Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial)

Background: Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. Methods: The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18–24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. Discussion: Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. Trial registration: ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020

Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial)

Abstract Background Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. Methods The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18–24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. Discussion Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. Trial registration ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020

Outcomes of children with acute myocarditis and dilated cardiomyopathy admitted to a tertiary hospital in the Western Cape south africa: an 8 year study

Thesis (MMed)--Stellenbosch University, 2017.Introduction: Approximately 27% of new cases of paediatric cardiac failure in well-resourced settings are due to abnormalities of the myocardium. Acute myocarditis and dilated cardiomyopathy (DCMO) may be clinically indistinguishable at presentation but are distinct diseases. The clinical presentations of myocarditis and DCMO can range from asymptomatic, to fulminant cardiac failure or sudden death. The diagnoses are dependent upon early clinical suspicion as cardiac failure is present in 90%-100% of cases and this is commonly misdiagnosed as respiratory disease. Viral infections (in the case of myocarditis) and the sequelae of viral myocarditis (in the case of DCMO) are the most important causes of myocardial failure, but there are a number of other infections and conditions as well as toxins that are implicated in both these diseases. The cause of myocardial failure may remain obscure, particularly if cases are not rigorously investigated. Entero- and adenoviruses remain important viral pathogens associated with viral myocarditis although there seems to be a viral shift with parvovirus B19 and herpes virus now being commonly implicated. Increasing sophistication of genetic and metabolic evaluations is reducing the number of idiopathic cases. Diagnostic tests are directed at confirming the diagnosis of myocardial dysfunction and identifying the cause. Chest radiographs (CXR) and electrocardiograms (ECG) are widely used initial investigations and are abnormal in above 90% of cases. Echocardiographic (ECHO) examination is used to confirm the diagnosis, exclude structural and other causes of cardiac failure and establish a baseline for follow-up. Polymerase chain reaction (PCR) can detect viral genomes in many tissues and PCR identification of viruses on respiratory specimens correlates well with those obtained from the myocardium. Supportive therapy focusing on treatment of fluid overload and under perfusion is the mainstay of care. Access to ventilatory support, extracorporeal membrane oxygenation (ECMO), ventricular assist devices (VAD) and cardiac transplantation has dramatically changed the outcomes in well-resourced settings where children who survive an initial hospitalization have survival at 1 year of 94% and 89% at 5 years. The predictors and risk factors for death are age (neonatal period and older age at presentation), congestive cardiac failure, lower shortening fraction (SF<15%) and ejection fraction (EF <30%) and in the case of DCMO the aetiology. Nearly all data on the outcome of children presenting with and treated for acute myocarditis and DCMO are reported from developed countries with sophisticated medical services and interventions. There is little data on the clinical presentation, course, outcomes and causes of myocarditis and DCMO in children in middle and low resourced settings, where high burdens of complicating infectious diseases including tuberculosis and HIV exist. A single study from South Africa reports only on children who required paediatric intensive care (PICU) and shows an initial hospital survival of 47% of children. There are no data on the longer-term outcomes. Aims and Objectives: The aim of this study is to investigate the clinical presentation, course and outcome; including morbidity and mortality of children with myocarditis and DCMO, and to attempt to determine factors that predict for outcome. The results hope to guide local clinicians in developing guidelines for children, assist prognostication and potentially identify areas where management and the utilization of scarce resources can be improved. Methods: We conducted a retrospective descriptive review of children from birth to 13 years, diagnosed with acute myocarditis and DCMO from 1 January 2008 to 31 December 2015 at Tygerberg Hospital, a tertiary hospital in the Western Cape, South Africa. For the purposes of this study myocarditis and DCMO were studied as a single entity due to various complexities in separating these entities clearly and the continutuum/overlap that often pursues. Inclusion criteria for this study were all patients with the diagnosis of myocarditis or DCMO, based on ECHO findings of an EF <55% and/or a SF <25%, or antemortem or postmortem histology. Children were excluded if there were