Nasal ventilation after extubation, does synchronisation matter?

Posted on 16 September 2015 by Keith Barrington

When we performed the trial of nasal ventilation post-extubation in San Diego we used the Infantstar ventilator, synchronised to the babies’ respiratory efforts with a Graseby capsule stuck on the abdomen. Two other trials also used the same system, and one trial used a non-synchronised system, but did also show benefit. I thank that synchronisation is probably an advantage, as delivering a positive pressure breath while the infant makes an effort, and therefore probably has the glottis open, is probably more efficacious than delivering positive pressure while the infant is trying to exhale.

In this new study from Ulm (Huang L, et al. Effects of Synchronization during Noninvasive Intermittent Mandatory Ventilation in Preterm Infants with Respiratory Distress Syndrome Immediately after Extubation. Neonatology. 2015;108(2):108-14.) a crossover design was used with 2 hour periods synchronised (using a Graseby capsule) and 2 hours non-synchronised, immediately after extubation of small preterm infants. The synchronised periods showed improved gas exchange, and reduced respiratory effort (as defined by deflections in oesophageal pressure), the results are similar to others using similar systems. I don’t think there is an RCT comparing the 2 methods effects on clinical outcomes, but it seems logical to use synchronised nasal ventilation in preference as that has been most studied post-extubation, and shown to be preferable to CPAP for re-intubation rates. This study confirms some physiologic advantages.

The big problem is how to do it. The infantstar is no longer available, and we don’t have access to the Sophie ventilator used in the new study from Ulm. Some studies have reported using flow triggering, but I can’t see how that would work over any significant period of time, as leaks are huge and variable. The only available option looks like being the NAVA system, but that requires a substantial financial investment, both in ventilators and in the nasogastric tubes with the oesophageal electrodes. A comparative trial using the NAVA, to determine if any clinical outcomes are improved with synchronization, would permit us to know if that investment is worthwhile.

Posted in Neonatal Research | Leave a comment

Lower oxygen resuscitation for preterms?

Posted on 15 September 2015 by Keith Barrington

A new publication from a group of us in the CNN, suggests that the answer to that query is ‘not so fast’. Rabi Y, Lodha A, Soraisham A, Singhal N, Barrington K, Shah PS, et al. Outcomes of preterm infants following the introduction of room air resuscitation. Resuscitation. 2015.
Around 2006 most tertiary hospitals in Canada introduced room air resuscitation for babies at term. At about the same time many then changed their practice for preterm babies, either starting in 21% or at some intermediate concentration such as 40%. We used the CNN database for babies between 23 and 27 weeks gestation, to examine the likelihood of death or a severe brain injury (grade 3 or 4 IVH or PVL), during the 2 years up to their change in practice, which was not exactly the same in the different units. We then gave each centre a 1 year washout period, and looked at the same outcome over a later 2 year period with resuscitation initiated at lower O2 concentration.

We found that survival without brain injury was reduced after lowering the initial O2 concentrations, and that was true whether the practice was to start with 21% or with some other higher concentration. The adjusted OR was about 1.33, or a 1/3 increase in the Odds of the adverse outcome (that is after adjustment for all the relevant risk factors). There was about a 4% increase in the primary outcome variable, and about 3% increase in death and 3% increase in severe brain injury (of course, a baby could have both which is why 3 and 3 don’t add up to 4!)

Now of course, these are observational data, and observational data are always questionable, as a source of truth, or to direct changes in practice.

A new meta-analysis published in the BMJ is a great example of this, on a completely different topic. Ziff OJ, et al. Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. BMJ. 2015;351:h4451. This was a review that compared the increase in mortality associated with treating congestive heart failure in adults with digoxin, between observational studies in 3 categories and the RCT data, the figure below shows a figure from their results.

As you can see observational studies show increased mortality with digoxin, in adjusted analyses there is less harm, in propensity matched analyses less harm again, and in RCTs no harm was shown.

F2.large

A commentary accompanying the article has the great title, “trials are best, ignore the rest”

I guess, having just published the article with Jack Rabi, I should clarify what “ignore” means in that phrase. It doesn’t mean that the data we have just published are useless, it means that to make policy decisions, and to change medical practice you should ignore them. But for providing evidence that we should not make wholesale changes to practice based on the little data we currently have, and for providing support to do the trials that are sorely needed, I think they are worthwhile, indeed that is what we said at the end of that paper: “The contrast between the results of published systematic reviews and our observational data highlights the importance of performing adequately powered studies.”

