Pain research in the newborn, what is ethical?

Posted on 21 October 2013 by Keith Barrington

Annie Janvier’s comment on my recent post made we wonder what are the ethical limits of pain research in the newborn.

Let me start with an adult analogy, if a researcher wanted to investigate the efficacy of a new analgesic agent, say for a fairly serious pain, such as the pain of a broken limb in the emergency room, would it be ethically acceptable to compare the analgesic to placebo? We know that placebos, especially elaborate magical placebos such as homeopathy and acupuncture, do have modest effects against pain. But I posit that for a serious painful event, comparison with placebo would be unacceptable.

Even though analgesia has not been proven to improve long term outcomes, reduce brain injury, or increase survival. Generally speaking in order to be ethical, research should compare to the current optimal therapy, or if there is no intervention generally considered the current optimal, to one of the acceptable adequate alternatives. When we are talking about analgesia, an appropriate comparison analgesic is essential.

And yet I still see articles about heelstick which have an untreated, or placebo group. To follow the adult analogy above, there is no way this should be acceptable, especially for children who cannot agree (and should not be asked to agree) to experience some pain for the good of science. One example is this very recent publication (Asmerom Y, Slater L, Boskovic DS, et al : Oral Sucrose for Heel Lance Increases Adenosine Triphosphate Use and Oxidative Stress in Preterm Neonates. The Journal of pediatrics 2013, 163(1):29-35.e21.)  I did not blog on this at the time, and I am still not going to discuss it in detail, because I am disturbed that anyone would randomize newborn babies to have more pain. The fact that the babies who received sucrose also had a very small increase in their hypoxanthine levels, compared to controls who had a slight decrease, in my mind is unimportant. Pain hurts, and if you can interrupt it, which we can, with sucrose, then studies looking at mechanisms and potential adverse effects should compare only to controls being actively treated with other interventions.

In this instance, breast milk is effective as an intervention, as is kangaroo care, neither of which are going to be withheld from preterm babies, even if they increase hypoxanthine concentrations! Either of them could have been used in this study. If you want to investigate effects of sucrose on some outcome as an analgesic in the newborn, it is unethical to do so with untreated controls. Use of breast milk, or kangaroo care would be an ethically acceptable comparison.

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“Saving extremely preterm babies by signing forms”

Posted on 21 October 2013 by Keith Barrington

This is great.  A journalist at the Tampa Bay Times who had an infant herself at 23 weeks gestation has just written one of the best articles about SUPPORT, from the point of view of someone who has experienced NICU from the other side, someone who is very articulate and thoughtful, and she gets it just right.

http://www.tampabay.com/news/perspective/saving-babies-by-signing-forms/2147897

The piece certainly rewards reading in its entirety. The last 2 paragraphs I reproduce below:

In the time we lived in the NICU, we learned to accept risk. Just to enter that place is to embrace terror and uncertainty. There may be risk to participating in a study, but there is also risk to not participating. I don’t believe that ethicists and doctors at two dozen institutions conspired to hurt babies. If they decide to tweak the language in their paperwork, so be it. But second-guessing and finger wagging should not hamstring further studies. At the frontier of human possibility, no form can make medicine a safe or predictable endeavor.

What protects our children most is solid research, and the wisdom drawn from babies who came before.

Kelley Bentham has written about her experiences before, I don’t think I have linked to the wonderful, moving series of articles that she wrote in her newspaper.

http://www.tampabay.com/specials/2012/reports/juniper/

She doesn’t whitewash the tough parts, and her daughter very nearly died, but her story and her musings are well worth a read.

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Pain hurts

Posted on 21 October 2013 by Keith Barrington

In 2010 a paper published in the Lancet called into question the use of sucrose as an analgesic for heelsticks. (I will use the US term as I think most people understand that it refers to lancing the heel of the infant in order to obtain blood for lab testing.)

That paper used multiple component analysis of the EEG to analyze brain wave responses to the procedure, and showed that the use of sucrose, in a randomized trial with about 30 newborn babies per group (44 total with interpretable results), did not change the EEG response to the heelstick.

I thought this was interesting information, but I was appalled by the suggestion of the authors that ‘ sucrose should not be used routinely for procedural pain in infants without further investigation’. Sucrose had already been proven to reduce behavioural responses to pain, in several thousand babies in randomized controlled trials. The fact that it did not change EEG responses was interesting, and called into question the site and mechanism of action, but not its efficacy. Giving sucrose before a heelstick reduces crying (can completely prevent it) inhibits other behavioural changes like the facial grimaces that babies make when they hurt, and reduces physiologic deterioration which occurs with pain.

