ETT position

I was very fortunate to do my fellowship in neonatology with Neil Finer. One of the (very many) things which he taught me, about the 3rd day of the fellowship I think, was how to determine ETT position. He showed me this technique, with a finger in the suprasternal notch, moving the tube slightly, you can determine if the ETT is in good position. I have used it ever since and tried to teach others. The way I do it is to make sure the infant’s head is in neutral position, then put an index finger in the notch, and you should be able to feel the firm resistance of the tube. Then you slowly pull the tube back until you feel the tip. Then advance the tip of the tube until it is just as far you can feel, just above the manubrium. I have never performed a study of this, but I have never had an endobronchial intubation in many years using this technique. It is very simple and accurate in small preterm infants, but a little more difficult to be sure of the detection of the tube tip in a large term baby.

Several years later Neil published a randomized study demonstrating the utility of the technique (Jain A, Finer NN, Hilton S, Rich W. A randomized trial of suprasternal palpation to determine endotracheal tube position in neonates. Resuscitation. 2004;60(3):297-302).

In a new trial, (Saboo AR, Dutta S, Sodhi KS. Digital palpation of endotracheal tube tip as a method of confirming endotracheal tube position in neonates: an open-label, three-armed randomized controlled trial. Pediatric Anesthesia. 2013;23(10):934-9) infants were randomized to have either tube position determined by either a weight based calculation, calculation plus palpation by ‘specially trained neonatology fellows’ or calculation plus palpation without extra training. There were many fewer malpositioned tubes in the second group.

This technique is simple, easy to learn, non-invasive and quick. It can practically eliminate endobronchial intubations, and ensure that surfactant is delivered via a tube above the carina. It should be more widely taught and used.

 

 

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Neonatal Updates

Gephart SM, Spitzer AR, Effken JA, Dodd E, Halpern M, McGrath JM. Discrimination of GutCheckNEC: a clinical risk index for necrotizing enterocolitis. J Perinatol. 2014. The Pediatrix group have developed a scoring system for predicting the risk of NEC; points are given for a number of different items, and then added. The process of developing it is well described, it took me a while to find where is the cut off for the score, but in figure 3 it is noted that the threshold is 32. If you have a score more than that you at increased risk, less than that you are at decreased risk. Interestingly, the positive risk factors, which reduce the risk, include probiotics! Also interestingly the background incidence of NEC in the individual NICU is by far the most important risk factor. Human milk feeding on both days 7 and 14 was another protective factor. Many of the risk factors are not modifiable, but those 2 certainly are.

van Ganzewinkel C, Derijks L, Anand KJS, van Lingen RA, Neef C, Kramer BW, et al. Multiple intravenous doses of paracetamol result in a predictable pharmacokinetic profile in very preterm infants. Acta Paediatrica. 2014. In much of the world, intravenous paracetamol (acetaminophen) is available. This study gives important pharmacokinetic data.

Hitzert MM, Van Braeckel KNJA, de Bok M, Maathuis CGB, Roze E, Bos AF. Functional outcome at school age of preterm-born children treated with high-dose dexamethasone. Early Human Development. 2014;90(5):253-8. Arie Bos is one of those exceptionally productive but self-effacing individuals who drive a large body of neonatal research. In this study the group he works with have analyzed outcomes of very preterm babies who received dexamethasone, compared to control infants. Overall cognitive and motor development were worse, with less effect on language skills. As always from observational data, it is not certain whether this is causative or not, but it is certainly biologically feasible.

Rollo DE, Radmacher PG, Turcu RM, Myers SR, Adamkin DH. Stability of lactoferrin in stored human milk. J Perinatol. 2014;34(4):284-6. Refrigerating breast milk decreases lactoferrin concentrations, but not by much. Freezing it has more of an effect, prolonged freezing at -20  reduces levels by half. The fresher the better, at least for lactoferrin.

