#450 - 📑 [Journal Club] - 🫀From The Heart - The Complete Episode from July 4th 2026

Neonatal sepsis physiology, steroids, vasopressors, and moms.gov. A full week on The Incubator Journal Club.

Adrianne and Nim open with a retrospective study from Toronto challenging the assumption that hypoxemic respiratory failure in septic preterm infants is driven by elevated pulmonary vascular resistance. The data points instead to left ventricular dysfunction as a key contributor, raising questions about the reflex to reach for nitric oxide first.

Nim then reviews a double-blind RCT from northern India evaluating early hydrocortisone versus placebo in neonatal fluid-refractory shock. The primary outcome did not reach statistical significance, but an 11 percent absolute reduction in mortality and a 70 percent open-label crossover rate tell a story of their own.

Adrianne closes the journal club with a double-blind RCT comparing norepinephrine to dopamine for neonatal septic shock, finding no significant difference in shock reversal at 30 minutes, though significant methodological limitations make the findings hard to act on.

Eli and Ben close the week on Neo News with a look at the newly launched moms.gov and what clinicians should know before their patients bring it up.

Transcript

Nim Goldshtrom (00:02.872) Hello, Adrianne. How have you been?

Adrianne Rahde Bischoff (00:04.100) Hi Nim. I'm good. How are you? It's getting warmer here.

Nim Goldshtrom (00:07.200) That's great. In New York it's also getting a little warmer and wetter, but doing great. Seeing lots of interesting patients, which several years into my career I didn't think was going to happen, but they're all still interesting and you're seeing things you haven't seen before. So I'm glad this job does not get stale, which is great.

Adrianne Rahde Bischoff (00:22.100) Definitely not. It's definitely a lifelong learning experience.

Nim Goldshtrom (00:25.100) Yeah, and when you have new tools to play with and evaluate different organ systems in different ways, you guys are learning a whole lot about cardiac physiology in the preterm population.

Adrianne Rahde Bischoff (00:45.080) Yeah, I get surprised even at the usual stuff. I think I had it figured out, and then the trainees start focusing on some other measurements and say, well, have you thought about that? And I think, well, not really, not traditionally, but yeah, I guess you have a point. And then you slowly change your practices. That's why science in all aspects is a team sport. You might do a lot of individual work, but the reality is it takes a village to deliver care and to do good evidence-based science.

Nim Goldshtrom (01:10.100) Yeah, and an open mind, right, to listen to what other people have to say and how they're thinking. That's how we all get better.

Adrianne Rahde Bischoff (01:18.100) Correct. If only we could spread that message to the world given the current climate of our general environment nowadays. But we digress and focus back on our journal club, which is centered on all these things today. So what do you have for us, Adrianne?

Adrianne Rahde Bischoff (01:54.100) . So the first article we are going to talk about, and we will link it in the show notes as per usual, is called Cardiopulmonary Physiology of Hypoxemic Respiratory Failure Among Preterm Infants with Septic Shock. The first author is Dr. Kharrat and the senior author is Dr. Jane, both dear friends and former colleagues of mine in Toronto. This was published very recently in the Journal of Pediatrics in March of 2025.

They start their introduction by discussing how sepsis requiring vasopressors or inotropes is associated with high mortality, 40 to 70 percent of infants. While organ dysfunction is common, hypoxemic respiratory failure affects at least 15 percent of septic babies. This is commonly assumed to be secondary to acute pulmonary hypertension, but there is very little data to support or guide the therapies we use in septic babies requiring high levels of oxygen.

This was a retrospective study over seven years at a single center, Mount Sinai in Toronto. They included babies born at less than 34 weeks with culture-positive sepsis, either blood or CSF, which was a strength of the study in that this was confirmed sepsis. They also included babies who needed vasoactive medications within 72 hours of sepsis onset or who had a comprehensive targeted neonatal echo in the same period. Babies were divided according to whether they had acute hypoxemic respiratory failure or not, defined as a need for an FiO2 of more than 60 percent for two consecutive hours despite invasive ventilation. Primary outcomes were targeted neonatal echo indices of pulmonary vascular resistance and pulmonary arterial pressure. Secondary outcomes included left and right ventricular function and clinical outcomes.

They had 52 babies over those seven years, and 19 of them, so 37 percent, had hypoxemic respiratory failure. The two groups had very similar perinatal baseline illness severity markers, except for a higher FiO2 and higher mean airway pressure in those who developed hypoxemic respiratory failure. If you look closely at table three, you can see that most babies had been fluid resuscitated prior to the echo being performed. Although it does not specify how many were already on inotropes or vasopressors in each group, the vasoactive inotropic score suggests that many of these patients were already on medications and were not necessarily hypotensive at the time of the echoes. In fact, mean blood pressure was 35 in both groups, and the mean postmenstrual age at the time of sepsis was 26 weeks. I would have liked to see how many were receiving medications and which ones, along with a better description of the usual practice for initiating medications at that center. Obviously I trained there, and I was still in Toronto during the last year of this study. But I think for readers, this information would have been valuable.

