Desperately Seeking Problems with Premies

Posted on 9 June 2012 by Keith Barrington

I don’t know about you, but I am getting really irritated with people searching desperately to find problems with the long term outcomes of preterm infants.

A new publication exemplifies this. A linked database study from Sweden has compared the frequency of hospitalisation for serious psychiatric disorders according to the gestational age at birth. (Nosarti C, Reichenberg A, Murray RM, Cnattingius S, Lambe MP, Yin L, MacCabe J, Rifkin L, Hultman CM: Preterm Birth and Psychiatric Disorders in Young Adult LifePreterm Birth and Psychiatric Disorders. Archives of General Psychiatry 2012, 69(6):610-617.) http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archgenpsychiatry.2011.1374

The first question to ask is whether the data appear likely to be reliable. The subjects were born between 1973 and 1985, at a time when few women were getting antenatal ultrasounds, so individual errors are likely to be frequent, but the overall distribution of gestational age should be OK. But, the distribution of gestational ages is highly suspect: 17% of the deliveries were at 42 weeks or more, whereas 4.1% were less than 37 weeks and 0.4% less than 32 weeks, this should immediately ring alarm bells about the reliability of these data. These distributions are so far from what we would expect to see; either there has been a huge change in human biology over the last 30 years, or these gestational ages are systematically wrong.

But if we were to assume for a moment that the gestational age data were reliable, what do they actually show?

Well let’s focus on what is supposed to be the most striking finding, an enormous increase in bipolar disorder, relative risk among infants less than 32 weeks of 7.2, ‘fully adjusted’ relative risk of 7.4.

If we examine these numbers a little closer, rather than looking at the ‘relative risk’ let us examine the actual frequencies. Among full term infants there were about 150 hospitalisations among just over 1 million individuals. Among infants of less than 32 weeks gestation, there were ….. wait for it… 4 hospitalisations among 5125 individuals. That’s right, this paper, considered worthy of a news item in the BMJ, this paper, which makes broad general comments about brain development in the preterm and how surveillance of preterm infants should continue for life, this paper is based on 4 cases of hospitalisation among over 5000 preterm patients.

In addition, apart from the unreliability of the gestational age data, the authors had little information to adjust the frequencies for other risk factors, many of which could easily differ between premature and full term individuals.

So even if it were all true, the actual attributable risk of being preterm is 1 admission for bipolar disorder per 10,000 patient years. Now as an exercise in epidemiology, perhaps there is some value here, if there is some tiny increase in risk of serious psychiatric disorder among preterm infants that could have some importance (though I have difficulty imagining what it is), but to state, as these authors do, that these data show some general abnormalities in brain development among preterm infants is ridiculous.

If we add together all of the disorders that the authors claim to be significantly related with prematurity, we find that the term individuals had 3,114 hospitalizations for depression, nonaffective psychosis, bipolar disorder and eating disorders, out of the same million people. The premature infants had 41 out of 5,125. Sure the relative risk is increased, but the actual attributable risk is about 10 admissions more for every 10,000 patient years.

Rather than the ludicrous generalizations that the authors make about premature infants brain development, and need for surveillance, these data (even if they were reliable, which I doubt) say exactly the opposite. as far as serious psychiatric illness is concerned there is almost no difference between premature infants and the full term.

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Head Ultrasound lesions and developmental progress: Predicting Long-Term Outcomes part 2

Posted on 7 June 2012 by Keith Barrington

Two recent articles that give much more information about the predictive capacity of head ultrasounds.

Many articles about head ultrasounds and outcomes use the Papile classification. This classification was developed for simple classification of periventricular hemorrhage types as seen on CT scan into broad categories. The fourth of of those broad categories is extremely broad.

There are 2 major problems with the current use of the Papile classification. The first being that a modestly sized intraventricular hemorrhage, which subsequently develops ventricular dilatation, may be referred to as a grade 3 hemorrhage. A large intraventricular hemorrhage which acutely dilates the ventricles is also referred to as a grade 3 hemorrhage. These 2 occurrences do not necessarily have the same consequences, and should be differentiated, but in many publications it is not clear whether such a discrimination has been made.

More importantly I think, a grade 4 hemorrhage can refer to a multitude of different injuries. A small localized intracerebral hemorrhage, and huge bilateral hemorrhagic destruction of the hemispheres are both referred to as grade 4 hemorrhage, and subsequently grouped together in outcome studies. It is self-evident that they must have different consequences for brain function, but finding the relative significance of these 2 variations is next to impossible in the literature.

It also seems very likely that frontal, parietal, temporal, and occipital hemorrhages may have different effects, but again there has been little published information to use to inform parents. Furthermore, an echodense lesion may appear to be a hemorrhage to one person, but may be thought to be infaction or oedema to another.

This huge problem has been addressed by the ELGAN study (a multi-center prospective cohort study of Extremely Low Gestational Age Newborns); that is, inter-rater variability in interpretation of head ultrasounds, both in how the findings are perceived, and how they are reported. By variations in how they are perceived I mean that even when sonologists are asked to just determine whether there is a parenchymal lesion, (which they can then note as being an echodensity or echolucency), they are often unable to agree. In one report from the study (Kuban K, Adler I, Allred E, Batton D, Bezinque S, Betz B, Cavenagh E, Durfee S, Ecklund K, Feinstein K et al: Observer variability assessing US scans of the preterm brain: the ELGAN study. Pediatr Radiol 2007, 37(12):1201-1208. http://www.springerlink.com/content/k2637421vj4vvq74/?MUD=MP) they noted that when one sonologist reported an echodense lesion, about 50% of the time the lesion was not reported by another sonologist. Similarly, about 40% of echolucent lesions were not reported by a second sonologist. We often make critical decisions based on these findings, so these discrepancies are very concerning.

