CRPs; are they CRaP?

Posted on 19 September 2012 by Keith Barrington

I was taught before asking for a test to always ask myself 2 questions.

What will I do if the result is negative?

What will I do if the result is positive?

The counsel was that if the 2 answers are the same: don’t do the test!

In neonatology we have for many years been trying to find accurate predictive tests for sepsis. In a child with possible clinical signs for sepsis, or a clinical situation that puts them at high risk, then an accurate test that could reduce antibiotic use, might be helpful. At present about 0.8% of cultures taken to rule out early onset sepsis, and 10% for late onset sepsis, are positive. So 99.2% and 90% of antibiotic courses do not help the infant, but select out resistant organisms. What we really need is a test which is rapidly positive, and specific for sepsis. A test which becomes positive the day after the antibiotics are already started, and which is sensitive but not specific is not much use to us.

It seems to be not much use in older children either. A publication in BMC Pediatrics reviewed the use of CRPs in neonates and older children in an acute care hospital. They showed that most of the tests did not have any impact on clinical management, and they cost a great deal of money.

They did not mention the blood loss, but in tiny preterm babies this can be a significant issue for any test we do. A blood test needing 0.6 mL of blood for example (such as the CRP requirement for the lab in our hospital) will often lead to the baby having substantially more than 0.6 mL taken, say 1 mL. And if repeated 10 times during a hospitalisation, lead to a substantial blood loss.

The Health Technology Assessment program in the UK is amazingly productive in many different areas of medicine. They have just published a systematic review of predictive tests for serious infections in children. Unfortunately for my purposes they excluded neonatal studies and patients under 1 month of age. But I am convinced they would find the same thing that they note in their discussion. ‘Both CRP and PCT offer similar diagnostic performance and are superior to WBCs. However, neither CRP nor PCT has sufficient diagnostic value to either confirm or exclude a serious infection, and thus their results must be interpreted in the light of clinical findings’.

Very often when CRP is requested, the answer to the 2 questions posed above will be ‘I will  start antibiotics and wait until the cultures are negative before stopping them’. If that is the case, save the money and reduce the blood loss!

Posted in Neonatal Research | Tagged , | 3 Comments

Homeopathy: not good medicine, not medicine at all!

Posted on 19 September 2012 by Keith Barrington

You might be a little interested in a rapid response I wrote to an article in the BMJ from a family doctor in Glasgow. In that article the author had been touting the benefits of homeopathy as an intervention for patients who had nothing wrong with them! He also made some ridiculous negative comments about actual effective medicine, quoting distorted information from quacks.

Posted in Neonatal Research | Leave a comment

Weekly updates #6

Posted on 19 September 2012 by Keith Barrington

van der Ham DP, van der Heyden JL, Opmeer BC, Mulder AL, Moonen RM, van Beek JH, Franssen MT, Bloemenkamp KW, Sikkema JM, de Groot CJ et al: Management of late-preterm premature rupture of membranes: the PPROMEXIL-2 trial. Am J Obstet Gynecol 2012(0). This is a follow-on to the trial I mentioned a few weeks ago, another  cohort of 200 women were randomized using the same protocol as PPROMEXIL, that is they were eligible if they had ruptured membranes, they were between 34 and 37 weeks and did not go into labour within 24 hours of membrane rupture (so some 17% of them ruptured before 34 weeks then were randomized when they passed 33 6/7. The were either induced or allocated to expectant management. They confirmed no differences in any outcome between groups. The expectant managament group only gained about 3.5 days of pregnancy on average. The authors also updated a meta-analysis of all similar trials in the discussion section (a practice that should be encouraged) which confirms no differences in neonatal sepsis or other outcomes.

Medeiros LF, Souza ACd, Souza Ad, Cioato SG, Scarabelot VL, Caumo W, Fernandes LC, Torres ILS: Fentanyl administration in infant rats produces long-term behavioral responses. International Journal of Developmental Neuroscience 2012, 30(1):25-30.
This is a bit concerning. 1 dose of fentanyl or ketamine to rats on day 14 of life led to behavioural changes that persisted into adulthood. Don’t know what that means for our babies, but we need to continue collecting data.

The latest issue of the Australian pediatric journal Paediatrics and Child Health has a number of interesting and well written pieces. (I am glad the Aussies know how to spell, unfortunately I keep forgetting, too long in North America I guess…must remember…oedema… haemoglobin…paediatrics….)  Nick Evans’ review of the therapy of PDA, Peter Dargaville and David Tingay’s review of lung protective ventilation, and Colm O’Donnel (who has outdone himself with the title of his review of neonatal resuscitation, I don’t know any other quotes of David Bowie songs in the neonatal literature)  Turn and face the strange – ch..Ch..Ch..Changes to neonatal resuscitation guidelines in the past decade are all to be particularly recommended.

