#005 - Journal Club - The latest research in neonatology (September 10th 2025)

In this episode of The Incubator India Podcast, hosts Dr. Anita Singh and Dr. Akanksha Verma review six recent studies led by Indian researchers that address key challenges in neonatal care.

The discussion begins with a randomized trial from SGPGI Lucknow comparing nasal DuoPAP with CPAP in preterm infants with respiratory distress syndrome. While DuoPAP was non-inferior to CPAP, it reduced the need for surfactant. A second trial from Safdarjung Hospital and PGI Chandigarh asked whether CPAP improves outcomes over oxygen hood therapy in mild to moderate meconium aspiration syndrome; most babies were managed safely with oxygen alone.

Attention then turns to neonatal shock. A study from AIIMS Rishikesh compared norepinephrine with dopamine as first-line agents, while a trial from PGI Chandigarh tested early hydrocortisone alongside vasoactive support. Both reflect the difficulty of improving survival in the setting of multidrug-resistant gram-negative sepsis but point toward norepinephrine as a safer choice.

The hosts also highlight findings from a multicenter Lancet Global Health study documenting the burden of sepsis and resistance patterns in district hospitals. The episode concludes with a QI project from St. John’s Bangalore, showing how structured implementation can improve “golden hour” care for preterm infants.

The articles covered on today’s episode of the podcast can be found here

1)Kaur H, Singh A, Naranje KM, Gupta G, Solanki PS, Mishra P. Nasal DUOPAP vs nasal continuous positive airway pressure in preterm neonates with respiratory distress syndrome - A randomized control trial. Early Hum Dev. 2025;207:106284. doi:10.1016/j.earlhumdev.2025.106284

https://linkinghub.elsevier.com/retrieve/pii/S0378-3782(25)00094-5

2)Mustaqeem A, Yadav A, Kumar J, Debata P. Continuous positive airway pressure versus conventional oxygen therapy in meconium aspiration syndrome: a randomized controlled trial. J Trop Pediatr. 2025;71(2):fmaf002. doi:10.1093/tropej/fmaf002

https://academic.oup.com/tropej/article-lookup/doi/10.1093/tropej/fmaf002

3)Mazhari MYA, Priyadarshi M, Singh P, Chaurasia S, Basu S. Norepinephrine versus Dopamine for Septic Shock in Neonates: A Randomized Controlled Trial. J Pediatr. 2025;282:114599. doi:10.1016/j.jpeds.2025.114599

https://linkinghub.elsevier.com/retrieve/pii/S0022-3476(25)00139-8

4)Dudeja S, Saini SS, Sundaram V, Dutta S, Sachdeva N, Kumar P. Early hydrocortisone verses placebo in neonatal shock- a double blind Randomized controlled trial. J Perinatol. 2025;45(3):342-349. doi:10.1038/s41372-025-02222-3

https://doi.org/10.1038/s41372-025-02222-3

5)Jain K, Kumar V, Plakkal N, et al. Multidrug-resistant sepsis in special newborn care units in five district hospitals in India: a prospective cohort study. Lancet Glob Health. 2025;13(5):e870-e878. doi:10.1016/S2214-109X(24)00564-3

https://linkinghub.elsevier.com/retrieve/pii/S2214-109X(24)00564-3

6)Amuji N, Appaji Rao S, Yemmethimmanahalli Nagaraju P, Gautham Suresh K, Steven S, Bada Shekharappa C. Improving the quality of care for preterm infants in the golden hour. BMJ Open Qual. 2025;14(1):e002277. Published 2025 Mar 23. doi:10.1136/bmjoq-2023-002277

https://bmjopenquality.bmj.com/lookup/pmidlookup?view=long&pmid=40122573

Transcript

Akanksha (00:03.463)

Hello and welcome back to Incubator India. It's always such a joy to connect with you through this podcast. I am Dr. Akanksha and I'm delighted to have you with us today for another engaging conversation. I hope you're all doing well. And here in Lucknow, it's actually raining as we record with that lovely monsoon weather outside. It's been about three months since our last episode and it feels wonderful to reconnect on such a refreshing day.

What say Dr Anita?

Anita Singh (00:35.886)

Hello everyone, I am Dr. Anita and it is such a pleasure to join you for this journal club edition. And yes, I have to say Akanksha, the mood is perfectly set with the picture of rains in Lucknow. It's really is the kind of weather where sitting down for the thoughtful discussion feels just right.

Akanksha (00:56.069)

Yeah, I perfectly right. without any further delay, so today's episode is a special journal club edition again. And we've lined up some six important studies led by the Indian authors. We'll be covering respiratory support strategies for both preterm and term babies, new insights into shock management, sepsis epidemiology from district hospitals.

and finally a quality improvement initiative that shows how implementation science can transform care at the bedside.

