Fresh! New! but not any better.

Posted on 11 October 2012 by Keith Barrington

A new multicenter RCT in preterm infants has just been published. The ARIPI trial which was led by Dean Fergusson from Ottawa and included our NICU as one of the sites (Christian Lachance was our local lead investigator and is a co-author). ARIPI stands for Age of Red cells In Preterm Infants. The study was a response to many observational publications in older children and adults, that showed worse outcomes in intensive care patients when they receive older red blood cell transfusions (we rarely give actual blood any more, blood cells are divided up before we transfuse, so what you might call a blood transfusion is a suspension of red cells in a mix of plasma and some special solution to preserve the red cell function and stop the blood from clotting) compared to if they receive freshly donated red cells.

The trial compared what has become the norm in NICU; which is to give the first transfusion that a baby needs from a relatively freshly donated unit of red cells, then to give subsequent transfusions from the same unit until it is very old (often as much as 42 days); the investigators compared this to giving relatively fresh blood for every transfusion.

Very old red cells look weird under the microscope (see image below taken from an article in ‘Transfusion’ in 2006) and also don’t work very well as oxygen transporters. So the idea in older patients has been that these weird looking red cells actually induce inflammation without having a real benefit, But all of the adult and older child data is observational stuff, not a single prospective RCT. The idea was that giving fresh blood each time might improve all of those diseases that are related to inflammation and reactive oxygen species, but would have the downside of increasing donor exposure. I don’t know if anyone non-medical will have read this far 😉 but each new donor increases the risk of a viral infection such as hepatitis or HIV. But, and it is a big but, blood transfusions, or should I say red cell transfusions, are now incredibly safe. The risk of HIV is less than 1 in 1,000,000 transfusions. Blood transfusions are one of the safest things that we do in medicine, (despite the hysteria generated by politicians that means we now, in Canada, have to get individual signed informed parental consent on government approved forms prior to giving any kind of blood product) much safer than other routine therapy such as giving antibiotics, or intubating patients….

Anyway, to return to the new study, the idea was that the fresh blood arm might well have fewer complications than the ‘old’ blood arm of the study, and that this might overcome the very tiny extra risks of being exposed to more donors. The study was powered to show a 15% difference in a combined outcome of bad stuff death or one of 4 major morbidities : bronchopulmonary dysplasia, retinopathy of prematurity stage 3 or more, necrotizing enterocolitis stage 2 or more, and intraventricular hemorrhage grade 3 or 4.

What they found was…. (drum roll)…. nothing. That is right not any whisper of a difference in outcomes between the groups. The primary outcome was found in 52.9% versus 52.7%, BPD was as you would expect the commonest of the components of the primary outcome, 33% vs 32%, IVH was slightly higher, and retinopathy slightly lower with fresh red cells, neither remotely significant. Now you could argue that the study was underpowered. That a sample size of 377 infants doesn’t give you enough power to say with confidence that there is no effect. That is true, but we can say with confidence that there is no very large difference in outcomes, and that there is no difference in outcomes anywhere near as large as the observational studies suggested. You could also criticize the composite primary outcome variable, as lumping together a number of things with different pathophysiology that could go wrong with a preterm baby. But the fact remains that this was a very difficult study to get organized (but once the blood banks were interested, the logistics were easier than I thought they were going to be), and a difficult study to design and get approved and get funded.

So congratulations to the investigators. Now we know that our standard practice is not substantially worse than giving fresh red blood cells; even though we still don’t really know when to give transfusions! The study does show, yet again, that observational data are of very limited value, they can give you a pointer as to what we should study, but then the studies that we need to direct therapy, are large RCTs. Preferably really large. simple, multinational, RCTs.

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Probiotics: enough is enough

Posted on 9 October 2012 by Keith Barrington

At the EAPS meeting in Istanbul, the Proprems trial results were just presented. Now this has not yet been subject to full peer-review, but as a report of a large multicenter RCT it is not likely that their main findings will change. The study was powered for a reduction in late-onset sepsis, which I would maintain was the wrong outcome, we already had good data that there is no effect of probiotics on this outcome from the 20 previous trials. However that was the decision of the investigators, so they had close to 550 babies per group: 1. placebo, 2. A mix of two Bifidobacteria,infantis and lactis, and Strep thermophilus.

The investigators had less definite NEC (grade 2 or more) than expected. 4.4% in the placebo group. Nevertheless they found even less NEC in the probiotic group (2.2%). Now I don’t have all the details or the exact sample sizes, but that reduction is pretty close to being significant at 0.05, and to be honest if it is 0.051 or 0.049 doesn’t matter a ha’penny (as an Mancunian might say).