We have an ethical obligation to reduce the pain of our patients, even if we can’t prove that the EEG responses are inhibited, a baby who cries less, grimaces less, has less desaturation and less tachycardia is a good thing.

Why write about this now? Well the original paper came out before I started blogging, and a new commentary has been published by the pain study group of the Italian Society of Neonatology, (Lago P, Garetti E, Pirelli A, et al for The Pain Study Group of the Italian Society of Neonatology: Sucrose for procedural pain control in infants: Should we change our practice? Acta Paediatrica 2013) The commentary focuses on the implications of the work by Slater, and comes to similar conclusion to my own, routine sucrose use of skin breaking procedures reduces pain responses, in a literature which now includes controlled trials in over 5000 babies, and systematic reviews which consistently show a reduction in pain responses.

One place I disagree with the Italian commentators is their repetition of the misinformation about the number of doses of sucrose and ‘outcomes’, suggesting that there is a maximum number of doses that should be given. This is based on a misleading interpretation by the original authors of their own controlled study published in 2002 (Johnston CC et al). That was a controlled trial of 107 very immature babies who routinely got sucrose for painful procedures over a 7 day period, starting in the first 48 hours of life, or received sterile water instead. It was a very well performed study that showed that the sucrose reduced pain responses, and continued to reduce pain responses over the entire week despite multiple doses being given, but did not affect the NAPI assessment of the babies (which is a neurobehavioural assessment performed in very early life) nor the NNBRS (the nursery neurobiologic risk scores) at 2 weeks of age or at discharge. What they did show on secondary analysis was that the infants who got more doses of sucrose had higher NNBRS. This has been interpreted by many, including the Italian commentary authors, that they had worse long-term outcomes. That is not the case. There was no long term outcome data collected in that study.

To know what that might mean you need to look at the NNBRS, which was constructed by Brazy et al in 1991. It is a composite score to predict risk for neurologic outcomes, and includes items for worst pH, Seizures, IVH, PVL, infection and hypoglycemia. So at discharge the babies who had more doses of sucrose had higher scores on those items. Also in the controls, the babies who had more invasive procedures had higher scores on those items.

In other words sicker babies, who had more invasive procedures, and in the sucrose group also had more sucrose, ended up with higher NNBRS.

That does not mean that multiple doses of sucrose worsened long term outcomes! This misinterpretation is widespread, and has led to unnecessary limitations of the total number of doses of sucrose to be given in a 24 hour period. A 2012 review for example gave the same limit (based on Celeste Johnston’s own re-analysis that the NNBRS was increased in those who got more than 10 doses per day). There is a statistical association between getting more than 10 doses of sucrose a day and having a higher NNBRS, that doesn’t mean that sucrose becomes toxic above 10 doses a day! It seems very unlikely that sucrose increased acidosis, IVH, PVL, seizures, infections or hypoglycemia, and none of these effects have ever been ascribed to sucrose.

What it does mean though is that if you are performing more than 10 painful skin breaking procedures per day you should try not to! Pain hurts.

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Do Probiotics prevent C difficile?

Posted on 18 October 2013 by Keith Barrington

My recent post about Bayesian analysis was in part prompted by this trial, just published in the Lancet, but I never got back to discussing this trial, being distracted by other things, like actual work. Nearly 3000 adults were randomized to either probiotics or placebo, with the primary outcome being antibiotic associated diarrhoea or C difficile. Previous studies have been generally positive for C diff, not so much for AAD overall.

If you look at the Cochrane review of probiotics for preventing intestinal complications of antibiotics, there is about a 60% reduction in C diff,but probably no major effect on overall antibiotic associated diarrhoea.

In this study there was about a 30% reduction in C diff: that has been interpreted as being entirely negative, as the results of this trial are not statistically significant. In fact the confidence intervals of this study overlap the CI of the prior meta-analysis, but the new trial had a far lower incidence of C diff than the previous trials, 1.2% in the controls reduced to 0.8% in the group receiving probiotics.

It is self-evident that with a control frequency of 1.2% it will be almost impossible to prove a reduction in adverse outcomes. Some of the previous studies had control group incidence as high as 25% of C diff.