Anita Singh (01:32.938)

Exactly! Think of this as guided discussion. We will walk you through each study, reflect on the methods and findings and highlight the practical takeaways for everyday NICU practice. So settle in, listen closely and let's get started with our very first paper of the episode.

Akanksha (01:53.011)

Absolutely. So let's start with a study that's really close to us from our own department here at SGPGI Lucknow and recently published in Early Human Development. The trial looked at a very practical question that we face every day. When managing preterm babies with respiratory distress syndrome, is nasal duopap any better than nasal CPAP?

Anita Singh (02:21.986)

Yeah, this was an open-labeled RCT designed as non-inferiority study. The team enrolled preterm VPs less than 35 weeks of gestation who had significant respiratory distress, which was defined by SAS score of 4 or more and randomized them to either nasal duopap or standard CPAP. The allocation was done using sealed opaque envelopes and although the intervention could not be blinded,

the outcome assessors and statisticians were blinded which was a strength.

Akanksha (02:54.449)

Yes, and I think the sample size was 122 babies, if I'm not wrong, 61 in each arm. That number was calculated based obviously on earlier studies showing differences in NIV failure rates with 90 % power and 5 % alpha error. But here's a behind the scenes insight. Recruitment was a real challenge. The study period spanned from February 2020

to June 2024, meaning COVID hit right in the middle. So that slowed admissions, made parental concerns harder, and even day-to-day NICU functioning was disrupted. So actually completing the trial with full follow-up of all randomized babies was a major achievement in itself. What say, Dr. Anita?

Anita Singh (03:47.778)

Yeah, I would say that was a difficult task because of the interruption due to COVID and the staggering because of the poor enrollment during the period. But subsequently, it cast up and it was ultimately finished with the achievement of the sample size for the required completion. So it was all about the teamwork for the purpose.

Akanksha (04:14.995)

Absolutely and that deserves to be said out loud. Now coming to the results, the primary outcome was the need for mechanical ventilation within the first 120 hours of life. The results actually showed no significant difference. The primary outcome of the need for mechanical ventilation was 18 % in the nasal DuOPAP group.

versus 19.7 % in the CPAP group. So statistically, it was not significant. So DuOPAP was non-inferior, but obviously not superior as well.

Anita Singh (04:55.511)

Yeah. that was the main outcome but let's see there is something else or not. So when we looked at the secondary outcome that was the need of surfactant it was significantly lower in the DOPAP group. You can see that it was 33 % compared to 45, 54 % with the standard CPAP with a significant VPP value. So it means that babies who were put on DuOPAP had fewer requirement of surfactant and it may ultimately translate into the

lower cost and of course also in terms of the procedural risk and the complication associated with the surfactant administration it can practically be helpful in the setups where the expertise for the such procedures are not available.

Akanksha (05:44.914)

Yes, I think very correctly said. mean, otherwise the groups were very similar. If we see all other parameters like the duration of non-invasive support, oxygen therapy, duration of hospital stay, rates of hemodynamically significant PDA, IVH grade three or four, necrotizing enterocolitis, BPD, ROP. So the other major outcomes were not significantly different.

Even mortality which was numerically lower in the DuoPAP group that was 10 percent compared to 21 percent in the CPAP group did not reach statistical significance.

Anita Singh (06:28.066)

Yes, so the strength of this study was a randomized design with proper concealment and inclusion of extremely preterm babies, making the results quite generalizable to the other setting because of the standardized protocols and severe perseverance to finish the recruitment despite COVID disruptions. So of course, the collaboration of the paramedical staff and the expertise of the researchers was good in this study.

Akanksha (06:47.376)

Absolutely.

Akanksha (06:59.463)

very correctly said. And if we talk of limitations, that included the high burden of sepsis and shock in the cohort from which over half the babies were affected, but which could have masked any subtle differences between the mode. But then that is something if we go on to do any similar study in the setting of LMIC

So, this would be a limitation or a challenge that every unit would be struggling. So, basically this is the basic parameter which will be actually be equally distributed between both arms. So, that should really not make a difference to the interventions that we are actually comparing. And also while surfactant requirement as you said

was lower, a cost effective analysis maybe that would have added a real world value to the study.

Anita Singh (08:04.46)

Yeah, dear Akanksha, being one of the primary author of this study, I would accept that the burden of sepsis and shock was something which is quite pertinent to be addressed and it is more so prevalent in the lower and middle income countries. However, it still gives the clear message that DuOPAP as a mode of respiratory support, it is safe and non-inferior to the CPAP.

Akanksha (08:35.379)

Absolutely, I think and that makes this study both relevant and memorable. And definitely I must say it is a trial that has, that is actually rooted in the Indian context, the settings that all of us day to day face and answers a very practical question. So with that, I think let's move on to our second paper.

