Influence of Early Total Enteral Feeding in Preterm Infants with Respiratory Distress Syndrome.

INTRODUCTION: Providing adequate nutrition in the management of preterm infants has been challenging. The objective of this secondary analysis of data from the randomized trial comparing "less invasive surfactant therapy (LISA) with InSurE method of surfactant administration" is to demonstrate the feasibility of early total enteral feeding (ETEF) in hemodynamically stable preterm neonates on respiratory support and to examine the factors associated with failure of ETEF. METHODS: Secondary analysis of a randomized controlled trial comparing "LISA versus InSurE among preterm infants between 26 and 34 weeks of gestation" enrolled 150 infants with 117 being hemodynamically stable. ETEF without any parenteral supplementation was started on day 1 of life using the mother's own milk (MoM) or donor human milk (<32 weeks of GA) and MoM or preterm formula (33-34 weeks of GA). The data were analyzed to assess the proportion of babies developing feed intolerance and/or necrotizing enterocolitis (NEC) and factors associated with failure of ETEF. All Infants were assessed for the day of attainment of full enteral feeding defined as receiving and tolerating 150 mL/kg of enteral feeds per day. RESULTS: Out of these 117 babies, 102 tolerated ETEF, and 15 had one or more episodes of FI requiring total parenteral nutrition, but none developed NEC till discharge or death. On the assessment of possible factors associated with ETEF failure, there were no differences in baseline characteristics but statistically significantly increased incidence of culture-positive sepsis as well as the requirement of antibiotic therapy for possible sepsis (early as well as late-onset sepsis) in babies with failure of ETEF. The babies who tolerated ETEF achieved full enteral feeding (150 mL/kg/day) significantly earlier (5.48 ± 1.1 days) compared to those with ETEF failure (7 ± 3.4 days) (p 0.001). The time to regain birth weight was earlier in the ETEF group without significant differences in growth parameters. There was also a reduction in the duration of hospital stay in babies who tolerated ETEF, but both these results were not statistically significant. CONCLUSION: ETEF is feasible in preterm neonates with respiratory distress syndrome who are on respiratory support. It resulted in earlier attainment of full enteral feeds and decreased the incidence of sepsis with reduced antibiotic usage.

Role of central endpoint adjudication and challenges in trials on neonatal sepsis-a case of ProSPoNS trial.

Despite progress in reducing the infant mortality in India, the neonatal mortality decline has been slower, necessitating concerted efforts to achieve Sustainable Development Goal-3. A promising strategy aiming to prevent neonatal sepsis in high-risk, vulnerable, low birth weight neonates through an innovative intervention includes probiotic supplementation. This article communicates the decision by the ProSPoNS trial investigators to establish a Central Endpoint Adjudication Committee (CEAC) as an addendum to the protocol published in Trials in 2021 for the purpose of clarifying the primary outcome. In the published protocol, the study hypothesis and primary objective are based on "sepsis," the primary outcome has been specified as sepsis/PSBI, whereas the sample size estimation was performed based on the "physician diagnosed sepsis." To align all the three above, the investigators meeting, held on 17th-18th August 2023, at MGIMS Sevagram, Wardha, deliberated and unanimously agreed that "physician diagnosed sepsis" is the primary study outcome which includes sepsis/PSBI. The CEAC, chaired by an external subject expert and members including trial statistician, a microbiologist, and all site principal investigators will employ four criteria to determine "physician diagnosed sepsis": (1) blood culture status, (2) sepsis screen status, (3) PSBI/non-PSBI signs and symptoms, and (4) the clinical course for each sickness event. Importantly, this clarification maintains consistency with the approved study protocol (Protocol No. 5/7/915/2012 version 3.1 dated 14 Feb 2020), emphasizing the commitment to methodological transparency and adherence to predefined standards. The decision to utilize the guidance of a CEAC is recommended as the gold standard in multicentric complex clinical trials to achieve consistency and accuracy in assessment of outcomes.Trial registrationClinical Trial Registry of India (CTRI) CTRI/2019/05/019197. Registered on 16 May 2019.

Nutrition and the gut-brain axis in neonatal brain injury and development.

