Internal Medicine News

This video transcript has been edited for clarity. 

Robert D. Glatter, MD: Hi and welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Joining me today to discuss a novel, plant-based approach to stopping moderate to severe bleeding is Joe Landolina, CEO and cofounder of Cresilon. Welcome, Joe. 

Joe Landolina, MS: Thank you so much for taking the time. It’s great to be here.

Educational Background and Inception of Cresilon

Glatter: It’s a pleasure to have you join me, and I want to congratulate you on your recent 510(k) FDA clearance for your novel product to save lives and stop bleeding. To begin with, can you explain how the idea for launching your company came about? 

Landolina: The way that Cresilon came about was a little bit unorthodox, because I was 17 years old when I invented the technology behind the product that eventually became Traumagel®. 

My grandfather was an ex-pharmaceutical executive, who later in life started a vineyard. I grew up on a vineyard with a winery chemistry lab across the street from my house and a grandfather who learned lab safety in the 60s. So, that meant that the day I learned how to walk, I was tossed into a lab and I fell head over heels in love with lab research.

That started experimentation and my academic pursuits. That led to discovering a blend of two plant-based polymers derived from algae that stop bleeding on contact, effectively creating a mechanical barrier and allowing anything from a gunshot wound to anything quite a bit more minor to stop in a matter of seconds.

Glatter: Your background is in biomedical engineering. How is it that you started tinkering and doing all this type of work? 

Landolina: That’s correct. I did my undergrad in chemical engineering, and my graduate studies were in biomedical engineering. For me, that was supposed to be a pathway into medical school. I always wanted to be a surgeon myself, and I love the field of medicine. 

As a freshman in college at NYU Engineering, I had this idea. I entered it into NYU’s business plan competition, and we won at the engineering school. That gave us just enough capital to start developing and researching Traumagel more, and Cresilon was born out of that research.

 

Techniques for Stopping Hemorrhage

Glatter: In terms of stopping hemorrhage, which takes so many lives in the United States and globally — certainly, uncontrolled hemorrhage — what are the techniques that you see, prior to the arrival of your product, as being effective? Can you elucidate some of these techniques? 

Landolina: In emergency medicine, the primary mode of controlling hemorrhage is passive. It’s what, in Brooklyn, we like to call “pressure and a prayer”, where you have a material that’s either gauze or an impregnated gauze in most cases, where the mode of action is absorbing blood, with the adjunct of pressure by the first responder or by the clinician who’s providing aid.

The idea is to stop the flow of blood to concentrate blood factors at the surface of the gauze product, and to promote either platelet activation or the production of fibrin to create a clot. 

These types of technologies are widespread. There are many versions of this technology carried by EMS agencies, trauma bays, US military soldiers, and soldiers across NATO countries. But these types of technologies tend to be relatively inefficient, meaning that they’re very difficult to get into wounds because of the gauze or the powder form of the devices, and it’s very hard to get them in contact with the form of bleeding.

On top of that, if the patient is clotting compromised or immunocompromised in some way, the ability to create a durable clot that will not be ripped off when you remove the product at the next level of care is also of concern. And so, this type of technology or the type of treatment of massive hemorrhage hasn’t changed in decades.

 

Current Applications and Potential Use

Glatter: I envision this product will be carried by paramedics, used on the battlefield at some point after your FDA clearance, and recently it went through.

Do you see any possibility that this could be an AED equivalent to Stop the Bleed? In other words, could the average lay person be trained to use your product if kits are available? 

Landolina: To be very clear, Traumagel today is only approved or cleared under a “prescription-only” indication, which means that it will not initially be available OTC. However, that is our goal. Our goal is to make this product available and usable by someone with no medical training whatsoever. 

The form factor of being a gel in a syringe lends itself well to that, meaning that we try to make it as easy as point and shoot to control hemorrhage, where there’s not as much technique to be learned in the application of a product like Traumagel as there is in current hemorrhage control techniques. 

 

Mechanism of Action and Physiology

Glatter: Once you apply Traumagel, can you explain what happens to the product after it’s applied and the bleeding has stopped? Does it get reabsorbed by the body? What’s the process here? 

Landolina: Under Traumagel’s indication, because it’s used in traumatic injury, it must be removed within 24 hours.

One of the big benefits of Traumagel is that when the patient produces a blood clot underneath Traumagel, it doesn’t become incorporated within the gel itself. To contrast that with the use of gauze, gauze is porous. The clot ends up wrapped around the fibers of the gauze, so if you peel the gauze away, it’s very likely that clot is coming off with it. The surgeon or the clinician at the next level of care is going to have to deal with the re-bleed. 

You can remove Traumagel cleanly and entirely without disturbing the underlying clot. That’s a major benefit, not only to the patient but also to the next level of care, to the next clinician or physician that is required to remove the product.

Glatter: How is it possible to remove the substance without disturbing the clot? Can you explain in more detail? 

Landolina: That’s one of the hallmarks of these plant-based polymers and the way that we design Traumagel itself. Traumagel is completely nonporous, and it has no fibrous nature to it. What that means is when the patient produces a blood clot or fibrin next to or on top of Traumagel, that fibrin ends up not incorporated within the polymers of Traumagel itself. 

Over time, because Traumagel is a hydrogel, meaning that by weight it’s mostly water, you end up having less adhesion to the clot over time. When it’s time to remove Traumagel from the injury, it has lost almost all of its adhesive capabilities, meaning that when you peel it away, that clot is going to stick better to tissue than it will to the gel itself. 

Glatter: Can you explain a little bit about the matrix that’s formed, the physiology, and how the polymers work to form this matrix? 

Landolina: Sure. Traumagel is made of two polysaccharides that are plant derived. One polysaccharide is polyanionic, and the other is polycationic, meaning one has negative charges and the other has positive charges, which together create almost a Lego block effect, where when the material comes in contact with tissue, it adheres strongly and allows for itself to effectively create a mechanical barrier against bleeding.

Courtesy of Cresilon

Landolina: Even in the face of major arterial blood flow, Traumagel will stay where it needs to stay, and it’s not going to get washed away. This means that it is much more easily appliable to these types of surfaces and will allow the patient to produce their own endogenous fibrin clot at that location.

Like I mentioned before, when that fibrin clot is formed, because the gel itself has no pores or fibers, it doesn’t become incorporated within the fibrin clot. You can take the gel away, leaving that clot behind without the chance of a rebleed.

 

Testing With Major Bleeds

Glatter: In terms of bleeding itself, have you tested your product with major aortic bleeds or carotid bleeds in preclinical work?

Landolina: We have used the US military’s model for lethal hemorrhage, and the idea there is to create a model that is just that — lethal. These are the worst types of bleeds that you can possibly imagine, where the patients are clotting compromised, and where you have, in most cases, a very strong arterial component, so something like a femoral artery bleed.

We’ve also tested in carotid artery, aortic applications, as well as combinations of venous and arterial bleeds. The idea here is to show the use of the product in the absolute worst-case scenario so that when this translates into the clinic, the models that we’ve used for evaluation, hopefully, are worse than what actually rolls into the trauma bay.

Glatter: Excellent. What’s the mean time to stop an arterial vs a venous bleed? Are we talking a matter of seconds?

Landolina: In the case of a healthy patient, meaning a patient without clotting compromise, you’re in a matter of seconds. It’s less than 10 seconds. 

In the case where you have clotting compromise, a deep, complicated wound geometry, we recommend holding a pressure bandage on for 3 minutes just because it increases the chance of Traumagel coming into contact with the bleed, especially when you can’t visualize the bleed in the bleed source. Because of that pressure time, that becomes the mean. But again, it’s highly dependent on the type of bleed and the style of application.

 

Failure Rates and Effectiveness

Glatter: As a segue to that, what is the failure rate based on your studies and internal research using Traumagel? Have there been cases where bleeding has not been able to be stopped? 

Landolina: It depends on the study, but the failure rates are incredibly low with Traumagel, assuming that it’s correctly used. That’s one of the benefits to this product, where with proper technique, with overwrap with gauze, you nearly always get control of hemorrhage with a product like this. 

Glatter: Is manual pressure required in that sense? From what you described earlier, manual pressure would not be required. 

Landolina: It depends on the injury. What we recommend is that, if you have a very deep wound where you cannot visualize the source of bleed, you use pressure to seat Traumagel into the source of bleeding, meaning that you’re following Committee on Tactical Combat Casualty Care (Co-TCCC) regulations or requirements, where you’re over wrapping with gauze, and you’re providing a pressure wrapping to ensure that the Traumagel is in contact with the bleed while it’s doing what it’s doing. 

In most cases, it doesn’t hurt to apply pressure on top of Traumagel as well. In more surface level bleeds, you don’t need pressure at all. 

 

Applications Beyond Trauma

Glatter: Interesting. In terms of further applications (eg, nose bleeds or GYN bleeding, which are life-threatening), do you see this coming as an application for the future? 

Landolina: That’s where we’re working. Traumagel is the successor to an animal health product called Vetigel. The formulations of the gel behind Vetigel and Traumagel are identical. Vetigel has a full surgical indication, and that’s everything from epistaxis to neuro and spine procedures, into cardiovascular and soft tissue surgeries, orthopedic medicine, and so on.

Cresilon’s goal is to eventually expand the indication of our technology to include surgical indications and other indications where we can help any patient that’s bleeding. 

Glatter: That’s important, because we use prehospital whole blood, low titer, specifically, when patients have life-threatening hemorrhage. With your product, that would reduce the amount of blood products that would need to be administered. This could be a real game changer. 

Landolina: Definitely, that’s the goal we’re working on. 

Infection Risks and Biocompatibility

Glatter: In terms of any risk for infection, has that been studied as well? Does Traumagel in any way lead to increased rates of infection?

Landolina: Traumagel is biocompatible. It’s a sterile product. We’ve done the full suite of biocompatibility testing as required by FDA. On top of that, remember that Vetigel, which is the same formulation, is an implantable product. As a result, that has even extended biocompatibility testing beyond what would be necessary for an external product.

In Vetigel’s use case, which has been used now in over 60,000 patients, primarily companion animals, dogs and cats, we haven’t seen instances of infection. There’s no reason to believe that we would see that clinically with Traumagel.

 

Research Collaborations and Future Applications

Glatter: In terms of other research that your company’s embarked on preclinically, I understand there were some studies done at Walter Reed Army Institute of Research. I was wondering if you could expand on these, specifically, in terms of traumatic brain injury (TBI) and hemorrhage related to that. For example, with shrapnel or even a gunshot wound. 

Landolina: The Walter Reed collaboration with Cresilon is something that I’m particularly excited about, because it marks Cresilon’s first project that’s outside the scope of just hemostasis. Walter Reed came to us with this proposal where there’s a big challenge in a subset of TBI called penetrating ballistic-like brain injury, where the brain has been penetrated by a bullet, shrapnel, or some other projectile, and there’s an injury that exposes the brain to the outside. 

Today, there is no standard of care to treat patients with those types of injuries. In many cases, mortality is caused through swelling of the brain, or collapse of the brain. What they came to us with was the potential of using our technology, not primarily as a hemostatic agent, but to be able to stabilize that patient enough to get to the next level of care to be treated by a neurosurgeon.

