Opinion

As we settle back into our daily routines following another fantastic DDW, I’d like to take a moment to congratulate this year’s AGA’s Recognition Award recipients, who have made outstanding contributions to the organization and to our field, including through excellence in clinical practice, research, mentorship, and DEI.

This month’s Member Spotlight column highlights one of these remarkable individuals, Dr. Scott Ketover, president and CEO of MNGI Digestive Health, who is the recipient of this year’s AGA Distinguished Clinician Award in Private Practice. We hope you enjoy learning more about Scott, as well as the other award recipients who were recognized at a special ceremony in DC last month.

University of Michigan

Also highlighted in our June issue is the FDA’s recent approval of subcutaneous vedolizumab for Crohn’s maintenance therapy, an exciting development that will provide us with more flexible treatment options for our patients. We also report on the 2024 AGA Tech Summit (Chicago, IL), and introduce the winners (survivors?) of its annual Shark Tank competition, Dr. Renu Dhanasekaran and Dr. Venthan Elango. Their company, Arithmedics, which developed technology that harnesses generative AI and data intelligence to streamline medical billing, was identified as the most promising among a robust field of entrants.

We also present some of the best clinically oriented content from our GI journals, including an observational study from Gastroenterology evaluating the effect of longitudinal alcohol use on risk of cirrhosis among patients with steatotic liver disease, and summarize recently released AGA Clinical Practice Updates on performance of high-quality upper endoscopy and treatment of cannabinoid hyperemesis syndrome. We hope you enjoy all the exciting content featured in this issue and take some well-deserved time to rest and recharge this summer!

Megan A. Adams, MD, JD, MSc

Editor-in-Chief

As we settle back into our daily routines following another fantastic DDW, I’d like to take a moment to congratulate this year’s AGA’s Recognition Award recipients, who have made outstanding contributions to the organization and to our field, including through excellence in clinical practice, research, mentorship, and DEI.

This month’s Member Spotlight column highlights one of these remarkable individuals, Dr. Scott Ketover, president and CEO of MNGI Digestive Health, who is the recipient of this year’s AGA Distinguished Clinician Award in Private Practice. We hope you enjoy learning more about Scott, as well as the other award recipients who were recognized at a special ceremony in DC last month.

University of Michigan

Also highlighted in our June issue is the FDA’s recent approval of subcutaneous vedolizumab for Crohn’s maintenance therapy, an exciting development that will provide us with more flexible treatment options for our patients. We also report on the 2024 AGA Tech Summit (Chicago, IL), and introduce the winners (survivors?) of its annual Shark Tank competition, Dr. Renu Dhanasekaran and Dr. Venthan Elango. Their company, Arithmedics, which developed technology that harnesses generative AI and data intelligence to streamline medical billing, was identified as the most promising among a robust field of entrants.

We also present some of the best clinically oriented content from our GI journals, including an observational study from Gastroenterology evaluating the effect of longitudinal alcohol use on risk of cirrhosis among patients with steatotic liver disease, and summarize recently released AGA Clinical Practice Updates on performance of high-quality upper endoscopy and treatment of cannabinoid hyperemesis syndrome. We hope you enjoy all the exciting content featured in this issue and take some well-deserved time to rest and recharge this summer!

Megan A. Adams, MD, JD, MSc

Editor-in-Chief

As we settle back into our daily routines following another fantastic DDW, I’d like to take a moment to congratulate this year’s AGA’s Recognition Award recipients, who have made outstanding contributions to the organization and to our field, including through excellence in clinical practice, research, mentorship, and DEI.

This month’s Member Spotlight column highlights one of these remarkable individuals, Dr. Scott Ketover, president and CEO of MNGI Digestive Health, who is the recipient of this year’s AGA Distinguished Clinician Award in Private Practice. We hope you enjoy learning more about Scott, as well as the other award recipients who were recognized at a special ceremony in DC last month.

University of Michigan

Also highlighted in our June issue is the FDA’s recent approval of subcutaneous vedolizumab for Crohn’s maintenance therapy, an exciting development that will provide us with more flexible treatment options for our patients. We also report on the 2024 AGA Tech Summit (Chicago, IL), and introduce the winners (survivors?) of its annual Shark Tank competition, Dr. Renu Dhanasekaran and Dr. Venthan Elango. Their company, Arithmedics, which developed technology that harnesses generative AI and data intelligence to streamline medical billing, was identified as the most promising among a robust field of entrants.

We also present some of the best clinically oriented content from our GI journals, including an observational study from Gastroenterology evaluating the effect of longitudinal alcohol use on risk of cirrhosis among patients with steatotic liver disease, and summarize recently released AGA Clinical Practice Updates on performance of high-quality upper endoscopy and treatment of cannabinoid hyperemesis syndrome. We hope you enjoy all the exciting content featured in this issue and take some well-deserved time to rest and recharge this summer!

Megan A. Adams, MD, JD, MSc

Editor-in-Chief

In Part 2 of this series on PCP Compensation, I concluded by saying that it is possible, maybe even likely, that growing your panel size will further endanger your health. When you share this concern with your boss, based purely on economic principles, he or she should answer, “How about charging more per visit?” However, your boss knows that third-party payers are going to look askance at that simple strategy. He or she may then suggest that you make each visit worth more to justify the increased charge.

Here is where the topic of Relative Value Units (RVUs) raises its ugly head.

Before the invention of “health insurance,” when the patient paid for his or her own office visits, it was an unspoken negotiation between patient and physician that decided the value of the care.

When third-party payers first came on the scene, the value of the visit was based roughly on the time spent with the patient. Coupling time spent with value gave no credit to more experienced or skilled physicians who were more efficient at managing their patients. If, on average, it took me 10 minutes to effectively manage an ear infection and my younger associate 20 minutes, should he or she be paid twice as much as I’m paid?

But, value spent on a crude estimate of time spent was a system ripe for abuse.

I have no way of knowing what other physicians were doing, but I suspect I was not alone in factoring my own assessment of “complexity” into the calculation when deciding what to bill for a visit, giving only a passing glance at the recommended time-based definitions of short, standard, and complex visits. The payers then began demanding a more definable method of determining complexity. The result was the RVU, the labor-intensive, but no more accurate, system in which the provider must build a case to defend his or her charges.

Unfortunately, the institution of the RVU system was a major contributor to the death of the short visit. The extra work required to submit and defend the coding of any visit meant that, from a strictly clerical point of view, the short visit became as costly to the business to process as a more complex visit. The result was that every astute business consultant worth his or her salt would begin with the recommendation to “Code up!” Do whatever it takes to build your case for a more complex visit even though it may be a stretch. (It would certainly mean a lot more time-gobbling documenting.) Stop doing short visits. They are your loss leaders.

Before there were RVUs, there was a way physicians could be profitable and include short visits in their schedule. But it meant the provider had to be efficient. But patients generally don’t like going to follow-up visits they see as needless. And, more often than not, the patients are correct. However, patients love the same-day availability that an abundance of short visits in a primary care provider’s schedule can offer. The patient who knows that he or she won’t have to wait weeks or months to see the provider is far less likely to show up at a visit with a laundry list as long as their arm of problems and questions they have saved up while they were waiting to get an appointment. It used to be possible to provide efficient and profitable care by including short visits in a PCP’s schedule. Whether it can still be done under the current RVU system is unclear and probably doubtful.

In the last and final Letter in this series, we will begin with a brief look at efficiency and a PCP’s contribution to overhead before exploring the more difficult subject of defining the quality of a provider’s care and how this could relate to compensation.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

In Part 2 of this series on PCP Compensation, I concluded by saying that it is possible, maybe even likely, that growing your panel size will further endanger your health. When you share this concern with your boss, based purely on economic principles, he or she should answer, “How about charging more per visit?” However, your boss knows that third-party payers are going to look askance at that simple strategy. He or she may then suggest that you make each visit worth more to justify the increased charge.

Here is where the topic of Relative Value Units (RVUs) raises its ugly head.

Before the invention of “health insurance,” when the patient paid for his or her own office visits, it was an unspoken negotiation between patient and physician that decided the value of the care.

When third-party payers first came on the scene, the value of the visit was based roughly on the time spent with the patient. Coupling time spent with value gave no credit to more experienced or skilled physicians who were more efficient at managing their patients. If, on average, it took me 10 minutes to effectively manage an ear infection and my younger associate 20 minutes, should he or she be paid twice as much as I’m paid?

But, value spent on a crude estimate of time spent was a system ripe for abuse.

I have no way of knowing what other physicians were doing, but I suspect I was not alone in factoring my own assessment of “complexity” into the calculation when deciding what to bill for a visit, giving only a passing glance at the recommended time-based definitions of short, standard, and complex visits. The payers then began demanding a more definable method of determining complexity. The result was the RVU, the labor-intensive, but no more accurate, system in which the provider must build a case to defend his or her charges.

Unfortunately, the institution of the RVU system was a major contributor to the death of the short visit. The extra work required to submit and defend the coding of any visit meant that, from a strictly clerical point of view, the short visit became as costly to the business to process as a more complex visit. The result was that every astute business consultant worth his or her salt would begin with the recommendation to “Code up!” Do whatever it takes to build your case for a more complex visit even though it may be a stretch. (It would certainly mean a lot more time-gobbling documenting.) Stop doing short visits. They are your loss leaders.

Before there were RVUs, there was a way physicians could be profitable and include short visits in their schedule. But it meant the provider had to be efficient. But patients generally don’t like going to follow-up visits they see as needless. And, more often than not, the patients are correct. However, patients love the same-day availability that an abundance of short visits in a primary care provider’s schedule can offer. The patient who knows that he or she won’t have to wait weeks or months to see the provider is far less likely to show up at a visit with a laundry list as long as their arm of problems and questions they have saved up while they were waiting to get an appointment. It used to be possible to provide efficient and profitable care by including short visits in a PCP’s schedule. Whether it can still be done under the current RVU system is unclear and probably doubtful.

In the last and final Letter in this series, we will begin with a brief look at efficiency and a PCP’s contribution to overhead before exploring the more difficult subject of defining the quality of a provider’s care and how this could relate to compensation.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

In Part 2 of this series on PCP Compensation, I concluded by saying that it is possible, maybe even likely, that growing your panel size will further endanger your health. When you share this concern with your boss, based purely on economic principles, he or she should answer, “How about charging more per visit?” However, your boss knows that third-party payers are going to look askance at that simple strategy. He or she may then suggest that you make each visit worth more to justify the increased charge.

Here is where the topic of Relative Value Units (RVUs) raises its ugly head.

Before the invention of “health insurance,” when the patient paid for his or her own office visits, it was an unspoken negotiation between patient and physician that decided the value of the care.

When third-party payers first came on the scene, the value of the visit was based roughly on the time spent with the patient. Coupling time spent with value gave no credit to more experienced or skilled physicians who were more efficient at managing their patients. If, on average, it took me 10 minutes to effectively manage an ear infection and my younger associate 20 minutes, should he or she be paid twice as much as I’m paid?

But, value spent on a crude estimate of time spent was a system ripe for abuse.

I have no way of knowing what other physicians were doing, but I suspect I was not alone in factoring my own assessment of “complexity” into the calculation when deciding what to bill for a visit, giving only a passing glance at the recommended time-based definitions of short, standard, and complex visits. The payers then began demanding a more definable method of determining complexity. The result was the RVU, the labor-intensive, but no more accurate, system in which the provider must build a case to defend his or her charges.

Unfortunately, the institution of the RVU system was a major contributor to the death of the short visit. The extra work required to submit and defend the coding of any visit meant that, from a strictly clerical point of view, the short visit became as costly to the business to process as a more complex visit. The result was that every astute business consultant worth his or her salt would begin with the recommendation to “Code up!” Do whatever it takes to build your case for a more complex visit even though it may be a stretch. (It would certainly mean a lot more time-gobbling documenting.) Stop doing short visits. They are your loss leaders.

Before there were RVUs, there was a way physicians could be profitable and include short visits in their schedule. But it meant the provider had to be efficient. But patients generally don’t like going to follow-up visits they see as needless. And, more often than not, the patients are correct. However, patients love the same-day availability that an abundance of short visits in a primary care provider’s schedule can offer. The patient who knows that he or she won’t have to wait weeks or months to see the provider is far less likely to show up at a visit with a laundry list as long as their arm of problems and questions they have saved up while they were waiting to get an appointment. It used to be possible to provide efficient and profitable care by including short visits in a PCP’s schedule. Whether it can still be done under the current RVU system is unclear and probably doubtful.

In the last and final Letter in this series, we will begin with a brief look at efficiency and a PCP’s contribution to overhead before exploring the more difficult subject of defining the quality of a provider’s care and how this could relate to compensation.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

This transcript has been edited for clarity.

As you all know by now, I’m always looking out for lifestyle changes that are both pleasurable and healthy. They are hard to find, especially when it comes to diet. My kids complain about this all the time: “When you say ‘healthy food,’ you just mean yucky food.” And yes, French fries are amazing, and no, we can’t have them three times a day.

So, when I saw an article claiming that olive oil reduces the risk for dementia, I was interested. I love olive oil; I cook with it all the time. But as is always the case in the world of nutritional epidemiology, we need to be careful. There are a lot of reasons to doubt the results of this study — and one reason to believe it’s true.

The study I’m talking about is “Consumption of Olive Oil and Diet Quality and Risk of Dementia-Related Death,” appearing in JAMA Network Open and following a well-trod formula in the nutritional epidemiology space.

Nearly 100,000 participants, all healthcare workers, filled out a food frequency questionnaire every 4 years with 130 questions touching on all aspects of diet: How often do you eat bananas, bacon, olive oil? Participants were followed for more than 20 years, and if they died, the cause of death was flagged as being dementia-related or not. Over that time frame there were around 38,000 deaths, of which 4751 were due to dementia.

The rest is just statistics. The authors show that those who reported consuming more olive oil were less likely to die from dementia — about 50% less likely, if you compare those who reported eating more than 7 grams of olive oil a day with those who reported eating none.
 

Is It What You Eat, or What You Don’t Eat?

And we could stop there if we wanted to; I’m sure big olive oil would be happy with that. Is there such a thing as “big olive oil”? But no, we need to dig deeper here because this study has the same problems as all nutritional epidemiology studies. Number one, no one is sitting around drinking small cups of olive oil. They consume it with other foods. And it was clear from the food frequency questionnaire that people who consumed more olive oil also consumed less red meat, more fruits and vegetables, more whole grains, more butter, and less margarine. And those are just the findings reported in the paper. I suspect that people who eat more olive oil also eat more tomatoes, for example, though data this granular aren’t shown. So, it can be really hard, in studies like this, to know for sure that it’s actually the olive oil that is helpful rather than some other constituent in the diet.

The flip side of that coin presents another issue. The food you eat is also a marker of the food you don’t eat. People who ate olive oil consumed less margarine, for example. At the time of this study, margarine was still adulterated with trans-fats, which a pretty solid evidence base suggests are really bad for your vascular system. So perhaps it’s not that olive oil is particularly good for you but that something else is bad for you. In other words, simply adding olive oil to your diet without changing anything else may not do anything.

The other major problem with studies of this sort is that people don’t consume food at random. The type of person who eats a lot of olive oil is simply different from the type of person who doesn›t. For one thing, olive oil is expensive. A 25-ounce bottle of olive oil is on sale at my local supermarket right now for $11.00. A similar-sized bottle of vegetable oil goes for $4.00.

Isn’t it interesting that food that costs more money tends to be associated with better health outcomes? (I’m looking at you, red wine.) Perhaps it’s not the food; perhaps it’s the money. We aren’t provided data on household income in this study, but we can see that the heavy olive oil users were less likely to be current smokers and they got more physical activity.

Now, the authors are aware of these limitations and do their best to account for them. In multivariable models, they adjust for other stuff in the diet, and even for income (sort of; they use census tract as a proxy for income, which is really a broad brush), and still find a significant though weakened association showing a protective effect of olive oil on dementia-related death. But still — adjustment is never perfect, and the small effect size here could definitely be due to residual confounding.
 

Evidence More Convincing

Now, I did tell you that there is one reason to believe that this study is true, but it’s not really from this study.

It’s from the PREDIMED randomized trial.

This is nutritional epidemiology I can get behind. Published in 2018, investigators in Spain randomized around 7500 participants to receive a liter of olive oil once a week vs mixed nuts, vs small nonfood gifts, the idea here being that if you have olive oil around, you’ll use it more. And people who were randomly assigned to get the olive oil had a 30% lower rate of cardiovascular events. A secondary analysis of that study found that the rate of development of mild cognitive impairment was 65% lower in those who were randomly assigned to olive oil. That’s an impressive result.

So, there might be something to this olive oil thing, but I’m not quite ready to add it to my “pleasurable things that are still good for you” list just yet. Though it does make me wonder: Can we make French fries in the stuff?
 

Dr. Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

As you all know by now, I’m always looking out for lifestyle changes that are both pleasurable and healthy. They are hard to find, especially when it comes to diet. My kids complain about this all the time: “When you say ‘healthy food,’ you just mean yucky food.” And yes, French fries are amazing, and no, we can’t have them three times a day.

So, when I saw an article claiming that olive oil reduces the risk for dementia, I was interested. I love olive oil; I cook with it all the time. But as is always the case in the world of nutritional epidemiology, we need to be careful. There are a lot of reasons to doubt the results of this study — and one reason to believe it’s true.

The study I’m talking about is “Consumption of Olive Oil and Diet Quality and Risk of Dementia-Related Death,” appearing in JAMA Network Open and following a well-trod formula in the nutritional epidemiology space.

Nearly 100,000 participants, all healthcare workers, filled out a food frequency questionnaire every 4 years with 130 questions touching on all aspects of diet: How often do you eat bananas, bacon, olive oil? Participants were followed for more than 20 years, and if they died, the cause of death was flagged as being dementia-related or not. Over that time frame there were around 38,000 deaths, of which 4751 were due to dementia.

The rest is just statistics. The authors show that those who reported consuming more olive oil were less likely to die from dementia — about 50% less likely, if you compare those who reported eating more than 7 grams of olive oil a day with those who reported eating none.
 

