Causes and Consequences of Bronchopulmonary Dysplasia

Sullivan K, et al. The Association between Positive Tracheal Aspirate Cultures and Adverse Pulmonary Outcomes in Preterm Infants with Severe Bronchopulmonary Dysplasia. American journal of perinatology. 2016(EFirst).  This is an interesting study, with many limitations. 121 intubated VLBW preterm infants who had at least one Endotracheal bacterial culture are included. Outcomes of the babies and relationship with the results of the cultures were studied. The cultures were not performed as a routine, but whenever the treating team felt that they needed one. Which is the first problem with the study, we don’t know why the team wanted to have an endotracheal culture. 80% of the cultures were positive for potential pathogens, 30% had more than one. 30% had Pseudomonas and another 14% Klebsiella. Babies who had Gram negative rods in the cultures were more likely to have the adverse outcome, which was death or going home on oxygen.  Babies who had gram positive cocci in the cultures, in contrast, were not more likely to have severe BPD or death.

Previous data has shown a correlation between Ureaplasma cultures and BPD, but I don’t think there are many data about other bacteria in the endotracheal tube. In order to know whether these data are really showing a causative relationship, I think you would need firstly a study with all intubated babies having routine cultures at the same postnatal age, and then redo this sort of analysis. Then a randomized trial of treating the positive cultures with effective antibiotics would be needed to confirm that any association may be causative, and that you can do something about it.

Sanchez-Solis M, et al. Lung function gain in preterm infants with and without bronchopulmonary dysplasia. Pediatr Pulmonol. 2016. 71 VLBW infants were studied at 6 months corrected age, and again a year later. The VLBW babies with BPD had significantly lower FVC and FEF25-75 (an indicator of small airways function). When they restudied them, the trajectory of changes in both groups was similar, as they babies length increased, the lungs grew, but the differences between the BPD and non-BPD groups remained about the same; there was no catch-up in lung function.

Poon CY, et al. Pulmonary arterial response to hypoxia in survivors of chronic lung disease of prematurity. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2016;101(4):F309-F13. In this study the pulmonary vascular reactivity to 12% oxygen inhalation (compared to 21%) of former preterm infants with and without BPD and controls was examined, there were 13 with BPD, 21 preterm without BPD, and 25 term born children examined at 9 to 12 years of age.

The technique that was used is completely new to me, using MRI, they measured the cross-sectional area of the pulmonary artery and the blood flow through the measured segment. They plot the changes in the 2 measurements during early systole,  and the slope of the regression is referred to as the pulse wave velocity (PWV). They then redo the PWV after exposing the children to hypoxia. Normal children, previously studied by this group have an increase in PWV with hypoxia. In this study the preterm born children with BPD had a greater increase in their PWV than the controls. The children were all healthy, but still have what appears to be an increase in pulmonary vascular reactivity (assuming that this technique is indeed reliable), even 10 years later.

Van Hus JWP, et al. Early intervention leads to long-term developmental improvements in very preterm infants, especially infants with bronchopulmonary dysplasia. Acta Paediatrica. 2016;105(7):773-81. This is a report of an RCT in a 176 infants who were either VLBW or less than 32 weeks. Infants were either enrolled in an Early Infant Behaviour and Intervention Program. and then followed at 6, 12 and 24 months with Bayley version 2, and at 5.5 years with the WPPSI IQ test and the Movement Assessment Battery for Children. Overall the motor scores were better in the group with the early intervention, and remained so throughout the follow up, The cognitive scores were a bit better with early intervention, but that may have been due to chance (“not significant”). In a subgroup analysis, of just the babies with BPD, both cognitive scores and motor function was improved with early intervention.