Pathak G, Upadhyay A, Pathak U, Chawla D, Goel SP. Phenobarbitone versus phenytoin for treatment of neonatal seizures: an open-label randomized controlled trial. Indian pediatrics. 2013;50(8):753-7. An RCT in about 110 babies with seizures. Clinical seizure control was better with phenobarb. Unfortunately no EEG data.

Wilson-Ching M, Pascoe L, Doyle LW, Anderson PJ. Effects of correcting for prematurity on cognitive test scores in childhood. Journal of Paediatrics and Child Health. 2014. I think that you should always correct for prematurity. It just has less and less impact as the child ages. 3 months of correction makes a big difference to a 2 year old, and not much for a 10 year old. But at least we all then talk about the same thing.

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Apneas are bad for you (probably), this might be part of the reason

I have published two articles that looked a the relationship between apneas and long term outcome. One was taken from pre-discharge recordings of very preterm babies. We compared the long term neurodevelopmental abilities of preterm babies 18 months later, and compared them to the pattern of apneas that babies, who were ready to be discharged, had on their recordings.

Infants with the more severe apneas had worse outcomes at long term.

Another study examined the number of days that apnea was recorded by the bedside nurse in the hospital chart, and again compared this to long term outcomes. There was a significant correlation, the more days of apnea, the worse the outcomes.

Quantifying apnea from hospital charts is fraught with risk. Many apneas are not noticed by the bedside nurse, especially obstructive apneas; overall about half of apneas are not noted in the charts. That is the reason we decided not to try to count apneas in the CAP trial, the only really reliable method is continuous recordings, which are then analyzed objectively.

Nevertheless, it is probably true that there is a correlation between the apneas recorded in the chart and the true number of apneas that a baby has had. The more ticks in the chart, the more apneas the baby had, probably.

So as a sort of surrogate of  true apnea incidence the number of recorded apneas, or the number of days of apnea, as we studied, is probably of some value.

A newly published study compared the total numbers and severity of bradycardia of apneas as derived from the hospital charts, as well as whether they received stimulation or vigorous stimulation, of extremely low birth weight babies, and their neurodevelopmental outcomes, using the Bayley 3 scales. They found worse language development in infants who had more severe, or more frequent apnea, at 8 months corrected, and at 20 months corrected age. From what I can tell, the authors did a large number of regression analyses, which makes a type 1 error more likely, nevertheless, the results are in the same direction as my older studies, as well as others by Pillekamp et al, and the CHIME study group. CHIME showed that both preterm and preterm babies who had serious apneas at home, had worse developmental outcomes.

Why this might be is presumably related to the frequent hypoxia/re-oxygenation episodes preterm infants experience, episodes which are less frequent with caffeine. This is presumably the reason for the beneficial effects of caffeine (even though other effects, on inflammation, for example, have been shown also.)

One other thing which I noticed previously, and have published 2 abstracts about, is that it is not rare, after an apnea, for a baby to become hyperoxic. I noted that some babies who had an average saturation in the low 90′s before an apnea, would oversaturate after they started breathing again. Although there are one or two possible reasons for this, I thought that some of it, at least, was probably due to caregivers increasing the FiO2 when the baby desaturated. From my data I wasn’t able to be sure, as I didn’t have a record of the oxygen concentration being administered, which is why I never proceeded to produce a full publication. And now I have been beaten to it!

In a study from Leiden the authors analyzed recordings of babies on CPAP who developed apnea, and noted whether they had an increase in SpO2, and whether the FiO2 had been changed around the episode. They found that FiO2 was increased around 11% of the apneas, and when that happened a large majority of the time (79%), the babies became hyperoxic (SpO2>95%) after the apnea, this lasted for an average of 13 minutes! The authors don’t tell us, I think, what happened to post-apneic hyperoxia if there was no change in FiO2, how common it was if the FiO2 was unchanged isn’t described.

