- Let me give you a little history.I go all the way back to CENTOXIN, which must have been mid 90s, wasn’t it? Centoxin too was a magic bullet that supposedly got between some of the flow products of sepsis and scotched it. At the time I had a friend who was a Roche (Pharma) Rep and he was always around (back in the day they could actually come into the hospital). He got all excited about the new company that was making Centoxin (Centocor biotech) who had offered him a big financial package to come to them. He asked my opinion and my opinion was that he had a good reliable job and this Centocor thing might turn out to be a flash in the pan. And that the magic bullet was being heavily marketed as a magic cure for sepsis, which given the fact that sepsis is a very multi-factoral disorder was highly unlikely. But the lure of was too much and the next time I saw him he was honchoing lots of Centoxin in the unit on a “Compassionate” protocol (giving the stuff away to get doctors used to using it). LOTS of hospital people pulled out their life savings and put it into Centocor stock.
Then as time progressed, there came an article/editorial in the New England Journal of Medicine stating flatly that Centoxin didn’t work, and was prohibitively expensive even if it did. When the NEJM nails your coffin shut, it stays shut. Within a couple of weeks, Centocor died miserably and everything it touched along with it, including my friend who, having burned his Roche bridge, went back to being a retail pharmacist. I know nurses that lost their life savings.
Then enter Activated Protein C (Xigris), said to be a higher grade version of Centoxin. As far as I could see, Xigris was essentially the same as Centoxin only with an infinitely more massive marketing push behind it. Now, at this point I must divulge that I am not a sepsis guy, have only rarely taken care of sepsis patients and I am absolutely not anything close to an expert in the field. But I started seeing the approaching battle strategy.
Lilly figured out early that this had the potential to put them into the upper ionosphere of Big Pharma and to get there they were going to have to spend a bundle in marketing. Mike Hansen will remember that the then Lilly Rep (the lovely and affable Rose) literally walked around the unit and pointed out patients she thought Xigris would be of value. Xigris was expensive enough to support several third world drug lords. The way to circumvent that was to pay a lot of doctors a LOT of money to advertise the drug on speaking circuits and in print. Like many of the articles in Crit Care, thinly veiled advertisements for favorite-son drugs. And have their Reps assure providers that the effectiveness of the drug was a foregone conclusion because it was desired. The cash flowed and soon the prevailing opinion was exactly that. The drug was a miracle cure because a lot of experts said so in print and in word. Lilly paid a LOT of doctors to publish and lecture on a LOT of anecdotal evidence that if used early and aggressively enough, Xigris was a strong positive. They blew off the expense by stating the fact that everything in an ICU was expensive and an extra US$8,000 a day or so was a drop in the bucket, especially if you get a survivor.
However, it quickly became clear that If every family practitioner or Internist used the drug for all their nursing home victims with UTIs (which is exactly where this was headed), it could easily break the drug budget in a few weeks. So the hospital (SFMC) started ratcheting down who could use Xigris and under what circumstances. The intent was to discourage use by inconvenience, and it worked. By the time any potential user jumped through all the mandatory hoops the patient would be long dead. So it actually wasn’t used much where I was for that reason. The relatively few times it was used, I was not terribly impressed that I saw any radical turn-arounds. Any turn-arounds that did occur were, of course, attributed to Xigris. And there were some bleeding problems that turned up. Then some articles by objective researchers………
Finally, when a lot of experience with the compound developed, the luster started to wear off (kind of like some of the Republican presidential candidates). Few in the other parts of the global medical village used it because of the expense and the sparse outcome numbers. Stephen Streat of New Zealand gave some interesting numbers on how many patients it would take to get one survivor, and the money spent to do so would break their bank quickly. They never used any of it. Then some studies started to show that outcomes weren’t exactly as everyone had been assured, and there were some problems that had been expertly glossed over. But the handwriting appeared on the wall. It only needed to be clarified.
Then the crash.
In the end, Lilly spent a LOT of money on this high stakes gamble to get to the top of the heap. How much they recouped will never be known. Those doctors that made careers on this compound inevitably will go on to other miracle cures, What’s the next highly touted medical miracle that doctors are now making careers on?
>>On 10/25/11 9:52 PM, Timothy G. Buchman, Ph.D., M.D. wrote:
>>I go back to HA-1A as well. And I was a participant in the study.
