Publications by authors named "Nicolas Joram"

24 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

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

Neisseria meningitidis inside neutrophils, revealing properdin deficiency.

Int J Infect Dis 2020 10 25;99:117-118. Epub 2020 Jul 25.

Service d'Hématologie Biologique, Centre Hospitalier Universitaire, Nantes, France. Electronic address:

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http://dx.doi.org/10.1016/j.ijid.2020.07.040DOI Listing
October 2020

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

Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System.

Front Immunol 2019 22;10:2007. Epub 2019 Aug 22.

Department of Molecular Biology and Genetics, Center for Structural Biology, Aarhus University, Aarhus, Denmark.

Properdin (FP) is a positive regulator of the immune system stimulating the activity of the proteolytically active C3 convertase C3bBb in the alternative pathway of the complement system. Here we present two crystal structures of FP and two structures of convertase bound FP. A structural core formed by three thrombospondin repeats (TSRs) and a TB domain harbors the convertase binding site in FP that mainly interacts with C3b. Stabilization of the interaction between the C3b C-terminus and the MIDAS bound Mg in the Bb protease by FP TSR5 is proposed to underlie FP convertase stabilization. Intermolecular contacts between FP and the convertase subunits suggested by the structure were confirmed by binding experiments. FP is shown to inhibit C3b degradation by FI due to a direct competition for a common binding site on C3b. FP oligomers are held together by two sets of intermolecular contacts, where the first is formed by the TB domain from one FP molecule and TSR4 from another. The second and largest interface is formed by TSR1 and TSR6 from the same two FP molecules. Flexibility at four hinges between thrombospondin repeats is suggested to enable the oligomeric, polydisperse, and extended architecture of FP. Our structures rationalize the effects of mutations associated with FP deficiencies and provide a structural basis for the analysis of FP function in convertases and its possible role in pattern recognition.
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http://dx.doi.org/10.3389/fimmu.2019.02007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713926PMC
September 2020

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

Am J Hum Genet 2019 02 10;104(2):213-228. Epub 2019 Jan 10.

Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.

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.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369446PMC
February 2019

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

The authors reply.

Pediatr Crit Care Med 2017 05;18(5):498-499

Department of Pediatric Intensive Care, Nantes University Hospital, Nantes, France, and Clinical Investigation, Women's, Children's and Adolescent's Hospital, Nantes University Hospital, Nantes, France.

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http://dx.doi.org/10.1097/PCC.0000000000001152DOI Listing
May 2017

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

BMC Pediatr 2016 11 8;16(1):180. Epub 2016 Nov 8.

Pediatric Intensive Care Unit, Hôpital Femme-Enfant-Adolescent, the University Hospital Center of Nantes (CHU), 38 bd Jean-Monnet, 44093, Nantes, France.

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, FiO, sedation or inotropic doses were allowed during these two periods. The challenge was to keep minute volumes constant, with no changes in blood CO 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 (ScvO < 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 ScvO (<65 %) tended to increase their cardiac index with NAVA compared to CV: 2.03 ± 0.30 vs. 1.91 ± 0.39 L/min.m (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.
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http://dx.doi.org/10.1186/s12887-016-0717-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100099PMC
November 2016

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

Pediatr Crit Care Med 2017 01;18(1):e9-e17

1Department of Pediatric Intensive Care, Nantes University Hospital, Nantes, France.2Department of Clinical Investigation, Women's, Children's and Adolescent's Hospital, CIC INSERM 1413, Nantes University Hospital, Nantes, France.

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.
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http://dx.doi.org/10.1097/PCC.0000000000000998DOI Listing
January 2017

Neonatal Marfan Syndrome: Report of a Case with an Inherited Splicing Mutation outside the Neonatal Domain.

Mol Syndromol 2016 Feb 2;6(6):281-6. Epub 2016 Feb 2.

Génétique Médicale, CHU de Nantes, Université de Nantes, Nantes, France.

We report a child and her mother affected by Marfan syndrome. The child presented with a phenotype of neonatal Marfan syndrome, revealed by acute and refractory heart failure, finally leading to death within the first 4 months of life. Her mother had a common clinical presentation. Genetic analysis revealed an inherited FBN1 mutation. This intronic mutation (c.6163+3_6163+6del), undescribed to date, leads to exon 49 skipping, corresponding to in-frame deletion of 42 amino acids (p.Ile2014_Asp2055del). FBN1 next-generation sequencing did not show any argument for mosaicism. Association in the same family of severe neonatal and classical Marfan syndrome illustrates the intrafamilial phenotype variability.
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http://dx.doi.org/10.1159/000443867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802997PMC
February 2016

Strategies to reduce curative antibiotic therapy in intensive care units (adult and paediatric).

