The acid test

Posted on 7 February 2013 by Keith Barrington

As well as avoiding putting anything untested in the intestinal tracts of preterm babies, we should also leave alone their intestinal function. My good friend Sanjay Patole has published, with his group of systematic reviewers in Perth, a review of the effects of gastric acid secretion blockers on the incidence of NEC. There were only 2 informative studies found, both focusing on histamine receptor blockers, and the analysis showed a substantial association between the use of this class of agent in the preterm and the occurrence of necrotising enterocolitis. Both the studies were observational, one case control, one  a prospective cohort. The size of the effect differed greatly between the 2 studies, which is not surprising for 2 observational studies especially with a different structure, but the effect size was substantial in each of the studies. More K, Athalye-Jape G, Rao S, Patole S: Association of inhibitors of gastric acid secretion and higher incidence of necrotizing enterocolitis in preterm very low-birth-weight infants. American journal of perinatology 2013(EFirst).

Gastric acid is there for a reason, as well as aiding in digestion it kills a lot of ingested organisms, so blocking it increases infection risk, and, as for NEC, presumably permits colonization with more pathogenic bacteria involved in the pathophysiology of NEC, but it is possible that other adverse effects of histamine receptor blockade are involved also.

A reminder that other adverse effects of acid blockade are systemic infections, (also see here) and increased mortality. They also seem to interfere with absorption of calcium, iron and vitamin B12. In older infants histamine blockers cause agitation and headache, PPI agents increase chest infections in asthmatic children, and they do not improve apnea or bradycardia in preterm infants, nor improve symptoms of GER in older infants.

So before blocking acid production we should really think of what clinical benefits we expect to counterbalance these known adverse effects… which sounds a lot like just good basic medical principles to me.

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Weekly Updates #22

Posted on 6 February 2013 by Keith Barrington

Milstone AM, Elward A, Song X, Zerr DM, Orscheln R, Speck K, Obeng D, Reich NG, Coffin SE, Perl TM et al: Daily chlorhexidine bathing to reduce bacteraemia in critically ill children: A multicentre, cluster-randomised, crossover trial. Lancet 2013(0). Nearly 5000 Children more than 2 months old who were admitted to the PICU for more than 2 days were randomized to either get a bath with chlorhexidine every day (or being wiped all over with a chlorhexidine cloth) or control. Actually it was the ICUs that were randomized and had periods with and without chlorhexidine. There was an almost significant reduction in sepsis with the ITT analysis, and a just significant reduction with the ‘actually treated as they were supposed to be according to the way they were randomized’ analysis. An accompanying editorial (Toltzis P, Goldmann D: Rethinking infection prevention research. Lancet 2013(0). Suggests that such trial should be done only when all the quality control initiatives have reduced central line infection rates to minimal levels. I am not so sure; despite the best efforts using evidence based interventions currently there are still substantial variations between hospitals. We need further evidence based interventions and good trials to show us what to do next.

Chong E, Reynolds J, Shaw J, Forur L, Delmore P, Uner H, Bloom BT, Gordon P: Results of a two-center, before and after study of piperacillin-tazobactam versus ampicillin and gentamicin as empiric therapy for suspected sepsis at birth in neonates <1500g. J Perinatol 2013. I think this is a Very Bad Idea. Giving broad spectrum antibiotics that are not indicated to infants with negative cultures for reasons that are questionable (one of the reasons given for changing empiric therapy of early onset sepsis was an increase in resistant organisms causing late onset sepsis). They didn’t show an adverse effects, but just wait a while! We should be focussing on giving fewer antibiotics, with narrower, appropriate, spectra, for shorter periods. And not giving them at all unless there is an indication.

Berardi A, Rossi C, Lugli L, Creti R, Bacchi Reggiani ML, Lanari M, Memo L, Pedna MF, Venturelli C, Perrone E et al: Group b streptococcus late-onset disease: 2003-2010. Pediatrics 2013, 131(2):e361-e368. An epidemiologic study from Italy of late onset GBS. Being preterm increased the risk, as we already know, there is a high incidence of serious brain lesions associated with late onset disease. If the mother had intrapartum antibiotics, the disease tended to be milder, and to present later.

