Predicting outcomes: Adults vs Babies

Posted on 11 July 2012 by Keith Barrington

An interesting article in Archives of Internal Medicine (Chan PS, Spertus JA, Krumholz HM, Berg RA, Li Y, Sasson C, Nallamothu BK, Investigators. GWTG-RR: A validated prediction tool for initial survivors of in-hospital cardiac arrest. Arch Intern Med 2012, 172(12):1-7. http://archinte.jamanetwork.com/article.aspx?articleid=1162169); using a prospective registry the authors analyzed 43,000 adults who had an in-hospital cardiac arrest and were resuscitated with initial success of the resuscitation, that is, return of a perfusing rhythm. They then produced a clinical prediction algorithm, by in-putting various data points from a randomly selected 2 thirds of the cohort. Using the other third they validated that the algorithm gave good prediction for survival without serious neurologic morbidity.

The authors use the Glasgow Outcome Scale to determine the degree of neurologic morbidity, in that scale a moderate outcome (level 2) is “some disability such as dysphasia, hemiparesis or epilepsy and/or deficits of memory or personality but are able to look after themselves, do shopping and travel by public transport. They may be able to work when special arrangements are made”. A severe outcome (level 3) is defined as “a conscious patient who is dependent for daily support from another person by reason of mental or physical disability, usually a combination of both ” and the more severe level of disability, level 4, is a persistent vegetative state or coma (level 5 being death or brain death).

Back to the study by Chan. The authors were able to construct a scale which predicted outcomes quite well, from 70% chance of a good outcome in the lowest decile of scores to 2.8% chance of good outcome in the worst decile.

I like to compare such things to the outcomes of preterm babies. A 2.8% chance of a survival without profound disability is equivalent to a 401 g male infant born at 23 weeks without steroids (using the Tyson calculator). Obviously the definitions of disability are not the same.

Two things that are quite different in this study compared to any similar neonatal study. Firstly it is impossible from the paper or even the supplementary data tables to find out how many severely disabled (or worse) survivors there are at each level of prediction. The presentation is just about relatively good survival and its likelihood. Much of our considerations in neonatology are to do with the survival of “handicappped” infants and our attempts to avoid that outcome. I think if this were a neonatal study we would have an indication at each prediction level of the number of deaths, the number of “severely” or “profoundly” impaired infants, as well as the numbers without impairments. We do however know that overall there was a 30% long term survival, and 6% were level 3 or worse, so 24% were level 2 or level 1 (level 1 is no significant impairment). But within each decile we do not know how many survivors were level 3 or worse, we are only informed of the proportion who were level 1 or 2.

The second thing to note is that the authors are able to calculate the impact of already being in a persistent vegetative state or brain dead on the neurological status post-resuscitation! (hint: it isn’t a positive risk factor). There were 2,223 of the patients who survived an arrest who were already in one of these 2 categories before the arrest. I find that scary, that so many patients in this cohort were already in a persistent vegetative state or worse, and still had cardiac massage. (I think I had better go and write my advance directives now).

The other thing that is startling is the commentary in the accompanying editorial: (Huszti E, Nichol G: Prediction of “mostly dead” vs “all dead” after in-hospital cardiac arrest: Comment on “a validated prediction tool for initial survivors of in-hospital cardiac arrest”. Arch Intern Med 2012, 172(12):8. http://archinte.jamanetwork.com/article.aspx?articleid=1162172). You might think that a rate of intact survival which is so low would lead the commentators to discuss the appropriateness of instituting a code when good outcomes are very rare. But no. The comments are of a quite different nature. The last few sentences of that editorial I quote here:

“We note that the easiest way to reduce the large regional variation in outcome after the onset of cardiac arrest are to not attempt resuscitation of any patient or to withdraw care from all patients who seemingly have a poor prognosis. But that strategy would obviously be unacceptable to most of the public and health care providers. Given the limitations described herein, we urge caution to those who consider applying the rule prospectively to guide clinical practice. As Miracle Max noted in Rob Reiner’s film, The Princess Bride (1987): “There’s a big difference between mostly dead and all dead. Mostly dead is slightly alive.” Most members of the public would want health care providers to persevere in caring for a patient who is slightly alive.”

I don’t know if that final comment is accurate, but if so, why do we get such heat for caring for babies who are “slightly alive”? Especially when “slightly alive” for a preterm baby is almost always dramatically better than a 2.8% chance of a good outcome. Maybe we should be lobbying for adults to be treated in the same way as we treat premature babies.

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How to Improve Ventilation of Babies during Resuscitation

Posted on 9 July 2012 by Keith Barrington

So how do we improve resuscitation of newborn babies, and specifically of the preterm? Although I am a “true believer (TM)”  in evidence based practice it is obvious that every individual change in neonatal practice will not (and cannot) be preceded by large RCTs showing improvement in life-long quality-of-life measures. We have to make some changes based on evidence of acute and/or physiologic effects and on likelihoods, that is, how likely is it that this improved short term finding, or improvement in physiology, will be harmful in the long term, and how much does it seem that the babies might benefit from changing practice. If we couple such considerations with on-going surveillance of outcomes to assure that we are not causing unexpected harm, then we can progress.