Almost 70 percent of the hypoxemic babies received nitric oxide. Five of them were already on it at the time of the echo, though it is not clear how many may have received it and stopped before the echo was done. Based on the data, clinical responsiveness to nitric oxide was very rare. The median time to initiate nitric oxide after the onset of hypoxemic respiratory failure was four hours. However, they do not mention at which time point from sepsis onset or from hypoxemic respiratory failure onset the echoes were performed. So I don't know if the echoes were done as soon as the babies were noted to be critically ill, or if the babies had been in high oxygen requirements overnight and the team had already tried nitric oxide before obtaining the echo. That information is not very clear, which is understandable given the retrospective nature of the study.

When we look at the echo variables, the hypoxemic respiratory failure patients had a higher frequency of bidirectional and right-to-left shunt across the PDA, which was not statistically significant. All markers for pulmonary vascular resistance and pulmonary arterial pressure were similar between the groups, and RV function was also similar. However, babies with hypoxemia had lower systolic and diastolic left ventricular performance, including ejection fraction, left ventricular output, and strain. They also checked for markers of preload, so it is unlikely this was a fluid status difference between the groups. They correlated FiO2 with LV markers and noted that specifically LV early diastolic strain rate, which is a measurement not routinely used for clinical purposes but gaining interest in the targeted neonatal echo literature, was significantly correlated.

Adrianne Rahde Bischoff (08:07.542)

Mortality was higher in the hypoxemic group, at 79 percent versus 48 percent. In the discussion, they hypothesized that the more frequent bidirectional or right-to-left shunt at the PDA level was not really related to elevated pulmonary vascular resistance. One hypothesis was that the shunt pattern could be more related to low systemic vascular resistance, which is a pattern we frequently see in profoundly hypotensive babies. I do wonder, though, whether this is actually true in this cohort, since most babies appeared to have normal blood pressure at the time of assessment, although it is possible that those with bidirectional or right-to-left shunt were hypotensive and that distinction is just hard to tease out from how the data is presented. Their second hypothesis was a post-capillary phenomenon, where secondary changes to LV systolic or diastolic function lead to increased pressure on the aortic side that is more related to LV disease than to classic pre-capillary pulmonary hypertension. Either way, the lack of improvement in hypoxemic respiratory failure following nitric oxide would be consistent with both hypotheses.

One of the limitations of the study is that there were not enough details about which therapies the babies were on when the echoes were done. This is the nature of retrospective work, but you could hypothesize that those therapies could negatively influence cardiac function and pulmonary hemodynamics, and therefore impact the echo findings and conclusions. I don't think this is a center that uses a lot of dopamine or indiscriminate vasopressors that could be causing left heart dysfunction, but we always have to raise that possibility with a critical mindset.

As a hemodynamics clinician, I appreciate the discussion and the education it offers readers that hypoxemic respiratory failure is not always related to classic pre-capillary pulmonary hypertension, and that nitric oxide should perhaps not be an immediate therapy in this population, especially given the low number of responders. I also wonder whether there would have been differences between early and late onset sepsis. A study by the same group, first author Baksinski, published in Archives in 2017, also suggested that nitric oxide did not work well in late onset sepsis. But I wonder if babies with early onset sepsis, who also have RDS and expected elevations in pulmonary pressures during the transitional period, might show a different rate of responsiveness.

Similarly, with small numbers, I think another area for future study would be the phenotypes of individual pathogens. Anecdotally, we see pathogens more likely to lead to warm shock versus cold shock, but to my knowledge there are no targeted neonatal echo studies examining this in detail, including the effect on pulmonary hemodynamics and responsiveness to vasodilators.

Overall, this is an interesting study. It is good to be reminded that unlike what is typically assumed, septic babies may not always fit the pre-capillary nitric-responsive phenotype, and that we should be considering the left heart more frequently and prior to initiating those therapies. There are methodological limitations inherent to any retrospective study of this nature, but the message is clinically meaningful.

Nim Goldshtrom (12:37.792)

It does, but retrospective studies are so easy to do, right? The data is all there. You put it together and find hypothesis-driving questions. Before we get into more details, I want to jump to the end. You have a limited-n study with really interesting data that challenges a paradigm, suggesting that hypoxemic respiratory failure in what appears to be a late onset sepsis group, with a mixture of organisms, is associated with more markers of left-sided strain and dysfunction than right-sided. Does this change your practice? In late onset sepsis with shock and hypoxemic respiratory failure, are you changing your inotropic management or your fluid management based on this kind of data?

Adrianne Rahde Bischoff (13:10.100)

I think it makes me think more critically before jumping straight to nitric oxide. The other thing I did not mention much is that we know these babies had worse lung disease to some extent. Could it also be that they were less likely to respond to nitric oxide because they had worse lung recruitment, or because cytokines were preventing nitric oxide from working at the capillary tissue level?

If I am stuck in the middle of the night and the echo machine is unavailable, and the baby is in 100 percent oxygen but not hypotensive, I might still give a trial of nitric oxide and see if it works. But I would be more inclined, as I think we all should be in any circumstance, to discontinue it promptly if it does not work, because we may actually cause more harm than good.

