SEATTLE – Women with knee osteoarthritis who took bisphosphonates were 27% less likely to undergo joint replacement surgery than were women who didn’t take bisphosphonates in a U.K. cohort study of 3,928 propensity-matched users and nonusers, according to a report at the World Congress on Osteoarthritis.

“In older women with incident knee osteoarthritis, incident bisphosphonate use may be associated with lower risk of knee replacement than in nonusers,” said Dr. Tuhina Neogi of Boston University.

Dr. Neogi and her colleagues used data from The Health Improvement Network (THIN), a U.K. database of primary care patients, to identify women aged 50-89 years who received a diagnosis of knee osteoarthritis between 2003 and 2012. Patients were excluded if they were poor surgical candidates or were taking disease-modifying antirheumatic drugs, biologic agents, or other bone-active agents.

The researchers compared 1,964 women who subsequently started bisphosphonate therapy with 1,964 propensity score–matched women who did not. In 85% of the former, the bisphosphonate was alendronate, marketed as Fosamax in the United States.

During a mean follow-up of 3 years, the incidence rate of knee replacement was 21 cases per 1,000 patient-years among bisphosphonate users and 29 cases per 1,000 patient-years among nonusers, according to results reported at the meeting, which was sponsored by Osteoarthritis Research Society International.

In adjusted analyses, users had a significantly lower relative risk of undergoing this surgery (hazard ratio, 0.73), reported Dr. Neogi, who disclosed that she had no relevant conflicts of interest.

Sensitivity analyses showed an even stronger association in a separate cohort of patients matched by age, body mass index, and the duration of osteoarthritis (hazard ratio, 0.33) and a nonsignificant benefit when bisphosphonate users were instead compared against an active user group of women who initiated any other bone-modulating therapy.

“Now of course this is observational data from electronic medical records, so we cannot rule out the potential for residual bias,” she acknowledged. “Our sensitivity analyses were fairly consistent and provide some reassurance, but nonetheless, the magnitude of effect is still likely to be biased due to residual confounding.”

In an interview, Dr. Rik Lories, one of the session’s comoderators and a professor at the University of Leuven, Belgium, said that the study “is still far from practice changing. But the great thing about this research is that we are starting to split up what you would call the osteoarthritic diseases, taking osteoarthritis as the outcome [and showing] the underlying mechanisms of the different phenotypes being different.”

Dr. Neogi noted that subchrondral bone changes are prominent in knee osteoarthritis and that mechanical factors play a central role in the disease. At the same time, findings of trials of antiresorptive agents, including bisphosphonates, in knee osteoarthritis have been conflicting.

“There are a number of limitations to this study, including the fact that The Health Improvement Network does not have bone mineral density results. We tried to address this by accounting for a prior diagnosis of osteoporosis, fracture history, potential risk for fractures, body mass index, age, number of bone mineral density tests ordered, et cetera,” Dr. Neogi said. “Another limitation is that of the secular trends in use of bone-modulating agents over this time frame, and that precluded robust evaluation of the active user comparator analysis.

“Bone mineral density is still a major potential confounder here that can’t be adequately addressed,” she acknowledged.

SEATTLE – Women with knee osteoarthritis who took bisphosphonates were 27% less likely to undergo joint replacement surgery than were women who didn’t take bisphosphonates in a U.K. cohort study of 3,928 propensity-matched users and nonusers, according to a report at the World Congress on Osteoarthritis.

“In older women with incident knee osteoarthritis, incident bisphosphonate use may be associated with lower risk of knee replacement than in nonusers,” said Dr. Tuhina Neogi of Boston University.

Dr. Neogi and her colleagues used data from The Health Improvement Network (THIN), a U.K. database of primary care patients, to identify women aged 50-89 years who received a diagnosis of knee osteoarthritis between 2003 and 2012. Patients were excluded if they were poor surgical candidates or were taking disease-modifying antirheumatic drugs, biologic agents, or other bone-active agents.

The researchers compared 1,964 women who subsequently started bisphosphonate therapy with 1,964 propensity score–matched women who did not. In 85% of the former, the bisphosphonate was alendronate, marketed as Fosamax in the United States.

During a mean follow-up of 3 years, the incidence rate of knee replacement was 21 cases per 1,000 patient-years among bisphosphonate users and 29 cases per 1,000 patient-years among nonusers, according to results reported at the meeting, which was sponsored by Osteoarthritis Research Society International.

In adjusted analyses, users had a significantly lower relative risk of undergoing this surgery (hazard ratio, 0.73), reported Dr. Neogi, who disclosed that she had no relevant conflicts of interest.

Sensitivity analyses showed an even stronger association in a separate cohort of patients matched by age, body mass index, and the duration of osteoarthritis (hazard ratio, 0.33) and a nonsignificant benefit when bisphosphonate users were instead compared against an active user group of women who initiated any other bone-modulating therapy.

“Now of course this is observational data from electronic medical records, so we cannot rule out the potential for residual bias,” she acknowledged. “Our sensitivity analyses were fairly consistent and provide some reassurance, but nonetheless, the magnitude of effect is still likely to be biased due to residual confounding.”

In an interview, Dr. Rik Lories, one of the session’s comoderators and a professor at the University of Leuven, Belgium, said that the study “is still far from practice changing. But the great thing about this research is that we are starting to split up what you would call the osteoarthritic diseases, taking osteoarthritis as the outcome [and showing] the underlying mechanisms of the different phenotypes being different.”

Dr. Neogi noted that subchrondral bone changes are prominent in knee osteoarthritis and that mechanical factors play a central role in the disease. At the same time, findings of trials of antiresorptive agents, including bisphosphonates, in knee osteoarthritis have been conflicting.

“There are a number of limitations to this study, including the fact that The Health Improvement Network does not have bone mineral density results. We tried to address this by accounting for a prior diagnosis of osteoporosis, fracture history, potential risk for fractures, body mass index, age, number of bone mineral density tests ordered, et cetera,” Dr. Neogi said. “Another limitation is that of the secular trends in use of bone-modulating agents over this time frame, and that precluded robust evaluation of the active user comparator analysis.

“Bone mineral density is still a major potential confounder here that can’t be adequately addressed,” she acknowledged.

SEATTLE – Women with knee osteoarthritis who took bisphosphonates were 27% less likely to undergo joint replacement surgery than were women who didn’t take bisphosphonates in a U.K. cohort study of 3,928 propensity-matched users and nonusers, according to a report at the World Congress on Osteoarthritis.

“In older women with incident knee osteoarthritis, incident bisphosphonate use may be associated with lower risk of knee replacement than in nonusers,” said Dr. Tuhina Neogi of Boston University.

Dr. Neogi and her colleagues used data from The Health Improvement Network (THIN), a U.K. database of primary care patients, to identify women aged 50-89 years who received a diagnosis of knee osteoarthritis between 2003 and 2012. Patients were excluded if they were poor surgical candidates or were taking disease-modifying antirheumatic drugs, biologic agents, or other bone-active agents.

The researchers compared 1,964 women who subsequently started bisphosphonate therapy with 1,964 propensity score–matched women who did not. In 85% of the former, the bisphosphonate was alendronate, marketed as Fosamax in the United States.

During a mean follow-up of 3 years, the incidence rate of knee replacement was 21 cases per 1,000 patient-years among bisphosphonate users and 29 cases per 1,000 patient-years among nonusers, according to results reported at the meeting, which was sponsored by Osteoarthritis Research Society International.

In adjusted analyses, users had a significantly lower relative risk of undergoing this surgery (hazard ratio, 0.73), reported Dr. Neogi, who disclosed that she had no relevant conflicts of interest.

Sensitivity analyses showed an even stronger association in a separate cohort of patients matched by age, body mass index, and the duration of osteoarthritis (hazard ratio, 0.33) and a nonsignificant benefit when bisphosphonate users were instead compared against an active user group of women who initiated any other bone-modulating therapy.

“Now of course this is observational data from electronic medical records, so we cannot rule out the potential for residual bias,” she acknowledged. “Our sensitivity analyses were fairly consistent and provide some reassurance, but nonetheless, the magnitude of effect is still likely to be biased due to residual confounding.”

In an interview, Dr. Rik Lories, one of the session’s comoderators and a professor at the University of Leuven, Belgium, said that the study “is still far from practice changing. But the great thing about this research is that we are starting to split up what you would call the osteoarthritic diseases, taking osteoarthritis as the outcome [and showing] the underlying mechanisms of the different phenotypes being different.”

Dr. Neogi noted that subchrondral bone changes are prominent in knee osteoarthritis and that mechanical factors play a central role in the disease. At the same time, findings of trials of antiresorptive agents, including bisphosphonates, in knee osteoarthritis have been conflicting.

“There are a number of limitations to this study, including the fact that The Health Improvement Network does not have bone mineral density results. We tried to address this by accounting for a prior diagnosis of osteoporosis, fracture history, potential risk for fractures, body mass index, age, number of bone mineral density tests ordered, et cetera,” Dr. Neogi said. “Another limitation is that of the secular trends in use of bone-modulating agents over this time frame, and that precluded robust evaluation of the active user comparator analysis.

“Bone mineral density is still a major potential confounder here that can’t be adequately addressed,” she acknowledged.

I heard somewhere that doctors are judged by patients as soon as we walk in the door. We are held to high standards of behavior and knowledge – and rightly so. After all, we are given this incredible responsibility of keeping people healthy. But our ability to do our job is limited by regulations that make up the business of medicine: time constraints, insurance hurdles, meaningful use requirements, and coding issues. Few of us would count those as part of the good doctor’s toolbox, but these are the hidden forces that shape how we conduct our jobs.

With that in mind, here is a wish list of sorts for how patients might do their part in making the interaction pleasant and productive:

• I wish patients arrived on time. I often hear the counter argument that we doctors do not run on time, but that’s not the same. When we run late it is often for reasons that are beyond our control. On the other hand, patients coming on time indicates a respect for the doctor’s time and a commitment to their own health and well-being.

• It would be helpful if patients brought a medication list and, along with that, a list of their medical conditions. A list of their doctors is helpful as well. Not infrequently, when I ask a patient how they came to need a rheumatologist, the answer is “It should be in my records.” This is problematic, in part because what counts for records these days is actually an auto-filled document containing pages upon pages of repetitive information that is not germane to the problem at hand.

• If your practice is anything like mine, patients often bring up another problem or two at the end of the visit. Twenty minutes into the visit, as they are stepping off the exam table, they throw in “one last question” or an “oh, by the way.” This can run the gamut from chest pain or weight loss to disability paperwork or medical marijuana. Our patients may not be aware that we can only afford to spend 15-20 minutes with them.

It is also difficult for patients to identify which problems are related to their rheumatologic condition and which are not, leading them to expect us to weigh in on issues that are perhaps better discussed with their primary care physicians. And because we are physicians and want to do what we can for them, we also feel obligated to address all of their concerns. It would be helpful if patients came to the visit prepared with the issues they want to discuss in order of priority. Otherwise, we will never be able to satisfactorily address all of their concerns and still run an efficient practice.

• I have seen many patients who were unhappy with their previous rheumatologist. I have also had unhappy patients fire me and seek care elsewhere. I completely support this system as it leads to a self-selection of sorts. This works out for everyone involved, particularly for the patients. Some patients, though, feel the need to denigrate their other doctors to me in a conspiratorial manner, as if waiting for me to confirm their opinions. This makes me very uncomfortable. I discourage this behavior by reminding patients that symptoms evolve and that the previous doctor, in all likelihood, already did some of the preliminary work that allows the next doctor to seem brilliant in comparison.

• My assistant is fantastic. She can almost read my mind. My mentor at the University of Massachusetts, Dr. Kathy Upchurch, used to say that she saw her assistant more than she saw her husband. This is probably true for most of us who work full time. Our staffs have the unenviable job of keeping both patients and doctors happy, and they are largely responsible for the seamless operations that we run. It is very important to me that my patients treat our staff with respect.

In the end it comes down to this: In this age of managed care, the business of medicine has gotten in the way of the art of medicine. But, as with any human interaction, courtesy and respect make the whole enterprise much more rewarding.

Dr. Chan practices rheumatology in Pawtucket, R.I.

I heard somewhere that doctors are judged by patients as soon as we walk in the door. We are held to high standards of behavior and knowledge – and rightly so. After all, we are given this incredible responsibility of keeping people healthy. But our ability to do our job is limited by regulations that make up the business of medicine: time constraints, insurance hurdles, meaningful use requirements, and coding issues. Few of us would count those as part of the good doctor’s toolbox, but these are the hidden forces that shape how we conduct our jobs.

With that in mind, here is a wish list of sorts for how patients might do their part in making the interaction pleasant and productive:

• I wish patients arrived on time. I often hear the counter argument that we doctors do not run on time, but that’s not the same. When we run late it is often for reasons that are beyond our control. On the other hand, patients coming on time indicates a respect for the doctor’s time and a commitment to their own health and well-being.

• It would be helpful if patients brought a medication list and, along with that, a list of their medical conditions. A list of their doctors is helpful as well. Not infrequently, when I ask a patient how they came to need a rheumatologist, the answer is “It should be in my records.” This is problematic, in part because what counts for records these days is actually an auto-filled document containing pages upon pages of repetitive information that is not germane to the problem at hand.

• If your practice is anything like mine, patients often bring up another problem or two at the end of the visit. Twenty minutes into the visit, as they are stepping off the exam table, they throw in “one last question” or an “oh, by the way.” This can run the gamut from chest pain or weight loss to disability paperwork or medical marijuana. Our patients may not be aware that we can only afford to spend 15-20 minutes with them.

It is also difficult for patients to identify which problems are related to their rheumatologic condition and which are not, leading them to expect us to weigh in on issues that are perhaps better discussed with their primary care physicians. And because we are physicians and want to do what we can for them, we also feel obligated to address all of their concerns. It would be helpful if patients came to the visit prepared with the issues they want to discuss in order of priority. Otherwise, we will never be able to satisfactorily address all of their concerns and still run an efficient practice.

• I have seen many patients who were unhappy with their previous rheumatologist. I have also had unhappy patients fire me and seek care elsewhere. I completely support this system as it leads to a self-selection of sorts. This works out for everyone involved, particularly for the patients. Some patients, though, feel the need to denigrate their other doctors to me in a conspiratorial manner, as if waiting for me to confirm their opinions. This makes me very uncomfortable. I discourage this behavior by reminding patients that symptoms evolve and that the previous doctor, in all likelihood, already did some of the preliminary work that allows the next doctor to seem brilliant in comparison.

• My assistant is fantastic. She can almost read my mind. My mentor at the University of Massachusetts, Dr. Kathy Upchurch, used to say that she saw her assistant more than she saw her husband. This is probably true for most of us who work full time. Our staffs have the unenviable job of keeping both patients and doctors happy, and they are largely responsible for the seamless operations that we run. It is very important to me that my patients treat our staff with respect.

In the end it comes down to this: In this age of managed care, the business of medicine has gotten in the way of the art of medicine. But, as with any human interaction, courtesy and respect make the whole enterprise much more rewarding.

Dr. Chan practices rheumatology in Pawtucket, R.I.

I heard somewhere that doctors are judged by patients as soon as we walk in the door. We are held to high standards of behavior and knowledge – and rightly so. After all, we are given this incredible responsibility of keeping people healthy. But our ability to do our job is limited by regulations that make up the business of medicine: time constraints, insurance hurdles, meaningful use requirements, and coding issues. Few of us would count those as part of the good doctor’s toolbox, but these are the hidden forces that shape how we conduct our jobs.