Is It What You Eat, or What You Don’t Eat?

And we could stop there if we wanted to; I’m sure big olive oil would be happy with that. Is there such a thing as “big olive oil”? But no, we need to dig deeper here because this study has the same problems as all nutritional epidemiology studies. Number one, no one is sitting around drinking small cups of olive oil. They consume it with other foods. And it was clear from the food frequency questionnaire that people who consumed more olive oil also consumed less red meat, more fruits and vegetables, more whole grains, more butter, and less margarine. And those are just the findings reported in the paper. I suspect that people who eat more olive oil also eat more tomatoes, for example, though data this granular aren’t shown. So, it can be really hard, in studies like this, to know for sure that it’s actually the olive oil that is helpful rather than some other constituent in the diet.

The flip side of that coin presents another issue. The food you eat is also a marker of the food you don’t eat. People who ate olive oil consumed less margarine, for example. At the time of this study, margarine was still adulterated with trans-fats, which a pretty solid evidence base suggests are really bad for your vascular system. So perhaps it’s not that olive oil is particularly good for you but that something else is bad for you. In other words, simply adding olive oil to your diet without changing anything else may not do anything.

The other major problem with studies of this sort is that people don’t consume food at random. The type of person who eats a lot of olive oil is simply different from the type of person who doesn›t. For one thing, olive oil is expensive. A 25-ounce bottle of olive oil is on sale at my local supermarket right now for $11.00. A similar-sized bottle of vegetable oil goes for $4.00.

Isn’t it interesting that food that costs more money tends to be associated with better health outcomes? (I’m looking at you, red wine.) Perhaps it’s not the food; perhaps it’s the money. We aren’t provided data on household income in this study, but we can see that the heavy olive oil users were less likely to be current smokers and they got more physical activity.

Now, the authors are aware of these limitations and do their best to account for them. In multivariable models, they adjust for other stuff in the diet, and even for income (sort of; they use census tract as a proxy for income, which is really a broad brush), and still find a significant though weakened association showing a protective effect of olive oil on dementia-related death. But still — adjustment is never perfect, and the small effect size here could definitely be due to residual confounding.
 

Evidence More Convincing

Now, I did tell you that there is one reason to believe that this study is true, but it’s not really from this study.

It’s from the PREDIMED randomized trial.

This is nutritional epidemiology I can get behind. Published in 2018, investigators in Spain randomized around 7500 participants to receive a liter of olive oil once a week vs mixed nuts, vs small nonfood gifts, the idea here being that if you have olive oil around, you’ll use it more. And people who were randomly assigned to get the olive oil had a 30% lower rate of cardiovascular events. A secondary analysis of that study found that the rate of development of mild cognitive impairment was 65% lower in those who were randomly assigned to olive oil. That’s an impressive result.

So, there might be something to this olive oil thing, but I’m not quite ready to add it to my “pleasurable things that are still good for you” list just yet. Though it does make me wonder: Can we make French fries in the stuff?
 

Dr. Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

As you all know by now, I’m always looking out for lifestyle changes that are both pleasurable and healthy. They are hard to find, especially when it comes to diet. My kids complain about this all the time: “When you say ‘healthy food,’ you just mean yucky food.” And yes, French fries are amazing, and no, we can’t have them three times a day.

So, when I saw an article claiming that olive oil reduces the risk for dementia, I was interested. I love olive oil; I cook with it all the time. But as is always the case in the world of nutritional epidemiology, we need to be careful. There are a lot of reasons to doubt the results of this study — and one reason to believe it’s true.

The study I’m talking about is “Consumption of Olive Oil and Diet Quality and Risk of Dementia-Related Death,” appearing in JAMA Network Open and following a well-trod formula in the nutritional epidemiology space.

Nearly 100,000 participants, all healthcare workers, filled out a food frequency questionnaire every 4 years with 130 questions touching on all aspects of diet: How often do you eat bananas, bacon, olive oil? Participants were followed for more than 20 years, and if they died, the cause of death was flagged as being dementia-related or not. Over that time frame there were around 38,000 deaths, of which 4751 were due to dementia.

The rest is just statistics. The authors show that those who reported consuming more olive oil were less likely to die from dementia — about 50% less likely, if you compare those who reported eating more than 7 grams of olive oil a day with those who reported eating none.
 

Is It What You Eat, or What You Don’t Eat?

And we could stop there if we wanted to; I’m sure big olive oil would be happy with that. Is there such a thing as “big olive oil”? But no, we need to dig deeper here because this study has the same problems as all nutritional epidemiology studies. Number one, no one is sitting around drinking small cups of olive oil. They consume it with other foods. And it was clear from the food frequency questionnaire that people who consumed more olive oil also consumed less red meat, more fruits and vegetables, more whole grains, more butter, and less margarine. And those are just the findings reported in the paper. I suspect that people who eat more olive oil also eat more tomatoes, for example, though data this granular aren’t shown. So, it can be really hard, in studies like this, to know for sure that it’s actually the olive oil that is helpful rather than some other constituent in the diet.

The flip side of that coin presents another issue. The food you eat is also a marker of the food you don’t eat. People who ate olive oil consumed less margarine, for example. At the time of this study, margarine was still adulterated with trans-fats, which a pretty solid evidence base suggests are really bad for your vascular system. So perhaps it’s not that olive oil is particularly good for you but that something else is bad for you. In other words, simply adding olive oil to your diet without changing anything else may not do anything.

The other major problem with studies of this sort is that people don’t consume food at random. The type of person who eats a lot of olive oil is simply different from the type of person who doesn›t. For one thing, olive oil is expensive. A 25-ounce bottle of olive oil is on sale at my local supermarket right now for $11.00. A similar-sized bottle of vegetable oil goes for $4.00.

Isn’t it interesting that food that costs more money tends to be associated with better health outcomes? (I’m looking at you, red wine.) Perhaps it’s not the food; perhaps it’s the money. We aren’t provided data on household income in this study, but we can see that the heavy olive oil users were less likely to be current smokers and they got more physical activity.

Now, the authors are aware of these limitations and do their best to account for them. In multivariable models, they adjust for other stuff in the diet, and even for income (sort of; they use census tract as a proxy for income, which is really a broad brush), and still find a significant though weakened association showing a protective effect of olive oil on dementia-related death. But still — adjustment is never perfect, and the small effect size here could definitely be due to residual confounding.
 

Evidence More Convincing

Now, I did tell you that there is one reason to believe that this study is true, but it’s not really from this study.

It’s from the PREDIMED randomized trial.

This is nutritional epidemiology I can get behind. Published in 2018, investigators in Spain randomized around 7500 participants to receive a liter of olive oil once a week vs mixed nuts, vs small nonfood gifts, the idea here being that if you have olive oil around, you’ll use it more. And people who were randomly assigned to get the olive oil had a 30% lower rate of cardiovascular events. A secondary analysis of that study found that the rate of development of mild cognitive impairment was 65% lower in those who were randomly assigned to olive oil. That’s an impressive result.

So, there might be something to this olive oil thing, but I’m not quite ready to add it to my “pleasurable things that are still good for you” list just yet. Though it does make me wonder: Can we make French fries in the stuff?
 

Dr. Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Observational studies on red meat consumption and lifespan are prime examples of attempts to find signal in a sea of noise. 

Randomized controlled trials are the best way to sort cause from mere correlation. But these are not possible in most matters of food consumption. So, we look back and observe groups with different exposures.

My most frequent complaint about these nonrandom comparison studies has been the chance that the two groups differ in important ways, and it’s these differences — not the food in question — that account for the disparate outcomes.

But selection biases are only one issue. There is also the matter of analytic flexibility. Observational studies are born from large databases. Researchers have many choices in how to analyze all these data.

A few years ago, Brian Nosek, PhD, and colleagues elegantly showed that analytic choices can affect results. His Many Analysts, One Data Set study had little uptake in the medical community, perhaps because he studied a social science question.
 

Multiple Ways to Slice the Data

Recently, a group from McMaster University, led by Dena Zeraatkar, PhD, has confirmed the analytic choices problem, using the question of red meat consumption and mortality. 

Their idea was simple: Because there are many plausible and defensible ways to analyze a dataset, we should not choose one method; rather, we should choose thousands, combine the results, and see where the truth lies. 

You might wonder how there could be thousands of ways to analyze a dataset. I surely did. 

The answer stems from the choices that researchers face. For instance, there is the selection of eligible participants, the choice of analytic model (logistic, Poisson, etc.), and covariates for which to adjust. Think exponents when combining possible choices.

Dr. Zeraatkar and colleagues are research methodologists, so, sadly, they are comfortable with the clunky name of this approach: specification curve analysis. Don’t be deterred. It means that they analyze the data in thousands of ways using computers. Each way is a specification. In the end, the specifications give rise to a curve of hazard ratios for red meat and mortality. Another name for this approach is multiverse analysis.

For their paper in the Journal of Clinical Epidemiology, aptly named “Grilling the Data,” they didn’t just conjure up the many analytic ways to study the red meat–mortality question. Instead, they used a published systematic review of 15 studies on unprocessed red meat and early mortality. The studies included in this review reported 70 unique ways to analyze the association. 
 

Is Red Meat Good or Bad?

Their first finding was that this analysis yielded widely disparate effect estimates, from 0.63 (reduced risk for early death) to 2.31 (a higher risk). The median hazard ratio was 1.14 with an interquartile range (IQR) of 1.02-1.23. One might conclude from this that eating red meat is associated with a slightly higher risk for early mortality. 

Their second step was to calculate how many ways (specifications) there were to analyze the data by totaling all possible combinations of choices in the 70 ways found in the systematic review. 

They calculated a total of 10 quadrillion possible unique analyses. A quadrillion is 1 with 15 zeros. Computing power cannot handle that amount of analyses yet. So, they generated 20 random unique combinations of covariates, which narrowed the number of analyses to about 1400. About 200 of these were excluded due to implausibly wide confidence intervals. 

Voilà. They now had about 1200 different ways to analyze a dataset; they chose an NHANES longitudinal cohort study from 2007-2014. They deemed each of the more than 1200 approaches plausible because they were derived from peer-reviewed papers written by experts in epidemiology. 
 

Specification Curve Analyses Results 

Each analysis (or specification) yielded a hazard ratio for red meat exposure and death.

• The median HR was 0.94 (IQR, 0.83-1.05) for the effect of red meat on all-cause mortality — ie, not significant.
• The range of hazard ratios was large. They went from 0.51 — a 49% reduced risk for early mortality — to 1.75: a 75% increase in early mortality.
• Among all analyses, 36% yielded hazard ratios above 1.0 and 64% less than 1.0.
• As for statistical significance, defined as P ≤.05, only 4% (or 48 specifications) met this threshold. Zeraatkar reminded me that this is what you’d expect if unprocessed red meat has no effect on longevity.
• Of the 48 analyses deemed statistically significant, 40 indicated that red meat consumption reduced early death and eight indicated that eating red meat led to higher mortality.
• Nearly half the analyses yielded unexciting point estimates, with hazard ratios between 0.90 and 1.10.

Paradigm Changing 

As a user of evidence, I find this a potentially paradigm-changing study. Observational studies far outnumber randomized trials. For many medical questions, observational data are all we have. 

Now think about every observational study published. The authors tell you — post hoc — which method they used to analyze the data. The key point is that it is one method. 

Dr. Zeraatkar and colleagues have shown that there are thousands of plausible ways to analyze the data, and this can lead to very different findings. In the specific question of red meat and mortality, their many analyses yielded a null result. 

Now imagine other cases where the researchers did many analyses of a dataset and chose to publish only the significant ones. Observational studies are rarely preregistered, so a reader cannot know how a result would vary depending on analytic choices. A specification curve analysis of a dataset provides a much broader picture. In the case of red meat, you see some significant results, but the vast majority hover around null. 

What about the difficulty in analyzing a dataset 1000 different ways? Dr. Zeraatkar told me that it is harder than just choosing one method, but it’s not impossible. 

The main barrier to adopting this multiverse approach to data, she noted, was not the extra work but the entrenched belief among researchers that there is a best way to analyze data. 

I hope you read this paper and think about it every time you read an observational study that finds a positive or negative association between two things. Ask: What if the researchers were as careful as Dr. Zeraatkar and colleagues and did multiple different analyses? Would the finding hold up to a series of plausible analytic choices? 

Nutritional epidemiology would benefit greatly from this approach. But so would any observational study of an exposure and outcome. I suspect that the number of “positive” associations would diminish. And that would not be a bad thing.

 

Dr. Mandrola, a clinical electrophysiologist at Baptist Medical Associates, Louisville, Kentucky, disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Observational studies on red meat consumption and lifespan are prime examples of attempts to find signal in a sea of noise. 

Randomized controlled trials are the best way to sort cause from mere correlation. But these are not possible in most matters of food consumption. So, we look back and observe groups with different exposures.

My most frequent complaint about these nonrandom comparison studies has been the chance that the two groups differ in important ways, and it’s these differences — not the food in question — that account for the disparate outcomes.

But selection biases are only one issue. There is also the matter of analytic flexibility. Observational studies are born from large databases. Researchers have many choices in how to analyze all these data.

A few years ago, Brian Nosek, PhD, and colleagues elegantly showed that analytic choices can affect results. His Many Analysts, One Data Set study had little uptake in the medical community, perhaps because he studied a social science question.
 

Multiple Ways to Slice the Data

Recently, a group from McMaster University, led by Dena Zeraatkar, PhD, has confirmed the analytic choices problem, using the question of red meat consumption and mortality. 

Their idea was simple: Because there are many plausible and defensible ways to analyze a dataset, we should not choose one method; rather, we should choose thousands, combine the results, and see where the truth lies. 

You might wonder how there could be thousands of ways to analyze a dataset. I surely did. 

The answer stems from the choices that researchers face. For instance, there is the selection of eligible participants, the choice of analytic model (logistic, Poisson, etc.), and covariates for which to adjust. Think exponents when combining possible choices.

Dr. Zeraatkar and colleagues are research methodologists, so, sadly, they are comfortable with the clunky name of this approach: specification curve analysis. Don’t be deterred. It means that they analyze the data in thousands of ways using computers. Each way is a specification. In the end, the specifications give rise to a curve of hazard ratios for red meat and mortality. Another name for this approach is multiverse analysis.

For their paper in the Journal of Clinical Epidemiology, aptly named “Grilling the Data,” they didn’t just conjure up the many analytic ways to study the red meat–mortality question. Instead, they used a published systematic review of 15 studies on unprocessed red meat and early mortality. The studies included in this review reported 70 unique ways to analyze the association. 
 

Is Red Meat Good or Bad?

Their first finding was that this analysis yielded widely disparate effect estimates, from 0.63 (reduced risk for early death) to 2.31 (a higher risk). The median hazard ratio was 1.14 with an interquartile range (IQR) of 1.02-1.23. One might conclude from this that eating red meat is associated with a slightly higher risk for early mortality. 

Their second step was to calculate how many ways (specifications) there were to analyze the data by totaling all possible combinations of choices in the 70 ways found in the systematic review. 

They calculated a total of 10 quadrillion possible unique analyses. A quadrillion is 1 with 15 zeros. Computing power cannot handle that amount of analyses yet. So, they generated 20 random unique combinations of covariates, which narrowed the number of analyses to about 1400. About 200 of these were excluded due to implausibly wide confidence intervals. 

Voilà. They now had about 1200 different ways to analyze a dataset; they chose an NHANES longitudinal cohort study from 2007-2014. They deemed each of the more than 1200 approaches plausible because they were derived from peer-reviewed papers written by experts in epidemiology. 
 

Specification Curve Analyses Results 

Each analysis (or specification) yielded a hazard ratio for red meat exposure and death.

• The median HR was 0.94 (IQR, 0.83-1.05) for the effect of red meat on all-cause mortality — ie, not significant.
• The range of hazard ratios was large. They went from 0.51 — a 49% reduced risk for early mortality — to 1.75: a 75% increase in early mortality.
• Among all analyses, 36% yielded hazard ratios above 1.0 and 64% less than 1.0.
• As for statistical significance, defined as P ≤.05, only 4% (or 48 specifications) met this threshold. Zeraatkar reminded me that this is what you’d expect if unprocessed red meat has no effect on longevity.
• Of the 48 analyses deemed statistically significant, 40 indicated that red meat consumption reduced early death and eight indicated that eating red meat led to higher mortality.
• Nearly half the analyses yielded unexciting point estimates, with hazard ratios between 0.90 and 1.10.

Paradigm Changing 

As a user of evidence, I find this a potentially paradigm-changing study. Observational studies far outnumber randomized trials. For many medical questions, observational data are all we have. 

Now think about every observational study published. The authors tell you — post hoc — which method they used to analyze the data. The key point is that it is one method. 

Dr. Zeraatkar and colleagues have shown that there are thousands of plausible ways to analyze the data, and this can lead to very different findings. In the specific question of red meat and mortality, their many analyses yielded a null result. 

Now imagine other cases where the researchers did many analyses of a dataset and chose to publish only the significant ones. Observational studies are rarely preregistered, so a reader cannot know how a result would vary depending on analytic choices. A specification curve analysis of a dataset provides a much broader picture. In the case of red meat, you see some significant results, but the vast majority hover around null. 

What about the difficulty in analyzing a dataset 1000 different ways? Dr. Zeraatkar told me that it is harder than just choosing one method, but it’s not impossible. 

The main barrier to adopting this multiverse approach to data, she noted, was not the extra work but the entrenched belief among researchers that there is a best way to analyze data. 

I hope you read this paper and think about it every time you read an observational study that finds a positive or negative association between two things. Ask: What if the researchers were as careful as Dr. Zeraatkar and colleagues and did multiple different analyses? Would the finding hold up to a series of plausible analytic choices? 

Nutritional epidemiology would benefit greatly from this approach. But so would any observational study of an exposure and outcome. I suspect that the number of “positive” associations would diminish. And that would not be a bad thing.

 

Dr. Mandrola, a clinical electrophysiologist at Baptist Medical Associates, Louisville, Kentucky, disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Observational studies on red meat consumption and lifespan are prime examples of attempts to find signal in a sea of noise. 