Posted in Neonatal Research | Leave a comment

Analgesia and co-bedding or kangaroo care

Posted on 11 September 2012 by Keith Barrington

Campbell-Yeo ML, Johnston CC, Joseph KS, Feeley N, Chambers CT, Barrington KJ: Cobedding and Recovery Time After Heel Lance in Preterm Twins: Results of a Randomized Trial. Pediatrics 2012. If I might be permitted a little self-promotion… this new study (which was certainly not my idea, and was accomplished as a result of the efforts of Marsha Campell-Yeo, certainly not mine) is, I think, of very high quality.

There is a lot of talk about Co-bedding of twins, but little reliable data about the effects, benefits or risks. This study was designed to see if co-bedding is analgesic. Now that may seem a strange objective, but we know that kangaroo care is analgesic, whether done by mothers or fathers (another study by Celeste Johnston, Marsha, and Francoise Filion). I thought that just the physical closeness of the other twin could have an effect, by the same mechanisms as kangaroo care, whatever they might be. So we randomized twins to be co-bedded or not, and then examined their responses to  a heel prick that they needed for their medical care.

The primary outcome was not different between study groups, those co-bedded or not. We noted that the pain scores after heel stick were rather low, because all of the babies got sucrose, automated lancets, etc. So although both groups still had a small pain response to the heelstick, we were unable to show any effect of the co-bedding. The main secondary outcome, that is how quickly the babies settled back down to baseline after the intervention, was, in contrast, different between groups, the co-bedded babies recovered significantly more quickly.

The nice thing about this study was that the pain scores (PIPP the premature infant pain profile) increased to  maximum that was quite low (average of about 7) suggesting only mild pain. So in a controlled situation, with the use of good technique and sucrose, pain can be reduced even when doing invasive procedures.

Similarly low scores were reported in another study now available on-line (also from Celeste Johnston and her collaborators) which showed that kangaroo care by mothers is slightly more analgesic than kangaroo care by non-related other women. As you might imagine they had a relatively low rate of consent from the mothers to do the study, I don’t know if they had any trouble getting the volunteers to be the alternate “kangaroos” but I don’t think the nurses in my unit would be too happy giving kangaroo care to the babies during their blood sampling! But maybe I’m wrong.

Posted in Neonatal Research | Tagged , | Leave a comment

A life worth living: myelomeningocele.

Posted on 10 September 2012 by Keith Barrington

Do handicapped persons’ lives have value?

Even asking that question is offensive, at least to me, and I just asked it!

It seems to me that much of the focus of programs of antenatal diagnosis is based on the premise that being ‘handicapped’ is worse than being dead. So we search for anomalies and terminate many pregnancies based on the information that we then give to the parents; information which is strongly influenced by our own prejudices. I am convinced, and there is some supportive evidence, that the prejudices of physicians influence the choices that parents make. We know that most women terminate pregnancy after a diagnosis of trisomy 13 or 18, for example; but when couples are told that the disorder is lethal, and that the rare short term survivor is a ‘vegetable’, is it surprising that so many abort?

Our prejudices as health care providers are not shared by the rest of the population, in particular they are not shared by impaired members of the population. Quality of life studies in children with various impairments have uniformly shown much higher quality of life scores when children are asked themselves about their own life, compared to what health care providers estimate.

Let’s take the example of meningomyelocele. A very thoughtful review article just published in Pediatrics describes how attitudes have changed and continue to change (and need to change further) Pruitt LJ: Living With Spina Bifida: A Historical Perspective. Pediatrics 2012. I am sure that around the world different programs are at different stages of that process. In certain hospitals parents are erroneously told that ‘the quality of life is miserable if they survive’ (a direct quote from a medical dossier) ; whereas in others active treatment is never even considered to be optional except for the rarest, most severe cases. Unfortunately we often see pregnant women referred to our hospital who have already received extremely prejudicial misinformation. Who have been mis-informed about the intellectual disability of children with meningomyelocele, and who have been mis-informed of the discomfort, pain and repeated surgeries that the children need if they are actively treated. Not surprisingly many choose to terminate the pregnancy.

Lets put this straight.