Similarly variable are the terms used by sonologists to report the same lesions. The same lesion may be referred to as early PVL, late PVL, or periventricular hemorrhagic infarction, by different sonologists. (Westra S, Adler I, Batton D, Betz B, Bezinque S, Durfee S, Ecklund K, Feinstein K, Fordham L, Junewick J et al: Reader variability in the use of diagnostic terms to describe white matter lesions seen on cranial scans of severely premature infants: The ELGAN study. Journal of Clinical Ultrasound 2010, 38(8):409-419. http://onlinelibrary.wiley.com/doi/10.1002/jcu.20708/abstract)

For this reason, the ELGAN study decided to describe simply whether or not there was an echolucent or echodense lesion; but as noted above this did not eliminate the differences in interpretation.

To get back to the two recent publications referred to at the start of this post:

Michael O’Shea and the ELGAN study investigators (O’Shea TM, Kuban KC, Allred EN, Paneth N, Pagano M, Dammann O, Bostic L, Brooklier K, Butler S, Goldstein DJ et al: Neonatal cranial ultrasound lesions and developmental delays at 2 years of age among extremely low gestational age children. Pediatrics 2008, 122(3):e662-669. http://pediatrics.aappublications.org/content/122/3/e662.long) have compared the location of echodense and echolucent lesions and the neurodevelopmental outcomes at 2 years of age, according to neurologic exam and Bayley 2 MDI and PDI.

They have shown that lesions in different areas of the brain have different impacts on the likelihood of low Bayley MDI and PDI scores. One example is the figure shown below showing the effects of an echolucent lesion in different locations on the scores on a 2 year Bayley exam (the proportions with an MDI <70 are on the left, PDI <70 on the right:

Percentage of children whose scan had an echolucency in a particular location and who had an MDI of <70 (black numbers on the left side of the brain) or a PDI of <70 (black numbers on the right side of the brain) on the BSID-II

The other article from Stephanie Merhar and others (Merhar SL, Tabangin ME, Meinzen-Derr J, Schibler KR: Grade and laterality of intraventricular haemorrhage to predict 18-22 month neurodevelopmental outcomes in extremely low birthweight infants. Acta Paediatr 2012, 101(4):414-418. http://onlinelibrary.wiley.com/doi/10.1111/j.1651-2227.2011.02584.x/abstract ) has examined the association between whether periventricular hemorrhages were unilateral or bilateral and Bayley Scores. They found several interesting things. Most importantly infants with grade 4 hemorrhage (referred to as PVHI in the ELGAN studies) did NOT have worse Bayley scores at 2 years, unless the lesion was bilateral. Infants with unilateral grade 4 hemorrhages had a range of Bayley MDI scores which was very similar to those with unilateral subependymal hemorrhage.

Secondly, even among those with bilateral PHVI if they did not develop either sepsis or receive postnatal steroids, then only 25% had an MDI less than 70. In contrast, those who had Bilateral PVHI and had either sepsis or steroids or both had an increasing proportion of children with low Bayley scores.

To me this means that the preterm brain has a huge potential for repair and recovery. When a serious injury occurs, even if a large part of the brain is affected,  there is a chance of recovery and good outcome, but if that repair is interrupted by sepsis or dexamethasone, then the outcomes are much worse. These results should make us pause and reflect: bilateral parenchymal hemorrhages do not necessarily lead to an MDI less than 70, even those with an MDI less than 70 will often have IQ in the “normal” range in later life. Very few will be profoundly multiply disabled. The addition of multiple other insults during hospitalisation progressively worsens outcome.

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Predicting Long Term Outcomes, General Observations

Posted on 7 June 2012 by Keith Barrington

Just back to blogging from a few days at a very successful conference in Geneva, organized by Annie Janvier. At the conference I gave a presentation about prediction of long term outcomes in preterm infants. Some of the issues that I raised will be the subjects of a series of posts over the next couple of weeks, so I will be discussing the usefulness of ultrasounds, MRIs, EEGs, amplitude integrated EEGs, clinical examinations and clinical complications and anything else that has been investigated as possibly being of value in predicting long term outcomes among preterm infants.

A few general observations to start with:

Most reports that you can analyze to determine the reliability of a particular test or finding are flawed, and flawed in one very important way. The usually do not report the number of  patients with a particular finding during their hospital course who either died, or had active therapy withdrawn or withheld before they reach follow up. So for example we may have information about the infants with intraparenchymal hemorrhage who reached 2 years of age, but we often do not know about those, who may be a substantial proportion, who acutely died or had palliative care. This could be important, if those who had care withdrawn or died were systematically different from those who had on-going care.

Indeed I think it is likely that there are such systematic differences. I think it is likely that in some centers many or even most infants with intraparenchymal hemorrhage were offered redirection of care. Meaning that the parents of those who refused will have had a different background or different motivations to the rest. I think it is likely that in other centers withdrawal of active care has been offered selectively, meaning that those with less severe lesions are more likely to have survived. I think it is likely that in other centers redirection of care is not the primary consideration of the neonatologists, and it is parents who make the suggestion, again the characteristics of the parents will differ between those who survive and those who do not.