The effect size of the Proprems trial on NEC, expressed as a relative risk, is well within the confidence limits of our expectations from prior systematic review (0.5 compared to 0.4; CI 0.29 to 0.55).  Now I don’t have all of the info about the trial and I don’t have the exact numbers, but slightly different exact numbers have almost no effect on the conclusions of an updated meta-analysis; the Proprems trial serves to narrow the confidence interval of the meta-analysis slightly. Shown below is an updated Forest plot using all of the available studies (Girish Deshpande is already working on doing this correctly, and most likely Khalid AlFaleh as well) but this is a very quick initial run at it, don’t quote me!Probiotics dec 2012

One of the interesting things that will no doubt be addressed by the authors is why the control group rate of NEC was so low? The ANZNN database reports previously showed that infants under 28 weeks (to be in Proprems you had to be under 1500 g and under 32 weeks) had a NEC incidence much higher than that, at around 10%. So either a lower risk group was enrolled, which is a possibility, or some other study characteristic decreased NEC in both groups. My first guess is that to be in Proprems you had to entered before 72 hours of age, so maybe infants who were more unstable and at higher risk tended not to be approached or did not consent.

In any case, one of the endless criticisms of previous trials was that they were in high risk groups. The new trial shows that probiotics work in a low risk situation also.

What now? All potential participants in other placebo controlled trials should be informed, MUST be informed, of this information. In a non-biased manner.

Are there still physicians who could honestly continue to randomize children to placebo? It has been many years since I would have been prepared to do so, and we have been giving probiotics routinely in my NICU now for 16 months. Our results, a prospective cohort study, are being prepared for presentation and publication as I speak, but they are not inconsistent with the systematic reviews.

Importantly NEC still exists, we might reduce it by about half with probiotics, but some babies, too many babies, still get this devastating disease. In fact it seems that the cases that we still get occur earlier than the mean age in the past (early analysis of my cohort study, to be confirmed), early onset NEC may not be affected by probiotics, perhaps the pathophysiology is different. Or maybe we need to be giving probiotics to the mothers before delivery to try and ensure normal early gut colonization, rather than waiting till they start feeds (which is our current policy) when they already have an abnormal microbiome, and it may take a while to replace the nasty little buggers with good friendly germs.

As for on-going and future studies? Enough is enough! We have more than enough data to stop randomizing babies to placebo. We need to start doing other studies to answer the important remaining questions:

  • Is one probiotic organism better than another?
  • Are 2 germs better than 1?
  • Do prebiotics make a difference? Giving probiotics with oligosaccharides that promote their growth might make them more effective, and help colonization to be more rapid.
  • Does the combination of lactoferrin and probiotics further enhance gut protection, and also reduce nosocomial sepsis, compared to probiotics alone?

Answering these questions will need very large trials, but current models of performing large trials make them very expensive, 3 million dollars for a trial of 1000 babies would not be unusual, our HIP trial of hypotension treatment in the preterm will cost about 5.6 million Euros for 800 babies. So we need to set up large permanent neonatal research networks that can perform trials that are simpler than in the past, on an ongoing basis, that are multinational, not just multicenter, that are freed from some of the excessive regulation and constraints that currently impede important research questions from being answered, but that still have mechanisms in place to protect babies from unexpected harms.

I can dream, can’t I?

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The Nobel Prize in Physiology or Medicine

Posted on 8 October 2012 by Keith Barrington

Alfred Nobel made his fortune, which he used to endow the Nobel prizes, from dynamite. He invented a way to stabilize nitroglycerine, which is very unstable and tends to explode unexpectedly. Towards the end of his life he was prescribed nitroglycerine as a treatment for his angina, which he found rather ironic; as he noted in a letter to a friend ‘

“It sounds like the irony of fate that I have been prescribed nitroglycerine internally. They have named it Trinitrin in order not to upset pharmacists and the public.Your affectionate friend,

A. Nobel

Nitroglycerine works by releasing nitric oxide in the tissues, so when Furchgott, Ignarro and Murad won the Nobel prize in 1998 for the discovery of the importance of nitric oxide in blood vessels and, among other things, how nitroglycerine helps angina by releasing nitric oxide, the irony was compounded.