It clearly doesn’t help to increase FiO2 if the baby is not breathing. Few of these apneas were likely to have been obstructive, as the babies were on CPAP, so oxygen was increased probably either when the baby was apneic, or afterward during the recovery phase. I guess that most often it was probably when the SpO2 wasn’t coming up as quickly as the nurse expected, so she(he) increased the oxygen, and then took on average 14 minutes to get it back down to the previous concentration.

One thing that I think is surprising is that we have no idea how to treat apneas. We have some idea how to prevent apneas, using caffeine, and CPAP, (I won’t discuss doxapram for the moment).

But when a baby stops breathing, how should we intervene to get him/her breathing again? What usually happens is that the baby is first stimulated (does this work? if so, how? what kind of stimulation works best?) and then, if still apneic, a variety of other interventions may be tried, including repositioning, suctioning, more vigorous stimulation, assisted ventilation, and increasing oxygen concentrations. Do any of these actually work? Which is best? This is one of the commonest interventions in the NICU, something done many times a day, but we have no idea what is the best approach.

I have a design written for a trial of ‘usual therapy’ compared to what I think might be optimal, that is, keeping a self-inflating bag next to the baby, in the same FiO2 as the baby is receiving, and immediately starting positive pressure ventilation. I think that only a couple of breaths would be required for most babies, that this might reduce post-apneic hyperoxia. Certainly some way of deciding how long to wait before increasing the FiO2 of a baby would be really useful.

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Oxygen, transfusions, and NEC

What causes NEC! The answer is ‘who knows?’, or perhaps a better one would be ‘its complicated…’ You probably need an immature gut, gut mucosal injury, inflammation and cytokine release, and an abnormal microbiome, all of which probably interact in complex ways.

In a comment on a previous post, John Lantos remarked that the majority of the increased mortality in the SUPPORT trial was from NEC. I replied that he was right, there were more also a few more  deaths from sepsis and from bronchopulmonary dysplasia, but the biggest difference was in NEC deaths, 23 vs 14. There wasn’t a big difference in diagnosis of NEC (stage 2 or 3), 11.9% vs 10.8%, just in mortality from NEC.

I seemed to remember that the pattern was the same in the BOOST 2 trials also, indeed the rate of NEC (requiring surgery or causing death, that is, more severe than in SUPPORT) was 12.2% vs 9.9%, with the new algorithm installed on the pulse oximeters, in the low saturation group compared to the high saturation group. There were 39 deaths from NEC in the low saturation group, and 22 in the high saturation group. There were also more deaths from septicaemia, 28 vs 15, and more deaths from BPD 18 vs 12.

In the COT trial there were also more cases of NEC overall (stage 2 or more) in the low saturation group than the high saturation group, 12.3% vs 9.3%, but I don’t know about causes of death, or whether the difference changed with the re-programming of the pulse oximeters.

The reason for going back over this is twofold, firstly, the observational study about TANEC that I mentioned in that previous post showed that babies who had a lower hemoglobin before their transfusion seemed to be more likely to develop TANEC; secondly a new commentary published in the Journal of Perinatology discusses the ‘limitations of the randomized clinical trial and the end of equipoise’ using the oxygen trials as an example.

That first point makes me think that there may be a common issue, that of intestinal re-oxygenation. If more severely anemic infants have somewhat hypoxic intestinal mucosa, and transfusion improves that, as well as supplying inflammatory mediators, then that could trigger the injury leading to NEC. Also it has been shown that infants in the low saturation arm of the SUPPORT trial had more frequent and severe intermittent hypoxia, with multiple episodes per day of hypoxia, re-oxygenation (and perhaps hyperoxia as well, more about that later). So there may be a common link, how that relates to sepsis or BPD I am not sure.

Although there are some issues in the commentary that I agree with, I think there are some fundamental errors also. The authors state that the oxygen trials were elegant, important, adequately powered, etc, but that clinicians seem reluctant to institute changes in practice, they suggest that this is because we thought that perhaps there would be less RoP with lower oxygenation, but that the mechanisms of the increase in mortality is uncertain. I am not sure that is likely to be true, I think therapeutic intertia is a bigger issue.

