Effects of bumetanide on neonatal seizures: A systematic review of animal and human studies.

BACKGROUND: Bumetanide, an inhibitor of the sodium-potassium-chloride cotransporter-1, has been suggested as an adjunct to phenobarbital for treating neonatal seizures. METHODS: A systematic review of animal and human studies was conducted to evaluate the efficacy and safety of bumetanide for neonatal seizures. PubMed, Embase, CINAHL and Cochrane databases were searched in March 2023. RESULTS: 26 animal (rat or mice) studies describing 38 experiments (28 in-vivo and ten in-vitro) and two human studies (one RCT and one open-label dose-finding) were included. The study designs, methods to induce seizures, bumetanide dose, and outcome measures were heterogeneous, with only 4/38 experiments being in animal hypoxia/ischaemia models. Among 38 animal experiments, bumetanide was reported to have antiseizure effects in 21, pro-seizure in six and ineffective in 11. The two human studies (n = 57) did not show the benefits of bumetanide as an add-on agent to phenobarbital in their primary analyses, but one study reported benefit on post-hoc analysis. Overall, hearing impairment was detected in 5/37 surviving infants in the bumetanide group vs. 0/13 in controls. Four of the five infants with hearing impairment had received aminoglycosides concurrently. Other adverse effects reported were diuresis, mild-to-moderate dehydration, hypotension, and electrolyte disturbances. The studies did not report on long-term neurodevelopment. The certainty of the evidence was very low. CONCLUSION: Animal data suggest that bumetanide has inconsistent effects as an antiseizure medication in neonates. Data from human studies are scarce and raise some concerns regarding ototoxicity when given with aminoglycosides. Well conducted studies in animal models of hypoxic-ischaemic encephalopathy are urgently needed. Future RCTs, if conducted in human neonates, should have an adequate sample size, assess neurodevelopment, minimize using aminoglycosides, be transparent about the potential ototoxicity in the parent information sheet, conduct early hearing tests and have trial-stopping rules that include hearing impairment as an outcome.

Retinopathy of prematurity in India - what can we learn from the polio legacy?

Retinopathy of prematurity (ROP) is a vasoproliferative disease of the preterm retina that has the potential to cause vision impairment and blindness. Timely screening and treatment are hence critical for infants at risk for ROP. Screening for ROP is challenging in India owing to the limited resources, a vast at-risk population and lack of awareness among paediatricians and the public. Addressing ROP in India requires a comprehensive approach involving multiple sectors, considering the magnitude of the problem and the expected increase in need for ROP services due to the increased survival of preterm infants following improvements in neonatal care. The success of the Global Polio Eradication Initiative (GPEI) offers valuable lessons for improving ROP services in developing nations by applying its strategies. An approach for primary and secondary prevention of ROP is proposed, and the current challenges and a neonatal-led care model for ROP are discussed.

Retinopathy of prematurity and placental histopathology findings: A retrospective cohort study.

Aim: Retinopathy of prematurity (ROP) is a biphasic vaso-proliferative disease that has the potential to cause blindness. In addition to prematurity and hyperoxia, perinatal infection and inflammation have been reported to play a critical role in the pathogenesis of ROP. The aim of this study was to assess the association between placental inflammation and the severity of ROP. Methods: A retrospective study of infants (<30 weeks of gestational age) born at the King Edward Memorial Hospital, a tertiary perinatal center in Western Australia. Results: A total of 878 infants were included in this study (ROP stage 0-2 = 829; 3 or more = 49). The presence of maternal chorioamnionitis appeared to show signs of an association with reduced odds of severe ROP: mild chorioamnionitis OR=0.43 (95% CI: 0.17, 1.05) and severe chorioamnionitis OR=0.68 (95% CI: 0.29, 1.60). A strong association was observed for oxygen supplementation at 36 weeks (OR: 5.16; p < 0.001), exposure to postnatal steroids (OR: 6.65; p < 0.001), and receipt of platelet transfusion (OR: 8.21; p < 0.001). Conclusion: Maternal chorioamnionitis or fetal chorioamnionitis was associated with reduced odds of severe ROP. A strong association was found in infants who needed oxygen supplementation at 36 weeks and those who required steroids or platelets in the postnatal period.

Artificial intelligence for the diagnosis of retinopathy of prematurity: A systematic review of current algorithms.