Randomized controlled trials are the best way to sort cause from mere correlation. But these are not possible in most matters of food consumption. So, we look back and observe groups with different exposures.

My most frequent complaint about these nonrandom comparison studies has been the chance that the two groups differ in important ways, and it’s these differences — not the food in question — that account for the disparate outcomes.

But selection biases are only one issue. There is also the matter of analytic flexibility. Observational studies are born from large databases. Researchers have many choices in how to analyze all these data.

A few years ago, Brian Nosek, PhD, and colleagues elegantly showed that analytic choices can affect results. His Many Analysts, One Data Set study had little uptake in the medical community, perhaps because he studied a social science question.
 

Multiple Ways to Slice the Data

Recently, a group from McMaster University, led by Dena Zeraatkar, PhD, has confirmed the analytic choices problem, using the question of red meat consumption and mortality. 

Their idea was simple: Because there are many plausible and defensible ways to analyze a dataset, we should not choose one method; rather, we should choose thousands, combine the results, and see where the truth lies. 

You might wonder how there could be thousands of ways to analyze a dataset. I surely did. 

The answer stems from the choices that researchers face. For instance, there is the selection of eligible participants, the choice of analytic model (logistic, Poisson, etc.), and covariates for which to adjust. Think exponents when combining possible choices.

Dr. Zeraatkar and colleagues are research methodologists, so, sadly, they are comfortable with the clunky name of this approach: specification curve analysis. Don’t be deterred. It means that they analyze the data in thousands of ways using computers. Each way is a specification. In the end, the specifications give rise to a curve of hazard ratios for red meat and mortality. Another name for this approach is multiverse analysis.

For their paper in the Journal of Clinical Epidemiology, aptly named “Grilling the Data,” they didn’t just conjure up the many analytic ways to study the red meat–mortality question. Instead, they used a published systematic review of 15 studies on unprocessed red meat and early mortality. The studies included in this review reported 70 unique ways to analyze the association. 
 

Is Red Meat Good or Bad?

Their first finding was that this analysis yielded widely disparate effect estimates, from 0.63 (reduced risk for early death) to 2.31 (a higher risk). The median hazard ratio was 1.14 with an interquartile range (IQR) of 1.02-1.23. One might conclude from this that eating red meat is associated with a slightly higher risk for early mortality. 

Their second step was to calculate how many ways (specifications) there were to analyze the data by totaling all possible combinations of choices in the 70 ways found in the systematic review. 

They calculated a total of 10 quadrillion possible unique analyses. A quadrillion is 1 with 15 zeros. Computing power cannot handle that amount of analyses yet. So, they generated 20 random unique combinations of covariates, which narrowed the number of analyses to about 1400. About 200 of these were excluded due to implausibly wide confidence intervals. 

Voilà. They now had about 1200 different ways to analyze a dataset; they chose an NHANES longitudinal cohort study from 2007-2014. They deemed each of the more than 1200 approaches plausible because they were derived from peer-reviewed papers written by experts in epidemiology. 
 

Specification Curve Analyses Results 

Each analysis (or specification) yielded a hazard ratio for red meat exposure and death.

• The median HR was 0.94 (IQR, 0.83-1.05) for the effect of red meat on all-cause mortality — ie, not significant.
• The range of hazard ratios was large. They went from 0.51 — a 49% reduced risk for early mortality — to 1.75: a 75% increase in early mortality.
• Among all analyses, 36% yielded hazard ratios above 1.0 and 64% less than 1.0.
• As for statistical significance, defined as P ≤.05, only 4% (or 48 specifications) met this threshold. Zeraatkar reminded me that this is what you’d expect if unprocessed red meat has no effect on longevity.
• Of the 48 analyses deemed statistically significant, 40 indicated that red meat consumption reduced early death and eight indicated that eating red meat led to higher mortality.
• Nearly half the analyses yielded unexciting point estimates, with hazard ratios between 0.90 and 1.10.

Paradigm Changing 

As a user of evidence, I find this a potentially paradigm-changing study. Observational studies far outnumber randomized trials. For many medical questions, observational data are all we have. 

Now think about every observational study published. The authors tell you — post hoc — which method they used to analyze the data. The key point is that it is one method. 

Dr. Zeraatkar and colleagues have shown that there are thousands of plausible ways to analyze the data, and this can lead to very different findings. In the specific question of red meat and mortality, their many analyses yielded a null result. 

Now imagine other cases where the researchers did many analyses of a dataset and chose to publish only the significant ones. Observational studies are rarely preregistered, so a reader cannot know how a result would vary depending on analytic choices. A specification curve analysis of a dataset provides a much broader picture. In the case of red meat, you see some significant results, but the vast majority hover around null. 

What about the difficulty in analyzing a dataset 1000 different ways? Dr. Zeraatkar told me that it is harder than just choosing one method, but it’s not impossible. 

The main barrier to adopting this multiverse approach to data, she noted, was not the extra work but the entrenched belief among researchers that there is a best way to analyze data. 

I hope you read this paper and think about it every time you read an observational study that finds a positive or negative association between two things. Ask: What if the researchers were as careful as Dr. Zeraatkar and colleagues and did multiple different analyses? Would the finding hold up to a series of plausible analytic choices? 

Nutritional epidemiology would benefit greatly from this approach. But so would any observational study of an exposure and outcome. I suspect that the number of “positive” associations would diminish. And that would not be a bad thing.

 

Dr. Mandrola, a clinical electrophysiologist at Baptist Medical Associates, Louisville, Kentucky, disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

A 59-year-old man presents with abdominal pain. He has a history of small bowel obstruction and diverticulitis. His medical history includes chronic kidney disease (CKD; baseline creatinine, 1.8 mg/dL), hypertension, type 2 diabetes, and depression. He had a colectomy 6 years ago for colon cancer.

He takes the following medications: Semaglutide (1 mg weekly), amlodipine (5 mg once daily), and escitalopram (10 mg once daily). On physical exam his blood pressure is 130/80 mm Hg, his pulse is 90, and his temperature is 37.2 degrees C. He has normal bowel sounds but guarding in the right lower quadrant.

What imaging would you recommend?

A) CT without contrast

B) CT with contrast

C) MRI

D) Abdominal ultrasound

This patient has several potential causes for his abdominal pain that imaging may clarify. I think a contrast CT scan would be the most likely to provide helpful information. It is likely that if it were ordered, there may be hesitation by the radiologist to perform the scan with contrast because of the patient’s CKD.

Concern for contrast-induced kidney injury has limited diagnostic testing for many years. How strong is the evidence for contrast-induced kidney injury, and should we avoid testing that requires contrast in patients with CKD? McDonald and colleagues performed a meta-analysis with 13 studies meeting inclusion criteria, involving 25,950 patients.¹ They found no increased risk of acute kidney injury (AKI) in patients who received contrast medium compared with those who did not receive contrast; relative risk of AKI for those receiving contrast was 0.79 (confidence interval: 0.62-1.02). Importantly, there was no difference in AKI in patients with diabetes or CKD.

Ehmann et al. looked at renal outcomes in patients who received IV contrast when they presented to an emergency department with AKI.² They found that in patients with AKI, receiving contrast was not associated with persistent AKI at hospital discharge. Hinson and colleagues looked at patients arriving at the emergency department and needing imaging.³ They did a retrospective, cohort analysis of 17,934 patients who had CT with contrast, CT with no contrast, or no CT. Contrast administration was not associated with increased incidence of AKI (odds ratio, 0.96, CI: 0.85-1.08).

Aycock et al. did a meta-analysis of AKI after CT scanning, including 28 studies involving 107,335 patients.⁴ They found that compared with noncontrast CT, CT scanning with contrast was not associated with AKI (OR, 0.94, CI: 0.83-1.07). Elias and Aronson looked at the risk of AKI after contrast in patients receiving CT scans compared with those who received ventilation/perfusion scans to evaluate for pulmonary embolism.⁵ There were 44 AKI events (4.5%) in patients exposed to contrast media and 33 events (3.4%) in patients not exposed to contrast media (risk difference: 1.1%, 95% CI: -0.6% to 2.9%; OR, 1.39, CI: 0.86-2.26; P = .18).

Despite multiple studies showing no increased risk, there is still a concern that contrast can cause AKI.⁶ Animal models have shown iodinated contrast can have a deleterious effect on mitochondria and membrane function.⁶ Criticisms of the retrospective nature of many of the studies I have shared, and the lack of randomized, controlled trials are that there may be bias in these studies, as the highest-risk patients are the ones most likely not to receive contrast. In a joint guideline from the American College of Radiology and the National Kidney Foundation, this statement was made: “The risk of acute kidney injury developing in patients with reduced kidney function following exposure to intravenous iodinated contrast media has been overstated.”⁷ Their recommendation was to give contrast if needed in patients with glomerular filtration rates (GFRs) greater than 30.



Myth: Contrast-induced renal injury is a concern.

Clinical impact: For CT scanning, it is OK to give contrast when needed. A conservative cutoff for contrast use would be a GFR less than 30.
 

Dr. Paauw is professor of medicine in the Division of General Internal Medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at dpaauw@uw.edu.

References

1. McDonald JS et al. Radiology. 2013:267:119-128.

2. Ehmann MR et al. Intensive Care Med. 2023:49(2):205-215.

3. Hinson JS et al. Ann Emerg Med. 2017;69(5):577-586.

4. Aycock RD et al. Ann Emerg Med. 2018 Jan;71(1):44-53.

5. Elias A, Aronson D. Thromb Haemost. 2021 Jun;121(6):800-807.

6. Weisbord SD, du Cheryon D. Intensive Care Med. 2018;44(1):107-109.

7. Davenport MS et al. Radiology. 2020;294(3):660-668.

A 59-year-old man presents with abdominal pain. He has a history of small bowel obstruction and diverticulitis. His medical history includes chronic kidney disease (CKD; baseline creatinine, 1.8 mg/dL), hypertension, type 2 diabetes, and depression. He had a colectomy 6 years ago for colon cancer.

He takes the following medications: Semaglutide (1 mg weekly), amlodipine (5 mg once daily), and escitalopram (10 mg once daily). On physical exam his blood pressure is 130/80 mm Hg, his pulse is 90, and his temperature is 37.2 degrees C. He has normal bowel sounds but guarding in the right lower quadrant.

What imaging would you recommend?

A) CT without contrast

B) CT with contrast

C) MRI

D) Abdominal ultrasound

This patient has several potential causes for his abdominal pain that imaging may clarify. I think a contrast CT scan would be the most likely to provide helpful information. It is likely that if it were ordered, there may be hesitation by the radiologist to perform the scan with contrast because of the patient’s CKD.

Concern for contrast-induced kidney injury has limited diagnostic testing for many years. How strong is the evidence for contrast-induced kidney injury, and should we avoid testing that requires contrast in patients with CKD? McDonald and colleagues performed a meta-analysis with 13 studies meeting inclusion criteria, involving 25,950 patients.¹ They found no increased risk of acute kidney injury (AKI) in patients who received contrast medium compared with those who did not receive contrast; relative risk of AKI for those receiving contrast was 0.79 (confidence interval: 0.62-1.02). Importantly, there was no difference in AKI in patients with diabetes or CKD.

Ehmann et al. looked at renal outcomes in patients who received IV contrast when they presented to an emergency department with AKI.² They found that in patients with AKI, receiving contrast was not associated with persistent AKI at hospital discharge. Hinson and colleagues looked at patients arriving at the emergency department and needing imaging.³ They did a retrospective, cohort analysis of 17,934 patients who had CT with contrast, CT with no contrast, or no CT. Contrast administration was not associated with increased incidence of AKI (odds ratio, 0.96, CI: 0.85-1.08).

Aycock et al. did a meta-analysis of AKI after CT scanning, including 28 studies involving 107,335 patients.⁴ They found that compared with noncontrast CT, CT scanning with contrast was not associated with AKI (OR, 0.94, CI: 0.83-1.07). Elias and Aronson looked at the risk of AKI after contrast in patients receiving CT scans compared with those who received ventilation/perfusion scans to evaluate for pulmonary embolism.⁵ There were 44 AKI events (4.5%) in patients exposed to contrast media and 33 events (3.4%) in patients not exposed to contrast media (risk difference: 1.1%, 95% CI: -0.6% to 2.9%; OR, 1.39, CI: 0.86-2.26; P = .18).

Despite multiple studies showing no increased risk, there is still a concern that contrast can cause AKI.⁶ Animal models have shown iodinated contrast can have a deleterious effect on mitochondria and membrane function.⁶ Criticisms of the retrospective nature of many of the studies I have shared, and the lack of randomized, controlled trials are that there may be bias in these studies, as the highest-risk patients are the ones most likely not to receive contrast. In a joint guideline from the American College of Radiology and the National Kidney Foundation, this statement was made: “The risk of acute kidney injury developing in patients with reduced kidney function following exposure to intravenous iodinated contrast media has been overstated.”⁷ Their recommendation was to give contrast if needed in patients with glomerular filtration rates (GFRs) greater than 30.



Myth: Contrast-induced renal injury is a concern.

Clinical impact: For CT scanning, it is OK to give contrast when needed. A conservative cutoff for contrast use would be a GFR less than 30.
 

Dr. Paauw is professor of medicine in the Division of General Internal Medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at dpaauw@uw.edu.

References

1. McDonald JS et al. Radiology. 2013:267:119-128.

2. Ehmann MR et al. Intensive Care Med. 2023:49(2):205-215.

3. Hinson JS et al. Ann Emerg Med. 2017;69(5):577-586.

4. Aycock RD et al. Ann Emerg Med. 2018 Jan;71(1):44-53.

5. Elias A, Aronson D. Thromb Haemost. 2021 Jun;121(6):800-807.

6. Weisbord SD, du Cheryon D. Intensive Care Med. 2018;44(1):107-109.

7. Davenport MS et al. Radiology. 2020;294(3):660-668.

A 59-year-old man presents with abdominal pain. He has a history of small bowel obstruction and diverticulitis. His medical history includes chronic kidney disease (CKD; baseline creatinine, 1.8 mg/dL), hypertension, type 2 diabetes, and depression. He had a colectomy 6 years ago for colon cancer.

He takes the following medications: Semaglutide (1 mg weekly), amlodipine (5 mg once daily), and escitalopram (10 mg once daily). On physical exam his blood pressure is 130/80 mm Hg, his pulse is 90, and his temperature is 37.2 degrees C. He has normal bowel sounds but guarding in the right lower quadrant.

What imaging would you recommend?

A) CT without contrast

B) CT with contrast

C) MRI

D) Abdominal ultrasound

This patient has several potential causes for his abdominal pain that imaging may clarify. I think a contrast CT scan would be the most likely to provide helpful information. It is likely that if it were ordered, there may be hesitation by the radiologist to perform the scan with contrast because of the patient’s CKD.

Concern for contrast-induced kidney injury has limited diagnostic testing for many years. How strong is the evidence for contrast-induced kidney injury, and should we avoid testing that requires contrast in patients with CKD? McDonald and colleagues performed a meta-analysis with 13 studies meeting inclusion criteria, involving 25,950 patients.¹ They found no increased risk of acute kidney injury (AKI) in patients who received contrast medium compared with those who did not receive contrast; relative risk of AKI for those receiving contrast was 0.79 (confidence interval: 0.62-1.02). Importantly, there was no difference in AKI in patients with diabetes or CKD.

Ehmann et al. looked at renal outcomes in patients who received IV contrast when they presented to an emergency department with AKI.² They found that in patients with AKI, receiving contrast was not associated with persistent AKI at hospital discharge. Hinson and colleagues looked at patients arriving at the emergency department and needing imaging.³ They did a retrospective, cohort analysis of 17,934 patients who had CT with contrast, CT with no contrast, or no CT. Contrast administration was not associated with increased incidence of AKI (odds ratio, 0.96, CI: 0.85-1.08).

Aycock et al. did a meta-analysis of AKI after CT scanning, including 28 studies involving 107,335 patients.⁴ They found that compared with noncontrast CT, CT scanning with contrast was not associated with AKI (OR, 0.94, CI: 0.83-1.07). Elias and Aronson looked at the risk of AKI after contrast in patients receiving CT scans compared with those who received ventilation/perfusion scans to evaluate for pulmonary embolism.⁵ There were 44 AKI events (4.5%) in patients exposed to contrast media and 33 events (3.4%) in patients not exposed to contrast media (risk difference: 1.1%, 95% CI: -0.6% to 2.9%; OR, 1.39, CI: 0.86-2.26; P = .18).

Despite multiple studies showing no increased risk, there is still a concern that contrast can cause AKI.⁶ Animal models have shown iodinated contrast can have a deleterious effect on mitochondria and membrane function.⁶ Criticisms of the retrospective nature of many of the studies I have shared, and the lack of randomized, controlled trials are that there may be bias in these studies, as the highest-risk patients are the ones most likely not to receive contrast. In a joint guideline from the American College of Radiology and the National Kidney Foundation, this statement was made: “The risk of acute kidney injury developing in patients with reduced kidney function following exposure to intravenous iodinated contrast media has been overstated.”⁷ Their recommendation was to give contrast if needed in patients with glomerular filtration rates (GFRs) greater than 30.



Myth: Contrast-induced renal injury is a concern.

Clinical impact: For CT scanning, it is OK to give contrast when needed. A conservative cutoff for contrast use would be a GFR less than 30.
 

Dr. Paauw is professor of medicine in the Division of General Internal Medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at dpaauw@uw.edu.

References

1. McDonald JS et al. Radiology. 2013:267:119-128.

2. Ehmann MR et al. Intensive Care Med. 2023:49(2):205-215.

3. Hinson JS et al. Ann Emerg Med. 2017;69(5):577-586.

4. Aycock RD et al. Ann Emerg Med. 2018 Jan;71(1):44-53.

5. Elias A, Aronson D. Thromb Haemost. 2021 Jun;121(6):800-807.

6. Weisbord SD, du Cheryon D. Intensive Care Med. 2018;44(1):107-109.

7. Davenport MS et al. Radiology. 2020;294(3):660-668.

This discussion was recorded on March 29, 2024. The transcript has been edited for clarity.