Intensive Care Med 2015 Jul 3;41(7):1181-96. Epub 2015 Jun 3.

Réanimation Médicale Polyvalente, Pôle Hospitalo-Universitaire 3, CHU-Immeuble Jean Monnet, 44093, Nantes, France,

Emerging resistance to antibiotics shows no signs of decline. At the same time, few new antibacterials are being discovered. There is a worldwide recognition regarding the danger of this situation. The urgency of the situation and the conviction that practices should change led the Société de Réanimation de Langue Française (SRLF) and the Société Française d'Anesthésie et de Réanimation (SFAR) to set up a panel of experts from various disciplines. These experts met for the first time at the end of 2012 and have since met regularly to issue the following 67 recommendations, according to the rigorous GRADE methodology. Five fields were explored: i) the link between the resistance of bacteria and the use of antibiotics in intensive care; ii) which microbiological data and how to use them to reduce antibiotic consumption; iii) how should antibiotic therapy be chosen to limit consumption of antibiotics; iv) how can antibiotic administration be optimized; v) review and duration of antibiotic treatments. In each institution, the appropriation of these recommendations should arouse multidisciplinary discussions resulting in better knowledge of local epidemiology, rate of antibiotic use, and finally protocols for improving the stewardship of antibiotics. These efforts should contribute to limit the emergence of resistant bacteria.
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http://dx.doi.org/10.1007/s00134-015-3853-7DOI Listing
July 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

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

Respiratory support by neurally adjusted ventilatory assist (NAVA) in severe RSV-related bronchiolitis: a case series report.

BMC Pediatr 2011 Oct 20;11:92. Epub 2011 Oct 20.

Unité de Réanimation Pédiatrique, Hôpital Mère-Enfant Faïencerie, CHU de Nantes, 38 Boulevard Jean-Monnet, 44093 Nantes, France.

Background: Neurally adjusted ventilatory assist (NAVA) is a new mode of mechanical ventilation controlled by diaphragmatic electrical signals. The electrical signals allow synchronization of ventilation to spontaneous breathing efforts of a child, as well as permitting pressure assistance proportional to the electrical signal. NAVA provides equally fine synchronization of respiratory support and pressure assistance varying with the needs of the child. NAVA has mainly been studied in children who underwent cardiac surgery during the period of weaning from a respirator.

Case Presentation: We report here a series of 3 children (1 month, 3 years, and 28 days old) with severe respiratory distress due to RSV-related bronchiolitis requiring invasive mechanical ventilation with a high level of oxygen (FiO2 ≥ 50%) for whom NAVA facilitated respiratory support. One of these children had diagnosis criteria for acute lung injury, another for acute respiratory distress syndrome.Establishment of NAVA provided synchronization of mechanical ventilatory support with the breathing efforts of the children. Respiratory rate and inspiratory pressure became extremely variable, varying at each cycle, while children were breathing easily and smoothly. All three children demonstrated less oxygen requirements after introducing NAVA (57 ± 6% to 42 ± 18%). This improvement was observed while peak airway pressure decreased (28 ± 3 to 15 ± 5 cm H2O). In one child, NAVA facilitated the management of acute respiratory distress syndrome with extensive subcutaneous emphysema.

Conclusions: Our findings highlight the feasibility and benefit of NAVA in children with severe RSV-related bronchiolitis. NAVA provides a less aggressive ventilation requiring lower inspiratory pressures with good results for oxygenation and more comfort for the children.
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http://dx.doi.org/10.1186/1471-2431-11-92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3207882PMC
October 2011

Betamethasone worsens chorioamnionitis-related lung development impairment in rabbits.

Am J Perinatol 2011 Sep 14;28(8):605-12. Epub 2011 Apr 14.

CIC mère-enfant, Children's Hospital, CHU Nantes, Creteil, France.