They then discuss whether there might be situations in which  a lower saturation target might be right for an individual baby,

The authors of the commentary use a very limited view of EBM

The idea of evidence-based medicine is straightforward—the clinician needs to use the best available evidence to determine optimal therapy for his or her patient

David Sackett, in contrast, puts it this way

Evidence Based Medicine is the integration of clinical expertise, patient values, and the best evidence into the decision making process for patient care. Clinical expertise refers to the clinician’s cumulated experience, education and clinical skills. The patient brings to the encounter his or her own personal and unique concerns, expectations, and values. The best evidence is usually found in clinically relevant research that has been conducted using sound methodology.

Which is a much richer understanding, and which actually addresses much of what they discuss. They make much of the fact that a particular RCT may not address the issues of an individual complex patient, which is obviously the case, and is the reason why exploratory sub-group analyses are performed on large RCTs, to try and identify patients for whom further investigation may be required. I emphsize, further investigation is required, subgroup analyses are fraught with problems and have sometimes been proved unreliable when those further studies are done.

They conclude with the following:

What we do as clinicians with the newest evidence about oxygen-saturation targets and ELGANs remains to be seen. As the product of elegantly designed and conducted international multicenter RCTs, the evidence for the benefit of higher oxygen saturation targets will be heavily weighted. But as the product of an RCT it may not necessarily be the best practice for every individual ELGAN.

I would respond to that: tell me when you think it is better for a baby to have lower saturation limits. Under what circumstances, for this particular issue should you expose the baby to higher risks of death, and lower risks of RoP? Of course it is likely to be true, as they point out in the commentary, that some babies who developed RoP would have escaped it if they had been in the lower group, and they may not have been the same babies who would have died. In other words, an individual baby, if you knew from the day of their birth that they would survive, and would not develop NEC or sepsis or BPD, but were at risk of severe retinopathy, would be better in the low oxygen group.

If you know how to identify such babies, then you should design an RCT to enroll them, and prove that they are indeed safer with lower saturations.

I can actually see that could be true, it could be that in a particular clinical situation a lower saturation might be beneficial. But unless you can define and test that possibility there doesn’t seem to me to be any reason to expose babies to the increased risks of death (from NEC sepsis and BPD) which accompany the lower saturations.

And to be honest, in their NICU do they really go round every day and decide which babies should have saturation targets of 85 to 89, 88 to 93, or 90 to 95%? I really doubt it, I don’t know anyone who does that. So their argument just falls flat, for this particular issue; I would bet you that they have standard oxygen saturation target ranges for preterm infants in their NICU, because we have no evidence for doing anything else. Of course clinical expertise is important in neonatology, and it is an essential part of evidence based practice, but I have no idea what kind of clinical expertise ‘cumulated experience, education and clinical skills’ you could use for assigning a different oxygen saturation target for an individual-complex baby, to use their term.

The authors discuss research equipoise and clinical equipoise as if they were different. I do not agree with their evaluation. Equipoise just means that there is a therapeutic choice and you do not know which is best for an individual baby. In such a circumstance it is appropriate to design an RCT or enter the baby in an RCT, or, if there isn’t one approved just make your best guess, by adding up all the pros and cons, and try and decide the least worst option.

For oxygen saturation targets we no longer have much uncertainty, the higher saturation targets decrease mortality and we can be 99% confident that this is true. If you are still using lower saturation limits then I think you should inform parents about this evidence and explain why you are have decided to use lower saturations.

Which brings me back to a sentence earlier in the commentary

‘If one were to consent parents to a trial arm for which there is now evidence for increased mortality, would any parent reasonably be expected to provide permission for their child to be enrolled?’

If the authors think is unlikely that parents would consent for such a trial, why should parents be expected to consent for individual treatment according to a standard ‘for which there is now evidence of increased mortality’? If my baby were in an NICU and the neonatologist informed me of that evidence, and then said, ‘but I have decided with my clinical experience that your baby should nevertheless have lower saturation targets’ I think we would have some serious discussions.