That study Walter Reed did was just a pilot that was done in small animals. In that pilot, they showed that over the period of treatment, there was no negative change in vital signs, no increase in edema or in swelling, or in any of the biomarkers that were being monitored at that time. 

At the very least, this is not full indication that this indication will work for Cresilon, but it shows that there’s promise. It’s something that we’re working on and hopefully we’ll be able to bring to market soon.

Glatter: Certainly, maintaining intracranial pressure and cerebral perfusion pressures are very critical. In the future, do you think this product would be able to be deployed endovascularly? Imagine this in terms of stopping bleeding from some source, whether it’s from a stroke or another intracranial source. 

Landolina: That’s been an area of interest for us. We have no evidence to prove that indication works at this point, but there’s also nothing to say that it wouldn’t be possible for our technology. At this point, we’ve only looked at a cursory level at those indications. 

Glatter: Does the use of Traumagel obviate the need for a more definitive repair (eg, with sutures) or something that’s more permanent?

Landolina: I always say that Traumagel — and Vetigel, for that matter — is not a replacement for good surgical technique. The surgeon always needs to make his or her best judgment when reviewing the patient. That doesn’t mean that there won’t need to be sutures or vascular repair in most of these cases, especially in major trauma.

Final Takeaways

Glatter: Do you have some bullet points or pearls you could give our audience as a takeaway? 

Landolina: When Cresilon looks at Traumagel — and for us, Traumagel is the next generation of hemostatic agent, especially in trauma care and in emergency medicine — it allows for a far-simplified application of the product and much faster control of hemorrhage with better patient outcomes.

As we roll this out through EMS agencies, trauma hospitals, military agencies, and eventually to the general public through a future indication, it’s something we’re very excited about. Personally, I started this business 14 years ago, and so it’s great to see our mission of saving lives transitioning to saving human lives.

Glatter: I look forward to seeing this product in the emergency department, but also in other settings, such as in the operating room where we can really help patients who are dying from hemorrhage, certainly on the battlefield, and the lay public. If someone were to come upon a patient who’s bleeding out, this could be certainly a game changer and a lifesaver. 

I want to thank you for your time. This is a really important product that’s transformed the lives of so many animals, but also people in the future.

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He reported no relevant conflicts of interest. Mr. Landolina is the CEO and co-founder of Cresilon, a biotechnology company specializing in plant-based solutions for emergency bleeding control.

A version of this article first appeared on Medscape.com.

This video transcript has been edited for clarity. 

Robert D. Glatter, MD: Hi and welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Joining me today to discuss a novel, plant-based approach to stopping moderate to severe bleeding is Joe Landolina, CEO and cofounder of Cresilon. Welcome, Joe. 

Joe Landolina, MS: Thank you so much for taking the time. It’s great to be here.

Educational Background and Inception of Cresilon

Glatter: It’s a pleasure to have you join me, and I want to congratulate you on your recent 510(k) FDA clearance for your novel product to save lives and stop bleeding. To begin with, can you explain how the idea for launching your company came about? 

Landolina: The way that Cresilon came about was a little bit unorthodox, because I was 17 years old when I invented the technology behind the product that eventually became Traumagel®. 

My grandfather was an ex-pharmaceutical executive, who later in life started a vineyard. I grew up on a vineyard with a winery chemistry lab across the street from my house and a grandfather who learned lab safety in the 60s. So, that meant that the day I learned how to walk, I was tossed into a lab and I fell head over heels in love with lab research.

That started experimentation and my academic pursuits. That led to discovering a blend of two plant-based polymers derived from algae that stop bleeding on contact, effectively creating a mechanical barrier and allowing anything from a gunshot wound to anything quite a bit more minor to stop in a matter of seconds.

Glatter: Your background is in biomedical engineering. How is it that you started tinkering and doing all this type of work? 

Landolina: That’s correct. I did my undergrad in chemical engineering, and my graduate studies were in biomedical engineering. For me, that was supposed to be a pathway into medical school. I always wanted to be a surgeon myself, and I love the field of medicine. 

As a freshman in college at NYU Engineering, I had this idea. I entered it into NYU’s business plan competition, and we won at the engineering school. That gave us just enough capital to start developing and researching Traumagel more, and Cresilon was born out of that research.

 

Techniques for Stopping Hemorrhage

Glatter: In terms of stopping hemorrhage, which takes so many lives in the United States and globally — certainly, uncontrolled hemorrhage — what are the techniques that you see, prior to the arrival of your product, as being effective? Can you elucidate some of these techniques? 

Landolina: In emergency medicine, the primary mode of controlling hemorrhage is passive. It’s what, in Brooklyn, we like to call “pressure and a prayer”, where you have a material that’s either gauze or an impregnated gauze in most cases, where the mode of action is absorbing blood, with the adjunct of pressure by the first responder or by the clinician who’s providing aid.

The idea is to stop the flow of blood to concentrate blood factors at the surface of the gauze product, and to promote either platelet activation or the production of fibrin to create a clot. 

These types of technologies are widespread. There are many versions of this technology carried by EMS agencies, trauma bays, US military soldiers, and soldiers across NATO countries. But these types of technologies tend to be relatively inefficient, meaning that they’re very difficult to get into wounds because of the gauze or the powder form of the devices, and it’s very hard to get them in contact with the form of bleeding.

On top of that, if the patient is clotting compromised or immunocompromised in some way, the ability to create a durable clot that will not be ripped off when you remove the product at the next level of care is also of concern. And so, this type of technology or the type of treatment of massive hemorrhage hasn’t changed in decades.

 

Current Applications and Potential Use

Glatter: I envision this product will be carried by paramedics, used on the battlefield at some point after your FDA clearance, and recently it went through.

Do you see any possibility that this could be an AED equivalent to Stop the Bleed? In other words, could the average lay person be trained to use your product if kits are available? 

Landolina: To be very clear, Traumagel today is only approved or cleared under a “prescription-only” indication, which means that it will not initially be available OTC. However, that is our goal. Our goal is to make this product available and usable by someone with no medical training whatsoever. 

The form factor of being a gel in a syringe lends itself well to that, meaning that we try to make it as easy as point and shoot to control hemorrhage, where there’s not as much technique to be learned in the application of a product like Traumagel as there is in current hemorrhage control techniques. 

 

Mechanism of Action and Physiology

Glatter: Once you apply Traumagel, can you explain what happens to the product after it’s applied and the bleeding has stopped? Does it get reabsorbed by the body? What’s the process here? 

Landolina: Under Traumagel’s indication, because it’s used in traumatic injury, it must be removed within 24 hours.

One of the big benefits of Traumagel is that when the patient produces a blood clot underneath Traumagel, it doesn’t become incorporated within the gel itself. To contrast that with the use of gauze, gauze is porous. The clot ends up wrapped around the fibers of the gauze, so if you peel the gauze away, it’s very likely that clot is coming off with it. The surgeon or the clinician at the next level of care is going to have to deal with the re-bleed. 

You can remove Traumagel cleanly and entirely without disturbing the underlying clot. That’s a major benefit, not only to the patient but also to the next level of care, to the next clinician or physician that is required to remove the product.

Glatter: How is it possible to remove the substance without disturbing the clot? Can you explain in more detail? 

Landolina: That’s one of the hallmarks of these plant-based polymers and the way that we design Traumagel itself. Traumagel is completely nonporous, and it has no fibrous nature to it. What that means is when the patient produces a blood clot or fibrin next to or on top of Traumagel, that fibrin ends up not incorporated within the polymers of Traumagel itself. 

Over time, because Traumagel is a hydrogel, meaning that by weight it’s mostly water, you end up having less adhesion to the clot over time. When it’s time to remove Traumagel from the injury, it has lost almost all of its adhesive capabilities, meaning that when you peel it away, that clot is going to stick better to tissue than it will to the gel itself. 

Glatter: Can you explain a little bit about the matrix that’s formed, the physiology, and how the polymers work to form this matrix? 

Landolina: Sure. Traumagel is made of two polysaccharides that are plant derived. One polysaccharide is polyanionic, and the other is polycationic, meaning one has negative charges and the other has positive charges, which together create almost a Lego block effect, where when the material comes in contact with tissue, it adheres strongly and allows for itself to effectively create a mechanical barrier against bleeding.

Courtesy of Cresilon

Landolina: Even in the face of major arterial blood flow, Traumagel will stay where it needs to stay, and it’s not going to get washed away. This means that it is much more easily appliable to these types of surfaces and will allow the patient to produce their own endogenous fibrin clot at that location.

Like I mentioned before, when that fibrin clot is formed, because the gel itself has no pores or fibers, it doesn’t become incorporated within the fibrin clot. You can take the gel away, leaving that clot behind without the chance of a rebleed.

 

Testing With Major Bleeds

Glatter: In terms of bleeding itself, have you tested your product with major aortic bleeds or carotid bleeds in preclinical work?

Landolina: We have used the US military’s model for lethal hemorrhage, and the idea there is to create a model that is just that — lethal. These are the worst types of bleeds that you can possibly imagine, where the patients are clotting compromised, and where you have, in most cases, a very strong arterial component, so something like a femoral artery bleed.

We’ve also tested in carotid artery, aortic applications, as well as combinations of venous and arterial bleeds. The idea here is to show the use of the product in the absolute worst-case scenario so that when this translates into the clinic, the models that we’ve used for evaluation, hopefully, are worse than what actually rolls into the trauma bay.

Glatter: Excellent. What’s the mean time to stop an arterial vs a venous bleed? Are we talking a matter of seconds?

Landolina: In the case of a healthy patient, meaning a patient without clotting compromise, you’re in a matter of seconds. It’s less than 10 seconds. 

In the case where you have clotting compromise, a deep, complicated wound geometry, we recommend holding a pressure bandage on for 3 minutes just because it increases the chance of Traumagel coming into contact with the bleed, especially when you can’t visualize the bleed in the bleed source. Because of that pressure time, that becomes the mean. But again, it’s highly dependent on the type of bleed and the style of application.

 

Failure Rates and Effectiveness

Glatter: As a segue to that, what is the failure rate based on your studies and internal research using Traumagel? Have there been cases where bleeding has not been able to be stopped? 

Landolina: It depends on the study, but the failure rates are incredibly low with Traumagel, assuming that it’s correctly used. That’s one of the benefits to this product, where with proper technique, with overwrap with gauze, you nearly always get control of hemorrhage with a product like this. 

Glatter: Is manual pressure required in that sense? From what you described earlier, manual pressure would not be required. 

Landolina: It depends on the injury. What we recommend is that, if you have a very deep wound where you cannot visualize the source of bleed, you use pressure to seat Traumagel into the source of bleeding, meaning that you’re following Committee on Tactical Combat Casualty Care (Co-TCCC) regulations or requirements, where you’re over wrapping with gauze, and you’re providing a pressure wrapping to ensure that the Traumagel is in contact with the bleed while it’s doing what it’s doing. 

In most cases, it doesn’t hurt to apply pressure on top of Traumagel as well. In more surface level bleeds, you don’t need pressure at all. 

