I guess the HIP trial should be about screening for congenital dislocation, but in reality, it stands for Hypotension In Preterm infants. The long road to the unsatisfactory conclusion of the trial started more than 10 years ago, in discussions with Gene Dempsey, after he left his fellowship with me in Montreal, we continued to discuss how best to answer the questions about the treatment of hypotension, which then was, and still is, a major controversy. We wanted a large pragmatic trial comparing usual therapy, which was to give a bolus of saline and then start dopamine if the mean BP remained below the gestational age in weeks, to an approach where treatment was only given if there were signs of poor perfusion. We realized that it would be ethically difficult to randomize, to placebo, babies with clinical signs of poor perfusion (even though we have no good idea how to treat hypotensive babies with poor perfusion either!) so the only eligible babies should be those without such signs.
The protocol that we thought best would be to allow rescue treatment for enrolled babies if they became profoundly hypotensive or developed other signs, but preferably with something other than dopamine.
Fortunately for me and the other investigators, Gene Dempsey didn’t leave this as a pipe dream, but put together an application to the EU under the FP7 scheme, and was successful in securing funding. Gene’s brilliance and his ability to get things done have recently been rewarded by Ireland’s first and only chair in Neonatology! Congratulations Professor Dempsey.
Part of the justification for granting these funds was that we should develop a specific neonatal formulation of dopamine. As you might imagine the clinician/investigators didn’t care a bit about that, we would have been happy to study off-the-shelf dopamine made by anybody, but as dopamine is not approved for use in the newborn in Europe, (or Canada or the USA in fact) we were mandated to perform the study as a basis for a neonatal approval for the drug.
Unfortunately, that led to enormous delays in getting the study started, as the company we were working with wanted a formulation without preservatives (as did we, if possible), and a manufacturer told them it was possible, but then it turned out not to be stable, so we waited for a formulation with a preservative but designed for newborns, and finally, as we were starting to get worried about running out of time, we received approval to use off-the-shelf dopamine, and had a one-year extension to the grant. Once we actually started recruitment it was slow going, which was somewhat expected, but the PIP (pediatric investigation plan) that had been approved by the EMA forced us to restrict the study to only babies with arterial catheters in place. I understood the restriction, non-invasive blood pressures are very unreliable in very tiny babies, especially when they are hypotensive! I will usually try to put in an arterial catheter in a baby if I start some inotrope/vasopressor treatment, but in my centre, generally for babies at 25 weeks and above we don’t otherwise routinely put in arterial catheters, we restrict them to those who have clinical compromise, who wouldn’t actually be eligible for the trial!
The PIP also mandated that babies have a head ultrasound prior to enrolment to document a lack of severe abnormalities. Again I can see the point, serious head ultrasound abnormalities were part of the primary outcome, but the reality of clinical practice is that babies are often hypotensive in the first few hours of life, and head ultrasounds are often not available when the decision to treat is made.
So in our centre, despite screening babies for many months we weren’t able to randomize anyone. Other centres were more successful, either because they used more arterial catheters or had more hypotensive babies, and often the attending neonatologist performed the head ultrasounds. Over the 2 years that the trial was recruiting there were over 800 babies less than 28 weeks gestation born in participating hospitals, 307 of whom had an arterial catheter in place, 91 of those were eligible for the trial, and finally 58 were randomized. We had planned for 830 babies, which would have been feasible if we had 3 times as many centres and twice as much time.
Finally, the grant expired and we had to terminate the trial, which was a huge disappointment. However, it is nevertheless the largest prospective RCT of hypotension in the preterm and the largest placebo-controlled RCT of dopamine use in newborn infants. (Dempsey EM, Barrington KJ, Marlow N, O’Donnell CPF, Miletin J, Naulaers G, et al. Hypotension in Preterm Infants (HIP) randomised trial. Archives of Disease in Childhood: Fetal and Neonatal Edition. 2021). I recount all these difficulties for anyone planning to study similar issues in the future. In older studies, about 50% of extremely preterm babies were hypotensive, whereas in HIP a bit less than 33% of extremely preterm babies with arterial catheters in place satisfied our criteria for enrolment, which were: 1. Less than 28 weeks 2. mean arterial pressure below the gestational age in completed weeks for at least 15 minutes 3. a head ultrasound without serious IVH.
In the 2 groups, the study drug (dopamine or placebo) was given in increasing doses (up to a maximum of 20 mcg/kg/min) until an acceptable BP was achieved, (above the GA) or they developed profound hypotension or signs of shock. That was quantified as a mean BP more than 5 below the treatment threshold, or at least 2 of the following: BP more than 3 below threshold; capillary filling time more than 4 seconds; serum lactate over 4 mmol/L.
The primary outcome was survival without severe brain injury on ultrasound, which was slightly more frequent among placebo infants, 69%, than among dopamine babies, 62%. Mortality was almost identical (7 babies vs 6), and other outcomes were also similar, obviously the final trial size was severely underpowered.
The only difference of note between groups was that the placebo babies were more likely to get back-up treatment 66% vs 38%.
The study illustrates some of the difficulties in doing such a study. We really wanted to do a pragmatic study that reflects current clinical practice, which was not consistent with the requirement to have a head ultrasound prior to starting treatment, at least in most North American sites where radiology organizes the imaging. Similarly the restriction to only babies with arterial lines while justifiable, I think does not reflect universal practice.
How could we do another study to get sufficient power to answer the questions? I think that a grant from an agency that commonly funds clinical trials in newborns, with a focus on just getting a clinical answer without concerns about specific neonatal formulations would help. Using the clinical research networks that are in place or currently developing would really help, although we have made some great relationships in planning and performing this trial.
The long term outcome of these babies is being collated and analysed at present, this was a co-primary outcome, and will also, of course, be greatly underpowered, but might be able to give us a hint as to whether avoiding dopamine in the first few days of life has a major impact on development. There will also be other publications addressing side studies, the first of them, which will be appearing soon, first author Liesbeth Thewissen, evaluates the impacts of hypotension and its treatment on cerebral NIRS signals. Watch this space!
Sir, why should we increase dopmine to 20 ugm/kg/min ( increasing the after load) without doing functional echo especially in preterms who have immature myocardium ?
The only mechanism by which dopamine increases blood pressure in the newborn is by increasing afterload. That is why I never use it myself! The reason for the trial protocol is that we tried to mimic what most people were doing at the time, not because I think it is necessarily the best approach. I think babies with circulatory compromise can be managed more rationally with the use of functional echo, including evaluation of responses to inotropes.
I love reading about the hypotension in extreme preterm. And the idea of use of dopamine , the highest dose of dopamine , the whats called renal dose of dopamine , the combined inotropic support as twinning dopamine to norepinephrine ,and their relationship to the abnormal head ultrasound . Amazing topics
Frustrating to get such poor recruitment for such an important trial. However, it happens as we found with Lex Doyle’s DART trial. Do you know why more babies were not recruited? Was it because the docs did not like something about the trial protocol?
By the way Colm O’Donnell in Dublin is a prof of Neonatology. I think Eleanor Malloy may be as well.
Hypotension is more frequent in intubated babies, and we use a lot more non-invasive ventilation now, also we place fewer arterial lines, and in many centres such as mine, I can’t get a head ultrasound at 3 in the morning unless I do it myself, which I can do but I’m no expert. My colleagues have never been trained. Hopefully, we learned some things that can help to design another trial.
I didn’t know that Colm and Eleanor had that title, I hope I haven’t annoyed them! I just accepted what the newspaper said as being true, always a mistake I guess.