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Leave my gut alone!

Posted on 5 February 2013 by Keith Barrington

Many things that we put in the intestines of preterm infants increase the risk of necrotising enterocolitis, including xanthan gum, kayexalate, and now, it seems, gastrografin.

A group from Vienna performed a masked RCT in 96 very low birth weight, preterm infants who were administered either 3 mL/kg of a hypertonic contrast agent (gastrografin) diluted 1:3 via the NG tube in the first 24 hours of life which they say gave 9 mL/kg of liquid, or the controls who got 9mL/kg of water. (Now I am not a mathematician, but I would have thought that 3 mL of gastrografin diluted 1:3 should give you 12 mL of liquid, not 9; I guess the authors and the reviewers aren’t mathematicians either!) Haiden N, Norooz F, Klebermass-Schrehof K, Horak AS, Jilma B, Berger A, Repa A: The effect of an osmotic contrast agent on complete meconium evacuation in preterm infants. Pediatrics 2012, 130(6):e1600-1606.

The idea behind this is that delayed meconium passage is associated with bad outcomes (delayed feeding intolerance, and in at least 1 study with NEC) and that therefore if you can speed up meconium clearance, maybe you can reduce those bad outcomes. The primary outcome of the study was time to clearance of meconium, which is rather questionable as an outcome of clinical significance. They also recorded other secondary outcomes, feeding tolerance, duration of hospital stay and NEC. The first thing to note is that they enrolled 96 babies out of 789 eligible infants, this immediately makes you wonder how representative the babies in the study were. The second thing to note is that the ‘intention to treat’ analysis showed no difference in anything. The only differences were in the ‘per protocol’ analysis (when they re-analyzed the data after excluding 18 infants with protocol violations) which showed a much shorter NICU stay in the gastrografin group, and some evidence of achieving full feeds faster. Here again there are some weird findings, the duration of hospital stay was as low as 4 days. So some babies in Vienna who weigh less than 1500 g at birth and are less than 32 weeks can go home in 4 days!! I don’t know how they do that. They are also clearly very fixated on stools, many of the babies in both groups also got glycerine suppositories, and in addition the babies averaged more than 1 enema each before discharge.

But most importantly, there were 8 cases of NEC in the gastrografin group vs 3 in the controls, and there were 5 NEC deaths in the gastrografin group. I would suggest that this is not a good thing to do!

Also just because slow clearance of stools might be associated with other signs of poor intestinal function and maybe with NEC, does not mean that enhancing meconium passage will improve feeding tolerance or NEC. The same authors have already investigated giving dilute glycerine enemas to their babies (Haiden N, Jilma B, Gerhold B, Klebermass K, Prusa AR, Kuhle S, Rohrmeister K, Kohlhauser-Vollmuth C, Pollak A: Small volume enemas do not accelerate meconium evacuation in very low birth weight infants. Journal of Pediatric Gastroenterology & Nutrition 2007, 44(2):270-273.), they gave the enemas every day until all the meconium was gone, and in the controls they left them alone. They showed no benefit of the intervention, even when they analyzed as ‘per protocol’ rather than intention to treat.

Which brings me back to the new study, why were the authors allowed to emphasize the non-ITT analysis in the abstract and to present this as a study showing decreased length of stay? In a small pilot study with a lot of exclusions, I am not averse to presenting a ‘per protocol’ analysis as a secondary suggestive analysis that might warrant a future study with more strict enforcement of a protocol. But the deviations from the protocol might well be a result of the intervention (indeed in this trial the exclusion was commonly because of vomiting after the large volume of fluid) so it is essential that the primary analysis which is presented is the intention to treat, only that way can a true estimate of the use of an intervention in the real world be estimated.

Finally a word about NEC prevention. I was surprised recently by an editorial in the Journal of Perinatology (Swanson JR: Necrotizing enterocolitis: Is it time for zero tolerance? J Perinatol 2013, 33(1):1-2) which made the following statement : ‘Experts have suggested that we could cut the incidence of NEC in half if neonatologists would just do four things: (1) practice as a group (instead of individuals), (2) promote breast-milk feeding and start it as trophic feeds early in life, (3) have a standardized feeding advance that is gestational age-based and (4) minimize the feeding intolerance episodes with liberal use of glycerin.’

