Multicentre pilot study evaluation of lung ultrasound for the management of paediatric pneumonia in low-resource settings: a study protocol

Introduction: Pneumonia is the leading infectious cause of death among children under 5 years of age worldwide. However, pneumonia is challenging to diagnose. Lung ultrasound (LUS) is a promising diagnostic technology. Further evidence is needed to better understand the role of LUS as a tool for the diagnosis of childhood pneumonia in low-resource settings. Methods and analysis: This study aims to pilot LUS in Mozambique and Pakistan and to generate evidence regarding the use of LUS as a diagnostic tool for childhood pneumonia. Children with cough \u3c14 days with chest indrawing (n=230) and without chest indrawing (n=40) are enrolled. World Health Organization Integrated Management of Childhood Illness assessment is performed at enrolment, along with a chest radiograph and LUS examination. Respiratory and blood specimens are collected for viral and bacterial testing and biomarker assessment. Enrolled children are followed for 14 days (in person) and 30 days (phone call) post-enrolment with LUS examinations performed on Days 2, 6 and 14. Qualitative and quantitative data are also collected to assess feasibility, usability and acceptability of LUS among healthcare providers and caregivers. The primary outcome is LUS findings at enrolment with secondary outcomes including patient outcomes, repeat LUS findings, viral and bacterial test results, and patient status after 14 and 30 days of follow-up. Ethics and dissemination: This trial was approved by the Western Institutional Review Board as well as local ethics review committees at each site. We plan to disseminate study results in peer-reviewed journals and international conferences. Trial registration number: NCT03187067

Evaluation of non-invasive continuous physiological monitoring devices for neonates in Nairobi, Kenya: a research protocol

Introduction: Continuous physiological monitoring devices are often not available for monitoring high-risk neonates in low-resource settings. Easy-to-use, non-invasive, multiparameter, continuous physiological monitoring devices could be instrumental in providing appropriate care and improving outcomes for high-risk neonates in these low-resource settings. Methods and analysis: The purpose of this prospective, observational, facility-based evaluation is to provide evidence to establish whether two existing non-invasive, multiparameter, continuous physiological monitoring devices developed by device developers, EarlySense and Sibel, can accurately and reliably measure vital signs in neonates (when compared with verified reference devices). We will also assess the feasibility, usability and acceptability of these devices for use in neonates in low-resource settings in Africa. Up to 500 neonates are enrolled in two phases: (1) a verification and accuracy evaluation phase at Aga Khan University—Nairobi and (2) a clinical feasibility evaluation phase at Pumwani Maternity Hospital in Nairobi, Kenya. Both quantitative and qualitative data are collected and analysed. Agreement between the investigational and reference devices is determined using a priori-defined accuracy thresholds. Ethics and dissemination: This trial was approved by the Aga Khan University Nairobi Research Ethics Committee and the Western Institutional Review Board. We plan to disseminate research results in peer-reviewed journals and international conferences

Assessment of neonatal respiratory rate variability

Accurate measurement of respiratory rate (RR) in neonates is challenging due to high neonatal RR variability (RRV). There is growing evidence that RRV measurement could inform and guide neonatal care. We sought to quantify neonatal RRV during a clinical study in which we compared multiparameter continuous physiological monitoring (MCPM) devices. Measurements of capnography-recorded exhaled carbon dioxide across 60-s epochs were collected from neonates admitted to the neonatal unit at Aga Khan University-Nairobi hospital. Breaths were manually counted from capnograms and using an automated signal detection algorithm which also calculated mean and median RR for each epoch. Outcome measures were between- and within-neonate RRV, between- and within-epoch RRV, and 95% limits of agreement, bias, and root-mean-square deviation. Twenty-seven neonates were included, with 130 epochs analysed. Mean manual breath count (MBC) was 48 breaths per minute. Median RRV ranged from 11.5% (interquartile range (IQR) 6.8–18.9%) to 28.1% (IQR 23.5–36.7%). Bias and limits of agreement for MBC vs algorithm-derived breath count, MBC vs algorithm-derived median breath rate, MBC vs algorithm-derived mean breath rate were − 0.5 (− 2.7, 1.66), − 3.16 (− 12.12, 5.8), and − 3.99 (− 11.3, 3.32), respectively. The marked RRV highlights the challenge of performing accurate RR measurements in neonates. More research is required to optimize the use of RRV to improve care. When evaluating MCPM devices, accuracy thresholds should be less stringent in newborns due to increased RRV. Lastly, median RR, which discounts the impact of extreme outliers, may be more reflective of the underlying physiological control of breathing