With that in mind, here is a wish list of sorts for how patients might do their part in making the interaction pleasant and productive:

• I wish patients arrived on time. I often hear the counter argument that we doctors do not run on time, but that’s not the same. When we run late it is often for reasons that are beyond our control. On the other hand, patients coming on time indicates a respect for the doctor’s time and a commitment to their own health and well-being.

• It would be helpful if patients brought a medication list and, along with that, a list of their medical conditions. A list of their doctors is helpful as well. Not infrequently, when I ask a patient how they came to need a rheumatologist, the answer is “It should be in my records.” This is problematic, in part because what counts for records these days is actually an auto-filled document containing pages upon pages of repetitive information that is not germane to the problem at hand.

• If your practice is anything like mine, patients often bring up another problem or two at the end of the visit. Twenty minutes into the visit, as they are stepping off the exam table, they throw in “one last question” or an “oh, by the way.” This can run the gamut from chest pain or weight loss to disability paperwork or medical marijuana. Our patients may not be aware that we can only afford to spend 15-20 minutes with them.

It is also difficult for patients to identify which problems are related to their rheumatologic condition and which are not, leading them to expect us to weigh in on issues that are perhaps better discussed with their primary care physicians. And because we are physicians and want to do what we can for them, we also feel obligated to address all of their concerns. It would be helpful if patients came to the visit prepared with the issues they want to discuss in order of priority. Otherwise, we will never be able to satisfactorily address all of their concerns and still run an efficient practice.

• I have seen many patients who were unhappy with their previous rheumatologist. I have also had unhappy patients fire me and seek care elsewhere. I completely support this system as it leads to a self-selection of sorts. This works out for everyone involved, particularly for the patients. Some patients, though, feel the need to denigrate their other doctors to me in a conspiratorial manner, as if waiting for me to confirm their opinions. This makes me very uncomfortable. I discourage this behavior by reminding patients that symptoms evolve and that the previous doctor, in all likelihood, already did some of the preliminary work that allows the next doctor to seem brilliant in comparison.

• My assistant is fantastic. She can almost read my mind. My mentor at the University of Massachusetts, Dr. Kathy Upchurch, used to say that she saw her assistant more than she saw her husband. This is probably true for most of us who work full time. Our staffs have the unenviable job of keeping both patients and doctors happy, and they are largely responsible for the seamless operations that we run. It is very important to me that my patients treat our staff with respect.

In the end it comes down to this: In this age of managed care, the business of medicine has gotten in the way of the art of medicine. But, as with any human interaction, courtesy and respect make the whole enterprise much more rewarding.

Dr. Chan practices rheumatology in Pawtucket, R.I.

We hear a lot about the pros and cons of cash-pay medicine. I’ve written about it in the past. So far, I haven’t made the leap of faith it would require in my own practice.

But recently I developed a gradually worsening toothache. For a while I ignored it, hoping it would go away. Like most doctors, my first thought was “I don’t have time for this.” But, as it progressed, I knew I didn’t have a choice.

I didn’t have a dentist, either, and have never had dental insurance. Now what?

So I called a family friend who’s a dentist. His actual charge for the visit was around $200, but he kindly charged me only $50. I sent him a $100 gift card to thank him for his help, and I’m well aware most folks don’t have the benefit of knowing a dentist on nonprofessional terms.

Unfortunately, he found he couldn’t help me. I had an upper molar that was busily reabsorbing itself, and needed to come out.

So I went to an oral surgeon. The first visit (“limited exam and counseling”) was $95. Two days later, I went back to get the tooth yanked for good. That was $275. I paid both in full by credit card.

Do I think any of these charges were unreasonable? Absolutely not. The transaction is done; the tooth is out. His office doesn’t have to bill my insurance, hope to collect part of it, and then bill me for the rest. I don’t have to worry about being billed for something my insurance didn’t pay, or spend an hour (or more) on hold to ask questions of an insurance representative as to why my claim was denied. And I get to put the $520 down on my 2015 taxes as a medical deduction.

It’s pretty simple, isn’t it? The guy pulls my tooth, and I pay a fair amount for his service. This is the same business relationship I have with a grocery store, car mechanic, or office landlord.

So why doesn’t this catch on for most of medicine? It would be nice if it were that simple.

I’m fortunate to be able to afford the total of $520 I’ve spent on the tooth. Many people don’t have that luxury, and have to rely on insurance coverage; $520 is also a pittance, compared with what other things may run. Multiple MRIs? An electromyogram/nerve conduction velocity test? Multiple sclerosis drugs? Chemotherapy? Neurosurgery? A hospital stay? In that group, you’re talking about things that can range from $1,000 to $100,000 (or more) – a far cry from what I spent on my tooth, but still medically necessary for many.

Some will argue these medical costs should all be cash pay, too. If patients can’t afford multiple sclerosis drugs out of pocket ($50,000/year and up for some), then the market will force the drug companies to lower their prices to where people will buy them. That may be, but the price an average person can likely afford isn’t going to support what the company spent to bring the drug to market or pay for trials of the next generation of treatments. So in the long run, it hurts people more than it helps.

Now if I apply this to my practice, I’m sure there are many who could afford my cash rates if I dropped their plan, but since there are other neurologists taking insurance in the area, people will generally go to whoever is best for their wallet. And a copay is going to trump my cash price for most – not to mention the costs of tests that may be needed.

For an office visit, cash pay would likely work for most. It’s simple, quick, and straightforward. But it’s the high costs of modern medicine – advanced tests, hospital stays, and upper-line pharmaceuticals (some patients don’t have other options) – that make it an unworkable proposition for many.

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

We hear a lot about the pros and cons of cash-pay medicine. I’ve written about it in the past. So far, I haven’t made the leap of faith it would require in my own practice.

But recently I developed a gradually worsening toothache. For a while I ignored it, hoping it would go away. Like most doctors, my first thought was “I don’t have time for this.” But, as it progressed, I knew I didn’t have a choice.

I didn’t have a dentist, either, and have never had dental insurance. Now what?

So I called a family friend who’s a dentist. His actual charge for the visit was around $200, but he kindly charged me only $50. I sent him a $100 gift card to thank him for his help, and I’m well aware most folks don’t have the benefit of knowing a dentist on nonprofessional terms.

Unfortunately, he found he couldn’t help me. I had an upper molar that was busily reabsorbing itself, and needed to come out.

So I went to an oral surgeon. The first visit (“limited exam and counseling”) was $95. Two days later, I went back to get the tooth yanked for good. That was $275. I paid both in full by credit card.

Do I think any of these charges were unreasonable? Absolutely not. The transaction is done; the tooth is out. His office doesn’t have to bill my insurance, hope to collect part of it, and then bill me for the rest. I don’t have to worry about being billed for something my insurance didn’t pay, or spend an hour (or more) on hold to ask questions of an insurance representative as to why my claim was denied. And I get to put the $520 down on my 2015 taxes as a medical deduction.

It’s pretty simple, isn’t it? The guy pulls my tooth, and I pay a fair amount for his service. This is the same business relationship I have with a grocery store, car mechanic, or office landlord.

So why doesn’t this catch on for most of medicine? It would be nice if it were that simple.

I’m fortunate to be able to afford the total of $520 I’ve spent on the tooth. Many people don’t have that luxury, and have to rely on insurance coverage; $520 is also a pittance, compared with what other things may run. Multiple MRIs? An electromyogram/nerve conduction velocity test? Multiple sclerosis drugs? Chemotherapy? Neurosurgery? A hospital stay? In that group, you’re talking about things that can range from $1,000 to $100,000 (or more) – a far cry from what I spent on my tooth, but still medically necessary for many.

Some will argue these medical costs should all be cash pay, too. If patients can’t afford multiple sclerosis drugs out of pocket ($50,000/year and up for some), then the market will force the drug companies to lower their prices to where people will buy them. That may be, but the price an average person can likely afford isn’t going to support what the company spent to bring the drug to market or pay for trials of the next generation of treatments. So in the long run, it hurts people more than it helps.

Now if I apply this to my practice, I’m sure there are many who could afford my cash rates if I dropped their plan, but since there are other neurologists taking insurance in the area, people will generally go to whoever is best for their wallet. And a copay is going to trump my cash price for most – not to mention the costs of tests that may be needed.

For an office visit, cash pay would likely work for most. It’s simple, quick, and straightforward. But it’s the high costs of modern medicine – advanced tests, hospital stays, and upper-line pharmaceuticals (some patients don’t have other options) – that make it an unworkable proposition for many.

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

We hear a lot about the pros and cons of cash-pay medicine. I’ve written about it in the past. So far, I haven’t made the leap of faith it would require in my own practice.

But recently I developed a gradually worsening toothache. For a while I ignored it, hoping it would go away. Like most doctors, my first thought was “I don’t have time for this.” But, as it progressed, I knew I didn’t have a choice.

I didn’t have a dentist, either, and have never had dental insurance. Now what?

So I called a family friend who’s a dentist. His actual charge for the visit was around $200, but he kindly charged me only $50. I sent him a $100 gift card to thank him for his help, and I’m well aware most folks don’t have the benefit of knowing a dentist on nonprofessional terms.

Unfortunately, he found he couldn’t help me. I had an upper molar that was busily reabsorbing itself, and needed to come out.

So I went to an oral surgeon. The first visit (“limited exam and counseling”) was $95. Two days later, I went back to get the tooth yanked for good. That was $275. I paid both in full by credit card.

Do I think any of these charges were unreasonable? Absolutely not. The transaction is done; the tooth is out. His office doesn’t have to bill my insurance, hope to collect part of it, and then bill me for the rest. I don’t have to worry about being billed for something my insurance didn’t pay, or spend an hour (or more) on hold to ask questions of an insurance representative as to why my claim was denied. And I get to put the $520 down on my 2015 taxes as a medical deduction.

It’s pretty simple, isn’t it? The guy pulls my tooth, and I pay a fair amount for his service. This is the same business relationship I have with a grocery store, car mechanic, or office landlord.

So why doesn’t this catch on for most of medicine? It would be nice if it were that simple.

I’m fortunate to be able to afford the total of $520 I’ve spent on the tooth. Many people don’t have that luxury, and have to rely on insurance coverage; $520 is also a pittance, compared with what other things may run. Multiple MRIs? An electromyogram/nerve conduction velocity test? Multiple sclerosis drugs? Chemotherapy? Neurosurgery? A hospital stay? In that group, you’re talking about things that can range from $1,000 to $100,000 (or more) – a far cry from what I spent on my tooth, but still medically necessary for many.

Some will argue these medical costs should all be cash pay, too. If patients can’t afford multiple sclerosis drugs out of pocket ($50,000/year and up for some), then the market will force the drug companies to lower their prices to where people will buy them. That may be, but the price an average person can likely afford isn’t going to support what the company spent to bring the drug to market or pay for trials of the next generation of treatments. So in the long run, it hurts people more than it helps.

Now if I apply this to my practice, I’m sure there are many who could afford my cash rates if I dropped their plan, but since there are other neurologists taking insurance in the area, people will generally go to whoever is best for their wallet. And a copay is going to trump my cash price for most – not to mention the costs of tests that may be needed.

For an office visit, cash pay would likely work for most. It’s simple, quick, and straightforward. But it’s the high costs of modern medicine – advanced tests, hospital stays, and upper-line pharmaceuticals (some patients don’t have other options) – that make it an unworkable proposition for many.

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

Necrobiosis lipoidica diabeticorum (NLD) is a rare granulomatous skin manifestation that is strongly associated with diabetes mellitus. Necrobiosis lipoidica diabeticorum is more common among females and occurs primarily in the pretibial area.¹ Necrobiosis lipoidica diabeticorum may clinically manifest as single or multiple lesions that begin as small red papules and progress into patches or plaques. Lesions ultimately develop into areas of yellowish brown atrophic tissue with central depression and telangiectasia. The etiology of NLD is not completely understood, but it is thought to be a presentation of diabetic microangiopathy.¹ Histologically, NLD demonstrates broad horizontal zones of necrobiosis with a surrounding inflammatory infiltrate that is principally composed of histiocytes but also may contain multinucleated giant cells, lymphocytes, and plasma cells (Figures 1 and 2). Occasionally, sarcoidal granulomas are seen in NLD. There also may be thickening of vessel walls and edema of the endothelial cells.¹

Figure 1. Broad horizontal arrangement of necrobiotic collagen with a surrounding inflammatory infiltrate of histiocytes and lymphocytes seen in necrobiosis lipoidica diabeticorum (H&E, original magnification ×20).

Figure 2. High-power view demonstrating lymphocytes and plasma cells at the inferior border of the necrobiotic collagen seen in necrobiosis lipoidica diabeticorum (H&E, original magnification ×200).

Cutaneous Rosai-Dorfman disease (RDD) is characterized by the presence of diffuse, large, pale histiocytes (commonly known as Rosai-Dorfman cells) with an admixed infiltrate of lymphocytes and plasma cells (Figure 3).² Additionally, Rosai-Dorfman cells display emperipolesis. They stain positively for S-100 protein and CD68 and negatively for CD1a.² Clinically, cutaneous RDD has a myriad of manifestations but most commonly presents as cutaneous nodules that can be tender or pruritic. It also may be associated with systemic symptoms. Patients with cutaneous RDD often have an elevated erythrocyte sedimentation rate and concomitant anemia.²

Figure 3. Sea of pale histiocytes with a patchy infiltrate of lymphocytes and plasma cells seen in cutaneous Rosai-Dorfman disease. Lymphocytes are seen within the cytoplasm of the histiocytes (emperipolesis)(H&E, original magnification ×200).

Granuloma annulare demonstrates necrobiosis and palisaded granulomatous dermatitis similar to NLD; however, the necrobiotic foci in granuloma annulare usually are more focal than in NLD and typically are surrounded by well-formed palisaded granulomas. There also is an increase in dermal mucin (Figure 4), which can be highlighted on colloidal iron or Alcian blue staining.¹ Granuloma annulare also typically has scattered eosinophils rather than plasma cells as seen in NLD. Granuloma annulare also may present in an interstitial pattern, with scattered histiocytes, mucin, and eosinophils between collagen bundles. Granuloma annulare clinically presents as variably colored papules arranged in an annular pattern on the distal extremities but also can present as widespread papules or plaques.

Figure 4. Necrobiotic collagen with abundant mucin surrounded by palisaded histiocytes, often with eosinophils characteristic of granuloma annulare (H&E, original magnification ×100).

Juvenile xanthogranuloma (JXG) is a benign condition typically seen in children that is characterized by the presence of 1 or more pink or yellow nodules, most commonly presenting on the head and neck. Histologically, JXG demonstrates a dermal collection of histiocytes, lymphocytes, eosinophils, and characteristic Touton giant cells, which contain nuclei that are arranged in a wreathlike pattern and exhibit peripheral xanthomatization (Figure 5).³ The histiocytes in JXG typically stain positive for CD68 and negative for S-100 protein, though occasional S-100–positive cases are reported.³

Figure 5. Touton giant cells and occasional eosinophils in a sea of histiocytes and lymphocytes characterize juvenile xanthogranuloma (H&E, original magnification ×200).

Necrobiotic xanthogranuloma presents as yellowish to brown plaques and nodules most commonly in the periorbital area. Necrobiotic xanthogranuloma is strongly associated with monoclonal gammopathy, typically IgGk monoclonal gammopathy. Necrobiotic xanthogranuloma is histologically similar to NLD but is distinguished by a nodular pattern of inflammation and the frequent presence of cholesterol clefts (Figure 6).⁴

Figure 6. Necrobiotic xanthogranuloma is distinguished by the nodularity
of the infiltrate, with necrobiotic collagen, palisaded histiocytes and giant
cells, and the presence of cholesterol clefts (H&E, original
magnification ×40).

