Core outcome set for perinatal interventions for congenital diaphragmatic hernia.

OBJECTIVE: To develop a core set of prenatal and neonatal outcomes for clinical studies evaluating perinatal interventions for congenital diaphragmatic hernia, using a validated consensus-building method. METHODS: An international steering group comprising 13 leading maternal-fetal medicine specialists, neonatologists, pediatric surgeons, patient representatives, researchers and methodologists guided the development of this core outcome set. Potential outcomes were collected through a systematic review of the literature and entered into a two-round online Delphi survey. A call was made for stakeholders with experience of congenital diaphragmatic hernia to review the list and score outcomes based on their perceived relevance. Outcomes that fulfilled the consensus criteria defined a priori were discussed subsequently in online breakout meetings. Results were reviewed in a consensus meeting, during which the core outcome set was defined. Finally, the definitions, measurement methods and aspirational outcomes were defined in online and in-person definition meetings by a selection of 45 stakeholders. RESULTS: Overall, 221 stakeholders participated in the Delphi survey and 198 completed both rounds. Fifty outcomes met the consensus criteria and were discussed and rescored by 78 stakeholders in the breakout meetings. During the consensus meeting, 93 stakeholders agreed eventually on eight outcomes, which constituted the core outcome set. Maternal and obstetric outcomes included maternal morbidity related to the intervention and gestational age at delivery. Fetal outcomes included intrauterine demise, interval between intervention and delivery and change in lung size in utero around the time of the intervention. Neonatal outcomes included neonatal mortality, pulmonary hypertension and use of extracorporeal membrane oxygenation. Definitions and measurement methods were formulated by 45 stakeholders, who also added three aspirational outcomes: duration of invasive ventilation, duration of oxygen supplementation and use of pulmonary vasodilators at discharge. CONCLUSIONS: We developed with relevant stakeholders a core outcome set for studies evaluating perinatal interventions in congenital diaphragmatic hernia. Its implementation should facilitate the comparison and combination of trial results, enabling future research to better guide clinical practice. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal endoscopic tracheal occlusion reduces pulmonary hypertension in severe congenital diaphragmatic hernia.

OBJECTIVE: Fetal endoscopic tracheal occlusion (FETO) is associated with increased perinatal survival and reduced need for extracorporeal membrane oxygenation (ECMO) in fetuses with severe congenital diaphragmatic hernia (CDH). This study evaluates the impact of FETO on the resolution of pulmonary hypertension (PH) in fetuses with isolated CDH. METHODS: We reviewed retrospectively the medical records of all fetuses evaluated for CDH between January 2004 and July 2017 at a single institution. Fetuses with additional major structural or chromosomal abnormalities were excluded. CDH cases were classified retrospectively into mild, moderate and severe groups based on prenatal magnetic resonance imaging indices (observed-to-expected total fetal lung volume and percentage of intrathoracic liver herniation). Presence of PH was determined based on postnatal echocardiograms. Logistic regression analyses were performed to evaluate the relationship between FETO and resolution of PH by 1 year of age while controlling for side of the CDH, use of ECMO, gestational age at diagnosis, gestational age at delivery, fetal gender, sildenafil use at discharge and CDH severity. Resolution of PH by 1 year of age was compared between a cohort of fetuses with severe CDH that underwent FETO and a cohort that did not have the procedure (non-FETO). A subanalysis was performed restricting the analysis to isolated left CDH. Parametric and non-parametric tests were used for comparisons. RESULTS: Of 257 CDH cases evaluated, 72% (n = 184) had no major structural or chromosomal anomalies of which 58% (n = 107) met the study inclusion criteria. The FETO cohort consisted of 19 CDH cases and the non-FETO cohort (n = 88) consisted of 31 (35%) mild, 32 (36%) moderate and 25 (28%) severe CDH cases. All infants with severe CDH, regardless of whether they underwent FETO, had evidence of neonatal PH. FETO (OR, 3.57; 95% CI, 1.05-12.10; P = 0.041) and ECMO (OR, 5.01; 95% CI, 2.10-11.96; P < 0.001) were independent predictors of resolution of PH by 1 year of age. A higher proportion of infants with severe CDH that underwent FETO had resolution of PH by 1 year after birth compared with infants with severe CDH in the non-FETO cohort (69% (11/16) vs 28% (7/25); P = 0.017). Similar results were observed when the analysis was restricted to cases with left-sided CDH (PH resolution in 69% (11/16) vs 28% (5/18); P = 0.032). CONCLUSION: In infants with severe CDH, FETO and ECMO are independently associated with increased resolution of PH by 1 year of age. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Fetal lung volume and quantification of liver herniation by magnetic resonance imaging in isolated congenital diaphragmatic hernia.

