#i could just go the normal steroid route but that can also cause the negative effects i Dont want

[prorevmakeouts]

T gel + DHT blocker looking more tempting by the minute

[brassash3]

Fake Tan And Also Melanotan Shots

How Long Does Melanotan 2 Take To Work

Content

Melanotan 2 Nasal Spray Kits (.

Box Nutan Three-way Strength Tanning Spots (10 Spots.

Vial Melanotan 2 Tanning Shot Package.

Picture And Performance Improving Medicine (ipeds).

Easy Tan Europe.

One of the most common Melanotan-II side effects include light queasiness and also warm flush in face. In situation you don't wish to experience this Melanotan 2 neutral result, take the medication right before going to bed. By so doing, in as much as the medicine will be activating your body to create an impulse to make love, your mind will be too inactive to process the called for action and so, you will not feel aroused. Otherwise, you can simply await the impact and also have some great time with your love.

Several of my member of the family utilize it and in my opinion, and i like my phony tan, it looks too orange. It doesn't look all-natural and u can inform a mile off that its been utilized. My skin highlighting after the last usage was one factor, plus I now appear to tan quicker. It's that solid and you still need to make use of the sunlight to bring the tan out. Normally a 10mg training course is sufficient however numerous go straight in there at too expensive a dose and also darken also quickly. If you have any kind of scar tissue or moles this will certainly darken at a much faster price. Melanotan II- A quick history as well as explanation of this peptide hormone.

Melanotan 2 Nasal Spray Kits (.

I just recently saw a person who, despite making use of skin-brightening products, saw noticeable skin dimming in an extremely brief time when taking melatonin for a few weeks. Top Qaulity Easy to Use Peptide Kits Ireland has actually not been fully evaluated, as well as due to its potential negative effects it is not advised that anybody use this medicine. No evidence exists for the use of melatonin II in pregnancy or bust feeding however it is suggested that it should be stayed clear of. He claims when people inject melanotan it can alter the look of their moles and also freckles. Melanotan resembles a material in our bodies, called "melanocyte-stimulating hormone." This hormone increases the production of skin-darkening pigments. Melanotan might likewise work in the brain to promote erections of the penis. If you are naturally really pale I would never ever trouble with sunbeds, it's a pointless and unneeded danger for a very little result.

As we have several satisfied customers throughout the UK, we pride ourselves in using an option to acquire an all-body tan that is basic and also efficient to utilize. Identification and characterization by LC‐UV‐MS/ MS of melanotan II skin‐tanning items marketed unlawfully on the web. When you reconstitute MT2 to the appropriate concentration, it's currently time to administer it, an activity that you'll do using an insulin syringe. One thing that you'll discover regarding the syringe is that it's not just small but calibrated in IU. so, if you want to carry out 0.3 mls, you'll gauge the medication approximately the 30 IU mark in the syringe. As discussed previously, starting at a high dosage raises your opportunities of experiencing a Melanotan-II issue such as queasiness.

Box Nutan Three-way Strength Tanning Spots (10 Spots.

All of these tanning variables can make it challenging to give the proper recommendations on an upkeep dose for every user. Consequently, a person's application frequency can be found with experimentation. The Melanotan 2 maintenance does are taken when the preferred pigmentation has been reached and also requires much less regular shots. Loading methods taking doses a lot more regularly to accumulate a first tan faster. This can imply the customer will certainly reach a tanning upkeep dosage sooner. If these adverse effects occur, the individual's dosage can be administered prior to going to sleep, so any undesirable results occur while the individual is asleep. With routine use, these side effects will certainly dissipate, as well as the item can be taken at any moment of the day.

Mercury is dangerous, not available on prescription as well as must never be utilized.

Using mercury in cosmetic products has been banned for over 3 years in the EU.

Possible side effects of making use of skin lightening products which contain mercury include raised pigmentation, foetal irregularities if made use of while pregnant and also scratchy breakouts.

In high doses, mercury can likewise cause psychological impacts.

It is a therapy which assures to leave you tanned, thin and also stimulated.

It is very important to mention that there is a series of skin lightening items that adhere to the lawful demands that allow them to be sold in the UK.

Melanotan II was initially created in the 1990s at the College of Arizona. The hormone caused the dimming of the pigments of the frogs used in the experiment. Unlike fellow tanning addict Martina Big - who revealed she is moving to Africa to "be with her individuals" last month - Hannah firmly insists that she's not in fact attempting to change race. This means any kind of that you do purchase have not been subjected to the rigorous testing necessary to ensure safety and security and efficacy. Real side effects as well as long-lasting consequences are actually unidentified. If one thing is for certain, it's that there's a lot of false details available on the web concerning the efficacy and also safety of melanin shots. " Within 6 days you will start to see your skin heating up to a natural-looking sunkissed glow."

Vial Melanotan 2 Tanning Shot Package.

MT2 is then taken in into the blood stream as well as spreads out uniformly throughout your body. It is a good idea that you make certain that a Melanotan-II resource is genuine before you purchase the peptide as there are several quack Melanotan-II vendors. By so doing, you'll make certain that you are using the real medication, not something that could end up doing even more injury than good to your body. Well, there are Read our page about everything to know about Melanotan -lasting Melanotan-II side effects that have ever before been reported thus far. Nonetheless, it's been discovered that some individuals are likely to experience some article injection effects throughout the initial couple of Melanotan dosages.

New eczema drug promising in early trial - Medical Xpress

New eczema drug promising in early trial.

Posted: Thu, 02 Mar 2017 08:00:00 GMT [source]

On the other hand, for those that might have an aversion to needles as well as the shot technique, the nasal and dental use MT-2 can assist to achieve an enjoyable, all-body tan. At MellowTan, we wholeheartedly think the longer-term usage of peptides in regard to supplying as well as maintaining a healthy tan. We feel that Melanotan 2 holds the key to safe showering and that far more analysis should be carried out right into Melanotan 2 and various peptides to aid customers achieve a healthy tan in the house. If you are seeking a tanning solution at cost effective rates, after that MellowTan can be your one-stop-shop for Melanotan 2 products in the UK.

Image And Also Performance Improving Medication (ipeds).

There are 3 positive impacts of Melanotan-II, but the major one is the ability to tan any kind of sort of skin regardless of how old a person is. They are pleased with the Melanotan-II results as well as go on suggesting the medication to others. As a result, the popularity of Melanotan supplement increases everyday. I can not say thanks to enough whoever created this product. Besides my skin looking darker as well as my body remains in prettier form. I have actually shed off some weight over the duration that I have been utilizing the medication.

When compared to the shot approach, where the absorption rate is 100%, dental or nasal administration is less effective. Please do not fall for a fast fix approach of using MT-2 injections as it is advised to make use of the routed application approach with the Melanotan 2 peptide. Reconstituting the tanning peptide belongs of the process needed for making use of Melanotan 2 and will need an individual's complete attention to get proper results. If you need an all body tan, Melanotan 2 can be a home tanning solution. This is what you need to find out about the MellowTan products prior to you purchase. You can infuse Melanotan peptide below the skin or into the muscle mass; anywhere you can comfortably get to on your body. Squeeze the skin loose from the muscle as well as raise it to enable the needle to penetrate the fat layer of the skin.