BACKGROUND/OBJECTIVES: With the increasing survival of premature infants, there is an increased demand to provide adequate retinopathy of prematurity (ROP) services. Wide field retinal imaging (WFDRI) and artificial intelligence (AI) have shown promise in the field of ROP and have the potential to improve the diagnostic performance and reduce the workload for screening ophthalmologists. The aim of this review is to systematically review and provide a summary of the diagnostic characteristics of existing deep learning algorithms. SUBJECT/METHODS: Two authors independently searched the literature, and studies using a deep learning system from retinal imaging were included. Data were extracted, assessed and reported using PRISMA guidelines. RESULTS: Twenty-seven studies were included in this review. Nineteen studies used AI systems to diagnose ROP, classify the staging of ROP, diagnose the presence of pre-plus or plus disease, or assess the quality of retinal images. The included studies reported a sensitivity of 71%-100%, specificity of 74-99% and area under the curve of 91-99% for the primary outcome of the study. AI techniques were comparable to the assessment of ophthalmologists in terms of overall accuracy and sensitivity. Eight studies evaluated vascular severity scores and were able to accurately differentiate severity using an automated classification score. CONCLUSION: Artificial intelligence for ROP diagnosis is a growing field, and many potential utilities have already been identified, including the presence of plus disease, staging of disease and a new automated severity score. AI has a role as an adjunct to clinical assessment; however, there is insufficient evidence to support its use as a sole diagnostic tool currently.

Time to regain birth weight - a marker to predict the severity of retinopathy of prematurity?

BACKGROUND: Poor weight gain in the first few weeks of life has been studied as a predictor of retinopathy of prematurity (ROP). Our aim was to assess whether time taken to regain birthweight (BW) be used as an additional marker to identify infants with type 1 ROP. METHODS: In this retrospective study, preterm infants (< 27 weeks gestational age at birth) born during the period from 1/1/2010-31/12/2015 at a tertiary neonatal intensive care unit in Australia were included. Twenty-seven preterm infants with Type 1 ROP were identified. Controls (No ROP or ROP other than type 1) were matched with cases on gestational age at birth and BW (1:4 ratio). Data were collected from the database and medical records. RESULTS: The median (IQR) gestational age for Type 1 ROP and control groups were 24 (24-26) and 25 (24-26) weeks respectively and median (IQR) BW for Type 1 ROP and control groups were 675 (635-810) and 773 (666-884) grams respectively. Preterm infants with Type 1 ROP were more likely to be small for gestational age (SGA) (18.5% vs 3.7%, p = 0.015) and had increased weeks on oxygen therapy (median 11.9 vs 9.1, p = 0.028). Time to regain BW was longer in preterm infants with type 1 ROP than controls but did not reach statistical significance (median 9 vs 7 days, OR 1.08, 95% CI 1.00-1.17, p = 0.059) adjusted for SGA and duration of oxygen therapy. The area under the curve from the time to regain BW model with adjustment for SGA and duration of oxygen therapy was 0.73 (95% CI 0.62-0.83). CONCLUSION: We hypothesize that time to regain BW has potential to aid prediction of Type 1 ROP and this warrants further investigation in a larger prospective study.

The Use of Postnatal Weight Gain Algorithms to Predict Severe or Type 1 Retinopathy of Prematurity: A Systematic Review and Meta-analysis.

