Palivizumab for late preterm infants, can we afford it?

Posted on 4 November 2013 by Keith Barrington

It is quite clear that palivizumab reduces the incidence of RSV disease, and probably also the severity, among those who still get it nevertheless. It is just as clear that it is extremely expensive.

If RSV is likely to make you very sick and end up in hospital then there is a definite cost saving from administration, other benefits are much harder to cost.  This is probably the first time I have written about health care costs in this blog, but it was stimulated by a new publication  ‘Yoshihara S, Kusuda S, Mochizuki H, Okada K, Nishima S, Simões EAF: Effect of palivizumab prophylaxis on subsequent recurrent wheezing in preterm infants. Pediatrics 2013, 132(5):811-818′ This was a prospective observational study funded by Abbott, which followed 349 late preterm infants who received three doses of palivizumab and 95 who received none. Recurrent wheezing occurred much more frequently in the untreated than in those who received the prophylaxis. Although this appears effective, and the study design is a reasonable second best compared to an RCT, the cost implications are enormous.

Earlier this year a proper masked RCT was published in the PNEJM (Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A, Kimpen JL, Bont L, Dutch RSVNN: Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. The Prestigious New England journal of medicine 2013, 368(19):1791-1799). That study (also funded by Abbott) also showed a significant reduction in the onset of recurrent wheezing, of a slightly smaller magnitude (11% vs 21%). The diagnosis of recurrent wheezing is not necessarily the best way to determine the benefit of the RSV prophylaxis: in the first year of life the controls wheezed for 4.5% of the days of the year, the treated babies for 1.8%. That is a 61% relative reduction, but a modest actual benefit.

An editorial in Pediatrics accompanying the new article is worth a read (Meissner HC, Kimberlin DW: RSV immunoprophylaxis: Does the benefit justify the cost? Pediatrics 2013, 132(5):915-918). For anyone who does not have full text access, I summarize: palivizumab is horrendously expensive, it is not at all clear that the benefits are worth it.

A number of cost-effectiveness analyses have been published regarding palivizumab prophylaxis with dramatically different conclusions. Cost-analyses sponsored by the manufacturer generally show cost neutrality or even cost saving. Among independently conducted cost analyses, the cost of prophylaxis with palivizumab is generally found to far exceed the economic benefit of hospital avoidance, even among infants at highest risk.

The authors of this commentary note the following among high risk groups, in whom for every 19 affected children there is one fewer hospital admission:

The acquisition cost of palivizumab is $202 635 to save $8530 in hospitalization cost.

In many jurisdictions there are ‘rebates’ which can be given in many different ways. I personally am very concerned about the way this works in Quebec. We pay an enormous amount for this medication, making huge profits for the manufacturer, in order to ensure that all the eligible infants receive their palivizumab the company then gives a subsidy to the hospital to support the salary of an ‘RSV nurse’ whose job is to ensure that no-one is missed. This is touted as being a public benefit, a ‘good deed’ on behalf of the manufacturer (I wouldn’t be surprised if it is tax-deductible). So, even in our public health care system, the manufacturers are themselves ensuring that they have the maximum uptake.

Currently in Québec there are guidelines in place, which assign risk scores to late preterm infants to decide which ones are eligible for palivizumab. The risk scores are a way of determining which infants are at highest risk of developing RSV and being hospitalized for it, but I am not at all sure that they discriminate according to whether there is a cost-benefit or not. In these days of cuts in our health care budget, this should be re-scrutinized.

On the other hand these new studies support the long held idea that RSV causes long lasting pulmonary dysfunction, and finding better, cheaper, ways to prevent it would be a good thing.

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Neonatal Mortality: good news… could do better.