There are go to blog article of melanin injections available, Melanotan I and II, which are weakened in water prior to being injected. Melatonin activates your skin's melanocytes, which are the cells that generate pigment.

Invictus Games powerlifter quits team over steroids, cocaine charges - ABC News

Invictus Games powerlifter quits team over steroids, cocaine charges.

Posted: Tue, 23 Oct 2018 07:00:00 GMT [source]

Along with raising the top quality of erection in a guy, Melanotan supplement can likewise provide him appreciate extra erections by reducing the refractory time. As a result, if you desire much better love-making and a wonderful skin that's much less vulnerable to skin cancer as well as sunlight burns, making use of Melanotan II is like eliminating 2 birds using one stone.

[kristinsimmons]

The EBM Wars: Manufacturing Equipoise (Part 1)

By ANISH KOKA

The phone rings.  It’s not supposed to be ringing.  It’s 2 am.   The voice on the other line is from an apologetic surgery resident.

Resident: There is this patient..

Me: Yes, go ahead. Please.

Resident: He’s tachycardic.

Me: How fast?

Resident: 160 ?

Me: What’s the blood pressure?

Resident: 130/90

Me: Rhythm?

Resident: An SVT I think.. I gave adenosine.  Nothing happened

Me: Audibly groaning.  I’ll be in..

Forty five minutes later I’m at the bedside of a decidedly ill appearing man.

I want to be triumphant that his heart rate is only 145, and a quick glance at the telemetry monitor above his bed uncovers juicy p waves in a cadence that suggests this is no primary electrical arrhythmia.

Something is very wrong somewhere – the heart in this case is an innocent bystander being whipped into a frenzy to compensate for something.

At the moment the whip is a norepinephrine infusion being used to keep his blood pressure up.

I ask the nurse if the amount of norepinephrine infusing has been stable.  She replies that his dose has been slowly escalating.

Eureka! I think – the heart rate response in this case is being driven by the norepinephrine – a powerful adrenaline that acts on beta receptors and alpha receptors within the body that increase heart rate and constrict the blood vessels to raise blood pressure.  Fix the cause of the low blood pressure, come down on the norepinephrine, and perhaps the heart rate would be better.

But it turns out this particular post surgical patient doesn’t have a medical cause of low blood pressure I can find.  I cycle through cardiac ultrasounds, blood gases, steroid and volume challenges, and try inching down on the norepinephrine.

All of it is to no avail.  I’m growing more and more convinced this problem is surgical in nature. Perhaps an infarcted piece of bowel?  All I know is that the man acts like he has no peripheral vascular tone.

An interesting thing happens shortly after.  The norepinephrine drip runs out.

As one nurse runs to get another bag from the pharmacy – a quick cascade of events unfolds.

The brisk upstroke from the arterial line that marks the pressure wave generated with every beat of the heart starts to dampen.  The color seems to visibly drain from the patients face, and he begins to complain that his vision is getting blurry.  His systolic blood pressure is 70 – an almost forty point drop within a minute of the norepinephrine running out.

I call for help.

I try to keep a level tone.  Project control, not panic.

“Open the code cart, I need a half a milligram of epinephrine”

“You’re going to be ok, sir.  Hang with me.”  I squeeze his hand.

He closes his eyes

The code cart – a fully stocked cabinet on wheels with almost everything you need for resuscitation efforts – is wheeled into the room. The epinephrine vial is handed to the nurse, and hurriedly pushed.

Within seconds, I can see the blood pressure and heart rate rise.  The patient’s grip on my hand relaxes.  Or maybe its my grip on his hand.  I forget which.  His vision returns to normal as his blood pressure ‘normalizes’.

Of course nothing has been fixed.  Why his blood pressure remains low continues to be a mystery.  The bag of norepinephrine soon isn’t enough even at its maximal dose.  The same scenario (hypotension -> pallor -> vision loss ) recurs 30 minutes later, and another bolus of epinephrine aborts a rapid spiral towards pulselessness.

This case is an anecdote, the weakest possible form of evidence apparently.  Yet there are powerful lessons learned that night. Blood flows in pulsatile fashion with a certain pressure head.  Below some threshold of pressure, the end organs of the body stop functioning.  Agents that are active on peripheral vasoconstrictor receptors (norepinephrine, epinephrine) raise blood pressure.  Epinephrine was keeping this patient alive while a team worked to understand why his blood pressure was so low.  My suspicion was that he was in something called distributive shock – a catastrophic life threatening syndrome that requires a furious hunt for cause to save the patient.  Overwhelming infection and an even more aggressive immune response renders normally relatively impervious vasculature to be a sieve.  At the present time the therapy is directed towards replacing the fluid lost in the intravascular space and using medications that act on peripheral vascular receptors that increase peripheral tone.

There is, of course, much that isn’t known about this process.  Hopefully it will come to pass that we will arrive at a better understanding of what specifically creates this mileu so our therapies may be more directed.  But for the time being, our solutions are limited by our current, always imperfect understanding of the world.

The culprit in this case was a leak of intestinal contents into the peritoneal space from two pieces of bowel that should have been exactly apposed.  The body had attempted to tell us this very thing with that high heart rate post-operatively.  It took us, the clinicians, some time to translate.

The uninformed prior: Unlearning what has been learned.

For many, medicine has for too long been an imperfect science.  The history of medicine is replete with physicians acting with certainty in a manner that – in hindsight – was ineffective, or even worse – harmful.  Blood letting to allow the release of bad humors is believed to have hastened the demise of the greatest American – George Washington.  The disconcerting part of this is that the physician players were not motivated by anything but the best intentions.  They relied on their experience, intuition and judgement to deliver exactly the wrong prescription.   Intuition fails.  No matter how many patients died soon after blood letting, operating biases didn’t let physicians link the two events.  After all, the patients may have died even sooner if blood letting hadn’t been done.

The idea that medicine had progressed – by the 1980’s – to the point that doctors were not engaged in the equivalent of blood letting came under heavy fire when it was demonstrated a number of standard practices of the time could indeed be ineffective.  Extra beats (also known as ectopic heart beats) after heart attacks were noted in cardiac units to portend a higher risk of dying suddenly.  The obvious approach to this was to use medications that effectively suppressed ectopic heart beats.  Testing this in a double blind randomized control trial did not just demonstrate ineffectiveness, but harm.  More people randomized to suppression of ectopic beats actually died.  It turns out the anti-arrhythmic drugs being used were actually proarrhythmic as well.  The attack on ‘expertise’ that relied on intuition and experience was on, and it was a rout.

Glue ear – a condition that developed in the middle ears of little kids after ear infections  was treated with insertion of a tube to drain that space.  The trial to determine efficacy using a randomized trial to blindly allocate patients to surgery or no treatment?

Negative.

Many of the children turned out to do just fine if you left them alone.  Given the fact that all procedures have a certain complication rate, the lack of efficacy here was no small matter.

And so it went – the populace had to be on guard not just against the afflictions of disease, but against the intuitions of its doctors.

Uncertainty reigned, and in search of certainty, the field fled to the warm embrace of ever greater empiricism.  In the early ’80s from the McMaster University in Canada, David Sackett gave voice to a new sheriff – Evidence Based Medicine (EBM).

