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00:00:00
thank you very much usable for that kind introduction and normally i would say thank you very much to the committee for giving
00:00:06
me the opportunity i'm i'm still it's not sure whether i should thank you um to do the contra talk after
00:00:12
the mother of lisa just um showed you the benefits of lisa
00:00:17
and on the other hand we will difficulties finding external speakers doing this talk and
00:00:22
we couldn't really think of somebody so quick decision was made probably based on
00:00:26
that kept clothing general obstructive behaviour in the committee that i would be a person
00:00:31
ah to do this and i'll try to do my best to um
00:00:35
to convince you that there are good arguments against lisa too
00:00:40
so i will i'll just show you the the the full methods that have mainly been
00:00:45
um that started in the literature in this um doctor trips has already alluded to
00:00:50
um there is you can apply um the surfactant lesson basically using different techniques for the
00:00:57
purpose of the store i will primarily focus on randomised control trials because we are
00:01:03
talking about therapies right so if we wanna decide whether or not the third one therapy is better than another
00:01:09
we should if possible look at stuff from randomised trials and that's
00:01:13
quite a bit of that are around for the purpose here
00:01:16
we'll have a look at the cologne and the whole what methods as introduced
00:01:20
by angela trips because all randomised control trials have used within those methods
00:01:26
no why lisa why would why would you do it um well maybe because it is less invasive that's
00:01:32
the the title isn't it i'm i'm not gonna talk about invasive miss here because that's something
00:01:39
um you have to make a judgement about about it's very hard to measure i would just try to encourage you to watch the video
00:01:46
that is associated with the um lots of publication likeable the first large a german
00:01:51
network try and have a look at the procedure itself there was a video
00:01:56
make your own my make up your own mind whether or not this is more
00:02:00
or less invasive then doing for instance in or integration and giving ensure
00:02:05
it's a matter of debate i'll talk about efficacy and the question
00:02:09
would be is it more effective than a control intervention
00:02:13
and it's important to consider the type of control interventions to so you can just lump everything together
00:02:19
and and draw a couple of diamonds and say what it has to be better because
00:02:23
see the time it is on the left hand side of the force plot
00:02:27
that the studies that have been done all the ah cities they used very
00:02:30
different settings different interventions different populations so we will have to look
00:02:35
at the details of those studies in yeah if it was more effective than it should
00:02:41
reduce the incidence of the compass it outcome of p. p. d. or death because that is
00:02:45
how are currently most robust short term outcome available to test the efficacy
00:02:51
really no c. t.s it could also be associated with few adverse
00:02:55
events for instance events related to the intervention itself but also
00:03:00
um interventions that a writer complications that arise
00:03:04
from using mechanical ventilation in control groups
00:03:09
the settings of the ah c. t.s that assessed lisa but
00:03:13
usually um look to get spontaneously breeding preterm infants
00:03:17
who had obvious based on clinical appearance schools and some
00:03:21
arbitrary harm um f. i. to cut off which
00:03:25
was uh which vary quite a bit and these babies usually require it's affected after delivery room here
00:03:32
so there are no studies on very early delivery rooms effect and
00:03:35
application in extremely preterm babies so we basically exclude preemptively
00:03:41
the most vulnerable population um if you look at the ah c. t.s
00:03:45
because the population at highest risk of p. p. d. or death
00:03:48
is excluded in most of the stuff most of published ah cities as of now
00:03:56
let's start into some really boring exercise will just go
00:04:00
through a couple of orange coloured um tables
00:04:02
and have a look at the top top i'm from those are cities i want you
00:04:09
on the first try was uh the mention german um network trial in
00:04:13
the trial um published in the lancet into that eleven i'm coming
00:04:18
eleven or twelve the german sentence 'em in rolling preterm infants between twenty six and
00:04:23
twenty i class six weeks who are less than twelve hours of agent enrolment
00:04:28
um the intervention group uh received lisa um classes and the treatment lisa was given by the cologne method
00:04:36
um as shown backup trips over one two three methods and the minimum effort to capture force all point three
00:04:42
control intervention receives state but usually c. pap um and rescue mechanical
00:04:48
ventilation and that's a fact and um based on local
00:04:51
protocols and the local protocols there is quite a bit if you look at the f. i. to range um
00:04:58
individual centres in the trial use their fire two captives between o. point three an open
00:05:02
six so that is that is quite a difference um in in clinical terms
00:05:08
and in the control intervention no baby at all was into but it's a lady forgiving surfactant
00:05:14
which is quite different from the intervention itself from so i'll
00:05:18
the primary outcome was c. cafe yeah from twenty five to
00:05:22
seventy two hours which was being either on mechanical ventilator
00:05:26
or requiring more than thirty percent of option or c. o. two
00:05:29
above sixty five and there was a range of secondary orchids
00:05:34
looking at the results you see that um these are reduced the primary outcome of c.