Necrobiosis lipoidica diabeticorum (NLD) is a rare granulomatous skin manifestation that is strongly associated with diabetes mellitus. Necrobiosis lipoidica diabeticorum is more common among females and occurs primarily in the pretibial area.¹ Necrobiosis lipoidica diabeticorum may clinically manifest as single or multiple lesions that begin as small red papules and progress into patches or plaques. Lesions ultimately develop into areas of yellowish brown atrophic tissue with central depression and telangiectasia. The etiology of NLD is not completely understood, but it is thought to be a presentation of diabetic microangiopathy.¹ Histologically, NLD demonstrates broad horizontal zones of necrobiosis with a surrounding inflammatory infiltrate that is principally composed of histiocytes but also may contain multinucleated giant cells, lymphocytes, and plasma cells (Figures 1 and 2). Occasionally, sarcoidal granulomas are seen in NLD. There also may be thickening of vessel walls and edema of the endothelial cells.¹

Figure 1. Broad horizontal arrangement of necrobiotic collagen with a surrounding inflammatory infiltrate of histiocytes and lymphocytes seen in necrobiosis lipoidica diabeticorum (H&E, original magnification ×20).

Figure 2. High-power view demonstrating lymphocytes and plasma cells at the inferior border of the necrobiotic collagen seen in necrobiosis lipoidica diabeticorum (H&E, original magnification ×200).

Cutaneous Rosai-Dorfman disease (RDD) is characterized by the presence of diffuse, large, pale histiocytes (commonly known as Rosai-Dorfman cells) with an admixed infiltrate of lymphocytes and plasma cells (Figure 3).² Additionally, Rosai-Dorfman cells display emperipolesis. They stain positively for S-100 protein and CD68 and negatively for CD1a.² Clinically, cutaneous RDD has a myriad of manifestations but most commonly presents as cutaneous nodules that can be tender or pruritic. It also may be associated with systemic symptoms. Patients with cutaneous RDD often have an elevated erythrocyte sedimentation rate and concomitant anemia.²

Figure 3. Sea of pale histiocytes with a patchy infiltrate of lymphocytes and plasma cells seen in cutaneous Rosai-Dorfman disease. Lymphocytes are seen within the cytoplasm of the histiocytes (emperipolesis)(H&E, original magnification ×200).

Granuloma annulare demonstrates necrobiosis and palisaded granulomatous dermatitis similar to NLD; however, the necrobiotic foci in granuloma annulare usually are more focal than in NLD and typically are surrounded by well-formed palisaded granulomas. There also is an increase in dermal mucin (Figure 4), which can be highlighted on colloidal iron or Alcian blue staining.¹ Granuloma annulare also typically has scattered eosinophils rather than plasma cells as seen in NLD. Granuloma annulare also may present in an interstitial pattern, with scattered histiocytes, mucin, and eosinophils between collagen bundles. Granuloma annulare clinically presents as variably colored papules arranged in an annular pattern on the distal extremities but also can present as widespread papules or plaques.

Figure 4. Necrobiotic collagen with abundant mucin surrounded by palisaded histiocytes, often with eosinophils characteristic of granuloma annulare (H&E, original magnification ×100).

Juvenile xanthogranuloma (JXG) is a benign condition typically seen in children that is characterized by the presence of 1 or more pink or yellow nodules, most commonly presenting on the head and neck. Histologically, JXG demonstrates a dermal collection of histiocytes, lymphocytes, eosinophils, and characteristic Touton giant cells, which contain nuclei that are arranged in a wreathlike pattern and exhibit peripheral xanthomatization (Figure 5).³ The histiocytes in JXG typically stain positive for CD68 and negative for S-100 protein, though occasional S-100–positive cases are reported.³

Figure 5. Touton giant cells and occasional eosinophils in a sea of histiocytes and lymphocytes characterize juvenile xanthogranuloma (H&E, original magnification ×200).

Necrobiotic xanthogranuloma presents as yellowish to brown plaques and nodules most commonly in the periorbital area. Necrobiotic xanthogranuloma is strongly associated with monoclonal gammopathy, typically IgGk monoclonal gammopathy. Necrobiotic xanthogranuloma is histologically similar to NLD but is distinguished by a nodular pattern of inflammation and the frequent presence of cholesterol clefts (Figure 6).⁴

Figure 6. Necrobiotic xanthogranuloma is distinguished by the nodularity
of the infiltrate, with necrobiotic collagen, palisaded histiocytes and giant
cells, and the presence of cholesterol clefts (H&E, original
magnification ×40).

Necrobiosis lipoidica diabeticorum (NLD) is a rare granulomatous skin manifestation that is strongly associated with diabetes mellitus. Necrobiosis lipoidica diabeticorum is more common among females and occurs primarily in the pretibial area.¹ Necrobiosis lipoidica diabeticorum may clinically manifest as single or multiple lesions that begin as small red papules and progress into patches or plaques. Lesions ultimately develop into areas of yellowish brown atrophic tissue with central depression and telangiectasia. The etiology of NLD is not completely understood, but it is thought to be a presentation of diabetic microangiopathy.¹ Histologically, NLD demonstrates broad horizontal zones of necrobiosis with a surrounding inflammatory infiltrate that is principally composed of histiocytes but also may contain multinucleated giant cells, lymphocytes, and plasma cells (Figures 1 and 2). Occasionally, sarcoidal granulomas are seen in NLD. There also may be thickening of vessel walls and edema of the endothelial cells.¹

Figure 1. Broad horizontal arrangement of necrobiotic collagen with a surrounding inflammatory infiltrate of histiocytes and lymphocytes seen in necrobiosis lipoidica diabeticorum (H&E, original magnification ×20).

Figure 2. High-power view demonstrating lymphocytes and plasma cells at the inferior border of the necrobiotic collagen seen in necrobiosis lipoidica diabeticorum (H&E, original magnification ×200).

Cutaneous Rosai-Dorfman disease (RDD) is characterized by the presence of diffuse, large, pale histiocytes (commonly known as Rosai-Dorfman cells) with an admixed infiltrate of lymphocytes and plasma cells (Figure 3).² Additionally, Rosai-Dorfman cells display emperipolesis. They stain positively for S-100 protein and CD68 and negatively for CD1a.² Clinically, cutaneous RDD has a myriad of manifestations but most commonly presents as cutaneous nodules that can be tender or pruritic. It also may be associated with systemic symptoms. Patients with cutaneous RDD often have an elevated erythrocyte sedimentation rate and concomitant anemia.²

Figure 3. Sea of pale histiocytes with a patchy infiltrate of lymphocytes and plasma cells seen in cutaneous Rosai-Dorfman disease. Lymphocytes are seen within the cytoplasm of the histiocytes (emperipolesis)(H&E, original magnification ×200).

Granuloma annulare demonstrates necrobiosis and palisaded granulomatous dermatitis similar to NLD; however, the necrobiotic foci in granuloma annulare usually are more focal than in NLD and typically are surrounded by well-formed palisaded granulomas. There also is an increase in dermal mucin (Figure 4), which can be highlighted on colloidal iron or Alcian blue staining.¹ Granuloma annulare also typically has scattered eosinophils rather than plasma cells as seen in NLD. Granuloma annulare also may present in an interstitial pattern, with scattered histiocytes, mucin, and eosinophils between collagen bundles. Granuloma annulare clinically presents as variably colored papules arranged in an annular pattern on the distal extremities but also can present as widespread papules or plaques.

Figure 4. Necrobiotic collagen with abundant mucin surrounded by palisaded histiocytes, often with eosinophils characteristic of granuloma annulare (H&E, original magnification ×100).

Juvenile xanthogranuloma (JXG) is a benign condition typically seen in children that is characterized by the presence of 1 or more pink or yellow nodules, most commonly presenting on the head and neck. Histologically, JXG demonstrates a dermal collection of histiocytes, lymphocytes, eosinophils, and characteristic Touton giant cells, which contain nuclei that are arranged in a wreathlike pattern and exhibit peripheral xanthomatization (Figure 5).³ The histiocytes in JXG typically stain positive for CD68 and negative for S-100 protein, though occasional S-100–positive cases are reported.³

Figure 5. Touton giant cells and occasional eosinophils in a sea of histiocytes and lymphocytes characterize juvenile xanthogranuloma (H&E, original magnification ×200).

Necrobiotic xanthogranuloma presents as yellowish to brown plaques and nodules most commonly in the periorbital area. Necrobiotic xanthogranuloma is strongly associated with monoclonal gammopathy, typically IgGk monoclonal gammopathy. Necrobiotic xanthogranuloma is histologically similar to NLD but is distinguished by a nodular pattern of inflammation and the frequent presence of cholesterol clefts (Figure 6).⁴

Figure 6. Necrobiotic xanthogranuloma is distinguished by the nodularity
of the infiltrate, with necrobiotic collagen, palisaded histiocytes and giant
cells, and the presence of cholesterol clefts (H&E, original
magnification ×40).

PHILADELPHIA—The tumor microenvironment may play a key role in treatment with CUDC-427, according to researchers.

Their experiments showed that certain diffuse large B-cell lymphoma (DLBCL) cell lines were sensitive to CUDC-427, and others were not.

However, co-culturing with stromal cells or TNF family ligands made resistant cell lines sensitive to CUDC-427.

And mice bearing cells that resisted CUDC-427 in vitro responded very well to treatment, experiencing complete tumor regression.

Ze Tian, PhD, and her colleagues from Curis, Inc. (the company developing CUDC-427) presented these findings at the AACR Annual Meeting 2015 (abstract 5502).

CUDC-427 is an inhibitor of apoptosis (IAP) antagonist that is in early stage clinical testing in patients with solid tumors and lymphomas.

For the current research, Dr Tian and her colleagues first evaluated the effects of CUDC-427 against a range of hematologic malignancies in vitro. They tested the drug in activated B-cell-like (ABC) DLBCL, germinal center B-cell-like (GCB) DLBCL, other non-Hodgkin lymphomas, Hodgkin lymphoma, multiple myeloma, and various leukemia cell lines.

DLBCL cells (both ABC and GCB) proved the most sensitive to treatment, and CUDC-427 induced apoptosis in these cells. However, certain DLBCL cell lines, such as Karpas 422, were not sensitive to treatment.

The researchers found they could remedy that in two ways. The presence of stromal cells in culture sensitized resistant DLBCL cells to treatment, as did TNF family ligands (TNFα or TRAIL). In previous research, TNF family ligands were shown to synergize with IAP antagonists.

The investigators then analyzed CUDC-427’s mechanism of action. In the sensitive WSU-DLCL2 cell line, the drug worked by activating caspases 3, 8, and 9 by inhibiting cIAP1 and XIAP, as well as activating the non-canonical NF-ĸB pathway and inducing TNFα.

In the resistant Karpas 422 cell line, there was no caspase activity following CUDC-427 treatment. However, when the researchers co-cultured the cell line with stromal cells, they saw caspase activity.

“Because of this finding, we think that the microenvironment may play a role in CUDC-427 treatment,” Dr Tian said.

So the investigators went on to test CUDC-427 in mouse models. The drug inhibited tumor growth by 94% in the WSU-DLCL2 xenograft model. But CUDC-427 induced complete tumor regression in the Karpas 422 xenograft model.

To further investigate the interaction between the tumor microenvironment and CUDC-427, the researchers tested the drug in the A20 B-cell lymphoma mouse syngeneic model.

They found that CUDC-427 induced tumor stasis in this fast-growing lymphoma. They believe this may be due, in part, to the high levels of TRAIL in this model.

Dr Tian and her colleagues said the interaction between CUDC-427 and TNF family ligands or stromal cells warrants further analysis. And this research supports additional investigation to improve outcomes in patients with DLBCL.

PHILADELPHIA—The tumor microenvironment may play a key role in treatment with CUDC-427, according to researchers.

Their experiments showed that certain diffuse large B-cell lymphoma (DLBCL) cell lines were sensitive to CUDC-427, and others were not.

However, co-culturing with stromal cells or TNF family ligands made resistant cell lines sensitive to CUDC-427.

And mice bearing cells that resisted CUDC-427 in vitro responded very well to treatment, experiencing complete tumor regression.

Ze Tian, PhD, and her colleagues from Curis, Inc. (the company developing CUDC-427) presented these findings at the AACR Annual Meeting 2015 (abstract 5502).

CUDC-427 is an inhibitor of apoptosis (IAP) antagonist that is in early stage clinical testing in patients with solid tumors and lymphomas.

For the current research, Dr Tian and her colleagues first evaluated the effects of CUDC-427 against a range of hematologic malignancies in vitro. They tested the drug in activated B-cell-like (ABC) DLBCL, germinal center B-cell-like (GCB) DLBCL, other non-Hodgkin lymphomas, Hodgkin lymphoma, multiple myeloma, and various leukemia cell lines.

DLBCL cells (both ABC and GCB) proved the most sensitive to treatment, and CUDC-427 induced apoptosis in these cells. However, certain DLBCL cell lines, such as Karpas 422, were not sensitive to treatment.

The researchers found they could remedy that in two ways. The presence of stromal cells in culture sensitized resistant DLBCL cells to treatment, as did TNF family ligands (TNFα or TRAIL). In previous research, TNF family ligands were shown to synergize with IAP antagonists.

The investigators then analyzed CUDC-427’s mechanism of action. In the sensitive WSU-DLCL2 cell line, the drug worked by activating caspases 3, 8, and 9 by inhibiting cIAP1 and XIAP, as well as activating the non-canonical NF-ĸB pathway and inducing TNFα.

In the resistant Karpas 422 cell line, there was no caspase activity following CUDC-427 treatment. However, when the researchers co-cultured the cell line with stromal cells, they saw caspase activity.

“Because of this finding, we think that the microenvironment may play a role in CUDC-427 treatment,” Dr Tian said.

So the investigators went on to test CUDC-427 in mouse models. The drug inhibited tumor growth by 94% in the WSU-DLCL2 xenograft model. But CUDC-427 induced complete tumor regression in the Karpas 422 xenograft model.

To further investigate the interaction between the tumor microenvironment and CUDC-427, the researchers tested the drug in the A20 B-cell lymphoma mouse syngeneic model.

They found that CUDC-427 induced tumor stasis in this fast-growing lymphoma. They believe this may be due, in part, to the high levels of TRAIL in this model.

Dr Tian and her colleagues said the interaction between CUDC-427 and TNF family ligands or stromal cells warrants further analysis. And this research supports additional investigation to improve outcomes in patients with DLBCL.

PHILADELPHIA—The tumor microenvironment may play a key role in treatment with CUDC-427, according to researchers.

Their experiments showed that certain diffuse large B-cell lymphoma (DLBCL) cell lines were sensitive to CUDC-427, and others were not.

However, co-culturing with stromal cells or TNF family ligands made resistant cell lines sensitive to CUDC-427.

And mice bearing cells that resisted CUDC-427 in vitro responded very well to treatment, experiencing complete tumor regression.

Ze Tian, PhD, and her colleagues from Curis, Inc. (the company developing CUDC-427) presented these findings at the AACR Annual Meeting 2015 (abstract 5502).

CUDC-427 is an inhibitor of apoptosis (IAP) antagonist that is in early stage clinical testing in patients with solid tumors and lymphomas.