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Meat the Munch Bunch

Being in a bilingual family has many great pleasures, but there are also extra opportunities for misunderstanding. Tonight, when reading a sequel to ‘Meet the Munch Bunch’ one of the kids asked me, ‘what does it mean (qu’est-ce que ça veut dire), la viande  munch bunch?

I thought they had understood the title of the first episode, part of a group of stories for young children, originally written by a young girl; characters include Professor Peabody (knowledgeable pea-pod) Sally Strawberry (gifted artist, likes the colour red) and Spud (potato with delusions of grandeur). The first book, which introduces the characters, I had read the previous night. The kids had just listened and nodded, it wasn’t till 24 hours later that I discovered they hadn’t understood the title, and maybe not much else either. Probably their little brains were wondering all along why the whole book was about talking vegetables, but the title was about ‘meat’!

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Transfusion Associated Necrotizing EnteroColitis?

I’m still not absolutely sure about TANEC, as it now seems to be called. It is certainly possible that transfusions could trigger gut injury in very preterm babies, but how to prove it? Even if the temporal association was absolutely clear, does the transfusion just change the timing of NEC rather than increasing incidence? And then what do you do about it?

The 2 RCTs of differing blood transfusion thresholds that I recall, Ed Bell’s study, and the PINT trial did not report any difference in NEC. There was no mention in Bell’s study, and the frequency of NEC was actually slightly lower in the high transfusion threshold PINT group (not significant) who got transfused more frequently as a result of their assigned group.

A recent systematic review of observational studies illustrates to me the difficulties in figuring this all out, their first question was ‘Are neonates who develop NEC more
likely to be exposed to PRBC transfusion within previous 48 hours compared
with those who do not develop NEC?’. My question is, for those who do not develop NEC, which 48 hours do you mean?

One study from the CNN (the database not the news channel) used a case control design, the controls were all patients who did not develop NEC at all, the controls had a transfusion within 2 days before their diagnosis. For the controls they examined the 2 days before the median age of developing NEC in the same birth weight stratum. According to this study 9% of cases of NEC occur within the 2 days after a transfusion. Of course, babies who get NEC as well as babies who have transfusions are smaller, more immature and sicker. You can try and correct for such things, but it is hard to convince me that you can eliminate all the confounding.

Even if it does exist what do you do about it? I have written on this blog on numerous occasions that there is no evidence that feeding patterns affect NEC. You can advance feeds fast or slow, feed trophically or advance immediately, or whatever you want to do, don’t expect any effect on NEC. Probably the only thing that you should not do is keep babies nil by mouth, to be honest there isn’t much evidence that this affects NEC, but it does affect growth, subsequent feeding tolerance and the duration of TPN and central catheter use.

Despite this, several individuals have suggested putting babies npo, to use the usual english-latin abbreviation. One stopped feeds during the transfusion and then started them again immediately afterward. They had a decrease in NEC from 9 cases of 171 LBW, to 2 out of 155. Which of course is a far bigger decrease than you could get from just preventing TANEC.

The most recent study, and the one which triggered this post, showed something quite similar. The authors instituted a policy of withholding feeds for 4 hours before and after the transfusion, and then half the previous volume for 12 hours, then advanced to the previous volume. They showed a  reduction in NEC after introducing this (from 12% of VLBWs to 7%). However, they showed just as much reduction in NEC not related to transfusion as in TANEC, and the actual reduction in TANEC was not significant. So clearly the change in the policy of withholding of feeds was just coincidental with something else that happened (I don’t know what, they don’t seem to either).

