What to give before intubation

The blog has been quiet recently, for various personal and professional reasons, but I will be getting back into the groove. I got really concerned over the last couple of days, my usually reliable personal PubNeoMed in my brain told me there was an article but whenever I tried to find it I came up with a zero. I kept saying to myself, I’m sure I’ve seen that article, and I’m sure it was by Neil Finer, Wade Rich and Tina Leone; I finally realized that I was searching using ‘newborn’ and not ‘neonatal’! One day computers will understand us better, until then I still have a role!

Le CN, Garey DM, Leone TA, Goodmar JK, Rich W, Finer NN: Impact of premedication on neonatal intubations by pediatric and neonatal trainees. J Perinatol 2014.

When I give presentations about premedication for endotracheal intubation, I sometimes get the comment that ‘we don’t use premedication because; what if the resident fails?’ I don’t understand the thinking behind such statements,  I wonder what the speaker would think if they were admitted to a teaching hospital with respiratory failure themselves, would they be happy having an awake intubation just in case the junior resident was unable to get the tube in the right hole? In any case this publication from San Diego shows that the success rate doubles when premedication is used, during intubations by trainees. So even if you are trying to teach this important skill to neonatal trainees, they have a much higher success rate, and more importantly the baby experiences much less pain and discomfort, if they get premedication than if they don’t.

But what to use? (Avino, D., et al. (2014). “Remifentanil versus Morphine-Midazolam Premedication on the Quality of Endotracheal Intubation in Neonates: A Noninferiority Randomized Trial.” J Pediatr).

This randomized trial compared remifentail, a very short duration opiate, to a morphine and midazolam combination. All infants in both groups received atropine, followed by either of the 2 opiate regimes. All the babies were intubated by neonatologists.

Overall there was very little differences between groups, most of the minor differences favoured remifentanil.

In this study, unlike some others, morphine was given 10 minutes before the intubation, which is reasonable as morphine takes at least this long to have a good effect.

On the other hand I have no idea why you would give midazolam for an intubation, I don’t think it has been recommended by any professional body, quite the opposite, as a sedative without analgesic properties, and an extremely variable, and often very prolonged duration of action, I think midazolam is a good example of a drug to avoid for intubation.

Also why did none of the infants, in either group, receive a muscle relaxant? This is never mentioned by the authors in their methods or their discussion, but muscle relaxation is routinely used in older patients, and has been shown to improve intubation conditions and shorten time to intubation in a number of studies in newborn infants.

Having said that this study does show, I think for the third time, that remifentainl can be used for intubation. Is it better for intubation conditions, and for weaning and extubating quickly, than other regimes? Not yet sure, but looks promising.

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New Lactoferrin Data

Two new articles addressing effects of lactoferrin. Both used bovine lactoferrin (bLF), one was in humans, the other in piglets.

In case you haven’t been following closely, lactoferrin is an iron transport protein that has multiple anti-infective properties, against bacteria, fungi and viruses. It reduces the formation of biofilms, and also has some immune modulatory effects. A single large (470 infants in 3 groups) multicenter RCT by Paolo Manzoni and his colleagues showed a major (80%) reduction in nosocomial sepsis with bovine lactoferrin prophylaxis among very preterm infants. Another trial in infants in Peru by Theresa Ochoa and others has also been presented, but not yet published, and also showed a reduction in late onset sepsis; they had a more modest 40% reduction in combined probable and possible sepsis, and they included babies with birth weights of 500 to 2500 g, mostly the babies were over 1000g.

At least 3 other large RCTs are starting up to see whether the effects can be confirmed.

In the meantime other smaller studies looking at mechanisms are being produced.

The study in piglets examined the effects of bovine lactoferrin in 3 different doses. The control diet of sow milk replacer already contains some bLF, giving about 100 mg/kg/d, compared to the 2 other groups that received 3 times as much or 10 times as much. The spleen cells from the highest dose group produced much more interleukin10 and TNFalpha than the controls, and lymph node cells also produced more IL-6 in response to being stimulated with endotoxin.

The other article is a very small RCT (25 per group, <32 weeks gestation or VLBW) that was not powered to examine differences in the incidence of sepsis even though that was the stated primary outcome. Secondary outcomes included changes in regulatory T cell populations. The number of babies who had at least one sepsis episode was not statistically different between groups (8 controls and 4 lactoferrin babies), Many of the control babies had a second sepsis, so when analyzed as sepsis episodes per 1000 patient days there were less frequent sepsis episodes in bLF-treated infants (4.4 vs. 17.3/1,000 patient days, p = 0.007) with none developing NEC, compared to 5 controls who had NEC (20% NEC under 32 weeks being an enormously high incidence).

