Neonatal Research

Snoek KG, et al. Conventional Mechanical Ventilation Versus High-frequency Oscillatory Ventilation for Congenital Diaphragmatic Hernia: A Randomized Clinical Trial (The VICI-trial). Ann Surg. 2015.

There a few few remarkable things about this study; the first is part of the preamble:

Since 2008, all CDH patients born in European countries represented in the CDH EURO consortium have been treated according to a standardized neonatal treatment protocol that was developed at a consensus meeting. After implementation of this protocol, mortality decreased from 33% to 12%. This decrease in mortality rate should be interpreted against of the year upon year variability in mortality rates. Nevertheless, standardization of care is an ideal backcloth to undertake multicenter randomized controlled trials (RCTs).

In this study full term babies with an antenatal diagnosis of CDH were randomized to start on either conventional ventilation (Initial settings were a positive inspiratory pressure (PIP) of 20 to 25 cmH2O and a positive end-expiratory pressure (PEEP) of 3 to 5 cmH2O, with a ventilator rate of 40 to 60/min) or high frequency ventilation (mean airway pressure 13 to 17 cmH2O, frequency 10 to 12 Hz, delta P 30 to 50 cmH2O depending on chest wall vibration). There were a fairly complex list of signs of failure of the initial ventilation mode (If these things happen for at least 3 hours: inability to maintain preductal saturations above 85% or postductal saturations above 70% ; increase in CO2 > 65 mm Hg despite optimization of ventilatory management; PIP > 28 cmH2O; mean airway pressure >17 cmH2O; inadequate oxygen delivery with metabolic acidosis defined as lactate 5 mmol/L and pH < 7.20; hypotension resistant to fluid therapy and inotropic support resulting in a urine output <0.5 ml/kg/hour; oxygenation index of 40). In which case they could be switched to the other ventilation mode, and if that didn’t work they could be placed on ECMO.

The primary outcome of the study was survival without chronic lung disease (oxygen requirement at 28 days). Over 5 years they enrolled 171 patients, far short of the hoped for 200 per group. In the Conventional group 45% died or had chronic lung disease compared to 53% in the HFO group, a difference which may have been due to chance, (p= 0.3). Many of the secondary outcomes were better in the conventional group, there was much less need for ECMO (26% vs 51%), they were ventilated for fewer days,
less often received inhaled nitric oxide, or sildenafil, had a shorter duration of
vasoactive drugs, and less often failed treatment.

I think the study is a remarkable achievement, as far as I can see this is by far the largest RCT of infants with CDH that has ever been performed. Even though it was unfortunately stopped before the full sample size, it looks unlikely that an advantage of initial HFO would have been shown. As we are unlikely to have any other data of this quality for a very long time, I think the conclusion should be that the starting assisted ventilation mode for infants with CDH should be conventional ventilation, unless there is some very good reason for choosing HFO.

We can only hope that this collaborative group will continue to perform important clinical studies in these babies, who remain a group with very high mortality despite the advances of the last several years. I would vote for a good trial of sildenafil, a comparison of different criteria for ECMO, and more studies of different aspects of assisted ventilation. Maybe a study of muscle relaxation as well, if that wasn’t asking too much!

Janvier A, Farlow B, Barrington KJ. Cardiac surgery for children with trisomies 13 and 18: Where are we now? Seminars in Perinatology. 2016. Annie and Barb and I have just published this review of the current situation regarding cardiac surgery for infants with the aneuploidies in the title. (For those who don’t know, Barb Farlow is a mother of a child, who has sadly died, who had trisomy 13.) In addition to discussing the literature we make some recommendations about how to help families making difficult decisions. The literature review is limited by the common practice of lumping together all kinds of cardiac surgery, from ASD repairs to Fontan procedures and Norwoods. Also few papers describe whether there was withholding or withdrawal of life-sustaining interventions at any time.

Nevertheless, it is clear that prolonged survival after cardiac surgery is possible.

Our hope is that we will move away from the universal denial of cardiac surgery, which still occurs in some places. On the other hand it is not appropriate, for any patient, to ignore their other problems pretending they don’t exist, infants with aneuploidies often have other difficulties, which may be serious, but which are very variable. Only by making a decision with the parents which is medically appropriate, likely to improve their life, and consistent with the families values, will we be able to truly act in their best interests.

