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. 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.
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).
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?
I have been mulling over this piece for some time. In my own practice I have long questioned the role for standard phototherapy (the equivalent of a single light source) vs intensive phototherapy (delivering >30 microwatts/cm2/nm and usually two light sources) when treating jaundice for all patients. I have bolded that last part to emphasize that I am not just talking about newborns with severe hyperbilirubinemia but rather all infants with treatable jaundice based on local treatment curves such as shown in the CPS and AAP statements.
When newborns are only 30 – 50 micromol/L above the treatment threshold as an example, I will see standard phototherapy ordered or after initiating treatment with intensive phototherapy as the level approaches no treatment required you will see people switch to standard phototherapy again. Why is that and does it make sense?
The rationale for using less intensive phototherapy has been to minimize side effects. Historically, these were retinal damage (hence the eye covers), electrolyte disturbances, increased insensible water loss and occasionally rashes. I use the word historically as they for the most part are no longer relevant today provided a narrow spectrum LED light source is utilized which is the technology used in most modern phototherapy light sources now. Backing up this claim, in 2008 Dr. Maisels, showed that in preterm infants receiving LED based light there were no increases in transepidermal water loss. By limiting the wavelength of light emitted to 430 – 490 nm and avoiding the infrared wavelengths. Whether the concern exists with respect to retinal effects is tough to say for sure so continued precautions with eye covers are recommended.
Go Big or Go Home
If there is little harm to phototherapy then is there a reason to use more? The effectiveness of phototherapy is generally based on three things. The first is the proximity of the light source to the patient (< 15 cm is ideal), the second is the intensity of the lamp and the third is the surface area covered. If you are using a single focused spot and covering only 15- 20% of the body you are missing out on a lot of skin that could be helping to lower an infants bilirubin more rapidly. As I see it, if there is little harm in giving phototherapy and the rate of bilirubin decline is faster with better phototherapy, why would you use anything less than intensive using two light sources? Also from a developmental care point of view, less time under the lights means more time for skin to skin and that is always a good thing.
Phototherapy and DNA damage
What prompted me to write this piece actually was the following paper Jaundice, phototherapy and DNA damage in full-term neonates by Ramy N et al from November of 2015. In this paper the authors used a validated measure of DNA damage and assessed infants both before and after phototherapy. Thirty six newborns with jaundice were compared to 30 controls. The results are shown in the following figure.
Figure B demonstrates that prior to initiation of phototherapy the extent of DNA damage in tested cells is no different whether you are jaundiced or not. In essence bilirubin is not toxic to cells which also makes sense knowing that bilirubin has antioxidant properties and hence one would think it might be protective against DNA damage. It is figure C and D that provide the most interesting information. Figure C demonstrates that phototherapy (conventional and intensive groups combined) leads to an increase in DNA damage. Figure D is important in that it illustrates that comparing conventional and intensive phototherapy groups there is no difference in rates of DNA damage. This would indicate that more intensive phototherapy is not hazardous to cells.
What was noted in the end though is what is most important here. As expected the duration of phototherapy differed between the two strategies. Infants in the conventional group were under lights for 62.2 ± 23.02 hrs vs 41.3 ± 22.9 hrs, P = 0.005 in the intensive group. When the authors analyzed the relationship between DNA damage and length of phototherapy there was a statistically significant relationship between the two.
In summary then
Intensive phototherapy is more effective than conventional at reducing levels of jaundice
Phototherapy is associated with minimal clinical side effects whether intensive or conventional.
Infants receiving conventional phototherapy require longer courses of treatment.
Longer courses are associated with greater levels of DNA damage.
The significance of this DNA damage is unknown based on this study but in principal avoiding such injury may be a wise thing to do.
One last benefit – less needle pokes and shorter lengths of stay!
If an infant spends an average of one less day under phototherapy lights do not underestimate the added benefit with respect to avoiding needle pokes. Typically such infants receive one poke a day to “check how the decline is going”. Shortening the course of phototherapy may translate into one or two less pokes or more and that is definitely a good thing!
Lastly I will leave you with a tip from my own practice which I have found very useful to eliminate at least one poke. When phototherapy is effective and the bilirubin is coming down (and is close to the threshold for stopping but not quite there yet) it is common for people on rounds to order another bilirubin for the morning and continue phototherapy until that result. The result comes back the following morning and the practitioner orders a follow-up bilirubin for the following day to check for the “rebound”.
An alternative strategy is to keep the infant on phototherapy overnight and rather than checking on the bilirubin in the morning just stop the phototherapy on rounds. Eight hours later check the bilirubin and if it is below the threshold for treatment send the infant home. You avoid an overnight stay and instead of poking twice in two days do it all in one.