Robert D. Glatter, MD: Joining me today to discuss the use of methoxyflurane (Penthrox), an inhaled nonopioid analgesic for the relief of acute pain, is Dr. William Kenneth (Ken) Milne, an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM).

Also joining me is Dr. Sergey Motov, an emergency physician and research director at Maimonides Medical Center in Brooklyn, New York, and an expert in pain management. I want to welcome both of you and thank you for joining me.
 

RAMPED Trial: Evaluating the Efficacy of Methoxyflurane

Dr. Glatter: Ken, your recent post on Twitter [now X] regarding the utility of Penthrox in the RAMPED trial really caught my attention. While the trial was from 2021, it really is relevant regarding the prehospital management of pain in the practice of emergency medicine, and certainly in-hospital practice. I was hoping you could review the study design but also get into the rationale behind the use of this novel agent.

William Kenneth (Ken) Milne, MD, MSc: Sure. I’d be happy to kick this episode off with talking about a study that was published in 2020 in Academic Emergency Medicine. It was an Australian study by Brichko et al., and they were doing a randomized controlled trial looking at methoxyflurane vs standard care.

They selected out a population of adults, which they defined as 18-75 years of age. They were in the prehospital setting and they had a pain score of greater than 8. They gave the participants methoxyflurane, which is also called the “green whistle.” They had the subjects take that for their prehospital pain, and they compared that with whatever your standard analgesic in the prehospital setting would be.

Their primary outcome was how many patients had at least 50% reduction in their pain score within 30 minutes. They recruited about 120 people, and they found that there was no statistical difference in the primary outcome between methoxyflurane and standard care. Again, that primary outcome was a reduction in pain score by greater than 50% at 30 minutes, and there wasn’t a statistical difference between the two.

There are obviously limits to any study, and it was a convenience sample. This was an unmasked trial, so people knew if they were getting this green whistle, which is popular in Australia. People would be familiar with this device, and they didn’t compare it with a sham or placebo group.

Pharmacology of Penthrox: Its Role and Mechanism of Action

Dr. Glatter: The primary outcome wasn’t met, but certainly secondary outcomes were. There was, again, a relatively small number of patients in this trial. That said, there was significant pain relief. I think there are issues with the trial, as with any trial limitations.

Getting to the pharmacology of Penthrox, can you describe this inhaled anesthetic and how we use it, specifically its role at the subanesthetic doses?

Sergey M. Motov, MD: Methoxyflurane is embedded in the green whistle package, and that whole contraption is called Penthrox. It’s an inhaled volatile fluorinated hydrocarbon anesthetic that was predominantly used, I’d say 40, 50 years ago, for general anesthesia and slowly but surely fell out of favor due to the fact that, when used for prolonged duration or in supratherapeutic doses, there were cases of severe or even fatal nephrotoxicity and hepatotoxicity.

In the late ‘70s and early ‘80s, all the fluranes came on board that are slightly different as general anesthetics, and methoxyflurane started slowly falling out of favor. Because of this paucity and then a subsequent slightly greater number of cases of nephrotoxicity and hepatotoxicity, [the US Food and Drug Administration] FDA made a decision to pull the drug off the market in 2005. FDA successfully accomplished its mission and since then has pretty much banned the use of inhaled methoxyflurane in any shape, form, or color in the United States.

Going back to the green whistle, it has been used in Australia probably for about 50-60 years, and has been used in Europe for probably 10-20 years. Ken can attest that it has been used in Canada for at least a decade and the track record is phenomenal.

We are using subanesthetic, even supratherapeutic doses that, based on available literature, has no incidence of this fatal hepatotoxicity or nephrotoxicity. We’re talking about 10 million doses administered worldwide, except in the United States. There are 40-plus randomized clinical trials with over 30,000 patients enrolled that prove efficacy and safety.

That’s where we are right now, in a conundrum. We have a great deal of data all over the world, except in the United States, that push for the use of this noninvasive, patient-controlled nonopioid inhaled anesthetic. We just don’t have the access in North America, with the exception of Canada.

Regulatory Hurdles: Challenges in FDA Approval

Dr. Glatter: Absolutely. The FDA wants to be cautious, but if you look at the evidence base of data on this, it really indicates otherwise. Do you think that these roadblocks can be somehow overcome?

Dr. Milne: In the 2000s and 2010s, everybody was focused on opioids and all the dangers and potential adverse events. Opioids are great drugs like many other drugs; it depends on dose and duration. If used properly, it’s an excellent drug. Well, here’s another excellent drug if it’s used properly, and the adverse events are dependent on their dose and duration. Penthrox, or methoxyflurane, is a subtherapeutic, small dose and there have been no reported cases of addiction or abuse related to these inhalers.

Dr. Glatter: That argues for the point — and I’ll turn this over to you, Sergey — of how can this not, in my mind, be an issue that the FDA can overcome.

Dr. Motov: I agree with you. It’s very hard for me to speak on behalf of the FDA, to allude to their thinking processes, but we need to be up to speed with the evidence. The first thing is, why don’t you study the drug in the United States? I’m not asking you to lift the ban, which you put in 2005, but why don’t you honor what has been done over two decades and at least open the door a little bit and let us do what we do best? Why don’t you allow us to do the research in a controlled setting with a carefully, properly selected group of patients without underlying renal or hepatic insufficiency and see where we’re at?

Let’s compare it against placebo. If that’s not ethical, let’s compare it against active comparators — God knows we have 15-20 drugs we can use — and let’s see where we’re at. Ken has been nothing short of superb when it comes to evidence. Let us put the evidence together.

Dr. Milne: If there were concerns decades ago, those need to be addressed. As science is iterative and as other information becomes available, the scientific method would say, Let’s reexamine this and let’s reexamine our position, and do that with evidence. To do that, it has to have validity within the US system. Someone like you doing the research, you are a pain research guru; you should be doing this research to say, “Does it work or not? Does this nonapproval still stand today in 2024?”

Dr. Motov: Thank you for the shout-out, and I agree with you. All of us, those who are interested, on the frontiers of emergency care — as present clinicians — we should be doing this. There is nothing that will convince the FDA more than properly and rightly conducted research, time to reassess the evidence, and time to be less rigid. I understand that you placed a ban 20 years ago, but let’s go with the science. We cannot be behind it.

Exploring the Ecological Footprint of Methoxyflurane

Dr. Milne: There was an Austrian study in 2022 and a very interesting study out of the UK looking at life-cycle impact assessment on the environment. If we’re not just concerned about patient care —obviously, we want to provide patients with a safe and effective product, compared with other products that are available that might not have as good a safety profile — this looks at the impact on the environment.

Dr. Glatter: Ken, can you tell me about some of your recent research regarding the environmental effects related to use of Penthrox, but also its utility pharmacologically and its mechanism of action?

Dr. Milne: There was a really interesting study published this year by Martindale in the Emergency Medicine Journal. It took a different approach to this question about could we be using this drug, and why should we be using this drug? Sergey and I have already talked about the potential benefits and the potential harms. I mentioned opioids and some of the concerns about that. For this drug, if we’re using it in the prehospital setting in this little green whistle, the potential benefits look really good, and we haven’t seen any of the potential harms come through in the literature.

This was another line of evidence of why this might be a good drug, because of the environmental impact of this low-dose methoxyflurane. They compared it with nitrous oxide and said, “Well, what about the life-cycle impact on the environment of using this and the overall cradle-to-grave environmental impacts?”

Obviously, Sergey and I are interested in patient care, and we treat patients one at a time. But we have a larger responsibility to social determinants of health, like our environment. If you look at the overall cradle-to-grave environmental impact of this drug, it was better than for nitrous oxide when looking specifically at climate-change impact. That might be another reason, another line of argument, that could be put forward in the United States to say, “We want to have a healthy environment and a healthy option for patients.”

I’ll let Sergey speak to mechanisms of action and those types of things.

Dr. Motov: As a general anesthetic and hydrocarbonated volatile ones, I’m just going to say that it causes this generalized diffuse cortical depression, and there are no particular channels, receptors, or enzymes we need to worry much about. In short, it’s an inhaled gas used to put patients or people to sleep.

Over the past 30 or 40 years — and I’ll go back to the past decade — there have been numerous studies in different countries (outside of the United States, of course), and with the recent study that Ken just cited, there were comparisons for managing predominantly acute traumatic injuries in pediatric and adult populations presenting to EDs in various regions of the world that compared Penthrox, or the green whistle, with either placebo or active comparators, which included parenteral opioids, oral opioids, and NSAIDs.

The recent systematic review by Fabbri, out of Italy, showed that for ultra–short-term pain — we’re talking about 5, 10, or 15 minutes — inhaled methoxyflurane was found to be equal or even superior to standard of care, primarily related to parenteral opioids, and safety was off the hook. Interestingly, with respect to analgesia, they found that geriatric patients seemed to be responding more, with respect to changing pain score, than younger adults — we’re talking about ages 18-64 vs 65 or older. Again, we need to make sure that we carefully select those elderly people without underlying renal or hepatic insufficiency.

To wrap this up, there is evidence clearly supporting its analgesic efficacy and safety, even in comparison to commonly used and traditionally accepted analgesic modalities that we use for managing acute pain.

US Military Use and Implications for Civilian Practice

Dr. Glatter: Do you think that methoxyflurane’s use in the military will help propel its use in clinical settings in the US, and possibly convince the FDA to look at this closer? The military is currently using it in deployed combat veterans in an ongoing fashion.

Dr. Motov: I’m excited that the Department of Defense in the United States has taken the lead, and they’re being very progressive. There are data that we’ve adapted to the civilian environment by use of intranasal opioids and intranasal ketamine with more doctors who came out of the military. In the military, it’s a kingdom within a kingdom. I don’t know their relationship with the FDA, but I support the military’s pharmacologic initiative by honoring and disseminating their research once it becomes available.

For us nonmilitary folks, we still need to work with the FDA. We need to convince the FDA to let us study the drug, and then we need to pile the evidence within the United States so that the FDA will start looking at this favorably. It wouldn’t hurt and it wouldn’t harm. Any piece of evidence will add to the existing body of literature that we need to allow this medication to be available to us.

Safety Considerations and Aerosolization Concerns

Dr. Glatter: Its safety in children is well established in Australia and throughout the world. I think it deserves a careful look, and the evidence that you’ve both presented argues for the use of this prehospital but also in hospital. I guess there was concern in the hospital with underventilation and healthcare workers being exposed to the fumes, and then getting headaches, dizziness, and so forth. I don’t know if that’s borne out, Ken, in any of your experience in Canada at all.

Dr. Milne: We currently don’t have it in our shop. It’s being used in British Columbia right now in the prehospital setting, and I’m not aware of anybody using it in their department. It’s used prehospital as far as I know.

Dr. Motov: I can attest to it, if I may, because I had familiarized myself with the device. I actually was able to hold it in my hands. I have not used it yet but I had the prototype. The way it’s set up, there is an activated charcoal chamber that sits right on top of the device, which serves as the scavenger for exhaled air that contains particles of methoxyflurane. In theory, but I’m telling how it is in practicality, it significantly reduces occupational exposure, based on data that lacks specifics.

Although most of the researchers did not measure the concentration of methoxyflurane in ambient air within the treatment room in the EDs, I believe the additional data sources clearly stating that it’s within or even below the detectable level that would cause any harm. Once again, we need to honor pathology. We need to make sure that pregnant women will not be exposed to it.

Dr. Milne: In 2024, we also need to be concerned about aerosolizing procedures and aerosolizing treatments, and just take that into account because we should be considering all the potential benefits and all the potential harms. Going through the COVID-19 pandemic, there was concern about transmission and whether or not it was droplet or aerosolized.

There was an observational study published in 2022 in Austria by Trimmel in BMC Emergency Medicine showing similar results. It seemed to work well and potential harms didn’t get picked up. They had to stop the study early because of COVID-19.

We need to always focus in on the potential benefits, the potential harms; where does the science land? Where do the data lie? Then we move forward from that and make informed decisions.

Final Thoughts

Dr. Glatter: Are there any key takeaways you’d like to share with our audience?

Dr. Milne: One of the takeaways from this whole conversation is that science is iterative and science changes. When new evidence becomes available, and we’ve seen it accumulate around the world, we as scientists, as a researcher, as somebody committed to great patient care should revisit our positions on this. Since there is a prohibition against this medication, I think it’s time to reassess that stance and move forward to see if it still is accurate today.

Dr. Motov: I wholeheartedly agree with this. Thank you, Ken, for bringing this up. Good point.

Dr. Glatter: This has been a really informative discussion. I think our audience will certainly embrace this. Thank you very much for your time; it’s much appreciated.
 

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is a medical adviser for Medscape and hosts the Hot Topics in EM series. Dr. Milne is an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM). Dr. Motov is professor of emergency medicine and director of research in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York. He is passionate about safe and effective pain management in the emergency department, and has numerous publications on the subject of opioid alternatives in pain management. Dr. Glatter, Dr. Milne, and Dr. Motov had no conflicts of interest to disclose.

A version of this article appeared on Medscape.com.

This discussion was recorded on March 29, 2024. The transcript has been edited for clarity.

Robert D. Glatter, MD: Joining me today to discuss the use of methoxyflurane (Penthrox), an inhaled nonopioid analgesic for the relief of acute pain, is Dr. William Kenneth (Ken) Milne, an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM).

Also joining me is Dr. Sergey Motov, an emergency physician and research director at Maimonides Medical Center in Brooklyn, New York, and an expert in pain management. I want to welcome both of you and thank you for joining me.
 

RAMPED Trial: Evaluating the Efficacy of Methoxyflurane

Dr. Glatter: Ken, your recent post on Twitter [now X] regarding the utility of Penthrox in the RAMPED trial really caught my attention. While the trial was from 2021, it really is relevant regarding the prehospital management of pain in the practice of emergency medicine, and certainly in-hospital practice. I was hoping you could review the study design but also get into the rationale behind the use of this novel agent.

William Kenneth (Ken) Milne, MD, MSc: Sure. I’d be happy to kick this episode off with talking about a study that was published in 2020 in Academic Emergency Medicine. It was an Australian study by Brichko et al., and they were doing a randomized controlled trial looking at methoxyflurane vs standard care.

They selected out a population of adults, which they defined as 18-75 years of age. They were in the prehospital setting and they had a pain score of greater than 8. They gave the participants methoxyflurane, which is also called the “green whistle.” They had the subjects take that for their prehospital pain, and they compared that with whatever your standard analgesic in the prehospital setting would be.

Their primary outcome was how many patients had at least 50% reduction in their pain score within 30 minutes. They recruited about 120 people, and they found that there was no statistical difference in the primary outcome between methoxyflurane and standard care. Again, that primary outcome was a reduction in pain score by greater than 50% at 30 minutes, and there wasn’t a statistical difference between the two.

There are obviously limits to any study, and it was a convenience sample. This was an unmasked trial, so people knew if they were getting this green whistle, which is popular in Australia. People would be familiar with this device, and they didn’t compare it with a sham or placebo group.

Pharmacology of Penthrox: Its Role and Mechanism of Action

Dr. Glatter: The primary outcome wasn’t met, but certainly secondary outcomes were. There was, again, a relatively small number of patients in this trial. That said, there was significant pain relief. I think there are issues with the trial, as with any trial limitations.

Getting to the pharmacology of Penthrox, can you describe this inhaled anesthetic and how we use it, specifically its role at the subanesthetic doses?

Sergey M. Motov, MD: Methoxyflurane is embedded in the green whistle package, and that whole contraption is called Penthrox. It’s an inhaled volatile fluorinated hydrocarbon anesthetic that was predominantly used, I’d say 40, 50 years ago, for general anesthesia and slowly but surely fell out of favor due to the fact that, when used for prolonged duration or in supratherapeutic doses, there were cases of severe or even fatal nephrotoxicity and hepatotoxicity.

In the late ‘70s and early ‘80s, all the fluranes came on board that are slightly different as general anesthetics, and methoxyflurane started slowly falling out of favor. Because of this paucity and then a subsequent slightly greater number of cases of nephrotoxicity and hepatotoxicity, [the US Food and Drug Administration] FDA made a decision to pull the drug off the market in 2005. FDA successfully accomplished its mission and since then has pretty much banned the use of inhaled methoxyflurane in any shape, form, or color in the United States.

Going back to the green whistle, it has been used in Australia probably for about 50-60 years, and has been used in Europe for probably 10-20 years. Ken can attest that it has been used in Canada for at least a decade and the track record is phenomenal.

We are using subanesthetic, even supratherapeutic doses that, based on available literature, has no incidence of this fatal hepatotoxicity or nephrotoxicity. We’re talking about 10 million doses administered worldwide, except in the United States. There are 40-plus randomized clinical trials with over 30,000 patients enrolled that prove efficacy and safety.

That’s where we are right now, in a conundrum. We have a great deal of data all over the world, except in the United States, that push for the use of this noninvasive, patient-controlled nonopioid inhaled anesthetic. We just don’t have the access in North America, with the exception of Canada.

Regulatory Hurdles: Challenges in FDA Approval

Dr. Glatter: Absolutely. The FDA wants to be cautious, but if you look at the evidence base of data on this, it really indicates otherwise. Do you think that these roadblocks can be somehow overcome?

Dr. Milne: In the 2000s and 2010s, everybody was focused on opioids and all the dangers and potential adverse events. Opioids are great drugs like many other drugs; it depends on dose and duration. If used properly, it’s an excellent drug. Well, here’s another excellent drug if it’s used properly, and the adverse events are dependent on their dose and duration. Penthrox, or methoxyflurane, is a subtherapeutic, small dose and there have been no reported cases of addiction or abuse related to these inhalers.

Dr. Glatter: That argues for the point — and I’ll turn this over to you, Sergey — of how can this not, in my mind, be an issue that the FDA can overcome.