 

Applications Beyond Trauma

Glatter: Interesting. In terms of further applications (eg, nose bleeds or GYN bleeding, which are life-threatening), do you see this coming as an application for the future? 

Landolina: That’s where we’re working. Traumagel is the successor to an animal health product called Vetigel. The formulations of the gel behind Vetigel and Traumagel are identical. Vetigel has a full surgical indication, and that’s everything from epistaxis to neuro and spine procedures, into cardiovascular and soft tissue surgeries, orthopedic medicine, and so on.

Cresilon’s goal is to eventually expand the indication of our technology to include surgical indications and other indications where we can help any patient that’s bleeding. 

Glatter: That’s important, because we use prehospital whole blood, low titer, specifically, when patients have life-threatening hemorrhage. With your product, that would reduce the amount of blood products that would need to be administered. This could be a real game changer. 

Landolina: Definitely, that’s the goal we’re working on. 

Infection Risks and Biocompatibility

Glatter: In terms of any risk for infection, has that been studied as well? Does Traumagel in any way lead to increased rates of infection?

Landolina: Traumagel is biocompatible. It’s a sterile product. We’ve done the full suite of biocompatibility testing as required by FDA. On top of that, remember that Vetigel, which is the same formulation, is an implantable product. As a result, that has even extended biocompatibility testing beyond what would be necessary for an external product.

In Vetigel’s use case, which has been used now in over 60,000 patients, primarily companion animals, dogs and cats, we haven’t seen instances of infection. There’s no reason to believe that we would see that clinically with Traumagel.

 

Research Collaborations and Future Applications

Glatter: In terms of other research that your company’s embarked on preclinically, I understand there were some studies done at Walter Reed Army Institute of Research. I was wondering if you could expand on these, specifically, in terms of traumatic brain injury (TBI) and hemorrhage related to that. For example, with shrapnel or even a gunshot wound. 

Landolina: The Walter Reed collaboration with Cresilon is something that I’m particularly excited about, because it marks Cresilon’s first project that’s outside the scope of just hemostasis. Walter Reed came to us with this proposal where there’s a big challenge in a subset of TBI called penetrating ballistic-like brain injury, where the brain has been penetrated by a bullet, shrapnel, or some other projectile, and there’s an injury that exposes the brain to the outside. 

Today, there is no standard of care to treat patients with those types of injuries. In many cases, mortality is caused through swelling of the brain, or collapse of the brain. What they came to us with was the potential of using our technology, not primarily as a hemostatic agent, but to be able to stabilize that patient enough to get to the next level of care to be treated by a neurosurgeon.

That study Walter Reed did was just a pilot that was done in small animals. In that pilot, they showed that over the period of treatment, there was no negative change in vital signs, no increase in edema or in swelling, or in any of the biomarkers that were being monitored at that time. 

At the very least, this is not full indication that this indication will work for Cresilon, but it shows that there’s promise. It’s something that we’re working on and hopefully we’ll be able to bring to market soon.

Glatter: Certainly, maintaining intracranial pressure and cerebral perfusion pressures are very critical. In the future, do you think this product would be able to be deployed endovascularly? Imagine this in terms of stopping bleeding from some source, whether it’s from a stroke or another intracranial source. 

Landolina: That’s been an area of interest for us. We have no evidence to prove that indication works at this point, but there’s also nothing to say that it wouldn’t be possible for our technology. At this point, we’ve only looked at a cursory level at those indications. 

Glatter: Does the use of Traumagel obviate the need for a more definitive repair (eg, with sutures) or something that’s more permanent?

Landolina: I always say that Traumagel — and Vetigel, for that matter — is not a replacement for good surgical technique. The surgeon always needs to make his or her best judgment when reviewing the patient. That doesn’t mean that there won’t need to be sutures or vascular repair in most of these cases, especially in major trauma.

Final Takeaways

Glatter: Do you have some bullet points or pearls you could give our audience as a takeaway? 

Landolina: When Cresilon looks at Traumagel — and for us, Traumagel is the next generation of hemostatic agent, especially in trauma care and in emergency medicine — it allows for a far-simplified application of the product and much faster control of hemorrhage with better patient outcomes.

As we roll this out through EMS agencies, trauma hospitals, military agencies, and eventually to the general public through a future indication, it’s something we’re very excited about. Personally, I started this business 14 years ago, and so it’s great to see our mission of saving lives transitioning to saving human lives.

Glatter: I look forward to seeing this product in the emergency department, but also in other settings, such as in the operating room where we can really help patients who are dying from hemorrhage, certainly on the battlefield, and the lay public. If someone were to come upon a patient who’s bleeding out, this could be certainly a game changer and a lifesaver. 

I want to thank you for your time. This is a really important product that’s transformed the lives of so many animals, but also people in the future.

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He reported no relevant conflicts of interest. Mr. Landolina is the CEO and co-founder of Cresilon, a biotechnology company specializing in plant-based solutions for emergency bleeding control.

A version of this article first appeared on Medscape.com.

This video transcript has been edited for clarity. 

Robert D. Glatter, MD: Hi and welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Joining me today to discuss a novel, plant-based approach to stopping moderate to severe bleeding is Joe Landolina, CEO and cofounder of Cresilon. Welcome, Joe. 

Joe Landolina, MS: Thank you so much for taking the time. It’s great to be here.

Educational Background and Inception of Cresilon

Glatter: It’s a pleasure to have you join me, and I want to congratulate you on your recent 510(k) FDA clearance for your novel product to save lives and stop bleeding. To begin with, can you explain how the idea for launching your company came about? 

Landolina: The way that Cresilon came about was a little bit unorthodox, because I was 17 years old when I invented the technology behind the product that eventually became Traumagel®. 

My grandfather was an ex-pharmaceutical executive, who later in life started a vineyard. I grew up on a vineyard with a winery chemistry lab across the street from my house and a grandfather who learned lab safety in the 60s. So, that meant that the day I learned how to walk, I was tossed into a lab and I fell head over heels in love with lab research.

That started experimentation and my academic pursuits. That led to discovering a blend of two plant-based polymers derived from algae that stop bleeding on contact, effectively creating a mechanical barrier and allowing anything from a gunshot wound to anything quite a bit more minor to stop in a matter of seconds.

Glatter: Your background is in biomedical engineering. How is it that you started tinkering and doing all this type of work? 

Landolina: That’s correct. I did my undergrad in chemical engineering, and my graduate studies were in biomedical engineering. For me, that was supposed to be a pathway into medical school. I always wanted to be a surgeon myself, and I love the field of medicine. 

As a freshman in college at NYU Engineering, I had this idea. I entered it into NYU’s business plan competition, and we won at the engineering school. That gave us just enough capital to start developing and researching Traumagel more, and Cresilon was born out of that research.

 

Techniques for Stopping Hemorrhage

Glatter: In terms of stopping hemorrhage, which takes so many lives in the United States and globally — certainly, uncontrolled hemorrhage — what are the techniques that you see, prior to the arrival of your product, as being effective? Can you elucidate some of these techniques? 

Landolina: In emergency medicine, the primary mode of controlling hemorrhage is passive. It’s what, in Brooklyn, we like to call “pressure and a prayer”, where you have a material that’s either gauze or an impregnated gauze in most cases, where the mode of action is absorbing blood, with the adjunct of pressure by the first responder or by the clinician who’s providing aid.

The idea is to stop the flow of blood to concentrate blood factors at the surface of the gauze product, and to promote either platelet activation or the production of fibrin to create a clot. 

These types of technologies are widespread. There are many versions of this technology carried by EMS agencies, trauma bays, US military soldiers, and soldiers across NATO countries. But these types of technologies tend to be relatively inefficient, meaning that they’re very difficult to get into wounds because of the gauze or the powder form of the devices, and it’s very hard to get them in contact with the form of bleeding.

On top of that, if the patient is clotting compromised or immunocompromised in some way, the ability to create a durable clot that will not be ripped off when you remove the product at the next level of care is also of concern. And so, this type of technology or the type of treatment of massive hemorrhage hasn’t changed in decades.

 

Current Applications and Potential Use

Glatter: I envision this product will be carried by paramedics, used on the battlefield at some point after your FDA clearance, and recently it went through.

Do you see any possibility that this could be an AED equivalent to Stop the Bleed? In other words, could the average lay person be trained to use your product if kits are available? 

Landolina: To be very clear, Traumagel today is only approved or cleared under a “prescription-only” indication, which means that it will not initially be available OTC. However, that is our goal. Our goal is to make this product available and usable by someone with no medical training whatsoever. 

The form factor of being a gel in a syringe lends itself well to that, meaning that we try to make it as easy as point and shoot to control hemorrhage, where there’s not as much technique to be learned in the application of a product like Traumagel as there is in current hemorrhage control techniques. 

 

Mechanism of Action and Physiology

Glatter: Once you apply Traumagel, can you explain what happens to the product after it’s applied and the bleeding has stopped? Does it get reabsorbed by the body? What’s the process here? 

Landolina: Under Traumagel’s indication, because it’s used in traumatic injury, it must be removed within 24 hours.

One of the big benefits of Traumagel is that when the patient produces a blood clot underneath Traumagel, it doesn’t become incorporated within the gel itself. To contrast that with the use of gauze, gauze is porous. The clot ends up wrapped around the fibers of the gauze, so if you peel the gauze away, it’s very likely that clot is coming off with it. The surgeon or the clinician at the next level of care is going to have to deal with the re-bleed. 

You can remove Traumagel cleanly and entirely without disturbing the underlying clot. That’s a major benefit, not only to the patient but also to the next level of care, to the next clinician or physician that is required to remove the product.

Glatter: How is it possible to remove the substance without disturbing the clot? Can you explain in more detail? 

Landolina: That’s one of the hallmarks of these plant-based polymers and the way that we design Traumagel itself. Traumagel is completely nonporous, and it has no fibrous nature to it. What that means is when the patient produces a blood clot or fibrin next to or on top of Traumagel, that fibrin ends up not incorporated within the polymers of Traumagel itself. 

Over time, because Traumagel is a hydrogel, meaning that by weight it’s mostly water, you end up having less adhesion to the clot over time. When it’s time to remove Traumagel from the injury, it has lost almost all of its adhesive capabilities, meaning that when you peel it away, that clot is going to stick better to tissue than it will to the gel itself. 

Glatter: Can you explain a little bit about the matrix that’s formed, the physiology, and how the polymers work to form this matrix? 

Landolina: Sure. Traumagel is made of two polysaccharides that are plant derived. One polysaccharide is polyanionic, and the other is polycationic, meaning one has negative charges and the other has positive charges, which together create almost a Lego block effect, where when the material comes in contact with tissue, it adheres strongly and allows for itself to effectively create a mechanical barrier against bleeding.

Courtesy of Cresilon

Landolina: Even in the face of major arterial blood flow, Traumagel will stay where it needs to stay, and it’s not going to get washed away. This means that it is much more easily appliable to these types of surfaces and will allow the patient to produce their own endogenous fibrin clot at that location.