You will note that I use a phrase 3 times in that paragraph that I rarely use in anything I publish “I think it is likely”, I try to be as evidence-based as possible, but in this instance I cannot be. I am not aware of data about differential characteristics of patients and families whose babies survive with significant brain injuries (or significantly abnormal EEG or anything else) and those who die. Or whether the brain injuries differ between survivors and non-survivors.

I think in the future that studies of early prediction of outcomes of preterm infants should report the total cohort, those who had the findings of interest, those who died, those who had care redirected and those who survive. They should report the findings on the particular test of each category of patient to demonstrate whether survivors really represent the group of all those who had that finding. If not we could be really misled by the data.

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What does a low Bayley Score Mean? Predicting Long term outcomes: part 1.

Posted on 2 June 2012 by Keith Barrington

The title of the commentary listed below might put off some neonatologists, it looks like it has to do with studies in full term babies of their nutrition, when it really has to do with the meaning of the Bayley Scores. Colombo J, Carlson SE. Is the Measure the Message: The BSID and Nutritional Interventions. Pediatrics 2012. http://pediatrics.aappublications.org/content/early/2012/05/23/peds.2012-0934 For many years now the Bayley Scales of Infant Development have been the standard for analyzing short to medium term outcomes of babies surviving intensive care. As a screen for developmental delay they can be helpful. What has not been helpful is the tendency to refer to a low Bayley score on the Mental Development Index (MDI) scale as being cognitive impairment. But as Colombo and Carlson point out:

The BSID is a global test designed to identify developmental delay. Its role and place within the field of developmental science is relatively well established. The BSID is, to be charitable, only modestly related to school-age cognitive development (ie, the outcome that is most meaningful to investigators in this field). The BSID is a global measure of developmental status in infancy that assesses and aggregates the timely attainment of relatively crude milestones in infancy and early childhood.

The lack of predictive ability of the Bayley has been pointed out by Maureen Hack, Laura Ment, and by the long term follow up of the CAP trial (references below) among many other examples. Many children with Bayley MDI more than 2 SD below the mean have intellectual abilities in the normal range at long term. The CAP trial showed that only 18% of those babies who had an MDI at 18 months which was more than 2SD below the mean had an IQ more than 2 SD below the mean at 5 years. The authors of the commentary go on to say :

Simply, the BSID is not an adequate indicant of specific cognitive skills that may be differentially affected by interventions or exposures, nutritional or otherwise, and so its use to evaluate the construct of infant cognition is seriously deficient in the context of recent advances in developmental science.

Apart from being unsure about the use of the word ‘indicant’ I agree absolutely with this. A low score on the Bayley does not equal cognitive impairment.

I think this is extremely important for our patients. Predictions of so-called ‘cognitive impairment’ sound terrifying for parents, and persuade physicians that there will be major effects on intelligence.

In fact, many infants in the past have had consideration of withdrawal of intensive care based on expected ‘Cognitive Impairment’. In other words, a baby has a finding on head ultrasound, or a medical complication (this is especially among preterm infants) and the doctors go to the medial literature and find that ‘Oh No, the baby has a very high risk of Cognitive Impairment, so we should counsel the parents about this, they might want to consider limiting intensive care’.

But there are very few studies of quality, with high retention rates, that go beyond an 18 to 24 month Bayley score and really investigate the impacts of a particular finding on the functioning of a baby. So few that the significance of much of what we see clinically, and then discuss with parents, is highly questionable if we really are considering the long term functional outcomes of our patients.

On the other hand, to hide behind prognostic uncertainty is also not serving our patients, and their parents, best interest. I don’t mean to suggest that we can never say anything about long term outcomes, and that we should never therefore consider limiting intensive care. We should be basing our decision making on reliable data.

We should consider which things actually have impacts on long term functional outcomes, and how severe those impacts really are.

Hack M, Taylor HG, Drotar D, Schluchter M, Cartar L, Wilson-Costello D, Klein N, Friedman H, Mercuri-Minich N, Morrow M: Poor Predictive Validity of the Bayley Scales of Infant Development for Cognitive Function of Extremely Low Birth Weight Children at School Age. Pediatrics 2005, 116(2):333-341.

Ment LR, Vohr B, Allan, Walter, Katz KH, Schneider KC, Westerveld M, Duncan CC, Makuch RW: Change in Cognitive Function Over Time In Very Low Birth Weight Infants. JAMA : the journal of the American Medical Association 2003, 289(6):705-711.

Schmidt B, Anderson PJ, Doyle LW, Dewey D, Grunau RE, Asztalos EV, Davis PG, Tin W, Moddemann D, Solimano A, Ohlsson A, Barringotn KJ, Roberts RS: Survival Without Disability to Age 5 Years After Neonatal Caffeine Therapy for Apnea of Prematurity. JAMA: The Journal of the American Medical Association 2012, 307(3):275-282.


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Fluid Restricting Babies: Part 2

Posted on 30 May 2012 by Keith Barrington

While I am on a roll…

Fluid restriction as a means of treating babies with BPD makes no sense.

It is also unsupported by any literature.