Nim Goldshtrom (13:55.100)

So here is my next question. Let's say you do the trial of nitric oxide and it doesn't work, and the baby is normotensive, just as the data showed. Would you then try an inotrope? If there is LV dysfunction, knowing this data, with normal blood pressure, if nitric oxide doesn't work and you're stuck, would you consider inotropy to support the concept of LV dysfunction as a co-contributor to hypoxemic respiratory failure in septic shock?

Adrianne Rahde Bischoff (14:25.100)

I think it is a paradigm shift, and many clinicians who are not thinking about the underlying physiology would have a hard time even considering it. But I think it would be reasonable. Low-dose epinephrine or low-dose dobutamine is unlikely to harm anyone, and if there is benefit to be gained from relieving pressure in a post-capillary type phenotype, then yes, I think it is worthwhile, especially since blood pressure alone is only part of the picture. You also have to ask how the lactate looks and how the end-organ perfusion is doing. So I think it is a reasonable approach.

Nim Goldshtrom (15:45.100)

Because the way I put it together, and I would love your feedback, is that this was point-in-time testing at essentially random time points in septic babies going through the treatment and physiology of septic shock with hypoxemic respiratory failure. To me, this is association and not causation. You might see it differently, and I am very curious whether these pictures of hypoxemic respiratory failure were actually partly driven by left-sided dysfunction. The data is showing diastolic and systolic dysfunction, kids with lower LV outputs and signs of diastolic strain, which could certainly lead to post-capillary congestion. LV end-diastolic pressure goes up, LA pressure goes up, venous congestion, and then you have pulmonary vascular edema from elevated left-sided pressures. It may not lead to classic left-sided causing right-sided pulmonary hypertension, but it could be that this LV strain and poor LV performance is driving that congested picture, where what you actually need is LV support. And I think you are right that it is a really big paradigm shift to think about starting epinephrine in a baby with normal blood pressure and potentially no lactate who is in hypoxemic respiratory failure, at least until you put a probe on and confirm LV dysfunction for yourself.

Nim Goldshtrom (17:17.292)

But to go back to our last journal club, the concept of compensated shock with normal hemodynamics until you are suddenly in uncompensated shock is very hard to identify on clinical picture alone. That is why this kind of data can help people move the needle and feel more comfortable. I take care of congenital hearts, so epinephrine is used here about as often as caffeine in the preterm world, and I am not averse to trying low doses. The problem is that without serial echo to adjust management with normal blood pressures, how do you treat a baby without TNE when you have hypoxemic respiratory failure symptoms that are going to take a long time to recover even with diuretics and LV support? There is no good endpoint. So to me, this could really move the needle, but when you think it through, to what end? Time itself will also help with hypoxemic respiratory failure alongside intubation and gentle fluid management. This drives me to think that what we really need are prospective studies that randomize these kids to continued medical management versus better standardized inotropic support, to see if that actually helps them come off the ventilator and recover function faster. It is very interesting to see how much TNE challenges so many of the ways we think and work clinically, pushing us toward identifying and treating compensated physiology that is really hard to recognize.

Adrianne Rahde Bischoff (18:55.100)

Yeah, and I think it highlights one of the key aspects of their discussion, which is looking at all components of the echo and not just one part of the picture and assuming a certain physiology. I see it over and over again. I am doing the echo, and someone asks me what the PDA looks like, and I say it is right to left. And the immediate response is: pulmonary hypertension, start nitric oxide. But actually, it is right to left because the aortic root pressure is 20 over 10, or because there is left-sided obstruction, or something else entirely. I think it is important to look at things comprehensively. Obviously that is harder if you do not have the ability to do TNE with quantitative measurements. But even in places with only qualitative echo capability, we need to educate our trainees better on how to appraise an echo report. If you have a right-to-left PDA shunt in the presence of a completely left-to-right atrial shunt, that cannot be pre-capillary pulmonary hypertension requiring nitric oxide. That must be at least partly left-side driven, and therefore nitric oxide is probably not the first choice. You can still ask the right questions from a qualitative standpoint, even where TNE is not fully available.

Nim Goldshtrom (20:05.100)

That is why fellowship takes time. You are so right. You cannot just treat individual numbers and individual surrogates or markers. We do the same thing with renal NIRS, right? Numbers can go down for a long time. You cannot just treat a number in isolation without the whole clinical picture. What are the saturations? What is the hemoglobin? What is the exam? Is the patient actually in low cardiac output, or are you seeing a variation of normal, or something else suggesting high mixed venous oxygen or high VA-VO2 difference? This is remarkable stuff. It challenges the physiologies we thought we were capturing all the time with heuristics and older data sets, and now we have much more robust data available to do better.

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Adrianne Rahde Bischoff (00:00.000)
All right, Nim. Are we ready for the next one?

Nim Goldshtrom (00:03.342)
I think so. So challenging paradigms in sepsis with TNE, now moving over to questioning the use of steroids in preterm infants. We are going to move on to the next paper, talking about hydrocortisone versus placebo, a topic with a lot of literature and established paradigms even at our hospital, in the setting of fluid-refractory shock.