In a sense this is how neonatology has progressed since the beginning; many of the things that we do now have not been based on RCTs, but rather on the observation that our outcomes are improving, so the last group of changes we made are probably OK. A publication (Battin MR, Knight DB, Kuschel CA, Howie RN. Improvement in mortality of very low birthweight infants and the changing pattern of neonatal mortality: The 50-year experience of one perinatal centre. Journal of Paediatrics and Child Health. 2012;48(7):596-9. http://onlinelibrary.wiley.com/doi/10.1111/j.1440-1754.2012.02425.x/abstract) recently documented and quantified the enormous advances in neonatal care that have occurred during the lifetime of many of the senior neonatologists who are still working (like me). I still remember my first 26 week survivor. We now expect over 90% survival at 26 weeks. Just think about that a minute. From 100% mortality to 90% survival in one professional career.

This has occurred in the context of very few individual trials that have documented improved mortality, and despite numerous well-documented disasters. When we have carefully and thoughtfully introduced modest changes in practice and evaluated them as we go along, we have been able to improve survival and improve outcomes.

A case in point is controlling and limiting tidal volumes during resuscitation. Animal models show that a few over-large breaths during resuscitation can initiate lung injury. We will never be able to prove this in actual clinical practice, and in fact the animal models are of questionable relevance. Some being mature, some with normal lungs etc. Nevertheless it seems that over-distending lungs is bad for them, especially fragile premature lungs. On the other hand if you give very large pressures, but don’t cause overdistension that is probably of not much concern. Unfortunately a manometer is an easy thing to make and use. A tidal volume monitor less so. We already know that just looking at the chest movement is an almost useless practice, we really can’t tell if a baby is getting adequate or inadequate tidal volumes. We can sometimes get an idea that a baby is getting much too large tidal volumes so we still need to keep our eyes open during resuscitation. But is it worth the cost, the training and the organisation required to have a working tidal volume monitor for every preterm resuscitation?

A group from England confirmed recently the enormous variability in achieved tidal volumes from 0 to 19 mL/kg. This group was using tidal volume monitors for the study, but they appear to have been resuscitating the babies in a conventional fashion, watching chest rise rather than trying to achieve a specific tidal volume. (Murthy V, Dattani N, Peacock JL, Fox GF, Campbell ME, Milner AD, Greenough A: The first five inflations during resuscitation of prematurely born infants. Archives of Disease in Childhood – Fetal and Neonatal Edition 2012, 97(4):F249-F253.http://fn.bmj.com/content/97/4/F249.full) The publication was specifically looking at whether applied breaths that occurred when the baby was also trying to breathe were different to those where the baby was apneic. As you might expect, if the baby helped then the tidal volumes were larger, and there was less leak around the mask. When the baby didn’t breathe, the breaths were enormously variable and there was often a large leak between the face mask and the baby’s face.

In a study from the amazing group in Melbourne, Georg Schmolzer and colleagues showed that if you actually take note of what the volume monitor shows you, then you adjust the mask position more frequently, leading to less leakage, and you have fewer over-large breaths. They did this study using a tidal volume monitor for every baby, but hiding the display for a randomized half of the babies. (Schmölzer GM, Morley CJ, Wong C, Dawson JA, Kamlin COF, Donath SM, Hooper SB, Davis PG: Respiratory function monitor guidance of mask ventilation in the delivery room: A feasibility study. The Journal of Pediatrics 2012, 160(3):377-381.e372.  http://www.sciencedirect.com/science/article/pii/S0022347611009310)

Another study, with a design that was not as strong, without randomization for example, also suggests that using a tidal volume monitor can help to reduce the over-large breaths that can otherwise occur. (Kelm M, Dold SK, Hartung J, Breckwoldt J, Schmalisch G, Roehr CC: Manual neonatal ventilation training: A respiratory function monitor helps to reduce peak inspiratory pressures and tidal volumes during resuscitation. J Perinat Med 2012, 0(0):1-4. http://www.degruyter.com/view/j/jpme.ahead-of-print/jpm-2012-0023/jpm-2012-0023.xml) After training with the tidal volume monitor the operators were less likely to give high pressure and high volume breaths.

Another study using a lung model has also shown that just displaying the tidal volume dramatically improves the number of appropriate breaths that providers give. (Bowman TA, Paget-Brown A, Carroll J, Gurka MJ, Kattwinkel J: Sensing and responding to compliance changes during manual ventilation using a lung model: Can we teach healthcare providers to improve? The Journal of Pediatrics 2012, 160(3):372-376.e371. http://www.sciencedirect.com/science/article/pii/S0022347611009425)

Now in the past I have been told by certain providers (doctors, RTs and others) that it is important to use a flow-inflating bag, because they can feel how stiff the lungs are when they ventilate with one. I myself was taught this way, but over the years have become very sceptical that this is true, if the bag is a bit more distended, or the resistance of the airway is changed, or there is more or less leak, we can easily be misled. I recently found this older study (Spears RS, Yeh A, Fisher DM, Zwass MS: The “educated hand”. Can anesthesiologists assess changes in neonatal pulmonary compliance manually? Anesthesiology 1991, 75(4):693-696) which clearly showed that even when the change in compliance is not at all subtle (i.e. complete tube occlusion) operators are not capable of detecting the change in compliance during manual ventilation. In this study with a lung model the investigators at some point clamped the tube. The subjects knew this was going to happen, they didn’t know when.  Even though they were expecting the tube to occlude at some point, they still were not able to tell when it occurred!