We offer some guidance which will hopefully be helpful, this is an abbreviated version of our suggestions.

(1) Words are important, avoid these words: “vegetable,” “futile,” “lethal,” “incompatible with life,” “waste of time/resources/emotions,” “Tee 13 or 18,” “it, that,” “product of conception,” “hopeless,” “nothing we can do.”

(2) Avoid unfounded and biased predictions: do not tell parents that this child will have a negative impact on their family, their other children, or their lives.

(3) Recognize that each child and family is unique

(4) Provide balanced counseling: which includes recent medical information, as well as the experience of families who live(d) with children with these conditions.

(5) Personalize the information: all infants are different, even if they carry the same label.

(6) One step at the time: decisions about potential complex cardiac interventions need not be discussed and decided upon prenatally, but be forthright about care options for stable children.

(7) Provide parents with different possible outcomes for their fetus/child (including stillbirth): emphasize the spectrum and uniqueness of each child and the lack of control you and they have on many of these outcomes.

(8) Empower parents: recognize that this diagnosis is difficult for parents, that they are doing their best.

(9) Offer reasonable hope:  hope that their child might defy the odds and hope that her life, however long, will have an enriching and positive influence on all who love her.

(10) Support parents: ask them how you can help them.

We hope that families facing these decisions will find caregivers who are sensitive to their needs, willing to consider the options, and supportive.

One recent publication states that 30% of all their babies under 30 weeks gestation had Acute Kidney Injury (AKI from now on). Another from a couple of years ago reports 40% of all their babies under 1500g had AKI.

Both of these publications based their definition of AKI on an increase in serum creatinine concentrations, an increase of over 0.3 mg/dl (that is about 26 micromol/L in modern units). Both of them included very preterm babies in the first couple of days of life. Both of them ignored the usual increase in creatinine that occurs during the first 2 to 3 days of the very immature infant.

The increase in serum creatinine has been described for several years, (Miall LS, et al. Plasma creatinine rises dramatically in the first 48 hours of life in preterm infants. Pediatrics. 1999;104(6):e76.) the mechanisms have been investigated (they include creatinine re-absorption from the tubules) and the usual profile of creatinine clearly described. This is what normal creatinine values in very preterm babies look like, according to (Thayyil S, et al. A gestation- and postnatal age-based reference chart for assessing renal function in extremely premature infants. J Perinatol. 2008;28(3):226-9).
.

. 

As you can see, on average plasma creatinine increases by about 40 micromol/L in the first 48 hours of life, which means, according to the definitions used in several recent articles, on average all very preterm babies have AKI!

The day to day changes were plotted like this (in the same publication).

So you can’t use a definition based on creatinine alone to diagnose AKI in very immature infants. According to one recent publication, 100% of babies at 22 and 23 weeks gestation had AKI, and 80% of 24 week infants. Most of those babies have good urine output, follow the usual postnatal weight loss trajectory, do not become hyperkalemic, in short they have no sign of renal dysfunction.

By day 2 to 3 tubular creatinine reabsorption is ending, and the creatinine starts to fall, after that you might be able to diagnose AKI from changes in the creatinine concentration alone, but it would be great to have some definition of AKI in the preterm that actually reflected renal injury and which was correlated with later renal problems, without that, it is hard to know what to do about a creatinine increase. Certainly creatinine increases in the first 2 days of life are almost universal under 28 weeks and do not mean Kidney Injury. Some years ago it was suggested that an increase in creatinine over 0.5 mg/dl, or 44 micromol/L could be used in the first 3 days, these graphs show that would be a more appropriate threshold, at least from a statistical point of view, if such a threshold is a good discriminator between those babies with and without true AKI needs to be investigated.

Support for the All trials campaign has been growing, but progress seems to be slow. There are still many trials that are not published, and the impacts on science based medicine are substantial.

Recently, two articles by former participants in trials have been published, a viewpoint that is very important for these campaigns, I believe.