This group is from northern India. The first author, and I hope I am pronouncing this correctly, is Sankalp Dudeja, and the last author is Praveen Kumar. This was published in 2025 in the Journal of Perinatology: Early Hydrocortisone versus Placebo in Neonatal Shock, a double-blind randomized controlled trial. Kudos to them for embarking on such an ambitious research question.

The background is that during septic shock, inappropriate hypothalamic-pituitary axis activation in severe stress states can lead to hemodynamic instability, and critically ill neonates with low cortisol levels receiving exogenous steroids have shown improved outcomes in a variety of studies. Hydrocortisone is part of an algorithm for pressor-resistant hypotension, where it can improve both vascular tone and myocardial contractility. In their introduction, which I highly recommend everyone read, they reference two trials that showed promising results and formed the basis of their protocol, which we will discuss at the end.

They set out to evaluate whether early hydrocortisone versus placebo in fluid-refractory shock could reduce 14-day mortality. Their cohort consisted of neonates with fluid-refractory shock, and I will note the first limitation here, which is that they did not clearly define the gestational age criteria, though the cohort ended up consisting of preterm infants. The intervention was early hydrocortisone at one milligram per kilo every six hours for 48 hours, followed by one milligram per kilo every 12 hours for the next three days, compared to a placebo, with randomization and double blinding for delivery. The primary outcome was 14-day all-cause mortality. They also collected echo parameters for outflow and PDA, NEC, and a variety of other clinical factors.

Exclusion criteria included obvious volume loss such as dehydration or blood loss after birth, HIE, cardiac disease, NEC, any exposure to postnatal steroids within the prior seven days. They had robust vital sign monitoring directly from the monitors, blood gases, serum cortisol levels, and a variety of echocardiographic function assessments. Enrolled infants were randomized using computer-generated sequences, with stratification by gestational age into less than 30 weeks and greater than 30 weeks. All investigators and outcome assessors were blinded to the intervention.

Vasoactive drug therapy was managed based on unit protocol, with dopamine as first line for hypotensive neonates and dobutamine for normotensive neonates with peripheral circulatory failure. Hypotension was defined as below the fifth percentile for gestational age plus additional clinical criteria, which you can find in the paper. They had planned a priori interim analysis after two-thirds of expected primary outcomes were reached.

Ultimately they enrolled 84 subjects, 43 in the placebo group and 41 in the hydrocortisone group. The mean gestational age was around 30 and a half weeks with a standard deviation of about three to three and a half weeks, so a fairly wide range, anywhere from roughly 26 to 27 weeks up to nearly 34 weeks. There was stratification across birth weight groups and equal distribution for SGA. There were few differences in clinical variables between the two groups, though the placebo group did trend toward having more culture-positive sepsis.

Their tables show vital sign variables with no statistical significance between groups, including LV outflow, SVR index, cortisol levels, and all-cause mortality at 14 days, which was 72 percent in the hydrocortisone group versus 83 percent in the placebo group. There was little to no gastrointestinal hemorrhage or perforation from steroid use. The difference in mortality of around 11 percent was not statistically significant but may be clinically meaningful. There was also no difference in catecholamine-resistant shock.

In adjusted models, mean vasoactive inotropic score at 24 hours was different between survivors and non-survivors, and those who received early hydrocortisone were more likely to be in the survivor group. However, the most important point comes toward the end of the results, which is that they did not account for crossover in the study design. Ultimately, 71 percent of the steroid group and 81 percent of the placebo group ended up receiving open-label hydrocortisone due to catecholamine-resistant shock. SNAP-2 score was also a significant predictor of mortality.

The authors concluded that while not statistically significant, the study showed a clinically important improvement in 14-day mortality of approximately 11 percent that did not hold up in regression models.

Nim Goldshtrom (06:42.258)
This is an interesting paper in a lot of ways, and while I want to be thoughtful to the authors, it raised a lot of things for me in terms of research and study design in general. First, I want to commend this group. In a country that I have to imagine has resources different from what we are used to in westernized modern medicine, they set out and performed a double-blind randomized study in a high-risk group of preterm infants. These are probably not the babies we are most often thinking about, the less than 28-week, less than 1000-gram infants in early transitional shock or late onset septic shock. This is a more varied group of moderate and late preterm infants. And yet they were able to institute double-blind randomization. The unfortunate part is the inability to control for open-label steroid use, and there are ways to plan for that prospectively.

Additionally, if you go back and read the two promising trials they cited in their introduction, one was essentially a very small case series of 11 or 22 infants comparing hydrocortisone to no hydrocortisone with a limited description showing early outcome benefit in smaller preterm infants. The second was a study on steroids for shock in term babies with HIE on therapeutic hypothermia. These are reasonable primary studies to build from, but all of them were limited by very small numbers.

What I take away for trainees and anyone reading this paper is that all the planning in the world may not be enough. Planning a study properly probably requires two to three times the work of actually executing it, because these problems arise. You invest a lot of time. You do not want the absence of an open-label crossover plan, or the failure to pre-specify an intention-to-treat analysis, to be the limiting factor that takes away your message and prevents you from finding statistical significance that may have been there with a stronger design.