The most important of the systematic reviews are those (here and here) which included only studies in preterm infants, they showed little detectable difference in outcomes between low oxygen and high oxygen groups, especially when studies without allocation concealment were eliminated.

On the other hand, studies like this one, Tataranno ML, et al. Resuscitating preterm infants with 100% oxygen is associated with higher oxidative stress than room air. Acta Paediatr. 2015;104(8):759-65 show much higher oxidative stress when babies were started in 100% oxygen and then titrated down, compared to being started in 21% oxygen then titrated up. This is data from a sub-study of the To2rpido study, of babies less than 32 weeks gestation, of whom about 120 had blood collection for oxidative stress analysis.

And, importantly the main To2rpido study was halted after the enrollment of nearly 300 babies because enrollment was very difficult and too slow. The interim results show a possible increase in mortality among the subgroup of babies less than 29 weeks gestation. Those interim results from an unplanned subgroup analysis (n=158), and our observational data, make a large prospective RCT an important priority.

It may be that the oxygen administration in those first few minutes after birth is very important for survival, and perhaps other outcomes of preterm babies. Even though oxidative stress is increased if you start with too much oxygen, adverse clinical outcomes might be worse with too low a starting oxygen. There really is only one way to find out.

Posted in Neonatal Research | Tagged , , , | 4 Comments

NICUs are working better: still room for improvement.

Posted on 11 September 2015 by Keith Barrington

As NICUs have become more effective, any proportional incremental improvements will necessarily get smaller, so larger and larger datasets will be needed to show any trends. The NICHD has just published data about survival and major acute morbidities among extremely preterm infants, going back to 1993, and ending in 2012.

The population was infants born at 22 to 28 weeks and 400 to 1500 g, so a few larger than average 27, 28 week infants would have been excluded.

Basically there are significant upward trends in survival, and reductions in many morbidities over the entire 20 years, and  continuing between 2009 and 2012. The best survival at every gestational age that they show in the table is from 2012.

This excerpt from the table shows the results from 1993 in the first column and 2012 in the second, the number in brackets is the percentage survival.

survival

Among major morbidities, a progressive reduction in late-onset sepsis, starting in about 2006, is shown very clearly. Instead of a 34% incidence, only 24% of extremely preterm infants now have an episode of sepsis. There is a less marked but still important reduction in severe intracranial haemorrhages, from 19% to 15%, and in severe retinopathy from 13% to 11%; Most of  the reduction of those 2 morbidities was in the more mature infants, and not in the 23 and 24 week babies.

But necrotizing enterocolitis hasn’t changed (it has gone up a bit from 7% to 10%), and bronchopulmonary dysplasia is increasing (from 32% to 45%). Roger Soll has written an editorial to accompany this publication. As usual I cannot argue with anything he says.

Except for one thing, he suggests that there is no breakthrough therapy on the horizon that is likely to change these morbidities. One simple breakthrough therapy that has been shown effective, but is still underused, is already with us. Widespread us of probiotics could reverse that minor trend to more NEC and lead to somewhere around a 50% reduction in NEC.

As he notes, the reduction in late-onset sepsis has followed the introduction of quality control initiatives, which treat an invasive infection as a failure, rather than inevitable. We need to do the same thing for our other morbidities.

Retinopathy is associated with poor early postnatal growth. Improving nutrition will likely reduce the incidence.

Gentle ventilation, and more non-invasive ventilation, have not yet led to the reduction in lung injury that we might have hoped, the details of exactly how we do CPAP and non-invasive ventilation, improved nursing and RT procedures, improved CPAP interfaces, and methods for detecting and avoiding lung overdistension (mostly during invasive ventilation) are needed. They are needed much more, I think, than adding another ventilatory mode that few people really understand to our latest ventilators.

One change associated with BPD however, has been a reduction in the use of postnatal steroids. As steroids reduce oxygen requirements, it may be that reducing steroid use has led to more babies being in oxygen at 36 weeks, and therefore more having a diagnosis of BPD. Which is not necessarily a bad thing in that context. Steroids have never been shown to improve lung repair, or to improve long-term pulmonary outcomes, so an increase in the somewhat artificial diagnosis of BPD may not reflect worse pulmonary outcomes in the long-term.

