从迷信到科学-光疗的历史，新生儿黄疸光疗的意外发现

From Superstition to Science - The History of Phototherapy

　

　

 

罗奇福德综合医院，1956年夏天。

 

Sister J. Ward听到儿科顾问的低沉声音和脚步声。她赶紧把她从早产儿病房外面带走的婴儿带进来。据她说，“没有新鲜空气和温暖的阳光”无法治愈的疾病”。

 

顾问们找到了沃德带来的婴儿，他们注意到那个特定的婴儿有一个奇怪的三角形黄色皮肤;比婴儿早产儿的皮肤更暗。在观察到这一点后，该医院顾问R. H. Dobbs医生问她：“姐姐，你给孩子涂了什么 - 碘或黄酮，为什么？”

 

沃德在面对这件事时立即感到不舒服，并采取了诚实的态度。 “先生，我带着婴儿出去呼吸新鲜空气和阳光;必定是阳光的原因“，她说，耸耸肩; Dobbs博士声称晒太阳通常需要更长的时间来形成红斑。但是沃德纠正了他，说：“但是没有，先生，这是我把孩子带到外面时身体被覆盖的一部分。”虽然有些解释看起来很奇怪，顾问们考虑到需要照顾的婴儿数量，以及这个特殊婴儿表现良好的事实，决定不再进一步追问。

　

 

Sister J. Ward

 

几周后，从黄疸婴儿抽取血液样本，并且在超过几小时的不寻常延迟后，血清胆红素报告值为13-14mg / dL。这让多布斯博士感到奇怪，原因有两个：一，这么简单的调查需要花费这么长的时间，而且有两个原因，根据他多年的经验，所报告的数值并不符合婴儿在临床上看起来的严重性;所以他抽出一份新鲜的血液样本，然后自己带到实验室，并与生物化学家负责人P. W. Perryman先生交谈。

 

当被问到时，Perryman先生说：“我真的很抱歉延迟，先生，我的一名助手似乎把它放在窗台附近，一定是忘记了。但数值不可能错！我自己运行了测试！“检查寄存器中的签名，然后继续添加，”我会重复测试剩下的样本，还有你带来的新样本“并取得了留在窗户下晒太阳的样品。

 

过了一会儿，佩里曼先生看起来相当惊讶，说：“我不确定怎么样，但这个样本的数值是9mg / dL;你带来的第二个样品读数为24mg / dL！“

 

***

 

这是新生儿学革命之一 - 光疗法背后的故事。

 

似乎是混乱的，显然不相关的事件，占据了20世纪50年代的两位儿科医生的天才头脑：D.H.Dobbs博士和Dr.R.多布斯博士的住院医师J. Kramer将其发展为具有临床意义和实用性。但他们确实有他们的路障要克服。

 

首先，他们需要确定太阳光线的某些成分，是热量或者是光线，导致胆红素水平的降低。一旦他们确定它是光线，他们需要确定哪个黄疸婴儿需要这种“光疗法”，那个婴儿需要交换输血，最后哪个黄疸婴儿不需要干预。第三，他们需要确定是否所有胆红素的形式受此影响，或者如果它的特定部分仅作出反应。最后，向同行群体证明它是科学的，而不仅仅是非理性的预感。

 

经过多年的实验，找出确切的光波长（温度控制环境中的蓝光），为婴儿创建安全的电气设备，同时确保持续的护理和其他需要的护理，创造了使用脚跟刺破鉴定血清胆红素的方法血液样本，绘制图表可用于绘制序列值（与单个胆红素值相反，用作开始治疗的任意截止点），以确定需要交换输血的婴儿需要光疗的婴儿，其中很多是在这两位绅士的愿景，有效地改变了未来几代儿童的成果。

 

如今，与五六十年前相比，新生儿的生理性黄疸不是引起关注的原因。

 

但这是怎么发生的？特定波长的光如何降低婴儿的胆红素水平，否则可能会导致破坏性后果，无论是由于换血治疗还是根本不进行任何形式的治疗？

 

基本原理是需要使不溶解的未结合胆红素溶解，以帮助婴儿在肝脏中形成结合系统。

 

当暴露于420-470nm的波长（可见光谱中的蓝光范围）时，胆红素分子在婴儿的皮肤中经历光化学反应，其中以下两个主要反应是重要的：

 

 

 

处于其主要“Z”构型的胆红素异构化为“E”构型，其可在胆汁中排泄而无需缀合。这是可逆的光异构化反应，并且有助于一些胆红素排泄。

 

 

 

胆红素被氧化成“Lumirubin”，它是结构异构体。这是一种不可逆的反应，这种lumirubin留可以在肾脏排泄而不需要结合。

 

在光疗期间，婴儿需要完全暴露，包括生殖器区域，但眼睛需要充分覆盖，同时通过定期监测总血清胆红素来照顾婴儿的营养和水合作用。

 

 

 

 

婴儿接受光疗

 

光疗虽然是一种有用的工具，但绝不应被视为替代交换输血;但它肯定证明可以减少需要换血的次数。必须持续守夜，连续监测血清胆红素密谋以确保婴儿不会进入危险区域。

 

 

 

 

授权：尼尔森儿科学教科书第20版

 

因此，这是一个故事，讲述了一个被认为是天真的思想如何改变新生儿学的面貌和未来几代人的未来。

 

　

　

Rochford General Hospital, the summer of 1956.

