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Has the Magic Bullet to Prevent Kernicterus Been (Re)Discovered?




As the saying goes "What is old is new again" and that may be applicable here when talking about prevention of kernicterus.  In the 1990s there was a great interest in a class of drugs called mesoporphyrins in the management of hyperbilirubinemia.  The focus of treatment for many years had been elimination of bilirubin through the use of phototherapy but this shifted with the recognition that one could work on the other side of the equation.  That is to prevent the production of bilirubin in the first place.

Tin mesoporphyrins (SnMP) have the characteristic of being able to inhibit the enzyme hemo oxygenase quite effectively. jp2013104f3th By achieving such blockade the breakdown of heme to carbon monoxide and biliverdin (the precursor of bilirubin) is inhibited.  In so doing, the production of bilirubin is reduced making one less dependent on phototherapy to rid the body of elevated levels.  So simple and as you might imagine a good reason for there to have been significant interest in the product.  One article by Martinez et al entitled Control of severe hyperbilirubinemia in full-term newborns with the inhibitor of bilirubin production Sn-mesoporphyrin. was published in 1999 and demonstrated that infants with severe hyperbilirubinemia between 48-96 hours could have their need for phototherapy eliminated by use of the product compared to 27% of the infants in the control group needing treatment.  Additionally, total bilirubin samples were reduced from a median of 5 to 3 with the use of one IM injection of SnMP.  This small study was hampered though by inability to really look at adverse outcomes despite its effectiveness.  What has been seen however is that SnMP if given to infants who are then treated with white lights can create a rash which is not seen however when special blue light is employed.

Two other studies followed exploring the use of SnMP in cases of severe hyperbilirubinemia in term infants and were the subject of a Cochrane review in 2003.  The conclusions of the review essentially became the death nell for the therapy as they were as follows.

"...may reduce neonatal bilirubin levels and decrease the need for phototherapy and hospitalization. There is no evidence to support or refute the possibility that treatment with a metalloporphyrin decreases the risk of neonatal kernicterus or of long-term neurodevelopmental impairment due to bilirubin encephalopathy... Routine treatment of neonatal unconjugated hyperbilirubinemia with a metalloporphyrin cannot be recommended at present."

The literature after this basically dries up, that is until this month when a paper emerges that is best described as a story of mystery and intrigue!

Prophylactic Use of SnMP From 2003 Published in 2016!

This paper as you read it almost seems like a conspiracy story.  The paper is by Bhutani et al (as in the nomogram) Clinical trial of tin mesoporphyrin to prevent neonatal hyperbilirubinemia.  The study set out to answer a different question than had been previously studied.  The question here was, if you provided a single IM dose of SnMP to infants who were at or above the 75%ile on the risk nomogram, could you prevent the need for phototherapy or exchange transfusion as the primary outcome.  Secondarily, the authors truly wanted to demonstrate safety of the product and planned on recruiting 800 patients per arm in the study.  The study appeared to be well planned and as with many studies had a safety monitoring committee which was to do interim analyses.  After the first analysis the FDA became involved and recommended studies to look at a prophylactic versus therapeutic approach.  Due to the interim analysis the study had been halted and after the FDA made their suggestion the study was simply never restarted as future studies were planned to look at the effectiveness and safety of the two approaches.  The authors state that they planned on reporting their results in 2006/7 but elected to wait until long term data emerged.  Now finally 9 years later they decided to release the results of the partially completed study.  The story around this study I find as interesting as the results they obtained!

So What Happened?

Before closing the study they managed to recruit 87 into the intervention arm and 89 into the placebo group and lost none to follow-up.  One dose of SnMP had a significant effect on the trajectory of curves for bilirubin production as can be seen in the first figure.

Fig 1


The graph below demonstrates what percentage of patients had a bilirubin level above 220 umol/L (12.9 mg/dl) after the single injection of SnMP (black bars) compared to placebo (white bars).

Fig 2

What can we do with these results?

It would be tough to argue anything other than this being an effective treatment to prevent significant hyperbilirubinemia.  Unfortunately, like many studies that were never completed this one remains underpowered to conclusively demonstrate that the use of SnMP is safe in both the short and long term periods.  The absence of such data make it very difficult to recommend SnMP as standard of care.  One has to add to this that while we have evidence to show it reduces the rate of rise of bilirubin, what we don't know is whether in a larger study the incidence of bilirubins > 425 umol/L or the need for exchange transfusion might be reduced.  If this were the case, it would make for a compelling argument to try SnMP.

That is the approach for standard of care though.  In the setting of a patient with a known blood group incompatibility who was at high risk for exchange transfusion, if they received IVIG and the bilirubin continued to climb might there be a role here?  I would tend to say yes if we could get our hands on some.  The authors by sharing this data have shown the medication is effective in doing what it is supposed to do.  Given that at least in our centre all of our lights are of the new variety, the risk of rash would be nonexistent.  The risk for kernicterus or at least an exchange transfusion though would not be minimal so if we have this in our toolbox I would after weighing the risks opt to give it.

I certainly wonder if there are places out there who have used it and if so what is your experience?

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Interesting post!

Given that bilirubin encephalopathy is a common problem in many parts of the world where either light therapy or exchange transfusion is possible, it is a bit strange that this drug has not been more researched. 

Was the rash considered a serious side-effect? Is this drug at all available (for other indications), for example in adult medicine?

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I would not consider the rash a serious side effect.  I am baffled as you are as to where the research went on this medication.  I am also curious if there are places it is still available to help treat those intractable cases of rising bilirubins

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