OBJECTIVE: To determine associations between fetal lung and liver herniation volumes measured by magnetic resonance imaging (MRI) and mortality/need for extracorporeal membrane oxygenation (ECMO) in cases of isolated congenital diaphragmatic hernia (CDH). A secondary objective was to compare prenatal MRI parameters with two-dimensional ultrasound lung measurements. METHODS: A retrospective review of medical records of all fetuses with isolated CDH evaluated between January 2004 and July 2012 was performed. The following MRI parameters were measured at 20-32 weeks: observed/expected total fetal lung volume (o/e-TLV), predicted pulmonary volume (PPV), percentage of liver herniated into the fetal thorax (%LH) and the liver/thoracic volume ratio (LiTR). These were compared with the ultrasound-determined lung-to-head ratio (LHR) and the observed/expected LHR (o/e-LHR) in the same cohort. The predictive value of MRI and ultrasound parameters for mortality and the need for ECMO was evaluated by univariate, multivariate and factor analysis and by receiver-operating characteristics curves. RESULTS: Eighty fetuses with isolated CDH were evaluated. Overall mortality was 18/80 (22.5%). Two newborns died a few hours after birth. ECMO was performed in 29/78 (37.2%) newborns, with a survival rate of 48.3% (14/29). The side of the diaphragmatic defect was not associated with mortality (P = 0.99) or the need for ECMO (P = 0.48). Good correlation was observed among o/e-TLV, PPV, LHR and o/e-LHR as well as between %LH and LiTR (r = 0.89; P < 0.01); however, fetal lung measurements and measures of liver herniation were not correlated (all P > 0.05). All parameters were statistically associated with mortality or the need for ECMO. The best combination of measurements to predict mortality was o/e-TLV and %LH, with 83% accuracy. CONCLUSION: Mortality and the need for ECMO in neonates with isolated CDH can be best predicted using a combination of MRI o/e-TLV and %LH.

Schistosomiasis associated pulmonary hypertension.

Schistosomiasis is one of the most prevalent infectious diseases, endemic in more than 70 countries, mainly within the developing world. More than 200 million people might be infected worldwide; about 20 million of those might develop severe disease. The hepatosplenic form of schistosomiasis is the most prevalent form of chronic disease, characterised by the presence of periportal fibrosis and portal hypertension. Pulmonary hypertension is a well-recognised complication of hepatosplenic schistosomiasis. Recent prevalent studies revealed that schistosomiasis patients may develop precapillary and postcapillary forms of pulmonary hypertension, reinforcing the role of invasive haemodynamic measurements for the proper diagnosis. These studies also demonstrated that schistosomiasis associated pulmonary arterial hypertension may represent the most prevalent form of pulmonary arterial hypertension (PAH). Many aspects regarding the appropriate management of Sch-PAH patients still remain to be elucidated, as the use of specific PAH therapy. Although the ongoing control programmes that started within the 1980s have clearly improved the schistosomiasis cenario worldwide, Sch-PAH will be seen for decades after proper control is reached, strengthening the current need for comprehensive studies aiming to clarify the multiple mechanisms involved in the pathophysiology of this particular subgroup of PAH.

Urinary F2-isoprostanes are poor prognostic indicators for the development of bronchopulmonary dysplasia.