Early nutritional exposures, including during embryogenesis and the immediate postnatal period, affect offspring outcomes in both the short- and long-term. Alterations of these modifiable exposures shape the developing gut microbiome, intestinal development, and even neurodevelopmental outcomes. A gut-brain axis exists, and it is intricately connected to early life feeding and nutritional exposures. Here, we seek to discuss the (1) origins of the gut-brain access and relationship with neurodevelopment, (2) components of human milk (HM) beyond nutrition and their role in the developing newborn, and (3) clinical application of nutritional practices, including fluid management and feeding on the development of the gut-brain axis, and long-term neurodevelopmental outcomes. We conclude with a discussion on future directions and unanswered questions that are critical to provide further understanding and insight into how clinicians and healthcare providers can optimize early nutritional practices to ensure children not only survive, but thrive, free of neurodevelopmental impairment.

Comparison between the for-profit human milk industry and nonprofit human milk banking: Time for regulation?

Human milk (HM) is a highly evolutionary selected, complex biofluid, which provides tailored nutrition, immune system support and developmental cues that are unique to each maternal-infant dyad. In the absence of maternal milk, the World Health Organisation recommends vulnerable infants should be fed with screened donor HM (DHM) from a HM bank (HMB) ideally embedded in local or regional lactation support services. However, demand for HM products has arisen from an increasing awareness of the developmental and health impacts of the early introduction of formula and a lack of prioritisation into government-funded and nonprofit milk banking and innovation. This survey of global nonprofit milk bank leaders aimed to outline the trends, commonalities and differences between nonprofit and for-profit HM banking, examine strategies regarding the marketing and placement of products to hospital and public customers and outline the key social, ethical and human rights concerns. The survey captured information from 59 milk bank leaders in 30 countries from every populated continent. In total, five companies are currently trading HM products with several early-stage private milk companies (PMCs). Products tended to be more expensive from PMC than HMB, milk providers were financially remunerated and lactation support for milk providers and recipients was not a core function of PMCs. Current regulatory frameworks for HM vary widely, with the majority of countries lacking any framework, and most others placing HM within food legislation, which does not include the support and care of milk donors and recipient prioritisation. Regulation as a Medical Product of Human Origin was only in place to prevent the sale of HM in four countries; export and import of HM was banned in two countries. This paper discusses the safety and ethical concerns raised by the commodification of HM and the opportunities policymakers have globally and country-level to limit the potential for exploitation and the undermining of breastfeeding.

Target product profiles for diagnosis of sepsis: Proposing a new approach for diagnostic innovation.

Background & objectives: Sepsis, including neonatal sepsis, remains a prevalent cause of morbidity and mortality in low- and middle-income countries such as India, representing 85 per cent of all sepsis-related deaths globally. Early diagnosis and timely initiation of treatment is challenging due to non-specific clinical manifestations and non-availability of rapid diagnostic tests. There is an urgent need for affordable diagnostics with fast turnaround time catering to the needs of end-users. Target product profiles (TPPs) have been found instrumental in developing 'fit-for-use' diagnostics, thus reducing the time taken to facilitate development and improving diagnosis. Hitherto, no such guidance or criteria has been defined for rapid diagnostics for sepsis/neonatal sepsis. We propose an innovative approach for developing the diagnostics for sepsis screening and diagnosis which can be utilized by diagnostic developers in the country. Methods: Thr@ee-round Delphi method, including two online surveys and one virtual consultation, was adopted to define criteria for minimum and optimum attributes of TPPs and build consensus on characteristics. Expert panel (n=23) included infectious disease physicians, public health specialists, clinical microbiologists, virologists, researchers/scientists and technology experts/innovators. Results: We present a three-component product profile for sepsis diagnosis, (i) screening with high sensitivity, (ii) detection of aetiological agent, and (iii) profiling of antimicrobial susceptibility/resistance, in adults and neonates with an option of testing different considerations. An agreement of >75 per cent was achieved for all TPP characteristics by Delphi. These TPPs are tailored to the Indian healthcare settings and can also be extrapolated to other resource-constraint and high-disease burden settings. Interpretation & conclusions: Diagnostics developed using these TPPs will facilitate utilization of invested resources leading to development of the products that have potential to ease the economic burden on patient and save lives.

New WHO Recommendations for the Care of Preterm and Low Birth Weight Infants - A Potential Strategy to Transform the Current Healthcare Needs of Neonates.

Despite major advances in the field of maternal and child health, preterm and lowbirth neonates still carry a substantial burden of both mortality and morbidity, especially in low and middle-income countries. In view of accumulating new evidence, there was a felt need for updating and expanding the previous World Health Organization recommendations of 2015. The new evidence-based recommendations for care of the preterm or low birthweight infant consist of 25 recommendations and one good practice statement and were published on 15 November, 2022. We herein provide the key recommendations for the benefit of the readers.

