OK, so I guess I had better blog about this article, that it seems almost everyone has been talking about since it was published…
I have heard for some years that someone at CHOP (for those who are not “in the know” that is the Children’s Hospital of Philadelphia) was working on an ECMO+ device, to keep very tiny preterm babies on extracorporeal support, without the need for pulmonary ventilation, and basically replacing placental function. I thought that the device was probably a couple of decades away, and hadn’t given it much thought, until this new publication.
It turns out to be far more advanced than I had thought, and, like ECMO, developed and pushed forward by a Pediatric Surgeon. (capitals intended, almost like G*d).
The latest iteration of their system requires cesarean delivery, cannulation of the umbilical vein, and both arteries, and then connection their device. When you deliver a fetus, they usually start to breathe, but for this procedure the mother is anesthetized and the fetus (in this case a fetal lamb) is given an intramsucular dose of an opiate.
The size of the umbilical catheters were 12 Fr or a specially modified catheter between 8 and 12 Fr, which is a 2.7 mm to 4 mm diameter catheter. The lambs, delivered by cesarean during the later part of their canalicular phase of lung development, weigh around 1.0 to 1.5 kg. The umbilical cord is isolated, treated with papaverine to prevent vascular spasm, (as well as maintenance of warmth and oxygenation) and the catheters (coated with an albumin heparin coating) are inserted a couple of centimeters and sutured in place. The lamb is then placed in a sterile plastic bag filled with artificial amniotic fluid and the catheters attached to a pump-less circuit with a very low resistance oxygenator (which is also, of course, a CO2 eliminator). Nutrition is added into this circuit and the lambs could be maintained for a prolonged period.
The lambs were also heparinized to an ACT of 150 to 180 seconds, and all received a prostaglandin infusion to keep the PDA open. They often needed blood transfusion, but fewer as time went on, probably because they started keeping the oxygen levels similar to the normal fetus, with less suppression of fetal erythropoietin.
They have created a model which does a lot of what the placenta does.
Except; the placenta does a lot of other things as well. The placenta supplies micro-nutrients and growth factors. The placenta metabolizes steroids very efficiently. The placenta regulates the movement of many molecules that pass from the mother to the fetus (and some in the other direction).
Which of these are critical to the developing fetus are unclear; whether your fetus is maintained in utero, in a plastic bag connected to an oxygenator, or in the NICU. One thing which is quite clearly critical to the future of this project is the nutritional aspect. The investigators were able to get the fetal lambs to grow with a combination of amino acid and glucose infusions, and by adding insulin were able to get respectable growth of the fetal lambs. Weaning of the lambs after many days of support was feasible, and succesful in transitioning them to more conventional care.
This is a huge technical achievement, which feels different to other potential advances in neonatology.
When Jere Mead and Mary-Ellen Avery showed that RDS was due to surfactant deficiency, the next step, which took many years, was to develop a replacement surfactant; this was a fairly typical medical advance. The “artificial placenta” is going a big leap further, replacing an entire organ system, the placenta and the uterus. I guess it is more analogous to renal dialysis, in a sense, than other neonatal advances. Other organ systems have been much more difficult to replace; hepatic replacement is much less effective, pulmonary replacement with ECMO or oxygenators is limited to how long they can be used. Even ECMO, when it becomes prolonged, is subject to a huge range of possible complications, even though many babies survive and do well.
One of my first thoughts was whether this would be technically feasible with much smaller subjects, but the last of the videos in the article is of a lamb that weighed 480 grams (much more immature also, of course), and was successfully supported using the system.
I don’t actually think this is going to be the end of neonatology, even neonatology of the most extremely immature babies. If this does eventually get translated to human use, then the procedures described need to be performed during a modified cesarean section delivery, which immediately limits the number of eligible babies. If the eventual plan is to take fetuses who have limited chances of ex-utero survival, which will include extremely preterm infants, then the maternal impacts of the delivery method also need to be considered.
Lambs don’t seem to be subject to intraventricular hemorrhage, which would be a concern for preterm babies getting heparinized, the ACT target ranges they aim for a substantially lower than ECMO, but mildly preterm babies on ECMO often have cerebral bleeds. I think they should try this technique on animals at risk of IVH (like the beagle puppy) before thinking of human trials.
During current ECMO treatment circuit changes, because of oxygenator failure or occlusion, are not rare, I can’t see in this manuscript if there is any report of the technical difficulties during the latest phase of their studies, including whether the oxygenator and circuit lasted the entire period without needing to be changed.
I think if this technique can be perfected, and this level of heparinization proven to be safe, then the plastic bag could be as good, or better, than being on a ventilator in the NICU, but will probably only ever apply to a small percentage of our babies. Now it only requires that the nutrition and oxygenation are varied to breed alphas, betas, gammas, deltas and epsilons!
Oh, wonder!How many goodly creatures are there here!How beauteous mankind is! O brave new world,That has such people in ’t!