And that would be.. so now let's shift the gaze from preterm RDS to term babies. Let's talk about Meconium Aspiration Syndrome or MAS. It's still one of the commonest reasons why term and near term babies land in the NICU. A big clinical dilemma is when a baby has MAS or Meconium Aspiration Syndrome with mild to moderate distress, should we straight away start CPAP?

or is conventional oxygen by hood enough? So, this new randomized controlled trial that we are going to discuss next is published in the Journal of Tropical Pediatrics this year and it came from the VMMC or the Vardhaman Mahavir Medical College and Safdarjung  Hospital in New Delhi in collaboration with PGI Chandigarh. And we know, I mean that anyone who knows about the Indian context that VMMC or Safdarjung is one of the busiest centers in the country catering to a massive population with very high delivery volumes. So that context makes their data very valuable.

Anita Singh (10:13.258)

exactly the study enrolled 80 newborns of more than 34 weeks of gestation who were born through meconium stained amniotic fluid and had developed respiratory distress within 24 hours with finding consisted with meconium aspiration syndrome. So see they are trying to include the babies who are likely to have their respiratory distress contributed to the meconium stained cycle or because of the meconium aspiration syndrome and it is important to note that babies with only mild to moderate distress with the Downy score of 3 to 6 were included which is quite understandable that these are the babies who can just be tried on the either the respiratory support on oxygen and severe cases where it excluded.

Akanksha (10:58.747)

I do.

Akanksha (11:03.931)

Yes, that is a key point. I think they deliberately left out the severe cases since I mean the prior studies had already shown a clear benefit of CPAP there. So, they just decided to took the area where dilemma is mild to moderate cases. Randomization was done using permuted blocks, allocation concealed in sealed opaque envelopes. Babies were assigned to either nasal CPAP using bubble CPAP.

with short binasal prongs or they were assigned to the oxygen hood therapy at 5 to 10 liters per minute. So, the CPAP group was started at 5 centimeters of water with an FiO2 of 30 percent which was titrated as per the saturation of the baby and the failure was defined stringently. Inability to maintain SpO2 above 90 percent despite CPAP of 8 centimeters and FiO2 of 0.6.

or worsening blood gases or shock. The hood oxygen group also had similar failure criteria, inability to maintain saturations despite. So, actually they initiated the hood, the babies randomized to the oxygen hood group at 5 liters per minute and then they subsequently rose it, increased it to 10 liter per minute. So, the failure was if the baby is unable to maintain saturations despite.

the flow of 10 liters per minute or if there is severe distress or acidosis.

Anita Singh (12:36.78)

Yeah, and if the primary support failed in either arm, babies were escalated to further to non-invasive post-depressor ventilation and then subsequently to invasive ventilation if still unstable. The primary outcome was the need for intubation and mechanical ventilation within the first 72 hours of life and secondary outcome included failure of the initial support, mortality, pulmonary hypertension, sepsis, shock, duration of respiratory support and hospital stay.

Akanksha (13:05.107)

Yeah, so I think so far so easy. Now coming to results. Of the 107 babies screened, 80 were randomized, 40 in each row. The baseline characteristics, like obviously the important ones, the birth weight was between, the mean birth weight was approximately around 2.7 to 2.8 kg.

The mean gestational age of the babies was around 38 weeks and Downes score distributionwere also well balanced. Most of the babies in this cohort were born by vaginal delivery and around 40 % of them had like moderate meconium aspiration syndrome. So that means 60 % had mild MAs.

Anita Singh (13:51.918)

So now coming to the primary outcome, the need of intubation was almost same that is 10 % in the CPAP group and 12.5 % in the oxygen hole group, being relative risk of 0.8 and that's the clearly non significant.

Akanksha (14:09.971)

Yes, and for the secondary outcomes like failure of the allocated mode happened in 10 % of CPAP babies versus it happened in 20 % of oxygen babies on oxygen by hood. So there was a trend toward fewer treatment failure with CPAP, but again that did not turn out to be statistically significant.

Mortality was low overall as we expect in mild to moderate MAS. There were two deaths in the CPAP group, one in oxygen and all of them were due to PPHN or refractory shock. Now coming to pulmonary hypertension requiring treatment that was seen in 7.5 % of the CPAP group versus 20 % of the babies on oxygen by hood, again trending lower but not turning out to be statistically significant. Importantly, there were no air leaks in either of the groups. The duration of respiratory support and hospital stay were very similar. So median around 26 hours of respiratory support and four to five days in the hospital.

Anita Singh (15:31.084)

Yeah, so essentially this study found that in the mild to moderate MAS, CPAP did not significantly reduce the need of mechanical ventilation compared to oxygen. In fact, nearly 80 % of these babies were managed well with oxygen alone.