structural or vascular abnormalities of the heart, or where the myocardial dysfunction was thought to be due to septicemia with septic shock. We identified cases through the admission/discharge diagnoses using the International Statistical Classification of Diseases codes (ICD10 codes), reviewing ECHO request records and manually reviewing the “Causes of deaths register”. Data were collected from the paper and electronic notes made by doctors, cardiology outpatient records and autopsy reports. Demographic, clinical, laboratory, ECHO, ECG and CXR data were collected on case report forms. Viral myocarditis, for the purposes of this study was a case where a significant virus, known to be associated with myocarditis, was isolated on either PCR of tracheal aspirate (TA)/nasopharyngeal aspirate (NPA), urine or on blood test. In children where cytomegalovirus was found on any specimens we considered it a significant infection only if the blood viral load was shown to be more than 1000 copies/ml (Log 3). The metabolic, autoimmune screens and ECGs in these cases were normal. Statistical analysis was performed with StataCorp. 2015. Stata Statistical Software: Release 14. Standard descriptive analysis, including measures of central tendency and dispersion, was performed for measured variables while frequencies and proportions were described for categorical variables. For comparisons based on mortality, chi-squared test (or exact tests for sparse data) and t-and rank sums for parametric and non-parametric data were used. Analysis of survival/mortality used time to event methods including Kaplan-Meier graphs. For patients lost to follow up, survival was censored at the last known date to be alive. For all hypothesis tests a significance level of 0.05 was used while the 95% Results: We identified 227 potential cases within the broad diagnoses groups of myocarditis, dilated cardiomyopathy, myocardial dysfunction etc. Based on the inclusion and exclusion criteria stated in the methods 117 cases were included. Nineteen children were diagnosed at postmortem only. The median overall age at presentation was 18.9 months (Interquartile range (IQR) 8.9-52.2), with the children diagnosed at post mortem only slightly younger with a median of 10.6 months (IQR 2.2-28.8). Ninety-five percent (n=94/99) were in cardiac failure at presentation and 85.7% (n=90/105) were noted to have cardiovascular instability. Admission left ventricular ejection fraction was less than 30% in 68.2% (n=60/88). Eighty out of 117 (68.4%) children survived the first admission till hospital discharge and 65/117 (55.6%) children where noted to be alive at the end of the review period. On multivariate analysis the only factors that predicted death where renal dysfunction and cardiac failure at presentation. Thirty-three of 117 (28.2%) children had a short history of symptoms of less than 3 days. CXR at presentation was always abnormal and of the 97 CXR reviewed 90 (92.8%) had an increase in the cardiothoracic ratio. Seventy of 108 cases (64.8%) for which data was clear required pediatric intensive care admission; with the median length of ICU being 7 days (IQR 4-11 days). Forty-six of 107 (43%) children required ventilation for a median of 4 days (IQR 1-5) and 70/101 (69.3%) required inotropic support with 59/94 (62.8%) receiving dopamine and/ or dobutamine, 23/89 (25.8%) adrenaline infusions and 22/88 (25.0%) received milrinone. The overall duration of initial admission was 10 days (IQR 3-18), 5 days (IQR 1-15) for children who died and 12 days (8-20) for those who survived. Complications during hospitalization included acute kidney injury in 82/108 (75.9%) (3 needed dialysis), liver enzyme derangement in 69/81 (85.2%). Fourteen of the 91 children who had blood cultures taken (15.4%) at the time of admission had positive cultures, with 7/14 (50.0%) only diagnosed at postmortem. Aetiology was presumed to be viral myocarditis in 54/117 (36.7%) of the children. In 34/117 (29.1%) of cases, either their investigations/work-up was not complete hence classified as “not determined” or their full screen (excluding genetic testing) was negative hence “idiopathic” classification. Viral studies were positive in 73 (76.8%) of the 95 children where specimens were sent however not all cases with positive viruses where classified as having viral myocarditis, it depended on the virus isolated and other factors. Parvovirus PCR was positive in 17/41 (41.5%), significant CMV viral load in 16/40 (40%), Adenovirus in 5/69 (7.2%) and enteroviruses in 6/69 (8.7%). Two or more viruses where found in 37/95 (38.9%) patients. Twenty-four of the 117 (20.5%) children were known to be HIV exposed and of these 7 (29.2%) were HIV infected. 4 of the HIV infected children died, 5 (71.4%) dying within 7 days of diagnosis. The median duration of follow up time from first diagnosis was 474 days (IQR 147-820). 