00:05:42
cafe yeah significantly primarily driven by in effect in the twenty eight week it's a
00:05:48
the trend in the twenty seven because it no difference at all in the twenty six week it's
00:05:53
secondary prescription outcomes indicated to the the trend towards would use number of days on oxygen
00:05:59
but no difference whatsoever in the incidence of p. p. d. okay thirty six weeks this is the um the trial
00:06:08
other secondary outcomes which we have to consider is that the lisa group um up babies
00:06:14
under the sub group were less likely to reef receive sedation or analogies yeah
00:06:19
and they received effort to at a much lower i'm cutoff um if i had to cut
00:06:24
off so the uh the the meeting cut off into the subgroup was open full
00:06:28
in the control group open for five and if you look at the into what had range that is quite a difference
00:06:34
i also th at the first those affected we all know that if we give it a yeah
00:06:40
um it works better be a chip getting surfactant was much lower into the subgroup all this indicates
00:06:46
that the threshold to give surfactant was lower indian in the intervention versus the control group
00:06:52
there were no differences in complications of preterm birth and no differences in serious adverse events now
00:07:00
my contract conclusion from day in the trial would be yes it reduce the risk of secret
00:07:05
failure in a non blinded study it had no effect on p. b. d. o. j.
00:07:11
and the set group was advantaged in terms of red mechanical ventilation reduction
00:07:15
because few infants was the day that which increases your chances of success success
00:07:21
they were given surfactant earlier and at low a fire to cut offs
00:07:24
which also increases increases your chances of success because it reduces
00:07:29
um this is the end is the severity of apart yes and no infant in the
00:07:33
control group at the chance to be too big it's a lady forgiving surfactant
00:07:39
this trial was at high risk of performance at detection biased because it was on mosque which had which had might have
00:07:44
an impact on the primary outcome and there were no long term you're the rent but to respect your outcomes reported
00:07:51
the second um german network try was run by hand coordinated but doctor trips
00:07:56
or um this was also done you know in a multi centre fashion
00:08:01
this time the network and wrote much younger much more immature babies of twenty three to twenty six
00:08:07
weeks gestation where on c. n. n. between ten and a hundred and twenty minutes old enrolment
00:08:13
infants here at um a clinical um hot yes and require at least thirty percent of
00:08:20
oxygen to see to achieve an oxygen saturation of eighty three percent intervention group again
00:08:28
receive realise that this time though that beat faster o. point five to two
00:08:31
minutes and they got at least a hundred milligrams per kilogram of yourself
00:08:36
in the original again the trial difference affected preparations were used this time it was just use
00:08:41
of um that that was was not standardise not infants small infants got larger doses generally
00:08:49
the control intervention um was to integrate the baby and give 'em surfactant on the conditions of
00:08:55
mechanical ventilation and this time the primary outcome and this was try was powered for
00:09:00
the proper outcome was survival without b. p. d. at thirty six weeks which basically still
00:09:06
the seat of p. p. deal deaf there was a range of secondary outcomes
00:09:13
primary outcome presented here survival without b. p. d. all the opposite p.
00:09:18
p. d. o. death was not produced in that means that trial
00:09:23
these other all the use of the results of the same after adjustment
00:09:27
for um how similar after adjusting for centre and a gestation extraction
00:09:34
there were however differences in secondary outcomes um at predefined
00:09:38
secondary outcome was the survival without major mobility
00:09:42
for the purpose of distraught the office to find a major mobility s.
00:09:47
n. e. the i. v. h. three or four p. p. l.