The newest Nobel prize doesn’t have that same resonance for me, I use nitric oxide for my patients, but I don’t know if I will ever use pluripotent stem cells derived from adult cells. Nevertheless one thing which is impressive is how fast an insititution can use the announcement of a Nobel prize to set up a new website! The same day as the announcement of the prize a web page has sprung up, from the insitution of one of the winners, I guess there must be money in there somewhere. The only other comment I have is that the other winner, John Gurdon from Cambridge UK has really bad hair.

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Saving Babies’ Lives, for Pennies a day.

Posted on 8 October 2012 by Keith Barrington

I am talking about Canada, not the third world!

Probiotics are cheap and reduce mortality.

Florababy(TM) costs about $25 per 60 gram tub.

One tub is enough for 120 days of prophylaxis, that is enough for the entire hospitalization of an extremely preterm infant.

Among babes who survive the first few days of life, the common causes of delayed death are sepsis, severe respiratory failure, and Necrotizing Enterocolitis. Probiotics decrease NEC frequency by about 60%. Probiotics decrease  delayed deaths by nearly half. For about 20 cents per day per baby.

(I have no conflicts of Interest: I have received no money or rewards of any kind from pharmaceutical or probiotic companies).

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Not neonatology: Brian Cox

Posted on 7 October 2012 by Keith Barrington

This week an American congressman, member of their science committee, stated that the earth was about 9000 years old, and that the big bang was a lie from the pits of hell. That might not touch me directly, but clearly he should not be in a position of authority over scientific matters.

One perfect response to him would be to make him watch, over and over again the acceptance speech of Brian Cox for the medal of the Institute of Physics in the UK. His speech is a wonderful brief description of the nature of science and his closing quote from Humphrey Davy is great. “Nothing is so fatal to the progress of the human mind as to suppose that our views of science are ultimate; that there are no mysteries in nature; that our triumphs are complete, and that there are no new worlds to conquer.” Brian Cox and the nature of science

I an a great fan of Brian Cox, a physicist from the University of Manchester. He is a wonderful communicator, he gives lectures with a clarity and a fluency that I can only envy, and in addition he has a strong Manchester accent, which is an added benefit (I still have a weak Manchester accent, more than 48 years after leaving the area). For a wonderful brief introduction to the recent history of physics and why it is important, you could do much worse than watching Brian Cox and the history of the universe.

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Who benefits from whole genome sequencing in the NICU? Who suffers?

Posted on 7 October 2012 by Keith Barrington

Annie and I recently published a letter to the editor of Pediatrics and Child Health about the ethical implications of using Complete Genome Hybridization (CGH) as the default test for possibly genetically determined disorders in pediatrics. CGH is a very high resolution way of examining the DNA of an individual, and finding abnormalities that do not hybridize to the standard DNA of the chip. Although much higher resolution than a standard high resolution karyotype there are several risks that come along with that increased resolution. Those risks are (as enumerated in our published letter):

  • CGH often reveals minor DNA anomalies that are of uncertain significance, leaving a child labelled with a DNA anomaly, but with no idea whether it is of medical importance.
  • CGH may reveal significant DNA anomalies that are not related to the condition being investigated; these unrelated DNA anomalies may have implications for the future health of the child.
  • Finding DNA anomalies in the infant will often lead to the parents being tested. This testing may reveal that they also carry the DNA anomaly, which may have implications for the parents’ future health or may impact their insurability.
  • Because CGH is often performed when the diagnosis is uncertain, it is impossible to counsel parents regarding potential implications of the hundreds of possible diagnoses that might follow, or the potential future health impacts.
  • CGH may reveal DNA anomalies that could affect (or will, in the future, be shown to affect) the health status of the infant including risks of cardiovascular disease or cancer risks.
  • CGH may reveal DNA anomalies that are associated with an increased risk of future mental health or behaviour problems, but with what is referred to as ‘reduced penetrance’, ie, they are not very specific. How can we (and do we currently) counsel parents that the CGH test we are performing might reveal that their child has an increased risk of future antisocial behaviour, bipolar disorder and schizophrenia,  (This is not theoretical, this has actually been demonstrated!) but that even if their child has the relevant microdeletion, the occurrence of these problems is not certain, and we cannot do anything to prevent them anyway?
  • CGH results provide a permanent record of DNA anomalies, and the test is performed on an infant who is unable to understand or consent.