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Survival and outcomes of extremely immature babies, glass half empty or…

Anderson JG, et al. Survival and Major Morbidity of Extremely Preterm Infants: A Population-Based Study. Pediatrics. 2016. This publication is derived from data in a public health database, the data for which comes from ICD-9 codes of the hospital discharge records. There were over 16,000 babies born in California between 22 and 28 weeks gestation in the years 2007-2011, but only 7000 are included as they had linked birth records and hospital discharge records. Of these 7000, there were a surprisingly large number, about 1,000, with major birth defects or chromosomal anomalies, which makes me wonder whether these babies are representative of the whole 16,000. The babies with major birth defects or chromosomal anomalies were not included in the remainder of the publication.

The first survival figures presented are of very little interest “Among the infants born at 22, 23, and 24 weeks, survival to 1 year of age was 6%, 27%, and 60%, respectively”, I say “of very little interest” because these figures include babies who were left to die in the delivery room. As the mortality of the babies of this gestation who don’t get intensive care is 100% there is little point including them in any survival statistics, the proportion who receive active care, and the proportion of those who survive are what is important. Which the authors do subsequently: “When examining survival after attempted resuscitation, the rate of survival to 1 year at 22, 23, and 24 weeks was 31%, 42%, and 64%, respectively”.

Morbidities were also more frequent with decreasing gestation, but I am not entirely sure how accurate all the diagnoses are, discharge record codes are not necessarily always reliable. The 22 and 23 week babies had severe IVH, PVL, NEC and BPD more frequently than at 24 weeks or later, RoP requiring surgery was more frequent at 22, 23 and 24 weeks.

Sepsis occurred in around 2/3 of the babies under 25 weeks, and in an extremely high proportion of all their babies (48% of all the infants from 22 to 28 weeks). They used the ICD-9 code for neonatal sepsis, which seems to include early and late onset sepsis, and doesn’t seem to require a positive culture. In one source I saw it seems to also include NEC, so NEC might have been counted twice in some of these records. In any case, this is an extremely high proportion of babies with a discharge diagnosis of sepsis, In comparison the CNN data in 2014 show about 20% of the same gestational age group with late onset sepsis (and about 2.5% with early onset). I don’t know why these sepsis figures are so high, I haven’t seen rates this high from anywhere in the world that I can think of, which makes me worry about the reliability of these figures. As funding may be related to the ICD-9 codes then there is a pressure on discharge coders to include anything that can be put under the code, and as there are no clear definitions for the neonatal sepsis code, could performing a septic work-up for a suspicion of sepsis end up being tagged?

Similarly the code for NEC includes the notoriously difficult to define stage 1 NEC, and may well be an over-estimate of what would be considered definite NEC in other reports, stage 2 and higher (although, even then, diagnostic accuracy of pneumatosis is poor).

I am emphasizing these points as the authors present the proportion of babies who survived without these major morbidities, but if the diagnoses are inflated then these proportions are much lower than the reality. Some of the diagnoses are probably accurate (coding for surgery for retinopathy for example) for others perhaps less so.

The authors also do not give an estimate of the precision of these numbers, as you will all see in an upcoming publication in Pediatrics, we (that is, a group of investigators led by Matt Rysavy) propose, among other things, that such reports should always include the confidence intervals of the outcomes.

Consistent with data from EpiCure2, and consistent with common sense, babies born at 22 to 28 weeks in a hospital with a regional NICU were more likely to survive than if they were born in hospital with an intermediate level NICU. The differences were even greater for infants from 22 to 24 weeks gestation.

Holsti A, et al. More than two-thirds of adolescents who received active perinatal care after extremely preterm birth had mild or no disabilities. Acta Paediatrica. 2016

In contrast to those data are these very optimistic results from Sweden, they have already published details of their approach which they refer to as “active perinatal care” a co-ordinated approach to supporting the extremely immature baby, just before and after birth. They describe it like this “a universal and consistent policy of APC after all deliveries at the threshold of viability at 23-25 weeks of gestation. This management includes the centralisation of all deliveries at less than 28 weeks whenever possible, the administration of antenatal corticosteroids and tocolytics, the presence of a certified neonatologist at all deliveries at less than 28 weeks of gestation and resuscitation of all infants at 23-25 weeks of gestation with any signs of life”. They have already shown that this policy increases survival, without increasing short-term complications and they now present the outcomes in early adolescence of 132 children born from 23 to 25 weeks in the mid 1990’s.