00:09:50
i'm a i'm a bit of an echo fit requiring surgery
00:09:55
all a retinal puffy of premature richie requiring laser treatment
00:09:59
and these compensate outcome was reduced in the sub group
00:10:04
interesting iteration of mechanical ventilation and see but would not different in the in both groups
00:10:09
um there was a higher incidence of short term complications in the services control group in terms
00:10:16
of body car yeah and oxygen saturation string to procedure but also interesting me again
00:10:22
the sub group was less likely all at the trends towards being less likely
00:10:26
of receiving sedation or analogies yeah which might affect outcomes of this trial
00:10:33
conclusions from this trial it did not lisa did not reduce the risk of p. p. d. or that the primary outcome there were
00:10:40
some differences in secondary outcomes the direction of the full effect buried
00:10:44
in the compass without complete was pointing towards a benefit
00:10:48
of lisa i'm in short term complications it was pointing towards a disadvantage of lisa however
00:10:55
they were quite um significant difference discrepancies in the timing of
00:10:59
cup coffee caffeine the loading to this might be more
00:11:02
important because all all um all of us know that kevin is effective in reducing p. p. d. all day
00:11:08
and it is most effective most effective if it is given already it's quite surprising that despite of
00:11:14
peace there would no differences in the primary outcome also and this is a of concern
00:11:19
the the risk of citation was reduced in the some which might affect
00:11:23
the risk of having brain injury to compensate outcome i showed you
00:11:28
does come visit them survival without major mobility was kept at the reduction
00:11:33
and the differences between groups were primarily driven by reviews straight
00:11:38
in i the h. three oh full so maybe sedation had an influence
00:11:43
um we know from the um new pain that sunny and
00:11:46
and published bomb nearly fifteen years ago that babies receiving
00:11:51
routine sedation and but well i move five morphine polite
00:11:55
had a high risk of brain injury in a large randomised international trial
00:12:00
also the trial was at high risk of performance and detection biased because it was on mask
00:12:05
and from the r. c. t. daughter we have no um but information on your development or scripture outcomes
00:12:14
all of the following trials compare lisa against some sort of ensure technique
00:12:21
wasn't always perfectly describe but it's generally the full remaining trials all these are versus ensure
00:12:28
and in terms of size um take a trial was that the next larger trial
00:12:33
published in pediatrics two thousand thirteen signal sent to try out from turkey
00:12:38
in rolling inference between twenty five and thirty two weeks of gestation who
00:12:42
had ah yes we stable and see pat after delivery room care
00:12:47
and required at least forty percent of oxygen they gave lee's up
00:12:50
by a modified version of the cologne method a modified because
00:12:54
um it's it's the administrative time of administration more shorter are
00:12:59
used to a shortened capita and didn't use makeup forceps
00:13:03
this was given within two hours after birth in compared to the inshore
00:13:06
technique in sure most of you will be aware means or the
00:13:10
into patient getting surfactant within a short period of time putting the baby
00:13:15
on mechanical ventilation and do a soon excavation after giving surfactant
00:13:22
priming out come here because the the ventilation within seventy two hours after birth a range of secondary outcomes
00:13:28
i'm just to mention delivery room integration excluded and no energies
00:13:32
yellow sedation given walking either control or intervention group
00:13:38
primary outcome of mechanical ventilation was reduced in the sub group but the secondary
00:13:44
outcome of p. p. d. what it was not produced there was um
00:13:50
reduce the incidence of p. p. d. views look at one of
00:13:53
the components of the composite secondary outcome on the other hand
00:13:57
i'm a slightly new more babies died in the sub group so the compass it
00:14:01
of p. p. d. o. that was not significant between those two groups
00:14:06
my conclusions would be the services ensure from to take care trial reduced the need
00:14:11
of mechanical ventilation but did not result in reduced rate of speech video death
00:14:16
distraught was the high risk of performance and particularly sound detection bias which is important if you look at
00:14:22