I commend the authors for pursuing and publishing this work, though I imagine it was difficult to defend the lack of open-label crossover consideration. The limitations make me wonder whether this really changes anything. We already have a lot of good data about low cortisol levels, stress states, shock, and hydrocortisone use in preterm infants. Fluid-refractory hydrocortisone use is a well-established tool, and we have plenty of supporting studies. It would have been great for this study to be more methodologically rigorous. I don't think it adds much beyond confirming what we already believe, that if you use it, you are probably going to get some benefit, and that at this five-day dosing strategy, you are probably not exposing infants to profoundly significant adverse effects. But Adrianne, how does this change your practice? What did you think?

Adrianne Rahde Bischoff (09:34.100)
I think it basically shows that we have no equipoise. We feel so strongly about this that it is nearly impossible to even study it. The fact that they gave steroids even to babies randomized to placebo tells you that neonatologists want to use it and believe in it. Belief is not the right way to do science, obviously, but it is a challenging thing to study.

Our practice here is very steroid-heavy and very early. I previously practiced in a place where we were truly using steroids for refractory shock, where you were on a first drug, considering a second, and then thinking about steroids at that point. I feel like more and more we are moving toward starting steroids while still on the first agent, in hopes of preventing the need for a second medication.

Nim Goldshtrom (10:13.100)
And this is all shock steroids, right? Not BPD, not respiratory failure management, not the preterm BPD picture. This is all shock. It is interesting.

Adrianne Rahde Bischoff (10:23.100)
We have a protocol here, including a fluid bolus to assess for preload-recruitable stroke volume, one or two agents, and then steroids for pressure-resistant shock. I do not think our use is as ubiquitous. We have a similar approach with the post-operative cardiac patient, where after multiple boluses and escalating inotropes you hit certain thresholds. Those patients are clearly in a stressed state, and steroids help not just for potentially low cortisol, since some of these are full-term surgical babies who may not have that, but because of the capillary leak and inflammatory response from bypass. But we try to be more judicious, because in that world high-dose steroids are clearly associated with poor wound healing and long-term post-surgical infections. There is a lot of dogma. We have tried to pull it back with evidence, but I understand why it is hard.

The practice I struggle with is the somewhat indiscriminate use of steroids for hypotension as first line, which I have seen in the transitional period. The reasoning being that a preterm infant probably has adrenal insufficiency, so let's start the steroid. The problem is that steroids may fix the blood pressure without fixing the underlying problem, which most often is not pure adrenal insufficiency. Most often there is cardiac dysfunction, pulmonary hypertension, low cardiac output, or something else that then becomes masked by that approach and can actually cause more harm than good.

Nim Goldshtrom (12:43.310)
Correct. Or preserved ejection fraction with low SVR, where what you actually need is an alpha agent. And the vasopressin data for hypotension with preserved ejection and systolic function comes to mind. It is complex physiology, and TNE opens up a world of assessment that we simply did not have before, and I hope it continues to pull us away from harder drugs with significant consequences, linear developmental consequences, hyperglycemia, and other things we want to avoid. These are not to say that some of these kids do not have low cortisol and a genuine need for steroids, but we have a lot of targeted drugs that can address vascular, hemodynamic, and cardiac problems and help these babies ride out their illness without necessarily reaching for steroids in situations that are not truly steroid-refractory.

I wonder if instead of steroids versus no steroids, what we should actually be studying is dose and duration. What is the effective dose to get what you want without running into issues like hyperglycemia and excessive cumulative dosing?

Adrianne Rahde Bischoff (13:47.100)
In combination with structured, standardized TNE to address the hemodynamics first. Fix the ejection fraction, fix the RV or LV problem, fix the vascular problem, and then in truly refractory states, ask whether there is evidence of low cortisol that would suggest a steroid is going to be additive rather than just a trade-off between side effects and a genuine stress-response medication.

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Nim Goldshtrom (00:00.000)
We have covered sepsis physiology and we have covered steroids. The only tool left to discuss is which drug to use during septic shock.

Adrianne Rahde Bischoff (00:44.356)
Yeah, so I am going to go straight into a controversial and hot topic. We are going to talk about a study that at the time of this recording has not officially been published yet, as it is coming out in the July edition of the Journal of Pediatrics. It is Norepinephrine versus Dopamine for Septic Shock in Neonates, also a randomized controlled trial. The first author, and I hope I am pronouncing this correctly, is Mohammed Yusuf Ali Masari, and the senior author is Shriparna Basou.
As we have touched on across the last two articles, a lot of practices for fluid-refractory shock are extrapolated from adult and pediatric guidelines, with recent guidelines favoring norepinephrine over dopamine as a first-line agent based on evidence showing benefit in all-cause mortality and a better cardiovascular profile in adults. In the NICU, historically, dopamine has been the most commonly used agent. Some of the concerns around dopamine include that it exerts its action through release of norepinephrine from sympathetic nerve endings, and neonates may have limited reserves of that. Additionally, the metabolism and clearance of dopamine is dependent on postmenstrual age. Finally, norepinephrine may have a more favorable pulmonary vascular resistance profile compared to dopamine, which may be beneficial in cases of pulmonary hypertension commonly seen in sepsis, though we just discussed from the Toronto paper that this may not always be the case.