Now that is for CGH, imagine the next step up in resolution, sequencing the entire genome.  Some of you may have seen press releases from Children’s Mercy Hospital in Kansas City about whole genome sequencing, available for newborn babies within 3 days. The hype from that center states things like ‘one third of babies in the NICU have genetic disorders’ and ‘physicians can make practical use of diagnostic results to tailor treatments to individual infants and children’

Well I must live on another planet. The large majority of babies in my unit are there for prematurity. Now unless you really want to hype your own research and stretch the meaning of the phrase ‘genetic disorders’ to include possible potential SNP’s in the mother that might in the future be shown to maybe increase the risk that she will deliver prematurely, then that is a downright lie. A lie that will disturb parents and helps no-one. The only people who will be helped by that are those making profits from the test, which costs “only” 13,500$. The entirely spurious comparison of the cost of the test to the cost of neonatal intensive care made during interviews by the authors is equally inane and self-serving.

It is very likely that there are genetic variants that increase the chances that you will develop BPD if you are born prematurely,  or variants that make you more susceptible to RoP or Group B Strep sepsis etc. etc. But that is entirely different to calling them genetic disorders. It is also entirely different from being able to tailor our treatment to the condition. Even in the case of what have previously considered genetic disorders, there are a minority that can be directly treated. The main advantage of a diagnostic label for many children is to be able to give a prognosis.

Lets imagine a case, a very realistic case that will happen one day soon. A baby in the NICU has a club foot. The genetics consultant isn’t sure if there is an underlying genetic cause (even though there was oligohydramnios and the neonatologist was quite happy that the cause was in utero constraint, but nevertheless the resident had filled out a consultation form for the geneticist before I could stop them) so they decide to sequence the genome of the baby. The lab reports 300 different unknown SNP’s none of which have previously been noted to be associated with club foot. They also find that the baby is heterozygous for a beta glucosidase mutation that increases risk of Parkinson’s disease to 16%.

Now what the hell do you do?

As far as we know there is nothing you can do about this. There is no prospect in the near future of being able to do anything about this. So do you keep quiet about it? Do you lie to the parents and say we didn’t find anything? Or do you leave the knowledge hanging over his head for the next 50 years?

If you actually read the article that this hype is based on you will probably be profoundly unimpressed. They actually report 4 babies in the NICU with possible genetic disorders. Three of the babies were critically ill and had active care discontinued, the 4th is having cardiac surgery. For the 3 babies that died 1 had a condition that could have been diagnosed from his clinical presentation, 1 they didn’t figure out, even with whole genome sequencing, one turned out to have an abnormality in a gene only reported once before as a cause of their problems. The baby with heart disease clearly had an autosomal recessive condition, and the authors may have discovered a new gene causing visceral heterotaxy.

So who benefitted from the whole genome sequencing?

None of those babies benefited.  3 of them had care withdrawn because of the severity of their clinical condition, the 4th still needed to have heart surgery.

We read in a tiny footnote to the article the following “J.F., S.H., P.S., Z.K., J.C.W., J.B., R.J.G., E.H.M., and K.P.H. are employees of Illumina Inc., which manufactures the HiSeq 2500 instrument.” The initials refer to 9 of the 23 authors of the article. (That’s right an article about 4 babies with 23 authors!) So Illumina Inc will benefit if they sell their machines.

Children’s Mercy Hospital will benefit if they get more referrals. (in the US medical “system” the more sick babies you get referred the more money you make, even at a wonderful non-profit organisation like the Mercy Hospital a lot is driven by money, because they have to stay open, so they have to keep working on their “market share”).

The authors benefit from having a publication in a high profile journal

Clinical scientific knowledge benefits from knowing a bit more about genes that can cause epilepsy and visceral heterotaxy.

But the babies? The families? There certainly is at least a risk that the babies and families might suffer, they might have findings that are of unknown significance, that cause only concern. They might have findings that are of known significance, but have nothing to do with the reason for doing the test. They might have findings that have profound implications for the future health or future life expectancy of the baby, and they will very often be untreatable.

I certainly wouldn’t have whole genome sequencing, nor accept it for my children. If there was a good research project, I would let them take my blood (or my mouth swab or whatever) but I don’t want to know the results thanks very much! A press release suggesting that this technique makes a difference in clinical management, that it is cost effective, and that it could be applied to 1 in 3 NICU patients serves no-one… except Illumina Inc.

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Not neonatology: the Ness of Brodgar

Posted on 6 October 2012 by Keith Barrington

I just heard about this from an article in the Guardian. A huge neolithic temple complex on the isle of Orkney has been discovered. A site, entirely man-made, covering more than 6 acres, which predates Stonehenge and the Pyramids. The site is just now being excavated, but  includes more than 12 buildings which have been called “temples” and bones of hundreds of cattle with signs of being butchered, perhaps sacrificed. Huge standing stones have been recognized here for a very long time, but the newer excavations have revealed something spectacular, and entirely unsuspected. The site dates from over 5000 years ago and was abandoned about 4,300 years ago.