The first is called “The Outcome of My Clinical Trial Is a Mystery” it is by someone who was part of a trial to evaluate an intracardiac device to close an ASD, the author says :

It’s more than a little unsettling to think that I’ll live for another 70 years or so with this device in my heart, but may never know what the research said about how it works.

The second is called “A Broken Covenant with Patients” from a woman who was part of a preliminary evaluation of a drug for ovarian cancer, and who gives other examples of “broken covenants”.

As for sharing of data, the International Committee of Medical Journal Editors are proposing new rules, the meat of their proposal is here:

As a condition of consideration for publication of a clinical trial report in our member journals, the ICMJE proposes to require authors to share with others the deidentified individual-patient data (IPD) underlying the results presented in the article (including tables, figures, and appendices or supplementary material) no later than 6 months after publication. The data underlying the results are defined as the IPD required to reproduce the article’s findings, including necessary metadata.

I agree with this approach, and I plan to comply, there are details to be worked out, but one that I think is important is how will this be policed and enforced? Many rules of ICMJE are not well followed, including, for example, the requirement for registration of trials, and that publications should follow CONSORT guidelines. There is no point adding new rules if they are just going to be ignored, as happens already with data sharing, in those situation where it is already required.

As one example of this failure you could look at the COMPare website. Ben Goldacre has, with a few colleagues, started to review the randomized controlled trials published in 5 leading medical journals. His team compare the outcomes published in the articles describing the research results to those available in the trial registration documents, or in a published protocol, if published before the trial started. Of course the outcomes described should be those that were initially planned, and if for some reason that was not the case, then any difference should be explained in the trial report. Changing outcomes for a trial means that it cannot necessarily be trusted to answer the question that was initially asked. That is particularly true when the primary outcome is changed when the investigators look at the results. Clearly, if the initially planned primary outcome is not significantly different between groups, but the authors find something else which looks cool, and then claim that was the primary outcome, the risks of making type 1 errors are enormously increased.

Journals are not doing a very good job of comparing reported outcomes to the pre-specified outcomes, nor of insisting that CONSORT standards are followed, and any changes clearly described and justified. The COMPare group as of today have checked 67 trials, they have found only 9 of them reported all the outcomes that were planned. There were 301 outcomes that were planned to be reported by the trials that were not reported, and there were 357 outcomes that appeared for the first time in the published articles.

The editors of the Annals of Internal Medicine have answered in a very haughty and inconsistent way to the letters from COMPare that pointed out the problems in several publications. At one point pointing out their “long experience”, as if that somehow makes them less fallible.

I can only hope that the COMPare team are successful in making journals check publications more carefully for consistency with the CONSORT standards. There are already some signs that they are having an impact.

A new publication from the CHYLD program that I blogged about previously:

Harris DL, et al. Outcome at 2 Years after Dextrose Gel Treatment for Neonatal Hypoglycemia: Follow-Up of a Randomized Trial. The Journal of pediatrics. 2015.

In this paper the authors describe the outcomes of infants who were in their Sugar Babies study, when they reached 2 years of age. The infants had Bayley scales of infant development version 3 performed, as well as tests of executive function and neurological exams.

To recap, the Sugar Babies study took infants at risk of hypoglycemia, and when the blood sugar was below 2.6 mmol/L (47 mg/dl) they were randomized to either get dextrose gel, or placebo. They could get treated more than once if necessary, and if the blood glucose fell to more severe levels the received standard therapy. 237 babies were in the original study, 78% of them returned for follow-up.

The babies of course, as mentioned, all had risk factors for hypoglycemia, so there were 40% whose mothers were diabetic, 1/3 were late preterms, 16% SGA, 8% LGA. The outcomes were not different between the two groups, but they were not very reassuring. 34% of the infants had a Bayley cognitive or language composite less than 85, (1 SD below the standardized mean value of 100, which we know is not the mean of the general New Zealand population) The mean language and cognitive composite scores of the subjects were between 94 and 96, Full term controls in a recent Australian study had means of 108 to 109.

So these babies, in both groups look like they did substantially worse on the Bayley test than you might expect. There were also a few babies with other problems, including 9 with seizures, and their executive function scores were abnormal also. Is this because the risk factors that they had select a group of babies who are higher risk? Is it because mild hypoglycemia, even if you treat with a rapidly effective intervention, such as the dextrose gel, has a direct adverse effect on the newborn brain? We know that infants who are small for gestational age, and late preterm infants are at risk for developmental delay, but there seems to be remarkably little data about the risks of infants of diabetic mothers.