62 of the 80 first admission survivors attended cardiac OPD. Fourteen of the 62 children (22.6%) recovered fully and were discharged from the service, and in total 38 of the 62 clinic attenders (61.3%) were noted at a point with a normalized EF. Twenty-four of the 80 initial survivors (30%) were lost to follow-up. The median EF at the latest ECHO was 53% (IQR 35%-59%). The change in EF from diagnosis to latest ECHO was a median increase of 22.5% (IQR 9%-34%). Conclusions This study confirms that myocarditis and DCMO are an important cause of cardiac morbidity and mortality in South African. This study emphasises the need for a high index of suspicion of myocarditis and rapid PICU access to improve mortality. Bacterial infections are important contributors to death in this cohort and must be considered. Although we may be underestimating the total deaths in this cohort the survival after the first admission was good and supports the current recommendation to provide a full set of interventions to these patients.Inleiding: Ongeveer 27% van nuwe gevalle van hartversaking in kinders van hulpbron-ryke lande is die gevolg van siektes van die miokardium. Dit is dikwels nie moontlik om akute miokarditis en gedilateerde kardiomiopatie (DCMO) klinies van mekaar te onderskei nie, tog is dit unieke siekte entiteite. Miokarditis en DCMO het verskeie oorsake, maar virale infeksie is die algeenste oorsaak van miokarditis, en virale miokarditis is die algemeenste oorsaak van DCMO Die oorsaak mag onbekend bly, veral wanneer gevalle nie deeglik ondersoek word nie. Entero-en adenoviruse is steeds belangrike oorsake van miokarditis maar mettertyd het die rol van parovirus B19 en herpes virusses al hoe duideliker geword. Toenemende ontwikkeling van genetiese en metaboliese evaluering het ook tot ‘n vermindering van die getal idiopatiese gevalle gelei. Die kliniese simptome van miokarditis en DCMO sluit die volle spektrum van asimptomaties, tot skielike hartversaking of dood in. Pasiente word dikwels inisieel foutiewelik met respiratoriese siekte gediagnoseer. Kinders met DCMO is gewoonlik uiters siek by diagnose, met hartversaking wat in 90%-100% van gevalle teenwoordig is. Diagnostiese toetse word gebruik om die diagnose van miokardiale disfunksie te maak en om die oorsaak te indentifiseer. Borskas radiografie (CXR) en elektrokardiogramme (EKG) word dikwels gebruik as voorlopige ondersoeke en is in meer as 90% van gevalle abnormaal. ECHO-ondersoeke word gebruik om die diagnose te maak, om strukturele en ander oorsake van hartversaking uit te skakel en ‘n basislyn te bepaal. Polimerase kettingreaksie (PCR) kan virale genome in verskeie weefsels identifiseer – PCR identifikasie van viruse op respiratoriese monsters korreleer sterk met virale infeksie in die miokardium. Terapie is gefokus op die behandeling van volume oorlading and swak perfusie. Toegang tot ventilatoriese ondersteuning, ekstrakorporeale membraan-oksigenasie (ECMO), ventrikulêre ondersteunings toestelle (VAD) en hartoorplantings het drastiese gevolge gehad vir die uitkomstes en resultate in hulpbronryke lande. Kinders wat in hulpbronryke lande gehospitaliseer word het ‘n oorlewingsyfer van 94% teen 1 jaar en 89% teen 5 jaar. Die risikofaktore en voorspellers vir dood is ouderdom (neonatale periode en ouer kinders), hartversaking, laer verkortingsfraksie (SF<15%) en uitwerpfraksie (EF <30%), en etiologie van DCMO. Byna alle data van die uitkomstes van kinders met – of wat behandeling ontvang vir – akute miokarditis en DCMO word kom van ontwikkelde lande met gesofistikeerde mediese dienste en intervensies. Daar is min data wat die kliniese uitbeelding, uitkomstes en oorsake van miokarditis en DCMO in kinders in middel- tot lae hulpbron instellings beskryf. Die enigste studie vanuit Suid-Afrika rapporteer die aanvanklike hospitaal-oorlewing as 47% van kinders in die pediatriese intensiewe sorgeenheid (PICU), met geen data oor langtermyn uitkomstes nie. Doelstellings en Doelwitte: Die doel van hierdie studie is om die kliniese uitbeelding, koers en uitkomste – insluitend siektekoers en sterftekoers van kinders met miokarditis en DCMO – te ondersoek en te probeer om vas te stel watter faktore n swak uitkoms voorspel. Die resultate hoop om plaaslike klinici te lei in die ontwikkeling van riglyne vir kinders, hulp met voorspelling van siektes, en potensieel te help om areas te identifiseer waar die bestuur en die gebruik van skaarse hulpbronne verbeter kan word. Metodes: Ons het gebruik gemaak van ‘n retrospektiewe, beskrywende studie in kinders vanaf geboorte tot 13 jaar, gediagnoseer met akute miokarditis en DCMO, vanaf 1 Januarie 2008 tot 31 Desember 2015 by Tygerberg Hospitaal – ‘n tersiêre sorg hospitaal in die Wes Kaap, Suid-Afrika. Insluitings-kriteria was die diagnose van miokarditis of DCMO, gebasseer op ECHO bevindinge of ‘n EF <55% en/of ‘n SF <25%, of antemortem of postmortem histologie. Kinders was uitgesluit indien daar strukturele of vaskulêre abnormaliteite van die hart was, of waar die miokardiale disfunksie toegeskryf was aan septisemie met kompliserende septiese skok. Ons het gevalle geïdentifiseer deur die opneem/ontslag diagnoses, die “International Statistical Classification of Diseases” kodes (ICD10), en deur handmatig die doodsoorsaak-register) te ondersoek. Die kardiologie-buitepasiënt rekords en nadoodse-ondersoek verslae was ook nagegaan en papier en digitale doktersnotas. Demografiese, kliniese, laboratorium, ECHO, EKG en CXR data was ingesamel op verslagvorms. Virale miokarditis was, vir die doel van hierdie studie, ‘n geval waar ‘n betekenisvolle virus, geassosieer met miokarditis, geïsoleer was op of PCR of trageale aspirasie/nasofaryngeale aspiraat, urine of bloed toetse. In kinders met sitomegalovirus op ‘n respiratoriese of urine monster het ons dit slegs as ‘n ernstige infeksie klassifiseer indien die virale vlak in die bloed bewys was om meer as 1 000 kopieë/ml (Log 3) te wees. Die metaboliese, outoimmuunsiftings en EKGs was in hierdie gevalle normaal. Statistiese analise was uitgevoer met StataCorp. 