We cannot tell during manual ventilation when compliance changes or how much tidal volume we are giving without a monitor. Does this matter? I think it might, compliance and tidal volumes change rapidly during resuscitation, leaks are common and airway obstruction is also very common. Sometimes we cause airway obstruction, not by our technique, but by giving surfactant. Georg Schmolzer and that amazing Melbourne group showed that when we give surfactant in the delivery room, 25% of the babies have episodes of complete airway obstruction, and have dramatic and rapid changes in tidal volume. (Schmölzer G, Kamlin C, Dawson J, Morley C, Davis P: Tidal volume delivery during surfactant administration in the delivery room. Intensive Care Medicine 2011, 37(11):1833-1839.  http://www.springerlink.com/content/m774p2642706275p/fulltext.html). Without the tidal volume monitor detection of such episodes is delayed and inadequate, and responses are likely to be partial.

Tidal volume monitoring during neonatal resuscitation is clearly an improvement in short term goals and in achieving more normal respiratory physiology. The equipment to be used, training and quality control will have to be studied so that we can institute this change most effectively.

I doubt that we will ever have large RCTs with long term clinical outcomes to support this change, but using the principle of likelihoods, it is time we figured out how to institute this change, made the change, and then evaluated if there really is an improvement in outcomes.

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A toxic placebo

Posted on 8 July 2012 by Keith Barrington

One very frequently used agent in the NICU is metoclopramide, prescribed almost exclusively for gastro-esophgeal reflux, (occasionally in an attempt to improve feeding tolerance).

Let us assume for a moment that a baby does have clinical signs which are due to reflux, that is, gastro-esophageal reflux disease (GERD). Now, this is not a simple clinical diagnosis to make, the literature overwhelmingly shows that apneas are not due to reflux; there is no reliable way to make a clinical diagnosis of reflux disease in premature infants.

But let’s say we got lucky, we thought a baby may have reflux, and we have done a multiple impedance study which clearly shows excessive reflux.  Is metoclopramide actually effective?

Anna Maria Hibbs published a systematic review a couple of years ago, and as far as I can see there are no new relevant studies since her review (Hibbs AM, Lorch SA. Metoclopramide for the Treatment of Gastroesophageal Reflux Disease in Infants: A Systematic Review. Pediatrics. 2006;118(2):746-52 http://pediatrics.aappublications.org/content/118/2/746.abstract) She showed that there is no reliable evidence that metoclopramide reduces reflux. Is this surprising?, well, not really. Metoclopramide is a prokinetic agent, it blocks D2 receptors in the gut and brain, which reduces vomiting; this is because D2 receptors are involved in the chemoreceptor trigger zone, and they trigger vomiting when the CTZ detects something noxious in your food. The CTZ is important on an evolutionary scale as it protected our forefathers and their grand-fore-fathers from the effects of poisonous berries and the like. But, just because the CTZ functions in this way, doesn’t mean that every time we puke it is a good idea to block it. Sometimes, for example, we vomit because we have been given toxins by our oncology doc.,  she might be trying to help us, but the CTZ senses that she is giving us a toxin, so it triggers vomiting, one of the distressing side effects of chemotherapy. Metoclopramide has a modest effect as an agent which reduces vomiting in this situation, which is presumably why it was first used for vomiting which occurs as a result of other mechanisms, such as GE reflux.

But is there any reason to think that a D2 blocker might decrease reflux? In general is there any reason to think that a prokinetic agent will decrease reflux? (D2 blockade has effects on gut motility as well). As reflux is largely a mechanical phenomenon, how could a drug fix it? I guess if a drug specifically increased lower esophageal sphincter tone, and decreased the number of relaxations of the sphincter, then it might have an effect on reflux (metoclopramide has 5HT and muscarinic actions as well, so might just possibly improve LES tone). If a drug just increases the strength of gastric contractions, without any specificity in its effects, then it is unlikely that GERD will be improved, indeed, an increase in gastric contractility without any change in LES function could easily INCREASE reflux. In fact a critical eye on the literature would say that the controlled studies of metoclopramide for reflux are generally very poor studies,with negative results. The only significant effect of metoclopramide on reflux that has been found in an individual study in infants is an increase. That’s right an INCREASE. Machida et al showed more reflux episodes during treatment with metoclopramide compared to control periods in a cross-over study. (Machida HM, Forbes DA, Gall DG, Scott RB. Metoclopramide in gastroesophageal reflux of infancy. J Pediatr. 1988;112(3):483-7. Epub 1988/03/01).

This might be why Eva Wheatley and Kathleen Kennedy showed that bradycardic episodes increased during metoclopramide (Wheatley E, Kennedy KA. Cross-Over Trial of Treatment for Bradycardia Attributed to Gastroesophageal Reflux in Preterm Infants. The Journal of Pediatrics. 2009;155(4):516-21  http://www.sciencedirect.com/science/article/pii/S0022347609003229 ). In a randomized cross-over study they showed that during the periods of metoclopramide treatment the babies had more bradycardias than during the control periods.  I think there  are 2 potential explanations for this. Either reflux causes bradycardias and there are MORE reflux episodes during metoclopramide treatment than during control: or the bradycardic episodes are not due to reflux, but metoclopramide acts directly to increase these episodes (or it was just a random effect in a small study).