For the current research, Dr Tian and her colleagues first evaluated the effects of CUDC-427 against a range of hematologic malignancies in vitro. They tested the drug in activated B-cell-like (ABC) DLBCL, germinal center B-cell-like (GCB) DLBCL, other non-Hodgkin lymphomas, Hodgkin lymphoma, multiple myeloma, and various leukemia cell lines.

DLBCL cells (both ABC and GCB) proved the most sensitive to treatment, and CUDC-427 induced apoptosis in these cells. However, certain DLBCL cell lines, such as Karpas 422, were not sensitive to treatment.

The researchers found they could remedy that in two ways. The presence of stromal cells in culture sensitized resistant DLBCL cells to treatment, as did TNF family ligands (TNFα or TRAIL). In previous research, TNF family ligands were shown to synergize with IAP antagonists.

The investigators then analyzed CUDC-427’s mechanism of action. In the sensitive WSU-DLCL2 cell line, the drug worked by activating caspases 3, 8, and 9 by inhibiting cIAP1 and XIAP, as well as activating the non-canonical NF-ĸB pathway and inducing TNFα.

In the resistant Karpas 422 cell line, there was no caspase activity following CUDC-427 treatment. However, when the researchers co-cultured the cell line with stromal cells, they saw caspase activity.

“Because of this finding, we think that the microenvironment may play a role in CUDC-427 treatment,” Dr Tian said.

So the investigators went on to test CUDC-427 in mouse models. The drug inhibited tumor growth by 94% in the WSU-DLCL2 xenograft model. But CUDC-427 induced complete tumor regression in the Karpas 422 xenograft model.

To further investigate the interaction between the tumor microenvironment and CUDC-427, the researchers tested the drug in the A20 B-cell lymphoma mouse syngeneic model.

They found that CUDC-427 induced tumor stasis in this fast-growing lymphoma. They believe this may be due, in part, to the high levels of TRAIL in this model.

Dr Tian and her colleagues said the interaction between CUDC-427 and TNF family ligands or stromal cells warrants further analysis. And this research supports additional investigation to improve outcomes in patients with DLBCL.

New research has revealed a direct link between telomere degeneration and myelodysplastic syndromes (MDS).

“MDS risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly causes MDS is unknown,” said Simona Colla, PhD, of the MD Anderson Cancer Center in Houston, Texas.

“Our study provided genetic evidence that DNA damage caused by telomere loss is linked to this disorder.”

Dr Colla and her colleagues described this study in Cancer Cell.

The team’s in vitro and in vivo work showed that DNA damage caused by dysfunctional telomeres resulted in repressed expression of the gene SRSF2.

SRSF2 is an RNA splicing gene that plays a role in cellular processes. This change impacted common myeloid progenitors (CMPs), affecting their ability to differentiate or fully mature.

“This study established an intimate link across telomere biology, aberrant RNA splicing, and CMP differentiation,” said Ron DiPinho, MD, also of the MD Anderson Cancer Center.

“This may suggest that strategies to mitigate this DNA damage may be useful for preventing and/or treating MDS.”

Dr Colla added that the researchers’ findings “were consistent with long-standing observations that poor prognosis in MDS correlates strongly with short telomeres and elevated DNA damage in CMP cells.”

“This improved understanding should provide highly specific risk biomarkers for preventing and treating this incurable disease,” she said.

New research has revealed a direct link between telomere degeneration and myelodysplastic syndromes (MDS).

“MDS risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly causes MDS is unknown,” said Simona Colla, PhD, of the MD Anderson Cancer Center in Houston, Texas.

“Our study provided genetic evidence that DNA damage caused by telomere loss is linked to this disorder.”

Dr Colla and her colleagues described this study in Cancer Cell.

The team’s in vitro and in vivo work showed that DNA damage caused by dysfunctional telomeres resulted in repressed expression of the gene SRSF2.

SRSF2 is an RNA splicing gene that plays a role in cellular processes. This change impacted common myeloid progenitors (CMPs), affecting their ability to differentiate or fully mature.

“This study established an intimate link across telomere biology, aberrant RNA splicing, and CMP differentiation,” said Ron DiPinho, MD, also of the MD Anderson Cancer Center.

“This may suggest that strategies to mitigate this DNA damage may be useful for preventing and/or treating MDS.”

Dr Colla added that the researchers’ findings “were consistent with long-standing observations that poor prognosis in MDS correlates strongly with short telomeres and elevated DNA damage in CMP cells.”

“This improved understanding should provide highly specific risk biomarkers for preventing and treating this incurable disease,” she said.

New research has revealed a direct link between telomere degeneration and myelodysplastic syndromes (MDS).

“MDS risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly causes MDS is unknown,” said Simona Colla, PhD, of the MD Anderson Cancer Center in Houston, Texas.

“Our study provided genetic evidence that DNA damage caused by telomere loss is linked to this disorder.”

Dr Colla and her colleagues described this study in Cancer Cell.

The team’s in vitro and in vivo work showed that DNA damage caused by dysfunctional telomeres resulted in repressed expression of the gene SRSF2.

SRSF2 is an RNA splicing gene that plays a role in cellular processes. This change impacted common myeloid progenitors (CMPs), affecting their ability to differentiate or fully mature.

“This study established an intimate link across telomere biology, aberrant RNA splicing, and CMP differentiation,” said Ron DiPinho, MD, also of the MD Anderson Cancer Center.

“This may suggest that strategies to mitigate this DNA damage may be useful for preventing and/or treating MDS.”

Dr Colla added that the researchers’ findings “were consistent with long-standing observations that poor prognosis in MDS correlates strongly with short telomeres and elevated DNA damage in CMP cells.”

“This improved understanding should provide highly specific risk biomarkers for preventing and treating this incurable disease,” she said.

SAN FRANCISCO—Obese patients have a higher risk of bleeding while taking warfarin than patients of normal weight, according to research presented at the ATVB/PVD 2015 Scientific Sessions.

In a study of more than 800 patients taking the anticoagulant, obese individuals were almost twice as likely as normal-weight individuals to experience a major bleed.

And patients in the highest obesity class had the greatest risk of bleeding.

Adedotun A. Ogunsua, MD, of the University of Massachusetts Medical School in Worcester, presented these findings at the meeting as abstract 388.

He and his colleagues analyzed 863 patients taking warfarin. The researchers divided patients according to their body mass index (BMI) and looked at the rate of abnormal bleeding, including major gastrointestinal and brain bleeds and minor bleeds.

According to BMI, 21% of the patients were of normal weight, 38% were overweight, and 41.3% were obese, including class I (21%), class II (9%), and class III (11.3%).

Overall, 8.2% of patients (n=71) had abnormal bleeding during the study. Among the reported bleeds, about a third (35.2%) were major and two-thirds (64.8%) were minor.

Multivariable analyses showed that obesity (having a BMI higher than 30) significantly increased the risk of having a major bleed. The hazard ratio was 1.84 (P<0.001).

In univariate analyses, the risk of major bleeding increased with higher obesity categories. The hazard ratios were 1.30 for class I, 1.85 for class II, and 1.93 for class III.

The researchers said these results do not suggest patients should stop taking warfarin because of their weight. However, future studies are needed to understand why obesity increases the bleeding risk for patients receiving warfarin and whether similar risks exist for other anticoagulants.

SAN FRANCISCO—Obese patients have a higher risk of bleeding while taking warfarin than patients of normal weight, according to research presented at the ATVB/PVD 2015 Scientific Sessions.

In a study of more than 800 patients taking the anticoagulant, obese individuals were almost twice as likely as normal-weight individuals to experience a major bleed.

And patients in the highest obesity class had the greatest risk of bleeding.

Adedotun A. Ogunsua, MD, of the University of Massachusetts Medical School in Worcester, presented these findings at the meeting as abstract 388.

He and his colleagues analyzed 863 patients taking warfarin. The researchers divided patients according to their body mass index (BMI) and looked at the rate of abnormal bleeding, including major gastrointestinal and brain bleeds and minor bleeds.

According to BMI, 21% of the patients were of normal weight, 38% were overweight, and 41.3% were obese, including class I (21%), class II (9%), and class III (11.3%).

Overall, 8.2% of patients (n=71) had abnormal bleeding during the study. Among the reported bleeds, about a third (35.2%) were major and two-thirds (64.8%) were minor.

Multivariable analyses showed that obesity (having a BMI higher than 30) significantly increased the risk of having a major bleed. The hazard ratio was 1.84 (P<0.001).

In univariate analyses, the risk of major bleeding increased with higher obesity categories. The hazard ratios were 1.30 for class I, 1.85 for class II, and 1.93 for class III.

The researchers said these results do not suggest patients should stop taking warfarin because of their weight. However, future studies are needed to understand why obesity increases the bleeding risk for patients receiving warfarin and whether similar risks exist for other anticoagulants.

SAN FRANCISCO—Obese patients have a higher risk of bleeding while taking warfarin than patients of normal weight, according to research presented at the ATVB/PVD 2015 Scientific Sessions.

In a study of more than 800 patients taking the anticoagulant, obese individuals were almost twice as likely as normal-weight individuals to experience a major bleed.

And patients in the highest obesity class had the greatest risk of bleeding.

Adedotun A. Ogunsua, MD, of the University of Massachusetts Medical School in Worcester, presented these findings at the meeting as abstract 388.

He and his colleagues analyzed 863 patients taking warfarin. The researchers divided patients according to their body mass index (BMI) and looked at the rate of abnormal bleeding, including major gastrointestinal and brain bleeds and minor bleeds.

According to BMI, 21% of the patients were of normal weight, 38% were overweight, and 41.3% were obese, including class I (21%), class II (9%), and class III (11.3%).

Overall, 8.2% of patients (n=71) had abnormal bleeding during the study. Among the reported bleeds, about a third (35.2%) were major and two-thirds (64.8%) were minor.

Multivariable analyses showed that obesity (having a BMI higher than 30) significantly increased the risk of having a major bleed. The hazard ratio was 1.84 (P<0.001).

In univariate analyses, the risk of major bleeding increased with higher obesity categories. The hazard ratios were 1.30 for class I, 1.85 for class II, and 1.93 for class III.

The researchers said these results do not suggest patients should stop taking warfarin because of their weight. However, future studies are needed to understand why obesity increases the bleeding risk for patients receiving warfarin and whether similar risks exist for other anticoagulants.

Researchers believe they have found a new way to treat anemias that are resistant to erythropoietin (EPO).

The team identified a pair of drugs, one that is already approved for use in the US, that can activate the cell receptor PPAR-α and synergize with low amounts of

glucocorticoids to increase red blood cell (RBC) production.

Their research is serving as the foundation for an upcoming clinical trial in patients with Diamond-Blackfan anemia (DBA).

Harvey Lodish, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues described the research in a letter to Nature.

The team noted that certain anemias, such as DBA, cannot be treated with EPO. EPO controls RBC production by causing colony-forming-unit erythroids (CFU-Es) to divide and differentiate into RBCs. In DBA, the CFU-Es die before they can make RBCs, and patients have too few CFU-Es to make EPO treatment effective.

In 2010, Dr Lodish and his colleagues determined that glucocorticoids increase RBCs in EPO-resistant anemias by acting on burst-forming-unit erythroids (BFU-Es).

Glucocorticoids increase the likelihood that, when BFU-Es divide, one or both of the resulting cells remains a BFU-E instead of differentiating into CFU-Es. Patients treated with glucocorticoids have more BFU-Es, which, in turn, produce more CFU-Es and, ultimately, more RBCs.

With this in mind, the researchers screened for drugs that could interact with and boost glucocorticoids’ activity.

Glucocorticoids act by binding to a receptor in the cytoplasm that migrates into the nucleus and affects the expression of multiple genes. So the team screened for drugs that inhibit or activate other nuclear receptors.

They found that two drugs used to treat lipid disorders worked with glucocorticoids to increase RBC production in vitro. Both of these drugs, GW7647 and fenofibrate, activate PPARα. Fenofibrate was approved by the US Food and Drug Administration in 2001 and has been used to treat high cholesterol in adults and children.

When the researchers studied the mechanism of action of glucocorticoids and GW7647/fenofibrate, they found the glucocorticoid receptor binds to approximately 1000 sites in the DNA and turns on a large number of genes.

Fenofibrate and GW7647 activate the PPARα receptor, which subsequently binds adjacent to the glucocorticoid receptor on the DNA. The receptors modulate genes that are critical for BFU-E cell self-renewal and ultimately produce more RBCs.

When combined with dexamethasone, treatment with either GW7647 or fenofibrate led to a 150-fold increase in erythroblast production, which is 3- to 5-fold greater than the increase observed with dexamethasone alone.

These results have led the researchers to begin a clinical trial to test the effectiveness of a glucocorticoid/fenofibrate treatment in children with DBA.

Beyond the treatment of DBA, the researchers are optimistic about the impact that glucocorticoid/fenofibrate treatment might have on seemingly unrelated conditions.

“Glucocorticoids represent one of the most prescribed classes of drugs,” said Xiaofei Gao, PhD, a researcher in the Lodish lab.

“Basically, if PPARα is important in a disease that is currently treated by glucocorticoids, we may have a new way to treat those diseases that reduces the harmful side effects of glucocorticoids. That could affect a lot of patients.”

Researchers believe they have found a new way to treat anemias that are resistant to erythropoietin (EPO).

The team identified a pair of drugs, one that is already approved for use in the US, that can activate the cell receptor PPAR-α and synergize with low amounts of

glucocorticoids to increase red blood cell (RBC) production.

Their research is serving as the foundation for an upcoming clinical trial in patients with Diamond-Blackfan anemia (DBA).

Harvey Lodish, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues described the research in a letter to Nature.

The team noted that certain anemias, such as DBA, cannot be treated with EPO. EPO controls RBC production by causing colony-forming-unit erythroids (CFU-Es) to divide and differentiate into RBCs. In DBA, the CFU-Es die before they can make RBCs, and patients have too few CFU-Es to make EPO treatment effective.

In 2010, Dr Lodish and his colleagues determined that glucocorticoids increase RBCs in EPO-resistant anemias by acting on burst-forming-unit erythroids (BFU-Es).

Glucocorticoids increase the likelihood that, when BFU-Es divide, one or both of the resulting cells remains a BFU-E instead of differentiating into CFU-Es. Patients treated with glucocorticoids have more BFU-Es, which, in turn, produce more CFU-Es and, ultimately, more RBCs.

With this in mind, the researchers screened for drugs that could interact with and boost glucocorticoids’ activity.

Glucocorticoids act by binding to a receptor in the cytoplasm that migrates into the nucleus and affects the expression of multiple genes. So the team screened for drugs that inhibit or activate other nuclear receptors.

They found that two drugs used to treat lipid disorders worked with glucocorticoids to increase RBC production in vitro. Both of these drugs, GW7647 and fenofibrate, activate PPARα. Fenofibrate was approved by the US Food and Drug Administration in 2001 and has been used to treat high cholesterol in adults and children.

When the researchers studied the mechanism of action of glucocorticoids and GW7647/fenofibrate, they found the glucocorticoid receptor binds to approximately 1000 sites in the DNA and turns on a large number of genes.

Fenofibrate and GW7647 activate the PPARα receptor, which subsequently binds adjacent to the glucocorticoid receptor on the DNA. The receptors modulate genes that are critical for BFU-E cell self-renewal and ultimately produce more RBCs.

When combined with dexamethasone, treatment with either GW7647 or fenofibrate led to a 150-fold increase in erythroblast production, which is 3- to 5-fold greater than the increase observed with dexamethasone alone.