Intellectual ability: infants in the control group of the MoMs study had a mean Bayley 2 MDI of about 87. This is a group of infants who had a fetal diagnosis of meningomyelocele with an upper level between T1 and S1 (almost all were lumbar) who also had hind-brain herniation, they were therefore among the group most severely affected. It is already well known that children with meningomyelocele often have multiple disorders of cerebral development. As well as the abnormality of closure of the neural tube, which is the primary problem, they have ‘abnormalities’ in other parts of brain development. If you do an MRI you will find other disorders of migration, and of cerebral structure. However. Even though the brains are structurally demonstrably different to infants who do not have a neural tube defect, they actually function quite well. So even if you select a group of children with an anomaly which is severe enough to be considered for antenatal surgery, the overall intellectual outcome is quite acceptable, and the large majority of the infants are close to the average of the general population. There are specific difficulties that the children face, but profound intellectual impairment is very rare.

Quality of Life: the health related quality of life of children (and adults) with meningomyelocele is reduced, but not disastrously lower, compared to those without the disorder. Subscales which are most affected by physical limitations are the most severely affected, which is hardly surprising. Other scales much less so. Interestingly there is not much difference between the QoL scores of children who are ambulant and those who are not. A recent Scandinavian study (Bartonek Å, Saraste H, Danielsson A: Health-related quality of life and ambulation in children with myelomeningocele in a swedish population. Acta Paediatrica 2012:no-no) asked parents to complete a QoL questionnaire for their 6 to 17 year old children. This study showed health related QoL scores which were lower than the scores from studies which asked the children themselves; such as the one mentioned below.  Other data note that quality of life of adolescents with spina bifida is much more related to their social interactions, such as by how many good friends they have, than it is by their impairments. (Muller-Godeffroy E, Michael T, Poster M, Seidel U, Schwarke D, Thyen U: Self-reported health-related quality of life in children and adolescents with myelomeningocele. Dev Med Child Neurol 2008, 50(6):456-461) which is probably the same as adolescents everywhere! The scores obtained from this study, which questioned the adolescents themselves, were somewhat lower than a healthy reference group, but not very much lower, and some scores were not statistically significantly different from the reference group.  

Pain: Both pre-op and post-op, children with spina bifida have very little pain. ( Ottenhoff MJ, Dammers R, Kompanje EJO, Tibboel D, de Jong THR: Discomfort and Pain in Newborns With Myelomeningocele: A Prospective Evaluation. Pediatrics 2012.) As the disorder interrupts some or all neural transmission below the level of the lesion, there is little discomfort associated with the actual abnormality.

When this diagnosis is made parents deserve accurate information. They deserve support and help. They deserve to hear the positives and not just the negatives. Annie Janvier hasn’t yet got round to doing her internet survey with parents of children with myelomeningocele (I don’t know if she will, she has about 20 projects on the go at present), but I would bet the responses after early antenatal diagnosis would not be much different to what she found with trisomy 13 and 18. I would wager that most parents who have an antenatal diagnosis before 20 weeks are repeatedly offered termination, and that those who decide against termination feel that they are judged by the medical community.

In contrast, I think that in most centers, once the child is born, active treatment options are usually offered with a positive attitude, and that multidisciplinary support is readily available in most developed countries. In this situation, at least, I think attitudes have changed somewhat. Sixty years ago, babies were often left to die, and parents were told that the infants would never have a life of quality. As the story told by that link proves, such predictions were often wrong. Fortunately, many parents chose not to believe them.

(In response to a comment from a reader, which you can see below, I edited this post on the 20th of September to replace some uses of the term ‘handicap’ with the term ‘impairment’- I however left the term in the introductory part as many physicians use that term, and I wanted the first paragraph or so to catch their attention.)
Posted in Advocating for impaired children | Tagged , | 9 Comments

Weekly Updates #5

Posted on 8 September 2012 by Keith Barrington

Ing C, DiMaggio C, Whitehouse A, Hegarty MK, Brady J, von Ungern-Sternberg BS, Davidson A, Wood AJJ, Li G, Sun LS: Long-term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia. Pediatrics 2012. Further data, again from Australia about the potential long term effects of anesthesia (or surgery or both), this time examining specific intellectual domains and showing associations of reduced language and abstract reasoning with having had anesthesia before the age of 3.

Morley CJ, Keszler M: Ventilators do not breathe. Archives of Disease in Childhood – Fetal and Neonatal Edition 2012. A well reasoned plea from Colin Morley and Marty Keszler to use different terminology when talking about assisted ventilation. Babies inspire, ventilators inflate, etc. I agree!