Interesting to think that we know so little about the distant past of Europe, and that it was probably warmer back then for so much activity to have taken place in Orkney!

Another item to add to my list of places I want to go, sometime soon.

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Assessing perfusion in the sick preterm baby

Posted on 6 October 2012 by Keith Barrington

I often give talks where I present my ‘data’, (notice the quotation marks, what I actually present are my prejudices, and uncontrolled observational information, along with systematic reviews of other people’s data) which suggest strongly that there is no need to treat preterm infants with numerically low blood pressure whose perfusion is adequate.

The most common question I get asked after these talks is: how do you define and evaluate perfusion? I am currently on my way to the EAPS meeting in Istanbul (don’t cry for me!!!) where the talk I have to give is about exactly this issue. So, as I haven’t finished preparing the talk yet, I will write this post as I think about what I am going to say. ***Update, I just finished giving the talk and told the audience that I would post about this issue and put the pptx file on this blog, it is on the “presentations by our group” page, References are listed below this post.***

Definition: this is the easy bit. Adequate perfusion means that there is enough oxygen delivery to the tissues to maintain all of their vital functions and to avoid any long term adverse consequences. Actually, writing that definition is easy, but putting it into real-life practice is hellishly difficult.

Evaluation: this is still a work in progress. There are 3 potential categories of methods of evaluating perfusion. 1, clinical exam and history. 2 non-invasive monitoring. 3. invasive tests. Before I discuss each category, we should ask the question, how do we determine if a method of evaluating perfusion is accurate?

Now there’s the rub (as someone who could write fairly well once said). How do we determine if evaluation, for example, of capillary filling is an accurate representation of perfusion? Is there a gold standard to compare cap filling to?

I would say no, we have no gold standard that really tells me if the mitochondria are receiving enough oxygen. But I do think we have something that comes fairly close, and which for the moment is as good as we can get. The measure which I believe comes closest to a gold standard for perfusion is a shunt independent measure of systemic blood flow. Now we do have to remember that oxygen delivery depends on perfusion, but also on saturation and hemoglobin concentration. And adequacy of oxygen delivery depends on supply as well as on demand, but if we assume that we are only measuring these things in babies with a reasonably normal hemoglobin, and a reasonably normal saturation, and a reasonably normal oxygen consumption, then systemic blood flow will reflect whether supply is normal, and hopefully whether it is adequate.

What shunt independent measures of systemic blood flow exist? The best, in terms of being completely unaffected by the usual intra-and extra-cardiac shunts which are present in the preterm newborn, is flow in the superior vena cava. However, in terms of precision and reproducibility of measurement there are problems. Accurate measurement of the diameter of the SVC, and accurate doppler measurements of blood flow velocity in the vessel are both difficult, and there are some concerns about how reproducible the measures might be, especially in less experienced hands. The PA is easier to measure the diameter reproducibly, but if there is a significant inter-atrial shunt this measure is less helpful; however, for most purposes PA flow seems to be adequate.

A number of collaborators from Sydney, Australia (Martin Kluckow, Nick Evans, David Osborn and others) have shown that there appears to be a cutpoint of 40 mL/kg/min in the SVC below which there are adverse consequences, in particular an increase in the frequency of late onset intraventricular hemorrhage, they have also shown an association with poorer neurodevelopmental outcome. Other groups have confirmed this.

So do the measures of clinical perfusion correlate well with our imperfect gold standard?

1. Clinical evaluation of perfusion relies on what can be directly observed, and observations of the consequences of good or poor perfusion. Direct observations of perfusion are capillary filling time and warmth of the extremities. observations of consequences include urine output (renal perfusion), and level of activity/alertness. (CNS perfusion).

Capillary filling does have some correlation with SVC flow, but it is quite imperfect by itself. Even in order to achieve that degree of imperfection it needs to be done as objectively as possible, over the sternum with a standard methodology, and a stop watch to time the refill.

Toe temperature and central peripheral temperature difference are probably of limited value for babies who are in warm incubators. There is no good way of quantifying level of activity, so it is not clear whether this is useful. Urine output is low because of low renal blood flow and GFR immediately after birth, but seems to be more reliable after the first day or so (as renal vascular resistance falls by more than half), again little published data to confirm this.