These results have led the researchers to begin a clinical trial to test the effectiveness of a glucocorticoid/fenofibrate treatment in children with DBA.

Beyond the treatment of DBA, the researchers are optimistic about the impact that glucocorticoid/fenofibrate treatment might have on seemingly unrelated conditions.

“Glucocorticoids represent one of the most prescribed classes of drugs,” said Xiaofei Gao, PhD, a researcher in the Lodish lab.

“Basically, if PPARα is important in a disease that is currently treated by glucocorticoids, we may have a new way to treat those diseases that reduces the harmful side effects of glucocorticoids. That could affect a lot of patients.”

Researchers believe they have found a new way to treat anemias that are resistant to erythropoietin (EPO).

The team identified a pair of drugs, one that is already approved for use in the US, that can activate the cell receptor PPAR-α and synergize with low amounts of

glucocorticoids to increase red blood cell (RBC) production.

Their research is serving as the foundation for an upcoming clinical trial in patients with Diamond-Blackfan anemia (DBA).

Harvey Lodish, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues described the research in a letter to Nature.

The team noted that certain anemias, such as DBA, cannot be treated with EPO. EPO controls RBC production by causing colony-forming-unit erythroids (CFU-Es) to divide and differentiate into RBCs. In DBA, the CFU-Es die before they can make RBCs, and patients have too few CFU-Es to make EPO treatment effective.

In 2010, Dr Lodish and his colleagues determined that glucocorticoids increase RBCs in EPO-resistant anemias by acting on burst-forming-unit erythroids (BFU-Es).

Glucocorticoids increase the likelihood that, when BFU-Es divide, one or both of the resulting cells remains a BFU-E instead of differentiating into CFU-Es. Patients treated with glucocorticoids have more BFU-Es, which, in turn, produce more CFU-Es and, ultimately, more RBCs.

With this in mind, the researchers screened for drugs that could interact with and boost glucocorticoids’ activity.

Glucocorticoids act by binding to a receptor in the cytoplasm that migrates into the nucleus and affects the expression of multiple genes. So the team screened for drugs that inhibit or activate other nuclear receptors.

They found that two drugs used to treat lipid disorders worked with glucocorticoids to increase RBC production in vitro. Both of these drugs, GW7647 and fenofibrate, activate PPARα. Fenofibrate was approved by the US Food and Drug Administration in 2001 and has been used to treat high cholesterol in adults and children.

When the researchers studied the mechanism of action of glucocorticoids and GW7647/fenofibrate, they found the glucocorticoid receptor binds to approximately 1000 sites in the DNA and turns on a large number of genes.

Fenofibrate and GW7647 activate the PPARα receptor, which subsequently binds adjacent to the glucocorticoid receptor on the DNA. The receptors modulate genes that are critical for BFU-E cell self-renewal and ultimately produce more RBCs.

When combined with dexamethasone, treatment with either GW7647 or fenofibrate led to a 150-fold increase in erythroblast production, which is 3- to 5-fold greater than the increase observed with dexamethasone alone.

These results have led the researchers to begin a clinical trial to test the effectiveness of a glucocorticoid/fenofibrate treatment in children with DBA.

Beyond the treatment of DBA, the researchers are optimistic about the impact that glucocorticoid/fenofibrate treatment might have on seemingly unrelated conditions.

“Glucocorticoids represent one of the most prescribed classes of drugs,” said Xiaofei Gao, PhD, a researcher in the Lodish lab.

“Basically, if PPARα is important in a disease that is currently treated by glucocorticoids, we may have a new way to treat those diseases that reduces the harmful side effects of glucocorticoids. That could affect a lot of patients.”

From the Department of Medicine, University of Pennsylvania, and the Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, PA.

 

Abstract

• Objective: To detail strategies to improve sepsis recognition and the quality of care provided to the septic patient.
• Methods: Review of the literature.
• Results: Severe sepsis affects nearly 3 million individuals each year in the United States, and cost estimates for these hospitalizations exceed $24 billion. Effective management is predicated on timely recognition. In this review, we detail strategies to improve early identification of potentially septic patients as well as the quality of care provided to the septic patient in the emergency department (ED). The strategies discussed are based upon an understanding of the signs and symptoms of sepsis and the clinical risk factors associated with sepsis, which can be used to design novel strategies to screen patients for sepsis and risk stratify patients at risk for clinical deterioration.
• Conclusion: ED structures and processes can be used to increase adherence with sepsis management guidelines to improve patient outcomes.

 

Severe sepsis affects nearly 3 million individuals each year in the United States and cost estimates for these hospitalizations exceed $24 billion [1–3]. Sepsis is a life-threatening condition characterized by a suspected or identified infection accompanied by a vigorous host inflammatory response. In severe sepsis, end-organ dysfunction manifests in myriad forms, including altered mental status, acute kidney injury, liver dysfunction, pulmonary dysfunction, and hemodynamic compromise [4,5]. This protean presentation of a deadly condition makes identification and risk stratification both challenging and essential to improving patient outcomes. The majority of patients with severe sepsis will receive their initial care within an emergency department (ED) [6,7]. It is essential that emergency medicine providers have the means to appropriately identify patients presenting with severe sepsis in a timely manner—thus facilitating life-saving measures such as early intravenous fluid resuscitation and administration of timely and appropriate antimicrobials.

In this review, we detail strategies to improve sepsis recognition and the quality of care provided to the septic patient in the ED. The strategies discussed are based upon an understanding of the signs and symptoms of sepsis and the clinical risk factors associated with sepsis, which can be used to design novel strategies to screen patients for sepsis and risk stratify patients for clinical deterioration. Then, we review suggested ED structures and processes to increase adherence with sepsis-based guidelines to improve patient outcomes. Successful implementation is predicated on hospital administrative support towards the efforts given the time and resources required and strong and committed leadership across the health care system.

Epidemiology of Severe Sepsis

Estimates of annual cases of severe sepsis vary, ranging from 1 million to 3 million cases in the United States [1–3]. In-hospital mortality for this condition ranges from 14% to 30% [5]. The incidence of severe sepsis in the United States has been increasing at a rate of 13% annually, with an estimated cost of greater than $24 billion per year [1,2]. In 2 large cohorts of hospitalized patients, it was found that sepsis contributed to 1 in every 2 to 3 deaths following inpatient admission [8]. Coincident with these increased estimates, advances in the early identification and treatment of sepsis have led to decreasing mortality rates over the past decade [1,9].

Of importance to the ED clinician, an episode of sepsis has long-term effects on cognitive and physical function, quality-of-life, and survival [10,11]. Post-discharge, approximately one-quarter of sepsis survivors will be readmitted within 30 days [12–14]. In as many as half of these instances, another life-threatening infection is the cause for readmission, making the past medical history, including a detailed accounting of recent episodes of sepsis, an important part of the initial ED evaluation [12]. Furthermore, severe sepsis survivors spend a large proportion of their time following discharge within a health care facility, and will frequently present to the ED with an acute condition from such an environment. Important factors for predicting readmission after a sepsis hospitalization include patient age, severity of illness, hospital length of stay, and the need for intensive care during the initial hospitalization [12–14].

Principles of Effective Sepsis Management

The principles of effective sepsis management begin with early identification in the pre-hospital setting, at triage, or when a patient begins to decompensate in the hospital. After the point of initial recognition, core principles include risk stratification, timely and appropriate antimicrobial administration, initial intravenous fluid boluses and ongoing resuscitation guided by physical examination and objective resuscitation end-points [4,5]. These practices have been operationalized in the care bundles of the Surviving Sepsis Campaign Guidelines [4]. Within 3 hours, the resuscitation bundle includes measuring serum lactate to risk stratify patients, obtaining blood cultures, administering broad-spectrum antibiotics, and administering 30 mL/kg crystalloid in patients with hypotension or hyperlactatemia [4]. The 6-hour bundle expands upon these initial measures and includes additional management recommendations based on resuscitation end-points.

As effective management is predicated on timely recognition, an understanding of the impact of delayed recognition is essential to provide optimal care for the severe sepsis patient in the ED. Decades of research has revealed that certain markers predict adverse outcomes, including transition to septic shock and death, as do delayed processes of care. Importantly, while early quantitative resuscitation was demonstrated to improve outcomes in a meta-analysis, there was no demonstrable benefit when resuscitation was initiated late (> 24 hours) in the course in the ICU (odds ratio of death, 1.16 [95% confidence interval, 0.60–2.22]) [15].

Strategies To Improve Recognition

Pre-Hospital Environment

As many as 40% of severe sepsis cases admitted to the hospital from the ED will present to the ED via emergency medical services (EMS) transport, and this rate appears to be increasing over time [16]. Thus, efforts to improve identification and risk-stratification of potential cases of severe sepsis should begin in the pre-hospital environment. These EMS encounters frequently exceed 45 minutes [16], pre-hospital interventions appear to be uncommon [16,17], and establishment of intravenous access paired with fluid resuscitation in the pre-hospital environment may improve survival [18]. Further, when EMS providers recognize sepsis, ED care processes (eg, time to antibiotics, protocol-directed resus-citation) are improved, with shorter time to antibiotics and initiation of early goal-directed therapy (EGDT) [19] and a trend towards achieving goal mean arterial pressure earlier [17]. In sum, while further investigation is required to facilitate this transition, efforts to improve sepsis outcomes should also include the interface between the pre-hospital environment and the ED (Figure).

From EMS to ED Triage

Borrowing the principle “time equals tissue” from a variety of time sensitive conditions (eg, myocardial infarction management [“time equals muscle”] and stroke care [“time equals brain”]), clinicians and researchers have realized that expedited recognition of severe sepsis patients begins at the time of initial contact with the health care system. For severe sepsis patients, clinicians need to think “time equals organ function.” Given the frequency with which sepsis patients arrive to the ED via EMS, effective communication between EMS and ED providers could be leveraged to prepare the ED team to provide timely care for the sepsis patient via a “sepsis alert.” While confirmation of its applicability to sepsis care is required in the absence of a regionalized network of sepsis centers, the rationale is based on the experience of the effectiveness of trauma and stroke alert systems [20–22]. For patients not recognized as potentially being infected by EMS providers during transport, repeat vital signs during ED triage can be screened to identify patients exhibiting signs of the systemic inflammatory response syndrome (SIRS) [4,23]. The same principles of effective communication apply for patients being sent from medical clinics to the ED for evaluation and treatment of potential severe sepsis. For patients arriving independent of EMS, focused triage and initial vital signs are the starting point for identifying severe sepsis at the most proximal phase of entry into the health care system.

Vital Signs and SIRS Criteria in the ED

The vast majority of patients who are hypotensive in triage are expedited to a treatment room and early resuscitation is begun. However, these patients represent a minority of severe sepsis patients seen in triage; therefore, all available data need to be analyzed to capture the highest percentage of severe sepsis patients. Acknowledging that SIRS criteria are not specific for sepsis [24], will miss as many as 1 out of 8 patients initially [25], and may not predict mortality [26], their presence is nonetheless characteristic of sepsis. As such, identifying the presence of SIRS at triage, or during the ED stay via serial vital signs, facilitates sepsis recognition, as do strategies that leverage routine vital signs to calculate predictors of instability including the shock index (heart rate/systolic blood pressure), where a shock index ≥ 0.7 has been associated with illness severity [27]. An increased respiratory rate has been demonstrated to identify risk for transfer from a floor bed to the ICU within 24 hours of ED admission [28]. Further, clinical manifestations of sepsis, including end-organ dysfunction, are protean, and patients frequently present with nonspecific, constitutional symptoms (eg, weakness, malaise, fever, chills, nausea) that could reflect one of many diseases (Table 1).

The Afferent Arm: Multimodal Screening Strategies

While institutional practice improvement initiatives to facilitate sepsis recognition and care should incorporate educational strategies, led by champions with expertise in sepsis, the complex presentation of sepsis requires multimodal approaches [29]. These multimodal approaches, beginning at the time of ED triage, should be designed to harness information technology to screen patients to improve severe sepsis recognition (the afferent arm) and to utilize structures and processes of care efficiently and effectively (the efferent arm) to guide severe sepsis management according to sepsis-care bundles espoused by guidelines (Figure) [4].

Operational processes to screen for sepsis in the ED will need to account for ED organizational flow (eg, average time from registration to triage, average time from triage to being seen by a physician, average length of stay in the ED, number of hospital beds) and hand-off practices (eg, care transition from ED team to floor or ICU team, or within ED at shift change). For ED organizations with shorter ED lengths of stay (eg, < 2 hours), screening practices at ED triage will serve as the focal point to identify cases of sepsis. Boarding, defined as caring for a patient in the ED pending transfer, is common, increasing as a result of ED closures [30,31], and associated with prolonged hospital length of stay and increased in-hospital mortality when ICU transfer is delayed [32]. Sepsis patients in particular appear to be a vulnerable group of patients. While many explanations exist to account for the relationship between delayed transfer and adverse outcomes, timely recognition and management of the septic patient could be compromised with prolonged boarding. To combat this potential effect, continual assessment during the entire ED stay may unmask an initially unclear presentation of sepsis.

One strategy to identify sepsis in ED organizations with prolonged ED lengths of stay is through the use of a track-and-trigger system, or early warning system. Traditionally, track-and-trigger systems were implemented on the hospital wards, as means to identify physiological deterioration in a timely manner to prevent clinical deterioration [33]. More recently, early warning systems have been used to identify patients with sepsis on the hospital wards and within EDs, as these systems rely on physiological parameters such as SIRS that are cardinal features of sepsis [34]. However, given the potential for alert fatigue, designing a system that operates with high accuracy is imperative.

Efforts are underway to redefine sepsis, using a simplified approach and readily available physiological variables, with the main goal of targeting those most at-risk of an adverse outcome during the hospitalization. Simultaneously, an understanding of the overt and more occult manifestations are essential to incorporate into the clinical decision-making and pattern recognition required to identify sepsis in a timely and accurate manner. In Table 2, the signs and symptoms that may serve as flags for severe sepsis are presented.

Mature early warning systems, designed to leverage the electronic medical record (EMR) by capturing vital signs, laboratory measures, (eg, elevated serum creatinine compared to a recent hospitalization) and symptoms (eg, altered mental status), are well-positioned to herald clinical deterioration (eg, cardiac arrest) with improved accuracy [35] and to be applied to sepsis specifically [34]. While sophisticated analytical strategies, such as machine learning, are being used to improve the test characteristics of these early warning systems, iterative, prospective chart review is an essential and complementary performance improvement step to refine the process. Further, chart review affords the opportunity to ensure compliance with sepsis care bundles.

Knowledge of the risk factors associated with development of sepsis is critical for the front-line emergency physician and nurse. Additionally, as many of these risk factors are associated with adverse outcomes, including unplanned ICU transfer and in-hospital mortality, which occur in as many as one out of 8 patients admitted directly to the ward, they have utility for early risk-stratification and triaging purposes in the ED. Advanced age and pre-existing comorbid conditions, particularly an oncologic diagnosis and/or chronic organ dysfunction, are major risk factors for sepsis and worse outcomes result in those who develop sepsis [2]. Further, illness severity, including an elevated serum lactate level, is associated with adverse outcomes. These factors can be incorporated into triage decisions and/or close monitoring for patients admitted to the general ward [36]. Conversely, because patients admitted to the ICU setting and subsequently stepped down through their hospitalization may experience better outcomes compared to patients admitted to the general ward who then require step-up to an ICU setting (37,38), attention to triage practices is critical.