Thomson T, Habeeb O, DeChristopher PJ, Glynn L, Yong S, Muraskas J: Decreased survival in necrotizing enterocolitis is significantly associated with neonatal and maternal blood group: the AB isoagglutinin hypothesis. J Perinatol 2012, 32(8):626-630. I was a bit surprised by this, but, if confirmed, it shows that mortality is different depending on infants blood group, specifically, worse if the infant is AB. The authors suggest that this may be due to increased concentrations of isoagglutinins in these babies.

Legrand C, Michaud L, Salleron J, Neut D, Sfeir R, Thumerelle C, Bonnevalle M, Turck D, Gottrand F: Long-term outcome of children with oesophageal atresia type III. Archives of Disease in Childhood 2012, 97(9):808-811. The long term complications of children who had a repair of the commonest type of oesphageal atresia are much more frequent than I realized. With reflux, dysphagia, and respiratory symptoms being very common.

Posted in Neonatal Research | Leave a comment

CPAP or PAF?

Posted on 7 September 2012 by Keith Barrington

Several devices marketed as CPAP devices are not in fact devices designed to deliver constant pressure. For example the Infant Flow device, widely used in NICUs, delivers a constant flow into its circuit, but there is no mechanism to respond to changes in resistance, and the pressure in the circuit is therefore very variable depending on down-stream resistance, and should therefore I think be called a positive airway flow device. It is often referred to as variable flow CPAP, as the flow into the baby varies depending on the phase of respiration of the infant, so this can get very confusing. However, as I said, the pressure is not constant, so CPAP is not the right terminology; and the flow into the circuit is actually constant, it is supposedly the flow into the baby that varies, based on the so-called ‘fluidic flip’.

Now the flow across the prongs changes according to this ‘fluidic flip’ principle, which is supposed to reduce expiratory work of breathing; but as others have pointed out, in normal use the baby does not breathe out through the prongs, most of the expiratory gas leaves the airway through the mouth, or around the prongs, wherever the resistance is lowest. So although under very specific experimental conditions there may be a reduction in respiratory work, I am unsure if this translates into any real advantage in clinical use. If the infants changes head or mouth position, or the prongs are slightly displaced, anything which changes the resistance, the delivered pressure may change dramatically, very often falling well below the desired pressure. I find this most problematic during non-invasive intermittent positive pressure ventilation, we might set up the device to give a peak pressure of 10 and an expiratory pressure of 5, but when I go round to review the baby a few minutes later the pressures being delivered may be 5 over 4, or even less.

In contrast using a ventilator to deliver CPAP uses a very expensive machine to deliver a constant pressure, the pressures can be maintained over a much wider range of infant conditions. A simple constant pressure circuit which is very much cheaper, and probably as good as ventilator derived CPAP, is the so-called bubble CPAP which delivers a constant pressure as a result of the height of the water column, and may deliver some pressure oscillations as a result of the bubbling, more of which below.

Does the difference between CPAP and PAF matter? A new multicenter RCT from Poland randomized 276 babies between 750 and 1500 g birth weight to either the Infant Flow, or CPAP using a Draeger Babylog within the first 6 hours of life. The primary outcome was never needing to be intubated, and there were no substantial differences in outcomes between the groups. (Bober K, Swietlinski J, Zejda J, Kornacka K, Pawlik D, Behrendt J, et al. A multicenter randomized controlled trial comparing effectiveness of two nasal continuous positive airway pressure devices in very-low-birth-weight infants. Pediatr Crit Care Med. 2012;13(2):191-6. Epub 2011/06/15.)

Another RCT from 3 years ago compared the Infant flow device to bubble CPAP. (Gupta S, Sinha SK, Tin W, Donn SM. A Randomized Controlled Trial of Post-extubation Bubble Continuous Positive Airway Pressure Versus Infant Flow Driver Continuous Positive Airway Pressure in Preterm Infants with Respiratory Distress Syndrome. The Journal of Pediatrics. 2009;154(5):645-50.e2.) Samir Gupta and colleagues from the NICU in Middlesborough randomized 140 babies of 24 to 29 weeks gestation when they were extubated. The primary outcome of extubation failure was not different between the groups, however, the failure rate was lower than expected, so the study was underpowered, the non-significant differences in outcomes favored the bubble CPAP group, and subgroup analyses also showed some benefits for bubble CPAP.