Posted on 3 November 2013 by Keith Barrington

The new report of the WHO Global Health Observatory notes that child mortality, infant mortality and neonatal mortality have all fallen substantially in the last 23 years. The efforts toward obtaining the millennium goals are bearing fruit. http://www.who.int/gho/child_health/mortality/neonatal_infant_text/en/index.html

The detailed report is available here:  http://www.who.int/maternal_child_adolescent/documents/levels_trends_child_mortality_2013.pdf

Annual neonatal deaths have fallen from 4 and a half million to just under 3 million. At the same time deaths of children under five have fallen from 12.4 million to 6.4 million, in 2000 they were at 9.6 million, so a substantial part of that fall is due to the efforts towards the millennium development goals. Nearly half of the remaining deaths were in Sub-Saharan Africa, where the under five mortality rate is still an appalling 97 per 1,000 births, including 32 per 1000 neonatal deaths (compared to 4 in the developed world).

So despite the fall in neonatal mortality, the proportion of pediatric deaths that are neonatal has increased, from 37 to 44%. Even though this is indeed encouraging, it shows that the improvement in neonatal mortality has not been as great as the overall child mortality improvements. Prevention of prematurity, ‘Helping Babies Breathe’, clean cord care, recognition of infections in the neonatal period, cooling for asphyxiated babies, and education of mothers. If we can do all these things we can make a huge difference for millions of babies.

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Neonatal Updates #40

Posted on 30 October 2013 by Keith Barrington

Oops, the last one was #40, except it wasn’t, this is the real #40, as we are heading to a big blog threshold soon, I will probably stop numbering these!

Field D: Neonatal ECMO Study of Temperature (NEST): A Randomized Controlled Trial. Pediatrics 2013. This was a UK multi-centre randomized trial of controlled hypothermia during ECMO, with just over 100 babies randomized, the 2 year outcomes showed that somewhat more babies died in the cooling arm, and the developmental scores were slightly lower with cooling than normothermia. Although none of the differences were significant, there is no evidence of benefit. I certainly thought this was worth studying, and that it might well be beneficial, it just shows again how important it is to do good trials like this one.

Wadhawan R, Oh W, Hintz SR, Blakely ML, Das A, Bell EF, Saha S, Laptook AR, Shankaran S, Stoll BJ et al: Neurodevelopmental outcomes of extremely low birth weight infants with spontaneous intestinal perforation or surgical necrotizing enterocolitis. J Perinatol 2013. We have known for a while that NEC is bad for your long term outcome, and that surgical NEC is worse; the data regarding spontaneous intestinal perforations  (SIP) has been less consistent, but worrying. This is probably the largest follow up study of SIP with nearly 300 cases, and nearly 500 surgical NEC. Both were bad, the SIP babies were a little less mature than the surgical NEC, but their long term outcomes were similarly worse than controls without SIP or NEC. The plot of the Odds ratios for neurological impairment or developmental delay on multiple logistic regression are revealing, SIP and surgical NEC are both serious risk factors for poor outcomes, with Odds similar to postnatal steroids, BPD, severe IVH and PVL.

Infantino BJ, Mercer DF, Hobson BD, Fischer RT, Gerhardt BK, Grant WJ, Langnas AN, Quiros-Tejeira RE: Successful Rehabilitation in Pediatric Ultrashort Small Bowel Syndrome. The Journal of pediatrics 2013, 163(5):1361-1366. If after a case of NEC (or for any other reason) you end up losing your bowel, make sure you are looked after by a multi-disciplinary intestinal rehabilitation team like this one. These authors report that after very prolonged intensive therapy they were able to get half of their babies, who had less than 20 cm of small bowel left, off TPN. It took up to 4 years, and many of the babies had surgery, sometimes more than once, but succesful TPN weaning, when the remaining bowel is this short, is a real success.

Konduri GG, Sokol GM, Van Meurs KP, Singer J, Ambalavanan N, Lee T, Solimano A: Impact of early surfactant and inhaled nitric oxide therapies on outcomes in term/late preterm neonates with moderate hypoxic respiratory failure. J Perinatol 2013. This is a secondary analysis of the early versus late iNO therapy. The original analysis showed no major difference between the groups. This analysis suggests that starting treatment earlier leads to improved outcomes.