A number of things bug me about this, first of all the ‘call to authority’ is not what we should be doing as scientists, secondly even if experts suggest this it had better be based on some evidence, which it clearly isn’t, and finally the reference given doesn’t even say these things! It NEVER mentions glycerin. (or indeed mentions working as a group rather than individuals, nor does it mention trophic feeds) Indeed the review article that the editorial references does refer to the data regarding having a feeding protocol and using more breast milk. It also neglects to mention the most effective intervention that we have for prevention of NEC: Probiotics.

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Nurses matter!

Posted on 4 February 2013 by Keith Barrington

There are a lot of qualitative studies that make huge generalizations from the very tiniest of samples; on the other hand, some studies of values and wishes of parents and patients can be valuable, and can be well studied only with qualitative techniques.  One example of the latter is a new study from 3 centers in France. (Guillaume S, Michelin N, Amrani E, Benier B, Durrmeyer X, Lescure S, Bony C, Danan C, Baud O, Jarreau P-H et al: Parents’ expectations of staff in the early bonding process with their premature babies in the intensive care setting: A qualitative multicenter study with 60 parents. BMC Pediatrics 2013, 13(1):18.) They interviewed 30 mothers and 30 fathers with very preterm babies in NICU. It is worth a read (freely available on BMC Pediatrics) and I will quote in its entirety the conclusion section of the abstract:

‘At birth and during the first weeks in the NICU, the creation of a bond between mothers and fathers and their premature baby is rooted in their relationship with the caregivers. Nurses’ caring attitude and regular communication adapted to specific needs are perceived by parents as necessary preconditions for parents’ interaction and development of a bond with their baby. These results might allow NICU staff to provide better support to parents and facilitate the emergence of a feeling of parenthood.’

Another study points out the importance of nurses attitudes to what happens in the NICU and to parental experiences. A US study, from an urban center, questioned nurses and mothers about things like whether parents should participate in care of the baby and whether they should be encouraged to be present and to do kangaroo care. (Hendricks-Munoz KD, Li Y, Kim YS, Prendergast CC, Mayers R, Louie M: Maternal and neonatal nurse perceived value of kangaroo mother care and maternal care partnership in the neonatal intensive care unit. American journal of perinatology 2013(EFirst).) I was very surprised by the results. Only 21% of nurses strongly agreed that parents should be encouraged to be present in the NICU, and only 67% of mothers! Knowledge and attitudes towards Kangaroo Care were also poor, and differed greatly between nurses and mothers. The authors identified many barriers to creation of maternal care partnerships that need to be overcome.

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Preventing Stillbirth

Posted on 4 February 2013 by Keith Barrington

A new observational study looking at the causes of Stillbirth in the UK (Gardosi J, Madurasinghe V, Williams M, Malik A, Francis A: Maternal and fetal risk factors for stillbirth: Population based study. BMJ 2013, 346:f108.) identifies potentially modifiable factors that were associated with stillbirth after 24 weeks; they were maternal obesity, smoking, and most importantly intra-uterine growth restriction. ‘195 of the 389 stillbirths in this cohort had fetal growth restriction, but in 160 (82%) it had not been detected antenatally.’

One of the reasons for the increase in prematurity in the developed world is an increase in medical indicated preterm deliveries, many of which are for concerns about fetal status. It looks like there is still much to do, to accurately screen and diagnose fetal growth restriction and develop strategies to avoid stillbirth, and do this without further increasing prematurity rates.

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Iron therapy for anemia of the preterm; now I’m confused!

Posted on 29 January 2013 by Keith Barrington

I thought I knew, sort of, what to do about iron supplementation in the preterm. Preterm babies outgrew their iron supply, there isn’t very much in breast milk, and you need to supplement to minimize the appearance of anemia of prematurity.

