To Save Or Let Die

Introduction

Medicine is a noble profession, perhaps noblest of all professions. The Hippocratic Oath, administered to all new physicians, exemplifies this tradition of nobility and benevolence:

I swear by Apollo Physician and Asclepius and Hygieia and Panaceia and all the gods and goddesses, making them my witnesses, that I will fulfill according to my ability and judgment this oath and this covenant:

To hold him who has taught me this art as equal to my parents and to live my life in partnership with him, and if he is in need of money to give him a share of mine, and to regard his offspring as equal to my brothers in male lineage and to teach them this art - if they desire to learn it - without fee and covenant; to give a share of precepts and oral instruction and all the other learning to my sons and to the sons of him who has instructed me and to pupils who have signed the covenant and have taken an oath according to the medical law, but no one else.

I will apply dietetic measures for the benefit of the sick according to my ability and judgment; I will keep them from harm and injustice.

I will neither give a deadly drug to anybody who asked for it, nor will I make a suggestion to this effect. Similarly I will not give to a woman an abortive remedy. In purity and holiness I will guard my life and my art.

I will not use the knife, not even on sufferers from stone, but will withdraw in favor of such men as are engaged in this work.

Whatever houses I may visit, I will come for the benefit of the sick, remaining free of all intentional injustice, of all mischief and in particular of sexual relations with both female and male persons, be they free or slaves.

What I may see or hear in the course of the treatment or even outside of the treatment in regard to the life of men, which on no account one must spread abroad, I will keep to myself, holding such things shameful to be spoken about.

If I fulfill this oath and do not violate it, may it be granted to me to enjoy life and art, being honored with fame among all men for all time to come; if I transgress it and swear falsely, may the opposite of all this be my lot.

This translation of the original Oath from ancient Greek has been replaced by more modern versions, but the sentiments are the same. All versions express the imperative, "Do no harm."

The only way to guarantee that one will do no harm is to do nothing. No doubt, Hippocrates had something else in mind.

Here is where we encounter the great dilemma of medicine. Should a physician risk doing harm in order to treat an illness? The answer lies in a consideration of the potential costs compared to the potential benefits in the face of incomplete information.

An important function performed by physicians is to educate their patients about the costs and benefits of a treatment. In fact, the word "doctor" comes from the Latin word "doctoris" which means teacher.

Clinical Trials

From where does the knowledge come that the doctor conveys to the patient? It comes from basic research and ultimately clinical trials.

Clinical trials are performed to assess the efficacy and safety of a medical device, procedure, or drug. The Federal Drug Administration (FDA) requires that clinical trials be conducted according to strict protocols before the device, procedure, or drug may be marketed in the United States.

The typical clinical trial protocol involves what is termed a double-blind design. Double-blind means that neither the subject nor the person administering the treatment knows what is being administered; it may be the test treatment or a fake treatment. This type of design obviates the possibility of observing the placebo effect or demand characteristics. The placebo effect is due to the subject's belief that the treatment will be effective, so they behave as though it were. Demand characteristics are due to the subject anticipating what the experimenter wants to observe and behaving accordingly.

By design, the double-blind study requires that half of the patient population will receive treatment, but also half will not. For patients suffering a life-threatening illness, being assigned to the wrong experimental group could be a death sentence. The question is which group of patients will be better off. What would Hippocrates think about this?

Granted, participants in the study are told up front that they may be assigned to the placebo group, so there should be no fostering of false hope if that is possible. Indeed, both groups may show no significant differences in which case the treatment would be found to be ineffective.

Adaptive Trials

Not all trials follow the randomization design in which patients are randomly assigned to each treatment group. In 1969, Marvin Zelen of Harvard University proposed an adaptive strategy for assigning patients to each group. Assume the study has 2 groups represented by a blue ball for one group and a red ball for the other. Both balls are put into a hat. The first patient is assigned to a group by randomly drawing one ball from the hat. That patient has a 50% chance of being assigned to either group. If the outcome for that patient is successful, another ball of the same color is added to the hat. The next patient has a 67% chance of being assigned to the same group as the first patient. If the outcome for the first patient is unsuccessful, than a ball of the other color is added to the hat. In this case the second patient has a 67% chance of being assigned to the other group. This win-stay-lose-switch strategy is pursued until all of the patients in the study have been tested.

The adaptive trial offers the advantage of providing the more beneficial treatment to a greater number of patients. This statement may sound tepid, but the implications can be profound.

For example, a technique for supporting respiration in premature infants was tested with adaptive trials. The technique is called extracorporeal membrane oxygenation (ECMO). As shown above, the baby whose lungs have not developed sufficiently to support adequate respiration is connected to an apparatus which oxygenates the baby's blood until the lungs have developed. With adaptive trials, the scorecard was ECMO-8 survived; conventional incubator technique-2 died. In another study 9 for 9 survived on ECMO; 4 of 10 died with the conventional method.

So, what's wrong with adaptive trials. One problem is that the trials must be conducted serially. One patient at a time is tested. This restriction could extend the length of the trials considerably. When dealing with life-and-death issues, time is critical.

Another problem is that for cases where one treatment far exceeds the effect of the other, the significance of the difference may be unobtainable statistically. However if the difference in treatments is that obvious, then who cares?

Thalidomide

ECMO may represent the best-case scenario where the primary issue is how to get ECMO to those who need it as quickly as possible.

What about the opposite case where the outcomes are so tragic that the problem is to limit the use of the treatment as quickly as possible. Perhaps the best example of this scenario is the case of thalidomide.

In 1956 the West German company Chemie Grünenthal began marketing a drug called Contergan (generic: thalidomide). This drug was intended to be used as a sedative or as a remedy for morning sickness in pregnant women.

It had cleared clinical trials without any indication of a problem. Red flags began to be raised when a high percentage of babies born to mothers who had used thalidomide during their pregnancies suffered from phocomelia (i.e. underdeveloped or absent extremities, c.f. photo below).

These babies also suffered from a high rate of mortality, as high as 50%.

How had the clinical trials failed to detect the high rate of birth defects in babies born to mothers who had used thalidomide? The drug had been rigorously tested with animals. It had been tested in human clinical trials as well.

One consideration is the Zeitgeist (i.e. prevailing view of the time). At that time, it was believed that big, bulky drug molecules did not cross the placental barrier despite the fact that it was known that alcohol did. As a consequence, there was no effort to observe the babies born to mothers taking the drug.

Another factor was that thalidomide was considered to be a "wonder drug". It had many beneficial effects. Besides treating morning sickness and insomnia, thalidomide was purported to be effective against anxiety, insomnia, gastritis, and tension. It still is prescribed as a treatment for leprosy and multiple myeloma. There may have been confusion regarding where to focus the testing.

Conclusion

Medicine is imperfect certainly in the sense of being incomplete but also in the sense of being flawed. Everyone desires favorable outcomes, but there is a price to be paid for those outcomes. There are not many who would be willing to sacrifice themselves to advance medical science even though we all would benefit by that sacrifice. The best medicine can do is to minimize the cost and to maximize the benefit.

I am guessing that Hippocrates would be okay with medicine as practiced today. What do you think?