um a secret fail within the first three days of life and the window long term outcomes reported
00:14:29
now these two trials were conducted in and he ron one bunyan yeah and can be and colleagues
00:14:35
and one by mohamed is that they um they uh in role somewhat similar patient populations
00:14:41
um many and rolled babies from twenty seven to thirty two weeks who had ah yes
00:14:46
it required thirty percent of option at least and one that is that the uh in role babies
00:14:51
less than thirty two weeks who had a birth weight of a thousand to eighteen hundred grams
00:14:56
i'm also um cannot yes and at least thirty percent of oxygen i'm
00:15:00
somewhat discrepancy um a saturation levels all babies stable and see that
00:15:06
these are was administered by the cologne method class giving
00:15:10
um actually been and a control intervention was ensure
00:15:14
um plus giving actually been a similar outcomes
00:15:20
describe here um the um delivery room excavations were excluded and babies
00:15:25
with quick transition after birth are also excluded no these
00:15:28
studies had some um some more limitations both where i'm blinded
00:15:33
opinion yeah there was no primary outcome uh described
00:15:36
um the run my station method wasn't clear the concealment of a location
00:15:40
was aren't clear and um the control intervention itself meaning ensure
00:15:46
was not described in indian yeah they just said it ensure that you didn't really know what to do it
00:15:53
looking at the results immune yeah mechanical ventilation time in lisa appears to be higher
00:15:59
then ensure they quote the p. value four point two you stick to some statistics program
00:16:04
you would you would end up normally with a highly significant value i'm not sure it's just the summary that
00:16:09
target is presented in the paper maybe that is the reason if anything it strains to what's up higher
00:16:16
um right higher duration in mechanical ventilation in the use of essential groups
00:16:22
the secondary outcome of p. p. d. or deaf was training to what's a benefit in the sub group but
00:16:27
look at the components this is not written by the p. d. at all this was driven by death
00:16:33
and they had a very high death rate actually had a nine to send any c. rate and they had a
00:16:38
a very high sepsis rate of forty percent in the unit with a and they mentioned that they
00:16:42
had a n. i. c. u. over due to overload at the time of doing the study
00:16:46
with the one in ten nursing so one notice looking after ten babies and and i'm not
00:16:51
entirely sure whether we can transfer the results of the study into our own settings
00:16:58
when it is okay on the other hand um had the same i just had had a pretty five primary outcome and this
00:17:04
was not changed so mechanical ventilation within the first three days
00:17:07
wasn't different um b. p. d. r. death wasn't different
00:17:12
and my conclusions would be decked out in any of these
00:17:15
others ensure probably result in increased direction of mechanical ventilation
00:17:20
did not significantly reduce the compensate of p. p. d. or death ah in one it is that they use other is essential
00:17:28
in in on average babies at thirty one weeks did not reduce the need for and
00:17:32
even did not result in a reduction of p. p. d. o. that again
00:17:36
issues in terms of methodological quality and no long term outcomes that is the last study
00:17:42
paul a single sent to study from china um published in b. m. c. pediatrics uh open access
00:17:49
patients of twenty eight to thirty two weeks of gestation age who also had arm
00:17:54
yes we're stable and see that at least thirty percent oxygen so quite similar
00:17:58
some of the other trials in the baby's about thirty weeks to fight to cut off um was
00:18:04
predefined to be slightly higher values lisa with a stiff catheter
00:18:10
um and um the control group got in shallow in both groups no creepy medication was used
00:18:16
and they used to standardise those of euro serve hadn't
00:18:20
um has recommended two hundred milligrams per kilogram um
00:18:25
carmel commute from mechanical ventilation um in the range of secondary outcomes distraught
00:18:30
was stopped early so we see sample size on top ninety
00:18:34
it was originally targeted to achieve a hundred and twenty babies and
00:18:37
this was the power calculation to use for the primary outcome
00:18:41
um but a change to s. p. o. two levels within uh the the
00:18:46
uh doing the trial and uh stopped after ninety patients
00:18:51
the primary outcome mechanical ventilation wasn't changed and um the secondary outcome of p.