OBJECTIVE: Oxygen toxicity is thought to contribute to the development of bronchopulmonary dysplasia (BPD). Oxidant injury leads to formation of F(2)-isoprostanes (F(2)-IsoP). We hypothesized that urinary excretion of the stable metabolite of F(2)-IsoP, 8-iso-PGF(2alpha), would be higher in infants who develop BPD than those who did not. METHODS: Forty infants <30-weeks gestational age (GA) were enrolled, 24 infants with BPD and 16 without BPD. Urine specimens were collected weekly and stored at -80 degrees C until analyzed. Urinary 8-iso-PGF(2alpha) was measured by gas chromatography/mass spectrometry (GC-MS) and normalized to creatinine excretion. RESULTS: GA and birth weight (BW) were lower in infants who developed BPD than those who did not. Urinary 8-iso-PGF(2alpha) levels in the first or third weeks of age were not significantly different between the two groups. CONCLUSION: Urinary excretion of 8-iso-PGF(2alpha) in early postnatal life in preterm infants is not correlated with the development of BPD.

Mind the gap: can videolaryngoscopy bridge the competency gap in neonatal endotracheal intubation among pediatric trainees? a randomized controlled study.

BACKGROUND: To study the impact of videolaryngoscopy (VL) on intubation success among pediatric trainees compared with direct laryngoscopy (DL). METHODS: One hundred pediatric residents were enrolled in a randomized, crossover, simulation study comparing VL to DL. Following a didactic session on neonatal intubation, residents intubated a standard neonatal mannequin. Three Neonatal Resuscitation Program (NRP) scenarios were then conducted, followed by a mannequin intubation with the alternate device. Number of attempts and time to intubation were recorded for all intubations. RESULTS: Proportion of successful intubations on first attempt was greater with VL compared with DL (88% versus 63%; P=0.008). The DL group increased success after crossover with VL (63% versus 89%; P=0.008). Exposure to VL also reduced intubation time after device crossover (median intubation time: 31 versus 17 s; P=0.048). CONCLUSIONS: VL increased the success of endotracheal intubation by pediatric residents in simulation, with skills transferrable to DL.

Titanium-released from dental implant enhances pre-osteoblast adhesion by ROS modulating crucial intracellular pathways.

It is important to understand the cellular and molecular events that occur at the cell-material interface of implants used for bone repair. The mechanisms involved in the initial stages of osteoblast interactions with the surface of the implant material must be decisive for cell fating surrounding them. In order to address this issue, we decided to investigate if conditioned medium for dental implants was able to modulate murine pre-osteoblast metabolism. First, we determined the concentration of titanium (Ti)-containing conditioned medium and found that it was 2-fold increased (p < 0.0001). We have reported that this conditioned medium significantly up-modulated pre-osteoblast adhesion up to 24 h (p < 0.0001). In parallel, our results showed that both phosphorylations of FAK (focal adhesion kinase) at Y397 (p < 0.0011) and Cofilin at Ser03 (p < 0.0053) were also up-modulated, as well as for Rac1 expression (p < 0.0175); both of them are involved with cell adaptation by rearranging cytoskeleton actin filaments. Thereafter, Ti-containing medium stimulated ROS (reactive oxygen species) production by pre-osteoblast cells, and it is very possible that ROS compromised PTP-1B (protein tyrosine phosphatase 1B) activation since PTP1B was down-phosphorylated (p < 0.0148). The low PTP activity guarantees the phosphorylation of FAK at Y-residue, causing better pre-osteoblast adhesion in response to Ti-containing medium. Altogether, these data indicate that ROS indirectly modulate FAK phosphorylation in response to Ti-released from dental implants. Taken the results in account, these data showed for the first time that the implanted dental device is able to dynamically affect surrounding tissues, mainly by promoting a better performance of the pre-osteoblast cells. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2968-2976, 2017.

Cardiac troponin: a new serum marker of myocardial injury in sepsis.