Dr. Motov: I agree with you. It’s very hard for me to speak on behalf of the FDA, to allude to their thinking processes, but we need to be up to speed with the evidence. The first thing is, why don’t you study the drug in the United States? I’m not asking you to lift the ban, which you put in 2005, but why don’t you honor what has been done over two decades and at least open the door a little bit and let us do what we do best? Why don’t you allow us to do the research in a controlled setting with a carefully, properly selected group of patients without underlying renal or hepatic insufficiency and see where we’re at?

Let’s compare it against placebo. If that’s not ethical, let’s compare it against active comparators — God knows we have 15-20 drugs we can use — and let’s see where we’re at. Ken has been nothing short of superb when it comes to evidence. Let us put the evidence together.

Dr. Milne: If there were concerns decades ago, those need to be addressed. As science is iterative and as other information becomes available, the scientific method would say, Let’s reexamine this and let’s reexamine our position, and do that with evidence. To do that, it has to have validity within the US system. Someone like you doing the research, you are a pain research guru; you should be doing this research to say, “Does it work or not? Does this nonapproval still stand today in 2024?”

Dr. Motov: Thank you for the shout-out, and I agree with you. All of us, those who are interested, on the frontiers of emergency care — as present clinicians — we should be doing this. There is nothing that will convince the FDA more than properly and rightly conducted research, time to reassess the evidence, and time to be less rigid. I understand that you placed a ban 20 years ago, but let’s go with the science. We cannot be behind it.

Exploring the Ecological Footprint of Methoxyflurane

Dr. Milne: There was an Austrian study in 2022 and a very interesting study out of the UK looking at life-cycle impact assessment on the environment. If we’re not just concerned about patient care —obviously, we want to provide patients with a safe and effective product, compared with other products that are available that might not have as good a safety profile — this looks at the impact on the environment.

Dr. Glatter: Ken, can you tell me about some of your recent research regarding the environmental effects related to use of Penthrox, but also its utility pharmacologically and its mechanism of action?

Dr. Milne: There was a really interesting study published this year by Martindale in the Emergency Medicine Journal. It took a different approach to this question about could we be using this drug, and why should we be using this drug? Sergey and I have already talked about the potential benefits and the potential harms. I mentioned opioids and some of the concerns about that. For this drug, if we’re using it in the prehospital setting in this little green whistle, the potential benefits look really good, and we haven’t seen any of the potential harms come through in the literature.

This was another line of evidence of why this might be a good drug, because of the environmental impact of this low-dose methoxyflurane. They compared it with nitrous oxide and said, “Well, what about the life-cycle impact on the environment of using this and the overall cradle-to-grave environmental impacts?”

Obviously, Sergey and I are interested in patient care, and we treat patients one at a time. But we have a larger responsibility to social determinants of health, like our environment. If you look at the overall cradle-to-grave environmental impact of this drug, it was better than for nitrous oxide when looking specifically at climate-change impact. That might be another reason, another line of argument, that could be put forward in the United States to say, “We want to have a healthy environment and a healthy option for patients.”

I’ll let Sergey speak to mechanisms of action and those types of things.

Dr. Motov: As a general anesthetic and hydrocarbonated volatile ones, I’m just going to say that it causes this generalized diffuse cortical depression, and there are no particular channels, receptors, or enzymes we need to worry much about. In short, it’s an inhaled gas used to put patients or people to sleep.

Over the past 30 or 40 years — and I’ll go back to the past decade — there have been numerous studies in different countries (outside of the United States, of course), and with the recent study that Ken just cited, there were comparisons for managing predominantly acute traumatic injuries in pediatric and adult populations presenting to EDs in various regions of the world that compared Penthrox, or the green whistle, with either placebo or active comparators, which included parenteral opioids, oral opioids, and NSAIDs.

The recent systematic review by Fabbri, out of Italy, showed that for ultra–short-term pain — we’re talking about 5, 10, or 15 minutes — inhaled methoxyflurane was found to be equal or even superior to standard of care, primarily related to parenteral opioids, and safety was off the hook. Interestingly, with respect to analgesia, they found that geriatric patients seemed to be responding more, with respect to changing pain score, than younger adults — we’re talking about ages 18-64 vs 65 or older. Again, we need to make sure that we carefully select those elderly people without underlying renal or hepatic insufficiency.

To wrap this up, there is evidence clearly supporting its analgesic efficacy and safety, even in comparison to commonly used and traditionally accepted analgesic modalities that we use for managing acute pain.

US Military Use and Implications for Civilian Practice

Dr. Glatter: Do you think that methoxyflurane’s use in the military will help propel its use in clinical settings in the US, and possibly convince the FDA to look at this closer? The military is currently using it in deployed combat veterans in an ongoing fashion.

Dr. Motov: I’m excited that the Department of Defense in the United States has taken the lead, and they’re being very progressive. There are data that we’ve adapted to the civilian environment by use of intranasal opioids and intranasal ketamine with more doctors who came out of the military. In the military, it’s a kingdom within a kingdom. I don’t know their relationship with the FDA, but I support the military’s pharmacologic initiative by honoring and disseminating their research once it becomes available.

For us nonmilitary folks, we still need to work with the FDA. We need to convince the FDA to let us study the drug, and then we need to pile the evidence within the United States so that the FDA will start looking at this favorably. It wouldn’t hurt and it wouldn’t harm. Any piece of evidence will add to the existing body of literature that we need to allow this medication to be available to us.

Safety Considerations and Aerosolization Concerns

Dr. Glatter: Its safety in children is well established in Australia and throughout the world. I think it deserves a careful look, and the evidence that you’ve both presented argues for the use of this prehospital but also in hospital. I guess there was concern in the hospital with underventilation and healthcare workers being exposed to the fumes, and then getting headaches, dizziness, and so forth. I don’t know if that’s borne out, Ken, in any of your experience in Canada at all.

Dr. Milne: We currently don’t have it in our shop. It’s being used in British Columbia right now in the prehospital setting, and I’m not aware of anybody using it in their department. It’s used prehospital as far as I know.

Dr. Motov: I can attest to it, if I may, because I had familiarized myself with the device. I actually was able to hold it in my hands. I have not used it yet but I had the prototype. The way it’s set up, there is an activated charcoal chamber that sits right on top of the device, which serves as the scavenger for exhaled air that contains particles of methoxyflurane. In theory, but I’m telling how it is in practicality, it significantly reduces occupational exposure, based on data that lacks specifics.

Although most of the researchers did not measure the concentration of methoxyflurane in ambient air within the treatment room in the EDs, I believe the additional data sources clearly stating that it’s within or even below the detectable level that would cause any harm. Once again, we need to honor pathology. We need to make sure that pregnant women will not be exposed to it.

Dr. Milne: In 2024, we also need to be concerned about aerosolizing procedures and aerosolizing treatments, and just take that into account because we should be considering all the potential benefits and all the potential harms. Going through the COVID-19 pandemic, there was concern about transmission and whether or not it was droplet or aerosolized.

There was an observational study published in 2022 in Austria by Trimmel in BMC Emergency Medicine showing similar results. It seemed to work well and potential harms didn’t get picked up. They had to stop the study early because of COVID-19.

We need to always focus in on the potential benefits, the potential harms; where does the science land? Where do the data lie? Then we move forward from that and make informed decisions.

Final Thoughts

Dr. Glatter: Are there any key takeaways you’d like to share with our audience?

Dr. Milne: One of the takeaways from this whole conversation is that science is iterative and science changes. When new evidence becomes available, and we’ve seen it accumulate around the world, we as scientists, as a researcher, as somebody committed to great patient care should revisit our positions on this. Since there is a prohibition against this medication, I think it’s time to reassess that stance and move forward to see if it still is accurate today.

Dr. Motov: I wholeheartedly agree with this. Thank you, Ken, for bringing this up. Good point.

Dr. Glatter: This has been a really informative discussion. I think our audience will certainly embrace this. Thank you very much for your time; it’s much appreciated.
 

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is a medical adviser for Medscape and hosts the Hot Topics in EM series. Dr. Milne is an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM). Dr. Motov is professor of emergency medicine and director of research in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York. He is passionate about safe and effective pain management in the emergency department, and has numerous publications on the subject of opioid alternatives in pain management. Dr. Glatter, Dr. Milne, and Dr. Motov had no conflicts of interest to disclose.

A version of this article appeared on Medscape.com.

This discussion was recorded on March 29, 2024. The transcript has been edited for clarity.

Robert D. Glatter, MD: Joining me today to discuss the use of methoxyflurane (Penthrox), an inhaled nonopioid analgesic for the relief of acute pain, is Dr. William Kenneth (Ken) Milne, an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM).

Also joining me is Dr. Sergey Motov, an emergency physician and research director at Maimonides Medical Center in Brooklyn, New York, and an expert in pain management. I want to welcome both of you and thank you for joining me.
 

RAMPED Trial: Evaluating the Efficacy of Methoxyflurane

Dr. Glatter: Ken, your recent post on Twitter [now X] regarding the utility of Penthrox in the RAMPED trial really caught my attention. While the trial was from 2021, it really is relevant regarding the prehospital management of pain in the practice of emergency medicine, and certainly in-hospital practice. I was hoping you could review the study design but also get into the rationale behind the use of this novel agent.

William Kenneth (Ken) Milne, MD, MSc: Sure. I’d be happy to kick this episode off with talking about a study that was published in 2020 in Academic Emergency Medicine. It was an Australian study by Brichko et al., and they were doing a randomized controlled trial looking at methoxyflurane vs standard care.

They selected out a population of adults, which they defined as 18-75 years of age. They were in the prehospital setting and they had a pain score of greater than 8. They gave the participants methoxyflurane, which is also called the “green whistle.” They had the subjects take that for their prehospital pain, and they compared that with whatever your standard analgesic in the prehospital setting would be.

Their primary outcome was how many patients had at least 50% reduction in their pain score within 30 minutes. They recruited about 120 people, and they found that there was no statistical difference in the primary outcome between methoxyflurane and standard care. Again, that primary outcome was a reduction in pain score by greater than 50% at 30 minutes, and there wasn’t a statistical difference between the two.

There are obviously limits to any study, and it was a convenience sample. This was an unmasked trial, so people knew if they were getting this green whistle, which is popular in Australia. People would be familiar with this device, and they didn’t compare it with a sham or placebo group.

Pharmacology of Penthrox: Its Role and Mechanism of Action

Dr. Glatter: The primary outcome wasn’t met, but certainly secondary outcomes were. There was, again, a relatively small number of patients in this trial. That said, there was significant pain relief. I think there are issues with the trial, as with any trial limitations.

Getting to the pharmacology of Penthrox, can you describe this inhaled anesthetic and how we use it, specifically its role at the subanesthetic doses?

Sergey M. Motov, MD: Methoxyflurane is embedded in the green whistle package, and that whole contraption is called Penthrox. It’s an inhaled volatile fluorinated hydrocarbon anesthetic that was predominantly used, I’d say 40, 50 years ago, for general anesthesia and slowly but surely fell out of favor due to the fact that, when used for prolonged duration or in supratherapeutic doses, there were cases of severe or even fatal nephrotoxicity and hepatotoxicity.

In the late ‘70s and early ‘80s, all the fluranes came on board that are slightly different as general anesthetics, and methoxyflurane started slowly falling out of favor. Because of this paucity and then a subsequent slightly greater number of cases of nephrotoxicity and hepatotoxicity, [the US Food and Drug Administration] FDA made a decision to pull the drug off the market in 2005. FDA successfully accomplished its mission and since then has pretty much banned the use of inhaled methoxyflurane in any shape, form, or color in the United States.

Going back to the green whistle, it has been used in Australia probably for about 50-60 years, and has been used in Europe for probably 10-20 years. Ken can attest that it has been used in Canada for at least a decade and the track record is phenomenal.

We are using subanesthetic, even supratherapeutic doses that, based on available literature, has no incidence of this fatal hepatotoxicity or nephrotoxicity. We’re talking about 10 million doses administered worldwide, except in the United States. There are 40-plus randomized clinical trials with over 30,000 patients enrolled that prove efficacy and safety.

That’s where we are right now, in a conundrum. We have a great deal of data all over the world, except in the United States, that push for the use of this noninvasive, patient-controlled nonopioid inhaled anesthetic. We just don’t have the access in North America, with the exception of Canada.

Regulatory Hurdles: Challenges in FDA Approval

Dr. Glatter: Absolutely. The FDA wants to be cautious, but if you look at the evidence base of data on this, it really indicates otherwise. Do you think that these roadblocks can be somehow overcome?

Dr. Milne: In the 2000s and 2010s, everybody was focused on opioids and all the dangers and potential adverse events. Opioids are great drugs like many other drugs; it depends on dose and duration. If used properly, it’s an excellent drug. Well, here’s another excellent drug if it’s used properly, and the adverse events are dependent on their dose and duration. Penthrox, or methoxyflurane, is a subtherapeutic, small dose and there have been no reported cases of addiction or abuse related to these inhalers.

Dr. Glatter: That argues for the point — and I’ll turn this over to you, Sergey — of how can this not, in my mind, be an issue that the FDA can overcome.

Dr. Motov: I agree with you. It’s very hard for me to speak on behalf of the FDA, to allude to their thinking processes, but we need to be up to speed with the evidence. The first thing is, why don’t you study the drug in the United States? I’m not asking you to lift the ban, which you put in 2005, but why don’t you honor what has been done over two decades and at least open the door a little bit and let us do what we do best? Why don’t you allow us to do the research in a controlled setting with a carefully, properly selected group of patients without underlying renal or hepatic insufficiency and see where we’re at?

Let’s compare it against placebo. If that’s not ethical, let’s compare it against active comparators — God knows we have 15-20 drugs we can use — and let’s see where we’re at. Ken has been nothing short of superb when it comes to evidence. Let us put the evidence together.

Dr. Milne: If there were concerns decades ago, those need to be addressed. As science is iterative and as other information becomes available, the scientific method would say, Let’s reexamine this and let’s reexamine our position, and do that with evidence. To do that, it has to have validity within the US system. Someone like you doing the research, you are a pain research guru; you should be doing this research to say, “Does it work or not? Does this nonapproval still stand today in 2024?”

Dr. Motov: Thank you for the shout-out, and I agree with you. All of us, those who are interested, on the frontiers of emergency care — as present clinicians — we should be doing this. There is nothing that will convince the FDA more than properly and rightly conducted research, time to reassess the evidence, and time to be less rigid. I understand that you placed a ban 20 years ago, but let’s go with the science. We cannot be behind it.

Exploring the Ecological Footprint of Methoxyflurane

Dr. Milne: There was an Austrian study in 2022 and a very interesting study out of the UK looking at life-cycle impact assessment on the environment. If we’re not just concerned about patient care —obviously, we want to provide patients with a safe and effective product, compared with other products that are available that might not have as good a safety profile — this looks at the impact on the environment.

Dr. Glatter: Ken, can you tell me about some of your recent research regarding the environmental effects related to use of Penthrox, but also its utility pharmacologically and its mechanism of action?

Dr. Milne: There was a really interesting study published this year by Martindale in the Emergency Medicine Journal. It took a different approach to this question about could we be using this drug, and why should we be using this drug? Sergey and I have already talked about the potential benefits and the potential harms. I mentioned opioids and some of the concerns about that. For this drug, if we’re using it in the prehospital setting in this little green whistle, the potential benefits look really good, and we haven’t seen any of the potential harms come through in the literature.

This was another line of evidence of why this might be a good drug, because of the environmental impact of this low-dose methoxyflurane. They compared it with nitrous oxide and said, “Well, what about the life-cycle impact on the environment of using this and the overall cradle-to-grave environmental impacts?”

Obviously, Sergey and I are interested in patient care, and we treat patients one at a time. But we have a larger responsibility to social determinants of health, like our environment. If you look at the overall cradle-to-grave environmental impact of this drug, it was better than for nitrous oxide when looking specifically at climate-change impact. That might be another reason, another line of argument, that could be put forward in the United States to say, “We want to have a healthy environment and a healthy option for patients.”

I’ll let Sergey speak to mechanisms of action and those types of things.

Dr. Motov: As a general anesthetic and hydrocarbonated volatile ones, I’m just going to say that it causes this generalized diffuse cortical depression, and there are no particular channels, receptors, or enzymes we need to worry much about. In short, it’s an inhaled gas used to put patients or people to sleep.

Over the past 30 or 40 years — and I’ll go back to the past decade — there have been numerous studies in different countries (outside of the United States, of course), and with the recent study that Ken just cited, there were comparisons for managing predominantly acute traumatic injuries in pediatric and adult populations presenting to EDs in various regions of the world that compared Penthrox, or the green whistle, with either placebo or active comparators, which included parenteral opioids, oral opioids, and NSAIDs.

The recent systematic review by Fabbri, out of Italy, showed that for ultra–short-term pain — we’re talking about 5, 10, or 15 minutes — inhaled methoxyflurane was found to be equal or even superior to standard of care, primarily related to parenteral opioids, and safety was off the hook. Interestingly, with respect to analgesia, they found that geriatric patients seemed to be responding more, with respect to changing pain score, than younger adults — we’re talking about ages 18-64 vs 65 or older. Again, we need to make sure that we carefully select those elderly people without underlying renal or hepatic insufficiency.

To wrap this up, there is evidence clearly supporting its analgesic efficacy and safety, even in comparison to commonly used and traditionally accepted analgesic modalities that we use for managing acute pain.

US Military Use and Implications for Civilian Practice

Dr. Glatter: Do you think that methoxyflurane’s use in the military will help propel its use in clinical settings in the US, and possibly convince the FDA to look at this closer? The military is currently using it in deployed combat veterans in an ongoing fashion.

Dr. Motov: I’m excited that the Department of Defense in the United States has taken the lead, and they’re being very progressive. There are data that we’ve adapted to the civilian environment by use of intranasal opioids and intranasal ketamine with more doctors who came out of the military. In the military, it’s a kingdom within a kingdom. I don’t know their relationship with the FDA, but I support the military’s pharmacologic initiative by honoring and disseminating their research once it becomes available.

