocytes, the frequency of B cells was significantly higher in BI patients compared to HV (p<0.001). B cells from BI patients displayed an activated profil on day 7 after BI, reflected by a significantly higher proportion of CD27(+) memory (p=0.01) and CD27(+) IgD(-) switched memory B cells (p=0.02), as well as a significantly higher blood level of IgA (p=0.001) and IgM (p<0.001) as compared to day 1. The frequency of IL-10 secreting B cells (IL-10(+) B cells) on day 1 and day 7 was significantly lower in BI patients compared to HV (p<0.05). Interestingly, we observed that all BI patients with high frequency of IL-10(+) B cells on day 1 displayed an episode of pneumonia, and had a longer duration of mechanical ventilation and ICU stay compared to BI patients with low proportion of IL-10(+) B cells.

Conclusion: This study provides an extensive description of the phenotype and function of B cells in BI patients. Our results suggest that IL-10(+) B cells could play a major role in immunosuppression after BI.
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http://dx.doi.org/10.1016/j.molimm.2015.09.001DOI Listing
December 2015

From splitting GLUT1 deficiency syndromes to overlapping phenotypes.

Eur J Med Genet 2015 Sep 17;58(9):443-54. Epub 2015 Jul 17.

AP-HP, Necker-Enfants Malades Hospital, Department of Pediatric Neurology, Paris, France.

Introduction: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare genetic disorder due to mutations or deletions in SLC2A1, resulting in impaired glucose uptake through the blood brain barrier. The classic phenotype includes pharmacoresistant epilepsy, intellectual deficiency, microcephaly and complex movement disorders, with hypoglycorrhachia, but milder phenotypes have been described (carbohydrate-responsive phenotype, dystonia and ataxia without epilepsy, paroxysmal exertion-induced dystonia). The aim of our study was to provide a comprehensive overview of GLUT1DS in a French cohort.

Methods: 265 patients were referred to the French national laboratory for molecular screening between July 2006 and January 2012. Mutations in SLC2A1 were detected in 58 patients, with detailed clinical data available in 24, including clinical features with a focus on their epileptic pattern and electroencephalographic findings, biochemical findings and neuroimaging findings.

Results: 53 point mutations and 5 deletions in SLC2A1 were identified. Most patients (87.5%) exhibited classic phenotype with intellectual deficiency (41.7%), epilepsy (75%) or movement disorder (29%) as initial symptoms at a medium age of 7.5 months, but diagnostic was delayed in most cases (median age at diagnostic 8 years 5 months). Sensitivity to fasting or exertion in combination with those 3 main symptoms were the main differences between mutated and negative patients (p < 0.001). Patients with myoclonic seizures (52%) evolved with more severe intellectual deficiency and movement disorders compared with those with Early Onset Absence Epilepsy (38%). Three patients evolved from a classic phenotype during early childhood to a movement disorder predominant phenotype at a late childhood/adulthood.

Conclusions: Our data confirm that the classic phenotype is the most frequent in GLUT1DS. Myoclonic seizures are a distinctive feature of severe forms. However a great variability among patients and overlapping through life from milder classic phenotype to paroxysmal-prominent- movement-disorder phenotype are possible, thus making it difficult to identify definite genotype-phenotype correlations.
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http://dx.doi.org/10.1016/j.ejmg.2015.06.007DOI Listing
September 2015

Tolerant Kidney Transplant Patients Produce B Cells with Regulatory Properties.

J Am Soc Nephrol 2015 Oct 2;26(10):2588-98. Epub 2015 Feb 2.

Joint Research Unit 1064, French Institute of Health and Medical Research, Nantes, France; Faculty of Medicine, Nantes University, Nantes, France; and Institute of Transplantation Urology and Nephrology, Nantes University Hospital, Nantes, France

Whereas a B cell-transcriptional profile has been recorded for operationally tolerant kidney graft patients, the role that B cells have in this tolerance has not been reported. In this study, we analyzed the role of B cells from operationally tolerant patients, healthy volunteers, and kidney transplant recipients with stable graft function on T cell suppression. Proliferation, apoptosis, and type I proinflammatory cytokine production by effector CD4(+)CD25(-) T cells were measured after anti-CD3/anti-CD28 stimulation with or without autologous B cells. We report that B cells inhibit CD4(+)CD25(-) effector T cell response in a dose-dependent manner. This effect required B cells to interact with T-cell targets and was achieved through a granzyme B (GzmB)-dependent pathway. Tolerant recipients harbored a higher number of B cells expressing GzmB and displaying a plasma cell phenotype. Finally, GzmB(+) B-cell number was dependent on IL-21 production, and B cells from tolerant recipients but not from other patients positively regulated both the number of IL-21(+) T cells and IL-21 production, suggesting a feedback loop in tolerant recipients that increases excessive B cell activation and allows regulation to take place. These data provide insights into the characterization of B cell-mediated immunoregulation in clinical tolerance and show a potential regulatory effect of B cells on effector T cells in blood from patients with operationally tolerant kidney grafts.
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http://dx.doi.org/10.1681/ASN.2014040404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587683PMC
October 2015

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

Pediatr Crit Care Med 2015 Feb;16(2):139-45

1Department of Pediatric Intensive Care, Nantes University Hospital, Nantes, France. 2Clinical Investigation Center, National Institute of Health and Medical Research, Nantes University Hospital, Nantes, France. 3Department of Pediatric Cardiology, Nantes University Hospital, Nantes, France. 4Department of Emergency Medicine, Nantes University Hospital, Nantes, France.