2. Non-invasive measures. NIRS has great promise I think, but despite many years of investigation there remain a number of limitations to its use. It isn’t clear to me which parameter is most appropriate. Fractional oxygen extraction for example will be decreased if there is better oxygen supply, or if there is reduced consumption. It may be that simple is best and tissue oxygen saturation the preferred measure. Direct measures of tissue oxygenation correlate well with cranial NIRS, but there is a +/- 17% error, which is clearly substantial. In any case there is a correlation between tissue oxygenation and SVC flow. There is also a correlation between fractional oxygen extraction and the occurrence of cerebral injury.

You could be forgiven for thinking that NIRS should be the gold standard. Surely oxygenation of cerebral tissues is the most important function of the cardiovascular system from minute to minute? However there are numerous limitations, and its use has not become widespread clinically, at least not in North America, despite many publications (Gorm Griesen recently discussed why this should be, and how we should go about determining whether we should be using it routinely). I guess we need more evidence that low NIRS cerebral oxygenation correlates with poor outcomes, and then some evidence that therapy directed to improving NIRS improves outcomes. This may be asking a lot, as we don’t have such evidence for most of the things that we already treat (such as low blood pressure!) Newer devices which are simpler to use, and have probes designed for preterm infants might allow us to collect such evidence. We need to define a trigger level for intervention, or a set of circumstances which include a NIRS number.

How about perfusion index? The Masimo pulse oximeter displays a number called the perfusion index. This is of uncertain derivation (seems to be a trade secret) but has something to do with how much pulsation is going on in the signal that the pulse oximeter interprets. (Other pulse oximeters have numbers as well, but the further evaluation of PI has only been done with the Masimo). PI seems to correlate broadly with SVC flow, may correlate with poor outcomes, and may turn out to be an easily monitored indicator of peripheral perfusion. A number that the nurses can write down from a clinical monitor could perhaps be quite helpful to flag babies for further evaluation.

3. Invasive testing. Blood tests: serum lactates are the most studied for evaluating overall adequacy of oxygen delivery. Single measurements of lactate are correlated with mortality, but a single lactate taken shortly after birth is of more limited use, as lactates may be very high after a complicated delivery, and then fall if perfusion is adequate, so the trend in lactate values may be more useful. A lactate of 5 for example might mean something very different if the previous was 10 or if the previous one was 1!

Other lab tests such as pH or base excess seem to be of little value.

Combining indicators

Perhaps the best thing to do would be to combine indicators, to construct a perfusion scale with capillary filling, serum lactate and how much it has changed, urine output, etc. Some preliminary work in this has been published by my good friend and colleague Gene Dempsey, he showed that a combination of a capillary filling time of >4 secs and a lactate of more than 4 correlated well with an SVC flow of less than 40. As well as being significant it is easy to remember!

In Summary

An SVC flow below 40 mL/kg/min is associated with poorer outcomes, but –Using the same limit for everyone is a bit simplistic, it ignores variations in HgB, Saturation and O2 demand: but it is by far the best evaluated and supported measure we have

SVC flow <40 mL/kg/min has become relatively uncommon in the small preterms (<20%) probably in association with less aggressive intervention.

Other measures have often been evaluated for their correlation with SVC flow: They should also be evaluated independently for their association with clinical outcomes

Capillary filling has some correlation with SVC flow

An overall clinical estimation of poor perfusion is associated with poor outcomes

Cap filling <4 AND lactate >4 is associated with low SVC flow

NIRS of brain and other regions? The method of analysis, and best parameter to use are uncertain. The Big Question of NIRS that needs to be asked is: Is there a single cutoff that predicts poorer outcome, therefore could be used to instigate (or investigate) therapy?

Perfusion Index from the pulse oximeter? Much more work needed.

What we need are prospective cohort studies analyzing all of these factors in a group of preterm infants. They should be compared with echo indices of flow.and more importantly with short and long term complications.

The research questions to be asked are: •Does this measure correspond with outcomes? Does it correlate with flow •Is it an appropriate measure to guide treatment?