These complementary strategies, which serve as the afferent arm of the system, summon health care providers to the bedside of a vulnerable patient. However, clinical effectiveness in the management of severe sepsis requires a robust, sophisticated, and mature efferent arm capable of delivering expert care to the now recognized septic patient.

Principles of Effective Management Post-Recognition

Risk Stratification

An elevated serum lactate level was initially described in pathological states in the mid 19th century by Johann Joseph Scherer [39] and has long been associated with increased mortality in hospitalized patients [40]. Lactate is a useful biomarker for risk stratification in a variety of patients arriving to the ED, particularly those who have been identified at high risk for sepsis. Jansen and colleagues examined the measurement of pre-hospital serum lactate at the time of paramedic on-scene assessment in a group of acutely ill patients [41]. Patients with point-of-care lactate levels of 3.5 mmol/L or greater were found to have an in-hospital mortality of 41% versus 12% for those with lactate levels less than 3.5 mmol/L. Within the population with an elevated lactate, patients with a systolic blood pressure greater than 100 mgHg experienced a mortality of nearly 30%, while it was greater than 50% in hypotensive patients with an elevated lactate, highlighting the value of both hemodynamic and serum lactate measures. Upon arrival to the ED, lactate measurements have a strong correlation with mortality. In one retrospective cohort, lactate level was linearly associated with mortality in a broad array of patients older than age 65 years [42]. An initial serum lactate level in the ED in the intermediate (2.0 – 3.9 mmol/L) or high range (≥ 4 mmol/L) has been associated with increased odds of death 2 to 5 times higher independent of organ dysfunction in severe sepsis specifically [43].

As the association between serum lactate levels and death is independent of organ dysfunction, serum lactate is a simple and reliable tool to both enhance detection and risk-stratify patients presenting to the ED with severe sepsis. Given the frequency with which hyperlactatemia is present in patients with suspected infection [43], operationalizing serum lactate measures with the initial phlebotomy draw is an important step to risk-stratify patients. This step can be coupled later with intravenous fluid resuscitation for those with marked elevations (≥ 4 mmol/L), in accord with guideline recommendations [4]. Screening of initial lactate values can be further expedited by utilizing fingerstick point-of-care lactate devices [44]. Last, while serial lactate measures can be incorporated into triage decisions, there is no clear threshold that warrants ICU admission. Rather, persistent elevations in serum lactate can be used to identify patients who require close observation regardless of their admission location.

Several scoring systems have been developed to augment sepsis risk stratification within the ED. The most prominent of these are the Predisposition Insult Response and Organ failure (PIRO), Sequential Organ Failure Assessment (SOFA), and Mortality in the Emergency Department Sepsis (MEDS) scores, and the National early warning score (NEWS) [45-48]. The MEDS score incorporates host factors including age and co-morbid illness, as well as physiologic and laboratory tests which can be obtained rapidly in an ED setting. Multiple prospective and retrospective examinations of the MEDS scoring systems have demonstrated that it performs optimally in ED patients with sepsis but not those with severe sepsis, in terms of predicting 30-day mortality [46,47]. The PIRO score more extensively incorporates predisposing co-morbidities, physiologic and laboratory parameters, and has been modified to consider presumed source of infection, leading to a stronger predictive ability for mortality in more severely ill patients. In patients presenting to the ED with severe sepsis and septic shock, a prospective observational study found the PIRO to be the best predictor of mortality, compared to SOFA and MEDS scores [45]. In a recent study by Corfield et al, sepsis patients with a higher NEWS, according to initial ED vital signs (temperature, pulse, respiratory rate, systolic blood pressure, oxyhemoglobin saturation) and consciousness level, were significantly more likely to be admitted to an ICU within 48 hours or to experience in-hospital mortality [48].

Timely and Appropriate Antibiotics

In a landmark study published by Kumar and colleagues in 2006, the relationship between timing of antibiotics and mortality was established [49]. In 2731 adult septic shock patients, mortality increased 7.6% for every hour delay in effective antimicrobial administration. A striking finding, given that the study population was limited to patients cared for in the ICU, was the fact that only 50% of patients received appropriate antibiotics within 6 hours of onset of shock and nearly one-quarter of patients did not receive antibiotics until the 15th hour. As a direct result, in-hospital mortality was observed to be 58% in this study.

Over the ensuing decade, a series of studies have demonstrated a narrowing of the quality gap in this regard, and the result has coincided with a significant improvement in survival. In 2010, Gaieski and colleagues demonstrated a significant improvement in the prompt administration of antibiotic delivery in patients presenting to an ED with severe sepsis, with the median time from shock onset (sustained hypotension or lactate ≥ 4 mmol/L) to antibiotics down to 42 minutes [50]. Importantly, consistent with the Kumar study, time to appropriate antibiotics, rather than simply initial antibiotics, remained associated with in-hospital mortality independent of initiating early goal-directed therapy. In 2011, Puskarich and colleagues revealed that time to antibiotics continued to improve and, as a result, the investigators did not identify a relationship between time from triage to antibiotics and in-hospital mortality [51]. However, when antibiotics were delayed until after shock recognition, consistent with the study by Kumar and colleagues, survival decreased. Until recently, this important observation was challenging to operationalize clinically as little was known about how to facilitate risk-stratification of those at risk to develop shock. However, Capp and colleagues recently found that deterioration to septic shock 48 hours after ED presentation occurs in approximately one out of eight patients and identified gender (female), transient hypotension, and/or hyperlactatemia upon presentation as risk factors associated with such a deterioration [52].

As an essential element of sepsis care bundles, a focus on timely use of antibiotics in patients with suspected infection, has the potential to increase the use of antibiotics in the ED in patients determined subsequently to not be infected. To combat this acknowledged downstream effect, reconsideration of the utility of empiric antibiotics 48 to 72 hours after admission is required. This step can be accomplished through the use of a sepsis care pathway and/or a formal antibiotic stewardship program.

Quantitative Resuscitation

Rivers and colleagues, in a landmark 2001 trial, examined the effectiveness of a protocolized resuscitation strategy in the most proximal phase of severe sepsis and septic shock [53]. A distinguishing characteristic between the usual care arm and the intervention in this ED-based study, in addition to whether mixed central venous oxygen saturation was measured as a resuscitation end-point, was the inclusion of an ED provider at the bedside to attend to clinical management. The intervention, aimed at achieving physiologic targets, resulted in significantly more fluid resuscitation (3.5 L vs. 5.0 L within the first 6 hours) and a significant decrease in in-hospital mortality compared to the usual care arm (46.5 vs. 30.5%). The study revolutionized the culture and practice of sepsis care, in part by shining a light on the importance of timely resuscitation at the most proximal point of contact between the patient and the healthcare system. It also highlighted the importance of integrating serum lactate measurement into the early screening and risk stratification processes for sepsis care delivery.

The 2014 randomized trial of Protocol-Based Care for Early Septic Shock (ProCESS) revisited this concept, comparing the Rivers 2001 protocol to both a current guideline-based non-invasive algorithmic protocol and what had become usual ED care in the interim [54]. The ProCESS trial, which operationalized a team of bedside providers to direct care for each of the 3 distinct arms, found no significant difference between the arms in terms of 90-day and 1-year mortality, but mortality was approximately 10% less in all arms compared with the intervention arm of the Rivers trial. Further, subjects in each of the 3 arms received in excess of 2 L intravenous fluid resuscitation pre-randomization and 4.4–5.5 L when resuscitation spanned from pre-randomization to 6 hours post-randomization. The conclusion drawn is that the commonalities between the arms—early fluid resuscitation, early antibiotics, and the option to use physiologic measures as markers of the adequacy of treatment, all guided by bedside ED providers—are the most important factors for surviving sepsis. And the result is that practitioners have refined these tools over a decade, leading to steady improvements in survival.

Consistent with the ProCESS trial, a recent Australia and New Zealand trial confirmed no significant difference in 90-day mortality between protocolized EGDT and current usual care for septic shock within an ED [55]. Consistent with ProCESS and ProMISe [56], subjects enrolled in ARISE received in excess of 2.5 L in resuscitation pre-randomization, which when paired with fluid resuscitation in the 0-6 hour post-randomization period (1.96 L in the EGDT arm and 1.71 in the usual-care arm) resulted in resuscitation in the 4.5 to 5L range during the initial resuscitation. The ARISE trial was unique in that appropriate antibiotic administration was a requirement prior to randomization, ensuring that this important driver of mortality reduction was standardized between the two arms of the trial. In summary, while the ideal fluid resuscitation amount is unknown, requires a personalized approach, and further investigation is required to effectively incorporate non-invasive measures to guide fluid responsiveness, early and aggressive resuscitation paired with early antibiotic administration are essential aspects of effective sepsis management.

The Efferent Arm: Structure And Processes To Improve Outcomes

The efferent arm of the system, beyond risk stratification, requires the implementation of optimal staffing and processes to care for the septic patient. While options will vary, preparation is a requisite, as are strategies that efficiently lead the clinician at the bedside to the use of evidence-based medicine (Table 2).

Personnel and Staffing

Quality care for the septic patient requires immediate availability of a multidisciplinary care team, including physicians and nurses with critical care experience who can be rapidly deployed to the bedside. The location of care provision may include on-going care in the initial ED room assignment or transfer to a dedicated area for the care of the critically ill patient within the ED.

To provide optimal care in the era of overcrowding and delayed transfer to an ICU, a movement towards ED intensive care units (ED-ICUs) has emerged [57]. The models of practice range from a model based upon ED intensivists, with expertise in critical care medicine, providing care within the traditional structure of an ED, to a model wherein a portion of the ED is assigned for the care of the critically ill for extended periods of time beyond the initial resuscitation. As these models mature from resuscitation bays capable of scaling up based on need to dedicated ED-ICUs, investments in shared Unit leadership (physician and nursing), staffing (physician, critical care nursing, respiratory therapy, critical care pharmacist) and processes of care (eg, multidisciplinary rounds) in line with established ICUs will be necessary.

While attractive conceptually, large-scale implementation of this movement is unlikely to occur outside of tertiary care academic medical centers. In the many EDs across the US without ED intensivists, and confronted with limited clinician resources, flexible physician and nursing staffing models will be necessary to ensure that care provisions are in accord with established guidelines. Potential solutions to provide the resources to meet the needs of these high-intensity patients include critical care consultation and a strategy traditionally applied to the ICU, telemedicine [58]. Last, given the relationship between hospital volume and mortality in severe sepsis [59,60], timely transfer to a high-volume center for specific cases may be appropriate, although the optimal timing, case selection, and impact of transfer on outcomes warrant further examination.

Clinical Decision Support Strategies

To complement the identification and risk-stratification available by screening and scoring systems, clinical decision support systems are novel tools to improve outcomes in the era of electronic medical records (EMR). Specific to sepsis care delivery, performance improvement initiatives including audit-and-feedback practice can increase severe sepsis guideline adherence, and even modest improvements in adherence appear to lead to sustained improvements that contributed to a 25% relative risk reduction in the observed mortality rate [61,62]. Clinical decision support tools can be used to link early recognition to optimal care processes, such as the Surviving Sepsis Campaign resuscitation and management bundles. The use of prompts as strategies to ensure that bundles of care are ordered and carried out is an important aspect to operationalize during the design phase [63].

Significant preparation is required to effectively carry out the clinical decision support design strategy. For example, to ensure timely antibiotic dispensing, a number of process steps will be required, including prompt notification to a central pharmacist or preferably, an ED pharmacist with access to a local pharmacy pre-stocked with commonly used antibiotics [64]. In addition, the use of an institution-specific antibiogram within the physician computer-order entry sepsis order set, that includes site-specific recommendations (eg, pulmonary, gastrointestinal source) and susceptibility patterns, is an essential aspect of optimal sepsis processes of care. Last, the antibiogram will need to be frequently updated to include season-specific (eg, oseltamivir administration for high-risk cases during influenza season) recommendations to ensure that providers are prompted with the most up-to-date clinical information.

Audit and Feedback and Continuous Performance Improvement

The multimodal approach required to translate knowledge (eg, guidelines) into sepsis care implemented at the bedside is an iterative process. An ED armed with a robust track-and-trigger system and an effective efferent arm, including sophisticated clinical decision support strategies, will require frequent auditing in the plan-do-study-act model of quality improvement to yield clinical effectiveness [61,62,65]. Auditing, paired with feedback to frontline providers, is essential to refine and improve the complex process required to provide expert care to the septic patient [29,65]. Sustained success in optimizing sepsis care delivery is the goal, yet significant work is required to determine the best strategies to achieve this endpoint.

Conclusion

Severe sepsis affects millions of individuals each year in the United States. Delays in recognition result in increased morbidity and mortality, at a tremendous cost to the patient and society. By designing strategies to identify sepsis in a timely, efficient, and effective manner, and by implementing ED structures and processes to increase adherence with sepsis-based guidelines, improved patient-centered outcomes can be realized.

 

Corresponding author: Mark E. Mikkelsen, MD, MSCE, Gates 05.042, 3400 Spruce St., Philadelphia, PA 19104, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JHM, MEM; analysis and interpretation of data, DFG; drafting of article, JHM, DFG, MEM; critical revision of the article, JHM, MEM.

From the Department of Medicine, University of Pennsylvania, and the Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, PA.

 

Abstract

• Objective: To detail strategies to improve sepsis recognition and the quality of care provided to the septic patient.
• Methods: Review of the literature.
• Results: Severe sepsis affects nearly 3 million individuals each year in the United States, and cost estimates for these hospitalizations exceed $24 billion. Effective management is predicated on timely recognition. In this review, we detail strategies to improve early identification of potentially septic patients as well as the quality of care provided to the septic patient in the emergency department (ED). The strategies discussed are based upon an understanding of the signs and symptoms of sepsis and the clinical risk factors associated with sepsis, which can be used to design novel strategies to screen patients for sepsis and risk stratify patients at risk for clinical deterioration.
• Conclusion: ED structures and processes can be used to increase adherence with sepsis management guidelines to improve patient outcomes.

 

Severe sepsis affects nearly 3 million individuals each year in the United States and cost estimates for these hospitalizations exceed $24 billion [1–3]. Sepsis is a life-threatening condition characterized by a suspected or identified infection accompanied by a vigorous host inflammatory response. In severe sepsis, end-organ dysfunction manifests in myriad forms, including altered mental status, acute kidney injury, liver dysfunction, pulmonary dysfunction, and hemodynamic compromise [4,5]. This protean presentation of a deadly condition makes identification and risk stratification both challenging and essential to improving patient outcomes. The majority of patients with severe sepsis will receive their initial care within an emergency department (ED) [6,7]. It is essential that emergency medicine providers have the means to appropriately identify patients presenting with severe sepsis in a timely manner—thus facilitating life-saving measures such as early intravenous fluid resuscitation and administration of timely and appropriate antimicrobials.

In this review, we detail strategies to improve sepsis recognition and the quality of care provided to the septic patient in the ED. The strategies discussed are based upon an understanding of the signs and symptoms of sepsis and the clinical risk factors associated with sepsis, which can be used to design novel strategies to screen patients for sepsis and risk stratify patients for clinical deterioration. Then, we review suggested ED structures and processes to increase adherence with sepsis-based guidelines to improve patient outcomes. Successful implementation is predicated on hospital administrative support towards the efforts given the time and resources required and strong and committed leadership across the health care system.