Importance: The currently recommended method for screening for retinopathy of prematurity (ROP) is binocular indirect ophthalmoscopy, which requires frequent eye examinations entailing a heavy clinical workload. Weight gain-based algorithms have the potential to minimize the need for binocular indirect ophthalmoscopy and have been evaluated in different setups with variable results to predict type 1 or severe ROP. Objective: To synthesize evidence regarding the ability of postnatal weight gain-based algorithms to predict type 1 or severe ROP. Data Sources: PubMed, MEDLINE, Embase, and the Cochrane Library databases were searched to identify studies published between January 2000 and August 2021. Study Selection: Prospective and retrospective studies evaluating the ability of these algorithms to predict type 1 or severe ROP were included. Data Extraction and Synthesis: Two reviewers independently extracted data. This meta-analysis was performed according to the Cochrane guidelines and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines. Main Outcomes and Measures: Ability of algorithms to predict type 1 or sever ROP was measured using statistical indices (pooled sensitivity, specificity, and summary area under the receiver operating characteristic curves, as well as pooled negative likelihood ratios and positive likelihood ratios and diagnostic odds ratios). Results: A total of 61 studies (>37 000 infants) were included in the meta-analysis. The pooled estimates for sensitivity and specificity, respectively, were 0.89 (95% CI, 0.85-0.92) and 0.57 (95% CI, 0.51-0.63) for WINROP (Weight, IGF-1 [insulinlike growth factor 1], Neonatal, ROP), 1.00 (95% CI, 0.88-1.00) and 0.60 (95% CI, 0.15-0.93) for G-ROP (Postnatal Growth and ROP), 0.95 (95% CI, 0.71-0.99) and 0.52 (95% CI, 0.36-0.68) for CHOP ROP (Children's Hospital of Philadelphia ROP), 0.99 (95% CI, 0.73-1.00) and 0.49 (95% CI, 0.03-0.74) for ROPScore, 0.98 (95% CI, 0.94-0.99) and 0.35 (95% CI, 0.22-0.51) for CO-ROP (Colorado ROP). The original PINT (Premature Infants in Need of Transfusion) ROP study reported a sensitivity of 0.98 (95% CI, 0.91-0.99) and a specificity of 0.36 (95% CI, 0.30-0.42). The pooled negative likelihood ratios were 0.19 (95% CI, 0.13-0.27) for WINROP, 0.0 (95% CI, 0.00-0.32) for G-ROP, 0.10 (95% CI, 0.02-0.53) for CHOP ROP, 0.03 (95% CI, 0.00-0.77) for ROPScore, and 0.07 (95% CI, 0.03-0.16) for CO-ROP. The pooled positive likelihood ratios were 2.1 (95% CI, 1.8-2.4) for WINROP, 2.5 (95% CI, 0.7-9.1) for G-ROP, 2.0 (95% CI, 1.5-2.6) for CHOP ROP, 1.9 (95% CI, 1.1-3.3) for ROPScore, and 1.5 (95% CI, 1.2-1.9) for CO-ROP. Conclusions and Relevance: This study suggests that weight gain-based algorithms have adequate sensitivity and negative likelihood ratios to provide reasonable certainty in ruling out type 1 ROP or severe ROP. Given the implications of missing even a single case of severe ROP, algorithms with very high sensitivity (close to 100%) and low negative likelihood ratios (close to zero) need to be chosen to safely reduce the number of unnecessary examinations in infants at lower risk of severe ROP.

Validation of WINROP (online prediction model) to identify severe retinopathy of prematurity (ROP) in an Australian preterm population: a retrospective study.

INTRODUCTION: Retinopathy of prematurity (ROP) is the most common disease leading to blindness in extreme preterm infants. Current screening guidelines recommend frequent eye examinations. There is a dearth of trained ophthalmologists for these frequent screening procedures. The ANZNN neonatal network report (2013) found that only 6.4% of all screened infants had severe ROP and less than half received treatment. WINROP (online prediction model, Sweden) uses the postnatal weight gain (surrogate marker for low insulin-like growth factor IGF-1 and poor retinal vascular growth) to identify ROP requiring treatment and aims to reduce the number of examinations. Our objective was to validate the WINROP model in an Australian cohort of preterm infants. METHODS: Birth weight, gestational age, and weekly weight measurements were retrieved retrospectively along with the final ROP outcomes and plotted on the online WINROP software. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value of WINROP were 85.7%, 59.0%, 6.98%, and 99.1% respectively for a cohort of 221 preterm infants (Median birth weight, 1040 g; Gestational age, 27.9 weeks). WINROP alarm was signaled in 42.6% of all infants. WINROP did not signal an alarm in one infant who needed treatment. This infant had intra ventricular hemorrhage grade 3-4 and temporary ventricular dilatation. CONCLUSIONS: This is the first Australian study validating WINROP model. Our findings suggest that it lacked sensitivity to be used alone. However, adjusting the algorithm for the Australian population may improve the efficacy and reduce the number of examinations when used along with the current screening guidelines.

Comparison of wide field imaging by nurses with indirect ophthalmoscopy by ophthalmologists for retinopathy of prematurity: a diagnostic accuracy study.