References

1. Greisen G, Leung T, Wolf M: Has the time come to use near-infrared spectroscopy as a routine clinical tool in preterm infants undergoing intensive care? Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 2011, 369(1955):4440-4451.
2. Wardle SP, Yoxall CW, Weindling AM: Determinants of Cerebral Fractional Oxygen Extraction Using Near Infrared Spectroscopy in Preterm Neonates. J Cereb Blood Flow Metab 2000, 20(2):272-279.
3. Victor S, Marson AG, Appleton RE, Beirne M, Weindling AM: Relationship Between Blood Pressure, Cerebral Electrical Activity, Cerebral Fractional Oxygen Extraction, and Peripheral Blood Flow in Very Low Birth Weight Newborn Infants. Pediatric Research 2006, 59(2):314-319.
4. Shah DM, Condò M, Bowen J, Kluckow M: Blood pressure or blood flow: Which is important in the preterm infant? A case report of twins. Journal of Paediatrics and Child Health 2011:no-no.
5. Kluckow M: Functional Echocardiography in Assessment of the Cardiovascular System in Asphyxiated Neonates. The Journal of Pediatrics 2011, 158(2, Supplement 1):e13-e18.
6. Groenendaal F, Lindemans C, Uiterwaal CSPM, de Vries LS: Early Arterial Lactate and Prediction of Outcome in Preterm Neonates Admitted to a Neonatal Intensive Care Unit. Neonatology 2003, 83(3):171-176.
7. Takahashi S, Kakiuchi S, Nanba Y, Tsukamoto K, Nakamura T, Ito Y: The perfusion index derived from a pulse oximeter for predicting low superior vena cava flow in very low birth weight infants. J Perinatol 2010, 30(4):265-269.
8. Moran M, Miletin J, Pichova K, Dempsey EM: Cerebral tissue oxygenation index and superior vena cava blood flow in the very low birth weight infant. Acta Pædiatrica 2009, 98(1):43-46.
9. Miletin J, Pichova K, Dempsey E: Bedside detection of low systemic flow in the very low birth weight infant on day 1 of life. European Journal of Pediatrics 2009, 168(7):809-813.
10. Miletin J, Dempsey EM: Low superior vena cava flow on day 1 and adverse outcome in the very low birthweight infant. Archives of Disease in Childhood – Fetal and Neonatal Edition 2008, 93(5):F368-F371.
11. Cresi F, Pelle E, Calabrese R, Costa L, Farinasso D, Silvestro L: Perfusion index variations in clinically and hemodynamically stable preterm newborns in the first week of life. Italian Journal of Pediatrics 2010, 36(1):6.
12. Weindling M, Paize F: Peripheral haemodynamics in newborns: Best practice guidelines. Early Human Development 2010, 86(3):159-165.
13. Miletin J, Pichova K, Doyle S, Dempsey EM: Serum cortisol values, superior vena cava flow and illness severity scores in very low birth weight infants. J Perinatol 2010.
14. Dempsey EM, Al Hazzani F, Barrington KJ: Permissive hypotension in the extremely low birthweight infant with signs of good perfusion. Arch Dis Child Fetal Neonatal Ed 2009, 94(4):F241-244.
15. Paradisis M, Evans N, Kluckow M, Osborn D: Randomized Trial of Milrinone Versus Placebo for Prevention of Low Systemic Blood Flow in Very Preterm Infants. The Journal of Pediatrics 2009, 154(2):189-195.
16. Dempsey EM, Barrington KJ: Evaluation and treatment of hypotension in the preterm infant. Clin Perinatol 2009, 36(1):75-85.
17. Dempsey EM, Barrington KJ: Treating hypotension in the preterm infant: when and with what: a critical and systematic review. J Perinatol 2007, 27(8):469-478.
18. Dempsey EM, Barrington KJ: Diagnostic criteria and therapeutic interventions for the hypotensive very low birth weight infant. J Perinatol 2006, 26(11):677-681.
19. Barrington KJ, Dempsey EM: Cardiovascular support in the preterm: treatments in search of indications. J Pediatr 2006, 148(3):289-291.
20. Osborn DA, Evans N, Kluckow M, Bowen JR, Rieger I: Low Superior Vena Cava Flow and Effect of Inotropes on Neurodevelopment to 3 Years in Preterm Infants. Pediatrics 2007, 120(2):372-380.
21. Hunt RW, Evans N, Rieger I, Kluckow M: Low superior vena cava flow and neurodevelopment at 3 years in very preterm infants. The Journal of Pediatrics 2004, 145(5):588-592.
22. Weindling AM, Kissack CM: Blood pressure and tissue oxygenation in the newborn baby at risk of brain damage. Biol Neonate 2001, 79:341-245.
23. Kluckow M, Evans N: Low superior vena cava flow and intraventricular haemorrhage in preterm infants. Arch Dis Child Fetal Neonatal Ed 2000, 82(3):F188-194.
24. Kluckow M, N. E: Superior vena cava flow in newborn infants:a novel marker of systemic blood flow. Arch Dis Child Fetal Neonatal Ed 2000, 82:F182-F187.
25. Deshpande SA, Platt MP: Association between blood lactate and acid-base status and mortality in ventilated babies. Arch Dis Child Fetal Neonatal Ed 1997, 76(1):F15-20.            26. de Boode W-P: Clinical monitoring of systemic hemodynamics in critically ill newborns. Early Human Development 2010, 86(3):137-141.