There was previously a trial which compared transfusions and iron status among 204 preterm infants (<1300g birth weight) who were randomized to start iron as soon as they were tolerating 100 mL/kg/d of milk, or to wait until they reached 61 days. The babies received 2 mg/kg/d at first and it was increased to 4 if the hematocrit was below 30. That trial showed fewer transfusions and less iron deficiency with early supplementation. They also published long term follow up, although not powered for that outcome, the 164 babies who were studied (most, 85%, of the survivors) tended to have better outcome in the early group.

There is also a Cochrane review showing improved hematocrits with routine enteral iron prophylaxis in the preterm.

Now a new trial has been published which compared giving 2 mg/kg/day of iron, started when the babies were tolerating 120 mL/kg/d of milk, to a multivitamin preparation without iron. The babies were 150 VLBW (<1500g) infants and the primary outcome was hematocrit at 36 weeks, transfusions were also noted. They note that the control group were receiving around 2 mg/kg/d already in the breast milk fortifier that they were adding to the breast milk. There were no differences in the results between the groups. The authors note that they have a ‘liberal’ transfusion policy, which they say is based on the previous evidence regarding ‘long-term benefits of maintaining higher hemoglobin levels in extremely low birth weight (<1000 g birth weight) infants’. What they don’t tell us is how many transfusions the infants received prior to entering the study. That info would have been helpful: a blood transfusion or two would have given substantial amounts of iron to the babies, and could be a reason for not finding a difference between the groups. that would make it less easy to extrapolate the findings to other NICUs, such as ours, where we have not liberalized our transfusion guidelines.

And just how good is that data about long term benefits of liberal transfusion? Although the authors reference the PINT trial and the Cochrane review, neither of those sources show an improved long term outcome! The PINT study showed slightly better 18 month Bayley scores, differences consistent with chance, p value about 0.09, and only when they looked at the proportion of babies less than 85 (not 70 which was pre-specified as the outcome of interest) did they show a difference that looked more convincing. The other trial that has reported some long term outcomes was the trial by Ed Bell and others, who followed only 56 of their 100 patients to early school age, and some measures of cognitive function were better in the liberal transfusion compared to the conservative group.

In summary I do think it seems possible that some outcomes are better with a higher transfusion threshold, but it certainly isn’t definite, and before using a lot more blood transfusions we should get better data. There are other trials in the works.

In the meantime, with a more restrictive transfusion policy, I think continuing to give iron supplementation early, in addition to what we have in the breast milk fortifier still makes sense.

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Not only Neonatology

Posted on 26 January 2013 by Keith Barrington

I really appreciate the writings of Atul Gawande, his articles and his books: ‘Complications’ ‘Better’ and ‘The checklist manifesto’.

I just saw a TED talk he gave in March last year, 19 minutes on how to fix medicine. Link here. I think a lot of his ideas can be used in the NICU, and the very complex care that we sometimes give there.

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Helping Babies Breathe is a Really Good Idea

Posted on 24 January 2013 by Keith Barrington

Two new articles showing that ‘Helping Babies Breathe‘ training really works.

Msemo G, Massawe A, Mmbando D, Rusibamayila N, Manji K, Kidanto HL, Mwizamuholya D, Ringia P, Ersdal HL, Perlman J: Newborn mortality and fresh stillbirth rates in tanzania after helping babies breathe training. Pediatrics 2013.

Goudar SS, Somannavar MS, Clark R, Lockyer JM, Revankar AP, Fidler HM, Sloan NL, Niermeyer S, Keenan WJ, Singhal N: Stillbirth and newborn mortality in india after helping babies breathe training. Pediatrics 2013.

Both used a before and after design, and both showed that stillbirth rates were lower after the HBB training. That may seem strange at first, how could stillbirths be reduced? Of course the answer is that after training, the health workers realize that some babies that were classified as stillbirths previously (either there wasn’t an attempt to resuscitate them or after a failed resuscitation they were called a stillbirth) are now being successfully resuscitated.

Wally Carlo has already shown that the infants who are resuscitated do well in the long run, in a study using a very similar resuscitation program, those babies who received assisted ventilation at birth had long term outcomes the same as the comparison group who had not resuscitation.