Procalcitonin for Detecting Culture-Positive Sepsis in Neonates: A Prospective, Multicenter Study.

INTRODUCTION: It is unclear if serum procalcitonin (PCT) estimated at sepsis suspicion can help detect culture-positive sepsis in neonates. We evaluated the diagnostic performance of PCT in culture-positive sepsis in neonates. METHODS: This was a prospective study (February 2016 to September 2020) conducted in four level-3 units in India. We enrolled neonates suspected of sepsis in the first 28 days of life. Neonates with birth weight <750 g, asphyxia, shock, and major malformations were excluded. Blood for PCT assay was drawn along with the blood culture at the time of suspicion of sepsis and before antibiotic initiation. The investigators labeled the neonates as having culture-positive sepsis or "no sepsis" based on the culture reports and clinical course. PCT assay was performed by electrochemiluminescence immunoassay, and the clinicians were masked to the PCT levels while assigning the label of sepsis. Primary outcomes were the sensitivity, specificity, and likelihood ratios to identify culture-positive sepsis. RESULTS: The mean birth weight (SD) and median gestation (IQR) were 2,113 (727) g and 36 (32-38) weeks, respectively. Of the 1,204 neonates with eligible cultures, 155 (12.9%) had culture-positive sepsis. Most (79.4%) were culture-positive within 72 h of birth. The sensitivity, specificity, and positive and negative likelihood ratios at 2 ng/mL PCT threshold were 52.3% (95% confidence interval: 44.1-60.3), 64.5% (60.7-68.1), 1.47 (1.23-1.76), and 0.74 (0.62-0.88), respectively. Adding PCT to assessing neonates with 12.9% pretest probability of sepsis generated posttest probabilities of 18% and 10% for positive and negative test results, respectively. CONCLUSION: Serum PCT did not reliably identify culture-positive sepsis in neonates.

Challenges in the Implementation of the NeoOBS Study, a Global Pragmatic Observational Cohort Study, to Investigate the Aetiology and Management of Neonatal Sepsis in the Hospital Setting.

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

Neonatal Meningitis Secondary to Elizabethkingia meningoseptica Infection.

Introduction: Elizabethkingia meningoseptica, a rare cause of sepsis and meningitis in neonates, often associated with a wide spectrum of clinical presentation. The objective of the study was to describe the clinical characteristics and outcome of neonates, who developed meningitis secondary to Elizabethkingia meningoseptica infection at a tertiary care Neonatal unit in India. Methods: This retrospective study was conducted in the neonatal unit of a tertiary care hospital in New Delhi. The clinical data including demographic data, clinical presentation, management, and outcome data were collected and analyzed. Results: During the study, 7 neonates with meningitis secondary to Elizabethkingia infection were identified. Majority of the neonates were preterm with a median gestational age of 31 (interquartile range: 29-33.5) weeks and a median birth weight of 1250 g (interquartile range: 1024-2065). The median age of onset of symptoms was 7 days. Lethargy (100%), apnea (85%), seizure (71%), and feeding difficulties (42%) were the common clinical presentations. Overall mortality during the period was 28.5%, and 60% of the survivor developed hydrocephalus. Isolated strains were resistant to the commonly used antibiotics (piperacillin-tazobactam, aminoglycosides, meropenem, and colistin) effective against Gram-negative organisms. The environmental screening was done but the potential source of infection could not be identified conclusively. Conclusion: Meningitis in neonates caused by Elizabethkingia represents a potentially life-threatening infection and is often associated with significant neurological impairment, especially in premature neonates. A prolonged duration of antibiotic therapy, longer hospital stay, and likelihood of adverse neurologic sequelae during the hospital stay and follow-up should be anticipated in such cases of meningitis.

SCOPE: Surveillance of COVID-19 in pregnancy- results of a multicentric ambispective case-control study on clinical presentation and maternal outcomes in India between April to November 2020.