2015. Stata Statistical Software: Release 14. Standaard beskrywende analise, insluitend mates van sentrale neiging en verspreiding, was uitgevoer op gemete veranderlikes, terwyl herhalings en verhoudings beskryf was vir kategoriese veranderlikes. In gevalle van vergelykings gebasseer op mortaliteit, was chi-squared toetsing (of presiese toetse vir skaars data), en T- en rang berekeninge vir parametriese en nie-parametriese data gebruik. Vir die analise van oorlewing/sterflikheid was gebruik gemaak van verskeie metodes, insluitend Kaplan-Meier beramings. In die gevalle waar pasiënte verlore gegaan het vir opvolg-ondersoeke, was oorlewing gesensuur teen die laaste bekende datum van oorlewing. Vir alle hipotetiewse toetse was ‘n betekenispeil van 0.05 gebruik, terwyl die 95% CI soos nodig gerapporteer was. Resultate: Ons het 227 potensiële gevalle identifiseer, waarvan 117 ingesluit was. Negentien kinders was slegs met postmortem gediagnoseer. Die mediaan-ouderdom teen die tyd van presentering was 18.9 maande (IQR 8.9-55.2), met die kinders gediagnoseer tydens postmortem slegs effens jonger, met ‘n mediaan van 10.6 maande (IQR 2.2-28.8). Vyf en negentig present (n=94/99) was in hartversaking tydens presentering en 85.7% (n=90/105) gediagnoseer met kardiovaskulêre onstabiliteit. Toelating ventrikulêre ejeksie was minder as 30% in 68.2% (n=60/88). Tagtig uit 117 (68.4%) kinders het hospitaal ontslaning oorleef op diagnosis toelating en die totale oorlewingssyfer was 65/117 (55.6%). Volgens meerveranderlike studie is nier- en hartversaking tydens presentasie die enigste voorspellers vir dood. Drie en dertig uit 117 (28.2%) kinders het ‘n kort geskiedenis van simptome gehad, oor ‘n tydperk van minder as drie dae. CXR by presentasie was altyd abnormaal en, van die 97 CXR wat bestudeer is, het 90 (92.8%) ‘n toename in kardiotorakale ratio getoon. Seventig van 108 (64.8%) van die pasiënte het pediatriese intensiewe sorg toelating benodig, met die mediaan PICU verblyf op 7 dae (IQR 4-11 dae). Ses en veertig van 107 (43%) kinders het ventilasie benodig vir ‘n mediaan van 4 dae (IQR 1-5) en 70/101 (69.3%) het inotropiese ondersteuning benodig, terwyl 59/94 (62.8%) dopamien en/of dobutamien ontvang, 23/89 (25.8%) ontvang adrenalien infusie, en 22/88 (25.0%) ontvang milrinone. Die algehele voortduring van aanvanklike toelating was 10 dae (IQR 3-18), 5 dae (IQR 1-15) vir dié kinders wat gesterf het en 12 dae (8-20) vir dié wat oorleef het. Komplikasies gedurende hospitalisering sluit in akute nierbesering in 82/108 (75.9%) kinders waarvan 3 pasiënte dialise benodig, lewer-ensiem versteuring in 69/81 (85.2%) en bakteriële sepsis. Veertien van die 91 kinders (15.4%) wat bloed kulture geneem het, het positiewe bloed kulture tydens opname, met sewe uit viertien (50.0%) hiervan wat eers tydens postmortem gediagnoseer word. Etiologie was aanvaar as virale miokarditis in 54/117 (36.7%) van die kinders. In 34/117 (29.4%) van gevalle was die ondersoeke of onvoltooid en dus geklassifiseer as “nie-vasgestel”, óf die volle toetse (uitsluitend genetiese toetsing) was negatief, dus die “idiopatiese” klassifisering. Virale studies was positief in 73 (76.8%) van die 95 kinders wie se monsters gestuur en ondersoek was. Parovirus PCR was positief in 17/41 (41.5%), beduidende CMV virale las in 16/40 (40%), Adenovirus in 5/69 (7.2%) en enteroviruse in 6/69 (8.7%). Twee of meer viruse is by 37/95 (38.9%) van die pasiënte gevind. Vier en twintig van 117 (20.5%) van die kinders was blootgestel aan MIV en, van die, was 7 (29.2%) geïnfekteer met MIV. Vier van die MIV-geïnfekteerde kinders het gesterf, 5 (71.4%) binne die eerste sewe dae na diagnose. Die mediaan-duur van opvolg-tyd vanaf die eerste diagnose was 474 dae (IQR 147-820). Twee en sestig van 80 eerste opname oorlewendes her hartpatiente bygewoon. Veertien van die twee en sestig kinders (20.3%) het herstel en was onstlaan vanuit die harteenheid, in 38/62 kinders (61.3%) het EF genormaliseer. Vier en twintig van die tagtig aanvanklike oorlewendes (34.7%) was verlore vir opvolgondersoeke. Die mediaan EF tydens die mees onlangse ECHO was 53% (IQR 35%-59%). Die verandering in EF vanaf diagnose tot die laaste ECHO was ‘n mediaan toename van 22.5% (IQR 9%-34%). Gevolgtrekkinge: Binne ons raamwerk en instellings is akute miokarditis en DCMO geassosieer met opmerklike morbiditeit en mortaliteit. Hierdie studie benadruk die behoefte na ‘n hoër indeks van agterdog van miokarditis en versnelde toelating tot PICU om sodoende oorlewing te verbeter. Bakteriële infeksies is belangrike bydraers tot dood in hierdie kohort en moet dus oorweeg word. Alhoewel ons moontlik die totale dodetal binne die kohort onderskat, was die oorlewing na eerste toelating goed en ondersteun dus die voorstel om ‘n volle stel intervensies daar te stel vir hierdie pasiënte