My interpretation as a non-involved clinician is that it seems very likely that probiotics prevent C diff in at-risk adults, but if the underlying frequency is very low the NNT will be very high (which is hardly surprising). If the control frequency is very low then the cost of the probiotics may become an issue, but if I were in that situation (which I might be in a year or two or thirty) the rather modest cost, the appalling personal cost which C diff sometimes causes, and the safety profile, would probably push me to eat my active culture yogourt every day.

Back to Bayesian analysis; if we take all the previous data in order to determine the significance of what we have from the new trial, it appears to be very close to what you would expect for a trial with a low background incidence of C diff. If you analyze it completely on its own it looks very unimpressive.

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Time is Brain

Posted on 17 October 2013 by Keith Barrington

That phrase, which has been used to denote the urgency of early stroke treatment in adults, has been purloined by Marianne Thoresen and her colleagues for their article about the importance of timely hypothermia treatment, and now by me for this blog post.

The Bristol group have recently published a prospective cohort study detailing the treatment and outcomes of about 80 babies who were treated with brain cooling. The 65 survivors were examined and evaluated with Bayley scores at 18 to 20 months of age. Frequent readers of this blog will know of my great concerns that the Bayley is a poor predictor of long term functioning in very preterm babies. It does, however, seem to be more useful as a predictor of long term outcomes in the asphyxiated term infant, as confirmed both by the Coolcap study group and the NICHD trial group.

The Bristol group performed an initial analysis which showed that survivors had cooling initiated at an average of 180 minutes, so they then divided the babies into those cooled before and after 180 minutes of age. The babies cooled earlier had more severe grades of encephalopathy, slightly lower first hour pH and no other real clinical differences to the later cooled infants.

The early cooled babies had about the same number of deaths as the late (8 vs 7) and the same number of overall poor outcomes, but the motor scores on the Bayley were significantly better in the early cooled group, despite them having more stage 3 HIE.

This is entirely consistent with some data from animal models, and with a secondary analysis of the Coolcap trial which did not show a significant difference, but did show a trend to improved outcomes with earlier randomization. However there wasn’t much spread in the randomization times in any of the RCTs, when they were being done we still had a lot of work to do to get timely referrals, so there were few babies cooled in the first 3 hours, median times of randomization being 4 to 4.5 hours of age.

Cooling on transport has been studied and can be done safely if you institute simple protocols.

The simple message is that ‘time is brain’, cooling is quite safe if carefully monitored, and should be started as soon as possible in affected infants.

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Feeding during PDA treatment

Posted on 15 October 2013 by Keith Barrington

Ron Clyman and a multicenter group have just published this DAFFII trial. Which is a rather tortuous light-hearted acronym for Ductus Arteriosus Feed or Fast with Indomethcain or Ibuprofen.   (Clyman R, Wickremasinghe A, Jhaveri N, Hassinger DC, Attridge JT, Sanocka U, Polin R, Gillam-Krakauer M, Reese J, Mammel M et al: Enteral feeding during indomethacin and ibuprofen treatment of a patent ductus arteriosus. The Journal of pediatrics 2013, 163(2):406-411.)

Despite the acronym this was a rather important trial. No-one knows what to do with enteral feeding when you treat a PDA with either ibuprofen or indomethacin. As a result there is a lot of variability in practice. These authors randomized 177 babies (400 to 1250g birth weight) who had started their enteral feeds (less than 60 mL/kg/d) to either go onto trophic feeds (15 mL/kg/d) and then advance according to a standard regime, or to be placed nil by mouth during the drug administration, before going back on the standard regime. They terminated the study early because of enrollment difficulties, partly due to people treating babies for the PDA later in their life than they used to, and due to the drugs not being available at different times.

The babies who continued trophic feeds during the PDA treatment reached their goal feeds (which the study decided was 120 mL/kg/d) about 3 days faster. There were no adverse effects of the continued feeding regime. Of interest in the results, there was a lot of NEC 13% in the fasted group, 10% in the trophic group, despite a high rate of breast milk feeding, 84%, and a lot of infections, 45% in each group. They also gave the first feeds fairly late, averaging 3.5 to 5 days of age when the first feed was given.

I think the next thing we need to study is to just keep feeding, and keep advancing the feeds during PDA treatment. My own practice has been to stop advancing the feeds, if we are still in the feed advancement stage, but not to reduce them, and then to restart the feed advancement after the indo or ibuprofen is stopped. Like many of us we are treating few PDAs in early life now, so many of the babies are well advanced on their feeds, or at full feeds when we give the ibuprofen.

It would be great to have good data on what we should really do.

