This podcast is a production of OPENPediatrics,
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Welcome to the World Shared Practice Forum Podcast on OPENPediatrics. I'm Dr. Jeff Burns,
Chief of Critical Care at Boston Children's Hospital, and Professor at Harvard Medical
School. We are very pleased to have with us today, Dr. Scott Watson. Dr. Watson is the
Associate Division Chief of the Division of Pediatric Critical Care Medicine at Seattle
Children's Hospital. He's also Professor at the University of Washington School of Medicine.
And finally, he is a Senior Investigator in the Center for Child Health, Behavior and Development,
all at the University of Washington and Seattle Children's Hospital. Scott, welcome.
Well, thanks, Jeff.
It's a pleasure to be here. I really appreciate the opportunity to talk about our study.
Scott, as you know, we have invited you to OPENPediatrics, and the podcast, because
we and colleagues around the world are extremely interested to hear about your study entitled The
Association of Acute Respiratory Failure in Early Childhood with Long Term Neurocognitive Outcomes,
as it appears in the March 1, 2022 issue of JAMA, the Journal of the American Medical Association.
And Dr. Watson, I know I speak for many colleagues that this was an incredibly impressive study,
filling a gap that I don't recall being reported in the literature and that is examining long term
neurocognitive outcomes amongst children with acute respiratory failure in early childhood.
Could you tell us about the background and the motivation for this study?
I'd be happy to Jeff, thanks so much for the kind words, and I want to
just start off by acknowledging this was, the study was a partnership, was co-led
by Dr. Martha Curley and myself. And then we had a huge group of collaborators across the country,
including reaching out to neuropsychologists and intensivists throughout the US, so this was
really a large group effort over many years, and it was motivated by, as you know, the increasing
survival after critical illness has been a huge victory for our field over the past
several decades. And we've become increasingly interested in the quality of that survival,
and how children and their families recover after critical illness. And specifically related to
neurocognitive outcomes, there are a number of things that happen in the
ICU to critically ill children that raise the risk long term neurodevelopmental problems,
children have greater substance susceptibility to oxidative stress and excitotoxicity. They
have greater risk from ischemia and inflammation than our older ICU survivors, as far as we know.
And then more recently, there have been concerning data, mostly from animal models, but also some
human data about neurotoxic effects of sedatives on the CNS, specifically, benzodiazepines,
ketamine, propofol, and even combinations of agents, which are often more toxic in the
animal models, and then some suggestion that a new, relatively new medication dexmedetomidine
may be protective. So all of this led Martha and me to really want to dive into this more deeply.
Well, Scott, you've laid out the problem and the motivation well, and I find myself sitting
on the edge of my seat wondering, you know, what's the solution here? You noted that the derivation
here in the course of reading the study, this is a derivation of the original RESTORE trial.
Could you take us through this, how you and Dr. Curley thought about designing the trial, what the
methodology was, how did you do follow-up, neurocognitive follow-up on this cohort?
That's a great question, Jeff. As you know, the RESTORE trial was led by Martha Curley, it was a
cluster randomized trial of goal-directed sedation in children with acute respiratory failure. And as
a part of that trial, Martha planned a priority to perform post-discharge follow-up on a subset
of children in the trial. I was involved in that and we consented 2,000 of the nearly 2,500
subjects in that trial for follow-up at six months after discharge, which meant that those families
agreed to give us their contact information and agreed to be contacted by our study team. One of
the strengths of that trial, in addition to its size and its geographic distribution - all across
the US at 31 sites - was that there was really detailed data on what happened to the children
in the ICU. There are more than 37,000 PICU days of data, including really detailed data
on sedation use, pain, agitation, and withdrawal. So we had a very, very rich in-hospital dataset on
these patients. So when we began to plan RESTORE cognition, we wanted to take advantage of that
cohort and decided specifically to try to get a handle on the potential effects of the ICU illness
and ICU care that we would study as a subset of RESTORE subjects who provided consent to be
contacted after discharge. And the subset was children that at baseline, as far as we could
tell, had normal cognitive function as part of the RESTORE trial. We collected pediatric cerebral
performance categories on all the subjects. So we focused on the children that were PCPC of 1,
which is normal. And we also wanted to make sure that they were not admitted with a diagnosis that
would be indicative of, or concerning for brain injury. So we excluded children after cardiac
arrest or children who had a traumatic brain injury. And then we also wanted to exclude
children that had severe neurologic injury on discharge, because we assumed that those children,
and we assume and hope that those children would be followed closely after discharge regardless.