This article needed some serious editing: The consort flow diagram in this article includes the term ‘give reason’ about 8 times. I guess the authors cut and pasted this from somewhere and didn’t realize that they were supposed to replace ‘give reasons’ with the actual reasons! The diagram also doesn’t say which group is which, they are both ‘intervention’. They also use terms in the text that I don’t understand such as ‘inappropriate sample’ (as a reason to not be enrolled in the study) and there are a few other sentences whose meaning is not clear.

Most importantly they also excluded 3 babies from analysis in the lactoferrin group as they are said to have become infected before they got the lactoferrin, infants were randomized before 72 hours, but only started getting the bLF when they were getting 20 mL/kg/d of enteral feeds, this is an unfortunate abrogation of the Intention To Treat principle; if those babies are included as they should be, then there is obviously no difference at all in sepsis episodes between groups. At least one of the babies in the control group also had a sepsis at 4 days of age also, but was not excluded from analysis.

The first and major analysis for a clinical trial has to be to include all the babies randomized in the group that they were randomized to. Otherwise this is not a fair test of whether using bLF in this way is actually effective. For mechanistic secondary analyses, sometimes a by treatment analysis can be appropriate, even then you should delete control babies if they became septic before getting placebo.

The other data presented are interesting, the authors showed that Treg levels at birth and discharge were similar, while preterm infants showed significantly lower levels than term controls. However, when they analyzed the percentage change in Treg levels, they were higher in the bLF group. Although this is soft data, it does suggest some effects of bLF on immune modulation.

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Filling Buckets

The title of this post is the title of a wonderful new article in JAMA; an article describing 3 patient encounters by 2 physicians at different stages of their career and a medical student. Read it if you have access, and if you want to be reminded why we do what we do (or if you are not a physician but you want to find out).

Richard Lehman’s weekly journal review had this to say about the article and the author of the quote that starts the article, the gloriously named Avedis Donabedian :

Donabedian spent his life trying to define and examine quality in medical systems, and at the end of his life wrote “Ultimately, the secret of quality is love.” Everything else he wrote is so rigorous, nuanced, endlessly detailed, and scrupulously analyzed that this simple, heartfelt assertion comes as a shock—and yet of course it explains what drove his immense effort. Do read this article: it is not soppy at all, though it deals with the central question in our lives as doctors. With so much suffering around us, and often so little we can do about it, how can we get the affirmation we need to carry on? It comes, of course, from the gratitude, understanding, and acceptance of the human beings we try to help. Take that away, and we are finished. So why is it not a central aim of every health system to nurture this exchange of compassion and mutual understanding? Answer: because it is the opposite of commerce.

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Low Cardiac Output after PDA ligation

Some babies after PDA ligation develop a low cardiac output, Patrick McNamara and his colleagues have defined that as being less than 200 mL/kg/min left ventricular output. This cohort study of 30 infants post-ligation, by Afif El-Khuffash and colleagues at Sick Kids hospital in Toronto had 19 with low and 11 with normal cardiac output. El-Khuffash AF, Jain A, Weisz D, Mertens L, McNamara PJ. Assessment and Treatment of Post Patent Ductus Arteriosus Ligation Syndrome. The Journal of pediatrics. 2014. Using tissue doppler and speckle tracking they analyzed cardiac function, and they demonstrated that babies who had a lower cardiac output had increased systemic vascular resistance, and this was associated with signs of myocardial strain, in particular reduced systolic tissue velocities.

The authors then report that all the infants with low LVO were given milrinone, and this was followed by a reduction in SVR, an increase in LVO and an increase in systolic tissue velocities. Which of course begs the question, what happens if you don’t give them milrinone. The Sick Kids group are very pro-milrinone for these babies, but I remain unconvinced. They have not randomized babies to milrinone or control, and even if there is an effect of milrinone, it could all be explained by vasodilatation. Phosphodiesterase 3 inhibitors have variable effects in different animal neonatal models, with very poor or no inotropic effect, and even negative inotropic effects in some. Mary Paradisis’ randomized trial of milrinone in early life in very preterm babies showed no increase in perfusion, a reduction in blood pressure and a dilatation of the PDA, suggesting vasodilatation without improvements in cardiac function. Vasodilatation and reduction of afterload might be enough to explain the improvements in cardiac function and output.