For us nonmilitary folks, we still need to work with the FDA. We need to convince the FDA to let us study the drug, and then we need to pile the evidence within the United States so that the FDA will start looking at this favorably. It wouldn’t hurt and it wouldn’t harm. Any piece of evidence will add to the existing body of literature that we need to allow this medication to be available to us.

Safety Considerations and Aerosolization Concerns

Dr. Glatter: Its safety in children is well established in Australia and throughout the world. I think it deserves a careful look, and the evidence that you’ve both presented argues for the use of this prehospital but also in hospital. I guess there was concern in the hospital with underventilation and healthcare workers being exposed to the fumes, and then getting headaches, dizziness, and so forth. I don’t know if that’s borne out, Ken, in any of your experience in Canada at all.

Dr. Milne: We currently don’t have it in our shop. It’s being used in British Columbia right now in the prehospital setting, and I’m not aware of anybody using it in their department. It’s used prehospital as far as I know.

Dr. Motov: I can attest to it, if I may, because I had familiarized myself with the device. I actually was able to hold it in my hands. I have not used it yet but I had the prototype. The way it’s set up, there is an activated charcoal chamber that sits right on top of the device, which serves as the scavenger for exhaled air that contains particles of methoxyflurane. In theory, but I’m telling how it is in practicality, it significantly reduces occupational exposure, based on data that lacks specifics.

Although most of the researchers did not measure the concentration of methoxyflurane in ambient air within the treatment room in the EDs, I believe the additional data sources clearly stating that it’s within or even below the detectable level that would cause any harm. Once again, we need to honor pathology. We need to make sure that pregnant women will not be exposed to it.

Dr. Milne: In 2024, we also need to be concerned about aerosolizing procedures and aerosolizing treatments, and just take that into account because we should be considering all the potential benefits and all the potential harms. Going through the COVID-19 pandemic, there was concern about transmission and whether or not it was droplet or aerosolized.

There was an observational study published in 2022 in Austria by Trimmel in BMC Emergency Medicine showing similar results. It seemed to work well and potential harms didn’t get picked up. They had to stop the study early because of COVID-19.

We need to always focus in on the potential benefits, the potential harms; where does the science land? Where do the data lie? Then we move forward from that and make informed decisions.

Final Thoughts

Dr. Glatter: Are there any key takeaways you’d like to share with our audience?

Dr. Milne: One of the takeaways from this whole conversation is that science is iterative and science changes. When new evidence becomes available, and we’ve seen it accumulate around the world, we as scientists, as a researcher, as somebody committed to great patient care should revisit our positions on this. Since there is a prohibition against this medication, I think it’s time to reassess that stance and move forward to see if it still is accurate today.

Dr. Motov: I wholeheartedly agree with this. Thank you, Ken, for bringing this up. Good point.

Dr. Glatter: This has been a really informative discussion. I think our audience will certainly embrace this. Thank you very much for your time; it’s much appreciated.
 

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is a medical adviser for Medscape and hosts the Hot Topics in EM series. Dr. Milne is an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM). Dr. Motov is professor of emergency medicine and director of research in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York. He is passionate about safe and effective pain management in the emergency department, and has numerous publications on the subject of opioid alternatives in pain management. Dr. Glatter, Dr. Milne, and Dr. Motov had no conflicts of interest to disclose.

A version of this article appeared on Medscape.com.

In my last column, I began to explore the factors affecting the compensation of primary care providers (PCPs). I described two apparent economic paradoxes. First, while most healthcare systems consider their primary care segments as loss leaders, they continue to seek and hire more PCPs. The second is while PCPs are in short supply, most of them feel that they are underpaid. Supply and demand doesn’t seem to be making them more valuable in the economic sense. The explanations for these nonintuitive observations are first, healthcare systems need the volume of patients stored in the practices of even unprofitable primary care physicians to feed the high-profit specialties in their businesses. Second, there is a limit to how large a gap between revenue and overhead the systems can accept for their primary care practices. Not surprisingly, this means that system administrators must continue to nudge those PCP practices closer toward profitability, usually by demanding higher productivity.

As I did in my last letter, I will continue to lean on a discussion for PCP compensation by a large international management consulting firm I found on the internet. I am not condoning the consultant’s advice, but merely using it as a scaffolding on which to hang the rather squishy topics of time, clinical quality, and patient satisfaction. I only intend to ask questions, and I promise no answers.

First, let me make it clear that I am defining PCPs as providers who are on a performance-based pathway, which is by far the most prevalent model. A fixed-salary arrangement hasn’t made sense to me since I was a 17-year-old lifeguard paid by the hour for sitting by a pool. Had I been paid by the rescue, I would have finished the summer empty handed. A fixed salary provided me a sense of security, but it offered no path for advancement and was boring as hell. The primary care provider I am talking about has an interest in developing relationships with his/her patients, building a practice, and offering some degree of continuity. In other words, I am not considering providers working in walk-in clinics as PCPs.
 

Size Matters

My high-powered management consultant is recommending to his healthcare system management clients that they emphasize panel size component as they craft their compensation packages for PCPs. Maybe even to the point of giving it more weight than the productivity piece. This, of course, makes perfect business sense if the primary value of a PCP to the system lies in the patients he/she brings into the system.

What does this emphasis on size mean for you as a provider? If your boss is following my consultant’s advice, then you would want to be growing your panel size to improve your compensation. You could do this by a marketing plan that makes you more popular. But, I can hear you muttering that you never wanted to be a contestant in a popularity contest. Although I must say that historically this was a fact of life in any community when new providers came to town.

A provider can choose his/her own definition of popularity. You can let it be known that you are a liberal prescription writer and fill your practice with drug-seeking patients. Or you could promote customer-friendly schedules and behaviors in your office staff. And, of course, you can simply exude an aura of caring, which has always been an effective practice-building tool.

On the other hand, you may believe that you have more patients than you can handle. You may fear that growing your practice runs the risk of putting the quality of your patients’ care and your own physical and mental health at risk.

Theoretically, you could keep your panel size unchanged and increase your productivity to enhance your value and therefore your compensation. In the next part of this miniseries we’ll look at the stumbling blocks that can make increasing productivity difficult.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

In my last column, I began to explore the factors affecting the compensation of primary care providers (PCPs). I described two apparent economic paradoxes. First, while most healthcare systems consider their primary care segments as loss leaders, they continue to seek and hire more PCPs. The second is while PCPs are in short supply, most of them feel that they are underpaid. Supply and demand doesn’t seem to be making them more valuable in the economic sense. The explanations for these nonintuitive observations are first, healthcare systems need the volume of patients stored in the practices of even unprofitable primary care physicians to feed the high-profit specialties in their businesses. Second, there is a limit to how large a gap between revenue and overhead the systems can accept for their primary care practices. Not surprisingly, this means that system administrators must continue to nudge those PCP practices closer toward profitability, usually by demanding higher productivity.

As I did in my last letter, I will continue to lean on a discussion for PCP compensation by a large international management consulting firm I found on the internet. I am not condoning the consultant’s advice, but merely using it as a scaffolding on which to hang the rather squishy topics of time, clinical quality, and patient satisfaction. I only intend to ask questions, and I promise no answers.

First, let me make it clear that I am defining PCPs as providers who are on a performance-based pathway, which is by far the most prevalent model. A fixed-salary arrangement hasn’t made sense to me since I was a 17-year-old lifeguard paid by the hour for sitting by a pool. Had I been paid by the rescue, I would have finished the summer empty handed. A fixed salary provided me a sense of security, but it offered no path for advancement and was boring as hell. The primary care provider I am talking about has an interest in developing relationships with his/her patients, building a practice, and offering some degree of continuity. In other words, I am not considering providers working in walk-in clinics as PCPs.
 

Size Matters

My high-powered management consultant is recommending to his healthcare system management clients that they emphasize panel size component as they craft their compensation packages for PCPs. Maybe even to the point of giving it more weight than the productivity piece. This, of course, makes perfect business sense if the primary value of a PCP to the system lies in the patients he/she brings into the system.

What does this emphasis on size mean for you as a provider? If your boss is following my consultant’s advice, then you would want to be growing your panel size to improve your compensation. You could do this by a marketing plan that makes you more popular. But, I can hear you muttering that you never wanted to be a contestant in a popularity contest. Although I must say that historically this was a fact of life in any community when new providers came to town.

A provider can choose his/her own definition of popularity. You can let it be known that you are a liberal prescription writer and fill your practice with drug-seeking patients. Or you could promote customer-friendly schedules and behaviors in your office staff. And, of course, you can simply exude an aura of caring, which has always been an effective practice-building tool.

On the other hand, you may believe that you have more patients than you can handle. You may fear that growing your practice runs the risk of putting the quality of your patients’ care and your own physical and mental health at risk.

Theoretically, you could keep your panel size unchanged and increase your productivity to enhance your value and therefore your compensation. In the next part of this miniseries we’ll look at the stumbling blocks that can make increasing productivity difficult.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

In my last column, I began to explore the factors affecting the compensation of primary care providers (PCPs). I described two apparent economic paradoxes. First, while most healthcare systems consider their primary care segments as loss leaders, they continue to seek and hire more PCPs. The second is while PCPs are in short supply, most of them feel that they are underpaid. Supply and demand doesn’t seem to be making them more valuable in the economic sense. The explanations for these nonintuitive observations are first, healthcare systems need the volume of patients stored in the practices of even unprofitable primary care physicians to feed the high-profit specialties in their businesses. Second, there is a limit to how large a gap between revenue and overhead the systems can accept for their primary care practices. Not surprisingly, this means that system administrators must continue to nudge those PCP practices closer toward profitability, usually by demanding higher productivity.

As I did in my last letter, I will continue to lean on a discussion for PCP compensation by a large international management consulting firm I found on the internet. I am not condoning the consultant’s advice, but merely using it as a scaffolding on which to hang the rather squishy topics of time, clinical quality, and patient satisfaction. I only intend to ask questions, and I promise no answers.

First, let me make it clear that I am defining PCPs as providers who are on a performance-based pathway, which is by far the most prevalent model. A fixed-salary arrangement hasn’t made sense to me since I was a 17-year-old lifeguard paid by the hour for sitting by a pool. Had I been paid by the rescue, I would have finished the summer empty handed. A fixed salary provided me a sense of security, but it offered no path for advancement and was boring as hell. The primary care provider I am talking about has an interest in developing relationships with his/her patients, building a practice, and offering some degree of continuity. In other words, I am not considering providers working in walk-in clinics as PCPs.
 

Size Matters

My high-powered management consultant is recommending to his healthcare system management clients that they emphasize panel size component as they craft their compensation packages for PCPs. Maybe even to the point of giving it more weight than the productivity piece. This, of course, makes perfect business sense if the primary value of a PCP to the system lies in the patients he/she brings into the system.

What does this emphasis on size mean for you as a provider? If your boss is following my consultant’s advice, then you would want to be growing your panel size to improve your compensation. You could do this by a marketing plan that makes you more popular. But, I can hear you muttering that you never wanted to be a contestant in a popularity contest. Although I must say that historically this was a fact of life in any community when new providers came to town.

A provider can choose his/her own definition of popularity. You can let it be known that you are a liberal prescription writer and fill your practice with drug-seeking patients. Or you could promote customer-friendly schedules and behaviors in your office staff. And, of course, you can simply exude an aura of caring, which has always been an effective practice-building tool.

On the other hand, you may believe that you have more patients than you can handle. You may fear that growing your practice runs the risk of putting the quality of your patients’ care and your own physical and mental health at risk.

Theoretically, you could keep your panel size unchanged and increase your productivity to enhance your value and therefore your compensation. In the next part of this miniseries we’ll look at the stumbling blocks that can make increasing productivity difficult.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

A recent review of the Open Payments database found that, over the last 10 years, the evil forces of Big Pharma have paid doctors $12.1 billion dollars.

That’s a lot.

Of course, there are also quite a few doctors out there, and the word “paid” is kind of a misnomer. Yes, some people did get paid directly — cash for research, speaking engagements, teaching other docs — but a lot of the money was really spent on marketing. It may show that Dr. Jones was “paid” $200 one day, when in reality that was the cost of providing lunch to her, her five-person office staff, and the medical student following her around that afternoon.

In the last 10 years, I’ve accepted “payments” of one pizza and three iced coffees, so I guess I’m on there, too.

When you actually break it down, this comes out to a national average of (drum roll) $48 per doctor over 10 years.

Let’s face it, if your prescribing habits can be bought for $4.80 a year ... that’s pretty sad. They say everyone has their price, but hopefully it’s not that of a Happy Meal.

I understand the reasons for tracking this sort of thing. The system certainly can be — and has been — gamed for abuse. If one doctor is getting a ridiculous amount of money for doing nothing but writing scripts for Walletgouge-XR, that certainly needs to be known. Something is rotten in the state of Denmark (or wherever).

But the headline, especially when used in the lay media, makes it sound like all docs are on payola, and further erodes trust in the medical field. The fact that it works out to $4.80 per doctor each year is going to buried deeper in the article, by which time most readers will have moved on to see what Taylor Swift is up to.

Perhaps I’ve taken it to an extreme, but since the pizza (2014) I haven’t done lunch at my office. I still meet with reps, but they’re told now that I don’t do lunch, or bagels, or even iced coffee anymore. Tell me what I need to know about the new drug, but at this point in my career I’d rather have time. By not meeting a rep over lunch, or coffee, it adds 30-60 minutes to my day to use for reviewing tests, returning calls, and typing up notes. Those are things I’m going to have to do at some point, so I’d rather do them at my office and have the extra time at home, even if it’s just to do a jigsaw puzzle with my daughter.

That’s worth more than $4.80 per year.

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

A recent review of the Open Payments database found that, over the last 10 years, the evil forces of Big Pharma have paid doctors $12.1 billion dollars.

That’s a lot.

Of course, there are also quite a few doctors out there, and the word “paid” is kind of a misnomer. Yes, some people did get paid directly — cash for research, speaking engagements, teaching other docs — but a lot of the money was really spent on marketing. It may show that Dr. Jones was “paid” $200 one day, when in reality that was the cost of providing lunch to her, her five-person office staff, and the medical student following her around that afternoon.

In the last 10 years, I’ve accepted “payments” of one pizza and three iced coffees, so I guess I’m on there, too.

When you actually break it down, this comes out to a national average of (drum roll) $48 per doctor over 10 years.

Let’s face it, if your prescribing habits can be bought for $4.80 a year ... that’s pretty sad. They say everyone has their price, but hopefully it’s not that of a Happy Meal.

I understand the reasons for tracking this sort of thing. The system certainly can be — and has been — gamed for abuse. If one doctor is getting a ridiculous amount of money for doing nothing but writing scripts for Walletgouge-XR, that certainly needs to be known. Something is rotten in the state of Denmark (or wherever).

But the headline, especially when used in the lay media, makes it sound like all docs are on payola, and further erodes trust in the medical field. The fact that it works out to $4.80 per doctor each year is going to buried deeper in the article, by which time most readers will have moved on to see what Taylor Swift is up to.

Perhaps I’ve taken it to an extreme, but since the pizza (2014) I haven’t done lunch at my office. I still meet with reps, but they’re told now that I don’t do lunch, or bagels, or even iced coffee anymore. Tell me what I need to know about the new drug, but at this point in my career I’d rather have time. By not meeting a rep over lunch, or coffee, it adds 30-60 minutes to my day to use for reviewing tests, returning calls, and typing up notes. Those are things I’m going to have to do at some point, so I’d rather do them at my office and have the extra time at home, even if it’s just to do a jigsaw puzzle with my daughter.

That’s worth more than $4.80 per year.

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

A recent review of the Open Payments database found that, over the last 10 years, the evil forces of Big Pharma have paid doctors $12.1 billion dollars.

That’s a lot.

Of course, there are also quite a few doctors out there, and the word “paid” is kind of a misnomer. Yes, some people did get paid directly — cash for research, speaking engagements, teaching other docs — but a lot of the money was really spent on marketing. It may show that Dr. Jones was “paid” $200 one day, when in reality that was the cost of providing lunch to her, her five-person office staff, and the medical student following her around that afternoon.

In the last 10 years, I’ve accepted “payments” of one pizza and three iced coffees, so I guess I’m on there, too.

When you actually break it down, this comes out to a national average of (drum roll) $48 per doctor over 10 years.

Let’s face it, if your prescribing habits can be bought for $4.80 a year ... that’s pretty sad. They say everyone has their price, but hopefully it’s not that of a Happy Meal.

I understand the reasons for tracking this sort of thing. The system certainly can be — and has been — gamed for abuse. If one doctor is getting a ridiculous amount of money for doing nothing but writing scripts for Walletgouge-XR, that certainly needs to be known. Something is rotten in the state of Denmark (or wherever).

But the headline, especially when used in the lay media, makes it sound like all docs are on payola, and further erodes trust in the medical field. The fact that it works out to $4.80 per doctor each year is going to buried deeper in the article, by which time most readers will have moved on to see what Taylor Swift is up to.

Perhaps I’ve taken it to an extreme, but since the pizza (2014) I haven’t done lunch at my office. I still meet with reps, but they’re told now that I don’t do lunch, or bagels, or even iced coffee anymore. Tell me what I need to know about the new drug, but at this point in my career I’d rather have time. By not meeting a rep over lunch, or coffee, it adds 30-60 minutes to my day to use for reviewing tests, returning calls, and typing up notes. Those are things I’m going to have to do at some point, so I’d rather do them at my office and have the extra time at home, even if it’s just to do a jigsaw puzzle with my daughter.

That’s worth more than $4.80 per year.

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

Let’s be honest: Although as physicians we have the power of the prescription pad, so much of health, in the end, comes down to lifestyle. Of course, taking a pill is often way easier than changing your longstanding habits. And what’s worse, doesn’t it always seem like the lifestyle stuff that is good for your health is unpleasant?

Two recent lifestyle interventions that I have tried and find really not enjoyable are time-restricted eating (also known as intermittent fasting) and high-intensity interval training, or HIIT. The former leaves me hangry for half the day; the latter is, well, it’s just really hard compared with my usual jog.

Yale University

But given the rule of unpleasant lifestyle changes, I knew as soon as I saw this recent study what the result would be. What if we combined time-restricted eating with high-intensity interval training?