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Registry Trials

Posted on 30 October 2013 by Keith Barrington

The latest PNEJM reports a large trial in adults (over 7000 patients randomized) in a very tasty trial, known as TASTE (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia).

The trial was among patients who were undergoing coronary angiography and intervention for an acute ST elevation Myocardial Infarction, whose data were already being entered into the SWEDEHEART database (I love that acronym, which stands for Swedish Web System for Enhancement and Development of Evidence-based Care in Heart Disease Evaluated According to Recommended Therapies, not bad for an acronym in a foreign language, but I guess most Swedes speak English as well as many native speakers) In one group they sucked out the clot before proceeding to stent, in the other group they did not.

Basically the study found no difference between the groups. The reason I though I would write about it is that this is an amazing study. Of the 7200-odd patients randomized the losses to follow up were zero! They managed to enroll about 2/3 of eligible patients, and because the patients were part of the registry they were able to really find out what happened to the non-enrolled patients as well. So they present results of the 4,700 non-enrolled patients as well as the randomized patients.

As this is an emergency procedure and you can’t spend a lot of time faffing about getting consent, they initially got oral consent, then randomized the patients, performed the procedure and then came back to get full signed consent later.

All of the data being collected was already being collected by the SWEDEHEARTs, so they were able to finish the study in record time for very low cost.

I think this is the way to go, we already have some well established comprehensive databases in Canada, Australia/NZ, VON, who could perform studies like this, as the accompanying editorial in the PNEJM puts it this the next disruptive technology in medical research. We could use our neonatal databases to do research which will be done faster, at lower cost, include a greater proportion of eligible babies and therefore be more generalizable. I think this would work best for comparative effectiveness research, if you are comparing things that are already being done in different centers then there is much less need for serious adverse event forms, over-detailed case report forms, and all of the structure that is imposed on clinical trials nowadays.

One other point, for those who think that being treated according to your doctor’s best guess is preferable to being in an RCT, the randomized patients had an overall mortality of 3%, the patients who were not enrolled and treated according to their doctors best guess (about sucking the clot out or not) had a mortality of over 10%. 6% of the patients who were randomized and treated according to the protocol developed heart failure, and over 10% of those treated outside the protocol. You are much better off being randomized and treated according to protocol.

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Reducing BPD by Avoiding Intubation

Posted on 29 October 2013 by Keith Barrington

Sometimes more than one article gets published almost simultaneously on the same topic, sometimes with similar methodology. Two systematic reviews of the effects of trying to avoid or curtail endotracheal intubation in order to protect the lungs have just been published.

One of the reviews (Schmolzer GM, Kumar M, Pichler G, Aziz K, O’Reilly M, Cheung PY: Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. BMJ 2013, 347:f5980) only included studies that intervened in the delivery room. They found 4 studies (COIN, SUPPORT, CURPAP, VONDR). All of the studies compared immediate intubation for surfactant to CPAP, one gave the surfactant using a brief intubation (the INSURE technique), one had 3 groups, CPAP vs intubation and conventional weaning vs INSURE. The other 2 studies compared CPAP to intubation with either selective or routine surfactant. They found a 9% reduction in the combined outcome of death or BPD in the groups that had an attempt to maintain on CPAP, rather than being intubated, the NNT was 25.

The other publication (Fischer HS, Bührer C: Avoiding Endotracheal Ventilation to Prevent Bronchopulmonary Dysplasia: A Meta-analysis. Pediatrics 2013) included 3 other trials, which are somewhat different, the Columbian Neonatal Research Network trial, which excluded infants under 27 weeks, and randomized babies to either CPAP or INSURE within 60 minutes of birth, and 2 trials which are somewhat different. Gopel et al compared CPAP to CPAP with minimally invasive surfactant treatment (I will call it MIST after Peter Dargaville) but in fact they also included infants who were already intubated, so it is not so comparable to the other trials. Kanmaz et al compared CPAP with MIST to INSURE. The systematic review concluded that there was a 17% reduction in the combined outcome of death or BPD, with an NNT of 35.