Those would be my prescriptions for further improving survival without morbidities: improving nutrition, improving how we do non-invasive and invasive ventilation, and universal use of probiotics.

Posted in Neonatal Research | Tagged , , , , | Leave a comment

How long is too long?

Posted on 11 September 2015 by Keith Barrington

When a baby is unexpectedly born without a heart beat, and resuscitation is initiated, the outcome may be a failed resuscitation. Even if everything is done correctly. If you are doing everything correctly, and the baby doesn’t respond right away, how long should you continue before you “call it off”?

The NRP, based on previous data which showed that survival was very rare after 10 minutes of asystole, and the few reported survivors were profoundly impaired, recommended in an older edition that  “if there is no heart rate after 10 minutes of complete and adequate resuscitation efforts, and there is no evidence of other causes of newborn compromise, discontinuation of resuscitation efforts may be appropriate. Current data indicate that, after 10 minutes of asystole, newborns are very unlikely to survive, or the rare survivor is likely to survive with severe disability”.

ILCOR in 2010 came up with this “In a newly born baby with no detectable heart rate which remains undetectable for 10 minutes, it is appropriate to then consider stopping resuscitation. The decision to continue resuscitation efforts when the infant has a heart rate of 0 for longer than 10 minutes is often complex and may be influenced by issues such as the presumed etiology of the arrest, gestation of the baby, potential reversibility of the situation, and the parents’ previously expressed feelings about acceptable risk of morbidity.”

Two recent publications report outcomes of full-term babies who had a return of circulation after more than 10 minutes, many of whom were then treated with therapeutic hypothermia. Kasdorf E, et al. Improving infant outcome with a 10 min Apgar of 0. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2015;100(2):F102-F5. Shah P, et al. Outcomes of infants with Apgar score of zero at 10 min: the West Australian experience. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2015. Another from the NICHD network a few years ago includes some similar data.
Laptook AR, et al. Outcome of Term Infants Using Apgar Scores at 10 Minutes Following Hypoxic-Ischemic Encephalopathy. Pediatrics. 2009;124(6):1619-26.

To be clear, none of these series include babies who were not successfully resuscitated. We can’t tell from these data what percentage of babies with 10 minutes of asystole will eventually respond to resuscitation and survive to go home. All we can tell is that there some who arrive in (or are born in) tertiary care centers, and then get intensive care provided. A good proportion of those survivors (varying between studies) do not have very profoundly abnormal outcomes. Some with developmental scores within 2 SD of the population mean, some with moderate and some with severely impaired outcomes. In the NICHD network paper, for example, there were 13 survivors out of 25 babies in the 2 arms of the hypothermia trial. 54% had “moderately or severely disability”, which means, obviously, that 46% did not.

Dominic Wilkinson and Ben Stenson in an editorial in the Archives accompanying the latest of these publications state the following:

An Apgar score of 0 at 10 min after birth is not a good enough predictor of outcome to be used as the main basis for decision-making about ongoing resuscitation. There is no clear answer to the question of how long resuscitation should continue after birth. We propose that in most circumstances, resuscitation at birth should continue until 20 min in the absence of a clinically detectable heartbeat. In the face of uncertainty about whether resuscitation should be discontinued, clinicians should opt to provide longer resuscitation, with later consideration of withdrawal of life-sustaining treatment if the clinical course indicates that the prognosis is poor.

I think in general I agree with that, I think we could perhaps curtail the resuscitation somewhat if there was a documented loss of heartbeat prior to delivery, and no response within perhaps 10 to 15 minutes. But it would be great to have some prospectively collected data, or even data from a well maintained database that included “failed” resuscitations, in order to know if there were characteristics that predicted failure before, or success after, 20 minutes.

I think the prior NRP recommendation which included an evaluation of whether the resuscitation was “complete and adequate” might also have some merit. I would hate to call off a resuscitation because it was being badly done.

In my own practice I must say that it has usually taken longer than 10 minutes to be fairly sure that it was not going to work, most failed resuscitations have lasted at least 15 minutes, and often longer. Especially the totally unexpected ones, where you hope that something very acute happened that might still give a chance of a response after the 3rd or 4th dose of epinephrine.