That's a practical point for many NICUs, but I think we should pause here and talk about one issue, the use of oxygen hood with unblended oxygen without any mention of the FiO2s per se. And this thing is quite significant to note that there could be issues with respect to their stability in terms of the overall apart from the respiratory status and hemodynamic instability, which should also be considered especially in the babies who are having meconium aspiration syndrome. So I don't know what should we go on with this oxygen issue with this study.

Akanksha (16:28.499)

Yes. Yes, actually they mentioned that those who received oxygen by hood, so that was an unblended oxygen. that means they were on 100 % oxygen. But I think that's really something to think about. Agree that CPAP requires equipment, expertise, and monitoring. And it may always not be possible for in the Indian settings or in the LMIC units. And still I think in many units if hood oxygen is enough for most mild cases and as per the results of this study it means that it avoids unnecessary escalation. But then I think we should take it with a pinch of salt. There are some nuances like the study had nearly 60 percent mild cases. So, which may have. diluted any benefit of CPAP in the moderate group. Also again it was underpowered to detect smaller differences because the sample size was actually calculated expecting a huge reduction based on the prior studies which did not really hold true in practice. What do you think Dr. Anita?

Anita Singh (17:47.447)

right.

we should also note the limitation that there was no planning of caregiver but that's quite understandable and there could be possible observational bias in deciding intubation and the Downe’s score is still a general score which is quite subjective for the assessment. There are components which requires a subjective assessment by the caregiver but the strengths are solid with respect to the methodology, clear inclusion criteria and its relevance for

source constraint setting where CPAP is especially not available. But I think we should pause here and talk about the issue with the use of oxygen hood with unblended oxygen. But we know that starting a term maybe with mas on 100 % oxygen may not be necessary and in fact could be harmful per se.

Akanksha (18:38.803)

That's true. In our unit, actually, we have moved away from using hood as a primary oxygen therapy. Maybe instead we prefer low flow nasal prongs with a blender so that FIO2 can be titrated precisely. I think it's safer, avoids unnecessary exposure to high oxygen, and it is also cost effective if we compare it to CPAP in settings where that resource is maybe limited.

Anita Singh (19:05.88)

Yeah, that's the great point and one thing which was not mentioned that is the humidification. So it is also important that whatever gases we give to the baby either through nasal flow, canula or oxygen that has to be humidified per se. So I think it's a good study with respect to the setting of LMIC, but we need to have more such things to be critically analyzed.

Akanksha (19:37.053)

Yeah, I mean, so it clearly shows that CPAP is not superior to oxygen in mild to moderate MAS. But then it also nudges us to think critically about how we deliver oxygen. And maybe that's a conversation worth having in every NICU team.

Anita Singh (19:55.555)

Yeah, so let's finish with the message that one can think of and consider just oxygen, especially in milder cases of MAS to start with and critically monitor the baby further.

Akanksha (20:10.663)

Definitely. So now that brings us to our next study then and that is again we move on to a topic that is absolutely crucial in the NICU that is the management of shock. Septic shock is unfortunately common often devastating and for years dopamine has been the default first line vasoactive drug.

But adult and pediatric sepsis guidelines now favor norepinephrine. The question is, what about neonates?

Anita Singh (20:45.912)

Yes, that's a very pertinent study and with the world moving in the adult and pediatric category away from the dopamine and focusing more towards the epinephrine and norepinephrine. This is very relevant study for the management of the neonatal shock. This comes as a double blind randomized trial from the AIIMS Rishikesh and has just been published in Journal of Pediatrics. They enrolled 80 newborn babies with fluid refractory shock randomized to receive either norepinephrine or dopamine as the first line agent.

randomization was stratified by gestation and blinding was carefully maintained with use of identical syringes and infusion protocols.

Akanksha (21:28.935)

Yeah, in fact, I must say, like they have in the study, if we go on, they have very, very distinctly defined what they define shock as. And the methodology has been very intricately detailed in the study. So that was wonderful. So for the study purpose, norepinephrine was started at 0.2 mikes per kg per minute and which was titrated up to 0.3.

Dopamine was started at 10 mcg per kg per minute and hiked up to 15. The primary outcome was reversal of shock at 30 minutes, I mean 30 minutes after starting the inotrope. The results showed no significant difference with 32 % in the norepi group versus 46 % in the dopamine group. So overall reversal rates, need for additional drugs and mortality were also similar with mortality tragically high in both arms around 58 % and 56%.

Anita Singh (22:38.744)

Yeah, here the interesting part was the secondary outcomes. Babies on dopamine had more tachycardia, worse acidosis, higher base deficit and what not significantly lower cerebral oxygen saturation at 24 hours. And I would say this last thing that is cerebral oxygenation measuring up that in a randomized controlled trial from India is particularly commendable because they have used NIRS to assess cerebral oxygenation and which is not something we often see as a monitoring tool in RCTs which basically deals with hemodynamic shock from India. So it really adds to the depth of the physiological assessment and overall monitoring of this study.