Evaluation of Sibel’s Advanced Neonatal Epidermal (ANNE) wireless continuous physiological monitor in Nairobi, Kenya

Background: Neonatal multiparameter continuous physiological monitoring (MCPM) technologies assist with early detection of preventable and treatable causes of neonatal mortality. Evaluating accuracy of novel MCPM technologies is critical for their appropriate use and adoption. Methods: We prospectively compared the accuracy of Sibel’s Advanced Neonatal Epidermal (ANNE) technology with Masimo’s Rad-97 pulse CO-oximeter with capnography and Spengler’s Tempo Easy reference technologies during four evaluation rounds. We compared accuracy of heart rate (HR), respiratory rate (RR), oxygen saturation (SpO2), and skin temperature using Bland-Altman plots and root-mean-square deviation analyses (RMSD). Sibel’s ANNE algorithms were optimized between each round. We created Clarke error grids with zones of 20% to aid with clinical interpretation of HR and RR results. Results: Between November 2019 and August 2020 we collected 320 hours of data from 84 neonates. In the final round, Sibel’s ANNE technology demonstrated a normalized bias of 0% for HR and 3.1% for RR, and a non-normalized bias of -0.3% for SpO2 and 0.2°C for temperature. The normalized spread between 95% upper and lower limits-of-agreement (LOA) was 4.7% for HR and 29.3% for RR. RMSD for SpO2 was 1.9% and 1.5°C for temperature. Agreement between Sibel’s ANNE technology and the reference technologies met the a priori-defined thresholds for 95% spread of LOA and RMSD. Clarke error grids showed that all HR and RR observations were within a 20% difference. Conclusion: Our findings suggest acceptable agreement between Sibel’s ANNE and reference technologies. Clinical effectiveness, feasibility, usability, acceptability, and cost-effectiveness investigations are necessary for large-scale implementation

A double blind community-based randomized trial of Amoxicillin Versus Placebo for fast breathing Pneumonia in children aged 2-59 months in Karachi, Pakistan (RETAPP)

Background: Fast breathing pneumonia is characterized by tachypnoea in the absence of danger signs and is mostly viral in etiology. Current guidelines recommend antibiotic therapy for all children with fast breathing pneumonia in resource limited settings, presuming that most pneumonia is bacterial. High quality clinical trial evidence to challenge or support the continued use of antibiotics, as recommended by the World Health Organization is lacking. Methods/Design: This is a randomized double blinded placebo-controlled non-inferiority trial using parallel assignment with 1:1 allocation ratio, to be conducted in low income squatter settlements of urban Karachi, Pakistan. Children 2-59 months old with fast breathing, without any WHO-defined danger signs and seeking care at the primary health care center are randomized to receive either three days of placebo or amoxicillin. From prior studies, a sample size of 2430 children is required over a period of 28 months. Primary outcome is the difference in cumulative treatment failure between the two groups, defined as a new clinical sign based on preset definitions indicating illness progression or mortality and confirmed by two independent primary health care physicians on day 0, 1, 2 or 3 of therapy. Secondary outcomes include relapse measured between days 5-14. Modified per protocol analysis comparing hazards of treatment failure with 95 % confidence intervals in the placebo arm with hazards in the amoxicillin arm will be done. Discussion:This study will provide evidence to support or refute the use of antibiotics for fast breathing pneumonia paving a way for guideline change