Stopping a resuscitation is a very difficult thing to do, personally, emotionally, professionally and for its impacts on the team. It’s almost impossible to counsel parents about the decision to take during the process, some better data about return of a perfusing circulation, and longer term survival after prolonged asystole would make it a little bit easier.

Posted in Neonatal Research | Tagged , , , | 5 Comments

The new AAP position statement concerning extremely preterm birth decision making. A great leap… sideways.

Posted on 8 September 2015 by Keith Barrington

To me, this new ‘clinical report’ was a major disappointment.

Even though there are some good parts to this statement, there is one huge, major failing: there is absolutely no evidence that parents were consulted or included in the process of statement development. In 2015 how can you possibly release a clinical practice guideline like this and not involve families?

As for the substance of the ‘clinical report’ there is good along with the less good.

First the good, the report goes into some detail about the limitations of gestational age assessment, and the limitations of gestational age as a prognostic factor. The discussion of these limitations is quite well done in general.

There is also a clear statement that decision making based on clinical evaluation in the delivery room is inappropriate.

It is recommended, therefore, that decisions regarding resuscitation be well communicated and agreed on before the birth, if possible, and not be conditional on the newborn infant’s appearance at birth.

There is also a discussion around communication skills, and the importance of parental values. However, even this part was written, it appears, without any parental contribution.

Also despite these parts which I think are valuable, there is still a statement that under 22 weeks infants are not viable, and resuscitation should be offered for infants born at or later than 25 weeks of gestation. I think that this statement largely destroys what they discuss elsewhere about the limitations of gestational age thresholds. Some babies at 25 weeks have much worse predicted outcomes than other babies born at 24 weeks. Putting this arbitrary limit goes directly against what they have just discussed in the rest of the document. It leaves us with the irrational situation that a baby with a good predicted outcome at 24 weeks and 6 days is considered “optional”, but an infant one day further on, even if smaller and with other serious negative risk factors, is considered a mandatory resuscitation.

Within the document another big problem is the use of terms which are not defined. Terms which are vitally important to the discussion such as:

futile

long term neurologic impairment

severe long term neurologic impairment

intact survival

neurodevelopmental impairment

severe neurodevelopmental impairment

significant long-term neurodevelopmental morbidity

There are also phrases which are written in a way that shows a negative bias, with a selective quoting of the literature, and often inaccurately quoted references. These problems sometimes occur all together:

… the fact that most surviving preterm infants born before 25 weeks’ gestation will have some degree of neurodevelopmental impairment and possibly long-term problems involving other organ systems. Infants born at 22 weeks’ gestation have reported rates of moderate to severe neurodevelopmental impairment of 85% to 90%; for infants born at 23 weeks’ gestation, these rates are not significantly lower. The risk of permanent, severe neurodevelopmental and other special health care needs affect both the infant and the family and, for some parents, may outweigh the benefit of survival alone.

If you don’t define neurodevelopmental impairment, then that first phrase is meaningless (even if you want to call it a “fact”). The reference they use (which is here) for that first phrase, is a review article which does not, as far as I can see, include any such statement, and, in fact I am not sure of any data set that would confirm that “fact”. Many cohorts show very different results. As one example, the EXPRESS study has reported outcomes to 2.5 years of babies in the 22 to 24 week GA group for a national cohort. Of the 138 babies between 22 and 24 weeks there were 59 that had “any neurodevelopmental impairment”, the others being defined as being without impairment. I don’t think that qualifies as “most have some degree” of impairment. A more unbiased and accurate evaluation would be that “most surviving preterm infants born before 25 weeks have no impairment”, and “those that are impaired usually have mild or moderate impairment”.

Another phrase which I think is biased is this, from that section above, “…infants born at 23 weeks’ gestation, these rates are not significantly lower [than the infants born at 22 weeks]”, why not put that the other way around? You could equally well say that “…infants born at 22 weeks’ gestation, these rates are not significantly higher” And if you actually look at the data that the outcomes of 22 week infants is based on, the numbers are minuscule. The systematic review by Greg Moore and co-workers in Ottawa (which is one of the references for this report) found 12 such babies with outcomes analyzed after 4 years of age; 31% of those 12 babies were severely impaired (and 43% moderately to severely impaired), which was not significantly different to the 17% (of 73 babies) at 23 weeks.