This was a double-blind parallel-group RCT enrolling both term and preterm neonates with fluid-refractory septic shock. Septic shock was defined as blood pressure below the third percentile for gestational age plus two additional features, which could include low urinary output, prolonged capillary refill time, elevated lactate or metabolic acidosis, or low SVC flow. Fluid refractoriness was defined as persistence of shock after one or more normal saline boluses of 10 cc per kilo, and the diagnosis of sepsis required either a positive blood culture or a positive sepsis screen with compatible clinical course, which we can discuss.

The primary outcome was shock reversal at 30 minutes, defined as correction of hypotension, normalization of capillary refill time, and normal pulses with warm extremities. Per protocol, norepinephrine was started at 0.2 micrograms per kilo per minute and dopamine at 10 micrograms per kilo per minute. If shock had not reversed at 15 minutes, norepinephrine was increased to 0.3 and dopamine to 15. If shock still had not reversed, other drugs could be added at attending discretion. Crossover was generally not permitted but could occur if infants were refractory to multiple vasoactive agents.
They enrolled 80 babies, 41 in the norepinephrine group and 39 in the dopamine group, with three crossovers in the norepinephrine group and five in the dopamine group due to refractory shock on at least three vasoactive drugs. Forty-nine percent of babies had culture-positive sepsis, which raises my first question: were the others actual sepsis or a different type of shock? I was not entirely clear on what sepsis screen positive meant here. Was it based on CRP, left shift, leukocytosis? That was not well defined.
I also found it a bit odd that the median age at enrollment was four days, with an interquartile range going from roughly 28 to 48 hours up to seven to eight days of life, which would suggest most were early onset sepsis. But then they report 65 percent late onset sepsis in each group, which does not quite add up. I am not sure where that discrepancy comes from.

Either way, the primary outcome was not different. Shock reversal was present in 32 percent of the norepinephrine group and 46 percent of the dopamine group. The need for additional vasoactive agents and hydrocortisone was similar between groups. Other outcomes including shock reversal at any time point, time to shock reversal, hyperglycemia, severe IVH, ROP, NEC, and all-cause mortality were all similar as well.
NIRS values were lower in the dopamine group after 24 hours, and those babies tended to be more acidotic, but other physiological variables were similar between groups. There is no description of underlying physiology, echo data, or clinical phenotyping. Was this vasodilatory shock? Cold shock? Myocardial dysfunction? Were there shunts, and in which direction? What were the pulmonary hemodynamics? Was there hypoxemic respiratory failure? This is also a mixed population of term and preterm infants, and the definitions remain unclear. What does sepsis screen positive mean? How was SVC flow assessed, and what is the reliability of that measurement? If they did echo to assess SVC flow as part of their shock definition, why were other echo parameters not reported? SVC flow assessment in the echo world is not highly standardized and has significant methodological limitations.

I commend the group for conducting an RCT on two very important drugs, but there are significant methodological problems. I do not think this will change my practice in any shape or form. I need more information. The starting doses also surprised me. I would not start a baby at 0.2 micrograms per kilo per minute of norepinephrine. That is an extremely high dose. And even at those high doses, shock was not reversing. I am not sure what to make of that.

Nim Goldshtrom (07:55.844)
Go big or go home. That is just their philosophy. I have to say, if I am at 0.2 of norepinephrine, I am calling ECMO. That is a dose.

Adrianne Rahde Bischoff (08:10.100)
Exactly. So what are your thoughts, Nim?

Nim Goldshtrom (08:13.100)
You know, I think in trying to focus on TNE, septic shock physiology, and the options available, we are showing just how hard this work is. We have to commend these authors for trying. As people who write and publish our own research, we know it is difficult and we get challenged on a lot of things. It is not to say you cannot or should not pursue these questions, but it is genuinely hard to do good quality work with limited subjects and complex exposures.

That said, all the planning in the world will still produce problems, and the lesson is to think four times as carefully about your methods before you pursue your study, because that is where the answers live. These papers are giving us indications, yes, maybe no difference between the two drugs, but dopamine continues to show time and again that it affects multiple organ systems in ways we do not fully control. From the pulmonary system to the cerebral system to the heart, it is a drug with unreliable receptor effects when we now have other choices and tools like TNE that allow targeted approaches focused on much narrower and better-defined receptor classes.

Adrianne Rahde Bischoff (09:41.126)
And objective data rather than subjective attending impression. Whether the cap refill has improved, whether the extremities are warm. I could be swayed one way or another depending on which drug I am more comfortable with.

Nim Goldshtrom (09:57.060)
I know. And it is funny, because I am sure you do this too. On rounds when we are teaching residents and clinical staff, we always point back to the clinical exam and clinical picture. And yet when we discuss it from a research standpoint, we have to admit it is not reliable, right? Not without good interoperator reliability, and even with the same person, the exam changes over time. A lot of data points, and I harp on NIRS here, can be objective numbers but still limited. With NIRS it is really the direction and trend over time that matters most, not a single value. You have to know how to use your data point in context.