OBJECTIVE: To determine the clinical manifestations, risk factors, treatment modalities and maternal outcomes in pregnant women with lab-confirmed COVID-19 and compare it with COVID-19 negative pregnant women in same age group. DESIGN: Multicentric case-control study. DATA SOURCES: Ambispective primary data collection through paper-based forms from 20 tertiary care centres across India between April and November 2020. STUDY POPULATION: All pregnant women reporting to the centres with a lab-confirmed COVID-19 positive result matched with controls. DATA QUALITY: Dedicated research officers extracted hospital records, using modified WHO Case Record Forms (CRF) and verified for completeness and accuracy. STATISTICAL ANALYSIS: Data converted to excel files and statistical analyses done using STATA 16 (StataCorp, TX, USA). Odds ratios (ORs) with 95% confidence intervals (CI) estimated using unconditional logistic regression. RESULTS: A total of 76,264 women delivered across 20 centres during the study period. Data of 3723 COVID positive pregnant women and 3744 age-matched controls was analyzed. Of the positive cases 56·9% were asymptomatic. Antenatal complications like preeclampsia and abruptio placentae were seen more among the cases. Induction and caesarean delivery rates were also higher among Covid positive women. Pre-existing maternal co-morbidities increased need for supportive care. There were 34 maternal deaths out of the 3723(0.9%) positive mothers, while covid negative deaths reported from all the centres were 449 of 72,541 (0·6%). CONCLUSION: Covid-19 infection predisposed to adverse maternal outcomes in a large cohort of Covid positive pregnant women as compared to the negative controls.

Assessment of Change in Practice of Routine Tracheal Suctioning Approach of Non-Vigorous Infants Born through Meconium-Stained Amniotic Fluid: A Pragmatic Systematic Review and Meta-Analysis of Evidence outside Randomized Trials.

AIM: The 2015 recommendation of the International Liaison Committee on Resuscitation of no routine tracheal suctioning in non-vigorous neonates born through meconium-stained amniotic fluid (MSAF) was based on very low certainty of evidence (CoE) necessitating ongoing monitoring. The aim of this systematic review was to perform a meta-analysis of observational studies comparing the effect of implementing immediate resuscitation without routine tracheal suctioning versus with routine suctioning in neonates born through MSAF. METHODS: MEDLINE, Embase, CENTRAL, and Web of Science were searched. Observational studies with a before-and-after design were included. Two authors extracted data independently. CoE based on GRADE recommendations was performed. RESULTS: 13 studies were included. Clinical benefit or harm could not be excluded for the composite primary outcome of mortality or requirement of extracorporeal membranous oxygenation (ECMO) (relative risk, 95% confidence interval: 0.74 [0.47-1.17]), and mortality (0.68 [0.42-1.11]). "Routine tracheal suctioning" epoch had possibly lesser risk of meconium aspiration syndrome (MAS) when compared to "no routine tracheal suctioning" epoch (0.68 [0.47-0.99]). "Routine tracheal suctioning" epoch also possibly had a lower risk of hospital admission for respiratory symptoms, requirement of non-invasive respiratory support, invasive mechanical ventilation, surfactant treatment, air leak, and low-flow oxygen therapy. Clinical benefit or harm could not be excluded for the outcome of mortality or ECMO among those diagnosed with MAS (1.09 [0.86-1.39]), but "routine tracheal suctioning" was possibly associated with lower risk of respiratory morbidities among those diagnosed with MAS. The CoE was very low for most of the outcomes evaluated. CONCLUSIONS: Due to the very low CoE for the outcomes evaluated, no definitive conclusions can be drawn warranting the need for additional studies.

Less invasive surfactant administration via infant feeding tube versus InSurE method in preterm infants: a randomized control trial.

There is growing evidence that less invasive surfactant administration (LISA) is a better alternative to the standard Intubate-surfactant-extubate (InSurE) procedure in spontaneously breathing preterm infants with RDS. The infant feeding tube is easily available and cost-effective in comparison to special catheters used for surfactant administration in various studies on LISA and cost-effective health care is the need of the hour for countries like ours which are Low and middle-income countries(LMICs).The present study was planned to compare the total duration of respiratory support in preterm babies between 26 to 34 weeks of gestation with RDS requiring surfactant therapy administered by LISA technique using an infant feeding tube or InSurE method. In this unblinded randomised controlled trial, 150 infants were allocated to LISA (n = 74) or InSurE group (n = 76). An 8F feeding tube was used for surfactant delivery in the LISA group. The primary outcome was the total duration of respiratory support required and secondary outcomes included the proportion of babies developing BPD, IVH, PDA, NEC, ROP, air leaks, CPAP failure, and those requiring a repeat dose of surfactant along with the duration of hospitalization, time to regain birth weight and Death. The baseline variables including birth weight and gestation age were similar in the two groups. Nearly 27% of the mothers did not receive any dose of antenatal steroids (ANS) while around 37% of the mothers received complete course of ANS. A high proportion of babies (57%) were delivered by cesarean section. Intrapharyngeal reflux was significantly more in babies who received surfactant with the LISA method in comparison to InSurE technique (32% v/s 3%, p < 0.001). There was no statistically significant difference in the primary outcome of the total duration of respiratory support in both groups with a median duration of 120 h, 95% CI (69-235), and p = 0.618. The need for invasive mechanical ventilation was significantly lower in the LISA group (p = 0.017) with RR (95% CI) 0.498 (0.259-0.958). The rate of CPAP failure was significantly lower in the LISA group (p = 0.005) with RR (95% CI) 0.55 (0.34-0.89). In this study, the total duration of hospital stay was reduced in the LISA group (19 days) compared to InSurE group (26 days), although the same was not statistically significant. LISA with an 8F feeding tube is feasible and an effective strategy for surfactant administration which resulted in a significant reduction in CPAP failure and the need for invasive mechanical ventilation.Trial registration: www.ctri.nic.in id CTRI/2020/05/025360. Trial was registered at CTRI on 26/05/2020. First case of trial was enrolled on 28/05/2020.