In other words the majority of the very small numbers of survivors are not seriously impaired. Which comes back to the lack of definitions, “severe long-term neurologic impairment” in many studies could, for example, mean a hemi-paresis. Most infants with hemi-paresis, and their families, would not, I bet, consider that their life was intolerable. Shouldn’t we be asking them?

Don’t we need to have a discussion about what impairments are sufficiently severe to consider withholding intensive care interventions? Don’t we need to have that discussion with parents and with other lay people?

Saroj Saigal has done so for one cohort of patients from her practice. Some of her work is referred to in this report. In her work, only one parent thought that their ELBW child (now adolescent) had a quality of life that was worse than death. All the others reported a positive quality of life, and overall there were only minor differences compared to offspring who had been born at term.

(There are several other references used in this statement that don’t say what the authors state. For example the “clinical report” states “In addition, attitudes may be changing; whereas earlier studies suggested that obstetricians and neonatologists tended to overestimate morbidity and mortality rates for extremely preterm infants, that no longer seems to be the case.7,8” Neither of those 2 references for “no longer seems to be the case” address that issue, there is no report in either publication of obstetric or neonatal estimates of morbidity and mortality. Both are reports of how those specialists practice; they show, for example, that many obstetricians in New York state do not know their local definitions of a live birth. That study asked respondents at what gestation or weight they considered a fetus viable, the other study reports what obstetricians and neonatologists said that they include in their usual antenatal counselling practice. Both are interesting, but neither reports the estimates of morbidity or mortality of extremely preterm infants.)

A trial of therapy?

One thing that I think is also missing is a discussion of the idea of a “trial of therapy”. The decision-making is presented in this clinical report as a dichotomy between full-blown intensive care, on the one hand, and palliative care on the other. But Bill Meadow, among others, has persuasively argued that the best time (in terms of accuracy of prognosis) to make a decision is rarely before birth, but rather afterward. Meadow W, et al. The value of a trial of therapy – football as a ‘proof-of-concept’. Acta Paediatrica. 2011;100(2):167-9. Not only does accuracy improve, but many parents find a moral value in at least trying to have a good outcome from a terrible situation. For extremely high-risk infants, that should at least be a part of the discussion. In my own practice for a couple of recent cases of extremely high risk patients (not preterms, but with very serious malformations) it was decided, with the parents, that the best approach would be to institute active intensive care, but if the pulmonary hypertension was too bad, or the associated malformations too severe, then we could limit the extent and duration of life-sustaining interventions. I don’t see why that kind of approach should not be a important option when discussing extreme prematurity, and indeed in our practice it often is.

 

 

 

Posted in Clinical Practice Guidelines | Tagged , , , | 2 Comments

Writing Clinical Practice Guidelines, who should be involved?

Posted on 3 September 2015 by Keith Barrington

Clinical Practice Guidelines are important for improving quality of care and uniformity of practice.

Or at least they should be. There have been studies of the impact of guidelines, and it is variable, and sometimes negligible. Why is that? Why do physicians and the families they treat not follow learned statements about best practice?

The barriers are many, and have been reviewed and studied by other experts but they include the following  as shown in this study. :

Lack of awareness/familiarity

Lack of agreement with guideline recommendation (mostly related to a lack of applicability )

Lack of self-efficacy (lack of belief that one is capable of adequately performing the recommendation in practice)

Lack of outcome expectancy

Inertia of previous practice/lack of motivation

Patients’ preferences do not match with the guideline recommendation.

Patient ability or behaviour perceived as a barrier

Recommendations which are unclear or confusing, not covering all relevant information, or not being up to date, or too complex or not easy to use in practice

Environmental factors, lack of time, resources or collaboration

There was a recent review in JAMA discussing some of these issues and how to improve the situation.

Classen DC, Mermel LA. Specialty society clinical practice guidelines: Time for evolution or revolution? JAMA. 2015.

One of the things they conclude is

to create CPGs that the public trusts, that clinicians and patients can readily implement, and for which compliance can be easily measured, the CPG development process should continue to be led by specialty societies but with a new model that integrates other stakeholders, including patients.