Whether you take this advice or not is up to you but if all that comes from this post is a decrease in the general fear of intensive phototherapy I may have gotten somewhere and the DNA of many babies out there will thank you!
Elon Musk, a name synonymous with technology in our time (as the brains behind the all-electric Tesla automobile), had this to say about the “Good Old Days”
“If anyone thinks they’d rather be in a different part of history, they’re probably not a very good student of history. Life sucked in the old days. People knew very little, and you were likely to die at a young age of some horrible disease…”
I wonder what he would say though about Sister J Ward who worked in the premature unit at Rochford General Hospital, Essex in the 1950s. It was during this time that she took a baby outside with her to enjoy a warm afternoon. Upon returning to the unit and taking off the sheet that accompanied the child she noticed a discrepancy between the yellow colour which remained under the covered skin and that which had been exposed to sunlight. Her observation led her to conclude that the sunlight had in fact been responsible for the change (and she was right!) but her conclusion was largely ignored.
Soon thereafter a tube of blood provided the convincing evidence that the sun was in fact directly responsible for such a change. This tube which had been left on the windowsill in the sun was tested for a bilirubin level and found to be low. As the care providers felt the test was inaccurate a repeat sample was drawn and the fresh tube contained a much higher level. A repeat sample of the blood that was again left in the sun showed an even lower level than previously seen inspiring researchers to seek out the effect of light on bilirubin. This ushered in the age of phototherapy lamps that are used around the world today. The design of such lamps has undergone many changes with the current models mostly focusing on the generation of light in the blue spectrum. Mostly gone in the developed world are the long phototherapy bright light tubes that were ubiquitous when I was in residency. It didn’t start off that way though. All you needed was a little golden sun!
A Randomized Trial of Sunlight to….
This month in the New England Journal of Medicine a non-inferiority study has been published comparing conventional phototherapy with BiliBlankets to you guessed it…sunlight. The study took place in Nigeria where such a study is both practical and possible. Conducting the study in Winnipeg for example would yield a treatment that could be used for 3-4 months a year at best but in a more temperate part of the world it indeed is a reasonable question to ask. The infants randomized to sunlight were placed under filtered light using either a canopy made of an Air Blue 80 film on overcast days or when sunny, in a Gila Titanium film. These films have been shown to essentially block all UV light while allowing light in the blue spectrum through. Aside from Sister Ward demonstrating that sunlight was an effective treatment for jaundice over 60 years ago, a significant motivation for determining if sunlight could be employed is the cost difference of the two strategies. A BiliBlanket will cost between 2-3000 dollars each while these canopies can be made for $0.55 and $1.50 per square foot of film type respectively and $44 and $120 for a canopy for six to eight mother–infant pairs with Titanium and Air Blue 80 films. In countries where resources are scarce one can see the compelling reason to try such a strategy.
The criteria for efficacy were twofold. The first outcome was achieving a rate of increase in total serum bilirubin of less than 0.2 mg per deciliter per hour for infants up to 72 hours of age or secondly a decrease in total serum bilirubin for infants older than 72 hours of age who were receiving at least 5 hours of phototherapy. After comparing 250 courses using sunlight to 311, five hour exposures to BiliBlankets, sunlight was found to be equally effective. Interestingly, the spectral irradiance (measure of the intensity of the light source) however was significantly higher in the group receiving sunlight 40 vs. 17 μW per square centimeter per nanometer, P<0.001. Additionally, the total area covered was greater under the canopy which may help to explain why in a secondary analysis the rate of decline in bilirubin was found to be faster with sunlight.
But is it safe?
Putting babies under the sun for 5 hours would seem to go against everything we have been taught but remember this was filtered light so sunburn was not a concern. Temperatures were monitored for all children and if necessary they were moved into the shade to cool off or in other cases on quite hot days prophylactic cool towels were applied intermittently. In the end though only one baby recorded a short-lived temperature over 39 degrees, no babies became dehydrated and in only one case was a doctor called to see a child.
We are blessed to live in a country where we have ready access to phototherapy blankets, overhead lights that are either independent free units or integrated into expensive neonatal beds. This is not always the case in the developing world. I find it simply amazing that a discovery over 50 years ago that led to the development of an entire industry would one day be simplified back to where it all began. We must not forget that while bilirubin encephalopathy leading to kernicterus is rare in the developed world, in places without access to phototherapy it is a real and present danger. We now know that the most naturopathic treatment of all; the sun which is free and readily available is just as effective and possibly more than our high-tech devices.
Elon Musk may be one of the most brilliant inventors of the modern era but with respect to caring for babies with yellowing of the skin, Sister Ward had a leg up on him.