We also were worried about the vulnerability of the immature brain. So we focused on the younger
subset of the RESTORE population aged two weeks to eight years at PICU admission.
And when we reached out to these families, we did more medical history, or obtain more medical
history, I should say, and confirmed that the subjects had no underlying conditions that were
associated with developmental delay or neurologic injury. Then we also asked families if they had
siblings that live with a patient that would be eligible. The eligibility criteria were similar
to the former patients. They had to be full biologic siblings living with the subject, no
history of cognitive problems, and in contrast to the subject, no history of ICU care, and neither
the former RESTORE patients nor their siblings were able to have any anesthesia exposure.
Well, Scott, I have to say, you and Dr. Martha Curley are known as being
two of the most, amongst the most expert outcomes researchers in our field.
And many of us were really intrigued by the design that you created here, this sibling-matched cohort
study, obviously, that was designed to control for, kind of, nature and nurture issues. But could
you tell us a little bit about that? Why you chose that study design and the challenges with that.
You're exactly right Jeff, it was designed specifically, as much as we could, to control for
environmental factors. The subjects would have grown up with socioeconomic status, and then
there's reasonably high correlation of neurocognitive function and IQ
between siblings. So we wanted as much as we could to get to the nature part of controlling
as much as possible for the biological factors that affect neurocognitive function.
As you know, it's challenging to study neurocognitive function in children in
critical illness because critical illness usually is unexpected. So we don't have the opportunity
to do testing beforehand, which would be ideal. And then coming up with control group is also
challenging because none of them are perfect, in the absence of perhaps identical twins,
which we had a handful of, but not enough to control for everything there.
Well, the other interesting feature here, of course, is the neurocognitive follow up.
As you're noting, this is difficult to begin with. Tell us a little bit about,
a little more detail on how the neurocognitive follow-up on this cohort was achieved.
We're extremely fortunate to have a phenomenal lead neuropsychologist as
an investigator on the trial, Dr. Sue Beers at the University of Pittsburgh,
who helped us reach neuropsychologists across the United States for a network
of experts to conduct this testing. And the neuropsychological testing battery
was performed a long time after discharge, three to eight years after the children had
survived their ICU stay, and all the subjects, but the former patients and their siblings had
to be at least four years of age so that we can use comparable tests throughout the age range.
Well, Scott, I have to say, I'm unaware of any literature in our field that has examined
critically ill children who, prior to the illness, were cognitively intact
without any comorbidities who had this kind of neurocognitive follow-up.
And so this is an extraordinary study design that you and Dr. Curley and your colleagues
undertook and so what should we know, what do you see as the salient findings of this study?
When I think about the salient findings, I want to start with population that we enrolled and tested.
So we had 121 patients and the siblings. The patients themselves were young, they had a median
age of one year, so half of them were infants when they were hospitalized. 28% were one-to-four years
of age, and 21% were four-to-eight years of age, and they were tested median age of
six and a half years. As you mentioned, most of the patients were previously healthy. The
main reasons for admission were bronchiolitis, asthma, or pneumonia. They were ventilated for
a median of five and a half days, and then in the ICU for a median of eight days. So they had
moderate degree of critical illness. And with that amount of time on the ventilator, you would think
that they were really our bread-and-butter patients with acute respiratory failure.
16 of the patients received ECMO or high frequency oscillator ventilation. And then in terms of ARDS,
it was about a third, a third, a third at-risk or mild, moderate and severe, so a nice spread there,
and almost three quarters of the patients had multiple organ dysfunction. The
primary finding was that the patients had a lower IQ than their siblings, 101.5
versus 104.3, so a difference of 2.8 points, and that was statistically significant.