A Metabolomic Approach in Search of Neurobiomarkers of Perinatal Asphyxia: A Review of the Current Literature.

Perinatal asphyxia and the possible sequelae of hypoxic-ischemic encephalopathy (HIE), are associated with high morbidity and mortality rates. The use of therapeutic hypothermia (TH) commencing within the first 6 h of life-currently the only treatment validated for the management of HIE-has been proven to reduce the mortality rate and disability seen at follow up at 18 months. Although there have been attempts to identify neurobiomarkers assessing the severity levels in HIE; none have been validated in clinical use to date, and the lack thereof limits the optimal treatment for these vulnerable infants. Metabolomics is a promising field of the "omics technologies" that may: identify neurobiomarkers, help improve diagnosis, identify patients prone to developing HIE, and potentially improve targeted neuroprotection interventions. This review focuses on the current evidence of metabolomics, a novel tool which may prove to be a useful in the diagnosis, management and treatment options for this multifactorial complex disease. Some of the most promising metabolites analyzed are the group of acylcarnitines: Hydroxybutyrylcarnitine (Malonylcarnitine) [C3-DC (C4-OH)], Tetradecanoylcarnitine [C14], L-Palmitoylcarnitine [C16], Hexadecenoylcarnitine [C16:1], Stearoylcarnitine [C18], and Oleoylcarnitine [C18:1]. A metabolomic "fingerprint" or "index," made up of 4 metabolites (succinate × glycerol/(β-hydroxybutyrate × O-phosphocholine)), seems promising in identifying neonates at risk of developing severe HIE