I’m referring to this study, appearing in PLOS ONE from Ranya Ameur and colleagues, which is a small trial that enrolled otherwise healthy women with a BMI > 30 and randomized them to one of three conditions.

First was time-restricted eating. Women in this group could eat whatever they wanted, but only from 8 a.m. to 4 p.m. daily.

Second: high-intensity functional training. This is a variant of high-intensity interval training which focuses a bit more on resistance exercise than on pure cardiovascular stuff but has the same vibe of doing brief bursts of intensive activity followed by a cool-down period.

Third: a combination of the two. Sounds rough to me.

The study was otherwise straightforward. At baseline, researchers collected data on body composition and dietary intake, and measured blood pressure, glucose, insulin, and lipid biomarkers. A 12-week intervention period followed, after which all of this stuff was measured again.

Now, you may have noticed that there is no control group in this study. We’ll come back to that — a few times.

Let me walk you through some of the outcomes here.

First off, body composition metrics. All three groups lost weight — on average, around 10% of body weight which, for a 12-week intervention, is fairly impressive. BMI and waist circumference went down as well, and, interestingly, much of the weight loss here was in fat mass, not fat-free mass.

Most interventions that lead to weight loss — and I’m including some of the newer drugs here — lead to both fat and muscle loss. That might not be as bad as it sounds; the truth is that muscle mass increases as fat increases because of the simple fact that if you’re carrying more weight when you walk around, your leg muscles get bigger. But to preserve muscle mass in the face of fat loss is sort of a Goldilocks finding, and, based on these results, there’s a suggestion that the high-intensity functional training helps to do just that.

The dietary intake findings were really surprising to me. Across the board, caloric intake decreased. It’s no surprise that time-restricted eating reduces calorie intake. That has been shown many times before and is probably the main reason it induces weight loss — less time to eat means you eat less.

But why would high-intensity functional training lead to lower caloric intake? Most people, myself included, get hungry after they exercise. In fact, one of the reasons it’s hard to lose weight with exercise alone is that we end up eating more calories to make up for what we lost during the exercise. This calorie reduction could be a unique effect of this type of exercise, but honestly this could also be something called the Hawthorne effect. Women in the study kept a food diary to track their intake, and the act of doing that might actually make you eat less. It makes it a little more annoying to snack a bit if you know you have to write it down. This is a situation where I would kill for a control group.

The lipid findings are also pretty striking, with around a 40% reduction in LDL across the board, and evidence of synergistic effects of combined TRE and high-intensity training on total cholesterol and triglycerides. This is like a statin level of effect — pretty impressive. Again, my heart pines for a control group, though.

Same story with glucose and insulin measures: an impressive reduction in fasting glucose and good evidence that the combination of time-restricted eating and high-intensity functional training reduces insulin levels and HOMA-IR as well.

Really the only thing that wasn’t very impressive was the change in blood pressure, with only modest decreases across the board.

Okay, so let’s take a breath after this high-intensity cerebral workout and put this all together. This was a small study, lacking a control group, but with large effect sizes in very relevant clinical areas. It confirms what we know about time-restricted eating — that it makes you eat less calories — and introduces the potential that vigorous exercise can not only magnify the benefits of time-restricted eating but maybe even mitigate some of the risks, like the risk for muscle loss. And of course, it comports with my central hypothesis, which is that the more unpleasant a lifestyle intervention is, the better it is for you. No pain, no gain, right?

Of course, I am being overly dogmatic. There are plenty of caveats. Wrestling bears is quite unpleasant and almost certainly bad for you. And there are even some pleasant things that are pretty good for you — like coffee and sex. And there are even people who find time-restricted eating and high-intensity training pleasurable. They are called masochists.

I’m joking. The truth is that any lifestyle change is hard, but with persistence the changes become habits and, eventually, those habits do become pleasurable. Or, at least, much less painful. The trick is getting over the hump of change. If only there were a pill for that.
 

Dr. Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Connecticut. He has disclosed no relevant financial relationships. This transcript has been edited for clarity.

A version of this article appeared on Medscape.com.

Let’s be honest: Although as physicians we have the power of the prescription pad, so much of health, in the end, comes down to lifestyle. Of course, taking a pill is often way easier than changing your longstanding habits. And what’s worse, doesn’t it always seem like the lifestyle stuff that is good for your health is unpleasant?

Two recent lifestyle interventions that I have tried and find really not enjoyable are time-restricted eating (also known as intermittent fasting) and high-intensity interval training, or HIIT. The former leaves me hangry for half the day; the latter is, well, it’s just really hard compared with my usual jog.

Yale University

But given the rule of unpleasant lifestyle changes, I knew as soon as I saw this recent study what the result would be. What if we combined time-restricted eating with high-intensity interval training?

I’m referring to this study, appearing in PLOS ONE from Ranya Ameur and colleagues, which is a small trial that enrolled otherwise healthy women with a BMI > 30 and randomized them to one of three conditions.

First was time-restricted eating. Women in this group could eat whatever they wanted, but only from 8 a.m. to 4 p.m. daily.

Second: high-intensity functional training. This is a variant of high-intensity interval training which focuses a bit more on resistance exercise than on pure cardiovascular stuff but has the same vibe of doing brief bursts of intensive activity followed by a cool-down period.

Third: a combination of the two. Sounds rough to me.

The study was otherwise straightforward. At baseline, researchers collected data on body composition and dietary intake, and measured blood pressure, glucose, insulin, and lipid biomarkers. A 12-week intervention period followed, after which all of this stuff was measured again.

Now, you may have noticed that there is no control group in this study. We’ll come back to that — a few times.

Let me walk you through some of the outcomes here.

First off, body composition metrics. All three groups lost weight — on average, around 10% of body weight which, for a 12-week intervention, is fairly impressive. BMI and waist circumference went down as well, and, interestingly, much of the weight loss here was in fat mass, not fat-free mass.

Most interventions that lead to weight loss — and I’m including some of the newer drugs here — lead to both fat and muscle loss. That might not be as bad as it sounds; the truth is that muscle mass increases as fat increases because of the simple fact that if you’re carrying more weight when you walk around, your leg muscles get bigger. But to preserve muscle mass in the face of fat loss is sort of a Goldilocks finding, and, based on these results, there’s a suggestion that the high-intensity functional training helps to do just that.

The dietary intake findings were really surprising to me. Across the board, caloric intake decreased. It’s no surprise that time-restricted eating reduces calorie intake. That has been shown many times before and is probably the main reason it induces weight loss — less time to eat means you eat less.

But why would high-intensity functional training lead to lower caloric intake? Most people, myself included, get hungry after they exercise. In fact, one of the reasons it’s hard to lose weight with exercise alone is that we end up eating more calories to make up for what we lost during the exercise. This calorie reduction could be a unique effect of this type of exercise, but honestly this could also be something called the Hawthorne effect. Women in the study kept a food diary to track their intake, and the act of doing that might actually make you eat less. It makes it a little more annoying to snack a bit if you know you have to write it down. This is a situation where I would kill for a control group.

The lipid findings are also pretty striking, with around a 40% reduction in LDL across the board, and evidence of synergistic effects of combined TRE and high-intensity training on total cholesterol and triglycerides. This is like a statin level of effect — pretty impressive. Again, my heart pines for a control group, though.

Same story with glucose and insulin measures: an impressive reduction in fasting glucose and good evidence that the combination of time-restricted eating and high-intensity functional training reduces insulin levels and HOMA-IR as well.

Really the only thing that wasn’t very impressive was the change in blood pressure, with only modest decreases across the board.

Okay, so let’s take a breath after this high-intensity cerebral workout and put this all together. This was a small study, lacking a control group, but with large effect sizes in very relevant clinical areas. It confirms what we know about time-restricted eating — that it makes you eat less calories — and introduces the potential that vigorous exercise can not only magnify the benefits of time-restricted eating but maybe even mitigate some of the risks, like the risk for muscle loss. And of course, it comports with my central hypothesis, which is that the more unpleasant a lifestyle intervention is, the better it is for you. No pain, no gain, right?

Of course, I am being overly dogmatic. There are plenty of caveats. Wrestling bears is quite unpleasant and almost certainly bad for you. And there are even some pleasant things that are pretty good for you — like coffee and sex. And there are even people who find time-restricted eating and high-intensity training pleasurable. They are called masochists.

I’m joking. The truth is that any lifestyle change is hard, but with persistence the changes become habits and, eventually, those habits do become pleasurable. Or, at least, much less painful. The trick is getting over the hump of change. If only there were a pill for that.
 

Dr. Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Connecticut. He has disclosed no relevant financial relationships. This transcript has been edited for clarity.

A version of this article appeared on Medscape.com.

Let’s be honest: Although as physicians we have the power of the prescription pad, so much of health, in the end, comes down to lifestyle. Of course, taking a pill is often way easier than changing your longstanding habits. And what’s worse, doesn’t it always seem like the lifestyle stuff that is good for your health is unpleasant?

Two recent lifestyle interventions that I have tried and find really not enjoyable are time-restricted eating (also known as intermittent fasting) and high-intensity interval training, or HIIT. The former leaves me hangry for half the day; the latter is, well, it’s just really hard compared with my usual jog.

Yale University

But given the rule of unpleasant lifestyle changes, I knew as soon as I saw this recent study what the result would be. What if we combined time-restricted eating with high-intensity interval training?

I’m referring to this study, appearing in PLOS ONE from Ranya Ameur and colleagues, which is a small trial that enrolled otherwise healthy women with a BMI > 30 and randomized them to one of three conditions.

First was time-restricted eating. Women in this group could eat whatever they wanted, but only from 8 a.m. to 4 p.m. daily.

Second: high-intensity functional training. This is a variant of high-intensity interval training which focuses a bit more on resistance exercise than on pure cardiovascular stuff but has the same vibe of doing brief bursts of intensive activity followed by a cool-down period.

Third: a combination of the two. Sounds rough to me.

The study was otherwise straightforward. At baseline, researchers collected data on body composition and dietary intake, and measured blood pressure, glucose, insulin, and lipid biomarkers. A 12-week intervention period followed, after which all of this stuff was measured again.

Now, you may have noticed that there is no control group in this study. We’ll come back to that — a few times.

Let me walk you through some of the outcomes here.

First off, body composition metrics. All three groups lost weight — on average, around 10% of body weight which, for a 12-week intervention, is fairly impressive. BMI and waist circumference went down as well, and, interestingly, much of the weight loss here was in fat mass, not fat-free mass.

Most interventions that lead to weight loss — and I’m including some of the newer drugs here — lead to both fat and muscle loss. That might not be as bad as it sounds; the truth is that muscle mass increases as fat increases because of the simple fact that if you’re carrying more weight when you walk around, your leg muscles get bigger. But to preserve muscle mass in the face of fat loss is sort of a Goldilocks finding, and, based on these results, there’s a suggestion that the high-intensity functional training helps to do just that.

The dietary intake findings were really surprising to me. Across the board, caloric intake decreased. It’s no surprise that time-restricted eating reduces calorie intake. That has been shown many times before and is probably the main reason it induces weight loss — less time to eat means you eat less.

But why would high-intensity functional training lead to lower caloric intake? Most people, myself included, get hungry after they exercise. In fact, one of the reasons it’s hard to lose weight with exercise alone is that we end up eating more calories to make up for what we lost during the exercise. This calorie reduction could be a unique effect of this type of exercise, but honestly this could also be something called the Hawthorne effect. Women in the study kept a food diary to track their intake, and the act of doing that might actually make you eat less. It makes it a little more annoying to snack a bit if you know you have to write it down. This is a situation where I would kill for a control group.

The lipid findings are also pretty striking, with around a 40% reduction in LDL across the board, and evidence of synergistic effects of combined TRE and high-intensity training on total cholesterol and triglycerides. This is like a statin level of effect — pretty impressive. Again, my heart pines for a control group, though.

Same story with glucose and insulin measures: an impressive reduction in fasting glucose and good evidence that the combination of time-restricted eating and high-intensity functional training reduces insulin levels and HOMA-IR as well.

Really the only thing that wasn’t very impressive was the change in blood pressure, with only modest decreases across the board.

Okay, so let’s take a breath after this high-intensity cerebral workout and put this all together. This was a small study, lacking a control group, but with large effect sizes in very relevant clinical areas. It confirms what we know about time-restricted eating — that it makes you eat less calories — and introduces the potential that vigorous exercise can not only magnify the benefits of time-restricted eating but maybe even mitigate some of the risks, like the risk for muscle loss. And of course, it comports with my central hypothesis, which is that the more unpleasant a lifestyle intervention is, the better it is for you. No pain, no gain, right?

Of course, I am being overly dogmatic. There are plenty of caveats. Wrestling bears is quite unpleasant and almost certainly bad for you. And there are even some pleasant things that are pretty good for you — like coffee and sex. And there are even people who find time-restricted eating and high-intensity training pleasurable. They are called masochists.

I’m joking. The truth is that any lifestyle change is hard, but with persistence the changes become habits and, eventually, those habits do become pleasurable. Or, at least, much less painful. The trick is getting over the hump of change. If only there were a pill for that.
 

Dr. Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Connecticut. He has disclosed no relevant financial relationships. This transcript has been edited for clarity.

A version of this article appeared on Medscape.com.

Amyloidosis is a condition marked by the accumulation of insoluble beta-sheet fibrillar protein aggregates in tissues that can be acquired or hereditary. Hereditary amyloidogenic transthyretin (hATTR) amyloidosis is an autosomal-dominant disease caused by pathogenic variants in the TTR gene. The TTR protein is essential for transporting thyroxine and retinol-binding protein and is primarily synthesized in the liver, becoming unstable as a result of the pathogenic mutations. Inherited pathogenic variants lead to the protein’s misfolding, aggregation, and deposition as amyloid fibrils in different organs, resulting in progressive multisystem dysfunction. hATTR amyloidosis is a heterogenous disease, characterized by a wide range of clinical manifestations affecting the peripheral (both somatic and autonomic) nervous system, heart, kidneys, and central nervous system (CNS); however, the heart and peripheral nerves appear to be the main targets of the TTR-related pathologic process. Without treatment, the prognosis is poor, with an average life expectancy of 7-11 years; however, in recent years, the development of new therapeutics has brought new hope to patients.

Here are five things to know about hereditary amyloidosis.
 

1. Diagnosis of hereditary amyloidosis requires a high level of suspicion.

The diagnosis of hATTR amyloidosis presents a significant challenge, particularly in nonendemic regions where a lack of family history and heterogeneity of clinical presentation can delay diagnosis by 4-5 years. A timely diagnosis requires clinicians to maintain a high index of suspicion, especially when evaluating patients with neuropathic symptoms. Early diagnosis is crucial to begin patients on recently available disease-modifying therapies that can slow the disease course. Failure to recognize is the major barrier to improved patient outcomes.

Confirming the diagnosis involves detecting amyloid deposits in tissue biopsy specimens from various possible sites, including the skin, nerves, myocardium, and others. However, the diagnosis can be challenging owing to the uneven distribution of amyloid fibrils, sometimes requiring multiple biopsies or alternative diagnostic approaches, such as TTR gene sequencing, to confirm the presence of an amyloidogenic pathogenic variant. Biopsy for hATTR amyloidosis is not required if imaging of the clinical phenotype and genetic testing are consistent.

Once diagnosed, the assessment of organ involvement is essential, using nerve conduction studies, cardiac investigations (eg, echocardiography, ECG, scintigraphy), ophthalmologic assessments, and complete renal function evaluations to fully understand the extent of disease impact.
 

2. Hereditary amyloidosis diseases are classified into two primary categories.

Hereditary amyloidosis represents a group of diseases caused by inherited gene mutations and is classified into two main types: ATTR (transthyretin-related) and non-TTR. Most cases of hereditary amyloidosis are associated with the TTR gene. Mutations in this protein lead to different forms of ATTR amyloidosis, categorized on the basis of the specific mutation involved, such as hATTR50M (genotype Val50Met), which is the most prevalent form.

ATTR mutations result in a variety of health issues, manifesting in three primary forms:

• Neuropathic ATTR (genotype Val50Met): Early symptoms include sensorimotor polyneuropathy of the legs, carpal tunnel syndrome, autonomic dysfunction, constipation/diarrhea, and impotence; late symptoms include cardiomyopathy, vitreous opacities, glaucoma, nephropathy, and CNS symptoms.
• Cardiac ATTR (genotype Val142Ile): This type is characterized by cardiomegaly, conduction block, arrhythmia, anginal pain, congestive heart failure, and sudden death.
• Leptomeningeal ATTR (genotype Asp38Gly): This is characterized by transient focal neurologic episodes, intracerebral and/or subarachnoid hemorrhages, dementia, ataxia, and psychosis.

Non-TTR amyloidoses are rarer than are ATTR variations and involve mutations in different genes that also have significant health impacts. These include proteins such as apolipoprotein AI, fibrinogen A alpha, lysozyme, apolipoprotein AII, gelsolin, and cystatin C. Each type contributes to a range of symptoms and requires individualized management approaches.
 

3. Heightened disease awareness has increased the recognized prevalence of hereditary amyloidosis.

hATTR amyloidosis has historically been recognized as a rare disease, with significant clusters in Portugal, Brazil, Sweden, and Japan and alongside smaller foci in regions such as Cyprus and Majorca. This disease›s variable incidence across Europe is now perceived to be on the rise. It is attributed to heightened disease awareness among healthcare providers and the broader availability of genetic testing, extending its recognized impact to at least 29 countries globally. The genetic landscape of hATTR amyloidosis is diverse, with over 140 mutations identified in the TTR gene. Among these, the Val50Met mutation is particularly notable for its association with large patient clusters in the endemic regions.

Morbidity and mortality associated with hATTR amyloidosis are significant, with an average lifespan of 7-11 years post diagnosis; however, survival rates can vary widely depending on the specific genetic variant and organ involvement. Early diagnosis can substantially improve outcomes; yet, for many, the prognosis remains poor, especially in cases dominated by cardiomyopathy. Genetics play a central role in the disease›s transmission, with autosomal-dominant inheritance patterns and high penetrance among carriers of pathogenic mutations. Research continues to uncover the broad spectrum of genetic variations contributing to hATTR amyloidosis, with ongoing studies poised to expand our understanding of its molecular underpinnings and potential treatment options.