I think this practice may have arisen because diuretics are given to infants with BPD (don’t get me started on that one) which may lead to modest improvements in pulmonary function. However, here again I think there is a confusion between the effects of changing sodium balance, and the effects of how much free water we give to babies. Diuretics decrease total body water by causing a natriuresis, the sodium depletion leads to reduced body water. Now it isn’t entirely clear that all the pulmonary function changes are because the babies are drier, therefore have less lung water; it may be direct effects of furosemide in particular on ion pumps in the lung (even inhaled furosemide has some effect, without causing a diuresis: Reference at the end).

I reiterate, any reasonable decrease in fluid intake will not affect total body water, and there is no reason to believe that it will affect pulmonary function. If you give 60 mL/kg of fluid less a day, then urine will be more concentrated, increasing risks of nephrocalcinosis, and nutrition is likely to be affected, compounding the growth failure common in BPD.

I have only ever found one relevant trial: Fewtrell MS, Adams C, Wilson DC, Cairns P, Mcclure G, Lucas A: Randomized trial of high nutrient density formula versus standard formula in chronic lung disease. Acta Paediatrica 1997, 86(6):577-582. http://onlinelibrary.wiley.com/doi/10.1111/j.1651-2227.1997.tb08937.x/abstract.

VLBW babies with BPD (O2 at 28 days) were randomized to either high density formula at 140 ml/kg/d or a low density formula at 180 ml/kg/d. the nutrition of the two groups was close to identical, the high-density formula group just had less free water intake. Although the low density group did not quite reach the desired volume, there were substantial differences in the volumes of liquid actually received. However, there were no detectable differences in respiratory outcomes (or indeed in growth).

Babies with BPD are often referred to as being ‘fluid sensitive’ I don’t actually know what that means!

Fluid restriction of babies with BPD may be thought to be a benign intervention, but I often see babies whose nutrition also gets restricted at the same time, nutrition they desperately need to repair their lungs.

Just like for the PDA, restricting sodium (but not free water) in the first few days of life decreases the development of BPD, but restricting free water administration when the condition has occurred has no demonstrated benefit, and no demonstrable effects at all except on urine output.

There is no evidence to support the common practice of fluid restricting babies with BPD, it should not be done.

Prabhu V, Keszler M, Dhaniereddy R: Pulmonary function changes after nebulised and intravenous fresemide in ventilated premature infants. Arch Dis Child 1997, 77:F32-F35. http://fn.bmj.com/content/77/1/F32.long

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Fluid Restricting Babies

Posted on 29 May 2012 by Keith Barrington

A study published online first in the Journal of Pediatrics questions a common practice, the practice of fluid restricting babies who have a patent ductus arteriosus.

De Buyst J, Rakza T, Pennaforte T, Johansson AB, Storme L: Hemodynamic Effects of Fluid Restriction in Preterm Infants with Significant Patent Ductus Arteriosus. J Pediatr 2012(0).
http://www.sciencedirect.com/science/article/pii/S0022347612002880

Julie De Buyst studied 18 very preterm babies before and 24 hours after a major reduction in their fluid intakes, from between 140 and 160 mL/kg/d to between 100 and 120 mL/kg/d.

Although this practice is frequent it is something I have never really been able to understand. We know that renal physiology in preterm babies is limited in many ways, but after the first couple of days, during which GFR is rapidly increasing, there is little limitation in the ability to excrete a water load. So giving more fluids has no real effect on total body water, it just increases urine output. Although the ability to concentrate the urine is more limited, with maximal concentrations far less than those seen in older children, administration of fluids within the range down to 100 mL/kg/d generally leads to no change in total body water, it just decreases urine output, leading to a more concentrated urine. How this is supposed to affect PDA patency or the hemodynamic effects of a PDA I do not understand. If we restrict a baby from 160 to 100 mL/kg/d then every hour they receive 2.5 mL/kg less fluid, and make 2.5 mL/kg less urine. Unless they are severely enough restricted to go beyond the renal concentrating ability, and become truly dehydrated, there will be no effect on circulating blood volume. The same arguments can be made for fluid restriction in BPD, and the lack of any likely effect on pulmonary function, more of which later.

So not surprisingly Julie De Buyst and her collaborators found no effect of fluid restriction on any of the ductal measurements, they did show a decrease in SVC flow, which I have difficulty understanding, it certainly is not likely to be a beneficial change; but there were several comparisons made, so perhaps it is a type 1 error.

To go back to the history of why people started fluid restricting babies with a PDA we probably need to return to studies done in the mid to late 1970’s.

There are a few small or modestly sized studies examining how much fluid we should give to preterm infants in the first few days of life. On first look there seems to be some evidence that giving less fluid might reduce the occurrence of a PDA (which is not the same thing as helping to manage it once it has occurred!) If the studies are examined carefully, however, the administration of sodium was also different between groups in several of the studies. Also the diagnosis of a PDA was often made clinically in some of the earlier studies, which we now know is very inaccurate.