OBJECTIVE: Echocardiogram-derived left ventricular ejection fraction (LVEF) is usually utilized to evaluate left ventricular function, including that of septic patients. However, LVEF is greatly influenced by afterload. The aim of this study was to test the hypothesis that troponin I, a serum marker of myocardial injury, may be able to detect left ventricular involvement by the septic process, being at least as sensitive an indicator of left ventricular dysfunction as LVEF in these patients. DESIGN: Comparison of echocardiogram-derived LVEF with serum levels of troponin I in ten critically ill septic patients. SETTING: General intensive care unit in a tertiary care private hospital. PATIENTS: Ten critically ill septic patients with no previous documented heart disease. MEASUREMENTS AND RESULTS: Patients were simultaneously submitted to a two-dimensional echocardiogram and troponin I determinations. LVEFs and troponin I levels were analyzed in a two-by-two table in order to validate troponin I as a new biochemical marker of myocardial injury in sepsis. All the patients whose LVEF was < 0.5 had elevated troponin I levels (kappa = 0.61, p = 0.035). CONCLUSIONS: Identification of myocardial dysfunction in septic patients has been a challenging task. Troponin I, a serum marker of myocardial injury, may be of great help in the recognition of myocardial involvement by sepsis in a noninvasive and readily available way.

Antibiotic resistance in Australia with special reference to sulbactam/ampicillin.

A survey of antibiotic resistance in Australian states was undertaken by the Microbiology Quality Assurance Program of the Royal College of Pathologists of Australasia. Data were obtained from hospitals and private pathology laboratories serving both in-patients and out-patients at community hospitals. The study showed that resistance varied from state to state; it was highest in the Eastern states of New South Wales, Victoria, and Queensland, and lowest in Tasmania and Western Australia. In South Australia, isolates of Escherichia coli demonstrated a high degree of cefoxitin resistance. Western Australia and Tasmania showed high levels of gentamicin resistance for Klebsiella spp., as well as trimethoprim resistance in Proteus mirabilis. The relationship between erythromycin resistance and clindamycin resistance also differed among various states. These studies demonstrated the activity of sulbactam/ampicillin against a wide variety of common pathogenic bacteria in which resistance was mediated by beta-lactamase.

In vitro studies of ciprofloxacin and survey of resistance patterns in current isolates.

We studied the activity of ciprofloxacin and other antibiotics against both routine and multiresistant (multi-R) clinical isolates. Ciprofloxacin inhibited more than 98% of most species of Enterobacteriaceae at a concentration of 2 micrograms/ml. Only Acinetobacter calcoaceticus, and to a much lesser degree, Providencia and Serratia, were resistant. Most Pseudomonas aeruginosa isolates were susceptible. Only 1% of staphylococci were resistant; the test panel included 1200 MRSA. For most species of streptococci, the MIC90 was 1 microgram/ml; for enterococci, it was 2 micrograms/ml. We also surveyed resistance in our current isolates. Resistance to ciprofloxacin has increased in A. calcoaceticus and Providencia, and in Streptococcus pneumoniae and group B streptococci. Ciprofloxacin-resistant isolates tended to show increased resistance to other antibiotics, including aminoglycosides and, later, cephalosporins.

Multi-centre collaborative study for the in vitro evaluation of new macrolides dirithromycin and erythromycylamine. Australian Group for Antimicrobial Resistance (AGAR).

A national study was conducted to determine the in vitro activity of 2 newer macrolides, dirithromycin and erythromycylamine compared with that of erythromycin, tetracycline and penicillin. Nineteen major teaching hospitals participated in the study. Minimal Inhibitory Concentrations (MICs) were determined by agar dilution, mostly using Iso-Sensitest Agar and an inoculum of 10(4) cells per spot. 2284 clinically significant strains were isolated in late 1991 and early 1992, comprising 1736 Gram-positive cocci, 355 Haemophilus influenzae, 97 Moraxella catarrhalis, 32 Listeria monocytogenes, 25 Neisseria meningitidis and 39 Neisseria gonorrhoeae were tested. The study indicates that dirithromycin and erythromycylamine possess antibacterial activity equivalent to that of erythromycin against most Gram-positive cocci and M. catarrhalis. Strains resistant to erythromycin were also resistant to dirithromycin and to erythromycylamine. Tetracycline was as active as the macrolides against both penicillin-resistant and penicillin-susceptible strains of Staphylococcus aureus. Coagulase-negative penicillin-resistant staphylococci, compared with tetracycline, were relatively resistant to the macrolides. H. influenzae was less susceptible than the Gram-positive cocci.