Although chorioamnionitis and glucocorticoids (GC) are both known to have potential adverse effects on alveolar development, the use of GC is generalized because of their demonstrated benefits in premature newborns. The objective of this study was to analyze the cumulative effects of GC and chorioamnionitis on lung development and infectious process. In a model of ESCHERICHIA COLI chorioamnionitis controlled by antibiotics, pregnant rabbits were randomized among five groups: (1) E. COLI infection alone, (2) infection plus one betamethasone injection (0.1 mg.kg(-1)), (3) infection plus two betamethasone injections, (4) betamethasone alone, (5) control. Lung morphometric analysis, bronchoalveolar lavage, and bacteriologic tissue cultures were performed after spontaneous delivery. In the context of chorioamnionitis, one betamethasone treatment significantly decreased birth weight and lung volume versus controls (30 ± 1.40 versus 52.40 ± 2.54 g, and 1.92 ± 0.67 versus 2.15 ± 0.74 cm(3), respectively, p < 0.05). Two betamethasone treatments significantly decreased specific alveolar area (279.8 ± 46 cm(2)/100 g versus 510.90 ± 54.1 cm(2)/100 g), specific interstitium volume (0.98 ± 0.09 cm(3)/100 g versus 1.78 ± 0.16 cm(3)/100 g), and specific elastin fiber length (57.4 ± 10.5 versus 183.6 ± 8.1 cm/100 g). These results suggest that glucocorticoid treatment might represent an additional risk factor for lung development in the instance of prenatal infection.
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http://dx.doi.org/10.1055/s-0031-1276734DOI Listing
September 2011

Procalcitonin as a marker of bacterial infection in children undergoing cardiac surgery with cardiopulmonary bypass.

Cardiol Young 2011 Aug 9;21(4):392-9. Epub 2011 Mar 9.

Pediatric Cardiology Unit, Nantes University Hospital, Nantes, France.

Background: Owing to systemic inflammatory response syndrome, the diagnosis of post-operative infection after cardiopulmonary bypass is difficult to assess in children with the usual clinical and biological tools. Procalcitonin could be informative in this context.

Methods: Retrospective study in a paediatric intensive care unit. Blood samples were collected as soon as infection was clinically suspected and a second assay was performed 24 hours later. Using referenced criteria, children were retrospectively classified into two groups: infected and non-infected.

Results: Out of the 95 children included, 14 were infected. Before the third post-operative day, procalcitonin median concentration was significantly higher in the infected group than in the non-infected group - 20.24 nanograms per millilitre with a 25th and 75th interquartile of 15.52-35.71 versus 0.72 nanograms per millilitre with a 25th and 75th interquartile of 0.28 to 5.44 (p = 0.008). The area under the receiver operating characteristic curve was 0.89 with 95% confidence intervals from 0.80 to 0.97. The best cut-off value to differentiate infected children from healthy children was 13 nanograms per millilitre with 100% sensitivity - 95% confidence intervals from 51 to 100 - and 85% specificity - 95% confidence intervals from 72 to 91. After the third post-operative day, procalcitonin was not significantly higher in infected children - 2 nanograms per millilitre with a 25th and 75th interquartile of 0.18 to 12.42 versus 0.37 nanograms per millilitre with a 25th and 75th interquartile of 0.24 to 1.32 (p = 0.26). The area under the receiver operating characteristic curve was 0.62 with 95% confidence intervals from 0.47 to 0.77. A procalcitonin value of 0.38 nanograms per millilitre provided a sensitivity of 70% with 95% confidence intervals from 39 to 89 for a specificity of 52% with 95% confidence intervals from 34 to 68. After the third post-operative day, a second assay at a 24-hour interval can improve the sensitivity of the test.

Conclusions: Procalcitonin seems to be a discriminating marker of bacterial infection during the post-operative days following cardiopulmonary bypass in children.
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http://dx.doi.org/10.1017/S104795111100014XDOI Listing
August 2011

Efficacy of ciprofloxacin in an experimental model of Escherichia coli chorioamnionitis in rabbits.

Antimicrob Agents Chemother 2009 Apr 21;53(4):1624-7. Epub 2009 Jan 21.

Département de Périnatologie, Hôpital Mère Enfant CHU Nantes, Nantes CEDEX 1, France.

Pregnant rabbits were treated with ciprofloxacin alone or with gentamicin in a model of Escherichia coli chorioamnionitis, and the results were compared with those for untreated rabbits. The survival rate increased and the bacteremia decreased significantly in treated fetuses in comparison to controls (P = 0.003). Nevertheless, rapid selection of resistant mutants is a major limit to ciprofloxacin applications.
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http://dx.doi.org/10.1128/AAC.00186-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663122PMC
April 2009