“EBM de-emphasizes intuition, unsystematic clinical expertise, and pathophysiologic rationale . . . and stresses the examination of evidence from clinical research. In 1960, the randomized trial was an oddity. It is now accepted that virtually no drug can enter clinical practice without a demonstration of its efficacy in clinical trials. Moreover the same randomized trial method is increasingly being applied to surgical therapies and diagnostic tests.” (Sackett et. al, Evidence Based Medicine)

The premise as outlined is simple – don’t believe anything that hasn’t been tested in a randomized control trial.  The only real evidence is that found within RCTs or in reviews that amalgamated RCTs.

The usual response from EBM experts can be found below in the response to the statement that real evidence may come from outside an RCT.

It is quite possible Professor Francis is right on here about the specific subject being discussed, but the point is that there is an established hierarchy of evidence on display.  The RCT is king, everything else is no better than the court jester.

While an RCT may certainly be better than anything cobbled together at a pub, the conventional parallel group RCT certainly isn’t always King of the Hill.   As nicely expounded on by the prolific statistician Stephen Senn, there are plenty of potential errors the conventional RCT finds itself humbled by.

The clinician may thus feel somewhat mollified about conclusions drawn about the effect of epinephrine in the earlier anecdote.

The idea that real evidence may live outside the confines of RCTs was also countered by none other than the godfather of EBM, David Sackett:

“Evidence based medicine is not restricted to randomized trials and meta-analyses. It involves tracking down the best external evidence with which to answer our clinical questions. To find out about the accuracy of a diagnostic test, we need to find proper cross sectional studies of patients clinically suspected of harboring the relevant disorder, not a randomized trial. For a question about prognosis, we need proper follow up studies of patients assembled at a uniform, early point in the clinical course of their disease. And sometimes the evidence we need will come from the basic sciences such as genetics or immunology. It is when asking questions about therapy that we should try to avoid the non-experimental approaches, since these routinely lead to false positive conclusions about efficacy. Because the randomized trial, and especially the systematic review of several randomized trials, is so much more likely to inform us and so much less likely to mislead us, it has become the “gold standard” for judging whether a treatment does more good than harm. However,some questions about therapy do not require randomized trials (successful interventions for otherwise fatal conditions) or cannot wait for the trials to be conducted. And if no randomized trial has been carried out for our patient’s predicament, we must follow the trail to the next best external evidence and work from there. (Sacket et al, Evidence based medicine: what it is.. )”

Sackett also noted that there were therapies whose ” ‘face validity’ is so great that randomized trials were unanimously judged by the team to be both unnecessary, and, if a placebo would have been involved, unethical”.

In effect, there was always an escape clause to let common sense prevail over EBM.  But as frequently happens in movements, the second generation of followers moves in directions unintended by the founders.  If the safeguards in place involve only areas where equipoise exists, but equipoise is itself determined by fallible judgement, the range of unacceptable experiments becomes very narrow.  This especially applies to new therapies where members of the community not involved in design and development have skeptical prior beliefs.  This is, of course, not a bad thing – it is entirely possible that the usually overoptimistic prior of the developers of a new therapy are farther from the truth than the skeptics.  But it is a major problem if we ask doctors to discard their prior beliefs that are not based in RCTs.  In doing so, we are manufacturing equipoise.  This means travel in dangerous ethical waters for physicians and their patients that is at best unwise, and at worst willfully foolish.

The EBM Wars: Manufacturing Equipoise (Part 1) published first on https://wittooth.tumblr.com/

[kristinsimmons]

The EBM Wars: Manufacturing Equipoise (Part 1)

By ANISH KOKA

The phone rings.  It’s not supposed to be ringing.  It’s 2 am.   The voice on the other line is from an apologetic surgery resident.

Resident: There is this patient..

Me: Yes, go ahead. Please.

Resident: He’s tachycardic.

Me: How fast?

Resident: 160 ?

Me: What’s the blood pressure?

Resident: 130/90

Me: Rhythm?

Resident: An SVT I think.. I gave adenosine.  Nothing happened

Me: Audibly groaning.  I’ll be in..

Forty five minutes later I’m at the bedside of a decidedly ill appearing man.

I want to be triumphant that his heart rate is only 145, and a quick glance at the telemetry monitor above his bed uncovers juicy p waves in a cadence that suggests this is no primary electrical arrhythmia.

Something is very wrong somewhere – the heart in this case is an innocent bystander being whipped into a frenzy to compensate for something.

At the moment the whip is a norepinephrine infusion being used to keep his blood pressure up.

I ask the nurse if the amount of norepinephrine infusing has been stable.  She replies that his dose has been slowly escalating.

Eureka! I think – the heart rate response in this case is being driven by the norepinephrine – a powerful adrenaline that acts on beta receptors and alpha receptors within the body that increase heart rate and constrict the blood vessels to raise blood pressure.  Fix the cause of the low blood pressure, come down on the norepinephrine, and perhaps the heart rate would be better.

But it turns out this particular post surgical patient doesn’t have a medical cause of low blood pressure I can find.  I cycle through cardiac ultrasounds, blood gases, steroid and volume challenges, and try inching down on the norepinephrine.

All of it is to no avail.  I’m growing more and more convinced this problem is surgical in nature. Perhaps an infarcted piece of bowel?  All I know is that the man acts like he has no peripheral vascular tone.

An interesting thing happens shortly after.  The norepinephrine drip runs out.

As one nurse runs to get another bag from the pharmacy – a quick cascade of events unfolds.

The brisk upstroke from the arterial line that marks the pressure wave generated with every beat of the heart starts to dampen.  The color seems to visibly drain from the patients face, and he begins to complain that his vision is getting blurry.  His systolic blood pressure is 70 – an almost forty point drop within a minute of the norepinephrine running out.

I call for help.

I try to keep a level tone.  Project control, not panic.

“Open the code cart, I need a half a milligram of epinephrine”

“You’re going to be ok, sir.  Hang with me.”  I squeeze his hand.

He closes his eyes

The code cart – a fully stocked cabinet on wheels with almost everything you need for resuscitation efforts – is wheeled into the room. The epinephrine vial is handed to the nurse, and hurriedly pushed.

Within seconds, I can see the blood pressure and heart rate rise.  The patient’s grip on my hand relaxes.  Or maybe its my grip on his hand.  I forget which.  His vision returns to normal as his blood pressure ‘normalizes’.

Of course nothing has been fixed.  Why his blood pressure remains low continues to be a mystery.  The bag of norepinephrine soon isn’t enough even at its maximal dose.  The same scenario (hypotension -> pallor -> vision loss ) recurs 30 minutes later, and another bolus of epinephrine aborts a rapid spiral towards pulselessness.

This case is an anecdote, the weakest possible form of evidence apparently.  Yet there are powerful lessons learned that night. Blood flows in pulsatile fashion with a certain pressure head.  Below some threshold of pressure, the end organs of the body stop functioning.  Agents that are active on peripheral vasoconstrictor receptors (norepinephrine, epinephrine) raise blood pressure.  Epinephrine was keeping this patient alive while a team worked to understand why his blood pressure was so low.  My suspicion was that he was in something called distributive shock – a catastrophic life threatening syndrome that requires a furious hunt for cause to save the patient.  Overwhelming infection and an even more aggressive immune response renders normally relatively impervious vasculature to be a sieve.  At the present time the therapy is directed towards replacing the fluid lost in the intravascular space and using medications that act on peripheral vascular receptors that increase peripheral tone.