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.
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http://dx.doi.org/10.1097/PCC.0000000000000301DOI Listing
February 2015

A Cause of Permanent Ketosis: GLUT-1 Deficiency.

JIMD Rep 2015 26;18:79-83. Epub 2014 Sep 26.

Pediatric Department, Nantes University Hospital, Boulevard Jean Monnet, 44093, Nantes, France,

GLUT-1-deficiency syndrome (GLUT1-DS; OMIM 606777) is a treatable metabolic disorder caused by a mutation of SLC2A1 gene. The functional deficiency of the GLUT1 protein leads to an impaired glucose transport into the brain, resulting in neurologic disorders.We report on a 6-month-old boy with preprandial malaises who was treated monthly by a sorcerer because of a permanent acetonemic odor. He subsequently developed pharmaco-resistant seizures with microcephaly and motor abnormalities. Metabolic explorations were unremarkable except for a fasting glucose test which revealed an abnormal increase of blood ketone bodies. At the age of 35 months, GLUT1-DS was diagnosed based on hypoglycorrhachia with a decreased CSF to blood glucose ratio, and subsequent direct sequencing of the SLC2A1 gene revealed a de novo heterozygous mutation, c.349A>T (p.Lys117X) on exon 4. It was noteworthy that the patient adapted to the deficient cerebral glucose transport by permanent ketone body production since early life. Excessive ketone body production in this patient provided an alternative energy substrate for his brain. We suggest a cerebral metabolic adaptation with upregulation of monocarboxylic acid transporter proteins (MCT1) at the blood-brain barrier provoked by neuroglycopenia and allowing ketone body utilization by the brain. This case illustrates that GLUT1-DS should be considered in the differential diagnosis of permanent ketosis.
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http://dx.doi.org/10.1007/8904_2014_352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361925PMC
March 2015

Neurodevelopmental impairment in preterm infants with late-onset infection: not only in extremely preterm infants.

Eur J Pediatr 2014 Aug 27;173(8):1017-23. Epub 2014 Feb 27.

Department of Neonatal Medicine, Hôpital Mère Enfant, CHU of Nantes, Boulevard Jean Monnet, 44093, Nantes, France.

Unlabelled: Late-onset infection is known to increase the risk of neurodevelopmental impairment in infants born extremely preterm. However, little data is available regarding infants born moderately preterm. The aim of this study was to determine whether late-onset infection in moderately preterm infants (<35 weeks of gestation) was associated with a non-optimal neurodevelopmental outcome at 2 years of age. We analyzed a regional, population-based cohort of infants (LIFT cohort) between January 2003 and December 2009, and we used a propensity score method to reduce bias. Among the 4,618 preterm infants assessed at 2 years, 618 had acquired late-onset infection (13.4 %), and 764 had a non-optimal outcome (16.5 %). The rate of non-optimal outcomes was significantly higher in preterm infants with late-onset infection, irrespective of subgroups of gestational age and birth weight Z-score. After adjusting for the propensity score, the relationship between late-onset infection and non-optimal neurodevelopmental outcome at 2 years among infants born before 35 weeks of gestation remained significant (aOR = 1.3; 95 % CI 1.01-1.7; p = .04).

Conclusion: Late-onset infection is associated with poor neurological outcome at 2 years of age among infants born moderately preterm before and after adjustment for the propensity score.
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http://dx.doi.org/10.1007/s00431-014-2284-8DOI Listing
August 2014

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

Pediatr Nephrol 2014 Sep 15;29(9):1625-31. Epub 2014 Feb 15.

Unité de Réanimation Pédiatrique, Pôle Femme-Enfant-Adolescent, Centre hospitalier universitaire (CHU) de Nantes, 38 Boulevard Jean-Monnet, 44093, Nantes, France,

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.
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http://dx.doi.org/10.1007/s00467-014-2770-2DOI Listing
September 2014

Renal phenotypic variability in HDR syndrome: glomerular nephropathy as a novel finding.

Eur J Pediatr 2013 Jan 5;172(1):107-10. Epub 2012 Oct 5.

Pediatric Department, Nantes University Hospital, Nantes, France.

Unlabelled: HDR syndrome (hypoparathyroidism, sensorineural deafness, renal abnormalities) (OMIM #146265) is a rare autosomal dominant disorder caused by mutations in the GATA-3 gene (OMIM 13120), a transcription factor coding for a protein involved in vertebrate embryonic development. More than a hundred cases with variable renal features have been described so far. Here, we report on a patient suffering from HDR syndrome with glomerular nephropathy. Hypoparathyroidism appeared early in childhood but the subsequent features of HDR occurred later in the form of bilateral sensorineural deafness and renal insufficiency associated with nephrocalcinosis. HDR was not initially diagnosed due to the appearance of a transitory cardiac involvement and atypical renal symptoms (diffuse proliferative glomerulonephritis characterized by a self-limiting nephrotic syndrome).

Conclusion: HDR syndrome with glomerular nephropathy has not yet been reported to our knowledge. Further studies of GATA-3 are needed to explore the involvement of this transcription factor in the development of HDR in humans, particularly in the kidneys.
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http://dx.doi.org/10.1007/s00431-012-1845-yDOI Listing
January 2013