An interesting case of 'strange lines' a neonate with oesophageal atresia, tracheo-oesophageal fistula, situs inversus abdominalis and azygos continuation.

We describe the case of a term baby boy born via vaginal delivery at 39 weeks gestation with oesophageal atresia, tracheaoesophageal fistula, situs inversus abdominalis and azygos continuation. The azygos continuation was diagnosed after cardiac echo and confirmed on cardiac catherisation after an unexpected umbilical line position on thoracoabdominal X-ray. The baby underwent a right-sided thoracotomy on day 1 of life for repair of the oesophageal atresia. A double fistula, of both the proximal and distal segments, of the oesophagus with short segment stenosis was confirmed. The tracheo-oesophageal fistulae were ligated and divided and the oesophageal atresia repaired by primary anastomosis without complications. The azygos vein was not ligated.status: Published onlin

How to minimize central line-associated bloodstream infections in a neonatal intensive care unit: a quality improvement intervention based on a retrospective analysis and the adoption of an evidence-based bundle.

Central line-associated bloodstream infection (CLABSI) is a significant cause of morbidity and mortality in neonatal intensive care units (NICUs). A "bundle" is defined as a combination of evidence-based interventions that provided they are followed collectively and reliably, are proven to improve patient outcomes. The aim of this quasi-experimental study was to assess the impact of new central line insertion, dressing, and maintenance "bundles" on the rate of CLABSI and catheter-related complications. We performed a quality improvement (QI), prospective, before-after study. In the first 9-month period, the old "bundles" and pre-existing materials were used/applied. An intervention period then occurred with changes made to materials used and the implementation of new "bundles" related to various aspects of central lines care. A second 6-month period was then assessed and the CLABSI rates were measured in the NICU pre- and post-intervention period. The QI measures were the rate of CLABSI and catheter-related complications. Data are still being collected after the study to verify sustainability. The implementation of the new "bundles" and the change of certain materials resulted in a significantly decreased rate of CLABSI (8.4 to 1.8 infections per 1000 central venous catheter (CVC) days, p = 0.02,) as well as decreased catheter-related complications (47 to 10, p < 0.007).Conclusions: The analysis of pre-existing "bundles" and the implementation of updated central line "bundles" based on best practice recommendations are crucial for reducing the rate of CLABSI in the NICU. The implementation of the new evidence-based central line "bundles" was associated with a significant reduction in CLABSI rate in our unit soon after implementation. What is Known: • Central line-associated bloodstream infection (CLABSI) is a major cause of morbidity and mortality in the neonatal population. • The implementation of evidence-based "bundles" in the NICU is associated with a reduction in the incidence of CLABSI. What is New: • For the improvement in quality care in the NICU, audits are necessary to assess the existing systems. • The "Plan-Do-Study-Act cycle" is an effective tool to use when tackling challenges in an existing system. Using this tool assisted in the approach to reducing CLABSI in our NICU

Cyanoacrylate glue as part of a new bundle to decrease neonatal PICC-related complications.