Reservoir Cannulas for Pediatric Oxygen Therapy: A Proof-of-Concept Study

Hypoxemia is a complication of pneumonia—the leading infectious cause of death in children worldwide. Treatment generally requires oxygen-enriched air, but access in low-resource settings is expensive and unreliable. We explored use of reservoir cannulas (RCs), which yield oxygen savings in adults but have not been examined in children. Toddler, small child, and adolescent breathing profiles were simulated with artificial lung and airway models. An oxygen concentrator provided flow rates of 0 to 5 L/min via a standard nasal cannula (NC) or RC, and delivered oxygen fraction (FdO2) was measured. The oxygen savings ratio (SR) and absolute flow savings (AFS) were calculated, comparing NC and RC. We demonstrated proof-of-concept that pendant RCs could conserve oxygen during pediatric therapy. SR mean and standard deviation were 1.1±0.2 to 1.4±0.4, 1.1±0.1 to 1.7±0.3, and 1.3±0.1 to 2.4±0.3 for toddler, small child, and adolescent models, respectively. Maximum AFS observed were 0.3±0.3, 0.2±0.1, and 1.4±0.3 L/min for the same models. RCs have the potential to reduce oxygen consumption during treatment of hypoxemia in children; however, further evaluation of products is needed, followed by clinical analysis in patients

Performance of lung ultrasound in the diagnosis of pediatric pneumonia in Mozambique and Pakistan

Introduction: Improved pneumonia diagnostics are needed in low-resource settings (LRS); lung ultrasound (LUS) is a promising diagnostic technology for pneumonia. The objective was to compare LUS versus chest radiograph (CXR), and among LUS interpreters, to compare expert versus limited training with respect to interrater reliability.Methods: We conducted a prospective, observational study among children with World Health Organization (WHO) Integrated Management of Childhood Illness (IMCI) chest-indrawing pneumonia at two district hospitals in Mozambique and Pakistan, and assessed LUS and CXR examinations. The primary endpoint was interrater reliability between LUS and CXR interpreters for pneumonia diagnosis among children with WHO IMCI chest-indrawing pneumonia.Results: Interrater reliability was excellent for expert LUS interpreters, but poor to moderate for expert CXR interpreters and onsite LUS interpreters with limited training.Conclusions: Among children with WHO IMCI chest-indrawing pneumonia, expert interpreters may achieve substantially higher interrater reliability for LUS compared to CXR, and LUS showed potential as a preferred reference standard. For point-of-care LUS to be successfully implemented for the diagnosis and management of pneumonia in LRS, the clinical environment and amount of appropriate user training will need to be understood and addressed

Serial lung ultrasounds in pediatric pneumonia in Mozambique and Pakistan

Lung ultrasound (LUS) is a promising point-of-care imaging technology for diagnosing and managing pneumonia. We sought to explore serial LUS examinations in children with chest-indrawing pneumonia in resource-constrained settings and compare their clinical and LUS imaging courses longitudinally. We conducted a prospective, observational study among children aged 2 through 23 months with World Health Organization Integrated Management of Childhood Illness chest-indrawing pneumonia and among children without fast breathing, chest indrawing or fever (no pneumonia cohort) at 2 district hospitals in Mozambique and Pakistan. We assessed serial LUS at enrollment, 2, 6, and 14 days, and performed a secondary analysis of enrolled children\u27s longitudinal clinical and imaging courses. By Day 14, the majority of children with chest-indrawing pneumonia and consolidation on enrollment LUS showed improvement on follow-up LUS (100% in Mozambique, 85.4% in Pakistan) and were clinically cured (100% in Mozambique, 78.0% in Pakistan). In our cohort of children with chest-indrawing pneumonia, LUS imaging often reflected the clinical course; however, it is unclear how serial LUS would inform the routine management of non-severe chest-indrawing pneumonia