Like I mentioned before, when that fibrin clot is formed, because the gel itself has no pores or fibers, it doesn’t become incorporated within the fibrin clot. You can take the gel away, leaving that clot behind without the chance of a rebleed.

 

Testing With Major Bleeds

Glatter: In terms of bleeding itself, have you tested your product with major aortic bleeds or carotid bleeds in preclinical work?

Landolina: We have used the US military’s model for lethal hemorrhage, and the idea there is to create a model that is just that — lethal. These are the worst types of bleeds that you can possibly imagine, where the patients are clotting compromised, and where you have, in most cases, a very strong arterial component, so something like a femoral artery bleed.

We’ve also tested in carotid artery, aortic applications, as well as combinations of venous and arterial bleeds. The idea here is to show the use of the product in the absolute worst-case scenario so that when this translates into the clinic, the models that we’ve used for evaluation, hopefully, are worse than what actually rolls into the trauma bay.

Glatter: Excellent. What’s the mean time to stop an arterial vs a venous bleed? Are we talking a matter of seconds?

Landolina: In the case of a healthy patient, meaning a patient without clotting compromise, you’re in a matter of seconds. It’s less than 10 seconds. 

In the case where you have clotting compromise, a deep, complicated wound geometry, we recommend holding a pressure bandage on for 3 minutes just because it increases the chance of Traumagel coming into contact with the bleed, especially when you can’t visualize the bleed in the bleed source. Because of that pressure time, that becomes the mean. But again, it’s highly dependent on the type of bleed and the style of application.

 

Failure Rates and Effectiveness

Glatter: As a segue to that, what is the failure rate based on your studies and internal research using Traumagel? Have there been cases where bleeding has not been able to be stopped? 

Landolina: It depends on the study, but the failure rates are incredibly low with Traumagel, assuming that it’s correctly used. That’s one of the benefits to this product, where with proper technique, with overwrap with gauze, you nearly always get control of hemorrhage with a product like this. 

Glatter: Is manual pressure required in that sense? From what you described earlier, manual pressure would not be required. 

Landolina: It depends on the injury. What we recommend is that, if you have a very deep wound where you cannot visualize the source of bleed, you use pressure to seat Traumagel into the source of bleeding, meaning that you’re following Committee on Tactical Combat Casualty Care (Co-TCCC) regulations or requirements, where you’re over wrapping with gauze, and you’re providing a pressure wrapping to ensure that the Traumagel is in contact with the bleed while it’s doing what it’s doing. 

In most cases, it doesn’t hurt to apply pressure on top of Traumagel as well. In more surface level bleeds, you don’t need pressure at all. 

 

Applications Beyond Trauma

Glatter: Interesting. In terms of further applications (eg, nose bleeds or GYN bleeding, which are life-threatening), do you see this coming as an application for the future? 

Landolina: That’s where we’re working. Traumagel is the successor to an animal health product called Vetigel. The formulations of the gel behind Vetigel and Traumagel are identical. Vetigel has a full surgical indication, and that’s everything from epistaxis to neuro and spine procedures, into cardiovascular and soft tissue surgeries, orthopedic medicine, and so on.

Cresilon’s goal is to eventually expand the indication of our technology to include surgical indications and other indications where we can help any patient that’s bleeding. 

Glatter: That’s important, because we use prehospital whole blood, low titer, specifically, when patients have life-threatening hemorrhage. With your product, that would reduce the amount of blood products that would need to be administered. This could be a real game changer. 

Landolina: Definitely, that’s the goal we’re working on. 

Infection Risks and Biocompatibility

Glatter: In terms of any risk for infection, has that been studied as well? Does Traumagel in any way lead to increased rates of infection?

Landolina: Traumagel is biocompatible. It’s a sterile product. We’ve done the full suite of biocompatibility testing as required by FDA. On top of that, remember that Vetigel, which is the same formulation, is an implantable product. As a result, that has even extended biocompatibility testing beyond what would be necessary for an external product.

In Vetigel’s use case, which has been used now in over 60,000 patients, primarily companion animals, dogs and cats, we haven’t seen instances of infection. There’s no reason to believe that we would see that clinically with Traumagel.

 

Research Collaborations and Future Applications

Glatter: In terms of other research that your company’s embarked on preclinically, I understand there were some studies done at Walter Reed Army Institute of Research. I was wondering if you could expand on these, specifically, in terms of traumatic brain injury (TBI) and hemorrhage related to that. For example, with shrapnel or even a gunshot wound. 

Landolina: The Walter Reed collaboration with Cresilon is something that I’m particularly excited about, because it marks Cresilon’s first project that’s outside the scope of just hemostasis. Walter Reed came to us with this proposal where there’s a big challenge in a subset of TBI called penetrating ballistic-like brain injury, where the brain has been penetrated by a bullet, shrapnel, or some other projectile, and there’s an injury that exposes the brain to the outside. 

Today, there is no standard of care to treat patients with those types of injuries. In many cases, mortality is caused through swelling of the brain, or collapse of the brain. What they came to us with was the potential of using our technology, not primarily as a hemostatic agent, but to be able to stabilize that patient enough to get to the next level of care to be treated by a neurosurgeon.

That study Walter Reed did was just a pilot that was done in small animals. In that pilot, they showed that over the period of treatment, there was no negative change in vital signs, no increase in edema or in swelling, or in any of the biomarkers that were being monitored at that time. 

At the very least, this is not full indication that this indication will work for Cresilon, but it shows that there’s promise. It’s something that we’re working on and hopefully we’ll be able to bring to market soon.

Glatter: Certainly, maintaining intracranial pressure and cerebral perfusion pressures are very critical. In the future, do you think this product would be able to be deployed endovascularly? Imagine this in terms of stopping bleeding from some source, whether it’s from a stroke or another intracranial source. 

Landolina: That’s been an area of interest for us. We have no evidence to prove that indication works at this point, but there’s also nothing to say that it wouldn’t be possible for our technology. At this point, we’ve only looked at a cursory level at those indications. 

Glatter: Does the use of Traumagel obviate the need for a more definitive repair (eg, with sutures) or something that’s more permanent?

Landolina: I always say that Traumagel — and Vetigel, for that matter — is not a replacement for good surgical technique. The surgeon always needs to make his or her best judgment when reviewing the patient. That doesn’t mean that there won’t need to be sutures or vascular repair in most of these cases, especially in major trauma.

Final Takeaways

Glatter: Do you have some bullet points or pearls you could give our audience as a takeaway? 

Landolina: When Cresilon looks at Traumagel — and for us, Traumagel is the next generation of hemostatic agent, especially in trauma care and in emergency medicine — it allows for a far-simplified application of the product and much faster control of hemorrhage with better patient outcomes.

As we roll this out through EMS agencies, trauma hospitals, military agencies, and eventually to the general public through a future indication, it’s something we’re very excited about. Personally, I started this business 14 years ago, and so it’s great to see our mission of saving lives transitioning to saving human lives.

Glatter: I look forward to seeing this product in the emergency department, but also in other settings, such as in the operating room where we can really help patients who are dying from hemorrhage, certainly on the battlefield, and the lay public. If someone were to come upon a patient who’s bleeding out, this could be certainly a game changer and a lifesaver. 

I want to thank you for your time. This is a really important product that’s transformed the lives of so many animals, but also people in the future.

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He reported no relevant conflicts of interest. Mr. Landolina is the CEO and co-founder of Cresilon, a biotechnology company specializing in plant-based solutions for emergency bleeding control.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

It’s just about the easiest, safest medical advice you can give: “Drink more water.” You have a headache? Drink more water. Tired? Drink more water. Cold coming on? Drink more water. Tom Brady famously attributed his QB longevity to water drinking, among some other less ordinary practices.

I’m a nephrologist — a kidney doctor. I think about water all the time. I can tell you how your brain senses how much water is in your body and exactly how it communicates that information to your kidneys to control how dilute your urine is. I can explain the miraculous ability of the kidney to concentrate urine across a range from 50 mOsm/L to 1200 mOsm/L and the physiology that makes it all work.

 

But I can’t really tell you how much water you’re supposed to drink. And believe me, I get asked all the time.

I’m sure of a couple of things when it comes to water: You need to drink some. Though some animals, such as kangaroo rats, can get virtually all the water they need from the food they eat, we are not such animals. Without water, we die. I’m also sure that you can die from drinking too much water. Drinking excessive amounts of water dilutes the sodium in your blood, which messes with the electrical system in your brain and heart. I actually had a patient who went on a “water cleanse” and gave herself a seizure. 

But, to be fair, assuming your kidneys are working reasonably well and you’re otherwise healthy, you’d need to drink around 20 liters of water a day to get into mortal trouble. The dose is the poison, as they say.

So, somewhere between zero and 20 liters of water is the amount you should be drinking in a day. That much I’m sure of.

But the evidence on where in that range you should target is actually pretty skimpy. You wouldn’t think so if you look at the online wellness influencers, with their Stanleys and their strict water intake regimens. You’d think the evidence for the benefits of drinking extra water is overwhelming.

The venerated National Academy of Medicine suggests that men drink thirteen 8 oz cups a day (that’s about 3 liters) and women drink nine 8 oz cups a day (a bit more than 2 liters). From what I can tell, this recommendation — like the old “8 cups of water per day” recommendation — is pulled out of thin air.

I’m not arguing that we shouldn’t drink water. Of course, water is important. I’m just wondering what data there are to really prove that drinking more water is better. 

Fortunately, a team from UCSF has finally done the legwork for us. They break down the actual evidence in this paper, appearing in JAMA Network Open. 

The team scoured the medical literature for randomized controlled trials of water intake. This is critical; we don’t want anecdotes about how clear someone’s skin became after they increased their water intake. We want icy cold, clear data. Randomized trials take a group of people and, at random, assign some to the intervention — in this case, drinking more water — and others to keep doing what they would normally do.

 

The team reviewed nearly 1500 papers but only 18 (!) met the rigorous criteria to be included in the analysis, as you can see from this flow chart.

 

This is the first important finding; not many high-quality studies have investigated how much water we should drink. Of course, water isn’t a prescription product, so funding is likely hard to come by. Can we do a trial of Dasani?

In any case, these 18 trials all looked at different outcomes of interest. Four studies looked at the impact of drinking more water on weight loss, two on fasting blood glucose, two on headache, two on urinary tract infection, two on kidney stones, and six studies on various other outcomes. None of the studies looked at energy, skin tone, or overall wellness, though one did measure a quality-of-life score.

And if I could sum up all these studies in a word, that word would be “meh.”

 

One of four weight loss studies showed that increasing water intake had no effect on weight loss. Two studies showed an effect, but drinking extra water was combined with a low-calorie diet, so that feels a bit like cheating to me. One study randomized participants to drink half a liter of water before meals, and that group did lose more weight than the control group — about a kilogram more over 12 weeks. That’s not exactly Ozempic.

For fasting blood glucose, although one trial suggested that higher premeal water intake lowered glucose levels, the other study (which looked just at increasing water overall) didn’t.

For headache — and, cards on the table here, I’m a big believer in water for headaches — one study showed nothing. The other showed that increasing water intake by 1.5 liters per day improved migraine-related quality of life but didn’t change the number of headache days per month.