Akanksha (23:22.639)

Absolutely. And I must also mention here the microbiology is also worth highlighting in this study. Nearly half the babies had culture proven sepsis with gram negative organisms predominating. So now that mirrors what most NICUs in India are facing at present. Gram negative organisms as the main drivers of late onset, in fact, even as early onset sepsis, I will say.

And very often these bugs are turning out to be multi-drug resistant. So again, that probably also explains the very high mortality in this cohort despite getting such a great intensive support.

Anita Singh (24:09.826)

Yes and that's where the comparison becomes even more meaningful even in this high acuity population where non-epinephrine showed a better physiological profile, less tachycardia, better cerebral oxygenation and less acidosis compared to dopamine. That's indeed a message.

Akanksha (24:28.657)

Yeah and just to add on to it, I think it echoes what we have seen in our unit as well. At SGPGI as well, we recently did a randomized pilot trial comparing norepinephrine versus epinephrine in fluid refractory septic shock. So since it was a pilot study, so we had around 25 babies and it was found that norepinephrine was just as effective as epinephrine for shock reversal, but again with fewer metabolic derangements and similar mortality. So taken together- the AIIMS norepinephrine versus dopamine trial and as we saw norepinephrine versus epinephrine. So both point towards norepinephrine being a safer and more physiologically balanced agent. What do you say Dr. Anita?

Anita Singh (25:22.456)

Yes, of course, I think it has a broader message. While dopamine has been the main lighthouse for decades, it may be a time for the Indian NICUs and the guideline groups to consider norepinephrine earlier in septic shock, especially given that we know about tachycardia, acidosis and perforation outcomes being more frequently observed with the use of dopamine.

This is something which everyone has subjectively felt so.

Akanksha (25:50.099)

it

Akanksha (25:55.742)

Yes, I absolutely agree with you Dr. Anita and I think this is a great trial from Rishikesh and encouraging to see in fact multiple Indian centers now like looking at this aspect and then again trying to answer this very pertinent question about the management of shock in neonates which leads to such higher mortality in the preterm babies.

Anita Singh (26:19.564)

Yeah Akanksha, let's move to our next paper.

Akanksha (26:23.251)

So, again continuing on the theme of neonatal shock, let us look at another important trial, this time from PGI MER Chandigarh published in the journal of Perinatology. The question they asked was, if we give hydrocortisone early right at the time of starting vasoactive support in fluid refractory shock, can it improve survival compared to the placebo?

Anita Singh (26:53.454)

Wow.

their rationale looks quite interesting. We know that many critically ill neonates, especially preterms have relative adrenal insufficiency at the onset of shock. Their cortisol levels are often inappropriately low for the degree of distress and cortisol normally supports vascular tone and enhances the responsiveness to catecholamines. So if it is low, babies may re main hypotensive despite fluids and inotropes. So that's why a thought that hydrocortisone may be widely used in catecholamine resistant shock. But the real debate here is that should we be using it earlier at the time of starting inotrope rather than waiting until the shock becomes refractory.

Akanksha (27:36.102)

Exactly. in fact, some prior pilot studies had suggested improved intermediate outcomes when hydrocortisone was given early. So that actually set the stage for this RCT, which was a double-blind placebo-controlled trial in a level 3 NICU at the Postgraduate Institute of Medical Education and Research, Chandigarh.

Between 2016 and 2018, they screened 142 babies with fluid refractory shock and randomized 84 of them. So 43 were randomized to hydrocortisone group and 41 to placebo. The babies were mostly very preterm with a median gestation of around 30 weeks and a median birth weight of around 1150 grams.

Anita Singh (28:26.958)

Yeah, so let me add further that the intervention was hydrocortisone 1 milligram per kg every 6 hour given for 48 hours, then 1 milligram per kg every 12 hourly for 3 more days. The placebo group got identical saline and importantly if any baby developed catecholamine resistant shock, the trial drug was stopped and open level hydrocortisone was started. So ethically no infant was denied steroid if they wasn't and that's is something which is really relevant.

Akanksha (28:58.855)

Yeah, I mean, absolutely. We obviously cannot deny a baby of steroids. So that was very intricately and distinctly mentioned that they made it open label steroid if any baby was first worsening with the after the interventions. So now coming to the results quickly, the primary outcome which the authors took was 14 day all cause mortality, which was 72 percent in the hydrocortisone arm versus 83 % in the placebo. So the odds ratio was 0.53, but again, it did not turn out to be statistically significant. And again, what we saw in the previous study that both the groups had devastatingly high mortality, reflecting how sick this population was.

