Oxygen for Preterm Infants; Top-Down Therapy in Crohn’s

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of Texas Tech Health El Paso, look at the top medical stories of the week.

This week’s topics include maternal diet to avoid peanut and egg allergy, oxygen for preterm infants, top-down therapy for Crohn’s disease, and neuroprotective therapy for stroke.

Program notes:

0:37 New stroke therapy

1:37 Use of IV for 10 days after stroke

2:37 Present late after a stroke

3:39 Long-term outcomes of top-down therapy in Crohn’s

4:40 Outcomes up to 5 years

5:40 Early tumor necrosis factor use from diagnosis improves outcomes

6:42 No real downside

7:38 How much oxygen for 32-35 week neonates?

8:34 Ongoing respiratory support needed?

9:34 Not hypoxic to begin with

9:50 Feeding eggs and peanuts during pregnancy

10:50 Did not impact risk for infant allergy

11:50 One-third dropped out

13:03 End

Transcript:

Elizabeth: So-called top-down therapy for Crohn’s disease.

Rick: What’s the optimal oxygen to give a preterm neonate?

Elizabeth: If we feed moms eggs and peanuts, can we avoid allergy in their infants?

Rick: And neuroprotective and neuroreparative therapy for stroke.

Elizabeth: That’s what we’re talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: And I’m Rick Lange, president of Texas Tech Health El Paso.

Elizabeth: We have some noteworthy stuff this week. Rick, which one would you like to start with?

Rick: Let me start with this new stroke therapy. That’s in JAMA.

We’ve talked a lot about stroke in the past and its treatment with regard to either dissolving clots and the appropriate time to do that, or using thrombectomy devices to get rid of clots. But many individuals don’t qualify for either thrombolysis or thrombectomy.

So there are two parts of the stroke. One is occluding the blood flow, and that’s what causes a stroke. The other is the neurodegeneration and lack of neural repair that occurs after that. This is a study that looked at loberamisal, which provides both neuroprotective and neuroreparative therapy in individuals that have a stroke.

It’s a small-molecule compound and it targets two different pathways. One is called the [PSD]-95 pathway, and that’s responsible for repairing damaged neurons. And the other is the GABA pathway (gamma-aminobutyric acid), also involved with repair. If you have individuals that don’t qualify for thrombolysis or thrombectomy, can the administration of this, this IV administration, for 10 days after the stroke help restore full functional capacity measured at 90 days?

This is a study conducted in China where there are just under 1,000 patients and they received either routine care or they received IV loberamisal for 10 days. How many of those recovered? That is a rank and scale of 0 to 1. That’s a scale of 0 means there’s no abnormality at all. And 6, by the way, is death.

Those that received the loberamisal, 70% of them had a rank and score of 0 to 1 compared to only 56% in the placebo group. What serious adverse events occur? There was really none.

Elizabeth: Is there any data in this paper relative to how many people who have an ischemic stroke would fall into this category?

Rick: In China quite a few, because there are fewer acute stroke centers. As you know, in the U.S. we have a spoke-and-hub. Individuals that present to outside communities that can’t provide thrombectomy or thrombolysis are rapidly shuttled to a center where that’s available. Nevertheless, there are some that don’t qualify because they present late after a stroke.

Elizabeth: It sounds like this is really an important advance, and I guess I’m wondering how this would compare to thrombolysis in stroke patients.

Rick: The largest benefit are going to be those in whom you can restore blood flow and restore it quickly before there’s irreversible brain damage. Regardless of whether they get thrombolysis therapy, what can we do to facilitate neuronal repair? And that neuroreparative therapy or neuroprotective therapy is what this offers.

Elizabeth: And does this suggest that maybe it ought to be used concomitantly with thrombolysis?

Rick: Elizabeth, I think the answer to that is probably yes. We need additional studies.