I am hoping the future in this data-centric world makes these studies better in profound ways. Take the hydrocortisone placebo paper. They had Phillips monitors, likely in a large regional hospital in India, pulling continuous data points, and they had a randomized trial and a system in place. It would have been interesting to think about secondary metrics that capture compensated shock beyond heart rate, blood pressure, and SpO2. Things like variance and skewness in data variability that can suggest compensated versus uncompensated shock. Integrating vital signs with TNE data in real time could be the future of how we design these studies. It is a huge lift and requires a completely different way of thinking about novel critical physiology in septic shock, hypoxemic respiratory failure, and cardiac dysfunction. But it allows a more standardized approach to analyzing data and telling a more complete picture.

Adrianne Rahde Bischoff (12:12.302)
And this is probably irrelevant for some of our audience, but in case we have younger learners who move fast, this is exactly the reason you cannot read just the abstract. If you go by the title and abstract only of a paper like this, you will conclude that norepinephrine and dopamine are equivalent for septic shock in neonates and it does not matter which you use. You have to read how the study was done, what the methods were, what the limitations are, and critically appraise the literature. Otherwise you will be led in the wrong direction and you will not make thoughtful decisions.

Nim Goldshtrom (12:50.100)
Because as you can tell from this one journal club alone, people have already made the mistakes and had them peer reviewed. You do not have to replicate them. You learn so much from getting into the nitty-gritty of what has already been done, and then you take it one step further and try to make it better with your next study. The beautiful part of research, as critical as we have tried to be for our audience in the context of hemodynamics, cardiac function, and congenital heart disease, is that these are solvable problems. It just takes time and investment and attention to detail. We hope this does not dissuade anyone from doing research. Our interpretation is not that people spend all this time and do not move the needle. They are moving the needle in ways that are not always obvious. It takes the mistakes to get to the successes. That is the fascinating and personally gratifying part of doing research. It is hard and it takes a long time. But to your point, Adrianne, you cannot read an abstract. You have to understand why the paper exists, and the methods section is probably the most important section, if not second most important, before everything else that comes from it.
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Eli Cahan (00:01.996)

We have got a wonderful, dense, frightening, scary, interesting, all the emotions kind of slate of articles. So we are just going to dive in.

We are recording about a week and a half after Mother's Day. And in case you were too busy having brunch or eating quiche with the moms in your life, the federal government held a really interesting press conference on Mother's Day during which they described a couple of things that I think frankly most of us would agree with.

Dr. Mehmet Oz, who is the administrator of the Centers for Medicare and Medicaid, said, and I quote: "Let me speak a little bit about the reality that one in three Americans are under-babied. What does under-babied mean? That means you either don't have the children or you have fewer children than you would normally want to have. We have a crisis that is causing our fertility rate to drop below 1.5. The replacement rate is 2.1. So we are way behind what we need just to even replace the people that we have in America."

That is interesting, and I think part of what has been an increasingly pronatalist bent within the current administration. The piece that a lot of us would agree with is that it is really hard to have a child in America today. There were voices at the conference, including a parent advocate named Olivia Walton, who described how in rural America it is really hard to have a baby. It is hard to get care. Moms are driving for hours to reach an OB. Most moms don't have the time or the money to do that. And after they have the baby, they are not going back for any kind of checkup.

So it was an interesting framing around the combination of difficulty in having children, maternal mortality, which they spoke about pretty strongly, and trends in fertility, which has been a source of much controversy. All of this then teed up the release of what the government has called moms.gov, a website for new and expecting mothers described by the administration as a groundbreaking resource that supports expecting parents navigating difficult or unexpected pregnancies. HHS Secretary Robert F. Kennedy said the Trump administration is strengthening its commitment to America's families by equipping mothers and fathers with the resources and information they need to build healthy, prosperous lives.

If you look at the website, it features information about pregnancy centers, federally qualified health centers, nutritional guidance, and other resources including financial and economic supports available after the child is born to help the infant thrive. The challenge, and the interesting piece that frankly none of us noticed on a first pass through the website, is that the site links at the top to an organization called Option Line, which is run by an organization called Heartbeat International. Heartbeat International was founded in 1971 to fight the legalization of abortion and used to be known as Alternatives to Abortion International before rebranding. It is an organization that has been sued by multiple parties, including the state of California in 2023, for pushing fraudulent and misleading claims to advertise unproven and largely experimental procedures, including one known as abortion pill reversal.

So a website that on its face is interesting is linking to an organization that comes from a particular place, feels politically engaged, and may hold views that people disagree with, or that may not even be legal according to the attorney general of California. Ben, I am curious what you make of the rhetoric at the Mother's Day conference, the release of the website, and the ties between a government website and organizations like Heartbeat International, formerly known as Alternatives to Abortion International.