Anita Singh (29:52.931)

Yeah, and what about the secondary outcomes? That was the duration of vasoactive therapy, vasoactive inotropes scores, both mean and total maximum vasoactive inotropes score and incidence of catecholamine resistance shock were all similar between the groups. About 71 % of the hydrocortisone group and 81 % in the placebo eventually developed catecholamine resistance shock, which is quite high and therefore received an open label steroids, which obviously diluted the trial effect.

baseline cortisol levels were measured were low in both the groups that is median of 6 mcg per dL confirming relative adrenal insufficiency in most babies.

Akanksha (30:37.393)

Yeah and they also looked very carefully at the safety outcomes as well like incidence of which obviously is a concern when we talk of steroids in babies. So, they looked at the incidence of gastrointestinal hemorrhage, intestinal perforation, necrotizing enterocolitis, hypertension and hyperglycemia. So, they looked at all the important adverse effects that a steroid could have.

again it was found to be comparable between both groups. Medium term complications like retinopathy of prematurity and bronchopulmonary dysplasia, they were also not increased with hydrocortisone. So, while it did not reduce the mortality, importantly we saw that it also did not add new risk in this group of highly sick neonates.

Anita Singh (31:31.874)

Yes, of course that was the strength of this trial as we cannot forget about the side effect of the using indiscriminate steroids. So the strength of this trial was rigorous methodology, proper blinding, stratified randomization, detailed hemodynamic profiling with functional echocardiography and systemic safety evaluation. Very few neonatal RCTs from our context go up to this level of the detail.

Akanksha (32:00.06)

Agreed and limitations as I would just mention maybe a relatively small sample size again very high background mortality driven by gram negative sepsis which we know is a huge issue in all the Indian NICUs and I think the confounding from three fourths of babies eventually needing open label steroids.

The long-term neurodevelopment had not been assessed, though prior data haven't shown any adverse effects with hydrocortisone.

Anita Singh (32:34.69)

Yeah, so I would say that the key take home from this study was that early hydrocortisone when given alongside first-line vasoactive support did not significantly reduce short-term mortality, but it was safe and it remains an important adjunct in case of refractory shock. This trial highlights both the difficulty of improving outcomes in gram-negative sepsis and the urgent need for the large multicentric studies.

Akanksha (33:04.029)

Yeah, absolutely. And it also reminds us that like shock in preterm neonates is often vasoplegic. I mean, it is compounded by the presence of PDA and sepsis. So, it may not just be classic cold shock and matching the therapy to physiology using bedside echocardiography, understanding the cortisol status. So, all of this may matter actually. So, looking at the larger picture, with inputs from all these available strategies that may actually matter more than any single drug to decide what is the best strategy for each baby.

Anita Singh (33:44.035)

Yeah, well said Akansha. So with this, we have covered two back-to-back Indian randomized controlled trials on shock management, one on norepinephrine versus dopamine, and another one was on early use of hydrocortisone in food refractory shock. So both add valuable pieces to the puzzle. Even though we do not have any solid answer yet, but they are a good start.

Akanksha (34:11.175)

Definitely can't agree more. now let's turn our attention now that brings us to our next study. Now this one explores the like we talked about the shock therapies. Now let's just zoom out and ask what's actually happening on the ground in the district hospitals. So this study that we're going to discuss next it was

published in Lancet Global Health very recently. And this study looked at five special newborn care units or the SNCUs across India and prospectively tackled the incidence, again looking at the prevalent bugs and the resistance patterns, which has been a huge gap area until now because all the data that we see or that we have till now that comes from higher centers where there are all facilities available. But then it is also important to look at the microbiology or the epidemiology of the SNCUs from where actually most of the babies when becoming sicker are referred to these higher centers. So it was very interesting to have a look at these.

Anita Singh (35:35.213)

Yeah, so coming to the methodology, this was a prospective multi-site cohort study with duration between October 2019 to December 21. So again, we have COVID pause here for the recruitment. They enrolled 6,612 units, is huge with 60 % of the inborn babies and 40 % of the outborn babies. So any baby who was meeting pre-specified clinical criteria for sepsis had blood culture drawn by research nurse before antibiotics and processed at link tertiary labs with Maldi- TOF. So the use of the advanced blood culture method that is Maldi TOF confirmation was used along with the standardized antibiotic sensitivity part testing. They used used STROBE NI guidance, cluster adjusted incidence estimates and expert adjudication to finalize culture positive sepsis. MDR was defined as resistance in more than or equal to three

including third generation cephalosporin, carbapenems and amino glycosides.

Akanksha (36:42.481)

Yeah, and so thank you for the methods. Now coming to the key results. About 51 % of all admissions were of suspected sepsis. Culture-positive sepsis occurred in 3.2 % overall. The site range was 0.6 to 10 % with a stark out-borne versus in-borne split.