Sodium administration, and sodium restriction have more effect on total body water than how much water is given, because babies have more limitations in their ability to excrete (or retain) sodium than water. In fact this is true throughout life, so adults with congestive heart failure are not told to restrict their water intake, but may be counselled to restrict their sodium intake. So, for example, the study of Tammela (Tammela OK, Koivisto ME. Fluid restriction for preventing bronchopulmonary dysplasia? Reduced fluid intake during the first weeks of life improves the outcome of low-birth-weight infants. Acta Paediatr. 1992;81(3):207-12. Epub 1992/03/01.) was a study of fluid restriction in 100 low birth weight babies (<1750g), but there was a standard concentration of sodium in the fluids (3 mmol/100mL for the fluid restricted group and for most of the high fluid group, but 4 mmol/kg for the infants in the high fluid group who were <1000g), so when fluids were restricted so was sodium. They showed more BPD and death in the high fluid/high sodium group, and more PDA 9/50 compared to 5/50.

In the study of fluid restriction by Jack Lorenz and others (Lorenz JM, Kleinman LI, Kotagal UR, Reller MD: Water balance in very low-birth-weight infants: Relationship to water and sodium intake and effect on outcome. J Pediatr 1982, 101(3):423-432. http://www.sciencedirect.com/science/article/pii/S0022347682800784) babies were given no sodium on day one, but then the high fluid group also received more sodium than the low fluid group. In this study 88 babies 750 to 1500 grams were enrolled; the high fluid/high sodium group had slightly more PDA, and slightly more BPD.

On the other hand Vasiliki Kavvadia (Kavvadia V, Greenough A, Dimitriou G, Hooper R: Randomised trial of fluid restriction in ventilated very low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2000, 83(2):F91-96.) randomized 168 VLBW infants to high or low fluid regimes, and gave no sodium to either group in the first 24 hours, and individualized the sodium intakes thereafter. They showed no difference in mortality or BPD. On the other hand the group that got more free water made more urine; see physiology works!

The study by Ed Bell (Bell EF, Warburton D, Stonestreet BS, Oh W: Effect of fluid administration on the development of symptomatic patent ductus arteriosus and congestive heart failure in premature infants. N Engl J Med 1980, 302(11):598-604.) randomized 170 babies between 750 and 2000 g birth weight to high and low fluid intakes starting at 72 hours of age. The paper doesn’t clearly describe how the sodium was managed. This is the only one that really showed a difference in PDA, but it seems that many of the diagnoses were clinical, which we know is not very sensitive, nor specific.

The other side of the evidence are the studies comparing different sodium intakes without changing fluid intakes. There are 2 (Costarino AT, Jr., Gruskay JA, Corcoran L, Polin RA, Baumgart S: Sodium restriction versus daily maintenance replacement in very low birth weight premature neonates: a randomized, blind therapeutic trial. J Pediatr 1992, 120(1):99-106. http://www.sciencedirect.com/science/article/pii/S0022347605806110 and Hartnoll G, Betremieux P, Modi N: Randomised controlled trial of postnatal sodium supplementation on oxygen dependency and body weight in 25-30 week gestational age infants. Arch Dis Child Fetal Neonatal Ed 2000, 82(1):F19.)

Both of these show adverse effects of giving more sodium earlier in life. The earlier sodium supplementation groups had more BPD in both studies, and more PDA, but not statistically significant. The Costarino study was tiny (17 babies) and the Hartnoll study was small (44 babies), nevertheless the differences in resolution of lung disease were significant. The high sodium babies lost less weight, even though fluid intakes were the same.

To get back to my point, it seems, from my evaluation of the evidence, that restricting sodium intake in the first few days of life leads to greater weight loss, a lower incidence of PDA and less BPD; but restricting fluids without changing sodium administration does nothing to PDA, or indeed to any other outcome.

The implications of this are as follows, during the first 3 days of life, babies need little or no exogenous sodium. They should be managed with as little sodium as possible, but the total volume of fluids is relatively unimportant, especially after ths first 24 hours during which renal blood flow, urine output, and glomerular filtration increase rapidly.

When a PDA becomes evident, several days later, there is no evidence whatsoever to support fluid restriction. This is a practice without physiologic rationale, without clinical studies to support it, and is potentially harmful. Effective renal solute load is increased by decreasing free water. If macro and micro nutrients are also restricted then the risks of undernutrition, undermineralization etc. are serious. In Ed Bell’s article from 1980, the calorie administration in the restricted group were substantially less than the non-restricted group (and both were far below what we would consider acceptable today). So babies with a PDA should NOT be fluid restricted.

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Neonatal Surgery and Long Term Outcomes

Posted on 27 May 2012 by Keith Barrington

A study from a group in Australia provides new data about the developmental outcomes of babies having surgery, in the medium long term. It is already clear that babies who need neonatal cardiac surgery have poorer developmental outcomes than control infants. Some of this is probably due to pre-existing abnormalities of cerebral development, but some is also probably due to peri-operative phenomena, and may be amenable to improvement by changing surgical or anesthetic techniques. In this new study more information about non-cardiac surgery outcomes is provided. Walker K, Badawi N, Halliday R, Stewart J, Sholler GF, Winlaw DS, et al. Early Developmental Outcomes following Major Noncardiac and Cardiac Surgery in Term Infants: A Population-Based Study. J Pediatr. 2012(0). Epub 2012/05/15. http://www.sciencedirect.com/science/article/pii/S0022347612003538

This was a very large regional cohort, and included a control group of infants who did not have surgery; this feature is very important as the authors performed the Bayley 3 scores for infant development on all of the babies. This was a major undertaking, and the authors are to be congratulated. Particularly for having a comparable control group; it is clear that we should not rely on the standardized scores of the Bayley 3 to determine whether an infant has developmental delay; scores (especially in Australia, where I guess they are smarter than average) in controls are usually substantially higher than the standardization would lead you to expect. Also the testing was done at 1 year, which is too early to have much predictive value for the very long term, but does on the other hand point out developmental delays at that time. Major non-cardiac surgery included thoracotomies, laparotomies and sclerotherapy for lymphatic abnormalities. So it excluded inguinal hernia repairs but included a lot of children who had pyloromyotomy for pyloric stenosis, which we often think of as being relatively minor surgery, but does involve opening the peritoneum.