For urinary tract infections, one positive trial and one negative one.

The best evidence comes from the kidney stone trials. Increasing water intake to achieve more than two liters of urine a day was associated with a significant reduction in kidney stone recurrence. I consider this a positive finding, more or less. You would be hard-pressed to find a kidney doctor who doesn’t think that people with a history of kidney stones should drink more water.

What about that quality-of-life study? They randomized participants to either drink 1.5 liters of extra water per day (intervention group) or not (control group). Six months later, the scores on the quality-of-life survey were no different between those two groups.

Thirsty yet?

So, what’s going on here? There are a few possibilities.

First, I need to point out that clinical trials are really hard. All the studies in this review were relatively small, with most enrolling fewer than 100 people. The effect of extra water would need to be pretty potent to detect it with those small samples.

I can’t help but point out that our bodies are actually exquisitely tuned to manage how much water we carry. As we lose water throughout the day from sweat and exhalation, our blood becomes a tiny bit more concentrated — the sodium level goes up. Our brains detect that and create a sensation we call thirst. Thirst is one of the most powerful drives we have. Animals, including humans, when thirsty, will choose water over food, over drugs, and over sex. It is incredibly hard to resist, and assuming that we have ready access to water, there is no need to resist it. We drink when we are thirsty. And that may be enough.

Of course, pushing beyond thirst is possible. We are sapient beings who can drink more than we want to. But what we can’t do, assuming our kidneys work, is hold onto that water. It passes right through us. In the case of preventing kidney stones, this is a good thing. Putting more water into your body leads to more water coming out — more dilute urine — which means it’s harder for stones to form. 

But for all that other stuff? The wellness, the skin tone, and so on? It just doesn’t make much sense. If you drink an extra liter of water, you pee an extra liter of water. Net net? Zero.

Some folks will argue that the extra pee gets rid of extra toxins or something like that, but — sorry, kidney doctor Perry here again — that’s not how pee works. The clearance of toxins from the blood happens way upstream of where your urine is diluted or concentrated.

 

If you drink more, the same toxins come out, just with more water around them. In fact, one of the largest studies in this JAMA Network Open review assessed whether increasing water consumption in people with chronic kidney disease would improve kidney function. It didn’t.

I am left, then, with only a bit more confidence than when I began. I remain certain that you should drink more than zero liters and less than 20 liters every day (assuming you’re not losing a lot of water in some other way, like working in the heat). Beyond that, it seems reasonable to trust the millions of years of evolution that have made water homeostasis central to life itself. Give yourself access to water. Drink when you’re thirsty. Drink a bit more if you’d like. But no need to push it. Your kidneys won’t let you anyway.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator in New Haven, Connecticut. He disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

It’s just about the easiest, safest medical advice you can give: “Drink more water.” You have a headache? Drink more water. Tired? Drink more water. Cold coming on? Drink more water. Tom Brady famously attributed his QB longevity to water drinking, among some other less ordinary practices.

I’m a nephrologist — a kidney doctor. I think about water all the time. I can tell you how your brain senses how much water is in your body and exactly how it communicates that information to your kidneys to control how dilute your urine is. I can explain the miraculous ability of the kidney to concentrate urine across a range from 50 mOsm/L to 1200 mOsm/L and the physiology that makes it all work.

 

But I can’t really tell you how much water you’re supposed to drink. And believe me, I get asked all the time.

I’m sure of a couple of things when it comes to water: You need to drink some. Though some animals, such as kangaroo rats, can get virtually all the water they need from the food they eat, we are not such animals. Without water, we die. I’m also sure that you can die from drinking too much water. Drinking excessive amounts of water dilutes the sodium in your blood, which messes with the electrical system in your brain and heart. I actually had a patient who went on a “water cleanse” and gave herself a seizure. 

But, to be fair, assuming your kidneys are working reasonably well and you’re otherwise healthy, you’d need to drink around 20 liters of water a day to get into mortal trouble. The dose is the poison, as they say.

So, somewhere between zero and 20 liters of water is the amount you should be drinking in a day. That much I’m sure of.

But the evidence on where in that range you should target is actually pretty skimpy. You wouldn’t think so if you look at the online wellness influencers, with their Stanleys and their strict water intake regimens. You’d think the evidence for the benefits of drinking extra water is overwhelming.

The venerated National Academy of Medicine suggests that men drink thirteen 8 oz cups a day (that’s about 3 liters) and women drink nine 8 oz cups a day (a bit more than 2 liters). From what I can tell, this recommendation — like the old “8 cups of water per day” recommendation — is pulled out of thin air.

I’m not arguing that we shouldn’t drink water. Of course, water is important. I’m just wondering what data there are to really prove that drinking more water is better. 

Fortunately, a team from UCSF has finally done the legwork for us. They break down the actual evidence in this paper, appearing in JAMA Network Open. 

The team scoured the medical literature for randomized controlled trials of water intake. This is critical; we don’t want anecdotes about how clear someone’s skin became after they increased their water intake. We want icy cold, clear data. Randomized trials take a group of people and, at random, assign some to the intervention — in this case, drinking more water — and others to keep doing what they would normally do.

 

The team reviewed nearly 1500 papers but only 18 (!) met the rigorous criteria to be included in the analysis, as you can see from this flow chart.

 

This is the first important finding; not many high-quality studies have investigated how much water we should drink. Of course, water isn’t a prescription product, so funding is likely hard to come by. Can we do a trial of Dasani?

In any case, these 18 trials all looked at different outcomes of interest. Four studies looked at the impact of drinking more water on weight loss, two on fasting blood glucose, two on headache, two on urinary tract infection, two on kidney stones, and six studies on various other outcomes. None of the studies looked at energy, skin tone, or overall wellness, though one did measure a quality-of-life score.

And if I could sum up all these studies in a word, that word would be “meh.”

 

One of four weight loss studies showed that increasing water intake had no effect on weight loss. Two studies showed an effect, but drinking extra water was combined with a low-calorie diet, so that feels a bit like cheating to me. One study randomized participants to drink half a liter of water before meals, and that group did lose more weight than the control group — about a kilogram more over 12 weeks. That’s not exactly Ozempic.

For fasting blood glucose, although one trial suggested that higher premeal water intake lowered glucose levels, the other study (which looked just at increasing water overall) didn’t.

For headache — and, cards on the table here, I’m a big believer in water for headaches — one study showed nothing. The other showed that increasing water intake by 1.5 liters per day improved migraine-related quality of life but didn’t change the number of headache days per month.

For urinary tract infections, one positive trial and one negative one.

The best evidence comes from the kidney stone trials. Increasing water intake to achieve more than two liters of urine a day was associated with a significant reduction in kidney stone recurrence. I consider this a positive finding, more or less. You would be hard-pressed to find a kidney doctor who doesn’t think that people with a history of kidney stones should drink more water.

What about that quality-of-life study? They randomized participants to either drink 1.5 liters of extra water per day (intervention group) or not (control group). Six months later, the scores on the quality-of-life survey were no different between those two groups.

Thirsty yet?

So, what’s going on here? There are a few possibilities.

First, I need to point out that clinical trials are really hard. All the studies in this review were relatively small, with most enrolling fewer than 100 people. The effect of extra water would need to be pretty potent to detect it with those small samples.

I can’t help but point out that our bodies are actually exquisitely tuned to manage how much water we carry. As we lose water throughout the day from sweat and exhalation, our blood becomes a tiny bit more concentrated — the sodium level goes up. Our brains detect that and create a sensation we call thirst. Thirst is one of the most powerful drives we have. Animals, including humans, when thirsty, will choose water over food, over drugs, and over sex. It is incredibly hard to resist, and assuming that we have ready access to water, there is no need to resist it. We drink when we are thirsty. And that may be enough.

Of course, pushing beyond thirst is possible. We are sapient beings who can drink more than we want to. But what we can’t do, assuming our kidneys work, is hold onto that water. It passes right through us. In the case of preventing kidney stones, this is a good thing. Putting more water into your body leads to more water coming out — more dilute urine — which means it’s harder for stones to form. 

But for all that other stuff? The wellness, the skin tone, and so on? It just doesn’t make much sense. If you drink an extra liter of water, you pee an extra liter of water. Net net? Zero.

Some folks will argue that the extra pee gets rid of extra toxins or something like that, but — sorry, kidney doctor Perry here again — that’s not how pee works. The clearance of toxins from the blood happens way upstream of where your urine is diluted or concentrated.

 

If you drink more, the same toxins come out, just with more water around them. In fact, one of the largest studies in this JAMA Network Open review assessed whether increasing water consumption in people with chronic kidney disease would improve kidney function. It didn’t.

I am left, then, with only a bit more confidence than when I began. I remain certain that you should drink more than zero liters and less than 20 liters every day (assuming you’re not losing a lot of water in some other way, like working in the heat). Beyond that, it seems reasonable to trust the millions of years of evolution that have made water homeostasis central to life itself. Give yourself access to water. Drink when you’re thirsty. Drink a bit more if you’d like. But no need to push it. Your kidneys won’t let you anyway.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator in New Haven, Connecticut. He disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

It’s just about the easiest, safest medical advice you can give: “Drink more water.” You have a headache? Drink more water. Tired? Drink more water. Cold coming on? Drink more water. Tom Brady famously attributed his QB longevity to water drinking, among some other less ordinary practices.

I’m a nephrologist — a kidney doctor. I think about water all the time. I can tell you how your brain senses how much water is in your body and exactly how it communicates that information to your kidneys to control how dilute your urine is. I can explain the miraculous ability of the kidney to concentrate urine across a range from 50 mOsm/L to 1200 mOsm/L and the physiology that makes it all work.

 

But I can’t really tell you how much water you’re supposed to drink. And believe me, I get asked all the time.

I’m sure of a couple of things when it comes to water: You need to drink some. Though some animals, such as kangaroo rats, can get virtually all the water they need from the food they eat, we are not such animals. Without water, we die. I’m also sure that you can die from drinking too much water. Drinking excessive amounts of water dilutes the sodium in your blood, which messes with the electrical system in your brain and heart. I actually had a patient who went on a “water cleanse” and gave herself a seizure. 

But, to be fair, assuming your kidneys are working reasonably well and you’re otherwise healthy, you’d need to drink around 20 liters of water a day to get into mortal trouble. The dose is the poison, as they say.

So, somewhere between zero and 20 liters of water is the amount you should be drinking in a day. That much I’m sure of.

But the evidence on where in that range you should target is actually pretty skimpy. You wouldn’t think so if you look at the online wellness influencers, with their Stanleys and their strict water intake regimens. You’d think the evidence for the benefits of drinking extra water is overwhelming.

The venerated National Academy of Medicine suggests that men drink thirteen 8 oz cups a day (that’s about 3 liters) and women drink nine 8 oz cups a day (a bit more than 2 liters). From what I can tell, this recommendation — like the old “8 cups of water per day” recommendation — is pulled out of thin air.

I’m not arguing that we shouldn’t drink water. Of course, water is important. I’m just wondering what data there are to really prove that drinking more water is better. 