There will very shortly appear in ‘Seminars in Perinatology’ a review article that I was asked to write for an NIH conference in January. I was asked to perform an evidence based review of interventions that improve outcomes in the extremely preterm infant. (It was supposed to appear in October so there are 2 days left!). One of the things I did in that review was to look at the same issue; unfortunately there are very few extremely immature babies in the studies, I included the 4 trials in Schmolzer et al’s review mentioned above, but I separated the analyses into those that compared CPAP to INSURE, and those that compared CPAP to intubation with conventional weaning.

Figure 3 CPAP

As you can see from this Forest plot, that suggests that there is an advantage of CPAP started in the DR compared to intubation and standard weaning, but if you have to intubate, you should strongly consider the INSURE technique, which may have similar benefits.

As you can also see if you are very perceptive, I included the VON-DRM CPAP babies twice, for the subgroup analyses that makes no difference, for the overall analysis, it is such a small number of babies that it makes no real difference to the final result. As you can see the confidence intervals include 1.0, just.

When I divide the analyses into those studies that mandated surfactant for all the infants, to those that had optional surfactant therapy (that is the COIN study, where the large majority did get surfactant) the overall result is the same, a very nearly significant reduction, even when including the VON-DRM CPAP babies only once.

Forest plot

UPDATE** review article has now been published. Barrington KJ. Management during the first 72h of age of the periviable infant: An evidence-based review. Seminars in Perinatology. 2014;38(1):17-24. If you want a copy and don’t have access, I can probably find you a source!

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Brain Death: a fiction that has outlived its usefuleness

Posted on 28 October 2013 by Keith Barrington

It may come as a surprise to some readers that I regard ‘Brain Death’ as a fiction. But brain death was invented by a US president’s commission as a way of deciding that patients were dead when they manifestly were not dead. That is they still had a heart beat. The sole reason for creating this new category of death was to provide an avenue for organ donation. If the patients were defined as being dead then we could apply the ‘dead donor rule’. The idea being that we cannot take organs from someone who is still alive, that would cause their death, and to cause the death of one person to save the life of another was not ethically acceptable.

So we are now in the situation where, as one example, a baby who is profoundly asphyxiated, who has no chance for recovery, and for whom intensive care will be discontinued and they will be allowed to die; if such a baby, on brain death testing, takes a few gasps when the CO2 hits 70, we are not allowed to use their organs, even when the parents want us to, and even when all the cortex of the baby, everything that makes us human, is irrevocably destroyed. Instead we have to shut off the ventilator, let the baby die, and then burn the organs that could have saved another baby’s life.

Is that, overall, a better outcome for humanity than using their organs to save the life of another infant? Is it a better outcome for that individual baby, or their family?

How was the concept of brain death developed? Human beings who have extremely severe brain injury may die without ever having regained consciousness. So the presidential commission decided that they were, therefore already dead. Such a decision is a 20th, 21st century consideration; before intensive care, such individuals would be truly dead already, that is their hearts would have stopped. But simply by breathing for them, we can keep alive those would previously have been dead, and create a new category of patients with profound, unrecoverable, brain injuries who continue to have cardiac activity. Tests were invented to show that the brain stem was not working, and, without a brain stem that works, consciousness does not return and the patient will soon die.

In the newborn, the brain stem is particularly resistant, so despite devastating lethal brain injury, many infants will continue to breathe a little, even when all other function has gone.

The ‘dead donor rule’ has become a mantra of organ donation. Even when we stretch the rule to breaking point.

A recent couple of articles in the PNEJM argue the issues. In one the author promotes keeping the DDR, but at the same time speaks positively about a new innovation, that, because taking out both kidneys does not immediately cause death, that could be done in patients who are not ‘Brain Dead’. But taking out the heart would not be acceptable, because that would destroy patients trust in doctors.