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Domperidone for GE reflux; toxic and worse than placebo!

Posted on 6 October 2012 by Keith Barrington

As mentioned in a previous post, to get cisapride for a patient in Canada, you have to contact Health Canada for special permission through the Special Access Program. The last time that I am aware of someone asking Health Canada for special access for cisapride for treatment of reflux in a preterm infant they were refused; this might sound like a good thing, but unfortunately the reason for refusal was that they hadn’t tried domperidone! I almost collapsed when I heard that one!

So is domperidone effective for GER in newborn infants? Is it safe?

You can probably guess the answers by now. No and No.

Domperidone is a drug closely related to metoclopramide, in the sense that it is a dopamine D2 antagonist, however it also has some cisapride like effects, in that it prolongs ventricular repolarization by interfering with a potassium channel. Are there any controlled studies examining domperidone effects on GER in the preterm? I found just one (Cresi F, Marinaccio C, Russo MC, Miniero R, Silvestro L: Short-term effect of domperidone on gastroesophageal reflux in newborns assessed by combined intraluminal impedance and ph monitoring. J Perinatol 2008, 28(11):766-770). A small trial that actually had controls! and randomization! And just like one of the metoclopramide studies, there was an increase in reflux in the domperidone group. This study has nice methodology with multiple intraluminal impedance combined with pH for quantifying the reflux. Domperidone does seem to be an effective prokinetic in the preterm, which may be why it increases GER.

So domperidone is ineffective for GER, indeed it is the opposite of effective, it is anti-effective! It also can prolong the QT interval, so it may be unsafe from a cardiac standpoint, and it can cause extrapyramidal side effects so probably not safe for the brain either.

Domperidone should never be used for reflux in the newborn, and probably not for other indications either. Studies of domperidone use in mothers should evaluate possible neonatal absorption and neonatal effects.

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Cisapride for GE reflux; more toxic placebos!

Posted on 6 October 2012 by Keith Barrington

I am currently writing a chapter for a textbook, the chapter will deal with GE reflux. So I have been reviewing the data around various treatment options. I have already written on this blog about the lack of physiologic rationale for using prokinetics, and the lack of efficacy and toxic complications of metoclopramide. Although cisapride is no longer readily available it is still possible to obtain it in Canada through the Special Access Program, which allows you to obtain critically important medications even if they are not currently licensed. I believe that similar programs exist in other jurisdictions also. Requests for special access to cisapride are sometimes made by doctors as it is believed that it will improve GERD in babies not “responding” to other treatments, and that the risks were overstated anyway.

So what about cisapride, does it really work? Is it safe? Should it continue to be available under Special Access Programs?

The simple answers to these questions are no, no and no.

Does it work: There are no good RCTs in preterm infants. This is despite the fact that at one point about 20 percent of all the preterm infants in NICUs in the USA were receiving cisapride. You would think that after all the disasters in neonatology since the 1950s (subject of an upcoming post I guess) we would be reticent about prescribing a new drug for which there are no neonatal data… Maybe we did so because there were such compelling data from older children? Is that the case? Does cisapride work in older infants? Here again the response has to be no, there is no reliable evidence of efficacy. The Cochrane review updated in 2010, could only find 8 tiny placebo controlled studies, with a total of 262 infants, that looked at symptoms of GER. There was some evidence of publication bias, so negative studies may well be missing from the published literature. Only 2 of those 8 studies were of good quality and were slightly larger (n=36, and 68).  There was no overall evidence of improvement, and the 2 less small, better quality, studies showed a tendency to worse symptoms in the cisapride group.

The few controlled studies that exist in the preterm show that gastric emptying is prolonged by cisapride, that feeding tolerance is not improved, and that transit time might be prolonged. So as well as being useless for GER it isn’t even prokinetic in the preterm! This might because of immaturity of certain 5-HT4 receptors, and stimulation of different receptors which slow intestinal function. There is some evidence that the toxicities of cisapride, that is the effects on QT interval, and more marked in the newborn, and occur at lower serum concentrations than older individuals.

So cisapride is ineffective for GER in the newborn, may actually slow intestinal transit and gastric emptying, and may well be more toxic than in older patients. So having it available on special access programs is senseless.

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