Whatever the mechanisms there is certainly no evidence of a benefit. So to summarize: metoclopramide might improve gastric motility, but there is no reason to believe that this would improve reflux; metoclopramide increases bradycardic episodes, and may increase reflux episodes; there has never been ANY evidence of benefit of metoclopramide for reflux in preterm infants. So metoclopramide for reflux may have a placebo effect (latin meaning ‘I please’) which doctors exploit to please parents and nurses and themselves. Unfortunately, unlike other placebos such as homeopathy and acupuncture, metoclopramide is toxic. In Anna Maria Hibbs’ systematic review there were several patients in the minority of studies that reported adverse effects, who had increased irritability, or other potentially extra-pyramidal side effects. Probably the leading world expert on GE reflux in children, Yves Vandenplas said the following “Metoclopramide should be considered contra-indicated as GOR medication in infants because of the high incidence of side-effects”. (Vandenplas Y, Salvatore S, Hauser B. The diagnosis and management of gastro-oesophageal reflux in infants. Early Human Development. 2005;81(12):1011-24 http://www.sciencedirect.com/science/article/pii/S0378378205002021) He also notes that “extrapolation from adult data makes it very unlikely that efficacy data in infants and young children will be convincing”.

If you are going to give a placebo for gastro-esophageal reflux, I think you should at least give something non-toxic! (maybe find a local homeopath).

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Reducing transfusions in the NICU

Posted on 6 July 2012 by Keith Barrington

I don’t know why I didn’t think of this, but it is sort of obvious, it just takes someone to think about it and then do it. We need to reduce blood draws in preterm infants, the blood we take for lab tests is one of the major causes of needing a blood transfusion. So whatever we can do to reduce blood draws is likely to be a benefit.

One way to do this is to find another source of blood, by which I mean the palcenta. On admission to the NICU we often draw a complete blood count, blood cultures, a cross-match, a glucose and occasionally other test. The inimitable Robert Christensen published a preliminary study recently (Christensen RD, Lambert DK, Baer VL, Montgomery DP, Barney CK, Coulter DM, et al. Postponing or eliminating red blood cell transfusions of very low birth weight neonates by obtaining all baseline laboratory blood tests from otherwise discarded fetal blood in the placenta. Transfusion. 2011;51(2):253-8. http://onlinelibrary.wiley.com/doi/10.1111/j.1537-2995.2010.02827.x/pdf) examining whether obtaining this blood from the placenta instead would improve the hemoglobin level of the baby, and therefore decrease blood transfusions. It may be common sense, but the results were quite interesting.

Now this wasn’t a formal randomized trial, rather a case-control study, so we should be raher skeptical about the results, and when you see the actual paper, the controls had more blood taken every day of the first week of life, not just on day one, so they were different in some way other than just the initial blood sampling. However Dr Christensen and colleagues did show that there was an increase in hemoglobin over the first 18 hours of life in the babies with admission bloods taken from the placenta, and a decrease in those who had an average of about 6 Ml more blood taken from the baby than the placenta sampling group. This difference I think is quite likely due to the different admission blood sampling.

They also showed fewer early blood transfusions and fewer intraventricular hemorrhages in the placenta sampling group. Now as I said this was not an RCT so these results are no more than interesting and probably worth pursuing with a larger study; but they are consistent with another observational study by Dr Christensen and his group which also suggested that there is a link between blood transfusion and IVH, specifically with whether a grade 1 hemorrhage might progress to a larger hemorrhage. (Baer VL, Lambert DK, Henry E, Snow GL, Christensen RD: Red blood cell transfusion of preterm neonates with a grade 1 intraventricular hemorrhage is associated with extension to a grade 3 or 4 hemorrhage. Transfusion 2011, 51(9):1933-1939. http://onlinelibrary.wiley.com/doi/10.1111/j.1537-2995.2011.03081.x/pdf)

Also importantly this group did not use delayed cord clamping, or umbilical cord stripping, which also have beneficial effects on hemoglobin levels, and perhaps on other outcomes as well. More on that another time.

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Outcomes of GBS meningitis; as good as 24 week premies.

Posted on 4 July 2012 by Keith Barrington

As several of you may know, I am co-author, with Annie Janvier, of a series of articles examining how our prejudices about the worth of individuals affect decision making in the critically ill. In some of those articles we compare how people (doctors in neonatology, doctors in other fields, medical students,  students in anthropology, ethics or law) say they would intervene when given certain information about the patient (see references at the end of the article).

We have shown, for example, that people are much more likely to intervene for a patient with a particular chance of survival and a particular chance of long term disability if they don’t know that the patient is a premature baby. Once informed that their patient is a ‘premie’ the wish to intervene goes way down (that’s the reference from Acta Paediatrica)

We also compared attitudes toward resuscitation of a hypothetical series of patients, and found that the premie, and to a lesser extent even the full term newborn were devalued compared to older patients, even compared to a baby of 2 months of age (the 2nd and 3rd references are to that study).