The numerous small case series of using acetaminophen (paracetamol for non-North Americans) for PDA closure are also intriguing, I don’t know if it really works, but it might be safer for the GI tract if it does. Allegaert K, Anderson B, Simons S, van Overmeire B: Paracetamol to induce ductus arteriosus closure: Is it valid? Archives of Disease in Childhood 2013, 98(6):462-466.

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Neonatal Updates #38

Posted on 15 October 2013 by Keith Barrington

Simons SHP, van der Lee R, Reiss IKM, van Weissenbruch MM: Clinical evaluation of propofol as sedative for endotracheal intubation in neonates. Acta Paediatrica 2013, 102(11):e487-e492 Many readers will know that I was the author of the recent CPS position statement on premedication for endotracheal intubation in the newborn. We did not say much about propofol, because there was so little data. This publication doesn’t change that very much, it is a report of the use of propofol as routine sedation prior to intubation, showing that you need high doses, and then you get a lot of hypotension. The authors say that we should study this properly, I think these data suggest that we should not!

Morelli A, Ertmer C, Westphal M, et al.: Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: A randomized clinical trial. JAMA 2013:-I would never even have thought of doing this. This is a trial in critically ill patients with septic shock, who often are tachycardic. I always just assumed that this was normal. In a very abnormal situation. That is, if you are in septic shock tachycardia is part of the physiologic adjustments, and you mess with those adjustments at your peril. Most of our efforts to improve outcomes in septic shock have been either unsuccessful or worse. This RCT included 154 critically ill adults who were on high dose norepinephrine to keep their mean blood pressure up, and gave the intervention group a continuous infusion of the short acting beta-1 blocker esmolol. The authors were able to reduce the heart rate, which was the primary outcome, and  they seemed to have less mortality (50% vs 80% at 28 days, 67% vs 90% died before going home, this is a bad disease). This may turn out to be a good thing to do.

Barrett JFR, Hannah ME, Hutton EK, Willan AR, Allen AC, Armson BA, et al. A Randomized Trial of Planned Cesarean or Vaginal Delivery for Twin Pregnancy. Prestigious New England Journal of Medicine. 2013;369(14):1295-305. This very large multicenter trial randomized 2800 women who were pregnant with twins at between 32 and 38 weeks gestation. The two groups were a plan for cesarean, or a plan for vaginal delivery, in both groups this was supposed to be between 37 weeks 5 days and 38 weeks 6 days, unless the mother went into preterm labour. The primary outcome was fetal or neonatal death or serious morbidity, which was expected in 4% of the vaginal delivery babies. There was no apparent difference in this outcome, which actually occurred in about 2% in each group. 40% of the vaginal delivery group actually had a cesarean, and about 5% had the first twin vaginally then had a cesarean for the second. There was also no real difference in maternal morbidities either. The babies and mothers were followed up to 28 days, and there is planned further follow up, including infants developmental testing. But for now it seems that planned vaginal delivery if the first twin is in cephalic presentation is just as safe as cesarean.

Rocha G, Flor-de-Lima F, Proenca E, Carvalho C, Quintas C, Martins T, et al. Failure of early nasal continuous positive airway pressure in preterm infants of 26 to 30 weeks gestation. J Perinatol. 2013 04//print;33(4):297-301.1. This is a nice multicenter prospective cohort study, looking at reasons for CPAP failure in very preterm babies. If the infant needed to be resuscitated in the delivery room with more than 30% oxygen, if they developed RDS needing oxygen and if they were a boy, they were more likely to fail CPAP. Why do boys get the worst of everything in the NICU?

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More extubation stuff

Posted on 11 October 2013 by Keith Barrington

Eduardo Banclari’s group have just published an RCT comparing success of extubation among 93 babies less than  1 kg birth weight who were put on low CPAP pressure (4 to 6) or high pressure (7 to 9 cm H2O). These were babies who were ready for extubation but still needed some oxygen (25% or more). Buzzella B, Claure N, D’Ugard C, Bancalari E: A randomized controlled trial of two nasal continuous positive airway pressure levels after extubation in preterm infants. The Journal of pediatrics 2013. There was much more extubation success with the higher pressure in this group of babies, especially among the smaller ones. Although this is a modestly sized trial, I can’t see any good reason for not using pressures of 7 to 9 when you extubate extremely low birth weight babies who are still needing some oxygen, at least until (and if) there are other studies published.