And to come back to the overall feeding management issue. As I understand the data, and Bill McGuire, who does many of these Cochrane reviews, can correct me if I am wrong, early commencement of trophic feeds has a number of advantages over keeping babies npo, but in terms of the most clinically important outcomes of death or NEC there is no proof of benefit. Many of the studies actually had 2 or 3 days of being npo even in the trophic group, though, so good data about starting feeds immediately after birth are lacking. Secondly, the data compare trophic feeds to no feeds. I don’t think there are good trials comparing trophic feeds, initiated early, to immediately starting to increase feed volume. That is a trial that I think we do need, infants would be randomized shortly after birth to a schedule which gives 3 or 4 days of trophic feeds, or would start at the same volume for the first feed, but immediately be on a schedule of increasing by 20 to 30 mL/kg/day.

 

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Septic Shock; 3 negative trials

Three trials back to back in the PNEJM (that’s the prestigious New England Journal of Medicine for any new readers) in adults with septic shock are disappointing:

Early Goal Directed Therapy has become a dogma in recent years; it even appeared on an episode of ER, as I recall. It promotes a protocol of early insertion of central catheters, fluid administration to certain hemodynamic measurements, and monitoring of central venous saturation. The original trial was a single center RCT of moderate size (260 adults with severe sepsis, septic shock, or sepsis syndrome) and had significantly more survivors in the intervention group than the usual treatment controls. I think the study was well-done, but includes individual items that could be, and were, challenged. In total there were about 20 more deaths in the control group than the intervention. Considering that this modest size single center trial, with a significant result, but a relatively small numerical difference in survival led to changes in approach that have affected many 10′s, maybe 100′s of thousands of patients, makes me pause. Smaller trials often tend to have results that are more impressive than larger ones, and the control group mortality in Rivers’ trial was very high, at 46.5%.

The new trial in the PNEJM, is a larger multicenter comparison of early goal directed therapy (a very similar protocol to Rivers et al) to 2 other approaches, one was another protocol which did not mandate a central catheter, and even if you needed a central venous catheter for venous access you weren’t supposed to measure CVP or central venous oxygen saturation, transfusions were given at much lower hemoglobin levels, management was based on clinical evaluation of the patient, including the ‘shock index’ (heart rate divided by systolic BP), and also the clinical signs of poor perfusion. The third arm was usual care, which has of course changed over the years since the original Rivers study. 1341 adults were randomized, they all were in shock, and the study found very little difference in outcomes. The primary outcome, which was whether you survived for 60 days, was not different. There were some minor differences between the groups, but nothing earth shattering. It seems that careful clinical evaluation and judicious standard care is as good as anything else. Of note the mortalities in the 3 groups were around 20%, much lower than the control group in the earlier study which was 44%.

The second study was a comparison of different blood pressure targets. In a multi-center trial from France of adults in septic shock, the 776 subjects were randomized to a target mean BP of 65 to 70mmHg, as recommended by the surviving sepsis campaign, or 80 to 85 mmHg. BP was raised for the most part using norepinephrine, if the patients were below target after fluid resuscitation. The high target group had more norepinephrine used, and some more atrial fibrillation, but no differences in survival to 28 days were seen, which was about 65% in each group. They also had less renal impairment in the high BP group. These patients seem to have been sicker at baseline than the first study, with shock refractory to fluid boluses and already receiving norepinephrine at 0.1 microg/kg/min or more when randomized. Observational data had previously suggested that you did better if the blood pressure was kept higher, which shows the importance, once again, of doing these sorts of trials.

The third trial was an Italian multi-center trial of adults with severe sepsis or septic shock, 1818 patients were randomized to either get crystalloid solution, or 20% albumin and crystalloids, with a goal of achieving a serum albumin of 30 g per liter. 28 day mortality was just over 30% in both groups. The only effect of giving albumin was that the serum albumin was higher!

As I said above, disappointing, as we don’t find clear advantages of one intervention (or bundle) over the other. The really important message from these trials is that we need to keep doing large pragmatic trials in septic shock, they are feasible, and they point out that septic shock is common, still has a high mortality, and we don’t have a lot of evidence based methods to treat it.

There is a message here for neonatology:  trials in critically ill unstable patients are feasible, and are absolutely essential if we are to move forward.

 

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