In that series of studies the comparison case of the 2 month old infant was an infant with meningitis. We based our survival and outcome statistics for that case on what data were available at the time, we were using data regarding outcomes of group B streptococcal meningits, but didn’t actually use the species name in the questionnaire.. A new study confirms that we were in the right ball-park. (Libster R, Edwards KM, Levent F, Edwards MS, Rench MA, Castagnini LA, et al. Long-term Outcomes of Group B Streptococcal Meningitis. Pediatrics. 2012;130(1):e8-e15.  http://pediatrics.aappublications.org/content/130/1/e8.long) About one half of the survivors of neonatal group B strep meningitis have no appreciable deficit, and among those with long term problems, about half have moderate and about half have major deficit; very similar to the impact of severe prematurity.

This confirms how much brain injury a GBS meningitis may cause, unfortunately perinatal prevention strategies will not have much effect on this, as most meningitis from GBS is late onset disease, and thus not acquired perinatally in general. Most of these children will be too young to get protection from postnatal immunization, so other prevention strategies such as maternal immunization will be required.

To return to the studies by Annie Janvier, the same questionnaire, or variants of it, has now been used in studies in Australia, the USA, Ireland, Norway and Italy. What is remarkable to me is how similar the results are in those very different countries with different cultural and religious realities. (There are some differences, but they are relatively minor). The major finding has consistently been that physicians in general find it to be in the best interests of the very preterm infant to be resuscitated, nevertheless they are still prepared to let the baby die if the parents request it. What is it about the preterm baby that leads physicians to violate the best-interest principle? Annie is still investigating this, but we think there are 2 reasons, preterm babies (and to a lesser extent all newborns) are not seen as being separate human beings in their own right, especially when we are discussing resuscitation immediately after the baby has left the mother’s body. There seems to me to also be a desensitizing effect which results from the position statements of medical societies, those societies and learned bodies have given doctors the right, the obligation even, to ask parents whether we should resuscitate, even when it is in the child’s best interest to be resuscitated.

Maybe it is time to reconsider this approach, and find a better way to respect the rights of families, including the baby.

Janvier A, Lantos J, Deschenes M, Couture E, Nadeau S, Barrington KJ: Caregivers attitudes for very premature infants: What if they knew? Acta Paediatr 2008, 97(3):276-279.

Janvier A, Leblanc I, Barrington KJ: Nobody likes premies: The relative value of patients’ lives. J Perinatol 2008, 28(12):821-826.

Janvier A, Leblanc I, Barrington KJ: The best-interest standard is not applied for neonatal resuscitation decisions. Pediatrics 2008, 121(5):963-969.

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Does the way we feed babies affect Necrotizing Enterocolitis?

Posted on 2 July 2012 by Keith Barrington

There is a widespread feeling that the method of introduction and advancement of feeds affects the frequency of necrotizing enterocolitis (known as NEC). Multiple observational studies have been published that seem to support this fear. However when we search for randomized controlled trials comparing feeding practices it is almost impossible to find any support for this idea.

One example is a nice new multicenter RCT called the ADEPT trial (Leaf A, Dorling J, Kempley S, McCormick K, Mannix P, Linsell L, Juszczak E, Brocklehurst P, Abnormal Doppler Enteral Prescription Trial Collaborative G: Early or delayed enteral feeding for preterm growth-restricted infants: A randomized trial. Pediatrics 2012, 129(5):e1260-1268. http://pediatrics.aappublications.org/content/129/5/e1260.long). This trial was enrolled 402 preterm infants with an increased risk of NEC. The risk was increased because they were growth restricted, and had abnormal antenatal dopplers. The increase in risk was born out in the results; the threshold gestational age for eligibility was 35 weeks, and the actual mean gestational age was about 31 weeks in each group, so you would suppose normally that the risk was lower than for say a group of babies of 28 weeks gestation, yet there was a 18% rate of NEC in one group and 15% in the other. If we just examine the stage 2 and 3 NEC, ie those often referred to as ‘definite’ NEC, there were 17 in the early feeding group and 18 in the late feeding group. The difference in feeding practices was as follows, the early feeding group were started on feeds at 24 to 48 hours, the late group had 5 days of not being fed, and started at 120 to 144 hours. Apart from the delay, the feeding protocol was then the same in both groups.

Obviously if you delay feeds the babies are liable to reach full feeds later, which was shown, the babies are also likely to have more prolonged IV feeding, and more complications of IV feeding, including cholestasis and secondary infections. All of these were shown, but the increase in infections was not statistically significant.

So the delay in introducing feeds only caused morbidity, with no benefit.

How about other studies of a similar intervention? Another much smaller study of infants with abnormal dopplers and delayed feeding, (Karagianni P, Briana DD, Mitsiakos G, Elias A, Theodoridis T, Chatziioannidis E, Kyriakidou M, Nikolaidis N: Early versus delayed minimal enteral feeding and risk for necrotizing enterocolitis in preterm growth-restricted infants with abnormal antenatal doppler results Amer J Perinatol 2010, 27:367-373. https://www.thieme-connect.com/ejournals/html/10.1055/s-0029-1243310) randomized 80 babies to start feeds either at < 6 days or at 6 days or more. The early group started on average on day 2 the late group on day 7. This was, as acknowledged by the authors an under-powered pilot study, nevertheless they showed no benefit.