3.8% of the extremely preterm adolescents had disabling CP (unable to walk), and no controls, 1.5% (2 subjects) had severe visual impairment, and 1.5% were deaf. As usual in these cohorts the most frequent impairments were cognitive; they performed Wechsler IQ tests on the preterm babies and the controls, 31% of the preterms and 5% of the controls were more than 2SD below the mean on full-scale IQ scores; 18% of them were more than 3SD below the mean (and no controls).

So you could say that these results are much worse than the general population, the glass is nearly 1/3 empty, or you could also say that they are remarkably good, and the large majority of the patients are doing extremely well, the glass is over 2/3 full.

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Moral Distress among nurses (and others).

This publication appeared on-line a couple of months ago, and still isn’t in print. Prentice T, et al. Moral distress within neonatal and paediatric intensive care units: a systematic review. Arch Dis Child. 2016. It is a systematic review from Melbourne, with the help of Annie Janvier, of the literature surrounding moral distress in health care workers in the NICU and the PICU. All of the studies included nurses, and some of them also studied other health care workers.

Moral Distress refers to subjective feelings of distress in response to the ethical challenges of health care work. It is a term which first appeared in the nursing literature, and, although other terms have been suggested, I think it fits. Moral residue is another term these authors refer to, which is the lingering feelings which persist after the “morally distressing” case has ended. As we deal with children and babies who are fragile, dependent, and may have life-long complications, the NICU and PICU are places where moral distress is likely to be frequent. How frequent it is, and what causes the situations most likely to lead to distress, where the questions that lay behind this systematic review.

They found 13 articles, of varying size and quality, (including one of ours); from the results of the systematic review article:

Common themes represented included disproportionate care, ‘aggressive’ use of technology, powerlessness, and communication around life and death issues. Interestingly, moral distress is generally reported as occurring because a provider feels she/he is ‘doing too much’….. The converse is rarely reported as causing moral distress, for example, deciding for palliative care in the face of uncertainty. Concepts of moral distress are expressed differently within nursing and medical literature.

One of their findings is the different ways in which moral distress is discussed in the articles, publications in the nursing literature frequently emphasize the subjective experience of the nurses, and the fact that they lack power and are having to provide interventions that they do not always agree with; they are sometimes portrayed as the victims of the aggressive care being perpetrated by the physicians. Whereas in the medical literature moral distress is described in terms of the objective situations that create confrontations or dilemmas. The reality is though, that physicians also experience moral distress (with about the same frequency as nurses), they also find themselves sometimes performing tasks and providing care which is against their own conception of what the best interest is for their patients.

What has been shown previously is that moral distress may lead to burnout, and decrease retention of staff. It is also probably unavoidable in intensive care, but we should, and could, work harder to minimize it, and minimize its impact.


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Neonatal nurses save lives, if you have enough of them.

In the UK an “intensive care” day for a newborn is defined as a day where the baby is intubated and ventilated, or is on non-invasive respiratory support (CPAP of non-invasive ventilation) AND parenteral nutrition, or on the day of surgery, or on the day of death, or a day when they have any of the following:

  • Presence of an umbilical arterial line
  • Presence of an umbilical venous line
  • Presence of a peripheral arterial line
  • Insulin infusion
  • Presence of a chest drain
  • Exchange transfusion
  • Therapeutic hypothermia
  • Prostaglandin infusion
  • Presence of replogle tube
  • Presence of epidural catheter
  • Presence of silo for gastroschisis
  • Presence of external ventricular drain
  • Dialysis (any type)

The next level of care is referred to as “high-dependency” and includes for example CPAP with full enteral feeds, or parenteral nutrition without positive pressure respiratory support.