Fortunately, a team from UCSF has finally done the legwork for us. They break down the actual evidence in this paper, appearing in JAMA Network Open. 

The team scoured the medical literature for randomized controlled trials of water intake. This is critical; we don’t want anecdotes about how clear someone’s skin became after they increased their water intake. We want icy cold, clear data. Randomized trials take a group of people and, at random, assign some to the intervention — in this case, drinking more water — and others to keep doing what they would normally do.

 

The team reviewed nearly 1500 papers but only 18 (!) met the rigorous criteria to be included in the analysis, as you can see from this flow chart.

 

This is the first important finding; not many high-quality studies have investigated how much water we should drink. Of course, water isn’t a prescription product, so funding is likely hard to come by. Can we do a trial of Dasani?

In any case, these 18 trials all looked at different outcomes of interest. Four studies looked at the impact of drinking more water on weight loss, two on fasting blood glucose, two on headache, two on urinary tract infection, two on kidney stones, and six studies on various other outcomes. None of the studies looked at energy, skin tone, or overall wellness, though one did measure a quality-of-life score.

And if I could sum up all these studies in a word, that word would be “meh.”

 

One of four weight loss studies showed that increasing water intake had no effect on weight loss. Two studies showed an effect, but drinking extra water was combined with a low-calorie diet, so that feels a bit like cheating to me. One study randomized participants to drink half a liter of water before meals, and that group did lose more weight than the control group — about a kilogram more over 12 weeks. That’s not exactly Ozempic.

For fasting blood glucose, although one trial suggested that higher premeal water intake lowered glucose levels, the other study (which looked just at increasing water overall) didn’t.

For headache — and, cards on the table here, I’m a big believer in water for headaches — one study showed nothing. The other showed that increasing water intake by 1.5 liters per day improved migraine-related quality of life but didn’t change the number of headache days per month.

For urinary tract infections, one positive trial and one negative one.

The best evidence comes from the kidney stone trials. Increasing water intake to achieve more than two liters of urine a day was associated with a significant reduction in kidney stone recurrence. I consider this a positive finding, more or less. You would be hard-pressed to find a kidney doctor who doesn’t think that people with a history of kidney stones should drink more water.

What about that quality-of-life study? They randomized participants to either drink 1.5 liters of extra water per day (intervention group) or not (control group). Six months later, the scores on the quality-of-life survey were no different between those two groups.

Thirsty yet?

So, what’s going on here? There are a few possibilities.

First, I need to point out that clinical trials are really hard. All the studies in this review were relatively small, with most enrolling fewer than 100 people. The effect of extra water would need to be pretty potent to detect it with those small samples.

I can’t help but point out that our bodies are actually exquisitely tuned to manage how much water we carry. As we lose water throughout the day from sweat and exhalation, our blood becomes a tiny bit more concentrated — the sodium level goes up. Our brains detect that and create a sensation we call thirst. Thirst is one of the most powerful drives we have. Animals, including humans, when thirsty, will choose water over food, over drugs, and over sex. It is incredibly hard to resist, and assuming that we have ready access to water, there is no need to resist it. We drink when we are thirsty. And that may be enough.

Of course, pushing beyond thirst is possible. We are sapient beings who can drink more than we want to. But what we can’t do, assuming our kidneys work, is hold onto that water. It passes right through us. In the case of preventing kidney stones, this is a good thing. Putting more water into your body leads to more water coming out — more dilute urine — which means it’s harder for stones to form. 

But for all that other stuff? The wellness, the skin tone, and so on? It just doesn’t make much sense. If you drink an extra liter of water, you pee an extra liter of water. Net net? Zero.

Some folks will argue that the extra pee gets rid of extra toxins or something like that, but — sorry, kidney doctor Perry here again — that’s not how pee works. The clearance of toxins from the blood happens way upstream of where your urine is diluted or concentrated.

 

If you drink more, the same toxins come out, just with more water around them. In fact, one of the largest studies in this JAMA Network Open review assessed whether increasing water consumption in people with chronic kidney disease would improve kidney function. It didn’t.

I am left, then, with only a bit more confidence than when I began. I remain certain that you should drink more than zero liters and less than 20 liters every day (assuming you’re not losing a lot of water in some other way, like working in the heat). Beyond that, it seems reasonable to trust the millions of years of evolution that have made water homeostasis central to life itself. Give yourself access to water. Drink when you’re thirsty. Drink a bit more if you’d like. But no need to push it. Your kidneys won’t let you anyway.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator in New Haven, Connecticut. He disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

Long COVID is a symptom-driven disease, meaning that with no cure, physicians primarily treat the symptoms their patients are experiencing. Effective treatments for long COVID remain elusive because what works for one patient may be entirely ineffective for another. But as 2024 winds down, researchers have begun to pinpoint a number of treatments that are bringing relief to the 17 million Americans diagnosed with long COVID.

Here’s a current look at what research has identified as some of the most promising treatments.

 

Low-Dose Naltrexone

Some research suggests that low-dose naltrexone may be helpful for patients suffering from brain fog, pain, sleep issues, and fatigue, said Ziyad Al-Aly, MD, a global expert on long COVID and chief of research and development at the Veterans Affairs St Louis Health Care System in Missouri.

Low-dose naltrexone is an anti-inflammatory agent currently approved by the Food and Drug Administration for the treatment of alcohol and opioid dependence.

“We don’t know the mechanism for how the medication works, and for that matter, we don’t really understand what causes brain fog. But perhaps its anti-inflammatory properties seem to help, and for some patients, low-dose naltrexone has been helpful,” said Al-Aly.

A March 2024 study found that both fatigue and pain were improved in patients taking low-dose naltrexone. In another study, published in the June 2024 issue of Frontiers in Medicine, researchers found that low-dose naltrexone was associated with improvement of several clinical symptoms related to long COVID such as fatigue, poor sleep quality, brain fog, post-exertional malaise, and headache.

 

Selective Serotonin Reuptake Inhibitors (SSRIs) and Antidepressants

In 2023, University of Pennsylvania researchers uncovered a link between long COVID and lower levels of serotonin in the body. This helped point to the potential treatment of using SSRIs to treat the condition.

For patients who have overlapping psychiatric issues that go along with brain fog, SSRIs prescribed to treat depression and other mental health conditions, as well as the antidepressant Wellbutrin, have been shown effective at dealing with concentration issues, brain fog, and depression, said Nisha Viswanathan, MD, director of the University of California, Los Angeles (UCLA) Long COVID Program at UCLA Health.

A study published in the November 2023 issue of the journal Scientific Reports found that SSRIs led to a “considerable reduction of symptoms,” especially brain fog, fatigue, sensory overload, and overall improved functioning. Low-dose Abilify, which contains aripiprazole, an antipsychotic medication, has also been found to be effective for cognitive issues caused by long COVID.

“Abilify is traditionally used for the treatment of schizophrenia or other psychotic disorders, but in a low-dose format, there is some data to suggest that it can also be anti-inflammatory and helpful for cognitive issues like brain fog,” said Viswanathan.

 

Modafinil

Modafinil, a medication previously used for managing narcolepsy, has also been shown effective for the treatment of fatigue and neurocognitive deficits caused by long COVID, said Viswanathan, adding that it’s another medication that she’s found useful for a number of her patients.

It’s thought that these cognitive symptoms are caused by an inflammatory cytokine release that leads to excessive stimulation of neurotransmitters in the body. According to a June 2024 article in the American Journal of Psychiatry, “Modafinil can therapeutically act on these pathways, which possibly contributed to the symptomatic improvement.” But the medication has not been studied widely in patients with long COVID and has been shown to have interactions with other medications.

 

Metformin

Some research has shown that metformin, a well-known diabetes medication, reduces instances of long COVID when taken during the illness’s acute phase. It seems to boost metabolic function in patients.

“It makes sense that it would work because it seems to have anti-inflammatory effects on the body,” said Grace McComsey, MD, who leads one of the 15 nationwide long COVID centers funded by the federal RECOVER (Researching COVID to Enhance Recovery) Initiative in Cleveland, Ohio. McComsey added that it may reduce the viral persistence that causes some forms of long COVID.

A study published in the October 2023 issue of the journal The Lancet Infectious Diseases found that metformin seemed to reduce instances of long COVID in patients who took it after being diagnosed with acute COVID. It seems less effective in patients who already have long COVID.

 

Antihistamines

Other data suggest that some patients with long COVID showed improvement after taking antihistamines. Research has shown that long COVID symptoms improved in 29% of patients with long COVID.

While researchers aren’t sure why antihistamines work to quell long COVID, the thought is that, when mast cells, a white blood cell that’s part of the immune system, shed granules and cause an inflammatory reaction, they release a lot of histamines. Antihistamine medications like famotidine block histamine receptors in the body, improving symptoms like brain fog, difficulty breathing, and elevated heart rate in patients.

“For some patients, these can be a lifesaver,” said David Putrino, the Nash Family Director of the Cohen Center for Recovery from Complex Chronic Illness and a national leader in the treatment of long COVID.

Putrino cautions patients toward taking these and other medications haphazardly without fully understanding that all treatments have risks, especially if they’re taking a number of them.

“Often patients are told that there’s no risk to trying something, but physicians should be counseling their patients and reminding them that there is a risk that includes medication sensitivities and medication interactions,” said Putrino.

The good news is that doctors have begun to identify some treatments that seem to be working in their patients, but we still don’t have the large-scale clinical trials to identify which treatments will work for certain patients and why.

There’s still so much we don’t know, and for physicians on the front lines of treating long COVID, it’s still largely a guessing game. “This is a constellation of symptoms; it’s not just one thing,” said Al-Aly. And while a treatment might be wildly effective for one patient, it might be ineffective or worse, problematic, for another.

A version of this article first appeared on Medscape.com.

Long COVID is a symptom-driven disease, meaning that with no cure, physicians primarily treat the symptoms their patients are experiencing. Effective treatments for long COVID remain elusive because what works for one patient may be entirely ineffective for another. But as 2024 winds down, researchers have begun to pinpoint a number of treatments that are bringing relief to the 17 million Americans diagnosed with long COVID.

Here’s a current look at what research has identified as some of the most promising treatments.

 

Low-Dose Naltrexone

Some research suggests that low-dose naltrexone may be helpful for patients suffering from brain fog, pain, sleep issues, and fatigue, said Ziyad Al-Aly, MD, a global expert on long COVID and chief of research and development at the Veterans Affairs St Louis Health Care System in Missouri.

Low-dose naltrexone is an anti-inflammatory agent currently approved by the Food and Drug Administration for the treatment of alcohol and opioid dependence.

“We don’t know the mechanism for how the medication works, and for that matter, we don’t really understand what causes brain fog. But perhaps its anti-inflammatory properties seem to help, and for some patients, low-dose naltrexone has been helpful,” said Al-Aly.

A March 2024 study found that both fatigue and pain were improved in patients taking low-dose naltrexone. In another study, published in the June 2024 issue of Frontiers in Medicine, researchers found that low-dose naltrexone was associated with improvement of several clinical symptoms related to long COVID such as fatigue, poor sleep quality, brain fog, post-exertional malaise, and headache.

