Roofthooft DW, et al. Limited effects of intravenous paracetamol on patent ductus arteriosus in very low birth weight infants with contraindications for ibuprofen or after ibuprofen failure. Eur J Pediatr. 2015:1-8.
In contrast to the previous study that I blogged about, this prospective cohort study of children who had failed ibuprofen, or who had contraindications to ibuprofen (but not iv paracetamol) shows very little evidence of a good effect. The practice in the Erasmus NICU (Rotterdam) was to give 2 courses of ibuprofen for the PDA if there was no contra-indication. Of the 33 infants there were 13 who did not get ibuprofen, and 20 who had previously had some exposure to ibuprofen and had either developed a contra-indication or had completed the 2 courses. All of the babies who had paracetamol after ibuprofen had no effect, and they all went to PDA ligation (except 2 who died). Of those who didn’t have ibuprofen first 6 of them had a response, and the other 7 had either a ligation (5), or were able to get ibuprofen (2), to which they responded.
This is all starting to get messy.
When I use the word “response” it means here that there was a temporal relationship between the drug and the PDA constricting. I don’t know what the natural history of the PDAs in those babies would have been if they had not had the drug in question. We need a placebo controlled trial. Preferably with echos performed by blind individuals (you know what I mean) as well as analyzing important clinical outcomes. And/or a comparative trial, with the same features.
It should be noted that some preparations of paracetamol for IV use contain propylene glycol, which as I noted yesterday is one of those potentially toxic excipients that should be avoided if there is an alternative. One preparation used in Europe has almost as much propylene glycol as it does paracetamol (800 mg for every 1000 mg), which gives high enough serum concentrations to be able to study the pharmacokinetics of propylene glycol in preterm infants. the preparation of paracetamol used in this study, in contrast, contains Mannitol, as well as a bit of HCL, NaOH, some cysteine and some dibasic phosphate for good measure. The version on sale in the USA, which has a different trade name (Ofirmev rather than Perfalgan), but seems to be exactly the same, has nearly 4 grams of Mannitol for each gram of paracetamol (or as we call it, acetaminophen).
Which sounds like a lot.
I have used Mannitol in the PICU for reducing intracranial pressure, I don’t know if that is a good idea in a small preterm baby. The dose used for ICP reduction in the PICU is of the order of 1 g/kg. Mannitol is also used as a diuretic, in a lower dose of around 200 mg/kg or so. An iv dose of 15 mg/kg of acetaminophen would give about 54 mg of mannitol, or a total of 216 mg in a day.
Which is a lot.
I’m starting to get more and more worried about all these things, I’m glad the ESNEE consortium is working on this issue, we have to find ways to produce medications with fewer excipients, and ones that are known to be innocuous.
It is even possible that the differences in efficacy of paracetamol in the different studies is because some of them contain a diuretic, mannitol (like the study by El-Khuffash and others), and some do not.
Since the first report on surprising effect of Paracetamol on PDA in preterm infants, we have used paracetamol in various clinical situations. We also have done a study in the similar lines of usage in conditions where Ibuprofen is contraindicated. I am aware of the various RCTs published showing benefits of Paracetamol. But, having used Paracetamol in many cases because of lack of options I still don’t see this treatment as very effective. However, there is one group of patients who responded well to Paracetamol. The infants where PDA is significant leading to ventilator dependency and decision has been made to close the PDA surgically responded well to Paracetamol. Out of 9 infants, PDA was closed in 6 infants. They all were more than 3 weeks old and had similar ductal echocardiographic features. As suggested by the original case report, Paracetamol may be effective in oxygen dependent infants with PDA. This clearly needs further evaluation.
On the other note, there is an increasingly worrying trend in the use of Paracetamol as the first line instead of the standard treatment. This might put these vulnerable infants at risk of significant complications.
Dr Praveen Venkatagiri
Neonatal Care&Research Institute Neonatal network
From your link – “What is known: • The ductus arteriosus fails to close after birth in 30 to 60 % of prematurely born neonates and is a significant cause of morbidity and mortality in these infants. •”
I would be interested in your thoughts on the contemporary evidence supporting this conclusion.
Using a endpoint of PDA closure, I can understand the concerns around acetaminophen efficacy in various clinical scenarios. But if you believe closure should be the endpoint to avoid significant morbidity and mortality, ligation would be the appropriate option in most PDA afflicted premies – a conclusion challenged by many.
Ray Sato, M.D.
Tacoma, Washington (USA)