A Cochrane review of 5 trials comparing early to delayed introduction of feeds in the preterm, including these 2 (the others did not select by the presence of growth restriction, but by birth weight alone), also found no evidence of benefit of delaying the introduction of feeds. (reference 1 below)

How about the rate of advancement of feeds? There are 4 trials that have compared advancing feeds at a goal of 20 mL/kg/d or less to a more rapid 30 mL/kg/d or more, also reviewed in a Cochrane review. No evidence of a benefit of slow advancement was found. These rapid versus slow trials were all in babies who were fed within the first 5 days of birth, and the total number of babies randomized is about 500. (Reference 2 below)

It is interesting that in the ADEPT trial mentioned above, by Alison Leaf and her colleagues, they used a feeding advancement regime that was slower than even the slow feeding protocol in those previous RCTs, that is after starting feeds they had a goal to advance feeds by about 11 mL/kg/d in the smallest babies less than 600 g birth weight, becoming more rapid with the larger babies up to a maximum of about 15 mL/kg/d in the babies over  1250 g.

Finally what about ‘trophic’ feeds. Should we start with trophic feeding of a small volume for a while before we start to progress the feeds? Given how widespread this practice is, it is remarkable how weak the evidence base for any benefit is. Most of the trials of trophic feeding have compared trophic feeds to remaining nil by mouth; the Cochrane review of 9 trials involving over 750 infants really doesn’t show any benefit, neither in age of achieving full feeds, nor in any clinically important outcomes, including NEC. (Reference 3 below)

I think the only trial which has ever shown a possible effect of a feeding protocol on NEC is a trial by Carol Berseth, published in 2003 . That study randomized infants, when they were due to start feeds, to either trophic feeding or immediate advancement of feeds, by 20 mL/kg/day. The study was designed to enter 250 infants but was stopped early (after 144 babies) as there were 7 cases of NEC in the immediate advancement group and 1 case in the trophic feeding group. Stopping studies early is always a potential problem, especially in an unblinded study, where the outcome is based on interpretation of a clinical state and an abdominal x-ray. Of note in that study the average age of starting feeds was over 9 days in each group. My interpretation of this is that if you keep babies nil by mouth for too long, you might possibly need to feed them more slowly when you start.

So overall then, there is little or no evidence to support keeping very preterm babies fasting during the first couple of days of life, even if they are growth restricted and had abnormal antenatal doppler studies. When you start feeds there is little evidence to support trophic feeds, and little evidence to support immediate advancement of feeds either, but when you start to advance it doesn’t seem to matter how fast you advance. This really is one clinical neonatal problem that has far more opinion than data, but in general there is no good evidence that how we feed babies has any influence on NEC. It is probably much more related to whether we give breast milk, what organisms we get colonized with, the avoidance of prolonged antibiotic courses and broad spectrum antibiotics, and avoidance of gastric acid reduction.
1: Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral
feeds to prevent necrotising enterocolitis in very low birth weight infants.
Cochrane Database Syst Rev. 2011 Mar 16;(3):CD001970.

2: Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to
prevent necrotising enterocolitis in very low birth weight infants. Cochrane
Database Syst Rev. 2011 Mar 16;(3):CD001241.

3: Bombell S, McGuire W. Early trophic feeding for very low birth weight infants.
Cochrane Database Syst Rev. 2009 Jul 8;(3):CD000504.

 

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What do babies die of in resource poor countries?

Posted on 28 June 2012 by Keith Barrington

Two very recent publications about neonatal mortality in resource poor countries. The first is from 6 different low resource countries and one medium resource country (Argentina) the authors presented the birth weight, gestational age and age at death of babies who died (Belizán JM, McClure EM, Goudar SS, Pasha O, Esamai F, Patel A, Chomba E, Garces A, Wright LL, Koso-Thomas M et al: Neonatal Death in Low- to Middle-Income Countries: A Global Network Study. Amer J Perinatol 2012(EFirst) https://www.thieme-connect.de/DOI/DOI?10.1055/s-0032-1314885). They show that around half of the deaths are of low birth weight infants, around a third of those being very low birth weight (less than 1500g), the remaining 46% of the deaths are of course normal birth weight (over 2500 g), gestational age at birth was also important, but a slightly higher percentage were considered term, 54%. The majority of babies who died did so early, 52% on the first day of life, followed by another third by the end of the first week.

The cause of death was not reported in that publication, but we know from other sources that the term babies will have died primarily of asphyxia followed by, as a second most frequent cause, by infection, the preterm infants will have died of complications of prematurity. I know that isn’t very specific, but prematurity is often listed as the cause of death in studies from low income countries, presumably a combination of hypothermia, hypoglycemia, respiratory distress, asphyxia and infections are involved in those babies.