 

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Are babies and children so different?

Posted on 24 January 2013 by Keith Barrington

Matteo Fontana and his collaborators have just published an interesting paper evaluating modes of death in the PICU and NICU at my hospital, Annie Janvier is, of course, the senior author (Fontana MS, Farrell C, Gauvin F, Lacroix J, Janvier A: Modes of death in pediatrics: Differences in the ethical approach in neonatal and pediatric patients. The Journal of pediatrics 2013). They defined modes of death using the same schema that Annie has published previously (with Eduard Verhagen): as follows (1) children who died because admission to an ICU was withheld; (2) children who died despite active cardiopulmonary resuscitation (CPR); (3) children who died while receiving mechanical ventilation, without active CPR; (4) children who died after withdrawal or withholding of LSI who were extremely sick and expected to die and (5) children who died after withdrawal and withholding LSI of infants who were stable, because of prediction of a poor quality of life.

In both units the proportion of patients who died during CPR was low. There was in contrast a very large difference in the proportion of patients who died during on-going intensive care, but without CPR (51% of deaths in the PICU and 5% in the NICU), and in the proportion who died after withdrawing or withholding intensive care for quality of life reasons (16% of deaths in the PICU and 53% in the NICU).

Why is this? Why do we frequently redirect care in the NICU when usually all we have are indications of increased probability of impairments, with an enormous amount of uncertainty, while in the PICU, even when the children are known to already have the same sort of impairments, intensive care continues to the very end? Maybe we have something to learn from each other.

I note that there will be an editorial accompanying this article when it is published, I guess I will be re-blogging at that point!

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Weekly Updates #21

Posted on 23 January 2013 by Keith Barrington

Van Hus JW, Jeukens-Visser M, Koldewijn K, Geldof CJ, Kok JH, Nollet F, Van Wassenaer-Leemhuis AG: Sustained developmental effects of the infant behavioral assessment and intervention program in very low birth weight infants at 5.5 years corrected age. The Journal of pediatrics 2013(0). Long term follow up of an RCT of an early intervention program for preterm infants. about 180 infants were randomized to post-discharge intervention or control, which lasted for 6 months. At 5.5 years there appear to be significant benefits form the program among the 136 infants reviewed, fewer babies with an IQ below 85, as well as better motor skills. Most programs have not shown benefits persisting this long in the past.

Jiang P, Smith B, Qvist N, Nielsen C, Wan JM-F, Sit W-H, Jensen TK, Wang H, Sangild PT: Intestinal proteome changes during infant necrotizing enterocolitis. Pediatr Res 2013. This proteome analysis of parts of bowel from preterm infants with NEC which were necrotic and parts which were adjacent yet unaffected, showed expression of heat-shock proteins was enhanced, and several other proteins were also affected. This might be important, or it might not, I am not sure how the expression of such proteins in necrotic parts of bowel is affected just by them being necrotic… It would be nice to know how they were affected as the necrosis was progressing, but that of course is impossible.

Bharadwaj SK, Vishnu Bhat B: Therapeutic hypothermia using gel packs for term neonates with hypoxic ischaemic encephalopathy in resource-limited settings: A randomized controlled trial. Journal of Tropical Pediatrics 2012, 58(5):382-388. Therapeutic hypothermia for term infants with encephalopathy can be done cheaply and safely. This study shows that even using cheap simple methods it is still effective; in an RCT of 130 babies, survival without severe disability (at 6 months) was better when the babies where cooled with gel packs than the controls. Asphyxia is a major cause of death and disability in the developing world, this cheap intervention could make a big difference.

van den Broek MPH, Rademaker CMA, van Straaten HLM, Huitema ADR, Toet MC, de Vries LS, Egberts ACG, Groenendaal F: Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: Efficacy, safety and dosing. Archives of Disease in Childhood – Fetal and Neonatal Edition 2013. Some centers use lidocaine frequently as an anticonvulsant in the newborn. This study documents the reduced clearance of lidocaine under hypothermia, and does suggest that it is effective. We really need better studies of comparative effectiveness of anticonvulsants and of long term outcomes.

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