The authors showed that there were many more infants with developmental delay after cardiac surgery than the controls, and a smaller increase in developmental delay after non-cardiac surgery. Now don’t panic if your baby had surgery, the delays were relatively minor, babies were a couple of months behind in their development. But the delays were seen in many areas of development, cognition, language and motor.

Now why should this be? If we assume that the large majority of the non-cardiac surgery babies, and most of the cardiac surgery babies, had a lesion that did not affect cerebral development before birth, then we are left to ask: is the cause of these problems the surgery and the hemodynamic and other physiologic changes that occur around surgery? Is the cause the drugs that are used for anesthesia? Or does the pain and discomfort of pain itself cause long term cerebral changes?

I think the answer to these questions is likely to be yes!

The Boston Circulatory Arrest Trial showed that being randomized to deep hypothermic circulatory arrest gave poorer developmental outcomes among a group of children with a single diagnosis (d-transposition), than the comparison group who had low-flow cardiopulmonary bypass. These infants were much less variable than most groups of children with congenital heart disease who have been studied, and the study gave strong evidence that the details of how the circulation is managed can affect brain development, with effects that last until school age. Bellinger DC, Wypij D, duPlessis AJ, Rappaport LA, Jonas RA, Wernovsky G, et al. Neurodevelopmental status at eight years in children with dextro-transposition of the great arteries: The Boston Circulatory Arrest Trial. The Journal of Thoracic and Cardiovascular Surgery. 2003;126(5):1385-96. http://www.sciencedirect.com/science/article/pii/S0022522303007116. This is a pretty extreme example, but many babies during surgery have periods of low cardiac output, hypo- or hyper-ventilation, they may have a lung deflated to enabled access to particular structure or have gas insufflated into the abdomen to allow laporoscopic access to an organ, which changes hemodynamics and increases IVC resistance.  They may become dehydrated by having huge insensible fluid losses while the abdomen is open, or become fluid overloaded because guessing how much fluid has been lost is a very inexact science. So it is quite conceivable that these changes and the endocrine stress responses that accompany surgery, and the systemic inflammation that we see also, could cause brain injuries, inflammatory, ischemic, embolic or other, and long term effects.

In animal models just the administration of drugs that are commonly used in neonatal anesthesia can lead to neuronal apoptosis and long term adverse effects. How important this is in babies is unclear: obviously you cannot do surgery without anesthesia, so studies to find the most effective, and least harmful anesthetics are needed, if indeed anesthesia has the same effects in humans as in the animal models.

A study from a north american cohort (Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128(5):e1053-61. Epub 2011/10/05. http://pediatrics.aappublications.org/content/128/5/e1053.long) compared the effects of having surgery before the age of 2 on whether or not children were classified as having a learning disability later on.

The differences between this study design and the previous one should be noted. Randall Flick and his coworkers examined data in 2 large and quite complete regional databases. Children were classified as having a learning disability based on results on standardised educational testing, performed as a routine in the educational system in Minnesota. In this study children who had a surgery before the age of 2 (not before 90 days as in the previous study) had no increased risk of being below this specific threshold, unless they had 2 or more surgeries. In which case learning disabilities were more frequent. Now using a threshold to classify children as having a problem or not, is less powerful than comparing average scores on a test. Also we could presume that surgery in the first 90 days is more likely to be followed by problems than surgery in larger older children up to 2 years.

Finally another study which looked at the number of painful procedures that children experience and how it might affect brain development. (Brummelte S, Grunau RE, Chau V, Poskitt KJ, Brant R, Vinall J, et al. Procedural pain and brain development in premature newborns. Annals of Neurology. 2012;71(3):385-96. http://onlinelibrary.wiley.com/doi/10.1002/ana.22267/abstract )

I’m not sure you can really statistically correct for all of the potential confounders and there probably was some residual confounding, so it is hard to ascribe the effects that were shown just to the painful procedures,but nevertheless, children who had more painful procedures had differences in white matter MRI features (fractional inosotropy) and grey matter metabolism both early in life and at term.

Having surgery is bad for your brain, in general the effects are relatively small, but surgery, anesthesia and pain may all contribute to the adverse effects.

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Septic Shock

Posted on 25 May 2012 by Keith Barrington

This study is not neonatal at all, not even pediatric, but I think it is really important.

Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al. Drotrecogin Alfa (Activated) in Adults with Septic Shock. N Engl J Med. 2012;0(0):null. Epub 2012/05/24.

There is a complicated history behind this study.

Previous studies were contradictory, but suggested that maybe there was a minor effect of activated protein C (Drotrecognin)  in the treatment of the sickest adults with sepsis. It was known that abnormalities of coagulation are common in septic adults, and the idea that correcting these abnormalities with activated protein C might improve outcomes was not crazy.