Another study from North-East Vietnam had an very similar age at death and distribution of birth weights, and they did attempt to determine the cause of death (Nga NT, Hoa DTP, Målqvist M, Persson L-Å, Ewald U: Causes of neonatal death: results from NeoKIP community-based trial in Quang Ninh province, Vietnam. Acta Paediatrica 2012, 101(4):368-373 http://onlinelibrary.wiley.com/doi/10.1111/j.1651-2227.2011.02513.x/abstract). Causes of death were determined from post death interviews with the mother. The most frequent cause was prematurity/low birth weight, closely followed by birth asphyxia and then infections.

These studies confirm the necessity of resuscitation training, (check out http://helpingbabiesbreathe.org/ ) and basic neonatal care, (check out http://www.healthynewbornnetwork.org/) to improve global neonatal survival. These programs could make an enormous difference for neonatal mortality in the world.

Survival of premature babies in low resource countries could be dramatically improved by the use of antenatal steroids, hand washing, cord care with chlorhexidine, kangaroo care. All of which are cheap and the main pre-requisite is education.

Currently the Millennium Development Goal 4, a reduction in child mortality by 2 thirds, is behind schedule. Although mortality has decreased, it is not sufficient to achieve the goal. Neonatal deaths are currently 41% of all the deaths below 5 years. The only way to make progress in reducing child mortality and approach MDG 4 is by reducing neonatal mortality.

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What next for birth asphyxia?

Posted on 27 June 2012 by Keith Barrington

Now that therapeutic hypothermia has been proven effective and safe for infants with Hypoxic Ischemic Encephalopathy, one might ask what next? We still are not sure if it is of any value to cool infants after 6 hours of age, or if a different duration and different temperature might be preferable. Given the efficacy of hypothermia we will need trials to address those issues. We should also determine whether cooling infants who are slightly preterm is useful, as they are not currently eligible but might benefit.

Other additional therapies also should be examined, to my mind there are 4 that are of interest: allopurinol, erythropoietin, phenobarbitone, and xenon.

As for allopurinol a new publication describes the outcomes at long term of infants enrolled in 2 similar trials. Joepe Kaandorp and associates (Kaandorp JJ, van Bel F, Veen S, Derks JB, Groenendaal F, Rijken M, Roze E, Venema MMU, Rademaker CM, Bos AF et al: Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials. Archives of Disease in Childhood – Fetal and Neonatal Edition 2012, 97(3):F162-F166 http://fn.bmj.com/content/97/3/F162.abstract) collected long term follow up to 4 to 8 years of age from infants in the 2 trials in Holland, both trials were very small and were, generally speaking, negative. Other studies have suggested some biochemical benefit in terms of interrupting the oxidative stress associated with reperfusion. These 2 studies showed no clinical benefit, but were very underpowered. Combining the studies does suggest that perhaps there was some long term benefit; again, even combined the studies were underpowered, but there is a hint that maybe we should be studying allopurinol. There is one other RCT that I am aware of, that also primarily examined biochemical effects of allopurinol, it was also underpowered, but the authors (Gunes T, Ozturk MA, Koklu E, Kose K, Gunes I: Effect of Allopurinol Supplementation on Nitric Oxide Levels in Asphyxiated Newborns. Pediatric Neurology 2007, 36(1):17-24 http://www.sciencedirect.com/science/article/pii/S0887899406004875) showed a possible clinical and biochemical positive effect of allopurinol. Now in none of these studies were the infants treated with whole body cooling, but these studies do suggest that investigations of allopurinol given as soon as a potential cooling candidate is identified, might be beneficial.

How might this work? Well allopurinol is an inhibitor of xanthine oxidase which is involved in the production of superoxide during reperfusion, so a reduction in reperfusion-reoxygenation injury is the putative mechanism.

Allopurinol is readily available and cheap, with a good safety profile, also important issues in deciding where to go next.

How about erythropoietin? A recent article reviews the neuroprotective potential of this molecule. (Subirós N, del Barco DG, Coro-Antich RM: Erythropoietin: still on the neuroprotection road. Therapeutic Advances in Neurological Disorders 2012, 5(3):161-173. http://tan.sagepub.com/content/5/3/161.abstract) Other pre-clinical articles and reviews also suggest that erythropoietin may have a role in HIE in newborn babies. In addition another very underpowered study in newborn infants, (15 babies per group: Elmahdy H, El-Mashad A-R, El-Bahrawy H, El-Gohary T, El-Barbary A, Aly H: Human Recombinant Erythropoietin in Asphyxia Neonatorum: Pilot Trial. Pediatrics 2010, 125(5):e1135-1142 http://pediatrics.aappublications.org/content/125/5/e1135.abstract ) also suggested some positive effects, but again there was no use of therapeutic hypothermia in either group in that trial. A much larger (but still underpowered) Chinese study (n=167) was also positive (Zhu C, Kang W, Xu F, Cheng X, Zhang Z, Jia L, Ji L, Guo X, Xiong H, Simbruner G et al: Erythropoietin Improved Neurologic Outcomes in Newborns With Hypoxic-Ischemic Encephalopathy. Pediatrics 2009, 124(2):e218-e226 http://pediatrics.aappublications.org/content/124/2/e218.abstract) with a reduction in adverse long term outcomes.

Erythropoietin has multiple potentially neuroprotective effects, including a reduction in apoptosis, protection from glutamate neurotoxicity, and promotion of angiogenesis and neurogenesis, among other effects. It is again, easily available, and in the doses required for newborn infants, cheap.