There is, of course, much that isn’t known about this process.  Hopefully it will come to pass that we will arrive at a better understanding of what specifically creates this mileu so our therapies may be more directed.  But for the time being, our solutions are limited by our current, always imperfect understanding of the world.

The culprit in this case was a leak of intestinal contents into the peritoneal space from two pieces of bowel that should have been exactly apposed.  The body had attempted to tell us this very thing with that high heart rate post-operatively.  It took us, the clinicians, some time to translate.

The uninformed prior: Unlearning what has been learned.

For many, medicine has for too long been an imperfect science.  The history of medicine is replete with physicians acting with certainty in a manner that – in hindsight – was ineffective, or even worse – harmful.  Blood letting to allow the release of bad humors is believed to have hastened the demise of the greatest American – George Washington.  The disconcerting part of this is that the physician players were not motivated by anything but the best intentions.  They relied on their experience, intuition and judgement to deliver exactly the wrong prescription.   Intuition fails.  No matter how many patients died soon after blood letting, operating biases didn’t let physicians link the two events.  After all, the patients may have died even sooner if blood letting hadn’t been done.

The idea that medicine had progressed – by the 1980’s – to the point that doctors were not engaged in the equivalent of blood letting came under heavy fire when it was demonstrated a number of standard practices of the time could indeed be ineffective.  Extra beats (also known as ectopic heart beats) after heart attacks were noted in cardiac units to portend a higher risk of dying suddenly.  The obvious approach to this was to use medications that effectively suppressed ectopic heart beats.  Testing this in a double blind randomized control trial did not just demonstrate ineffectiveness, but harm.  More people randomized to suppression of ectopic beats actually died.  It turns out the anti-arrhythmic drugs being used were actually proarrhythmic as well.  The attack on ‘expertise’ that relied on intuition and experience was on, and it was a rout.

Glue ear – a condition that developed in the middle ears of little kids after ear infections  was treated with insertion of a tube to drain that space.  The trial to determine efficacy using a randomized trial to blindly allocate patients to surgery or no treatment?

Negative.

Many of the children turned out to do just fine if you left them alone.  Given the fact that all procedures have a certain complication rate, the lack of efficacy here was no small matter.

And so it went – the populace had to be on guard not just against the afflictions of disease, but against the intuitions of its doctors.

Uncertainty reigned, and in search of certainty, the field fled to the warm embrace of ever greater empiricism.  In the early ’80s from the McMaster University in Canada, David Sackett gave voice to a new sheriff – Evidence Based Medicine (EBM).

“EBM de-emphasizes intuition, unsystematic clinical expertise, and pathophysiologic rationale . . . and stresses the examination of evidence from clinical research. In 1960, the randomized trial was an oddity. It is now accepted that virtually no drug can enter clinical practice without a demonstration of its efficacy in clinical trials. Moreover the same randomized trial method is increasingly being applied to surgical therapies and diagnostic tests.” (Sackett et. al, Evidence Based Medicine)

The premise as outlined is simple – don’t believe anything that hasn’t been tested in a randomized control trial.  The only real evidence is that found within RCTs or in reviews that amalgamated RCTs.

The usual response from EBM experts can be found below in the response to the statement that real evidence may come from outside an RCT.

It is quite possible Professor Francis is right on here about the specific subject being discussed, but the point is that there is an established hierarchy of evidence on display.  The RCT is king, everything else is no better than the court jester.

While an RCT may certainly be better than anything cobbled together at a pub, the conventional parallel group RCT certainly isn’t always King of the Hill.   As nicely expounded on by the prolific statistician Stephen Senn, there are plenty of potential errors the conventional RCT finds itself humbled by.

The clinician may thus feel somewhat mollified about conclusions drawn about the effect of epinephrine in the earlier anecdote.

The idea that real evidence may live outside the confines of RCTs was also countered by none other than the godfather of EBM, David Sackett:

“Evidence based medicine is not restricted to randomized trials and meta-analyses. It involves tracking down the best external evidence with which to answer our clinical questions. To find out about the accuracy of a diagnostic test, we need to find proper cross sectional studies of patients clinically suspected of harboring the relevant disorder, not a randomized trial. For a question about prognosis, we need proper follow up studies of patients assembled at a uniform, early point in the clinical course of their disease. And sometimes the evidence we need will come from the basic sciences such as genetics or immunology. It is when asking questions about therapy that we should try to avoid the non-experimental approaches, since these routinely lead to false positive conclusions about efficacy. Because the randomized trial, and especially the systematic review of several randomized trials, is so much more likely to inform us and so much less likely to mislead us, it has become the “gold standard” for judging whether a treatment does more good than harm. However,some questions about therapy do not require randomized trials (successful interventions for otherwise fatal conditions) or cannot wait for the trials to be conducted. And if no randomized trial has been carried out for our patient’s predicament, we must follow the trail to the next best external evidence and work from there. (Sacket et al, Evidence based medicine: what it is.. )”

Sackett also noted that there were therapies whose ” ‘face validity’ is so great that randomized trials were unanimously judged by the team to be both unnecessary, and, if a placebo would have been involved, unethical”.

In effect, there was always an escape clause to let common sense prevail over EBM.  But as frequently happens in movements, the second generation of followers moves in directions unintended by the founders.  If the safeguards in place involve only areas where equipoise exists, but equipoise is itself determined by fallible judgement, the range of unacceptable experiments becomes very narrow.  This especially applies to new therapies where members of the community not involved in design and development have skeptical prior beliefs.  This is, of course, not a bad thing – it is entirely possible that the usually overoptimistic prior of the developers of a new therapy are farther from the truth than the skeptics.  But it is a major problem if we ask doctors to discard their prior beliefs that are not based in RCTs.  In doing so, we are manufacturing equipoise.  This means travel in dangerous ethical waters for physicians and their patients that is at best unwise, and at worst willfully foolish.

The EBM Wars: Manufacturing Equipoise (Part 1) published first on https://wittooth.tumblr.com/

[kristinsimmons]

The EBM Wars: Manufacturing Equipoise (Part 1)

By ANISH KOKA

The phone rings.  It’s not supposed to be ringing.  It’s 2 am.   The voice on the other line is from an apologetic surgery resident.

Resident: There is this patient..

Me: Yes, go ahead. Please.

Resident: He’s tachycardic.

Me: How fast?

Resident: 160 ?

Me: What’s the blood pressure?

Resident: 130/90

Me: Rhythm?

Resident: An SVT I think.. I gave adenosine.  Nothing happened

Me: Audibly groaning.  I’ll be in..

Forty five minutes later I’m at the bedside of a decidedly ill appearing man.

I want to be triumphant that his heart rate is only 145, and a quick glance at the telemetry monitor above his bed uncovers juicy p waves in a cadence that suggests this is no primary electrical arrhythmia.

Something is very wrong somewhere – the heart in this case is an innocent bystander being whipped into a frenzy to compensate for something.

At the moment the whip is a norepinephrine infusion being used to keep his blood pressure up.