The British Association of Perinatal Medicine standards state that on an intensive care day a baby should have a 1:1 nurse ratio, on a high-dependency day they should have 1 nurse per 2 babies.

A new publication from a group in the UK has found that in 2008 only 9% of intensive care days had 1:1 staffing, and in 2012 that had fallen to 6%, when examining data from 30 to 40 NICUs around the country. As you are all aware, the severity of illness of babies who would be classified as “intensive care” using the BAPM criteria varies hugely. In order to determine whether there is an impact of nursing ratios on outcomes, it is necessary to try to adjust for this severity. But just crudely, if the reduction of days of 1:1 ratio is because the babies are less sick (and someone thought they didn’t really need 1:1) then mortality should have fallen. In fact it increased. Over the years where the proportion of days with less 1:1 nursing was falling mortality increased from 4 out of every 100 babies receiving intensive care to 4.5, passing a peak of 5.3 in 2010 and 2011.

Of course the authors have much more sophisticated analysis than that, and after doing all the adjustments that they could, they calculate that, from a median mortality rate of 4.5, every time you decrease the proportion of 1:1 days by 10% you increase mortality by 0.6, that is, to 5.1, then to 5.7… An accompanying editorial says it all:

..there is already a sufficient body of evidence to justify a renewed focus on working towards achieving the national standards set for one-to-one nurse staffing in neonatal intensive care. If not now, when?

The data may not be directly applicable to other health care systems, where some of the roles of NICU nurses in the UK are covered by other professionals, in the UK, for example they do not have respiratory therapists, and it is the nurses who do the tasks that RTs do in our NICU. Nevertheless I am convinced that the same principle applies in North American NICUs, when the workload is higher, and we can provide fewer 1:1 nurse assignments, then infection rates are higher, and probably, mortality also.

I also think that maybe the BAPM should rethink their criteria. Does every child with an Umbilical Venous Line really need 1:1 nursing? A full term baby with hypoglycemia who has a UVC placed for glucose administrator would be classified as “intensive care” and would be supposed to have 1:1. A nurse could probably safely look after 2 babies whose only criteria for “intensive care” was the presence of a chest tube. If you could rationalize the criteria you would probably be able to put more pressure on the system to provide 1:1 for those babies that really need it.

On the other hand a baby who no longer needs parenteral nutrition, but who has just been extubated to CPAP would not be “intensive care” but really needs expert dedicated nursing at a high ratio to prevent re-intubation, and should maybe be considered “intensive care” if they are under 28 weeks for the first 48 hours at least.

I have said many times that I think the most important factor in mortality and morbidity of the extremely immature babies is the quality of the nursing care they receive. In order to give care of good quality, as this study shows, you need adequate quantity.

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Is your brain really necessary?

I remember years ago watching a BBC documentary (I think it was BBC) with the tabloid-type title “is your brain really necessary?” it focused on patients with severe hydrocephalus who had normal neurological examinations and normal intellect. One was, if I remember right, a university student, in geography or some-such, who had a cortical mantle thickness of about 1 cm.

A recent article, discussed by Neuroskeptic, has reported some new cases, and made ridiculous claims suggesting that this is evidence that our memories are stored in the cloud and accessed by magic (or some unknown electromagnetic wave particle).

A new case report in the Lancet is of a 62 year old with this MRI, a woman with apparently normal function:

Full-size image (104 K)

Which just shows again how little correlation there is between images and function, under some circumstances. Another one of those circumstances for example is patients with meningomyelocele:

This very recent article for example looked at young adolescents with meningomyelocele who were all shunted for hydrocephalus. The average IQ was about 1SD below controls. The study showed poor correlation between mantle thickness in most areas and IQ, and no correlation at all in some areas of the brain. This study also looked at gyrification, and at fine motor skills. There are a number of very interesting associations, which confirm that, in general, cerebral development is disturbed in meningomyelocele, and that the more disturbed it is, the more affected are fine motor skills. Some of the associations start to get complicated, but I just wanted to point out that the statistically significant correlations are interesting from a research point of view, but are not all that strong; as in many other situations, we should be very circumspect about making individual predictions of outcome from brain imaging findings.