 

Selective Serotonin Reuptake Inhibitors (SSRIs) and Antidepressants

In 2023, University of Pennsylvania researchers uncovered a link between long COVID and lower levels of serotonin in the body. This helped point to the potential treatment of using SSRIs to treat the condition.

For patients who have overlapping psychiatric issues that go along with brain fog, SSRIs prescribed to treat depression and other mental health conditions, as well as the antidepressant Wellbutrin, have been shown effective at dealing with concentration issues, brain fog, and depression, said Nisha Viswanathan, MD, director of the University of California, Los Angeles (UCLA) Long COVID Program at UCLA Health.

A study published in the November 2023 issue of the journal Scientific Reports found that SSRIs led to a “considerable reduction of symptoms,” especially brain fog, fatigue, sensory overload, and overall improved functioning. Low-dose Abilify, which contains aripiprazole, an antipsychotic medication, has also been found to be effective for cognitive issues caused by long COVID.

“Abilify is traditionally used for the treatment of schizophrenia or other psychotic disorders, but in a low-dose format, there is some data to suggest that it can also be anti-inflammatory and helpful for cognitive issues like brain fog,” said Viswanathan.

 

Modafinil

Modafinil, a medication previously used for managing narcolepsy, has also been shown effective for the treatment of fatigue and neurocognitive deficits caused by long COVID, said Viswanathan, adding that it’s another medication that she’s found useful for a number of her patients.

It’s thought that these cognitive symptoms are caused by an inflammatory cytokine release that leads to excessive stimulation of neurotransmitters in the body. According to a June 2024 article in the American Journal of Psychiatry, “Modafinil can therapeutically act on these pathways, which possibly contributed to the symptomatic improvement.” But the medication has not been studied widely in patients with long COVID and has been shown to have interactions with other medications.

 

Metformin

Some research has shown that metformin, a well-known diabetes medication, reduces instances of long COVID when taken during the illness’s acute phase. It seems to boost metabolic function in patients.

“It makes sense that it would work because it seems to have anti-inflammatory effects on the body,” said Grace McComsey, MD, who leads one of the 15 nationwide long COVID centers funded by the federal RECOVER (Researching COVID to Enhance Recovery) Initiative in Cleveland, Ohio. McComsey added that it may reduce the viral persistence that causes some forms of long COVID.

A study published in the October 2023 issue of the journal The Lancet Infectious Diseases found that metformin seemed to reduce instances of long COVID in patients who took it after being diagnosed with acute COVID. It seems less effective in patients who already have long COVID.

 

Antihistamines

Other data suggest that some patients with long COVID showed improvement after taking antihistamines. Research has shown that long COVID symptoms improved in 29% of patients with long COVID.

While researchers aren’t sure why antihistamines work to quell long COVID, the thought is that, when mast cells, a white blood cell that’s part of the immune system, shed granules and cause an inflammatory reaction, they release a lot of histamines. Antihistamine medications like famotidine block histamine receptors in the body, improving symptoms like brain fog, difficulty breathing, and elevated heart rate in patients.

“For some patients, these can be a lifesaver,” said David Putrino, the Nash Family Director of the Cohen Center for Recovery from Complex Chronic Illness and a national leader in the treatment of long COVID.

Putrino cautions patients toward taking these and other medications haphazardly without fully understanding that all treatments have risks, especially if they’re taking a number of them.

“Often patients are told that there’s no risk to trying something, but physicians should be counseling their patients and reminding them that there is a risk that includes medication sensitivities and medication interactions,” said Putrino.

The good news is that doctors have begun to identify some treatments that seem to be working in their patients, but we still don’t have the large-scale clinical trials to identify which treatments will work for certain patients and why.

There’s still so much we don’t know, and for physicians on the front lines of treating long COVID, it’s still largely a guessing game. “This is a constellation of symptoms; it’s not just one thing,” said Al-Aly. And while a treatment might be wildly effective for one patient, it might be ineffective or worse, problematic, for another.

A version of this article first appeared on Medscape.com.

Long COVID is a symptom-driven disease, meaning that with no cure, physicians primarily treat the symptoms their patients are experiencing. Effective treatments for long COVID remain elusive because what works for one patient may be entirely ineffective for another. But as 2024 winds down, researchers have begun to pinpoint a number of treatments that are bringing relief to the 17 million Americans diagnosed with long COVID.

Here’s a current look at what research has identified as some of the most promising treatments.

 

Low-Dose Naltrexone

Some research suggests that low-dose naltrexone may be helpful for patients suffering from brain fog, pain, sleep issues, and fatigue, said Ziyad Al-Aly, MD, a global expert on long COVID and chief of research and development at the Veterans Affairs St Louis Health Care System in Missouri.

Low-dose naltrexone is an anti-inflammatory agent currently approved by the Food and Drug Administration for the treatment of alcohol and opioid dependence.

“We don’t know the mechanism for how the medication works, and for that matter, we don’t really understand what causes brain fog. But perhaps its anti-inflammatory properties seem to help, and for some patients, low-dose naltrexone has been helpful,” said Al-Aly.

A March 2024 study found that both fatigue and pain were improved in patients taking low-dose naltrexone. In another study, published in the June 2024 issue of Frontiers in Medicine, researchers found that low-dose naltrexone was associated with improvement of several clinical symptoms related to long COVID such as fatigue, poor sleep quality, brain fog, post-exertional malaise, and headache.

 

Selective Serotonin Reuptake Inhibitors (SSRIs) and Antidepressants

In 2023, University of Pennsylvania researchers uncovered a link between long COVID and lower levels of serotonin in the body. This helped point to the potential treatment of using SSRIs to treat the condition.

For patients who have overlapping psychiatric issues that go along with brain fog, SSRIs prescribed to treat depression and other mental health conditions, as well as the antidepressant Wellbutrin, have been shown effective at dealing with concentration issues, brain fog, and depression, said Nisha Viswanathan, MD, director of the University of California, Los Angeles (UCLA) Long COVID Program at UCLA Health.

A study published in the November 2023 issue of the journal Scientific Reports found that SSRIs led to a “considerable reduction of symptoms,” especially brain fog, fatigue, sensory overload, and overall improved functioning. Low-dose Abilify, which contains aripiprazole, an antipsychotic medication, has also been found to be effective for cognitive issues caused by long COVID.

“Abilify is traditionally used for the treatment of schizophrenia or other psychotic disorders, but in a low-dose format, there is some data to suggest that it can also be anti-inflammatory and helpful for cognitive issues like brain fog,” said Viswanathan.

 

Modafinil

Modafinil, a medication previously used for managing narcolepsy, has also been shown effective for the treatment of fatigue and neurocognitive deficits caused by long COVID, said Viswanathan, adding that it’s another medication that she’s found useful for a number of her patients.

It’s thought that these cognitive symptoms are caused by an inflammatory cytokine release that leads to excessive stimulation of neurotransmitters in the body. According to a June 2024 article in the American Journal of Psychiatry, “Modafinil can therapeutically act on these pathways, which possibly contributed to the symptomatic improvement.” But the medication has not been studied widely in patients with long COVID and has been shown to have interactions with other medications.

 

Metformin

Some research has shown that metformin, a well-known diabetes medication, reduces instances of long COVID when taken during the illness’s acute phase. It seems to boost metabolic function in patients.

“It makes sense that it would work because it seems to have anti-inflammatory effects on the body,” said Grace McComsey, MD, who leads one of the 15 nationwide long COVID centers funded by the federal RECOVER (Researching COVID to Enhance Recovery) Initiative in Cleveland, Ohio. McComsey added that it may reduce the viral persistence that causes some forms of long COVID.

A study published in the October 2023 issue of the journal The Lancet Infectious Diseases found that metformin seemed to reduce instances of long COVID in patients who took it after being diagnosed with acute COVID. It seems less effective in patients who already have long COVID.

 

Antihistamines

Other data suggest that some patients with long COVID showed improvement after taking antihistamines. Research has shown that long COVID symptoms improved in 29% of patients with long COVID.

While researchers aren’t sure why antihistamines work to quell long COVID, the thought is that, when mast cells, a white blood cell that’s part of the immune system, shed granules and cause an inflammatory reaction, they release a lot of histamines. Antihistamine medications like famotidine block histamine receptors in the body, improving symptoms like brain fog, difficulty breathing, and elevated heart rate in patients.

“For some patients, these can be a lifesaver,” said David Putrino, the Nash Family Director of the Cohen Center for Recovery from Complex Chronic Illness and a national leader in the treatment of long COVID.

Putrino cautions patients toward taking these and other medications haphazardly without fully understanding that all treatments have risks, especially if they’re taking a number of them.

“Often patients are told that there’s no risk to trying something, but physicians should be counseling their patients and reminding them that there is a risk that includes medication sensitivities and medication interactions,” said Putrino.

The good news is that doctors have begun to identify some treatments that seem to be working in their patients, but we still don’t have the large-scale clinical trials to identify which treatments will work for certain patients and why.

There’s still so much we don’t know, and for physicians on the front lines of treating long COVID, it’s still largely a guessing game. “This is a constellation of symptoms; it’s not just one thing,” said Al-Aly. And while a treatment might be wildly effective for one patient, it might be ineffective or worse, problematic, for another.

A version of this article first appeared on Medscape.com.

This video transcript has been edited for clarity. 

Dear colleagues, I am Christoph Diener, from the Faculty of Medicine at the University Duisburg-Essen in Germany. In this video, I would like to cover six publications on stroke, which were published this fall. 

The Best Thrombolytic?

Let me start with systemic thrombolysis. We now have two thrombolytic agents available. One is the well-known alteplase, and newly approved for the treatment of stroke is tenecteplase. The ATTEST-2 study in the United Kingdom, published in The Lancet Neurology, compared tenecteplase 0.25 mg/kg body weight as a bolus with alteplase 0.9 mg/kg body weight as an infusion over 60 minutes in the 4.5-hour time window in 1777 patients with ischemic stroke.

There was no significant difference between the two thrombolytics for the primary endpoint of modified Rankin Scale score after 90 days. There was also no difference with respect to mortality, intracranial bleeding, or extracranial bleeding. 

We finally have 11 randomized controlled trials that compared tenecteplase and alteplase in acute ischemic stroke. A meta-analysis of these randomized trials was published in Neurology. The analysis included 3700 patients treated with tenecteplase and 3700 patients treated with alteplase. For the primary endpoint, excellent functional outcome defined as modified Rankin Scale score 0-1 after 90 days, there was a significant benefit for tenecteplase (relative risk, 1.05), but the absolute difference was very small, at 3%. There was no difference in mortality or bleeding complications. 

In conclusion, I think both substances are great. They are effective. Tenecteplase is most probably the drug which should be used in people who have to transfer from a primary stroke center to a dedicated stroke center that provides thrombectomy. Otherwise, I think it’s a choice of the physician as to which thrombolytic agent to use. 

 

Mobile Stroke Units

A highly debated topic is mobile stroke units. These stroke units have a CT scanner and laboratory on board, and this makes it possible to perform thrombolysis on the way to the hospital. A retrospective, observational study collected data between 2018 and 2023, and included 19,400 patients with acute stroke, of whom 1237, or 6.4%, were treated in a mobile stroke unit. This study was published in JAMA Neurology. 