It may be that at later postnatal ages the effects of milrinone may be different, but I think that needs to be proven, and even if vasodilatation is all that is needed in these infants to improve cardiac function, it might turn out that milrinone is a good way to vasodilate these babies; or maybe we should just wait and let them improve spontaneously; or maybe they should all get a touch of steroids; or maybe…. So many questions, so little time…

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Neonatal Updates

Dardas M, Gill SR, Grier A, Pryhuber GS, Gill AL, Lee Y-H, et al. The Impact of Postnatal Antibiotics on the Preterm Intestinal Microbiome. Pediatr Res. 2014. It will be no surprise to readers of this blog that antibiotics are bad for your bugs, and not just the ones that you don’t want. This study of postnatal development of the intestinal microbiome took samples at 10 days and 30 days in very preterm infants. They show that babies that received more than 7 days of antibiotics, compared to those who received only 2 days, had reduced diversity in their intestinal flora. Reduced diversity has been linked to the development of NEC in some studies.

Victor S, McKeering CM, Roberts SA, Fullwood C, Gaydecki PA. Effect of permissive hypercapnia on background cerebral electrical activity in premature babies. Pediatr Res. 2014. Higher CO2 had little effect on EEG activity in this study, there may have been an increase in delta activity with higher CO2, but as the authors tested many correlations of different aspects of the EEG, his may have been spurious, as they acknowledge.

Czaba-Hnizdo C, Olischar M, Rona Z, Weninger M, Berger A, Klebermass-Schrehof K. Amplitude-integrated electroencephalography shows that doxapram influences the brain activity of preterm infants. Acta Paediatrica. 2014. As I started my research career studying doxapram I have stayed interested, even though it is no longer available in Canada. The results of this study are quite are concerning, an increase in continuous background activity, and a major increase in seizure like episodes was seen on aEEG monitoring of preterm babies receiving doxapram. Both compared to the same babies when not receiving doxapram, and compared to similar control babies. At first I wondered if they had used a high dose, as we used to think that low doses affect the peripheral chemoreceptor and higher doses had a direct CNS stimulant effect, but the dose they used, of 0.5 to 1 mg/kg/h was what we devised from pharmacokinetic studies years ago. So it doesn’t seem too high. The electrical seizure like activity disappeared after the doxapram was stopped. You can’t be 100% definite about seizures from an aEEG it is possible, I guess, that doxapram induces EEG changes that look like seizures on the EEG but are really some other phenomenon, but maybe its a good thing that I can’t prescribe it any more!

Vendettuoli V, Bellù R, Zanini R, Mosca F, Gagliardi L, Italian Neonatal Network. Changes in ventilator strategies and outcomes in preterm infants. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014. This study of data from the Italian database compared interventions and outcomes in 2006 and 2010. Despite similar babies, fewer babies had invasive ventilation, more received non-invasive ventilation, and the outcomes of mortality and combined mortality and BPD were reduced.

Chollat C, Enser M, Houivet E, Provost D, Bénichou J, Marpeau L, et al. School-Age Outcomes following a Randomized Controlled Trial of Magnesium Sulfate for Neuroprotection of Preterm Infants. The Journal of pediatrics. 2014. Follow up to an average of 11 years of children who had been enrolled in the French antenatal magnesium for neuroprotection study. About 73% of the surviving subjects were seen in follow-up, n=431. Most of the outcomes were a little better in the magnesium exposed group, although there was nothing that could not easily have been due to chance. I think this is re-assuring.

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All trials reported, all results available

The ‘All trials’ campaign is picking up steam, a new video is embedded below. I think the inclusion of a patient volunteer was a great idea, the altruistic aspect of consent for clinical trials, and the betrayal of that altruism when a trial is not published, are so important in this campaign. All those parents who consented for their children, thinking that medical science would be advanced by their participation are being betrayed.

Please follow the link and sign the petition.


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Probiotics in preterm infants: not just for NEC prevention any more

A new RCT in more mature preterm infants 32 to 37 weeks compared the incidence of viral respiratory infections during the first year of life between infants who received prebiotics (galacto-oligosaccharide and polydextrose) probiotics (lactobacillus rhamnosus) or placebo between the 3rd and the 60th days of life.  Luoto R, Ruuskanen O, Waris M, Kalliomaki M, Salminen S, Isolauri E. Prebiotic and probiotic supplementation prevents rhinovirus infections in preterm infants: a randomized, placebo-controlled trial. The Journal of allergy and clinical immunology. 2014;133(2):405-13.

There were only just over 20 in each group that completed the follow up period, but there was a significant reduction in total respiratory infections, and particularly in rhinovirus infections. The prebiotic group did better than the probiotic group, but both had a significant reduction in rhinovirus and overall respiratory infections than the controls, over the first year of life.

The authors include a systematic review of previous studies in the discussion, of either prebiotics or probiotics or both: of the 7 previous studies (in full term infants) 5 have shown a reduction in respiratory infections, for some reason 3 of the previous studies were from Finland, including the largest which had 1000 babies enrolled (and showed a reduction in respiratory infections).

Maybe we shouldn’t be limiting our probiotics to just the early preterms, the late preterms may have advantages too!

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