Now we had a lot of questions as we were putting the paper together about what is a roughly
three point IQ difference mean, that might just be the equivalent of being post-call
or not getting your coffee in the morning. But the key here is that that difference
was an average difference. And so to get that average difference, really the curve
of IQ scores shifted substantially in the patients. So 16% of patients had an IQ of
less than 85 versus only 7% of their siblings. But that was also statistically significant.
And then we looked at large differences between patients and their siblings to see
what proportion of patients had an IQ score a standard deviation below their siblings versus
a standard deviation higher. That's a 15 point difference. As you know, IQs are centered at 100.
And they're centered on the population with a standard deviation of 15. So it's quite a
difference. And more than twice as many patients had IQ 15 points below their siblings versus above
their siblings. So 17% versus 8%. So concerningly, we saw a shift in the curve of IQ after ICU care.
Well, Scott, those are fascinating findings. And of concern, obviously, that a large cohort 20%
are left in a significantly worse cognitive position than their sibling matched peers.
But in Figure 2 of your paper in JAMA, you also highlight that there is an age effect here.
Could you take us through that as one of the salient findings of your study?
The difference was really age-related. So the largest difference between patients and
their siblings was among the patients that were hospitalized at less than a year of age, and they
scored on average 4.6 points below their siblings. The difference was a little less
in the one to almost four-year-olds. And that difference was 1.9 points that the
patients scored lower. And then the older patients hospitalized at age four to eight,
there really was no difference at all. And it's clear that the findings were
really driven by outcome differences in children hospitalized at younger ages.
Well, again, these findings are just so thought provoking, and I must say
has face validity, at least with me. At least for the course of the question,
Scott, where do you and Dr. Martha Curley and your colleagues, where do you go next
on this? What's the next step in trying to unpack this and understand it better?
That's great question, Jeff. We're actually in the midst right now of analyzing the
full cohort that was tested. So we had a total of 257 former RESTORE subjects that underwent
neurocognitive testing. The study we just talked about was the 121 that had matched siblings. In
the full cohort, we really want to dive deep into what their exposures were in the ICU
and the relationship between those exposures and their outcomes specifically
related to sedation, whether the amount, magnitude, the type of sedation they received,
or a certain combinations of drugs are associated with their downstream neurocognitive function.
Well, Dr. Scott Watson, I know I'm speaking for colleagues around the world
that we eagerly look forward to this next phase of your
research. As you've just outlined, you and Dr. Martha Curley and your colleagues,
we eagerly look forward to hearing what you find in that analysis. But Scott, I have to ask you,
as a colleague, and a close friend over the years, has this changed your practice, these findings?
Another great question, Jeff. I have to say, not yet. I think we don't have enough information yet
about specific medications themselves, if there's an interaction between not just the medications,
but everything else that happens in the ICU. We know we don't want children to be
in pain or agitated after discharge, especially children that have respiratory failure at less
than a year of age, and really, probably less than four years of age. They warrant evaluation
as they age and special care as they enter school.
Well, Dr. Scott Watson on behalf of colleagues around the world, we thank you for being on
OPENPediatrics today to review again the findings. Again, the citation is March 1,
2022, JAMA, and the article is entitled Association of Acute Respiratory Failure
in Early Childhood with Long Term Neurocognitive Outcomes. And again, Scott, as we acknowledge your
role in this research with your colleagues, Dr. Martha Curley and others, thank you
for really all the excellent outcomes research that you have done over the last several decades,
and eagerly look forward to the results of the analysis that you're working on now to
dig deeper into this problem. Thanks for being with OPENPediatrics today.
Well, thank you so much, Jeff. It's really been an honor and a pleasure to be here and talk about the
study. What you're doing with OPENPediatrics is just phenomenal, and it's terrific to be a part
of it. So thank you so much for the opportunity. This has been a production of OPENPediatrics,
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