A child with an antenatal diagnosis of meningomyelocele can have a range of developmental and neurologic challenges, but the degree of hydrocephalus and other findings on ante- or post-natal cerebral imaging do not closely predict their eventual function.

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Lactoferrin again, this time the human kind

Sherman MP, et al. Randomized Controlled Trial of Talactoferrin Oral Solution in Preterm Infants. The Journal of pediatrics. 2016.

This should be characterized as a pilot trial, as there were only 60 patients per group, and as a trial of prophylaxis against infections, you need many more than that to have adequate power (which is stated by the authors). The study was otherwise of high quality, and was the first clinical trial of this agent in human babies, so a pilot trial is quite appropriate. They used human recombinant lactoferrin, called talactoferrin, tLF (apparently manufactured by some helpful fungi), to try and prevent infections; enrolled babies received it on days 1 through 28 of life, the tLF dose was 150 mg/kg every 12 hours. Eligible babies were between 750 and 1500 grams birth weight. Basically tLF was safe, there were no adverse events related to the protein recorded. The rate of significant infections was 17% in the tLF group, and 33% in the controls. The rate of blood culture positive sepsis was 10% compared to 17%. These differences could be due to chance, in a study of this size, but they are suggestive of a possible real effect.

Sherman MP, et al. Randomized Control Trial of Human Recombinant Lactoferrin: A Substudy Reveals Effects on the Fecal Microbiome of Very Low Birth Weight Infants. The Journal of pediatrics. 2016;173, Supplement:S37-S42. This sub-study included 21 of the babies in the trial, and only in 2 NICUs not 3 as in the original trial. Stool was collected on day 21 and the microbiome analyzed using molecular techniques. There were differences between tLF and control babies, and also differences between the 2 hospitals. In NICU 2 the antibiotics in this group of babies were used for twice as long, and TPN continued for twice as long; NICU 2’s babies had much lower bacterial density than the other hospital. In addition, “tLF prophylaxis reduced the fecal composition of staphylococci to nearly undetectable levels. A reduction in staphylococci in the bloodstream and central-line infections in our VLBW infants was associated with this finding”.

This adds to the data supporting further large trials of lactoferrin, both talactoferrin and bovine lactoferrrin warrant investigation. A head to head trial afterward is probably too much to hope for, but, as tLF is likely to be immensely more expensive than bLF, it would be important to prove it more effective in order to buy it.

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RV function in BPD

Sehgal A, et al. Right Ventricular Function in Infants with Bronchopulmonary Dysplasia: Association with Respiratory Sequelae. Neonatology. 2016;109(4):289-96.

Babies with BPD frequently have some degree of pulmonary hypertension, which may lead to right ventricular dysfunction. Arvind Seghal and colleagues studied 18 infants with severe BPD and 10 preterms without at 36 weeks post-menstrual age. Multiple echocardiographic indices were measured to evaluate RV function, including tissue doppler indices. RV function was impaired in the infants with BPD, and correlated with the duration of respiratory support, 13 of the babies when home on oxygen.

Villeneuve A, et al. Echocardiographic Right Ventricular Pressure Ratio Correlates with Prolonged Oxygen Therapy in Patients with Moderate to Severe Bronchopulmonary Dysplasia. Annals of Pediatrics and Child Health. 2015;3(9). In a similar study from our hospital, we concentrated on measures of pulmonary hypertension, 29 babies with moderate or severe BPD were enrolled around 36 weeks of age. We found that the most predictive measure for prolonged oxygen therapy was the right ventricular pre-ejection period/ejection time ratio [RVPEP/RVET].

Evaluation of pulmonary hypertension and of right ventricular function can help to predict duration of oxygen therapy, and could perhaps be used  to screen patients for controlled trials of newer therapies such as sildenafil.

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