A national collaborative study of the in vitro activity of oral cephalosporins and loracarbef (LY 163892). Australian Group for the Study of Antimicrobial Resistance (AGAR).

A national collaborative study involving the laboratories of 17 Australian hospitals examined the in vitro activity of loracarbef, cefaclor, cephalexin, amoxycillin and amoxycillin/clavulanate against 2661 recently isolated common bacterial pathogens. Loracarbef was the most active agent against Escherichia coli (MIC90 = 1 mg/l) and had activity comparable to other agents against Klebsiella pneumoniae and Proteus mirabilis. Like the oral cephalosporins, it had no activity against species of Enterobacter and Serratia. beta-lactamase-producing Staphylococcus aureus and Haemophilus influenzae were moderately sensitive to loracarbef (MIC90 = 8 mg/l for both species). Streptococcus pneumoniae was moderately sensitive to loracarbef (MIC90 = 2 mg/l) but strains which were insensitive to penicillin were often highly resistant.

Evaluation of the MRSA-Screen Test in detecting oxacillin resistance in community and hospital isolates of Staphylococcus aureus.

The MRSA-Screen Test (Denka Seiken Co., Japan), a latex agglutination test to detect penicillin-binding protein 2a, was compared with PCR for the detection of oxacillin resistance in Staphylococcus aureus. A total of 77 oxacillin-sensitive and 269 oxacillin-resistant (ORSA) isolates were evaluated. Of the ORSA isolates, 186 were non-multiresistant (NORSA), defined as being resistant to two or fewer antibiotics other than beta-lactams. Eighty-three were multiresistant ORSA (MORSA) strains. If PCR is considered the gold standard test, then the sensitivity, specificity, positive and negative predictive values of the MRSA-Screen Test were 100, 99, 99 and 100%, respectively. The endpoint was hard to read with NORSA strains that took longer than 60 s to react. MORSA strains took a median 12 s (range 5-60 s) to give a positive reaction with the MRSA-Screen Test, whereas NORSA strains took a median 30 s (range 5-180 s), a difference which was significantly different (P < 0.0001, two-tailed Mann-Whitney unpaired two sample test). NORSA strains had an MIC50 of 128 mg/l and MIC90 of 256mg/l, whereas MORSA strains had an MIC50 and MIC90 of >256mg/l. The time that the MRSA-Screen Test took to agglutinate with ORSA strains correlated weakly with the MIC (r2 = 0.26). Detection of methicillin resistance cost AUD$9 per isolate with the MRSA-Screen Test, compared with AUD$13 per isolate with mecA PCR. The MRSA-Screen Test gave excellent sensitivity and specificity, and was quicker and cheaper than PCR. The full 3 min should be allowed to elapse before calling a test negative. Organisms giving indeterminate reactions should be tested for the mecA gene by PCR.

In vitro antibacterial activity of enoxacin (CI-919).

Antibacterial activity of enoxacin was evaluated against more than 3,700 clinical isolates using the agar-dilution method and an inoculum of 10(4)-10(5) cells per site. For comparison other antibiotics appropriate for each species were also included. For most enterobacteria and for Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa, the MIC90 of enoxacin was below 2 mg/l. Serratia marcescens was more resistant; the MIC90 being 4 mg/ml. Enoxacin also showed high activity against Campylobacter jejuni and Neisseria gonorrhoeae. Streptococci were comparatively resistant, 32 mg/l to 64 mg/l of the compound being required to inhibit 90% of strains.

Clinical profile of severe birth asphyxia.