Epidemiology of Severe Sepsis

Estimates of annual cases of severe sepsis vary, ranging from 1 million to 3 million cases in the United States [1–3]. In-hospital mortality for this condition ranges from 14% to 30% [5]. The incidence of severe sepsis in the United States has been increasing at a rate of 13% annually, with an estimated cost of greater than $24 billion per year [1,2]. In 2 large cohorts of hospitalized patients, it was found that sepsis contributed to 1 in every 2 to 3 deaths following inpatient admission [8]. Coincident with these increased estimates, advances in the early identification and treatment of sepsis have led to decreasing mortality rates over the past decade [1,9].

Of importance to the ED clinician, an episode of sepsis has long-term effects on cognitive and physical function, quality-of-life, and survival [10,11]. Post-discharge, approximately one-quarter of sepsis survivors will be readmitted within 30 days [12–14]. In as many as half of these instances, another life-threatening infection is the cause for readmission, making the past medical history, including a detailed accounting of recent episodes of sepsis, an important part of the initial ED evaluation [12]. Furthermore, severe sepsis survivors spend a large proportion of their time following discharge within a health care facility, and will frequently present to the ED with an acute condition from such an environment. Important factors for predicting readmission after a sepsis hospitalization include patient age, severity of illness, hospital length of stay, and the need for intensive care during the initial hospitalization [12–14].

Principles of Effective Sepsis Management

The principles of effective sepsis management begin with early identification in the pre-hospital setting, at triage, or when a patient begins to decompensate in the hospital. After the point of initial recognition, core principles include risk stratification, timely and appropriate antimicrobial administration, initial intravenous fluid boluses and ongoing resuscitation guided by physical examination and objective resuscitation end-points [4,5]. These practices have been operationalized in the care bundles of the Surviving Sepsis Campaign Guidelines [4]. Within 3 hours, the resuscitation bundle includes measuring serum lactate to risk stratify patients, obtaining blood cultures, administering broad-spectrum antibiotics, and administering 30 mL/kg crystalloid in patients with hypotension or hyperlactatemia [4]. The 6-hour bundle expands upon these initial measures and includes additional management recommendations based on resuscitation end-points.

As effective management is predicated on timely recognition, an understanding of the impact of delayed recognition is essential to provide optimal care for the severe sepsis patient in the ED. Decades of research has revealed that certain markers predict adverse outcomes, including transition to septic shock and death, as do delayed processes of care. Importantly, while early quantitative resuscitation was demonstrated to improve outcomes in a meta-analysis, there was no demonstrable benefit when resuscitation was initiated late (> 24 hours) in the course in the ICU (odds ratio of death, 1.16 [95% confidence interval, 0.60–2.22]) [15].

Strategies To Improve Recognition

Pre-Hospital Environment

As many as 40% of severe sepsis cases admitted to the hospital from the ED will present to the ED via emergency medical services (EMS) transport, and this rate appears to be increasing over time [16]. Thus, efforts to improve identification and risk-stratification of potential cases of severe sepsis should begin in the pre-hospital environment. These EMS encounters frequently exceed 45 minutes [16], pre-hospital interventions appear to be uncommon [16,17], and establishment of intravenous access paired with fluid resuscitation in the pre-hospital environment may improve survival [18]. Further, when EMS providers recognize sepsis, ED care processes (eg, time to antibiotics, protocol-directed resus-citation) are improved, with shorter time to antibiotics and initiation of early goal-directed therapy (EGDT) [19] and a trend towards achieving goal mean arterial pressure earlier [17]. In sum, while further investigation is required to facilitate this transition, efforts to improve sepsis outcomes should also include the interface between the pre-hospital environment and the ED (Figure).

From EMS to ED Triage

Borrowing the principle “time equals tissue” from a variety of time sensitive conditions (eg, myocardial infarction management [“time equals muscle”] and stroke care [“time equals brain”]), clinicians and researchers have realized that expedited recognition of severe sepsis patients begins at the time of initial contact with the health care system. For severe sepsis patients, clinicians need to think “time equals organ function.” Given the frequency with which sepsis patients arrive to the ED via EMS, effective communication between EMS and ED providers could be leveraged to prepare the ED team to provide timely care for the sepsis patient via a “sepsis alert.” While confirmation of its applicability to sepsis care is required in the absence of a regionalized network of sepsis centers, the rationale is based on the experience of the effectiveness of trauma and stroke alert systems [20–22]. For patients not recognized as potentially being infected by EMS providers during transport, repeat vital signs during ED triage can be screened to identify patients exhibiting signs of the systemic inflammatory response syndrome (SIRS) [4,23]. The same principles of effective communication apply for patients being sent from medical clinics to the ED for evaluation and treatment of potential severe sepsis. For patients arriving independent of EMS, focused triage and initial vital signs are the starting point for identifying severe sepsis at the most proximal phase of entry into the health care system.

Vital Signs and SIRS Criteria in the ED

The vast majority of patients who are hypotensive in triage are expedited to a treatment room and early resuscitation is begun. However, these patients represent a minority of severe sepsis patients seen in triage; therefore, all available data need to be analyzed to capture the highest percentage of severe sepsis patients. Acknowledging that SIRS criteria are not specific for sepsis [24], will miss as many as 1 out of 8 patients initially [25], and may not predict mortality [26], their presence is nonetheless characteristic of sepsis. As such, identifying the presence of SIRS at triage, or during the ED stay via serial vital signs, facilitates sepsis recognition, as do strategies that leverage routine vital signs to calculate predictors of instability including the shock index (heart rate/systolic blood pressure), where a shock index ≥ 0.7 has been associated with illness severity [27]. An increased respiratory rate has been demonstrated to identify risk for transfer from a floor bed to the ICU within 24 hours of ED admission [28]. Further, clinical manifestations of sepsis, including end-organ dysfunction, are protean, and patients frequently present with nonspecific, constitutional symptoms (eg, weakness, malaise, fever, chills, nausea) that could reflect one of many diseases (Table 1).

The Afferent Arm: Multimodal Screening Strategies

While institutional practice improvement initiatives to facilitate sepsis recognition and care should incorporate educational strategies, led by champions with expertise in sepsis, the complex presentation of sepsis requires multimodal approaches [29]. These multimodal approaches, beginning at the time of ED triage, should be designed to harness information technology to screen patients to improve severe sepsis recognition (the afferent arm) and to utilize structures and processes of care efficiently and effectively (the efferent arm) to guide severe sepsis management according to sepsis-care bundles espoused by guidelines (Figure) [4].

Operational processes to screen for sepsis in the ED will need to account for ED organizational flow (eg, average time from registration to triage, average time from triage to being seen by a physician, average length of stay in the ED, number of hospital beds) and hand-off practices (eg, care transition from ED team to floor or ICU team, or within ED at shift change). For ED organizations with shorter ED lengths of stay (eg, < 2 hours), screening practices at ED triage will serve as the focal point to identify cases of sepsis. Boarding, defined as caring for a patient in the ED pending transfer, is common, increasing as a result of ED closures [30,31], and associated with prolonged hospital length of stay and increased in-hospital mortality when ICU transfer is delayed [32]. Sepsis patients in particular appear to be a vulnerable group of patients. While many explanations exist to account for the relationship between delayed transfer and adverse outcomes, timely recognition and management of the septic patient could be compromised with prolonged boarding. To combat this potential effect, continual assessment during the entire ED stay may unmask an initially unclear presentation of sepsis.

One strategy to identify sepsis in ED organizations with prolonged ED lengths of stay is through the use of a track-and-trigger system, or early warning system. Traditionally, track-and-trigger systems were implemented on the hospital wards, as means to identify physiological deterioration in a timely manner to prevent clinical deterioration [33]. More recently, early warning systems have been used to identify patients with sepsis on the hospital wards and within EDs, as these systems rely on physiological parameters such as SIRS that are cardinal features of sepsis [34]. However, given the potential for alert fatigue, designing a system that operates with high accuracy is imperative.

Efforts are underway to redefine sepsis, using a simplified approach and readily available physiological variables, with the main goal of targeting those most at-risk of an adverse outcome during the hospitalization. Simultaneously, an understanding of the overt and more occult manifestations are essential to incorporate into the clinical decision-making and pattern recognition required to identify sepsis in a timely and accurate manner. In Table 2, the signs and symptoms that may serve as flags for severe sepsis are presented.

Mature early warning systems, designed to leverage the electronic medical record (EMR) by capturing vital signs, laboratory measures, (eg, elevated serum creatinine compared to a recent hospitalization) and symptoms (eg, altered mental status), are well-positioned to herald clinical deterioration (eg, cardiac arrest) with improved accuracy [35] and to be applied to sepsis specifically [34]. While sophisticated analytical strategies, such as machine learning, are being used to improve the test characteristics of these early warning systems, iterative, prospective chart review is an essential and complementary performance improvement step to refine the process. Further, chart review affords the opportunity to ensure compliance with sepsis care bundles.

Knowledge of the risk factors associated with development of sepsis is critical for the front-line emergency physician and nurse. Additionally, as many of these risk factors are associated with adverse outcomes, including unplanned ICU transfer and in-hospital mortality, which occur in as many as one out of 8 patients admitted directly to the ward, they have utility for early risk-stratification and triaging purposes in the ED. Advanced age and pre-existing comorbid conditions, particularly an oncologic diagnosis and/or chronic organ dysfunction, are major risk factors for sepsis and worse outcomes result in those who develop sepsis [2]. Further, illness severity, including an elevated serum lactate level, is associated with adverse outcomes. These factors can be incorporated into triage decisions and/or close monitoring for patients admitted to the general ward [36]. Conversely, because patients admitted to the ICU setting and subsequently stepped down through their hospitalization may experience better outcomes compared to patients admitted to the general ward who then require step-up to an ICU setting (37,38), attention to triage practices is critical.

These complementary strategies, which serve as the afferent arm of the system, summon health care providers to the bedside of a vulnerable patient. However, clinical effectiveness in the management of severe sepsis requires a robust, sophisticated, and mature efferent arm capable of delivering expert care to the now recognized septic patient.

Principles of Effective Management Post-Recognition

Risk Stratification

An elevated serum lactate level was initially described in pathological states in the mid 19th century by Johann Joseph Scherer [39] and has long been associated with increased mortality in hospitalized patients [40]. Lactate is a useful biomarker for risk stratification in a variety of patients arriving to the ED, particularly those who have been identified at high risk for sepsis. Jansen and colleagues examined the measurement of pre-hospital serum lactate at the time of paramedic on-scene assessment in a group of acutely ill patients [41]. Patients with point-of-care lactate levels of 3.5 mmol/L or greater were found to have an in-hospital mortality of 41% versus 12% for those with lactate levels less than 3.5 mmol/L. Within the population with an elevated lactate, patients with a systolic blood pressure greater than 100 mgHg experienced a mortality of nearly 30%, while it was greater than 50% in hypotensive patients with an elevated lactate, highlighting the value of both hemodynamic and serum lactate measures. Upon arrival to the ED, lactate measurements have a strong correlation with mortality. In one retrospective cohort, lactate level was linearly associated with mortality in a broad array of patients older than age 65 years [42]. An initial serum lactate level in the ED in the intermediate (2.0 – 3.9 mmol/L) or high range (≥ 4 mmol/L) has been associated with increased odds of death 2 to 5 times higher independent of organ dysfunction in severe sepsis specifically [43].

As the association between serum lactate levels and death is independent of organ dysfunction, serum lactate is a simple and reliable tool to both enhance detection and risk-stratify patients presenting to the ED with severe sepsis. Given the frequency with which hyperlactatemia is present in patients with suspected infection [43], operationalizing serum lactate measures with the initial phlebotomy draw is an important step to risk-stratify patients. This step can be coupled later with intravenous fluid resuscitation for those with marked elevations (≥ 4 mmol/L), in accord with guideline recommendations [4]. Screening of initial lactate values can be further expedited by utilizing fingerstick point-of-care lactate devices [44]. Last, while serial lactate measures can be incorporated into triage decisions, there is no clear threshold that warrants ICU admission. Rather, persistent elevations in serum lactate can be used to identify patients who require close observation regardless of their admission location.

Several scoring systems have been developed to augment sepsis risk stratification within the ED. The most prominent of these are the Predisposition Insult Response and Organ failure (PIRO), Sequential Organ Failure Assessment (SOFA), and Mortality in the Emergency Department Sepsis (MEDS) scores, and the National early warning score (NEWS) [45-48]. The MEDS score incorporates host factors including age and co-morbid illness, as well as physiologic and laboratory tests which can be obtained rapidly in an ED setting. Multiple prospective and retrospective examinations of the MEDS scoring systems have demonstrated that it performs optimally in ED patients with sepsis but not those with severe sepsis, in terms of predicting 30-day mortality [46,47]. The PIRO score more extensively incorporates predisposing co-morbidities, physiologic and laboratory parameters, and has been modified to consider presumed source of infection, leading to a stronger predictive ability for mortality in more severely ill patients. In patients presenting to the ED with severe sepsis and septic shock, a prospective observational study found the PIRO to be the best predictor of mortality, compared to SOFA and MEDS scores [45]. In a recent study by Corfield et al, sepsis patients with a higher NEWS, according to initial ED vital signs (temperature, pulse, respiratory rate, systolic blood pressure, oxyhemoglobin saturation) and consciousness level, were significantly more likely to be admitted to an ICU within 48 hours or to experience in-hospital mortality [48].

Timely and Appropriate Antibiotics

In a landmark study published by Kumar and colleagues in 2006, the relationship between timing of antibiotics and mortality was established [49]. In 2731 adult septic shock patients, mortality increased 7.6% for every hour delay in effective antimicrobial administration. A striking finding, given that the study population was limited to patients cared for in the ICU, was the fact that only 50% of patients received appropriate antibiotics within 6 hours of onset of shock and nearly one-quarter of patients did not receive antibiotics until the 15th hour. As a direct result, in-hospital mortality was observed to be 58% in this study.

Over the ensuing decade, a series of studies have demonstrated a narrowing of the quality gap in this regard, and the result has coincided with a significant improvement in survival. In 2010, Gaieski and colleagues demonstrated a significant improvement in the prompt administration of antibiotic delivery in patients presenting to an ED with severe sepsis, with the median time from shock onset (sustained hypotension or lactate ≥ 4 mmol/L) to antibiotics down to 42 minutes [50]. Importantly, consistent with the Kumar study, time to appropriate antibiotics, rather than simply initial antibiotics, remained associated with in-hospital mortality independent of initiating early goal-directed therapy. In 2011, Puskarich and colleagues revealed that time to antibiotics continued to improve and, as a result, the investigators did not identify a relationship between time from triage to antibiotics and in-hospital mortality [51]. However, when antibiotics were delayed until after shock recognition, consistent with the study by Kumar and colleagues, survival decreased. Until recently, this important observation was challenging to operationalize clinically as little was known about how to facilitate risk-stratification of those at risk to develop shock. However, Capp and colleagues recently found that deterioration to septic shock 48 hours after ED presentation occurs in approximately one out of eight patients and identified gender (female), transient hypotension, and/or hyperlactatemia upon presentation as risk factors associated with such a deterioration [52].

As an essential element of sepsis care bundles, a focus on timely use of antibiotics in patients with suspected infection, has the potential to increase the use of antibiotics in the ED in patients determined subsequently to not be infected. To combat this acknowledged downstream effect, reconsideration of the utility of empiric antibiotics 48 to 72 hours after admission is required. This step can be accomplished through the use of a sepsis care pathway and/or a formal antibiotic stewardship program.