OBJECTIVES: Retinopathy of prematurity (ROP) is a vasoproliferative disease of the preterm retina with the potential to cause irreversible blindness. Timely screening and treatment of ROP are critical. Neonatal nurses trained in wide field digital retinal photography (WFDRP) for screening may provide a safe and effective strategy to reduce the burden of ophthalmologists in performing binocular indirect ophthalmoscopy (BIO). The objective of the study was to determine the diagnostic accuracy of WFDRP in the diagnosis of referral warranting ROP (RWROP). DESIGN: Prospective diagnostic accuracy study. SETTING: A tertiary neonatal intensive care unit in Perth, Western Australia. PARTICIPANTS: Preterm infants who fulfilled the Australian ROP screening criteria (gestational age (GA) <31 weeks, birth weight (BW) <1250 g). INTERVENTION: Sets of 5-6 images per eye (index test) were obtained within 24-48 hours prior to or after the BIO (reference standard), and uploaded onto a secured server. A wide field digital camera (RetCam, Natus, Pleasanton, California, USA) was used for imaging. A paediatric ophthalmologist performed the BIO. The ophthalmologists performing BIO versus reporting the images were masked to each other's findings. PRIMARY OUTCOME: The area under the receiver operating characteristic (ROC) curve was used as a measure of accuracy of WFDRP to diagnose RWROP. RESULTS: A total of 85 infants (mean BW; 973.43 g, mean GA; 29 weeks) underwent a median of two sessions of WFDRP. There were 188 episodes of screening with an average of five images per eye. WFDRP identified RWROP in 7.4% (14/188 sessions) of examinations. In one infant, BIO showed bilateral plus disease and WFDRP did not pick up the plus disease. WFDRP image interpretation had a sensitivity of 80%, specificity of 94.5% for the detection of RWROP. The 'area under the ROC curve' was 88% when adjusted for covariates. CONCLUSIONS: WFDRP by neonatal nurses was feasible and effective for diagnosing RWROP in our set up. TRIAL REGISTRATION NUMBER: ACTRN12616001386426.

Inter-rater reliability of amplitude-integrated EEG for the detection of neonatal seizures.

BACKGROUND: Amplitude-integrated electroencephalogram (aEEG) is being used increasingly for seizure detection in neonates. However, data regarding inter-rater reliability among neonatologists for the use of aEEG for the detection of neonatal seizures is lacking. METHODS: Term and late-preterm infants at risk of seizures were monitored simultaneously with 24-h video-electroencephalography (vEEG) and aEEG. vEEG was interpreted by an experienced neurologist. Five neonatologists with experience in aEEG interpretation from four different neonatal units interpreted aEEG recordings independently. The Brennan and Prediger kappa coefficient and Intra-class Correlation Coefficients (ICC) were used to assess inter-rater reliability between the neonatologists. RESULTS: Thirty-five infants at risk of seizure with gestational age at birth 35-42 weeks were recruited for the study after informed parental consent. vEEG detected seizures in seven infants with a total of 169 individual seizure episodes. Neonatologists detected seizures in 10 to 15 infants on aEEG. The sensitivities for the detection of individual seizures by neonatologists ranged from 18% to 38%. The inter-rater reliability for detection of: individual seizure was "fair" (kappa = 0.37; 95% CI: 0.32-0.42), infant with seizure was "moderate" (kappa = 0.60; 95% CI: 0.44-0.75), duration of individual seizure (ICC: 0.22; 95% CI: 0.18-0.28) and total duration of seizures in an infant (ICC: 0.46; 95% CI: 0.30-0.63) was "poor". The neonatologists missed 77-90% of the duration of seizures. CONCLUSION: The inter-rater reliability of aEEG for the detection of neonatal seizures was suboptimal. Even when interpreted by experienced and trained clinicians, seizure detection with aEEG has limitations and can miss large number and duration of seizures.

Duration of anaemia during the first week of life is an independent risk factor for retinopathy of prematurity.

AIM: This study evaluated the correlation between retinopathy of prematurity (ROP), anaemia and blood transfusions in extremely preterm infants. METHODS: We included 227 infants born below 28 weeks of gestation at King Edward Memorial Hospital, Perth, Australia, from 2014-2016. Birth characteristics and risk factors for ROP were retrieved, and anaemia and severe anaemia were defined as a haemoglobins of <110 g/L and <80 g/L, respectively. Logistic regression was used for the analysis. RESULTS: Retinopathy of prematurity treatment was needed in 11% of cases and the mean number of blood transfusions (p < 0.01), and mean number of weeks of anaemia (p < 0.001) and of severe anaemia (p < 0.05), had positive associations with ROP cases warranting treatment. In the multivariate logistic regression analysis, the best-fit model of risk factors included anaemic days during first week of life, with an odds ratio (OR) of 1.46% and 95% confidence interval (CI) of 1.16-1.83 (p < 0.05), sepsis during the first 4 weeks of life (OR 3.14, 95% CI 1.10-9.00, p < 0.05) and days of ventilation (OR 1.03, 95% CI 1.01-1.06, p < 0.05). CONCLUSION: The duration of anaemia during the first week of life was an independent risk factor for ROP warranting treatment and preventing early anaemia may decrease this risk.

Using a modified Seldinger technique is an effective way of placing femoral venous catheters in critically ill infants.