A very contentious decision by the FDA to approve the sale of Drotrecognin, after the initial suggestive trials, has been widely criticized, largely because of a perception that the decision was not adequately supported by the clinical data, and that it was tainted by conflicts of interest, and serious pressure from commercial interests.

The FDA made it clear that they wanted further confirmatory studies, and the result of that is the new study by Ranieri and colleagues. Nearly 1700 critically ill adults with septic shock were randomized to either Drotrecognin or placebo.

There was no benefit in any measurable outcome from the intervention.

This result is striking, the study has sufficient power to eliminate any important benefit of the drug in adults with severe sepsis. (A negative pediatric study has already been published). Drotrecognin now joins a long list of interventions which do not improve outcomes in severe sepsis. These include: high dose steroids; antagonists to TNF, IL-1 , platelet-activating factor, bradykinin, and cyclooxygenase; immunoglobulins; anti-lipopolysaccharide interventions; and so on.  Suffredini AF, Munford RS. Novel Therapies for Septic Shock Over the Past 4 Decades. JAMA: The Journal of the American Medical Association. 2011;306(2):194-9. http://jama.jamanetwork.com/article.aspx?volume=306&issue=2&page=194

My interpretation of this is that we need to be super careful.

Many of the physiologic changes which occur in severe sepsis, which we think are part of the problem, are probably adaptive and part of a normal response. So attempting to interrupt what we think are excessive or harmful responses will not necessarily be beneficial.

This actually also applies to things which are much more low tech than recombinant activated protein C. Such as fluid boluses.

In what I think is one of the most important studies in the history of scientific medicine Kathryn Maitland and her collaborators showed that fluid boluses, given to african children with early septic shock, actually increased mortality, rather than the expected decrease. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364(26):2483-95. Epub 2011/05/28. http://www.nejm.org/doi/full/10.1056/NEJMoa1101549

So why are these studies so important?

They show firstly that studies in critically ill patients can be performed, if there is enough will to do so. They are very difficult, and there are all sorts of roadblocks and inhibitions, but they are possible.

They shows secondly that haemodynamic, metabolic, and biochemical changes in severe shock may be helpful and adaptive rather than maladaptive.

What are the implications for neonatal sepsis?

To my knowledge there has never been a substantial controlled trial in neonatal severe sepsis. This is even though a major cause of mortality and long term morbidity in newborn infants is sepsis. Our commonly used interventions have to be studied.

Even interventions which have not yet been proven ineffective may be ineffective, such as low dose steroids. They need to be investigated in newborn infants. I think the major preliminary questions to be addressed are the following:

What are the hemodynamic changes that usually occur during septic shock in the newborn? are they different to older patients? are they different between gram negative and gram positive infections? Are newborns truly effectively hypovolemic during sepsis? Do babies benefit from low dose steroids? Should we give steroids early or only after failure to respond to the usual inotropes? Is one inotrope better than any other?

To answer these questions will require clinical trials networks committed to performing these difficult trials. However, one thing I do not think we need to study in newborn infants is activated protein C!

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15,000,000 preterm babies a year

Posted on 25 May 2012 by Keith Barrington

A new report from the World Health Organisation highlights the importance of prematurity as a major health problem around the world. http://www.who.int/pmnch/media/news/2012/preterm_birth_report/en/index.html Fifteen million babies are born prematurely in the world each year, and the number is increasing everywhere. You can use an interactive map on the following page to find out how various countries are doing. http://www.marchofdimes.com/mission/globalpreterm.html?utm_source=Healthy%2BNewborn%2BNetwork%2BNewsletter%26utm_campaign=10505b16f0-HNN_express_May%2B4%26utm_medium=email The report points out that prematurity is a huge problem in low-resource countries as well as middle and high resource countries. Millennium development goal 4, reducing child deaths by 2/3 is far from being realized. Much of the failure has been because newborn babies are not considered to be of much value, and the loss of human life, when it is newborn babies, is never considered to be as serious as when it is older children or ‘productive’ adults.

The majority of neonatal deaths in the world are due to lack of access to basic medical care. Many millions of those deaths could be prevented with simple inexpensive interventions: breast feeding, basic temperature management, early treatment of infections and more importantly, education. This includes preterm babies, most preterm babies are only slightly preterm, and they do not need expensive intensive care to survive, but kangaroo care, assistance with feeding and knowledge of simply treated complications could make a difference to millions of babies.

Simple interventions also make a difference to full term babies, Five percent of term babies need a little help to start breathing on their own. In many countries, babies who don’t breathe immediately after birth are left to die. A new program for such babies ‘heliping babies breathe’ holds great potential to improve survival and decrease long term handicap. http://www.helpingbabiesbreathe.org/

This program has been developed with careful evaluation of the skills gained by providers and evaluation of how to best institute it.

Singhal N, Lockyer J, Fidler H, Keenan W, Little G, Bucher S, et al. Helping Babies Breathe: Global neonatal resuscitation program development and formative educational evaluation. Resuscitation. 2012;83(1):90-6.
http://www.sciencedirect.com/science/article/pii/S0300957211004266

With programs like Helping Babies Breathe and simple ways to improve outcomes of preterm babies, we have a chance to make a dent in the millennium goals.

It must be recognized that neonatal resuscitation not only reduces death but also reduces long term handicap.

It has sometimes been difficult in the past to start resuscitation programs because people worry that resuscitating babies who do not breathe at birth is to risk resuscitating babies who will have serious long term brain injury. It has even been difficult to get funds to start programs to train people.