The modified Rankin Scale score at the time of discharge was better in patients treated with a mobile stroke unit, but the absolute benefit was only 0.03 points on the modified Rankin Scale. The question is whether this is cost-effective, and can we really do this at times when there is a traumatic shortage of physicians and nursing staff in the hospital? 

 

DOAC Reversal Agents

Oral anticoagulation, as you know, is usually considered a contraindication for systemic thrombolysis. Idarucizumab, a monoclonal antibody, was developed to reverse the biological activity of dabigatran and then allow systemic thrombolysis.

A recent publication in Neurology analyzed 13 cohort studies with 553 stroke patients on dabigatran who received idarucizumab prior to systemic thrombolysis, and the rate of intracranial hemorrhage was 4%. This means it’s obviously possible to perform thrombolysis when the activity of dabigatran is neutralized by idarucizumab.

Unfortunately, until today, we have no data on whether this can also be done with andexanet alfa in people who are treated with a factor Xa inhibitor like, for example, apixaban, rivaroxaban, or edoxaban. 

 

Anticoagulation in ESUS 

My next topic is ESUS, or embolic stroke of undetermined source. We have four large randomized trials and three smaller trials that compared antiplatelet therapy with DOACs in patients with ESUS. A group in Neurology published a meta-analysis of seven randomized controlled studies with, altogether, 14,800 patients with ESUS. 

The comparison between antiplatelet therapy and anticoagulants showed no difference for recurrent ischemic stroke, and also not for major subgroups. This means that people with ESUS should receive antiplatelet therapy, most probably aspirin. 

 

Anticoagulation Post–Ischemic Stroke With AF 

My final topic is the optimal time to start anticoagulation in people with atrial fibrillation who suffer an ischemic stroke. The OPTIMAS study, published in The Lancet, randomized 3650 patients who were anticoagulated with DOACs early (which means less than 4 days) or delayed (between 7 and 14 days). There was no difference in the primary endpoint, which was recurrent ischemic stroke, intracranial hemorrhage, or systemic embolism at 90 days.

The conclusion is that, in most cases, we can probably initiate anticoagulation in people with ischemic stroke and atrial fibrillation within the first 4 days. 

Dear colleagues, this is an exciting time for the stroke field. I presented six new studies that have impact, I think, on the management of patients with ischemic stroke.

Dr. Diener is a professor in the Department of Neurology, Stroke Center-Headache Center, University Duisburg-Essen in Germany. He reported conflicts of interest with Abbott, AbbVie, Boehringer Ingelheim, Lundbeck, Novartis, Orion Pharma, Teva, WebMD, and The German Research Council. He also serves on the editorial boards of Cephalalgia, Lancet Neurology, and Drugs.

A version of this article first appeared on Medscape.com.

This video transcript has been edited for clarity. 

Dear colleagues, I am Christoph Diener, from the Faculty of Medicine at the University Duisburg-Essen in Germany. In this video, I would like to cover six publications on stroke, which were published this fall. 

The Best Thrombolytic?

Let me start with systemic thrombolysis. We now have two thrombolytic agents available. One is the well-known alteplase, and newly approved for the treatment of stroke is tenecteplase. The ATTEST-2 study in the United Kingdom, published in The Lancet Neurology, compared tenecteplase 0.25 mg/kg body weight as a bolus with alteplase 0.9 mg/kg body weight as an infusion over 60 minutes in the 4.5-hour time window in 1777 patients with ischemic stroke.

There was no significant difference between the two thrombolytics for the primary endpoint of modified Rankin Scale score after 90 days. There was also no difference with respect to mortality, intracranial bleeding, or extracranial bleeding. 

We finally have 11 randomized controlled trials that compared tenecteplase and alteplase in acute ischemic stroke. A meta-analysis of these randomized trials was published in Neurology. The analysis included 3700 patients treated with tenecteplase and 3700 patients treated with alteplase. For the primary endpoint, excellent functional outcome defined as modified Rankin Scale score 0-1 after 90 days, there was a significant benefit for tenecteplase (relative risk, 1.05), but the absolute difference was very small, at 3%. There was no difference in mortality or bleeding complications. 

In conclusion, I think both substances are great. They are effective. Tenecteplase is most probably the drug which should be used in people who have to transfer from a primary stroke center to a dedicated stroke center that provides thrombectomy. Otherwise, I think it’s a choice of the physician as to which thrombolytic agent to use. 

 

Mobile Stroke Units

A highly debated topic is mobile stroke units. These stroke units have a CT scanner and laboratory on board, and this makes it possible to perform thrombolysis on the way to the hospital. A retrospective, observational study collected data between 2018 and 2023, and included 19,400 patients with acute stroke, of whom 1237, or 6.4%, were treated in a mobile stroke unit. This study was published in JAMA Neurology. 

The modified Rankin Scale score at the time of discharge was better in patients treated with a mobile stroke unit, but the absolute benefit was only 0.03 points on the modified Rankin Scale. The question is whether this is cost-effective, and can we really do this at times when there is a traumatic shortage of physicians and nursing staff in the hospital? 

 

DOAC Reversal Agents

Oral anticoagulation, as you know, is usually considered a contraindication for systemic thrombolysis. Idarucizumab, a monoclonal antibody, was developed to reverse the biological activity of dabigatran and then allow systemic thrombolysis.

A recent publication in Neurology analyzed 13 cohort studies with 553 stroke patients on dabigatran who received idarucizumab prior to systemic thrombolysis, and the rate of intracranial hemorrhage was 4%. This means it’s obviously possible to perform thrombolysis when the activity of dabigatran is neutralized by idarucizumab.

Unfortunately, until today, we have no data on whether this can also be done with andexanet alfa in people who are treated with a factor Xa inhibitor like, for example, apixaban, rivaroxaban, or edoxaban. 

 

Anticoagulation in ESUS 

My next topic is ESUS, or embolic stroke of undetermined source. We have four large randomized trials and three smaller trials that compared antiplatelet therapy with DOACs in patients with ESUS. A group in Neurology published a meta-analysis of seven randomized controlled studies with, altogether, 14,800 patients with ESUS. 

The comparison between antiplatelet therapy and anticoagulants showed no difference for recurrent ischemic stroke, and also not for major subgroups. This means that people with ESUS should receive antiplatelet therapy, most probably aspirin. 

 

Anticoagulation Post–Ischemic Stroke With AF 

My final topic is the optimal time to start anticoagulation in people with atrial fibrillation who suffer an ischemic stroke. The OPTIMAS study, published in The Lancet, randomized 3650 patients who were anticoagulated with DOACs early (which means less than 4 days) or delayed (between 7 and 14 days). There was no difference in the primary endpoint, which was recurrent ischemic stroke, intracranial hemorrhage, or systemic embolism at 90 days.

The conclusion is that, in most cases, we can probably initiate anticoagulation in people with ischemic stroke and atrial fibrillation within the first 4 days. 

Dear colleagues, this is an exciting time for the stroke field. I presented six new studies that have impact, I think, on the management of patients with ischemic stroke.

Dr. Diener is a professor in the Department of Neurology, Stroke Center-Headache Center, University Duisburg-Essen in Germany. He reported conflicts of interest with Abbott, AbbVie, Boehringer Ingelheim, Lundbeck, Novartis, Orion Pharma, Teva, WebMD, and The German Research Council. He also serves on the editorial boards of Cephalalgia, Lancet Neurology, and Drugs.

A version of this article first appeared on Medscape.com.

This video transcript has been edited for clarity. 

Dear colleagues, I am Christoph Diener, from the Faculty of Medicine at the University Duisburg-Essen in Germany. In this video, I would like to cover six publications on stroke, which were published this fall. 

The Best Thrombolytic?

Let me start with systemic thrombolysis. We now have two thrombolytic agents available. One is the well-known alteplase, and newly approved for the treatment of stroke is tenecteplase. The ATTEST-2 study in the United Kingdom, published in The Lancet Neurology, compared tenecteplase 0.25 mg/kg body weight as a bolus with alteplase 0.9 mg/kg body weight as an infusion over 60 minutes in the 4.5-hour time window in 1777 patients with ischemic stroke.

There was no significant difference between the two thrombolytics for the primary endpoint of modified Rankin Scale score after 90 days. There was also no difference with respect to mortality, intracranial bleeding, or extracranial bleeding. 

We finally have 11 randomized controlled trials that compared tenecteplase and alteplase in acute ischemic stroke. A meta-analysis of these randomized trials was published in Neurology. The analysis included 3700 patients treated with tenecteplase and 3700 patients treated with alteplase. For the primary endpoint, excellent functional outcome defined as modified Rankin Scale score 0-1 after 90 days, there was a significant benefit for tenecteplase (relative risk, 1.05), but the absolute difference was very small, at 3%. There was no difference in mortality or bleeding complications. 

In conclusion, I think both substances are great. They are effective. Tenecteplase is most probably the drug which should be used in people who have to transfer from a primary stroke center to a dedicated stroke center that provides thrombectomy. Otherwise, I think it’s a choice of the physician as to which thrombolytic agent to use. 

 

Mobile Stroke Units

A highly debated topic is mobile stroke units. These stroke units have a CT scanner and laboratory on board, and this makes it possible to perform thrombolysis on the way to the hospital. A retrospective, observational study collected data between 2018 and 2023, and included 19,400 patients with acute stroke, of whom 1237, or 6.4%, were treated in a mobile stroke unit. This study was published in JAMA Neurology. 

The modified Rankin Scale score at the time of discharge was better in patients treated with a mobile stroke unit, but the absolute benefit was only 0.03 points on the modified Rankin Scale. The question is whether this is cost-effective, and can we really do this at times when there is a traumatic shortage of physicians and nursing staff in the hospital? 

 

DOAC Reversal Agents

Oral anticoagulation, as you know, is usually considered a contraindication for systemic thrombolysis. Idarucizumab, a monoclonal antibody, was developed to reverse the biological activity of dabigatran and then allow systemic thrombolysis.

A recent publication in Neurology analyzed 13 cohort studies with 553 stroke patients on dabigatran who received idarucizumab prior to systemic thrombolysis, and the rate of intracranial hemorrhage was 4%. This means it’s obviously possible to perform thrombolysis when the activity of dabigatran is neutralized by idarucizumab.

Unfortunately, until today, we have no data on whether this can also be done with andexanet alfa in people who are treated with a factor Xa inhibitor like, for example, apixaban, rivaroxaban, or edoxaban. 

 

Anticoagulation in ESUS 

My next topic is ESUS, or embolic stroke of undetermined source. We have four large randomized trials and three smaller trials that compared antiplatelet therapy with DOACs in patients with ESUS. A group in Neurology published a meta-analysis of seven randomized controlled studies with, altogether, 14,800 patients with ESUS. 

The comparison between antiplatelet therapy and anticoagulants showed no difference for recurrent ischemic stroke, and also not for major subgroups. This means that people with ESUS should receive antiplatelet therapy, most probably aspirin.