00:18:57
p. t. or death wasn't changed you don't know where the components
00:19:02
conclusions here the services ensure did not reduce the need for and he did not result in reduction of b. b. d. o. death
00:19:10
to try to stop the early again at high risk of performance and detection biased because it was on blinded
00:19:15
like all other trials and we have no long term information now if you learn all this started
00:19:23
from all those trials into a single makes analysis without thinking about anything
00:19:27
and just punch in the numbers then yes you end up with the benefit of the services control but as i hopefully have
00:19:34
shown to you you can just use those six trials and stick them into one single makes on others is because the
00:19:40
did quite different things and methodological quality of those trials
00:19:45
which is commented on in the same data analysis um was
00:19:49
um not consistent i mean the german network tryouts will
00:19:52
generally in terms of methodological quality much better than the other trials but still
00:19:57
there was a high risk of performance and detection by us and if you look at the
00:20:01
whole picture there was considerable amount of bias in five out of six domains covered here
00:20:07
so if we use the great approach reference standard of giving
00:20:11
recommendations and specifying the strength of recommendations based on the quality of evidence great
00:20:17
would say our confidence in the results should be very seriously reduced
00:20:24
no one thing i haven't talked about his i mean lisa might be reasonable treatment
00:20:29
the question is what are people doing with the control and in none
00:20:34
of the studies volume guarantee ventilation for instance was used as a
00:20:38
standard method of ventilation i mean if you wanna argue about the
00:20:43
dots are and um outcomes and look at this um
00:20:47
update from i'm clinging but this is a peter davis group from from melbourne
00:20:52
um which was just published in two thousand and sixteen comparing
00:20:55
volume targeted versus pressure limited ventilation most of those studies
00:21:00
use some sort of more or less specified form of oppression limited ventilation then
00:21:07
volume talkative ventilation has a huge effect on p. p. d. what death and
00:21:10
it's in fact the only currently the only published um type of
00:21:15
and what would a ventilation that reduces the incidence of the video death in preterm infants
00:21:21
it also has an effect on i. v. h. three or full
00:21:25
in this meta analysis would actually reduce risk of that
00:21:28
less hyper copy yeah less p. v. l. less newman thorax and reduce duration of
00:21:34
mechanical ventilation so if babies into control we group don't receive optimum standard treatment
00:21:41
something that's reasonably good as a counter opponent i would say something recently good reasonably good again something that
00:21:48
is poorly done which would would usually result in the
00:21:53
reasonably good treatment being superior against the control
00:21:58
no
00:21:59
on some in summary i would say that the size the modern and not harmful technique based on the current evidence
00:22:05
there is no evidence to show that liza results in
00:22:08
less pharaoh long term outcomes compared to standard treatment
00:22:12
on the other hand there is no robust evidence suggesting relevant
00:22:15
long term benefits of lisa over angel who control treatments
00:22:21
we have no long term outcomes from our city only from observation of studies that we have no
00:22:26
the the delivery room surfactant the control groups in some of the tryouts were really disadvantaged
00:22:32
as they did not have stand volume target ventilation some in some tries to get had caffeine
00:22:37
at a later time at highest affecting threshold and receives more sedation potentially causing additional problems
00:22:44
and i believe that we need more trials and there is currently a large trial
00:22:47
on the way the optimistic trial which is wrong but couldn't argue from what
00:22:52
which will hopefully give us additional information on this issue and we need high quality systematic reviews
00:22:59
including and incorporating in their conclusions the methodological quality of studies
00:23:04
and there is a protocol in the corporate database
00:23:07
so thank you very much for your attention

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Conference program

Opening
Matthias Roth-Kleiner, Lausanne
16 Jan. 2018 · 9:34 a.m.
Welcome words
Mathias Nelle, Bern
16 Jan. 2018 · 9:36 a.m.
Personalised prediction of weight changes in the first week of life
Severin Kasser, UKBB
16 Jan. 2018 · 9:41 a.m.
Neurofilament serum levels as biomarker of neuronal injury in very preterm born infants
Antoinette Depoorter, PhD Candidate
16 Jan. 2018 · 9:49 a.m.
Neonatal red blood cell (RBC) transfusion practices in Switzerland
L. Gosztonyi, C. Rüegger, R. Arlettaz, Neonatology USZ
16 Jan. 2018 · 9:58 a.m.
NEO (Neonatal Esophageal Observation) Tube - A feeding tube with monitoring function
Patrizia Simmen, Department of Neonatology, University of Basel Children's Hospital
16 Jan. 2018 · 10:25 a.m.
Less invasive surfactant Application - Pro
Angela Kribs, Köln (DE)
16 Jan. 2018 · 11:33 a.m.
Less invasive surfactant Application - Contra
Sven Schulzke, Basel
16 Jan. 2018 · 11:51 a.m.
Q&A - Less invasive surfactant Application
Panel
16 Jan. 2018 · 12:14 p.m.
Stem cells and birth
Martin Müller, Bern
16 Jan. 2018 · 2:32 p.m.
Stem cells and white matter disease
Raphael Guzman, Basel
16 Jan. 2018 · 3:16 p.m.
Protect the neurons: The challenge of the neonatologist and the researcher
Anita Truttmann, Service de Néonatologie, CHUV
16 Jan. 2018 · 4:12 p.m.

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