So 5 % culture positivity in outborn versus 2 % in inborn babies. Early onset made up 58 % of culture positives and the case fatality rate for culture positive sepsis was a sobering 36.6 % higher definitely with gram negatives and in the outborns.

Anita Singh (37:37.753)

So...

Let me talk about the pathogen subset. It's again gram negative bacilli. Up to 70 % of the isolate which we have been struggling along at every place in India. The big three are Klebsiella pneumoniae in 23%, E. coli in 15%, and Enterobacter 12%. And when we see at the resistance picture, it is again very sad to say that a striking 75 to 88 % were the multi-drug across this gram negative pathogens. Even carbapenem and beta-lactam and lactamase inhibitor resistance were common. And what not alarmingly high colistin resistance also appeared in a subset of Klebsiella. If this is a district-prospector data, what can we say about the tertiary carrier resistance pattern with this?

Akanksha (38:30.713)

Absolutely, mean nothing can be more alarming like looking at this picture and actually these are the babies who are being referred to a tertiary care center. the scenario would not be much different even if we look at the resistance patterns of a tertiary care. So, which is mean saddening and they also showed in the study that how

culture negative sepsis also dominates practice. I 31 % of all enrolled babies received for five or more than five days of antibiotics with negative cultures and mortality there was approximately 20 % versus 3 % in babies who were never suspected of sepsis. Adjusted hazard for all cause mortality.

7.4 for culture positive, 4.6 for culture negative, both versus no sepsis suspicion. So translation, mean negative culture does not mean low risk, it often means low yield or late sampling in very sick babies. So that actually makes practicing the antimicrobial stewardship practices difficult because if you have so high mortality in babies with presumed sepsis. So that means definitely we're going like we're not heading in a right direction. And we definitely need to look at the practices of blood culture collection or the timing that the time these samples are being collected.

Anita Singh (40:23.096)

Yeah.

From a JC point of view, this paper explained why our shock trials struggle to move mortality, the baseline microbiology, it's stacked against us, that is Klebsiella, E. coli, Enterobacter, often MDR frequently in outborn babies arriving late. It also validates the antibiotic time-out culture we push, if cultures are negative and baby improves, deescalate or stop if it's sick and culture negative, consider repeat cultures, ensure adequate blood volume and reassess source control/ infection prevention practices.

Akanksha (40:58.033)

Yeah, so again, just to summarize the three big contributions from the study. First is district level truth, not just the tertiary snapshots. So it gave us the incidence, bugs, and the antimicrobial resistance in SNCUs caring for more than 1 million newborns per year. The model was quite interesting, the mentor-dyad model. So a district which is linked to a

tertiary lab with all the advanced techniques such as Maldi TOF for the confirmation and central adjudication which is a replicable surveillance architecture. Now, for the policy grade signals, a high rate of the multi-drug resistance bacteria even to the carbapenems and high mortality again mandates the infection prevention control scale up in-house blood culture capacity building and stewardship tailored to the essentials.

Anita Singh (42:02.179)

Yeah.

So strength of the study was that it was a multi-site prospective design with pre-antibiotic cultures, cluster adjusted incidence, central export adjudication, standardized antibiotic sensitivity testing, and explicit MDR definition with a clear policy implication. So these are really, really good strengths. The limitation being heterogeneity across sites, which is really difficult task to adjust.

with possible overestimation of CONS, case of Staphylococcus as pathogens. being the logistic of transporting the culture samples to have a good and accurate yield and no say on the long term outcomes in this study. Still at the district level it is something which is really really heartening to see such papers coming from a study from the SNCUs.

Akanksha (43:02.259)

Absolutely. mean, the practical takeaways would be like we really need to build and link the culture capacities like as it was shown in this, the mentor-dYAD. And for infection prevention control, we need to see how we can improve upon our nurse-patient ratios, the reduction of bed sharing and obvious emphasis on hand hygiene bundles. And for the context-specific stewardship, maybe

to have more stricter rules for starting and stopping the antibiotics, having local antibiograms, avoiding reflex escalation to carbapenems or colistIN unless indicated. So, maybe this is how we bend the MDR curve before babies go into the refractory septic shocks with devastatingly high mortality.

Anita Singh (43:58.499)

Yeah, very aptly summarized here Akansha. This study gives the epidemiologic backbone to everything we have discussed today from respiratory support decisions to SOC algorithm and it is why behind our, it is the way behind our daily choices.