A "bundle" is defined as a combination of evidence-based interventions that, if followed collectively and reliably, improve patient outcomes. The aim of this quasi-experimental study, conducted in a level-III NICU in Belgium, was to assess the impact of central line dressing and maintenance bundle implementation on the rate of catheter-related mechanical complications. We performed a quality improvement (QI) project. Prior to bundle implementation, neonatal PICC lines were secured by Steri-Strip® and occlusive dressing. We implemented a new PICC bundle consisting of the use of glue, sutureless device (Griplock®), and a transparent dressing to secure the catheter to the skin. We compared the rate of infections, mechanical complications, and dislocations before and after bundle implementation (periods 1 and 2, respectively). The use of glue resulted in a significantly decreased rate of central line-associated bloodstream infection (CLABSI) (p < 0.001), dislocations, and mechanical complications (p < 0.0001). During period 2, there was a significant increase for the average number of days the catheter stayed in place (p < 0.05). We did not observe catheter breakage or patient skin irritations attributable to the use of glue (not even in ELBW infants). CONCLUSION: The implementation of the new bundle to secure neonatal PICCs in our NICU was associated with a significant reduction in CLABSI and dislodgment rates, without glue-related complications. Active surveillance of CVC placement procedure, positioning, and management, as well as analysis of related complications is crucial for improving patient safety. Continuous implementation of up-to-date central line bundles based on best practice recommendations is a key for quality improvement in NICUs

Assessing Neurovascular Coupling Using Wavelet Coherence in Neonates with Asphyxia.

Brain monitoring is important in neonates with asphyxia in order to assess the severity of hypoxic ischaemic encephalopathy (HIE) and identify neonates at risk of adverse neurodevelopmental outcome. Previous studies suggest that neurovascular coupling (NVC), quantified as the interaction between electroencephalography (EEG) and near-infrared spectroscopy (NIRS)-derived regional cerebral oxygen saturation (rSO) is a promising biomarker for HIE severity and outcome. In this study, we explore how wavelet coherence can be used to assess NVC. Wavelet coherence was computed in 18 neonates undergoing therapeutic hypothermia in the first 3 days of life, with varying HIE severities (mild, moderate, severe). We compared two pre-processing methods of the EEG prior to wavelet computation: amplitude integrated EEG (aEEG) and EEG bandpower. Furthermore, we proposed average real coherence as a biomarker for NVC. Our results indicate that NVC as assessed by wavelet coherence between EEG bandpower and rSO can be a valuable biomarker for HIE severity in neonates with peripartal asphyxia. More specifically, average real coherence in a very low frequency range (0.21-0.83 mHz) tends to be high (positive) in neonates with mild HIE, low (positive) in neonates with moderate HIE, and negative in neonates with severe HIE. Further investigation in a larger patient cohort is needed to validate our findings

Partial wavelet coherence as a robust method for assessment of neurovascular coupling in neonates with hypoxic ischemic encephalopathy

Abstract In neonates with hypoxic ischemic encephalopathy, the computation of wavelet coherence between electroencephalogram (EEG) power and regional cerebral oxygen saturation (rSO2) is a promising method for the assessment of neurovascular coupling (NVC), which in turn is a promising marker for brain injury. However, instabilities in arterial oxygen saturation (SpO2) limit the robustness of previously proposed methods. Therefore, we propose the use of partial wavelet coherence, which can eliminate the influence of SpO2. Furthermore, we study the added value of the novel NVC biomarkers for identification of brain injury compared to traditional EEG and NIRS biomarkers. 18 neonates with HIE were monitored for 72 h and classified into three groups based on short-term MRI outcome. Partial wavelet coherence was used to quantify the coupling between C3–C4 EEG bandpower (2–16 Hz) and rSO2, eliminating confounding effects of SpO2. NVC was defined as the amount of significant coherence in a frequency range of 0.25–1 mHz. Partial wavelet coherence successfully removed confounding influences of SpO2 when studying the coupling between EEG and rSO2. Decreased NVC was related to worse MRI outcome. Furthermore, the combination of NVC and EEG spectral edge frequency (SEF) improved the identification of neonates with mild vs moderate and severe MRI outcome compared to using EEG SEF alone. Partial wavelet coherence is an effective method for removing confounding effects of SpO2, improving the robustness of automated assessment of NVC in long-term EEG-NIRS recordings. The obtained NVC biomarkers are more sensitive to MRI outcome than traditional rSO2 biomarkers and provide complementary information to EEG biomarkers