The reality is exactly the opposite. Neonatal resuscitation programs reduce death AND reduce disability.  Wally Carlo and his colleagues have shown this very clearly, Carlo WA, Goudar SS, Pasha O, Chomba E, McClure EM, Biasini FJ, et al. Neurodevelopmental outcomes in infants requiring resuscitation in developing countries. J Pediatr. 2012;160(5):781-5 e1. http://www.jpeds.com/article/S0022-3476(11)01046-8/abstract 

Teaching neonatal resuscitation in low resource countries reduces the numbers of babies who are classified as stillborn, and reduces the numbers of babies who have long term neurological and developmental problems.

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Pulse Oximetry Screening for Congenital Heart Disease, an idea whose time has come

Posted on 24 May 2012 by Keith Barrington

It is now several years since the first study of using pulse oximeters to screen for congenital heart disease were published. The initial response was a little skeptical, and appropriately cautious. It was immediately clear that there would be numerous false positives (which is common in universal screening programs) but also false negatives (which need to be minimized in screening to make it worthwhile). Also, and in contrast with some other screening programs, numerous children were already being diagnosed, either in utero by ultrasound or by routine neonatal exam.

The purpose of the screening program then, is to detect children who are not otherwise being diagnosed, and who are at risk of serious health consequences if undetected. This mostly occurs in infants who have ductus dependent conditions, such as pulmonary atresia and interrupted aortic arch. The cyanotic forms should be readily detectable with pulse oximetry screening. But even the acyanotic forms may have right to left ductal shunting with reduced saturations in the feet, despite normal saturation in the right hand.

So costs and benefits need to be weighed carefully, “are the numbers of children detected by routine pulse oximetry, and who would then avoid an early post-discharge collapse at home and therefore have a better chance of surviving and doing well long-term, sufficient to justify the costs, and the stress caused to parents by a false positive screen?”.

A new systematic review in the lancet included 13 studies with over a quarter of  a million babies.  Thangaratinam S, Brown K, Zamora J, Khan KS, Ewer AK: Pulse oximetry screening for critical congenital heart defects in asymptomatic newborn babies: a systematic review and meta-analysis. Lancet 2012(0). http://www.sciencedirect.com/science/article/pii/S014067361260107X

This review confirmed what I felt was already clear 3 years ago,  Barrington KJ: Neonatal screening for life threatening congenital heart disease. BMJ 2009, 338:a2663. http://www.bmj.com/content/338/bmj.a2663?view=long&pmid=19131381 There is sufficient evidence of efficacy, and sufficiently low false positives (they can be reduced to 0.05% if the screening is performed after 24 hours of age) to institute universal screening.

The remaining questions need to be addressed, should we screen just one foot, or follow with the right hand under certain circumstances? Which precise saturation threshold should be used? How will parents who have a false positive screening test, but a normal echocardiogram react? Is it cost-effective? The last two questions have also been addressed by Andrew Ewer and his coworkers.

Powell R, Pattison HM, Bhoyar A, Furmston AT, Middleton LJ, Daniels JP, Ewer AK: Pulse oximetry screening for congenital heart defects in newborn infants: an evaluation of acceptability to mothers. Archives of Disease in Childhood – Fetal and Neonatal Edition 2012. http://fn.bmj.com/content/early/2012/05/17/fetalneonatal-2011-301225

Roberts TE, Barton PM, Auguste PE, Middleton LJ, Furmston AT, Ewer AK: Pulse oximetry as a screening test for congenital heart defects in newborn infants: a cost-effectiveness analysis. Archives of Disease in Childhood 2012, 97(3):221-226.
http://adc.bmj.com/content/97/3/221

These studies showed that screening was very well accepted by parents, even those who experienced a false positive. Interestingly this was also previously shown for false positives during neonatal hearing screening, and I think shows that when parents are well-informed, they are capable of understanding false positives, and appreciate the fact that the universal screening is designed to help the true positives. Also, in this case, the false positives have had a cardiac echo and can be very confident that their babies heart is fine. In addition in most studies there are some of the supposed “false positives” that actually have an important diagnosis and are aided by the test.

The cost effectiveness analysis came up with a cost of around 20000 pounds sterling per critical congenital heart disease detected. Many undetected cases present with serious illness, and have an increase in long-term morbidity or mortality. So the benefits are significant, and the costs are relatively modest and in line with other neonatal screening programs.

In terms of the details of technique, a threshold of 94, 95, or 96% has been used, with some studies adding a difference between leg and right hand, (such as a >3%) difference, which would mean that if the leg was 95, or 96% then the hand would be measured as well, but if the leg was 97% no further testing would be required, and if less than 95% then an echocardiogram is required whatever the hand shows.

If you combine the information in the Supplemental Table from the new meta-analysis published in the lancet with the information in the Table in the print version, it seems that a threshold of 96%, i.e. 96% and above is fine, 95% and below requires further testing, increases sensitivity compared to a 95% threshold with very little effect on the false positives.

Again among the large studies it doesn’t seem that adding the right hand saturation adds much in terms of sensitivity, but also does not seem to affect false positives. It does significantly prolong and complicate the process.

Adding universal pulse oximetry screening in the second 24 hours of life to other screening programs appears to be acceptable to parents, as cost-effective as other neonatal screening programs, widely applicable, and could prevent death, morbidity and disability.

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