And this is where I am (finally) getting to my main point. CPG development must include input from patients, and of course in neonatology that means parents. CPGs which don’t include parents in their development may well fail, and maybe should fail. I think this is most critical when we are discussing life and death ethical issues. Not including parents in the process of developing such guidelines is a major mistake. I don’t think we have the right to develop and issue such guidelines without including parents, parent group representatives, the general public, former preterm infants and so on.

Its probably a bit less critical when you are developing a guideline for a specific technical issue, but even there parent values may turn out to be different to ours.

I was pleased to be invited with Annie a couple of years ago to participate in a  Joint Workshop of the  National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists, which produced some useful publications. (Especially mine) But I was surprised and very disappointed to find that there were no parent representatives there. (Apart from Annie and me!)

4 years ago the Institute of Medicine produced a report about making CPGs that people will use. They make some important recommendations, a few of which I copy below.

STANDARD 3
Guideline development group composition

3.1 The GDG should be multidisciplinary and balanced, comprising a variety of methodological experts and clinicians, and populations expected to be affected by the CPG.

3.2 Patient and public involvement should be facilitated by including (at least at the time of clinical question formulation and draft CPG review) a current or former patient and a patient advocate or patient/consumer organization representative in the GDG.

3.3 Strategies to increase effective participation of patient and consumer representatives, including training in appraisal of evidence, should be adopted by GDGs. –

7.1 External reviewers should comprise a full spectrum of relevant stakeholders, including scientific and clinical experts, organizations (e.g., health care, specialty societies), agencies (e.g., federal government), patients, and representatives of the public.

7.4 A draft of the CPG at the external review stage or immediately following it (i.e., prior to the final draft) should be made available to the general public for comment. Reasonable notice of impending publication should be provided to interested public stakeholders.

Guidelines for clinical practice, and especially those discussing whether or not babies should have a chance to survive or not, MUST include parents and representatives of other stakeholder groups.

 

In my next post it will become clear why I decided to talk about this now.

Posted in Clinical Practice Guidelines | Tagged | 2 Comments

Pain is bad for you, sucrose makes it better (even if you are a rat).

Posted on 2 September 2015 by Keith Barrington

I rarely discuss animal research in this blog, but occasionally something striking stimulates a new post.

I have discussed sucrose not that long ago, in particular I emphasized the over-interpretation of a secondary analysis of a non-randomized comparison of very early follow up data from an RCT of the use of sucrose as an analgesic. I will quote myself as I think I am worth quoting:

I am taking this long excursion into the results of an older study because it has been quoted many times as perhaps showing an adverse effect of sucrose on what is often referred to as “neurodevelopmental outcome”. So lets be completely clear, on secondary analysis of a small RCT, data from 2/3 of the preterm babies enrolled showed a statistically significant correlation between the number of sucrose doses given and one item of the 7 items of the NAPI at 40 weeks PMA.

I emphasize that the randomized comparison in that trial showed no difference on any of those items.

Sucrose is an effective analgesic, with no known toxicities. Long term outcome effects are “uncertain” according to the latest Cochrane review. It is difficult to believe that recurrent use of tiny quantities of sucrose would be harmful in the long term, but I guess we need to be cautious with preterm babies.

We can be a lot less cautious with rats.

In this study rats were divided at birth to receive either chronic pain, with a needle stuck into a foot paw 4 times a day for 8 weeks (sounds like being in the NICU), or they got sucrose 4 times a day, or they got the foot pricks but they were preceded by sucrose, or they got a dose of paracetamol then the foot pricks (there was also a non-foot prick no analgesia control group). The sucrose was given on the rats’ tongues so they experienced the sweetness, just like our babies.

The rats that got the foot pricks without analgesia had impaired short term memory when they were tested as adults. Sucrose prevented the decline associated with repeated pain.

Sucrose had no effect on its own, without the pain. The sucrose groups had higher endorphins in the blood. The authors also dissected out the hippocampus on the rats and measured some neurotrophic factors including brain-derived neurotrophic factor BDNF.

…results of the current study showed a significant decrease in BDNF levels in the hippocampus of chronic pain exposed animals. Sucrose treatment, on the other hand, normalized this decline in BDNF levels.

Which gives some idea of possible mechanisms, the endorphin link has been seen before, I believe, but I am new to the BDNF stuff, it sounds like this is a novel finding, but it seems to link up with other research that the authors quote. It certainly looks like BDNF is important for developing learning and memory formation.