I ask the nurse if the amount of norepinephrine infusing has been stable.  She replies that his dose has been slowly escalating.

Eureka! I think – the heart rate response in this case is being driven by the norepinephrine – a powerful adrenaline that acts on beta receptors and alpha receptors within the body that increase heart rate and constrict the blood vessels to raise blood pressure.  Fix the cause of the low blood pressure, come down on the norepinephrine, and perhaps the heart rate would be better.

But it turns out this particular post surgical patient doesn’t have a medical cause of low blood pressure I can find.  I cycle through cardiac ultrasounds, blood gases, steroid and volume challenges, and try inching down on the norepinephrine.

All of it is to no avail.  I’m growing more and more convinced this problem is surgical in nature. Perhaps an infarcted piece of bowel?  All I know is that the man acts like he has no peripheral vascular tone.

An interesting thing happens shortly after.  The norepinephrine drip runs out.

As one nurse runs to get another bag from the pharmacy – a quick cascade of events unfolds.

The brisk upstroke from the arterial line that marks the pressure wave generated with every beat of the heart starts to dampen.  The color seems to visibly drain from the patients face, and he begins to complain that his vision is getting blurry.  His systolic blood pressure is 70 – an almost forty point drop within a minute of the norepinephrine running out.

I call for help.

I try to keep a level tone.  Project control, not panic.

“Open the code cart, I need a half a milligram of epinephrine”

“You’re going to be ok, sir.  Hang with me.”  I squeeze his hand.

He closes his eyes

The code cart – a fully stocked cabinet on wheels with almost everything you need for resuscitation efforts – is wheeled into the room. The epinephrine vial is handed to the nurse, and hurriedly pushed.

Within seconds, I can see the blood pressure and heart rate rise.  The patient’s grip on my hand relaxes.  Or maybe its my grip on his hand.  I forget which.  His vision returns to normal as his blood pressure ‘normalizes’.

Of course nothing has been fixed.  Why his blood pressure remains low continues to be a mystery.  The bag of norepinephrine soon isn’t enough even at its maximal dose.  The same scenario (hypotension -> pallor -> vision loss ) recurs 30 minutes later, and another bolus of epinephrine aborts a rapid spiral towards pulselessness.

This case is an anecdote, the weakest possible form of evidence apparently.  Yet there are powerful lessons learned that night. Blood flows in pulsatile fashion with a certain pressure head.  Below some threshold of pressure, the end organs of the body stop functioning.  Agents that are active on peripheral vasoconstrictor receptors (norepinephrine, epinephrine) raise blood pressure.  Epinephrine was keeping this patient alive while a team worked to understand why his blood pressure was so low.  My suspicion was that he was in something called distributive shock – a catastrophic life threatening syndrome that requires a furious hunt for cause to save the patient.  Overwhelming infection and an even more aggressive immune response renders normally relatively impervious vasculature to be a sieve.  At the present time the therapy is directed towards replacing the fluid lost in the intravascular space and using medications that act on peripheral vascular receptors that increase peripheral tone.

There is, of course, much that isn’t known about this process.  Hopefully it will come to pass that we will arrive at a better understanding of what specifically creates this mileu so our therapies may be more directed.  But for the time being, our solutions are limited by our current, always imperfect understanding of the world.

The culprit in this case was a leak of intestinal contents into the peritoneal space from two pieces of bowel that should have been exactly apposed.  The body had attempted to tell us this very thing with that high heart rate post-operatively.  It took us, the clinicians, some time to translate.

The uninformed prior: Unlearning what has been learned.

For many, medicine has for too long been an imperfect science.  The history of medicine is replete with physicians acting with certainty in a manner that – in hindsight – was ineffective, or even worse – harmful.  Blood letting to allow the release of bad humors is believed to have hastened the demise of the greatest American – George Washington.  The disconcerting part of this is that the physician players were not motivated by anything but the best intentions.  They relied on their experience, intuition and judgement to deliver exactly the wrong prescription.   Intuition fails.  No matter how many patients died soon after blood letting, operating biases didn’t let physicians link the two events.  After all, the patients may have died even sooner if blood letting hadn’t been done.

The idea that medicine had progressed – by the 1980’s – to the point that doctors were not engaged in the equivalent of blood letting came under heavy fire when it was demonstrated a number of standard practices of the time could indeed be ineffective.  Extra beats (also known as ectopic heart beats) after heart attacks were noted in cardiac units to portend a higher risk of dying suddenly.  The obvious approach to this was to use medications that effectively suppressed ectopic heart beats.  Testing this in a double blind randomized control trial did not just demonstrate ineffectiveness, but harm.  More people randomized to suppression of ectopic beats actually died.  It turns out the anti-arrhythmic drugs being used were actually proarrhythmic as well.  The attack on ‘expertise’ that relied on intuition and experience was on, and it was a rout.

Glue ear – a condition that developed in the middle ears of little kids after ear infections  was treated with insertion of a tube to drain that space.  The trial to determine efficacy using a randomized trial to blindly allocate patients to surgery or no treatment?

Negative.

Many of the children turned out to do just fine if you left them alone.  Given the fact that all procedures have a certain complication rate, the lack of efficacy here was no small matter.

And so it went – the populace had to be on guard not just against the afflictions of disease, but against the intuitions of its doctors.

Uncertainty reigned, and in search of certainty, the field fled to the warm embrace of ever greater empiricism.  In the early ’80s from the McMaster University in Canada, David Sackett gave voice to a new sheriff – Evidence Based Medicine (EBM).

“EBM de-emphasizes intuition, unsystematic clinical expertise, and pathophysiologic rationale . . . and stresses the examination of evidence from clinical research. In 1960, the randomized trial was an oddity. It is now accepted that virtually no drug can enter clinical practice without a demonstration of its efficacy in clinical trials. Moreover the same randomized trial method is increasingly being applied to surgical therapies and diagnostic tests.” (Sackett et. al, Evidence Based Medicine)

The premise as outlined is simple – don’t believe anything that hasn’t been tested in a randomized control trial.  The only real evidence is that found within RCTs or in reviews that amalgamated RCTs.

The usual response from EBM experts can be found below in the response to the statement that real evidence may come from outside an RCT.

It is quite possible Professor Francis is right on here about the specific subject being discussed, but the point is that there is an established hierarchy of evidence on display.  The RCT is king, everything else is no better than the court jester.

While an RCT may certainly be better than anything cobbled together at a pub, the conventional parallel group RCT certainly isn’t always King of the Hill.   As nicely expounded on by the prolific statistician Stephen Senn, there are plenty of potential errors the conventional RCT finds itself humbled by.

The clinician may thus feel somewhat mollified about conclusions drawn about the effect of epinephrine in the earlier anecdote.