Sequential interventions to maintain the safety and service provisions of human milk banking in India: keeping up with the call to action in response to the COVID-19 pandemic.

BACKGROUND: WHO recommends donor milk as the next best choice if Mothers' own milk (MOM) is unavailable. At our milk bank, during the COVID 19 pandemic, we observed a steep decline in the collection of donor milk, while Pasteurised Donor human milk (PDHM) demand increased. This called for active intervention. METHODS: We employed the quasi-experimental quality improvement initiative. During September 2020 (baseline period) the team members identified modifiable bottlenecks and suggested interventions (using WhatsApp to increase follow up, telehealth and digital tools) which were implemented in October 2020 and the impact was evaluated till March 2021. The SMART aim was "to meet the demand (estimated as 15,000 ml/month) of donor milk for adjoining 80-bedded NICU". Process measures were; daily amount of donor milk collected, pasteurized donor milk disbursed to NICU, number of donors and frequency of donations. The balancing measure was that the collection of donor milk should not undermine the provision of freshly expressed MOM for babies. RESULTS: Collection of donor milk increased by 180% from baseline during the Intervention phase. This was sustained throughout the sustenance phase (November 2020 and March 2021) with an average monthly collection of 16,500 ml. Strikingly, the increased follow-up of mothers with emphasis on MOM decreased the NICU's donor milk requirement from 13,300 ml (baseline) to 12,500 ml (intervention) to 8,300 ml (sustenance). Monitoring of daily MOM used in the NICU revealed a 32% surge from 20,000 ml (baseline) to 27,000 ml (intervention) sustained at 25,000 ml per month. CONCLUSION: By improving the provisions of human milk banks, near-exclusive human milk feeding can be ensured even during the pandemic time.

Prenatal Ultrasound Markers: A Comparative Study for Prediction of Respiratory Distress in Early Preterm Newborns.

Purpose of Study: This study aimed to compare the prenatal ultrasound parameters- fetal lung biometry and pulmonary artery Doppler in preterm newborns for prediction of respiratory distress (RD). Methods: A prospective analytic study was conducted in Department of Obstetrics and Gynecology in collaboration with Department of Neonatalogy. Fetal ultrasound and Doppler parameters were evaluated in women predisposed to have preterm delivery at or before 34 weeks. The neonates were followed for occurrence of RD. Result: Out of 100 study population, neonates who developed RD were taken as cases (n = 36) and rest were grouped as controls (n = 64). The gestational age at delivery, mean birth weight and Apgar score were significantly less in cases than controls. All the fetal lung biometric parameters were significantly less in cases than controls (p value < 0.001). The fetal lung volume had highest sensitivity (72.22%) and negative predictive value (83%). The right lung area had highest specificity (89%) and positive predictive value (72%). Among the Doppler parameters, the At/Et ratio showed high degree of accuracy (68%). The sensitivity and specificity were 55.56% and 75%, respectively. The positive and negative predictive values were 72% and 60%, respectively. Conclusions: Both fetal lung biometry and pulmonary artery Doppler offer an excellent noninvasive approach for assessment of fetal lung maturity, clinically assessed by RD. On comparison of all the ultrasound parameters, fetal lung volume and At/Et ratio showed highest degree of accuracy in prediction of RD.

Outcomes of Nonvigorous Neonates Born through Meconium-Stained Amniotic Fluid after a Practice Change to No Routine Endotracheal Suctioning from a Developing Country.