There has never been any evidence that sucrose adversely effects human long term outcomes, on the other hand there is substantial evidence that pain does. Although this is a rat study, it does suggest that there is a chance that effective analgesia, using sucrose, will decrease those adverse effects. Even with 4 doses a day for 8 weeks.

Posted in Neonatal Research | Tagged , , | 6 Comments

Oxygen is good for you

Posted on 28 August 2015 by Keith Barrington

Of course you can have too much of a good thing, but you should also try and stay above the minimum.

The COT trial investigators, led by Christian Poets, have published a secondary analysis of the results, examining in particular data from the study oximeters. Despite the relatively low fidelity of the oximeter data (1 sample each 10 seconds) they were able to analyze the number and duration of hypoxic episodes among the 1020 babies who were randomized and who survived to 36 weeks PMA.

An episode of hypoxemia was diagnosed when the saturation was below 80%, and of bradycardia when below 80. There was a clear correlation between a longer time with a saturation under 80 and poorer outcomes at 18 months PMA. Cognitive and Language scores below 85 on the Bayley version3, motor disability and severe retinopathy were all associated with longer durations of hypoxia.

The effects were mostly associated with longer episodes, so when the authors looked at hypoxic episodes where 6 or more consecutive readings (taken as you recall every 10 seconds) were hypoxic, the effects were substantial, whereas shorter episodes of 5 readings or fewer, were less important.

What causes these hypoxic episodes? Most are probably due to apnea of prematurity, although those occurring during assisted ventilation may additionally have other mechanisms, including forced expiration and loss of lung volume.

I have published 2 articles (here and here) trying to determine if there is a relationship between apnea and long term outcomes, both seemed to show a relationship. The improved outcomes in the CAP trial among preterm babies who were treated with caffeine, could also have been due to the babies having fewer hypoxic episodes, although there were no recordings of oximetry to confirm that.

I also wonder if the problem with prolonged episodes may be related to post-desaturation hyperoxia, I and others have shown that apneas are often followed by hyperoxia, possibly leading to re-oxygenation injury, and free radical mediated CNS injury. In my 2 studies that I published only as abstracts, I analyzed recordings of babies who usually had saturations below 95%, and showed that after apneas, they were often over 95%. I thought that the FiO2 of the babies was probably being increased by the bedside staff in response to the apneic hypoxia, but I couldn’t be sure as we didn’t have FiO2 recorded. A much better study was published last year, van Zanten HA, et al. The risk for hyperoxaemia after apnoea, bradycardia and hypoxaemia in preterm infants. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014. in that study babies on nCPAP who had apneas often had hyperoxia after the apnea, and the hyperoxia was much longer than the hypoxia! The hypoxia (less than 80%) lasted on average 2 minutes, and the post-apneic hyperoxia lasted 13 minutes.

The always perceptive Lex Doyle has written an editorial to accompany the article, he points out that the association may not be causative, and that we really have only a limited number of ways to prove whether it is. A therapy proven to reduce the number and duration of hypoxic episodes, and then prospective randomized trials to demonstrate whether outcomes are improved. We are already part way there with the CAP trial, but most of the babies in this new trial will have been getting caffeine, for substantial periods of time, and they were still having lots of hypoxic episodes.

Higher doses of caffeine have been touted, but the concerning results of a pilot trial which showed an increase in cerebellar injury should make us pause. Other agents such as doxapram are suggested by Christian Poets in the discussion section of the article, which sort of brings me full circle, as I made my start in clinical research studying doxapram. But while it is effective in reducing apneas, long term effects are uncertain, infants who received doxapram have been reported in observational studies to have worse outcomes. Which again of course, does not mean causation, but does mean that any studies should be performed with adequate safety protections, and long-term outcome evaluations.

Posted in Neonatal Research | Tagged , , , , | Leave a comment

How the mighty are fallen

Posted on 26 August 2015 by Keith Barrington

It is sad to see a venerable publication like Pediatric Research publishing total drivel.

For reasons that escape me, the latest, August 2015, edition starts with an “overview of the systematic reviews of acupuncture in children“.

The problem with a high quality journal, dedicated to good science, publishing this sort of nonsense is that it gives the impression that it is worth considering that acupuncture might have a real effect.