The idea that real evidence may live outside the confines of RCTs was also countered by none other than the godfather of EBM, David Sackett:

“Evidence based medicine is not restricted to randomized trials and meta-analyses. It involves tracking down the best external evidence with which to answer our clinical questions. To find out about the accuracy of a diagnostic test, we need to find proper cross sectional studies of patients clinically suspected of harboring the relevant disorder, not a randomized trial. For a question about prognosis, we need proper follow up studies of patients assembled at a uniform, early point in the clinical course of their disease. And sometimes the evidence we need will come from the basic sciences such as genetics or immunology. It is when asking questions about therapy that we should try to avoid the non-experimental approaches, since these routinely lead to false positive conclusions about efficacy. Because the randomized trial, and especially the systematic review of several randomized trials, is so much more likely to inform us and so much less likely to mislead us, it has become the “gold standard” for judging whether a treatment does more good than harm. However,some questions about therapy do not require randomized trials (successful interventions for otherwise fatal conditions) or cannot wait for the trials to be conducted. And if no randomized trial has been carried out for our patient’s predicament, we must follow the trail to the next best external evidence and work from there. (Sacket et al, Evidence based medicine: what it is.. )”

Sackett also noted that there were therapies whose ” ‘face validity’ is so great that randomized trials were unanimously judged by the team to be both unnecessary, and, if a placebo would have been involved, unethical”.

In effect, there was always an escape clause to let common sense prevail over EBM.  But as frequently happens in movements, the second generation of followers moves in directions unintended by the founders.  If the safeguards in place involve only areas where equipoise exists, but equipoise is itself determined by fallible judgement, the range of unacceptable experiments becomes very narrow.  This especially applies to new therapies where members of the community not involved in design and development have skeptical prior beliefs.  This is, of course, not a bad thing – it is entirely possible that the usually overoptimistic prior of the developers of a new therapy are farther from the truth than the skeptics.  But it is a major problem if we ask doctors to discard their prior beliefs that are not based in RCTs.  In doing so, we are manufacturing equipoise.  This means travel in dangerous ethical waters for physicians and their patients that is at best unwise, and at worst willfully foolish.

The EBM Wars: Manufacturing Equipoise (Part 1) published first on https://wittooth.tumblr.com/

[kristinsimmons]

The EBM Wars: Manufacturing Equipoise (Part 1)

By ANISH KOKA

The phone rings.  It’s not supposed to be ringing.  It’s 2 am.   The voice on the other line is from an apologetic surgery resident.

Resident: There is this patient..

Me: Yes, go ahead. Please.

Resident: He’s tachycardic.

Me: How fast?

Resident: 160 ?

Me: What’s the blood pressure?

Resident: 130/90

Me: Rhythm?

Resident: An SVT I think.. I gave adenosine.  Nothing happened

Me: Audibly groaning.  I’ll be in..

Forty five minutes later I’m at the bedside of a decidedly ill appearing man.

I want to be triumphant that his heart rate is only 145, and a quick glance at the telemetry monitor above his bed uncovers juicy p waves in a cadence that suggests this is no primary electrical arrhythmia.

Something is very wrong somewhere – the heart in this case is an innocent bystander being whipped into a frenzy to compensate for something.

At the moment the whip is a norepinephrine infusion being used to keep his blood pressure up.

I ask the nurse if the amount of norepinephrine infusing has been stable.  She replies that his dose has been slowly escalating.

Eureka! I think – the heart rate response in this case is being driven by the norepinephrine – a powerful adrenaline that acts on beta receptors and alpha receptors within the body that increase heart rate and constrict the blood vessels to raise blood pressure.  Fix the cause of the low blood pressure, come down on the norepinephrine, and perhaps the heart rate would be better.

But it turns out this particular post surgical patient doesn’t have a medical cause of low blood pressure I can find.  I cycle through cardiac ultrasounds, blood gases, steroid and volume challenges, and try inching down on the norepinephrine.

All of it is to no avail.  I’m growing more and more convinced this problem is surgical in nature. Perhaps an infarcted piece of bowel?  All I know is that the man acts like he has no peripheral vascular tone.

An interesting thing happens shortly after.  The norepinephrine drip runs out.

As one nurse runs to get another bag from the pharmacy – a quick cascade of events unfolds.

The brisk upstroke from the arterial line that marks the pressure wave generated with every beat of the heart starts to dampen.  The color seems to visibly drain from the patients face, and he begins to complain that his vision is getting blurry.  His systolic blood pressure is 70 – an almost forty point drop within a minute of the norepinephrine running out.

I call for help.

I try to keep a level tone.  Project control, not panic.

“Open the code cart, I need a half a milligram of epinephrine”

“You’re going to be ok, sir.  Hang with me.”  I squeeze his hand.

He closes his eyes

The code cart – a fully stocked cabinet on wheels with almost everything you need for resuscitation efforts – is wheeled into the room. The epinephrine vial is handed to the nurse, and hurriedly pushed.

Within seconds, I can see the blood pressure and heart rate rise.  The patient’s grip on my hand relaxes.  Or maybe its my grip on his hand.  I forget which.  His vision returns to normal as his blood pressure ‘normalizes’.

Of course nothing has been fixed.  Why his blood pressure remains low continues to be a mystery.  The bag of norepinephrine soon isn’t enough even at its maximal dose.  The same scenario (hypotension -> pallor -> vision loss ) recurs 30 minutes later, and another bolus of epinephrine aborts a rapid spiral towards pulselessness.

This case is an anecdote, the weakest possible form of evidence apparently.  Yet there are powerful lessons learned that night. Blood flows in pulsatile fashion with a certain pressure head.  Below some threshold of pressure, the end organs of the body stop functioning.  Agents that are active on peripheral vasoconstrictor receptors (norepinephrine, epinephrine) raise blood pressure.  Epinephrine was keeping this patient alive while a team worked to understand why his blood pressure was so low.  My suspicion was that he was in something called distributive shock – a catastrophic life threatening syndrome that requires a furious hunt for cause to save the patient.  Overwhelming infection and an even more aggressive immune response renders normally relatively impervious vasculature to be a sieve.  At the present time the therapy is directed towards replacing the fluid lost in the intravascular space and using medications that act on peripheral vascular receptors that increase peripheral tone.

There is, of course, much that isn’t known about this process.  Hopefully it will come to pass that we will arrive at a better understanding of what specifically creates this mileu so our therapies may be more directed.  But for the time being, our solutions are limited by our current, always imperfect understanding of the world.

The culprit in this case was a leak of intestinal contents into the peritoneal space from two pieces of bowel that should have been exactly apposed.  The body had attempted to tell us this very thing with that high heart rate post-operatively.  It took us, the clinicians, some time to translate.

The uninformed prior: Unlearning what has been learned.

For many, medicine has for too long been an imperfect science.  The history of medicine is replete with physicians acting with certainty in a manner that – in hindsight – was ineffective, or even worse – harmful.  Blood letting to allow the release of bad humors is believed to have hastened the demise of the greatest American – George Washington.  The disconcerting part of this is that the physician players were not motivated by anything but the best intentions.  They relied on their experience, intuition and judgement to deliver exactly the wrong prescription.   Intuition fails.  No matter how many patients died soon after blood letting, operating biases didn’t let physicians link the two events.  After all, the patients may have died even sooner if blood letting hadn’t been done.

The idea that medicine had progressed – by the 1980’s – to the point that doctors were not engaged in the equivalent of blood letting came under heavy fire when it was demonstrated a number of standard practices of the time could indeed be ineffective.  Extra beats (also known as ectopic heart beats) after heart attacks were noted in cardiac units to portend a higher risk of dying suddenly.  The obvious approach to this was to use medications that effectively suppressed ectopic heart beats.  Testing this in a double blind randomized control trial did not just demonstrate ineffectiveness, but harm.  More people randomized to suppression of ectopic beats actually died.  It turns out the anti-arrhythmic drugs being used were actually proarrhythmic as well.  The attack on ‘expertise’ that relied on intuition and experience was on, and it was a rout.