My friend Guilherme Sant’Anna at McGill has also published a study, this time looking at extubation readiness. (Kaczmarek J, Chawla S, Marchica C, Dwaihy M, Grundy L, Sant’Anna GM: Heart rate variability and extubation readiness in extremely preterm infants. Neonatology 2013, 104(1):42-48). We know there are features of heart rate variability that predict sepsis, this study used a recording of 60 minutes of the ECG just prior to extubating the baby, and found a much lower variability of the heart rate in those who failed. This needs confirmation, but it might turn out to be a useful way of predicting which babies are likely to succeed on their own.

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High Flow Nasal Cannulae; finally learning about them

Posted on 11 October 2013 by Keith Barrington

The Melbourne group must get fed up of publishing important research, here is another in the PNEJM.

Manley BJ, Owen LS, Doyle LW, Andersen CC, Cartwright DW, Pritchard MA, Donath SM, Davis PG: High-flow nasal cannulae in very preterm infants after extubation. Prestigious New England Journal of Medicine 2013, 369(15):1425-1433

This is one of the first non-inferiority studies in neonatology, they designed a trial with 303 very preterm babies (less than 32 weeks) who were randomized at the time of extubation to either HFNC with the Optiflow device at either 5 or 6 liters per minute, or CPAP at 7 cm H2O. The study was designed to find out if HFNC were worse at preventing re-intubation than CPAP or not. They expected a 25% failure rate in the CPAP group, which was what they actually found, 25.8%, and they found a 34% failure rate in the HFNC group, which was not significantly worse.

Many of the HFNC failures were rescued by starting CPAP, and there was much less nasal trauma with HFNC than CPAP.

Of note, most of the treatment failures were in the first day after extubation, and failures were very common in both groups of infants less than 26 weeks (61% CPAP, 81% HFNC). Which goes to show that we need better ways of predicting which extremely preterm infants are ready for extubation, and better ways for keeping them breathing, most of the failures being for apnea.

This study can be added to another trial from Melbourne (this time from the Mercy Hospital, although the ubiquitous Peter Davis manages to be an author on both) and also the multicenter RCT of Yoder and others. Clare Collins’ study also included infants under 32 weeks, with no stated minimum and randomized babies to the Vapotherm at 8 liters per minute or CPAP at 7 or 8 cm H2O; Brad Yoder’s study only included infants over 27 weeks and over 1 kg, but went right up to term, they used whatever device the NICU had for HFNC at 3, 4, or 5 liters per minute depending on size, and used CPAP at 5 to 6 cmH2O.

Extubation failure was equally common in those trials also.

It appears that we finally have sufficient evidence of efficacy of HFNC for post-extubation care of the preterm neonate, including the very preterm, and even including a few term babies. The non-significant differences in Collins’ study were in the opposite direction to Brett Manley’s data, and the numbers in Yoder’s trial were almost identical. So an eye-ball meta-analysis (Barrington method) shows no difference in extubation failure.

HFNC lead to less nasal trauma, and it doesn’t look like there is any other clinically important difference in outcomes.

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Therapeutic Hypothermia: not a panacea

Posted on 11 October 2013 by Keith Barrington

If hypothermia protects the brain, maybe we should use it for anyone who is at risk of brain injury during acute illness? Fortunately other potential uses of hypothermia are being investigated, such as this:  Mourvillier B, Tubach F, van de Beek D, et al.: Induced hypothermia in severe bacterial meningitis: A randomized clinical trial. JAMA 2013:-

100 comatose adults with meningitis were randomized to either cooling to 33.5 degrees or not. The study was stopped early as there seemed to be more deaths in the hypothermia patients. The early stopping could be criticized as the p-value was only 0.04 at that point, but it is always a difficult decision to stop early for a very serious potential complication, do you go on and confirm the complication but have more patients suffer, or continue and find that it was just a statistical fluke, or stop the study and risk being inconclusive, which means the included patients have not been able to contribute to the body of knowledge which was why they volunteered in the first place.

Anyway final analysis shows that the difference in death was non-significantly increased after correcting for other factors. The authors analyzed their data as best they could and concluded that there was very little likelihood that cooling was beneficial.

So it looks like we should avoid it in meningitis, and it is quite uncertain in brain trauma. Acute global hypoxia/ischemia in adults and term newborns is the only clinical situation where it is proven to improve outcomes. Before we start using it for necrotising enterocolitis, for example,  we need the kind of scrupulous study that the French multi-center group did for meningitis… and we need to figure out stopping rules first.

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