It certainly looks like being a newborn infant in a group at risk for hypoglycemia, who then has a blood sugar under 2.6 is a risk factor for developmental delay and for executive function disturbances.

A prolonged break, which occurred for various reasons, is at an end. I have a few posts lined up for the next few days, but will start with news about a new publication, an editorial I wrote with one of our fellows, Marie Janaillac (Barrington KJ, Janaillac M. Treating hypotension in extremely preterm infants. The pressure is mounting. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2016). The editorial was written to accompany another article about the outcomes of very preterm infants with low blood pressures. That article appeared on-line in the Archives in November, (Batton B, et al. Early blood pressure, antihypotensive therapy and outcomes at 18–22 months’ corrected age in extremely preterm infants. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2015).

We summarized the paper like this :

… the authors examined survival without neurological injury or developmental delay at 18–22 months in their cohort of infants less than 27 weeks gestation. They divided infants into 4 groups: those who received or did not receive antihypotensive therapy, and within each of those groups, those who had a slower than average rise in their blood pressure, and those with a faster increase. The primary outcome was not associated with a slower rise in blood pressure among untreated infants, but was strongly associated with hypotension treatment. Babies who received antihypotensive treatment, those with a good, and those with a poor response, were more likely to die, to have motor dysfunction, or to have developmental delay (in cognitive and language domains) than untreated infants. A potential mechanistic explanation is that the treated patients had a much higher incidence of brain injury on ultrasound (severe IVH or periventricular leukomalacia). These associations remained after adjusting for severity of illness measures.

You can never, of course, be sure that there is a causative relationship between the use of an intervention and an adverse outcome based on observational data alone. But the data are worrying, they follow on the heels of data from the German Neonatal Network (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;100(5):F388-92), that defined hypotension differently, but also showed that treatment of hypotension was associated with an increase in severe intraventricular hemorrhage and bronchopulmonary dysplasia. In the German study there was also an association with lower blood pressure and more complications also among infants who were not treated, but the associations with treatment were much stronger than the associations with lower BP. Odds Ratios for treatment effects were between 1.5 and 2.4, but for low blood pressure they were 0.94 to 0.97 (all significant at <0.01).

Where does this leave us? With the necessity to perform prospective trials. As we put it in the editorial

For hypotension treatment, there are many who will say that they do not have ‘equipoise’; those who are convinced that not treating, in the face of poor autoregulation, risks cerebral ischaemia, and others who are convinced that treating the numbers is irrational and risks drug toxicity. But we should all be able to agree that, if reasonable people hold differing opinions, there is real uncertainty. Even if we have strong hunches or preferences for one treatment approach over another, the lack of certainty should enable us, indeed force us, to perform the research we need to reduce that uncertainty and improve care for our babies.

We end the editorial with a plea to perform trials like HIP, and others that are needed to be able to provide an evidence base for future care.

As a lifelong socialist, I couldn’t bring myself to vote Liberal in our last election. I would have been severely tempted, but I was fortunate to live in the constituency of Tom Mulcair, my primary motivation was “anybody but Harper”. Justin Trudeau took the liberal party platform to the left, and if he follows through on everything in their election platform, well the many years of destruction of Canadian values by Harper and the Tories should be erased from history.

Trudeau is already fulfilling some of his promises, and in a way that gives me some hope for the future of Canada.

This is what he said to a group of Syrian refugees a couple of nights ago as they arrived in Canada:

This is a  wonderful night where we get to show, not just a plane load of new Canadians what Canada’s all about, we get to show the world how to open our hearts and welcome in people who are fleeing extraordinarily difficult situations. They step off the plane as refugees, but they walk out of this terminal as permanent residents of Canada. With social insurance numbers, with health cards and with the opportunity to become full Canadians. This is something we are able to do in this country because we define a Canadian not by his skin color or language or religion or background, but by a shared set of values, aspirations, hopes and dreams that, much like Canadians, people around the world share.