Glue ear – a condition that developed in the middle ears of little kids after ear infections  was treated with insertion of a tube to drain that space.  The trial to determine efficacy using a randomized trial to blindly allocate patients to surgery or no treatment?

Negative.

Many of the children turned out to do just fine if you left them alone.  Given the fact that all procedures have a certain complication rate, the lack of efficacy here was no small matter.

And so it went – the populace had to be on guard not just against the afflictions of disease, but against the intuitions of its doctors.

Uncertainty reigned, and in search of certainty, the field fled to the warm embrace of ever greater empiricism.  In the early ’80s from the McMaster University in Canada, David Sackett gave voice to a new sheriff – Evidence Based Medicine (EBM).

“EBM de-emphasizes intuition, unsystematic clinical expertise, and pathophysiologic rationale . . . and stresses the examination of evidence from clinical research. In 1960, the randomized trial was an oddity. It is now accepted that virtually no drug can enter clinical practice without a demonstration of its efficacy in clinical trials. Moreover the same randomized trial method is increasingly being applied to surgical therapies and diagnostic tests.” (Sackett et. al, Evidence Based Medicine)

The premise as outlined is simple – don’t believe anything that hasn’t been tested in a randomized control trial.  The only real evidence is that found within RCTs or in reviews that amalgamated RCTs.

The usual response from EBM experts can be found below in the response to the statement that real evidence may come from outside an RCT.

It is quite possible Professor Francis is right on here about the specific subject being discussed, but the point is that there is an established hierarchy of evidence on display.  The RCT is king, everything else is no better than the court jester.

While an RCT may certainly be better than anything cobbled together at a pub, the conventional parallel group RCT certainly isn’t always King of the Hill.   As nicely expounded on by the prolific statistician Stephen Senn, there are plenty of potential errors the conventional RCT finds itself humbled by.

The clinician may thus feel somewhat mollified about conclusions drawn about the effect of epinephrine in the earlier anecdote.

The idea that real evidence may live outside the confines of RCTs was also countered by none other than the godfather of EBM, David Sackett:

“Evidence based medicine is not restricted to randomized trials and meta-analyses. It involves tracking down the best external evidence with which to answer our clinical questions. To find out about the accuracy of a diagnostic test, we need to find proper cross sectional studies of patients clinically suspected of harboring the relevant disorder, not a randomized trial. For a question about prognosis, we need proper follow up studies of patients assembled at a uniform, early point in the clinical course of their disease. And sometimes the evidence we need will come from the basic sciences such as genetics or immunology. It is when asking questions about therapy that we should try to avoid the non-experimental approaches, since these routinely lead to false positive conclusions about efficacy. Because the randomized trial, and especially the systematic review of several randomized trials, is so much more likely to inform us and so much less likely to mislead us, it has become the “gold standard” for judging whether a treatment does more good than harm. However,some questions about therapy do not require randomized trials (successful interventions for otherwise fatal conditions) or cannot wait for the trials to be conducted. And if no randomized trial has been carried out for our patient’s predicament, we must follow the trail to the next best external evidence and work from there. (Sacket et al, Evidence based medicine: what it is.. )”

Sackett also noted that there were therapies whose ” ‘face validity’ is so great that randomized trials were unanimously judged by the team to be both unnecessary, and, if a placebo would have been involved, unethical”.

In effect, there was always an escape clause to let common sense prevail over EBM.  But as frequently happens in movements, the second generation of followers moves in directions unintended by the founders.  If the safeguards in place involve only areas where equipoise exists, but equipoise is itself determined by fallible judgement, the range of unacceptable experiments becomes very narrow.  This especially applies to new therapies where members of the community not involved in design and development have skeptical prior beliefs.  This is, of course, not a bad thing – it is entirely possible that the usually overoptimistic prior of the developers of a new therapy are farther from the truth than the skeptics.  But it is a major problem if we ask doctors to discard their prior beliefs that are not based in RCTs.  In doing so, we are manufacturing equipoise.  This means travel in dangerous ethical waters for physicians and their patients that is at best unwise, and at worst willfully foolish.

The EBM Wars: Manufacturing Equipoise (Part 1) published first on https://wittooth.tumblr.com/

[kristinsimmons]

The EBM Wars: Manufacturing Equipoise (Part 1)

By ANISH KOKA

The phone rings.  It’s not supposed to be ringing.  It’s 2 am.   The voice on the other line is from an apologetic surgery resident.

Resident: There is this patient..

Me: Yes, go ahead. Please.

Resident: He’s tachycardic.

Me: How fast?

Resident: 160 ?

Me: What’s the blood pressure?

Resident: 130/90

Me: Rhythm?

Resident: An SVT I think.. I gave adenosine.  Nothing happened

Me: Audibly groaning.  I’ll be in..

Forty five minutes later I’m at the bedside of a decidedly ill appearing man.

I want to be triumphant that his heart rate is only 145, and a quick glance at the telemetry monitor above his bed uncovers juicy p waves in a cadence that suggests this is no primary electrical arrhythmia.

Something is very wrong somewhere – the heart in this case is an innocent bystander being whipped into a frenzy to compensate for something.

At the moment the whip is a norepinephrine infusion being used to keep his blood pressure up.

I ask the nurse if the amount of norepinephrine infusing has been stable.  She replies that his dose has been slowly escalating.

Eureka! I think – the heart rate response in this case is being driven by the norepinephrine – a powerful adrenaline that acts on beta receptors and alpha receptors within the body that increase heart rate and constrict the blood vessels to raise blood pressure.  Fix the cause of the low blood pressure, come down on the norepinephrine, and perhaps the heart rate would be better.

But it turns out this particular post surgical patient doesn’t have a medical cause of low blood pressure I can find.  I cycle through cardiac ultrasounds, blood gases, steroid and volume challenges, and try inching down on the norepinephrine.

All of it is to no avail.  I’m growing more and more convinced this problem is surgical in nature. Perhaps an infarcted piece of bowel?  All I know is that the man acts like he has no peripheral vascular tone.

An interesting thing happens shortly after.  The norepinephrine drip runs out.

As one nurse runs to get another bag from the pharmacy – a quick cascade of events unfolds.

The brisk upstroke from the arterial line that marks the pressure wave generated with every beat of the heart starts to dampen.  The color seems to visibly drain from the patients face, and he begins to complain that his vision is getting blurry.  His systolic blood pressure is 70 – an almost forty point drop within a minute of the norepinephrine running out.

I call for help.

I try to keep a level tone.  Project control, not panic.

“Open the code cart, I need a half a milligram of epinephrine”

“You’re going to be ok, sir.  Hang with me.”  I squeeze his hand.

He closes his eyes

The code cart – a fully stocked cabinet on wheels with almost everything you need for resuscitation efforts – is wheeled into the room. The epinephrine vial is handed to the nurse, and hurriedly pushed.