Phenobarbitone? Phenobarb is an anticonvulsant which decreases brain oxygen requirements, and has been shown to reduce adverse outcomes in asphyxiated infants in one small trial when given in high dose before the occurrence of seizures. (Hall RT, Hall FK, Daily DK: High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up. J Pediatr 1998, 132(2):345-348http://www.sciencedirect.com/science/article/pii/S0022347698704585 ). Interestingly in that trial, phenobarbitone wasn’t very good at preventing seizures! There was an improvement in outcomes at 3 years of age, with a few infants lost to follow-up, which in a trial of only 40 babies, even a few losses to follow up could be potentially important. Other trials of phenobarbitone have not reported follow up, and other barbiturates are not necessarily equivalent. Phenobarbitone is also cheap, readily available (most of the time, there have been some problems with availability over the last few years) and is often given anyway to infants with asphyxia. It may reduce the time it takes to make a baby hypothermic, probably because of a reduction in metabolic rate.

Finally xenon has been the focus of a great deal of activity. It is thought to act mostly as an anesthetic agent, but it is very expensive, so special equipment is required to scavenge and recycle the gas. Why xenon has been investigated rather than other neuroprotective agents is not entirely clear to me, it does appear promising in animal models (for example: Faulkner S, Bainbridge A, Kato T, Chandrasekaran M, Kapetanakis AB, Hristova M, Liu M, Evans S, De Vita E, Kelen D et al: Xenon augmented hypothermia reduces early lactate/N-acetylaspartate and cell death in perinatal asphyxia. Annals of Neurology 2011, 70(1):133-150 http://onlinelibrary.wiley.com/doi/10.1002/ana.22387/abstract). A recent study in rats even gave the agent to the mother before birth in a perinatal asphyxia model, and seemed to show some benefit. (Yang T, Zhuang L, Rei Fidalgo AM, Petrides E, Terrando N, Wu X, Sanders RD, Robertson NJ, Johnson MR, Maze M et al: Xenon and Sevoflurane Provide Analgesia during Labor and Fetal Brain Protection in a Perinatal Rat Model of Hypoxia-Ischemia. PLoS One 2012, 7(5):e37020 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0037020) In contrast to the other agents discussed, it will be long time before enough centers could have the equipment an expertise to use this agent. Also in contrast with the other agents, xenon has been investigated in combination with hypothermia, and seems to give additional benefit in the animal models.



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Perinatal outcomes of IVF twins

Posted on 22 June 2012 by Keith Barrington

Another post about twins and IVF. I’ll back off soon, I promise. A systematic review published just last year notes that the outcomes of twins conceived after IVF is worse than those who are conceived naturally. (Rossi AC, D’Addario V. Neonatal outcomes of assisted and naturally conceived twins: systematic review and meta-analysis. J Perinat Med. 2011;39(5):489-93. http://www.degruyter.com/view/j/jpme.2011.39.issue-5/jpm.2011.058/jpm.2011.058.xml)

One of the problems with doing this kind of analysis is that twins after IVF are almost all fraternal, rather than identical. Identical twins that are monochorionic almost all have anastomoses in the placental circulation, which is probably the main cause for the increase in morbidity and mortality among identical twins, compared to fraternal twins.

So to look at the outcomes of twins after IVF you need to compare just non-identical twins, which is not necessarily obvious at birth, unless the twins are of different sex. (There are a few identical twins after IVF, the frequency of identical twins is increased compared to spontaneous twins, I guess messing around with embryos makes them a bit more likely to divide in two).

When you do this analysis you find that there are more twins born prematurely after IVF, there are more born extremely prematurely, there are more very low birth weight, and there is more perinatal mortality among IVF twins than among non-identical twins conceived spontaneously. And of course all of those outcomes are much higher than among singeltons, either IVF or spontaneously conceived.

Why is this? Well there is some data that primigravidae who have twins deliver earlier than multigravidae. (That is even true for women having their first baby when they are just having one, the average duration of the first pregnancy is about 1 week more than the average duration of  subsequent pregnancies). So the major difference between women having twins after IVF and those with a spontaneous conception, is principally because most of the IVF mothers have not had a baby before, so they deliver even earlier, and have more complications of prematurity.

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Twins and triplets five times more likely to die within first year

Posted on 21 June 2012 by Keith Barrington

Twins and triplets five times more likely to die within first year | Society | The Guardian.

To most of us in neonatology, this news item, published in the Guardian, based on data from the UK national database,  is no real surprise. (I write this as an uncle of twins who are great, thanks very much, but they are well out of the first year of life).

A target of 24% multiple deliveries after IVF in the UK, as mentioned in this news item is PATHETIC.

The Canadian IVF centres, outside of Quebec,  have an equally pathetic goal of 26%.

It is not difficult to attain 5% or less, it just requires some political will, we have achieved under 5% twins in Quebec (after IVF) within the first year of a provincial IVF program. The Swedes have less than 5% for many years, even the Aussies, (yes even the Aussies) with a less draconian approach, are down to just over 8%. We need a global approach, with an acceptable limit of multiple gestation of maybe 4% after IVF, and zero triplets.

This is achievable! Babies will benefit. Only the vested financial interests will suffer.

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