There were a small group of individuals in the Chinese study that did receive thrombolytic therapy or thrombectomy, and in those in whom blood flow was restored, this was equally efficacious. So I suspect in the future we’re going to both restore blood flow as quickly as possible and in all individuals provide some neuroprotective or neuroreparative therapy.

Elizabeth: Since we’re talking about benefits of different interventions, let’s turn to The Lancet and this long-term outcomes of top-down therapy versus a conventional step-up strategy in adults with newly diagnosed Crohn’s disease. And this is a 5-year follow-up of this so-called PROFILE trial.

They wanted to look at whether top-down treatment resulted in significant, actually, changes in the long-term disease course. And so in this trial completed in 40 hospitals in the U.K. with patients ranging in age from 16 to 80 years with newly diagnosed Crohn’s disease, they were randomly assigned to the top-down, which was infliximab [Remicade] plus an immunomodulator right at the get-go of the diagnosis of their disease, or a more traditional step-up protocolized treatment strategy. And this took place for 48 weeks, and after that their participants reverted to their local standards of care. They looked at outcome data for up to 5 years after the week-48 visit, including the need for Crohn’s-related abdominal surgery as their primary outcome, but there were numbers of secondary outcomes.

So they had 193 top-down treatment folks and 193 step-up treatments. A lot of them, 93%, had post-week-48 records available. They had a substantial number of benefits relative to this top-down strategy. During their follow-up, there were 28 Crohn’s disease-related abdominal surgeries in 26 patients treated with the step-up approach versus only six surgeries in six patients treated with the top-down approach. The time to surgery was shorter in the step-up group, so they had to go to that more often, and the incidence of Crohn’s disease-related hospital admissions was higher in those in whom it was the traditional approach. And finally, that time to first hospital admission was shorter with the step-up treatment rather than the top-down treatment. What the authors conclude, of course, is that early top-down anti-tissue necrosis factor treatment from diagnosis is associated with a number of improved long-term outcomes at 5 years. It sounds like this is pretty practice-changing to me.

Rick: Elizabeth, I agree with you entirely. There’s been some hesitance to use this — what you call top-down suppression and immunomodulation — because there was some concern that that would increase the risk of both infection and malignancy. And so we start off treating a little bit lighter, using primarily steroids, and then we would advance that if people didn’t respond.

But what this study shows is, if you do that, you have a higher risk of the complications that you mentioned. So if we start with a more intensive therapy, we can actually modulate the outcome with regard to Crohn’s disease. This is regardless of what stage Crohn’s disease was initially found. This, as you mentioned, I think is a game changer in terms of how we’re going to initially treat patients with newly discovered Crohn’s disease.

Elizabeth: I absolutely agree. There also were no differences in adverse side effects between the groups. It doesn’t seem like there was any real downside to doing this. This notion that somehow this treatment is going to actually change the disease course is pretty persuasive.

Rick: It is. And it’s interesting. Those that involve the step-up therapy, more than 90% required some maintenance immunosuppression therapies. They’re going to eventually get to it. You might say, well, let’s predict for those high-risk patients. But what this study shows is every patient benefited, whether they were considered to be “high-risk” or “low-risk” Crohn’s, is the top-down therapy modulated the outcomes.

Elizabeth: And the authors, of course, suggest that this is really easy to implement. And so there ought to be the ability to implement this in all sorts of clinical settings.

Rick: And lastly, Elizabeth, it’s durable. In other words, they treated the individuals with top-down therapy for 48 weeks, but followed these individuals for up to 5 years.

Elizabeth: Good news. On to your next one.

Rick: How much oxygen do we need to give kids that are preterm neonates born at 32 to 35 weeks? When they’re in the delivery room, many of these kids, approximately 70%, receive oxygen. We know that if you give really preterm, younger than 32 weeks, if you use 100% oxygen, it increases the risk of having intracranial hemorrhage and increases the risk of having blindness. What about those preterm kids that aren’t quite that young? How much oxygen should you give them?