In this retrospective analysis, 56 babies with Apgar score 3 and less were studied. In 33, successful bag-mask ventilation was carried out. Seventeen babies received endotracheal IPPV. In 9 out of them bag-mask ventilation was never tried whereas in 8 bag-mask ventilation had failed. In 6 babies physical stimulation and blast of oxygen on the face was adequate. Following this experience, in the subsequent years, endotracheal intubation was required mainly in extremely low birth weight babies or babies with Apgar score 0 at birth. During the study period, drugs were used in about 50% babies. In subsequent years this figure has come down to 10%, that too in special situations. This study helped us to evolve a policy in resuscitations severely asphyxiated babies. Bag-mask ventilation is the first choice. Failure to achieve progressively improving Apgar score by 1 minute, usually 4-5, is an indication for endotracheal intubation. Drugs are required in special situations only.

Tight glucose control versus intermediate glucose control: a quasi-experimental study.

Intensive insulin treatment is associated with an increased risk of hypoglycaemia. The purpose of this study was to evaluate two different strategies: tight glucose control (TGC) versus intermediate glucose control (IGC). In this quasi-experimental study, 130 critically ill patients were assigned to receive either the TGC protocol (n=65), according to which blood glucose levels were maintained between 4.4 and 6.1 mmol/l, or the IGC protocol (n=65), according to which blood glucose levels were maintained between 4.4 and 8.0 mmol/l. A total of 52 subjects (40%) were diabetic and 63 (49%) were septic. In the IGC group, glucose levels were stabilised in the target range for a longer period of time when compared to the TGC group (63 vs. 41%, P < 0.001). The median capillary blood glucose level was 6.7 mmol/l in the TGC group (6.2 to 7.2) and 7.9 mmol/l (7.0 to 8.5) in the IGC group (P < 0.001). The incidence of hypoglyacemia less than 2.2 mmol/l was 21.5% in the TGC group and 1.5% in the IGC group (P < 0.001), and the incidence of hypoglycaemia less than 3.3 mmol/l was 67.7 and 26.2% (P < 0.001) in the two groups, respectively. Diabetes (odds ratio 2.88, CI 1.22 to 6.84) and the TGC protocol (odds ratio 7.39, CI 3.15 to 1735) were identified as independent risk factors for hypoglycaemia less than 3.3 mmol/l. Mechanical ventilation (odds ratio 4.33, CI 1.16 to 16.13), medical illness (odds ratio 2.88, CI 1.20 to 6.99) and hypoglycaemia (< 3.3 mmol/l) (odds ratio 299, CI 1.21 to 7.41) were independent factors associated with mortality. TGC is difficult to accomplish in routine intensive care unit settings and is associated with a significant increase in the incidence of hypoglycaemia. Hypoglycaemia < 3.3 mmol/l is an independent risk factor for in-hospital mortality.

Effect of sitaxsentan treatment on quality of life in pulmonary arterial hypertension.

In recent years new therapeutic options have been developed for the management of pulmonary arterial hypertension (PAH). Sitaxsentan is an oral, once daily, highly selective endothelin A receptor antagonist that recently demonstrated a positive effect on functional capacity and haemodynamics of PAH patients. The aim of this study is to evaluate the effect of sitaxsentan in the quality of life (QOL) of PAH patients. Twenty-three patients with idiopathic PAH or PAH associated to collagen vascular diseases were evaluated at baseline and after 16 weeks of treatment with sitaxsentan 100 mg orally, once daily. 6-min walk test distance (6MWD) and QOL questionnaire (QOLQ) (SF-36) were obtained at baseline and at week 16. There was a significant improvement in functional capacity evaluated by 6MWD (472 m vs. 490 m, p = 0.03) and also in the physical component of the QOLQ (p < 0.01). Evaluating each of the domains of the SF-36 QOLQ, those more related to physical capacity presented a significant increase while the domains related to the mental component presented a trend of improvement, without reaching statistical significance. Sitaxsentan improves QOL in patients with PAH mainly through the domains related to functional capacity.

Clinical response to sildenafil in pulmonary hypertension associated with Gaucher disease.

There are few reports of pulmonary hypertension in Gaucher disease. We report a patient who showed significant clinical improvement after treatment with sildenafil.