AIM: Femoral venous catheters (FVCs) provide multilumen access in critically ill infants with difficult venous access. This study reports our experiences of using a modified Seldinger technique to insert FVCs in our neonatal unit. METHODS: This was a retrospective case series of 34 infants who had FVCs inserted using the modified Seldinger technique during a 4-year period. RESULTS: The median (range) post-natal age and weight at the time of insertion were 66 days (1-314) and 3080 g (865-8000). The FVC remained in situ for a median duration of 21 days (1-63). There were nine infants who died while the FVC remained in situ. The FVCs were removed from four infants due to complications. In three cases, they became dislodged, and in one case, the line became blocked. In 16 infants, the FVC was removed when it was no longer required and one infant was transferred out of the unit with the FVC in situ. Transient venous congestion of the distal limb occurred in four infants. In one infant, the FVC was accidently placed in the femoral artery and removed without complications. CONCLUSIONS: Femoral venous catheter insertion using a modified Seldinger technique appeared to provide alternate and immediate central venous access in critically ill infants.

Screening for retinopathy of prematurity (ROP) using wide-angle digital retinal photography by non-ophthalmologists: a systematic review.

Retinopathy of prematurity (ROP) is one of the leading and preventable causes of blindness. The investigation of choice for diagnosing ROP is binocular indirect ophthalmoscope (BIO) done by ophthalmologists. Since the number of ophthalmologists available to do BIO examination is limited, especially in developing countries, there is a need for an alternate, cheap, reliable and feasible test. Telemedicine imaging with Digital Retinal Photography (DRP) is one such alternate diagnostic test which can be performed easily by non-ophthalmologists, with adequate training. Our objective was to conduct a systematic review to evaluate the accuracy of DRP performed by trained personnel (non-ophthalmologists) in diagnosing clinically significant ROP. Medline, EMBASE, CINAHL and Cochrane databases were searched independently by two authors. Eligible studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2, an evidence-based tool for the assessment of quality in systematic reviews of diagnostic accuracy studies. Six were included in the review (three prospective; N=120, three retrospective; N=579). Studies had methodological limitations on QUADAS-2. Because of the heterogeneity of studies, data could not be pooled to derive single-effect size estimates for sensitivity and specificity. The included studies reported sensitivity of 45.5-100% with the majority being more than 90%; specificity 61.7-99.8% with the majority being more than 90%, positive predictive value 61.5-96.6% and negative predictive value of 76.9-100% for diagnosing clinically significant ROP. We conclude that diagnostic accuracy of DRP must be established in prospective studies with adequate sample size where DRP is compared against the simultaneously performed BIO examination.

Neonatal presentation of chromosome 9q33.2-q34.3 duplication.

Partial terminal duplication of chromosome 9 is a rare anomaly that is known to be associated with specific dysmorphic features. While having common characteristics, these patients also have inconsistent phenotypic features. These inconsistent features may be attributed to the length and the region of the duplicated segment of chromosome 9. We discuss a case of an infant with similar physical features to those previously reported including dysmorphology of the craniofacial region, hands and feet. However we also describe findings of malrotation and renal anomalies. Microarray demonstrated duplication of 9q33.2-q34.3 with normal parental karyotyping. This is the first reported case of duplication of this specific region of chromosome 9q and the phenotypic presentation represents a new constellation of clinical findings.

Global myocardial function is compromised in infants with pulmonary hypertension.

AIM: Persistent pulmonary hypertension of the newborn is a serious clinical entity with significant mortality and long-term morbidity. The objective was to study the profile of myocardial function, especially diastolic function, in term infants with pulmonary hypertension treated with nitric oxide. METHODS: Unit electronic database was accessed to identify infants ≥34 weeks gestation who were administered nitric oxide for pulmonary hypertension over the last 6 years. Medical records and archived echocardiographic images were retrieved. Those with no echocardiogram on the day of administration of nitric oxide, concomitant congenital heart disease or ≥2 weeks of age at the time of nitric administration were excluded. RESULTS: Low biventricular outputs were noted in >2/3rd infants. Tricuspid regurgitation was noted in 20/25 (80%) infants, and ductal shunt was bidirectional in the majority of cases. Right ventricular diastolic function was assessed by systolic to diastolic duration ratio; dysfunction was widely prevalent. CONCLUSIONS: A large percentage of infants were haemodynamically severely compromised. This is the first study to detail right ventricular diastolic dysfunction in infants with pulmonary hypertension and highlights the therapeutic role of milrinone, a lusitropic drug with myocardial relaxation properties. Comprehensive evaluation of cardiovascular haemodynamics can optimize clinical care.