Influenza is crap. Especially when you get it even though you have had the vaccine! The break in blog posts has been due to an assortment of viral illnesses, culminating in the “flu” and then followed by spring break, followed closely by a period of very intense clinical service.

There are a few things to post about, so I will probably post a few shorter posts over the next few days, rather than my usual longer dissections of published neonatal research, at least if I can restrain myself.

One of the things that happened during my service was a cluster of cases (3) of sepsis with shock and disseminated intravascular coagulation (caused by 3 different organisms!) the cases had different clinical backgrounds also. The mini-cluster sent me to the literature to see what is new in coagulation in the newborn and made me think about the recent history of the trials of activated protein C therapy, and other potential therapies for sepsis.

For anything to do with neonatal hematology I always look in my database for articles by Dr Robert Christensen (he publishes a lot of other quality non-hematological research also), which led me to an article I had downloaded a while ago Christensen RD, et al. Reference intervals for common coagulation tests of preterm infants. Transfusion. 2014;54(3):627-32 This is a very useful article detailing the normal values in preterm infants (at least from cord blood sampling). One thing that became clear to me during this review was the variability in some measures (in particular the aPTT) from one lab to another, depending on reagents and the details of lab protocols. One of the other things which became clear to me is that I was right to minimize the role of d-dimers in diagnosis of DIC in the newborn, values are enormously variable among healthy infants (which I was led to believe as a young neonatal fellow was due to reduced clearance of d-dimers by the neonatal, especially preterm, liver; which I cannot find evidence to support at present).

Another useful review article is this : Rajagopal R, et al. Disseminated intravascular coagulation in paediatrics. Arch Dis Child. 2017;102(2):187-93. With links to other articles and a relatively brief review of various aspects of the literature.

There are published scoring systems for diagnosing DIC in adults, they don’t seem to work very well in children, and I don’t think they have been tested in the newborn.

I found published guidelines on how to treat DIC, which mention newborns, but are based mostly on expert advice. The main lines of all the guidelines seem to be :

• Treat the underlying cause (which I think could be classified as a “no-brainer”)
• Don’t treat the numbers on coagulation tests, but only for bleeding, in which case FFP is good for most things, and cryoprecipitate is good for fibrinogen.
• In bleeding patients use FFP with a dose of at least 15 mL/kg, and 20 to 25 is often needed for the first dose to approach normal values, multiple treatments are often needed.
• Transfuse platelets for a count < 50,000 in infants with DIC at risk of bleeding, otherwise platelet counts which are much lower can be tolerated
• In DIC with thrombotic complications consideration of heparin (old-fashioned unfractionated), but with a low standard dose, rather than trying to increase the aPTT.
• More research is needed… (could be classified as “complete absence of cerebral tissue”)

One thing that often happens in sepsis is a consumption of clotting and anti-clotting factors, including a consumption of protein C. When protein C levels become very low you can get purpura fulminans, with microcirculatory occlusion leading to skin infarcts and hemorrhage, which can lead to long term disability among survivors. replacement of protein C (usually with FFP, but sometimes with protein C concentrates) has been reported.

Activated protein C has various non-clotting functions as well, interacting with several immune related phenomena (the vague statement reflects the vagueness of my knowledge in this area), early clinical studies of activated protein C replacement suggested a benefit in sepsis, so a number of clinical trials followed. Although the treatment was initially approved by the previously conservative FDA, the evidence base was quite limited, follow up studies have shown

1. No benefit on survival, or other important outcomes in adults with sepsis
2. No benefit and a possible increase in bleeding complications, particularly intracranial bleeding in the very young (<60 days of age) in children with sepsis.

At this point any other ongoing studies were stopped, and the product (also known as drotrecogin alpha) was taken off the market.

Protein C concentrates, which are available in some parts of the world for treatment for congenital protein C deficiency, have occasionally been tried in sepsis with DIC, but are of uncertain utility. Infants with purpura fulminans or DIC as a complication of sepsis will usually have a whole range of clotting, and anticoagulation factors, consumed, FFP is probably a more useful treatment than protein C concentrates.

When drotrecogin alpha was taken off the market there was a European trial one third of the way through completion, a factorial 2×2 trial of the “drot-” stuff and steroids, in this case a combination of hydrocortisone (50 mg q6h) and fludrocortisone (50 microg daily). The investigators decided to continue with just the steroids versus placebo comparison. The results of that steroids versus no steroids comparison have now been published. Those results showed a significant survival benefit of steroids compared to control; 90 day all cause mortality decreased from 49% to 43% with the combined steroid regime. Interestingly in the same issue of the FPNEJM another, Australian and New Zealand trial was published. This trial compared 200 mg per day of hydrocortisone to placebo in adults with sepsis, mortality at 90 days was no different between groups (29% placebo, 28% steroids). Other secondary outcomes were not different between groups, but tended to favour the steroids, in particular a somewhat shorter duration of assisted ventilation (6 days instead of 7).

I don’t know if the differences between the results of these 2 high-quality trials is because of the fludrocortisone in one trial, or the higher baseline mortality in that trial, but there are clearly still uncertainties to be addressed with regard to steroid supplementation in adults with sepsis, and clearly even more questions with regard to newborns.

Also interacting with the protein C cascade is pentoxifylline, a TNF inhibitor which has been shown to increase protein C levels in sepsis, and might improve coagulation profiles in septic neonates.  A multi-center clinical trial is currently underway in Australia (and hopefully soon in Canada) to determine if this molecule might improve clinical outcomes, I think it might possibly improve outcomes specifically among infants with DIC.

The outcomes of the babies I have treated recently have been very variable, and long term impacts are important, prevention of neonatal sepsis, especially among the highest risk groups, the most immature babies, is a priority for the future of our discipline.