On the other side of the argument are those who consider ‘brain death’ to be a convenient fiction, and promote the idea that once (and only once) we have decided to stop ongoing intensive care, that consideration of organ donation could then follow without these restraints. This might sound like a sort of utilitarism, making use of patients and their organs in the most convenient way possible, but honestly I can’t see it. I can’t see any doctor deciding to interrupt intensive care for a patient just in order to take out their viable bits to give to someone else… that happens in movies, but in real life, not so much. Would such a change really affect the public’s trust in intensive care doctors? I am not so sure.

The somewhat less controversial new approach of stopping intensive care in the operating room for a potential donor who is ‘not quite Brain Dead’ and then waiting for their heart to stop with scalpels at the ready, and quickly whipping out their organs before their organs deteriorate is, to me, just as problematic. It is also less efficient, and also without a crystal clear definition of how long you have to wait after the last slow heart beat has passed to be sure there will not be another one; or even whether you should wait until after mechanical activity of the heart has stopped, or must you wait until all electrical activity has stopped.

I hope these articles in the PNEJM are the start of a new debate, that can start where the realities of intensive care have now brought us, where lethal brain injuries do not cause instant death, nor necessarily lead to ‘Brain Death’, but frequently lead to interruption of intensive care and the death of the patient, whose family occasionally might be given the option of helping another person with the organs which still function.

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How to deliver CPAP

Posted on 25 October 2013 by Keith Barrington

Two almost simultaneous articles, one from the Melbourne group. One from Colm O’Donnell in Dublin who has worked with the Melbourne group in the past

Kamlin COF, Schilleman K, Dawson JA, Lopriore E, Donath SM, Schmölzer GM, Walther FJ, Davis PG, te Pas AB: Mask Versus Nasal Tube for Stabilization of Preterm Infants at Birth: A Randomized Controlled Trial. Pediatrics 2013, 132(2):e381-e388. If you are able to stabilize a small preterm infant with CPAP, how should you maintain it while you are transferring the baby to the NICU? This study was stopped early as there was no difference between groups, i think that makes sense as long as you are careful  to maintain distending pressure, it doesn’t matter very much how you do it during the transition period.

McCarthy LK, Twomey AR, Molloy EJ, Murphy JFA, O’Donnell CPF: A Randomized Trial of Nasal Prong or Face Mask for Respiratory Support for Preterm Newborns. Pediatrics 2013, 132(2):e389-e395. This is a similar trial looking at how to give distending pressure in the delivery room, again showing that it doesn’t matter much, as long as you are careful to ensure that there is real positive pressure being delivered.

So if your very premature baby can avoid intubation, giving CPAP by either a face mask or a single nasal tube are equally effective, you just need to ensure that you have procedures in place to provide uninterrupted distending pressure during the transfer to the NICU, and starting CPAP once you are there.

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I have to change my opinion of Russell Brand

Posted on 25 October 2013 by Keith Barrington

Turns out he is bright, thoughtful, and can articulate the disillusionment of many millions. Watch his interview with Jeremy Paxman. I certainly don’t agree with everything he has to say, but his passion for the fight against economic disparity, entrenched privilege and the destruction of our planet is palpable.

I might even vote for him (you have to watch the interview to find out why that is ironic).

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Neonatal Updates #39

Posted on 25 October 2013 by Keith Barrington

Storme L, Aubry E, Rakza T, Houeijeh A, Debarge V, Tourneux P, Deruelle P, Pennaforte T: Pathophysiology of persistent pulmonary hypertension of the newborn: Impact of the perinatal environment. Archives of Cardiovascular Diseases 2013, 106(3):169-177.  An excellent review article by someone who has been instrumental in this field for many years, Laurent Storme, and one of our fellows, Thomas Pennaforte.