 

Sister. J. Ward, heard muffled voices and shuffling footsteps of the pediatric consultants. She hurriedly brought in the infant she had taken outside the Premature Baby Unit. According to her, there was nothing that couldn’t be cured by “fresh air and warm sunlight.”

 

The consultants got to the baby that Sister Ward had just brought in, and they noticed that that specific infant had a rather odd triangular patch of yellow skin; darker than the rest of the baby’s premature skin. On observing this, Dr. R. H. Dobbs, the consultant pediatrician of the hospital asked her, “Sister, what did you paint the baby with - Iodine or flavine and why?”

 

Sister Ward felt instantly uncomfortable at being confronted about this, and resorted to being honest. “Sir, I had taken the infant out to get some fresh air, and sunlight; it must be the Sun”, she said, shrugging; Dr. Dobbs claimed that sun-tans usually take a longer time to develop. But Sister Ward corrected him, saying “But no sir, it’s the part of the body that I had covered when I took the child outside.” Though something about the claim seemed odd, the consultants, considering the number of babies that were in need of attention, and also the fact that this particular baby was doing well, decided not to probe it further.

　

　

Sister J. Ward

 

A few weeks later, a blood sample was drawn from a jaundiced infant, and after an uncharacteristic delay of over a few hours, the serum bilirubin value was reported to be 13-14 mg/dL. This struck Dr. Dobbs as odd, for two reasons: one, that such a simple investigation took so long, and two, that the value reported did not, in his years of experience, correspond to how deeply icteric the infant clinically seemed; so he drew up a fresh blood sample and took it to the lab himself, and spoke to the biochemist in-charge, Mr. P. W. Perryman.

 

When asked, Mr. Perryman said, “I am truly sorry about the delay, sir, one of my assistants seem to have left it near the window sill and must’ve forgotten about it. But the value cannot be wrong! I ran the test myself!” checking the signature in the register, and went on to add, “I’ll repeat the test with whatever remaining sample there is, and also with the new sample that you have brought with you” and took the left over sample that was basking under the English sun by the window.

 

After a while, Mr. Perryman, looking rather flabbergasted, said, “I am not sure how, but this sample’s value reads 9mg/dL; the second sample you had brought with you reads 24mg/dL!”

 

***

 

This, is the story behind one of the revolutions in neonatology - Phototherapy.

 

What seemed to be chaotic, apparently unrelated events, took the genius minds of two pediatricians of the 1950s: Dr. D. H. Dobbs, and Dr.R. J. Kramer, Dr. Dobbs’ resident, to develop this to be clinically relevant and useful. But they did have their road-blocks to overcome.

 

Firstly, they needed to identify that some component of the sun’s rays, either the heat or the light, contributed to this reduction of bilirubin levels. Once they identified it was infact, the light rays, they needed to establish which infant with jaundice needed this “phototherapy", which infants needed exchange transfusion, and finally which of the icteric babies needed no intervention. Thirdly, they needed to establish if all forms of bilirubin were affected by this or if specific fractions of it only responded. Finally, proving to a peer group that it was scientific, and not just brute hunch.

 

After years of experimenting, finding out the exact wavelength of light (blue light in temperature controlled environments), creating safe electrical equipment for the babies while ensuring continued nursing and other care required were delivered, creating methods to identify serum bilirubin using a heel-prick blood sample, making a graph available to plot serial values (as opposed to single bilirubin values used as arbitrary cut-off points for commencement of treatment) to identify the infants needing phototherapy from the infants needing exchange transfusion, a lot of this were done under the vision of these two gentlemen, which effectively has altered the outcome of children, generations to come.

 

Nowadays, the physiological jaundice of the newborn isn’t something that is a cause of concern as opposed to how it was five or six decades ago.

 

But how does this happen? How does a specific wavelength of light reduce the levels of bilirubin in the baby, that would otherwise potentially lead to devastating consequences, either due to treatment with exchange transfusion or not instituting any form of treatment at all?

 

The basic principle is that unconjugated bilirubin, which is insoluble, needs to be made soluble in order to aid the infant’s developing conjugating systems in the liver.

 

On exposure to a wavelength of 420-470nm (blue light range in the visible spectrum), the bilirubin molecule undergoes photochemical reactions in the baby’s skin of which two of the following major reactions are important:

　

 

The bilirubin which is in its predominant “Z” configuration, isomerizes to the “E” configuration, which can be excreted in the bile without conjugation. This is a reversible photoisomerisation reaction, and contributes to some of the bilirubin excretion.

　

　

　

The bilirubin gets oxidized to “Lumirubin” which is a structural isomer. This is an irreversible reaction, and this lumirubin can be excreted in the kidneys without the need for conjugation.

　

During phototherapy, the baby needs to be fully exposed, including the genital area, but the eyes need to be sufficiently covered, while taking care of the nutrition and hydration of the baby with regular monitoring of the Total Serum Bilirubin.

　

　

　

Baby undergoing Phototherapy

 

Phototherapy, though a useful tool, should never be considered a replacement for Exchange Transfusion; but it definitely proved to reduce the number of times exchange transfusion was needed. A constant vigil is a must, with serial serum bilirubin plotting to make sure the infant isn’t going into the danger region.

　

　

　

Courtesy: Nelson Textbook of Paediatrics 20th Edition

 

So this is the story of how a supposedly innocent thought, armed with the quest to make a difference, changed the face of neonatology and the futures of generations to come.

　

Author: Anirudh Murali (Facebook)

Sources and citations

From Superstition to Science - The History of Phototherapy — Firstclass  https://www.firstclassmed.com/articles/2018/phototherapy-history