OBJECTIVE: The International Liaison Committee on Resuscitation (ILCOR) 2015 gave a weak recommendation based on low certainty of evidence against routine endotracheal (ET) suctioning in non-vigorous (NV) neonates born through meconium-stained amniotic fluid (MSAF) and suggested for immediate resuscitation without direct laryngoscopy. A need for ongoing surveillance post policy change has been stressed upon. This study compared the outcomes of NV MSAF neonates before and after implementation of the ILCOR 2015 recommendation. STUDY DESIGN: This was a prospective cohort study of term NV MSAF neonates who underwent immediate resuscitation without ET suctioning (no ET group, July 2018 to June 2019, n = 276) compared with historical control who underwent routine ET suction (ET group, July 2015 to June 2016, n = 271). RESULTS: Baseline characteristics revealed statistically significant higher proportion of male gender and small for gestational age neonates in the prospective cohort. There was no significant difference in the incidence of primary outcome of meconium aspiration syndrome (MAS) between the groups (no ET group: 27.2% vs ET group: 25.1%; p = 0.57). NV MSAF neonates with hypoxic ischemic encephalopathy (HIE) was significantly lesser in the prospective cohort (no ET group: 19.2% vs ET group: 27.3%; p = 0.03). Incidence of air leaks and need for any respiratory support significantly increased after policy change. In NV MSAF neonates with MAS, need for mechanical ventilation (MV) (no ET group: 24% vs ET group: 39.7%; p = 0.04) and mortality (no ET group: 18.7% vs ET group: 33.8%; p = 0.04) were significantly lesser. CONCLUSION: Current study from a developing country indicates that immediate resuscitation and no routine ET suctioning of NV MSAF may not be associated with increased risk of MAS and may be associated with decreased risk of HIE. Increased requirement of any respiratory support and air leak post policy change needs further deliberation. Decreased risk of MV and mortality among those with MAS was observed. KEY POINTS: · Not performing ET suction in NV MSAF infants is not associated with increase in the incidence of MAS.. · Initiating immediate resuscitation without ET suctioning was associated with decreased risk of HIE but increased receipt of any respiratory support and air leak.. · Large multicentric trial is required to generate robust evidence..

Comparison of efficacy of a 7-day versus a 14-day course of intravenous antibiotics in the treatment of uncomplicated neonatal bacterial sepsis: study protocol of a randomized controlled non-inferiority trial.

BACKGROUND: Neonatal sepsis is a global public health problem. There is no consensus regarding the optimum duration of antibiotics for culture-proven neonatal sepsis. Published randomized controlled trials (RCTs) comparing shorter versus longer courses of antibiotics provide low-quality evidence with serious risk of bias. We hypothesized that among neonates with uncomplicated culture-proven sepsis, antibiotic duration of 7 days is not inferior to 14 days. METHODS: This is a multi-centric, parallel-group, stratified, block-randomized, active-controlled, non-inferiority trial with outcome assessment blinded. Stratification is by center and birth weight. Neonates weighing ≥1000 g at birth, with blood-culture-proven sepsis (barring Staphylococcus aureus and fungi), without conditions warranting > 14 days antibiotics, and who clinically remit, are enrolled in the RCT on day 7 of administration of sensitive antibiotics. They are randomly allocated to no further antibiotics (intervention arm: total 7 days) or 7 more days of the same antibiotics (control arm: total 14 days). Allocation is concealed by opaque, sealed envelopes. The primary outcome is "definite or probable relapse" within 21 days after antibiotic completion. Secondary outcomes include definite and probable relapses at various timepoints until day 35 post-randomization, secondary infections, and adverse events. The neonatologist adjudicating probable relapses and lab personnel are blinded. Three hundred fifty subjects will be recruited in each arm, assuming a non-inferiority margin of 7%, one-sided alpha error 5%, and power of 90%. Analysis will be per protocol and by intention-to-treat. An independent Data Safety Monitoring Board monitors adverse events and will perform one interim analysis when 50% of expected primary outcomes have occurred or 50% of subjects have completed follow-up, whichever is earlier. O'Brien-Fleming criteria will be used to stop for mid-term benefit and Pocock's to stop for mid-term harm. A priori subgroup analyses are planned by birth weight categories, gram-stain status of pathogens, and radiological pneumonia. DISCUSSION: This trial will provide evidence to guide practice regarding optimum duration of antibiotics for culture-proven neonatal bacterial sepsis. If a 7-day regime is proved to be non-inferior to a 14-day regime, it is likely to reduce hospital stay, costs, adverse effects of drugs, and nosocomial infections. TRIAL REGISTRATION: Clinical Trials Registry India CTRI/2017/09/009743 . Registered on 13 September 2017.