McMorrow A, Smirk C, Davis PG, Fox LM: Outcomes of preterm infants receiving positive pressure support at term corrected gestation. Journal of Paediatrics and Child Health 2013. I know Peter Davis as a regular guy… so how come he never sleeps, or if he does he must be revising articles in his sleep. This article shows that to still be on positive pressure support when you reach term isn’t a good outcome, but if you are extubated and on non-invasive support it isn’t all that bad unless you need a lot of oxygen, babies needing more than 50%, and especially more than 70% oxygen, or those who are still intubated, don’t do well. Being on CPAP with less oxygen, the majority of babies eventually survived to go home.

Fung ME, Thebaud B: Stem cell-based therapy for neonatal lung disease-it’s in the juice. Pediatr Res 2013. interesting review of the current state of stem cell therapy for lung repair in the preterm. Notes the surprising fact that the cells aren’t important! The media in which the cells are grown looks like it is just as effective. Whod’ve thought.

Pineda RG, Neil J, Dierker D, Smyser CD, Wallendorf M, Kidokoro H, Reynolds LC, Walker S, Rogers C, Mathur AM et al: Alterations in Brain Structure and Neurodevelopmental Outcome in Preterm Infants Hospitalized in Different Neonatal Intensive Care Unit Environments. The Journal of pediatrics 2013. This may just be observational data, but obvious bias I cannot see (as Yoder might put it) babies in single rooms had a number of apparently poorer outcomes, EEG maturation, language development, even after adjustment for risk factors, than similar babies in a more traditional NICU. There are certainly advantages to a single room approach, we need to make sure there aren’t also adverse effects.

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More Pain

Posted on 25 October 2013 by Keith Barrington

One comment on a previous post was about pain control for, among other things, nasogastric tube insertion. Lo and behold a new publication (Ravishankar A, Thawani R, Dewan P, Das S, Kashyap A, Batra P, Faridi MMA: Oral dextrose for analgesia in neonates during nasogastric tube insertion: A randomised controlled trial. Journal of Paediatrics and Child Health 2013). Oral glucose solution reduced the pain responses to nasogastric tube insertion.

In this randomized trial 25% dextrose reduced PIPP scores compared to 10% dextrose when given prior to nasogastric tube insertion. The PIPP scores were still quite high, with a median of 10, despite the 25% dextrose, (12 in the placebo and 10% dextrose groups) showing that it wasn’t all that effective. A previous study, using the facial coding system NCFS showed that sucrose was effective. The authors of the new study suggest that glucose might be a better choice for low income countries as 24% sucrose solution is not readily available. I don’t really understand this, you don’t need to buy some commercial preparation, you can make your own with boiled water and table sugar. I think that should be available everywhere. We used to do that in one of my previous hospitals before the commercial preparation became available, it works, it’s dirt cheap and it’s just as safe.

The osmolarity of 24% sucrose is also about half of 25% dextrose. Whether that matters or not I am not sure, another comment on a previous post asked about whether the high osmolarity of concentrated sucrose solutions is an issue. I replied that it didn’t seem to be, the small volumes given in the mouth will be diluted by saliva before being swallowed and then further diluted with gastric secretions, and although there are some reports of high osmolarity solutions, and high osmolarity milk (like the older formulation of nutramigen) leading to an increase in NEC, there is no evidence of an increase in NEC in the trials of sucrose solutions.

Another study, (Lago P, Garetti E, Boccuzzo G, et al: Procedural pain in neonates: the state of the art in the implementation of national guidelines in Italy. Pediatric Anesthesia 2013, 23(5):407-414.) from the Italian neonatal pain group showed that, although most NICUs knew the guidelines for pain control, actual usage, as determined by their response to a questionnaire was very poor. Seriously painful events were often not treated ‘Pain medication was routinely administered at 34.3% NICUs for tracheal intubation … 71.4% for chest tube insertion, 33.0% for lumbar puncture, and 64.0% for postoperative pain. I find it surprising and disturbing that a third of postop babies are not getting pain medications.

Celeste Johnston and a group of people interested in neonatal pain (including yours truly) published an article a couple of years back based on direct observation in several Canadian NICUs. The results were just as bad. Lumbar Punctures and even chest tubes without analgesia.

We really must do better.

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