And that’s what this study did. It was in 26 different Australian maternity hospitals. They looked at all neonates that were born 32 to 35 weeks’ gestation. They didn’t have any major congenital abnormalities, but they required some respiratory support within the first 3 minutes of birth. And they randomized them to either receive room air, that’s 21% inspired oxygen, versus supplemental that was 30%. The primary outcome was the ongoing respiratory support after they left the delivery room. And then they have 12 secondary outcomes.

They looked at over 1,800 eligible newborns. About 73% required ongoing respiratory support when leaving the delivery room. And when they looked at the overall outcomes with 21% versus 30%, there was really no significant difference. And when they looked at the 12 secondary outcomes, 10 were no different. There was a very modest benefit with 30% oxygen in two of the 12, and the primary endpoint wasn’t met. That’s hypothesis-generating, but it doesn’t particularly show that 30% is better than 21%.

Elizabeth: This is such a curious area to me because there’s just so much discussion about — and not just in neonates but also in older people — about what is the appropriate level of oxygenation for these folks, because there are deleterious outcomes.

Rick: Right, Elizabeth. And we reported years ago that when people came in with a heart attack and they’re routinely put on supplemental oxygen, is that they weren’t hypoxic to begin with. That didn’t help, and in fact it increases their mortality for reasons that are unclear. So finding the right amount of oxygen in the right patients is incredibly important. And you just can’t assume that more is better.

Elizabeth: No doubt more coming on that. And that, of course, is in JAMA.

Let’s turn finally to the New England Journal of Medicine, this disappointing trial on feeding moms a diet rich in eggs and peanuts to reduce allergy in their infants. And in this Australian study, they enrolled pregnant women whose unborn child had at least two biologic family members with medically diagnosed allergic disease, so at high risk for the development of egg and peanut allergy.

They assigned their participants 1:1 to follow a diet high in eggs and peanuts, that was six eggs a week and 60 peanuts per week, or a standard control egg and peanut diet that included no more than three eggs and 30 peanuts in a week. And they did that from their before 23 weeks’ gestation until 4 months postnatally during lactation. And their primary outcome was IgE [immunoglobulin E]-mediated egg or peanut allergy in the infant at 1 year of age. Over a thousand participants in each of their arms. It did not appear that the ingestion of high amounts of egg or peanut during pregnancy and lactation resulted in a lower risk of the development of these allergies in their infants by the age of 1.

Rick: You can actually detect food allergens in amniotic fluid. And then, obviously, when the kids swallow, it reaches the GI [gastrointestinal] tract. And in the postnatal period, you can detect food allergens in secreted breast milk. So it would seem just natural that if you could expose the children early on it would decrease allergies. It really didn’t have any beneficial effects at all. It didn’t decrease IgE-mediated egg or peanut allergy, or even the medical diagnosis of eczema that oftentimes kids get as well. So it is disappointing.

Elizabeth: I thought it was noteworthy that in both groups 99% of their participants commenced breastfeeding, with 88% continuing to 4 months of postnatal infant age. They only had 64.4% standard diet and 66.6% of the high-egg-peanut group who continued for the whole study. I’m wondering if that one-third might have modified, if they had all completed the follow-up, the data at all.

Rick: Yeah. There are obvious statistical ways of handling dropout. It would be nice to know whether those third that didn’t complete it were any different. But it doesn’t appear, at least statistically, that there was any significant difference between the groups.

Elizabeth: And then I would finally note that the authors identify a potential limitation of this trial was the lower-than-anticipated prevalence of egg or peanut allergy, which they saw 8% actual versus 16% anticipated in those infants with a dual family history of allergic disease.

Rick: Yes, half of what we expected. Nevertheless, the patient population was large enough — almost 2,000 individuals enrolled in this trial — so statistically, if there was a difference between the groups, we would have found it.

Elizabeth: On that note then, that’s a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.