Akanksha (44:16.987)

Okay, absolutely. So now let's move on to our final paper for today. Now this one takes into a very practical space, quality improvement. This study from St. John's Medical College Hospital, Bangalore, published in BMJ Open Quality is titled, Improving the Quality of Care for Preterm Infants in the Golden Hour. The rationale was simple but powerful. The first 60 minutes of a preterm baby's life.

the so-called golden hour is critical. So this is the window where thermoregulation, respiratory stabilization, nutrition and infection prevention must all come together. Yet in most busy units, this care is actually fragmented. So the team asked, can a structured QI initiative change that?

Anita Singh (45:12.974)

Yeah, they use the point of care quality improvement methodology, which is now widely promoted by World Health Organization and also from the National Neonatology Forum India. It is built on a simple four step cycle to identify the problem, analyze cause, death changes using PDSA cycles and sustain improvements, which is the mostly key element of the in quality improvement initiative. At ST John’s Hospital, they ran this project over 28 months, focusing on goals that is reducing admission, hypothermia, improving adherence to the respiratory care bundle and ensuring parental nutrition and antibiotics were started within the first hour of life.

Akanksha (45:55.262)

Yes, and as you said about the testing changes using PDSA cycle, so they broke this down into targeted PDSA cycles. So for hypothermia, pre-warmed transport incubators, polythene wraps and warm linen, servo-controlled warmers and real-time feedback on admission temperatures. For respiratory care, it was targeted around structured bundle with airway positioning.

delivery room CPAP with T piece resuscitator, oxygen targeting, and bedside audits using a checklist. Moving on to nutrition and antibiotics, pre-prepared parenteral nutrition orders and antibiotic kits, a dedicated golden hour nurse role at high-risk deliveries, and visual reminders to ensure timely initiation. So each of these was tested refined and then standardized before moving to the next.

Anita Singh (46:59.458)

Well.

So let me talk about the outcome indicators that were clearly defined. So primary outcome being rate of admission hypothermia, respiratory bundle adherence, time to start parental nutrition and time to first antibiotics and composite outcome being babies received receiving all four golden hour elements within 60 minutes balancing outcomes where that hypothermia rates and complications from the earlier period is parental nutrition initiation.

results were impressive with hypothermia decreasing from a rate of 79 % to 22 % respiratory bundle adherence which should up to 13 % to 77 % and the initiation time of PN was reduced from 102 minutes to 62 minutes and antibiotics times from 162 to 74 minutes. So, most strikingly the result was the composite compliance

which rose from 2.5 % to hope in 66%. That's quite amazing.

Akanksha (48:06.147)

Wow, yeah, that's actually commendable. And I think, like, those of us who have done a QI, they know that this does not happen without an enormous effort from the team. Because doing a QI at your unit really means squeezing out time off your busy clinical shifts, training new staff over and over again, keeping momentum when fatigue sets in and then sustaining improvements through regular feedback.

In fact, in our own very recently concluded QI project to improve the rates of kangaroo mother care in the unit, we faced exactly these hurdles. At first, the changes look promising, but sustaining them was a real challenge. So I think if we talk of QI methodology, what works is actually continuous audits, sharing feedback with the staff, and celebrating small wins.

So this experience makes me appreciate even more like what the St. John's team achieved because we know firsthand how much persistence QI demands.

Anita Singh (49:18.612)

Exactly, that's a great balance. I would also like to add up that our team also had another QI at our unit, was included the nursing handover at the time of shift change, which also faced COVID disruption at that moment. But the essence of the QI is that it is not a one time job, but it is a cultural shift. The trend has to shift. And in this study, it is important

to highlight that balancing measures which were which were quite reassuring too- that there was no increase in hypothermia and also there were no added complication from the earlier start of parietal nutrition therapy. So it is really good that these things are achievable without any significant scientific. So not only the processes improved but they were safe too.

Akanksha (50:14.749)

Yes, and actually the take home is twofold. Firstly, structured QI using like as they used here the point of care QI model. So that can transform critical care processes even in busy and resource limited in ICUs. And again, emphasizing that sustaining change requires teamwork, training and relentless feedback. So this paper shows that how implementation science is as important.

as clinical science in improving the neonatal outcomes.

Anita Singh (50:47.596)

Yeah, and it's a perfect note to end this journey from respiratory support trials to shock management to sepsis epidemiology and finally the quality improvement. We have seen how Indian research and innovations are shaping neonatal care. Science plus teamwork, that's the way forward.

Akanksha (51:06.631)

Yeah, so that brings us to the end of this journal club edition. And as already said, we've traveled across various studies. And I think what ties them all together is this, that the Indian unit research is not just growing, it's now shaping practice. So these studies remind us that improving outcomes requires both robust science and practical implementation.

from RCTs and surveillance to bedside QI.

Anita Singh (51:41.464)

Yeah, and that's really wonderful. So thank you all for joining us today. Until next time, keep reflecting, keep questioning and keep working together to give our babies the best possible start. 

Akanksha (51:56.231)

This is Incubator India signing off. Thank you.