A recent review by Thomas Shaffer and his colleagues reviews many of the physiologic effects of non-invasive respiratory support.  (Shaffer TH, Alapati D, Greenspan JS, Wolfson MR: Neonatal non-invasive respiratory support: Physiological implications. Pediatric Pulmonology 2012 http://onlinelibrary.wiley.com/doi/10.1002/ppul.22610/abstract) this very complete and clearly written review covers all forms of non-invasive support, including oxygen, CPAP, nIMV and high flow cannulae. They point out that the pressure oscillations which occur during the bubbling of bubble CPAP are far less than those which are produced by a high frequency ventilator, and that under usual circumstances it seems unlikely that there is measurable ventilation from the oscillations caused by the bubbles.

So overall, I think that a true constant pressure system is probably preferable, and that bubble CPAP is as good, and may be preferable, to a ventilator, and is very much cheaper. The main limitation being that bubble CPAP can’t do non-invasive ventilation.

Posted in Neonatal Research | Tagged , | 1 Comment

Not neonatology: Hermit Crab Migration

Posted on 5 September 2012 by Keith Barrington

I saw this link on one of my favorite websites (the owner doesn’t want it called a blog!) which is Why Evolution is True.

The annual hermit crab migration in St John in the U.S. Virgin Islands. St John is an island without an airport, which protects it from too many visitors, and allows natural phenomena like this to continue. the photographer is Steve Simonsen and you can see the original web submission at the link above.

Posted in Neonatal Research | Leave a comment

Predicting Long Term Outcomes: MRI at term for very preterm babies

Posted on 4 September 2012 by Keith Barrington

The most recent Acta Paediatrica includes 2 articles. One from parents of a very preterm infant that we looked after at Sainte Justine. They recount their experiences of having a baby at 25 weeks, and what happened to them when they had a brain MRI when their daughter reached term.

This story is accompanied by an article by Annie and me, discussing how that situation affected us, and what the evidence is regarding whether or not the information that we gain from a term MRI actually helps parents or not. If you read the article you will see photos of neonatology’s very attractive power couple (Annie and me), and also our skepticism about routine MRI just before discharge of very preterm babies. An investigation that is now being used as a screening test in many centers, but which does not fit any criteria for a screening test, as there are many false positives and many false negatives (if long term impairment is the problem that we are screening for) and nothing treatable (or very rarely anything treatable) to be discovered.

I have been reviewing the articles regarding this issue for a while, and the best large cohort studies have very low positive predictive value for developmental delay (almost always less than 50%) and very low positive predictive value for movement disorders. In contrast the negative predictive value for cerebral palsy is high, but as most cerebral palsy among preterm infants is relatively mild, and does not lead to serious disability, I am not sure how useful it is to do a test which reduces the probability of having that diagnosis. Especially when the PPV for other abnormalities is so low. There is also no standardized way of doing the test (with many sequences available) and no standardized way of interpreting them.

One thing that many want to screen for is cerebellar injury as it is said to have a much higher PPV for long term problems, indeed that is what Maren Baardsnes had. But as you can see from the article, and appreciate from the great photo of Maren, that hasn’t actually happened. She is great. (In fact another article from earlier this year Hou D, Shetty U, Phillips M, Gray PH: Cerebellar haemorrhage in the extremely preterm infant. J Paediatr Child Health 2012, 48(4):350-355. showed that infants with cerebellar hemorrhage may actually do quite well, even though it was very rare in their cohort, and therefore few affected babies to evaluate).

We would be much better off using the resources currently used for doing the MRI to provide services to the families, including early intervention programs for families who have limited means.

Posted in Neonatal Research | Tagged , | 1 Comment

‘Do everything’

Posted on 3 September 2012 by Keith Barrington

A wonderful article just published by Chris Feudtner, who dissects a phrase that we hear all too often. ‘I want you to do everything’. He examines what families mean when they say this, and how we might respond as medical professionals. As he explains we can’t ‘do everything’ as everything includes therapies that may be themselves in conflict, or harmful or ineffective. Families will often mean that they aren’t ready to give up, they don’t want to withdraw or limit active care, and if there remains a flicker of hope for survival they want us to follow it. He particularly states that we should refrain ourselves from using the term as it is ‘dangerous nonsense. If we really don’t mean it, then we really must not say it. A moratorium is warranted, halting all medical personnel from further casual utterances of “do everything” ‘.

Chris writes very well; clear, thoughtful and stimulating. I would also recommend his article from 3 years ago in the New England Journal, ‘the Breadth of Hopes‘, which addresses some of the same issues, of examining what families hope for, and finding common, realistic hopes that we can share.

Posted in Neonatal Research | Tagged , | Leave a comment