It is quite clear that acupuncture is nothing but a theatrical placebo. There is no physiologic basis for any real effect, there is no anatomic basis to the supposed existence of acupoints, and despite a whole slew of studies, no evidence of a real effect, for any disease.

Indeed it has been clearly shown that the tiny effects obtained in some studies are obtained no matter where you put the needles, or even if you don’t use needles at all, either not puncturing the skin or using toothpicks. Untrained operators are just as (in)effective as those with years of experience, effectiveness is related to how pleasant the person is who is sticking needles into you, not on where they put them, or how many or how often.

The published overview concludes that further studies are necessary because those published so far are crap, and non-one has actually died. I think that is a very poor justification for wasting time and resources and the goodwill of families. The authors of this overview do show that better quality systematic reviews show less effect, which is a clear red flag.

Studies of acupuncture in children are unethical. No more should be done. Sticking needles into children rather than giving them effective care, for whatever their illness may be, is a deluded practice that risks delaying appropriate therapy. Maybe no-one died in the studies that these systematic reviews included, but at least 90 deaths have occurred due to acupuncture. Ineffective interventions like acupuncture are certainly not worth dying for.

Steve Novella on the excellent blog “Science Based Medicine” dissects another recent study, and notes that acupuncture promoters have created “An industry of worthless studies“. He notes :

acupuncture should be abandoned as a scientific concept. It is a failed hypothesis that has added no real knowledge to our understanding of health and disease.

Come on Pediatric Research, lets return to reality-based medicine.

Posted in Neonatal Research | Leave a comment

Under Pressure….

Posted on 26 August 2015 by Keith Barrington

Colm O’Donnell once wrote an article with a whole line from a David Bowie song embedded in the article’s title (O’Donnell CPF. Turn and face the strange – ch..ch..ch..changes to neonatal resuscitation guidelines in the past decade. Journal of Paediatrics and Child Health. 2012;48(9):735-9), I think Gene Dempsey is following suit, but using only the title this time, see below! It might have been difficult to include the line “this is our last dance, this is ourselves, under pressure” to treat hypotension.

Faust K, et al. Short-term outcome of very-low-birthweight infants with arterial hypotension in the first 24 h of life. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2015. There have been a number of observational studies of the association between hypotension and clinical outcomes in the very preterm infant. The results have been variable, as the accompanying editorial from Gene Dempsey (Dempsey EM. Under pressure to treat? Archives of Disease in Childhood – Fetal and Neonatal Edition. 2015) points out. One of the reasons for that variability has been the variation in the criteria used for the diagnosis of hypotension. There have been several biases in other published studies, and all observational studies risk biases which are not necessarily obvious.

This particular study was well performed, but of course cannot determine causality, and suffers from not being able to report the duration of the hypotension. What they showed was that there was a statistical association between having a lower blood pressure during the first 24 hours of life, and having more complications (specifically IVH, BPD and death). One of the questions that has been asked about previous data is whether the association might be explained by adverse effects of the interventions that were used for the hypotension. In this data set treatment with pressor agents had a very strong association with IVH and BPD, even after multivariate correction. As Gene points out in his editorial, there were many infants who were hypotensive who were not treated with pressors. Hypotension remains very common, depending on the definition, using the common definition of a mean blood pressure less than the gestational age in weeks, there were about half of the babies who were hypotensive, much as shown in other studies. nevertheless less than 9% of the babies received pressor agents.

So the neonatologists in the network were already selecting who to treat based on some factors other than just the blood pressure. One of the nice things about this study is that they analyze their data among those who did not receive BP support in the first 24 hours, they showed a minor increase in risk of IVH, BPD and death in hypotensive babies who did not receive inotropes, compared to the normotensive. The Odds ratios are between 0.95 and 0.97 and are statistically significant. I think that is the first time this has been shown. Of course it doesn’t mean that the hypotension was causally related to those outcomes, and it certainly doesn’t mean that treatment with inotropes improves the risks. Indeed the Odds ratios for those same complications are much greater for treatment with inotropes, 1.5 to 2.4, which might be because the babies were more unwell, or might be due to the intervention.

This valuable additional data reinforces the need to get prospective trials completed, no matter how difficult they may be.

Posted in Neonatal Research | Tagged , , , , | Leave a comment