Ben Courchia (05:29.662)

Thank you, Eli. I think this push by the administration is not entirely unfamiliar. In France, this has also been very much at the forefront of debate. President Emmanuel Macron coined a term that was shocking to many, which he called demographic rearmament, essentially calling for more natality, more babies. So it seems like this is along the same lines. It is very interesting that governments are now looking at fertility and at ways to influence the ability of families to have more children. In France, the approach has been to incentivize having families through financial benefits. That appears to be the intention here as well.

Now, the website, as you said, is a bit of a dual process and always a little confusing, because it ends in .gov and feels like a government information website, but it is more than just information. It is very much a direction the administration wants to push, and there is a lot in it. There are two things in particular that struck me. One is the mention of Trump Accounts, which as I understand it would provide roughly one thousand dollars from the US Treasury for every baby born. The other is the mention of more affordable fertility treatment through Trump Rx, though I am not entirely clear on where that stands in terms of progress or access to medication discounts.

The bottom line is that the website sits at an interesting intersection. It does provide some genuinely valuable information. For example, nutritional guidance linking out to CDC pages and similar resources. But it also takes a clear position against abortion and in favor of fertility treatment. And as you mentioned, the link to Heartbeat International is not just an opinion. When you get into the details of what that organization advocates, including the abortion pill reversal protocol, which claims that repeated high doses of progesterone given within 72 hours can reverse a medical abortion, things start to feel a little less straightforward. The front page is well designed and pleasing to the eye, but as you dig deeper, questions arise. It is an interesting positioning from the administration, and their intentions are fairly clear.

Eli Cahan (10:09.856)

Yeah, totally. I mean, you kind of are who you are friends with, or you are who you give a platform to at a Mother's Day press conference. At a basic level, the question is what information are we sending to people? The link on moms.gov goes to Option Line, run by Heartbeat International, which will only show people where crisis pregnancy centers are. As we have discussed before, crisis pregnancy centers tend to be oriented toward supporting continuation of pregnancy rather than providing the full slate of options, including abortion. Planned Parenthood, for example, is not findable through Option Line. And there are millions of Americans who have relied on Planned Parenthood for comprehensive education and healthcare in these situations. So as you said, the devil is very much in the details.

Ben Courchia (11:33.112)

It also feels a little bit like when a bill gets passed and there are a few items everyone agrees on, but then there is a long list of other things bundled in, and you find yourself wondering why all of this is being squeezed together. That is how this website feels to me as well. There are things where you think, okay, providing financial infrastructure for people to have more children, improving access to nutrition, fine. But then a lot of other things come with it, and you have to decide whether you are willing to take the whole package.

Eli Cahan (12:26.378)

Yeah. And I think you made another point that I want to spend a moment on, which is that there is actually some real alignment here in an interesting way. There is a fundamental message in all of this that I find genuinely hopeful, which is that the government is interested in supporting families. After all the rhetoric over the years about welfare dependency and people taking advantage of social benefits, here is a website that contains and supports access to resources for expanding families who could genuinely use that support from the social safety net. They would never frame moms.gov as a socialist endeavor, but there are hints of it. And to the extent that the government's job is to support people who are vulnerable and struggling, there is common ground here. We can all agree that part of the challenge around families is the difficulty of accessing maternal healthcare, including the fact that 35 percent of counties in the US, according to the March of Dimes, are maternal healthcare deserts. Part of the problem is also that having children is expensive and hard. And if we want people to do that, we need to support them rather than simply telling them it is their responsibility to figure it out.

The last thing I want to flag, and to be direct about it, is some of the language that you have to read carefully. When Dr. Oz says we are way behind what we need just to even replace the people that we have in America, that echoes what you described about Macron's demographic rearmament comment. According to research from the Center for Immigration Studies, the total fertility rate in the United States is around 1.8. The fertility rate of immigrants is about 2.2. The fertility rate for US-born individuals is about 1.7. So I am not sure where the 1.5 figure came from, but the general agreement is that a rate of 2.1 is needed to replace the existing population.

When you hear that rhetoric, it makes you think about the fact that the only reason America has continued to grow is because since the dawn of the country, in the modern era, we have relied on the ambition, hope, and contributions of immigrants. And it raises the question of why, in a pro-fertility agenda, there is not more inclusion of people who come from other places and who are desperate to be a part of this society, sometimes literally risking their lives to get here, rather than a focus solely on the demographics of certain individuals.

Ben Courchia (17:05.648)

Yeah, and without getting too political, this gets at the root of how strict immigration reform can coincide with continued economic growth, when so many countries actually function precisely because of an influx of immigrants who become productive contributors to society. That is where the rubber really meets the road. Who goes where and who does what? It is an interesting economic problem for these politicians to navigate, especially given how carefully the rhetoric around immigration has to be crafted.

Eli Cahan (17:55.370)

Well, we are not a political show. moms.gov is a new website. Your patients may see it. You should be ready to talk to them about it. Ben, this has been great.

Ben Courchia (17:58.179)

Agreed. And just to clarify one thing you mentioned about the Option Line link, it is not immediately obvious on the website, but the connection appears in the first few links when you go to find a pregnancy center near you. That is where you will see it. So for anyone looking for it, that is where to find it.