Within seconds, I can see the blood pressure and heart rate rise.  The patient’s grip on my hand relaxes.  Or maybe its my grip on his hand.  I forget which.  His vision returns to normal as his blood pressure ‘normalizes’.

Of course nothing has been fixed.  Why his blood pressure remains low continues to be a mystery.  The bag of norepinephrine soon isn’t enough even at its maximal dose.  The same scenario (hypotension -> pallor -> vision loss ) recurs 30 minutes later, and another bolus of epinephrine aborts a rapid spiral towards pulselessness.

This case is an anecdote, the weakest possible form of evidence apparently.  Yet there are powerful lessons learned that night. Blood flows in pulsatile fashion with a certain pressure head.  Below some threshold of pressure, the end organs of the body stop functioning.  Agents that are active on peripheral vasoconstrictor receptors (norepinephrine, epinephrine) raise blood pressure.  Epinephrine was keeping this patient alive while a team worked to understand why his blood pressure was so low.  My suspicion was that he was in something called distributive shock – a catastrophic life threatening syndrome that requires a furious hunt for cause to save the patient.  Overwhelming infection and an even more aggressive immune response renders normally relatively impervious vasculature to be a sieve.  At the present time the therapy is directed towards replacing the fluid lost in the intravascular space and using medications that act on peripheral vascular receptors that increase peripheral tone.

There is, of course, much that isn’t known about this process.  Hopefully it will come to pass that we will arrive at a better understanding of what specifically creates this mileu so our therapies may be more directed.  But for the time being, our solutions are limited by our current, always imperfect understanding of the world.

The culprit in this case was a leak of intestinal contents into the peritoneal space from two pieces of bowel that should have been exactly apposed.  The body had attempted to tell us this very thing with that high heart rate post-operatively.  It took us, the clinicians, some time to translate.

The uninformed prior: Unlearning what has been learned.

For many, medicine has for too long been an imperfect science.  The history of medicine is replete with physicians acting with certainty in a manner that – in hindsight – was ineffective, or even worse – harmful.  Blood letting to allow the release of bad humors is believed to have hastened the demise of the greatest American – George Washington.  The disconcerting part of this is that the physician players were not motivated by anything but the best intentions.  They relied on their experience, intuition and judgement to deliver exactly the wrong prescription.   Intuition fails.  No matter how many patients died soon after blood letting, operating biases didn’t let physicians link the two events.  After all, the patients may have died even sooner if blood letting hadn’t been done.

The idea that medicine had progressed – by the 1980’s – to the point that doctors were not engaged in the equivalent of blood letting came under heavy fire when it was demonstrated a number of standard practices of the time could indeed be ineffective.  Extra beats (also known as ectopic heart beats) after heart attacks were noted in cardiac units to portend a higher risk of dying suddenly.  The obvious approach to this was to use medications that effectively suppressed ectopic heart beats.  Testing this in a double blind randomized control trial did not just demonstrate ineffectiveness, but harm.  More people randomized to suppression of ectopic beats actually died.  It turns out the anti-arrhythmic drugs being used were actually proarrhythmic as well.  The attack on ‘expertise’ that relied on intuition and experience was on, and it was a rout.

Glue ear – a condition that developed in the middle ears of little kids after ear infections  was treated with insertion of a tube to drain that space.  The trial to determine efficacy using a randomized trial to blindly allocate patients to surgery or no treatment?

Negative.

Many of the children turned out to do just fine if you left them alone.  Given the fact that all procedures have a certain complication rate, the lack of efficacy here was no small matter.

And so it went – the populace had to be on guard not just against the afflictions of disease, but against the intuitions of its doctors.

Uncertainty reigned, and in search of certainty, the field fled to the warm embrace of ever greater empiricism.  In the early ’80s from the McMaster University in Canada, David Sackett gave voice to a new sheriff – Evidence Based Medicine (EBM).

“EBM de-emphasizes intuition, unsystematic clinical expertise, and pathophysiologic rationale . . . and stresses the examination of evidence from clinical research. In 1960, the randomized trial was an oddity. It is now accepted that virtually no drug can enter clinical practice without a demonstration of its efficacy in clinical trials. Moreover the same randomized trial method is increasingly being applied to surgical therapies and diagnostic tests.” (Sackett et. al, Evidence Based Medicine)

The premise as outlined is simple – don’t believe anything that hasn’t been tested in a randomized control trial.  The only real evidence is that found within RCTs or in reviews that amalgamated RCTs.

The usual response from EBM experts can be found below in the response to the statement that real evidence may come from outside an RCT.

It is quite possible Professor Francis is right on here about the specific subject being discussed, but the point is that there is an established hierarchy of evidence on display.  The RCT is king, everything else is no better than the court jester.

While an RCT may certainly be better than anything cobbled together at a pub, the conventional parallel group RCT certainly isn’t always King of the Hill.   As nicely expounded on by the prolific statistician Stephen Senn, there are plenty of potential errors the conventional RCT finds itself humbled by.

The clinician may thus feel somewhat mollified about conclusions drawn about the effect of epinephrine in the earlier anecdote.

The idea that real evidence may live outside the confines of RCTs was also countered by none other than the godfather of EBM, David Sackett:

“Evidence based medicine is not restricted to randomized trials and meta-analyses. It involves tracking down the best external evidence with which to answer our clinical questions. To find out about the accuracy of a diagnostic test, we need to find proper cross sectional studies of patients clinically suspected of harboring the relevant disorder, not a randomized trial. For a question about prognosis, we need proper follow up studies of patients assembled at a uniform, early point in the clinical course of their disease. And sometimes the evidence we need will come from the basic sciences such as genetics or immunology. It is when asking questions about therapy that we should try to avoid the non-experimental approaches, since these routinely lead to false positive conclusions about efficacy. Because the randomized trial, and especially the systematic review of several randomized trials, is so much more likely to inform us and so much less likely to mislead us, it has become the “gold standard” for judging whether a treatment does more good than harm. However,some questions about therapy do not require randomized trials (successful interventions for otherwise fatal conditions) or cannot wait for the trials to be conducted. And if no randomized trial has been carried out for our patient’s predicament, we must follow the trail to the next best external evidence and work from there. (Sacket et al, Evidence based medicine: what it is.. )”

Sackett also noted that there were therapies whose ” ‘face validity’ is so great that randomized trials were unanimously judged by the team to be both unnecessary, and, if a placebo would have been involved, unethical”.

In effect, there was always an escape clause to let common sense prevail over EBM.  But as frequently happens in movements, the second generation of followers moves in directions unintended by the founders.  If the safeguards in place involve only areas where equipoise exists, but equipoise is itself determined by fallible judgement, the range of unacceptable experiments becomes very narrow.  This especially applies to new therapies where members of the community not involved in design and development have skeptical prior beliefs.  This is, of course, not a bad thing – it is entirely possible that the usually overoptimistic prior of the developers of a new therapy are farther from the truth than the skeptics.  But it is a major problem if we ask doctors to discard their prior beliefs that are not based in RCTs.  In doing so, we are manufacturing equipoise.  This means travel in dangerous ethical waters for physicians and their patients that is at best unwise, and at worst willfully foolish.

The EBM Wars: Manufacturing Equipoise (Part 1) published first on https://wittooth.tumblr.com/