>>And there were a couple of patients who seemed to respond, Lazarus-like.
I think there was an article a while back on one of the journals, maybe not even mainstream, the thesis of which was that if researchers wanted to believe something intensely enough, they can subjectively prove it in their studies, even if they’re trying to be objective. I tend to believe in the ability of humans to prove what they believe. I do it all the time .
There was an article in Neurocritical Care recently in which the authors actually did a review f the literature suggesting a bunch of anecdotal evidence that a hematocrit of 30 or above improved outcome in subarachnoid bleeds. Even enhancing hematocrit with 30 day old banked blood that doesn’t carry oxygen, which is of course nonsense. They then announced that their future research efforts would prove this thesis!!! Of course it will!
I’m by nature very jaded about fads. I’ve seen ’em come and I’ve seen ’em go. Again, I hasten to add that I am not an expert in sepsis and I am not a researcher, although years ago I did some bench research on rats with Peter Safar and wrote two papers with him in Resuscitaton that others built on later. BTW, did you know that the lowly Ratus ratus is God’s favored creature? Anyone hurting a rat is in big trouble with God. Lots of additional purgatory time per rat. That was in one of the Dead Sea Scrolls a while back. I don’t expect to do well postmortem.
I’m old enough to have seen fads come and go, and I’m jaded enough not to believe much of the latest iterations thereof at face value. I remember “small bowel bypasses” for obesity that was the supposed cure for obesity and the death and disability that followed. Then came the balloons-in-the-stomach fad that my dad bought into, followed thereafter by the perforations. Now comes the staples and other high tech manipulations via endoscopy for obese patients looking for a miracle cure. Others see the weight loss. I see the perforations, leaks, systemic sepsis, renal failure, weeks in an ICU and end-stage co-morbidities. Maybe a few such patients lose weight, are happy and lose their diabetes. I see the ones with perpetual diarrhea, constant abdominal cramps, dietary nightmares and reversals when they’ve had enough. Sorry, surgery guys. despite glowing journal articles, I’m just not impressed.
I don’t deal with sepsis often, but when I do, I’m impressed that there are a LOT of multi-factorial issues.
I have had two memorable such patients, both accidental tourists in my unit. One was a big, 300 pound plus biker that trashed his Harley drunk, had multi-system trauma and landed in my unit because there was not a bed available in the Trauma ICU. Over two months I (and a bunch of other people) got that guy over respiratory failure (I trached him), renal failure (dialysis) and multiple other disasters. He comes back twice since and his wife keeps in touch with me on Facebook. I’m encouraging him to get a three-wheeler and get back on the road (but you knew that).
The second was a young guy in his 30s from South America here looking for a job as a lawyer who had a AV fistula blow, went down, aspirated and ended up with ARDS, renal failure and all that. The on-call intensivist told the patient’s wife at one point there was little chance the patient would get through the night alive. I (and a lot of other people) got his ass through the night and he comes to visit me every so often.
I FIRMLY BELIEVE THAT TITRATED CRITICAL CARE SAVED BOTH THESE PATIENTS, NOT A MAGIC BULLET.
Now the new fad is hypothermia for all ills. I take heat all the time for this from guys like Kuiper and Darwin. Some of my own colleagues here too. I say again I am less than impressed. I was with Safar when after years of intense study he came to the conclusion that hypothermia was only of value if instituted immediately after a brain insult. In my bench research with rats, I showed that hypothermia was not protective against hypoxic brain insult. Look up the cite. It’s in Resuscitation somewhere near the end of the 80s. I’m the first author.
FWIW, here’s my take on hypothermia. There were a couple of articles a while back that seemed to show benefit. Some researchers wanted so badly to believe it that they jumped on it with the intent to prove it was true, invoking the Rule of the True Believer. In fact, there is probably a very small group of brain injured patients that might marginally benefit from hypothermia but in 2011 the True Believers are in charge, and their initial research is as optimistic as the PROWESS was initially. One of my colleagues is trying to prove it is beneficial in myocardial infarction. After a while when more data inevitably comes in, the current belief that hypothermia is a cure all for everything from hangnails to belly button lint will do pretty much the same thing the date for Activated Protein C did. Dwindle. then they will all find something else to hang a career on.
I know I will get a three page harassment from Darwin no later than tomorrow calling me ten varieties of a philistine and heathen. But FWIW, hat’ my honest take on it.