4. The effect on quality of life is significant both in patients living with hATTR amyloidosis and their caregivers.

hATTR amyloidosis imposes a multifaceted burden on patients and their caregivers as the disease progresses. Symptoms range from sensorimotor impairment and gastrointestinal or autonomic dysfunction to heart failure, leading to significant health-related quality-of-life deficits. The systemic nature of hATTR amyloidosis significantly affects patients› lifestyles, daily activities, and general well-being, especially because it typically manifests in adulthood — a crucial time for occupational changes. The progression of hATTR amyloidosis exacerbates the challenges in maintaining employment and managing household chores, with symptomatic patients often unable to work and experiencing difficulties with absenteeism and presenteeism when they are able to work.

hATTR amyloidosis leads to physical, mental, occupational, and social limitations for patients, and it also places a considerable strain on their families and caregivers, who report poor mental health, work impairment, and a high time commitment (mean, 45.9 h/wk) to providing care.

5. There have been significant advancements in therapeutic options for early-stage hATTR amyloidosis.

After diagnosis, prompt initiation of treatment is recommended to delay the progression of hATTR amyloidosis; a multidisciplinary approach is essential, incorporating anti-amyloid therapy to inhibit further production and/or deposition of amyloid aggregates. Treatment strategies also include addressing symptomatic therapy and managing cardiac, renal, and ocular involvement. Although many therapies have been developed, especially for the early stages of hATTR amyloidosis, therapeutic benefits for patients with advanced disease remain limited.

Recent advancements in the treatment of hATTR amyloidosis have introduced RNA-targeted therapies including patisiran, vutrisiran, and eplontersen, which have shown efficacy in reducing hepatic TTR synthesis and the aggregation of misfolded monomers into amyloid deposits. These therapies, ranging from small interfering RNA formulations to antisense oligonucleotides, offer benefits in managing both cardiomyopathy and neuropathy associated with hATTR amyloidosis , administered through various methods, including intravenous infusions and subcutaneous injections. In addition, the stabilization of TTR tetramers with the use of drugs such as tafamidis and diflunisal has effectively prevented the formation of amyloidogenic monomers. Moreover, other investigational agents, including TTR stabilizers like acoramidis and tolcapone, as well as novel compounds that inhibit amyloid formation and disrupt fibrils, are expanding the therapeutic landscape for hATTR amyloidosis , providing hope for improved management of this complex condition.

Dr. Gertz is a professor and consultant in the Department of Hematology, Mayo Clinic, Rochester, Minnesota. He has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from AstraZeneca, Ionis, and Alnylym.

A version of this article appeared on Medscape.com.

Amyloidosis is a condition marked by the accumulation of insoluble beta-sheet fibrillar protein aggregates in tissues that can be acquired or hereditary. Hereditary amyloidogenic transthyretin (hATTR) amyloidosis is an autosomal-dominant disease caused by pathogenic variants in the TTR gene. The TTR protein is essential for transporting thyroxine and retinol-binding protein and is primarily synthesized in the liver, becoming unstable as a result of the pathogenic mutations. Inherited pathogenic variants lead to the protein’s misfolding, aggregation, and deposition as amyloid fibrils in different organs, resulting in progressive multisystem dysfunction. hATTR amyloidosis is a heterogenous disease, characterized by a wide range of clinical manifestations affecting the peripheral (both somatic and autonomic) nervous system, heart, kidneys, and central nervous system (CNS); however, the heart and peripheral nerves appear to be the main targets of the TTR-related pathologic process. Without treatment, the prognosis is poor, with an average life expectancy of 7-11 years; however, in recent years, the development of new therapeutics has brought new hope to patients.

Here are five things to know about hereditary amyloidosis.
 

1. Diagnosis of hereditary amyloidosis requires a high level of suspicion.

The diagnosis of hATTR amyloidosis presents a significant challenge, particularly in nonendemic regions where a lack of family history and heterogeneity of clinical presentation can delay diagnosis by 4-5 years. A timely diagnosis requires clinicians to maintain a high index of suspicion, especially when evaluating patients with neuropathic symptoms. Early diagnosis is crucial to begin patients on recently available disease-modifying therapies that can slow the disease course. Failure to recognize is the major barrier to improved patient outcomes.

Confirming the diagnosis involves detecting amyloid deposits in tissue biopsy specimens from various possible sites, including the skin, nerves, myocardium, and others. However, the diagnosis can be challenging owing to the uneven distribution of amyloid fibrils, sometimes requiring multiple biopsies or alternative diagnostic approaches, such as TTR gene sequencing, to confirm the presence of an amyloidogenic pathogenic variant. Biopsy for hATTR amyloidosis is not required if imaging of the clinical phenotype and genetic testing are consistent.

Once diagnosed, the assessment of organ involvement is essential, using nerve conduction studies, cardiac investigations (eg, echocardiography, ECG, scintigraphy), ophthalmologic assessments, and complete renal function evaluations to fully understand the extent of disease impact.
 

2. Hereditary amyloidosis diseases are classified into two primary categories.

Hereditary amyloidosis represents a group of diseases caused by inherited gene mutations and is classified into two main types: ATTR (transthyretin-related) and non-TTR. Most cases of hereditary amyloidosis are associated with the TTR gene. Mutations in this protein lead to different forms of ATTR amyloidosis, categorized on the basis of the specific mutation involved, such as hATTR50M (genotype Val50Met), which is the most prevalent form.

ATTR mutations result in a variety of health issues, manifesting in three primary forms:

• Neuropathic ATTR (genotype Val50Met): Early symptoms include sensorimotor polyneuropathy of the legs, carpal tunnel syndrome, autonomic dysfunction, constipation/diarrhea, and impotence; late symptoms include cardiomyopathy, vitreous opacities, glaucoma, nephropathy, and CNS symptoms.
• Cardiac ATTR (genotype Val142Ile): This type is characterized by cardiomegaly, conduction block, arrhythmia, anginal pain, congestive heart failure, and sudden death.
• Leptomeningeal ATTR (genotype Asp38Gly): This is characterized by transient focal neurologic episodes, intracerebral and/or subarachnoid hemorrhages, dementia, ataxia, and psychosis.

Non-TTR amyloidoses are rarer than are ATTR variations and involve mutations in different genes that also have significant health impacts. These include proteins such as apolipoprotein AI, fibrinogen A alpha, lysozyme, apolipoprotein AII, gelsolin, and cystatin C. Each type contributes to a range of symptoms and requires individualized management approaches.
 

3. Heightened disease awareness has increased the recognized prevalence of hereditary amyloidosis.

hATTR amyloidosis has historically been recognized as a rare disease, with significant clusters in Portugal, Brazil, Sweden, and Japan and alongside smaller foci in regions such as Cyprus and Majorca. This disease›s variable incidence across Europe is now perceived to be on the rise. It is attributed to heightened disease awareness among healthcare providers and the broader availability of genetic testing, extending its recognized impact to at least 29 countries globally. The genetic landscape of hATTR amyloidosis is diverse, with over 140 mutations identified in the TTR gene. Among these, the Val50Met mutation is particularly notable for its association with large patient clusters in the endemic regions.

Morbidity and mortality associated with hATTR amyloidosis are significant, with an average lifespan of 7-11 years post diagnosis; however, survival rates can vary widely depending on the specific genetic variant and organ involvement. Early diagnosis can substantially improve outcomes; yet, for many, the prognosis remains poor, especially in cases dominated by cardiomyopathy. Genetics play a central role in the disease›s transmission, with autosomal-dominant inheritance patterns and high penetrance among carriers of pathogenic mutations. Research continues to uncover the broad spectrum of genetic variations contributing to hATTR amyloidosis, with ongoing studies poised to expand our understanding of its molecular underpinnings and potential treatment options.

4. The effect on quality of life is significant both in patients living with hATTR amyloidosis and their caregivers.

hATTR amyloidosis imposes a multifaceted burden on patients and their caregivers as the disease progresses. Symptoms range from sensorimotor impairment and gastrointestinal or autonomic dysfunction to heart failure, leading to significant health-related quality-of-life deficits. The systemic nature of hATTR amyloidosis significantly affects patients› lifestyles, daily activities, and general well-being, especially because it typically manifests in adulthood — a crucial time for occupational changes. The progression of hATTR amyloidosis exacerbates the challenges in maintaining employment and managing household chores, with symptomatic patients often unable to work and experiencing difficulties with absenteeism and presenteeism when they are able to work.

hATTR amyloidosis leads to physical, mental, occupational, and social limitations for patients, and it also places a considerable strain on their families and caregivers, who report poor mental health, work impairment, and a high time commitment (mean, 45.9 h/wk) to providing care.

5. There have been significant advancements in therapeutic options for early-stage hATTR amyloidosis.

After diagnosis, prompt initiation of treatment is recommended to delay the progression of hATTR amyloidosis; a multidisciplinary approach is essential, incorporating anti-amyloid therapy to inhibit further production and/or deposition of amyloid aggregates. Treatment strategies also include addressing symptomatic therapy and managing cardiac, renal, and ocular involvement. Although many therapies have been developed, especially for the early stages of hATTR amyloidosis, therapeutic benefits for patients with advanced disease remain limited.

Recent advancements in the treatment of hATTR amyloidosis have introduced RNA-targeted therapies including patisiran, vutrisiran, and eplontersen, which have shown efficacy in reducing hepatic TTR synthesis and the aggregation of misfolded monomers into amyloid deposits. These therapies, ranging from small interfering RNA formulations to antisense oligonucleotides, offer benefits in managing both cardiomyopathy and neuropathy associated with hATTR amyloidosis , administered through various methods, including intravenous infusions and subcutaneous injections. In addition, the stabilization of TTR tetramers with the use of drugs such as tafamidis and diflunisal has effectively prevented the formation of amyloidogenic monomers. Moreover, other investigational agents, including TTR stabilizers like acoramidis and tolcapone, as well as novel compounds that inhibit amyloid formation and disrupt fibrils, are expanding the therapeutic landscape for hATTR amyloidosis , providing hope for improved management of this complex condition.

Dr. Gertz is a professor and consultant in the Department of Hematology, Mayo Clinic, Rochester, Minnesota. He has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from AstraZeneca, Ionis, and Alnylym.

A version of this article appeared on Medscape.com.

Amyloidosis is a condition marked by the accumulation of insoluble beta-sheet fibrillar protein aggregates in tissues that can be acquired or hereditary. Hereditary amyloidogenic transthyretin (hATTR) amyloidosis is an autosomal-dominant disease caused by pathogenic variants in the TTR gene. The TTR protein is essential for transporting thyroxine and retinol-binding protein and is primarily synthesized in the liver, becoming unstable as a result of the pathogenic mutations. Inherited pathogenic variants lead to the protein’s misfolding, aggregation, and deposition as amyloid fibrils in different organs, resulting in progressive multisystem dysfunction. hATTR amyloidosis is a heterogenous disease, characterized by a wide range of clinical manifestations affecting the peripheral (both somatic and autonomic) nervous system, heart, kidneys, and central nervous system (CNS); however, the heart and peripheral nerves appear to be the main targets of the TTR-related pathologic process. Without treatment, the prognosis is poor, with an average life expectancy of 7-11 years; however, in recent years, the development of new therapeutics has brought new hope to patients.

Here are five things to know about hereditary amyloidosis.
 

1. Diagnosis of hereditary amyloidosis requires a high level of suspicion.

The diagnosis of hATTR amyloidosis presents a significant challenge, particularly in nonendemic regions where a lack of family history and heterogeneity of clinical presentation can delay diagnosis by 4-5 years. A timely diagnosis requires clinicians to maintain a high index of suspicion, especially when evaluating patients with neuropathic symptoms. Early diagnosis is crucial to begin patients on recently available disease-modifying therapies that can slow the disease course. Failure to recognize is the major barrier to improved patient outcomes.

Confirming the diagnosis involves detecting amyloid deposits in tissue biopsy specimens from various possible sites, including the skin, nerves, myocardium, and others. However, the diagnosis can be challenging owing to the uneven distribution of amyloid fibrils, sometimes requiring multiple biopsies or alternative diagnostic approaches, such as TTR gene sequencing, to confirm the presence of an amyloidogenic pathogenic variant. Biopsy for hATTR amyloidosis is not required if imaging of the clinical phenotype and genetic testing are consistent.

Once diagnosed, the assessment of organ involvement is essential, using nerve conduction studies, cardiac investigations (eg, echocardiography, ECG, scintigraphy), ophthalmologic assessments, and complete renal function evaluations to fully understand the extent of disease impact.
 

2. Hereditary amyloidosis diseases are classified into two primary categories.

Hereditary amyloidosis represents a group of diseases caused by inherited gene mutations and is classified into two main types: ATTR (transthyretin-related) and non-TTR. Most cases of hereditary amyloidosis are associated with the TTR gene. Mutations in this protein lead to different forms of ATTR amyloidosis, categorized on the basis of the specific mutation involved, such as hATTR50M (genotype Val50Met), which is the most prevalent form.

ATTR mutations result in a variety of health issues, manifesting in three primary forms:

• Neuropathic ATTR (genotype Val50Met): Early symptoms include sensorimotor polyneuropathy of the legs, carpal tunnel syndrome, autonomic dysfunction, constipation/diarrhea, and impotence; late symptoms include cardiomyopathy, vitreous opacities, glaucoma, nephropathy, and CNS symptoms.
• Cardiac ATTR (genotype Val142Ile): This type is characterized by cardiomegaly, conduction block, arrhythmia, anginal pain, congestive heart failure, and sudden death.
• Leptomeningeal ATTR (genotype Asp38Gly): This is characterized by transient focal neurologic episodes, intracerebral and/or subarachnoid hemorrhages, dementia, ataxia, and psychosis.

Non-TTR amyloidoses are rarer than are ATTR variations and involve mutations in different genes that also have significant health impacts. These include proteins such as apolipoprotein AI, fibrinogen A alpha, lysozyme, apolipoprotein AII, gelsolin, and cystatin C. Each type contributes to a range of symptoms and requires individualized management approaches.
 

3. Heightened disease awareness has increased the recognized prevalence of hereditary amyloidosis.

hATTR amyloidosis has historically been recognized as a rare disease, with significant clusters in Portugal, Brazil, Sweden, and Japan and alongside smaller foci in regions such as Cyprus and Majorca. This disease›s variable incidence across Europe is now perceived to be on the rise. It is attributed to heightened disease awareness among healthcare providers and the broader availability of genetic testing, extending its recognized impact to at least 29 countries globally. The genetic landscape of hATTR amyloidosis is diverse, with over 140 mutations identified in the TTR gene. Among these, the Val50Met mutation is particularly notable for its association with large patient clusters in the endemic regions.

Morbidity and mortality associated with hATTR amyloidosis are significant, with an average lifespan of 7-11 years post diagnosis; however, survival rates can vary widely depending on the specific genetic variant and organ involvement. Early diagnosis can substantially improve outcomes; yet, for many, the prognosis remains poor, especially in cases dominated by cardiomyopathy. Genetics play a central role in the disease›s transmission, with autosomal-dominant inheritance patterns and high penetrance among carriers of pathogenic mutations. Research continues to uncover the broad spectrum of genetic variations contributing to hATTR amyloidosis, with ongoing studies poised to expand our understanding of its molecular underpinnings and potential treatment options.

4. The effect on quality of life is significant both in patients living with hATTR amyloidosis and their caregivers.

hATTR amyloidosis imposes a multifaceted burden on patients and their caregivers as the disease progresses. Symptoms range from sensorimotor impairment and gastrointestinal or autonomic dysfunction to heart failure, leading to significant health-related quality-of-life deficits. The systemic nature of hATTR amyloidosis significantly affects patients› lifestyles, daily activities, and general well-being, especially because it typically manifests in adulthood — a crucial time for occupational changes. The progression of hATTR amyloidosis exacerbates the challenges in maintaining employment and managing household chores, with symptomatic patients often unable to work and experiencing difficulties with absenteeism and presenteeism when they are able to work.

hATTR amyloidosis leads to physical, mental, occupational, and social limitations for patients, and it also places a considerable strain on their families and caregivers, who report poor mental health, work impairment, and a high time commitment (mean, 45.9 h/wk) to providing care.

5. There have been significant advancements in therapeutic options for early-stage hATTR amyloidosis.

After diagnosis, prompt initiation of treatment is recommended to delay the progression of hATTR amyloidosis; a multidisciplinary approach is essential, incorporating anti-amyloid therapy to inhibit further production and/or deposition of amyloid aggregates. Treatment strategies also include addressing symptomatic therapy and managing cardiac, renal, and ocular involvement. Although many therapies have been developed, especially for the early stages of hATTR amyloidosis, therapeutic benefits for patients with advanced disease remain limited.

Recent advancements in the treatment of hATTR amyloidosis have introduced RNA-targeted therapies including patisiran, vutrisiran, and eplontersen, which have shown efficacy in reducing hepatic TTR synthesis and the aggregation of misfolded monomers into amyloid deposits. These therapies, ranging from small interfering RNA formulations to antisense oligonucleotides, offer benefits in managing both cardiomyopathy and neuropathy associated with hATTR amyloidosis , administered through various methods, including intravenous infusions and subcutaneous injections. In addition, the stabilization of TTR tetramers with the use of drugs such as tafamidis and diflunisal has effectively prevented the formation of amyloidogenic monomers. Moreover, other investigational agents, including TTR stabilizers like acoramidis and tolcapone, as well as novel compounds that inhibit amyloid formation and disrupt fibrils, are expanding the therapeutic landscape for hATTR amyloidosis , providing hope for improved management of this complex condition.

Dr. Gertz is a professor and consultant in the Department of Hematology, Mayo Clinic, Rochester, Minnesota. He has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from AstraZeneca, Ionis, and Alnylym.

A version of this article appeared on Medscape.com.