Quantitative Resuscitation

Rivers and colleagues, in a landmark 2001 trial, examined the effectiveness of a protocolized resuscitation strategy in the most proximal phase of severe sepsis and septic shock [53]. A distinguishing characteristic between the usual care arm and the intervention in this ED-based study, in addition to whether mixed central venous oxygen saturation was measured as a resuscitation end-point, was the inclusion of an ED provider at the bedside to attend to clinical management. The intervention, aimed at achieving physiologic targets, resulted in significantly more fluid resuscitation (3.5 L vs. 5.0 L within the first 6 hours) and a significant decrease in in-hospital mortality compared to the usual care arm (46.5 vs. 30.5%). The study revolutionized the culture and practice of sepsis care, in part by shining a light on the importance of timely resuscitation at the most proximal point of contact between the patient and the healthcare system. It also highlighted the importance of integrating serum lactate measurement into the early screening and risk stratification processes for sepsis care delivery.

The 2014 randomized trial of Protocol-Based Care for Early Septic Shock (ProCESS) revisited this concept, comparing the Rivers 2001 protocol to both a current guideline-based non-invasive algorithmic protocol and what had become usual ED care in the interim [54]. The ProCESS trial, which operationalized a team of bedside providers to direct care for each of the 3 distinct arms, found no significant difference between the arms in terms of 90-day and 1-year mortality, but mortality was approximately 10% less in all arms compared with the intervention arm of the Rivers trial. Further, subjects in each of the 3 arms received in excess of 2 L intravenous fluid resuscitation pre-randomization and 4.4–5.5 L when resuscitation spanned from pre-randomization to 6 hours post-randomization. The conclusion drawn is that the commonalities between the arms—early fluid resuscitation, early antibiotics, and the option to use physiologic measures as markers of the adequacy of treatment, all guided by bedside ED providers—are the most important factors for surviving sepsis. And the result is that practitioners have refined these tools over a decade, leading to steady improvements in survival.

Consistent with the ProCESS trial, a recent Australia and New Zealand trial confirmed no significant difference in 90-day mortality between protocolized EGDT and current usual care for septic shock within an ED [55]. Consistent with ProCESS and ProMISe [56], subjects enrolled in ARISE received in excess of 2.5 L in resuscitation pre-randomization, which when paired with fluid resuscitation in the 0-6 hour post-randomization period (1.96 L in the EGDT arm and 1.71 in the usual-care arm) resulted in resuscitation in the 4.5 to 5L range during the initial resuscitation. The ARISE trial was unique in that appropriate antibiotic administration was a requirement prior to randomization, ensuring that this important driver of mortality reduction was standardized between the two arms of the trial. In summary, while the ideal fluid resuscitation amount is unknown, requires a personalized approach, and further investigation is required to effectively incorporate non-invasive measures to guide fluid responsiveness, early and aggressive resuscitation paired with early antibiotic administration are essential aspects of effective sepsis management.

The Efferent Arm: Structure And Processes To Improve Outcomes

The efferent arm of the system, beyond risk stratification, requires the implementation of optimal staffing and processes to care for the septic patient. While options will vary, preparation is a requisite, as are strategies that efficiently lead the clinician at the bedside to the use of evidence-based medicine (Table 2).

Personnel and Staffing

Quality care for the septic patient requires immediate availability of a multidisciplinary care team, including physicians and nurses with critical care experience who can be rapidly deployed to the bedside. The location of care provision may include on-going care in the initial ED room assignment or transfer to a dedicated area for the care of the critically ill patient within the ED.

To provide optimal care in the era of overcrowding and delayed transfer to an ICU, a movement towards ED intensive care units (ED-ICUs) has emerged [57]. The models of practice range from a model based upon ED intensivists, with expertise in critical care medicine, providing care within the traditional structure of an ED, to a model wherein a portion of the ED is assigned for the care of the critically ill for extended periods of time beyond the initial resuscitation. As these models mature from resuscitation bays capable of scaling up based on need to dedicated ED-ICUs, investments in shared Unit leadership (physician and nursing), staffing (physician, critical care nursing, respiratory therapy, critical care pharmacist) and processes of care (eg, multidisciplinary rounds) in line with established ICUs will be necessary.

While attractive conceptually, large-scale implementation of this movement is unlikely to occur outside of tertiary care academic medical centers. In the many EDs across the US without ED intensivists, and confronted with limited clinician resources, flexible physician and nursing staffing models will be necessary to ensure that care provisions are in accord with established guidelines. Potential solutions to provide the resources to meet the needs of these high-intensity patients include critical care consultation and a strategy traditionally applied to the ICU, telemedicine [58]. Last, given the relationship between hospital volume and mortality in severe sepsis [59,60], timely transfer to a high-volume center for specific cases may be appropriate, although the optimal timing, case selection, and impact of transfer on outcomes warrant further examination.

Clinical Decision Support Strategies

To complement the identification and risk-stratification available by screening and scoring systems, clinical decision support systems are novel tools to improve outcomes in the era of electronic medical records (EMR). Specific to sepsis care delivery, performance improvement initiatives including audit-and-feedback practice can increase severe sepsis guideline adherence, and even modest improvements in adherence appear to lead to sustained improvements that contributed to a 25% relative risk reduction in the observed mortality rate [61,62]. Clinical decision support tools can be used to link early recognition to optimal care processes, such as the Surviving Sepsis Campaign resuscitation and management bundles. The use of prompts as strategies to ensure that bundles of care are ordered and carried out is an important aspect to operationalize during the design phase [63].

Significant preparation is required to effectively carry out the clinical decision support design strategy. For example, to ensure timely antibiotic dispensing, a number of process steps will be required, including prompt notification to a central pharmacist or preferably, an ED pharmacist with access to a local pharmacy pre-stocked with commonly used antibiotics [64]. In addition, the use of an institution-specific antibiogram within the physician computer-order entry sepsis order set, that includes site-specific recommendations (eg, pulmonary, gastrointestinal source) and susceptibility patterns, is an essential aspect of optimal sepsis processes of care. Last, the antibiogram will need to be frequently updated to include season-specific (eg, oseltamivir administration for high-risk cases during influenza season) recommendations to ensure that providers are prompted with the most up-to-date clinical information.

Audit and Feedback and Continuous Performance Improvement

The multimodal approach required to translate knowledge (eg, guidelines) into sepsis care implemented at the bedside is an iterative process. An ED armed with a robust track-and-trigger system and an effective efferent arm, including sophisticated clinical decision support strategies, will require frequent auditing in the plan-do-study-act model of quality improvement to yield clinical effectiveness [61,62,65]. Auditing, paired with feedback to frontline providers, is essential to refine and improve the complex process required to provide expert care to the septic patient [29,65]. Sustained success in optimizing sepsis care delivery is the goal, yet significant work is required to determine the best strategies to achieve this endpoint.

Conclusion

Severe sepsis affects millions of individuals each year in the United States. Delays in recognition result in increased morbidity and mortality, at a tremendous cost to the patient and society. By designing strategies to identify sepsis in a timely, efficient, and effective manner, and by implementing ED structures and processes to increase adherence with sepsis-based guidelines, improved patient-centered outcomes can be realized.

 

Corresponding author: Mark E. Mikkelsen, MD, MSCE, Gates 05.042, 3400 Spruce St., Philadelphia, PA 19104, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JHM, MEM; analysis and interpretation of data, DFG; drafting of article, JHM, DFG, MEM; critical revision of the article, JHM, MEM.

From the Department of Medicine, University of Pennsylvania, and the Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, PA.

 

Abstract

• Objective: To detail strategies to improve sepsis recognition and the quality of care provided to the septic patient.
• Methods: Review of the literature.
• Results: Severe sepsis affects nearly 3 million individuals each year in the United States, and cost estimates for these hospitalizations exceed $24 billion. Effective management is predicated on timely recognition. In this review, we detail strategies to improve early identification of potentially septic patients as well as the quality of care provided to the septic patient in the emergency department (ED). The strategies discussed are based upon an understanding of the signs and symptoms of sepsis and the clinical risk factors associated with sepsis, which can be used to design novel strategies to screen patients for sepsis and risk stratify patients at risk for clinical deterioration.
• Conclusion: ED structures and processes can be used to increase adherence with sepsis management guidelines to improve patient outcomes.

 

Severe sepsis affects nearly 3 million individuals each year in the United States and cost estimates for these hospitalizations exceed $24 billion [1–3]. Sepsis is a life-threatening condition characterized by a suspected or identified infection accompanied by a vigorous host inflammatory response. In severe sepsis, end-organ dysfunction manifests in myriad forms, including altered mental status, acute kidney injury, liver dysfunction, pulmonary dysfunction, and hemodynamic compromise [4,5]. This protean presentation of a deadly condition makes identification and risk stratification both challenging and essential to improving patient outcomes. The majority of patients with severe sepsis will receive their initial care within an emergency department (ED) [6,7]. It is essential that emergency medicine providers have the means to appropriately identify patients presenting with severe sepsis in a timely manner—thus facilitating life-saving measures such as early intravenous fluid resuscitation and administration of timely and appropriate antimicrobials.

In this review, we detail strategies to improve sepsis recognition and the quality of care provided to the septic patient in the ED. The strategies discussed are based upon an understanding of the signs and symptoms of sepsis and the clinical risk factors associated with sepsis, which can be used to design novel strategies to screen patients for sepsis and risk stratify patients for clinical deterioration. Then, we review suggested ED structures and processes to increase adherence with sepsis-based guidelines to improve patient outcomes. Successful implementation is predicated on hospital administrative support towards the efforts given the time and resources required and strong and committed leadership across the health care system.

Epidemiology of Severe Sepsis

Estimates of annual cases of severe sepsis vary, ranging from 1 million to 3 million cases in the United States [1–3]. In-hospital mortality for this condition ranges from 14% to 30% [5]. The incidence of severe sepsis in the United States has been increasing at a rate of 13% annually, with an estimated cost of greater than $24 billion per year [1,2]. In 2 large cohorts of hospitalized patients, it was found that sepsis contributed to 1 in every 2 to 3 deaths following inpatient admission [8]. Coincident with these increased estimates, advances in the early identification and treatment of sepsis have led to decreasing mortality rates over the past decade [1,9].

Of importance to the ED clinician, an episode of sepsis has long-term effects on cognitive and physical function, quality-of-life, and survival [10,11]. Post-discharge, approximately one-quarter of sepsis survivors will be readmitted within 30 days [12–14]. In as many as half of these instances, another life-threatening infection is the cause for readmission, making the past medical history, including a detailed accounting of recent episodes of sepsis, an important part of the initial ED evaluation [12]. Furthermore, severe sepsis survivors spend a large proportion of their time following discharge within a health care facility, and will frequently present to the ED with an acute condition from such an environment. Important factors for predicting readmission after a sepsis hospitalization include patient age, severity of illness, hospital length of stay, and the need for intensive care during the initial hospitalization [12–14].

Principles of Effective Sepsis Management

The principles of effective sepsis management begin with early identification in the pre-hospital setting, at triage, or when a patient begins to decompensate in the hospital. After the point of initial recognition, core principles include risk stratification, timely and appropriate antimicrobial administration, initial intravenous fluid boluses and ongoing resuscitation guided by physical examination and objective resuscitation end-points [4,5]. These practices have been operationalized in the care bundles of the Surviving Sepsis Campaign Guidelines [4]. Within 3 hours, the resuscitation bundle includes measuring serum lactate to risk stratify patients, obtaining blood cultures, administering broad-spectrum antibiotics, and administering 30 mL/kg crystalloid in patients with hypotension or hyperlactatemia [4]. The 6-hour bundle expands upon these initial measures and includes additional management recommendations based on resuscitation end-points.

As effective management is predicated on timely recognition, an understanding of the impact of delayed recognition is essential to provide optimal care for the severe sepsis patient in the ED. Decades of research has revealed that certain markers predict adverse outcomes, including transition to septic shock and death, as do delayed processes of care. Importantly, while early quantitative resuscitation was demonstrated to improve outcomes in a meta-analysis, there was no demonstrable benefit when resuscitation was initiated late (> 24 hours) in the course in the ICU (odds ratio of death, 1.16 [95% confidence interval, 0.60–2.22]) [15].

Strategies To Improve Recognition

Pre-Hospital Environment

As many as 40% of severe sepsis cases admitted to the hospital from the ED will present to the ED via emergency medical services (EMS) transport, and this rate appears to be increasing over time [16]. Thus, efforts to improve identification and risk-stratification of potential cases of severe sepsis should begin in the pre-hospital environment. These EMS encounters frequently exceed 45 minutes [16], pre-hospital interventions appear to be uncommon [16,17], and establishment of intravenous access paired with fluid resuscitation in the pre-hospital environment may improve survival [18]. Further, when EMS providers recognize sepsis, ED care processes (eg, time to antibiotics, protocol-directed resus-citation) are improved, with shorter time to antibiotics and initiation of early goal-directed therapy (EGDT) [19] and a trend towards achieving goal mean arterial pressure earlier [17]. In sum, while further investigation is required to facilitate this transition, efforts to improve sepsis outcomes should also include the interface between the pre-hospital environment and the ED (Figure).

From EMS to ED Triage

Borrowing the principle “time equals tissue” from a variety of time sensitive conditions (eg, myocardial infarction management [“time equals muscle”] and stroke care [“time equals brain”]), clinicians and researchers have realized that expedited recognition of severe sepsis patients begins at the time of initial contact with the health care system. For severe sepsis patients, clinicians need to think “time equals organ function.” Given the frequency with which sepsis patients arrive to the ED via EMS, effective communication between EMS and ED providers could be leveraged to prepare the ED team to provide timely care for the sepsis patient via a “sepsis alert.” While confirmation of its applicability to sepsis care is required in the absence of a regionalized network of sepsis centers, the rationale is based on the experience of the effectiveness of trauma and stroke alert systems [20–22]. For patients not recognized as potentially being infected by EMS providers during transport, repeat vital signs during ED triage can be screened to identify patients exhibiting signs of the systemic inflammatory response syndrome (SIRS) [4,23]. The same principles of effective communication apply for patients being sent from medical clinics to the ED for evaluation and treatment of potential severe sepsis. For patients arriving independent of EMS, focused triage and initial vital signs are the starting point for identifying severe sepsis at the most proximal phase of entry into the health care system.

Vital Signs and SIRS Criteria in the ED

The vast majority of patients who are hypotensive in triage are expedited to a treatment room and early resuscitation is begun. However, these patients represent a minority of severe sepsis patients seen in triage; therefore, all available data need to be analyzed to capture the highest percentage of severe sepsis patients. Acknowledging that SIRS criteria are not specific for sepsis [24], will miss as many as 1 out of 8 patients initially [25], and may not predict mortality [26], their presence is nonetheless characteristic of sepsis. As such, identifying the presence of SIRS at triage, or during the ED stay via serial vital signs, facilitates sepsis recognition, as do strategies that leverage routine vital signs to calculate predictors of instability including the shock index (heart rate/systolic blood pressure), where a shock index ≥ 0.7 has been associated with illness severity [27]. An increased respiratory rate has been demonstrated to identify risk for transfer from a floor bed to the ICU within 24 hours of ED admission [28]. Further, clinical manifestations of sepsis, including end-organ dysfunction, are protean, and patients frequently present with nonspecific, constitutional symptoms (eg, weakness, malaise, fever, chills, nausea) that could reflect one of many diseases (Table 1).

The Afferent Arm: Multimodal Screening Strategies

While institutional practice improvement initiatives to facilitate sepsis recognition and care should incorporate educational strategies, led by champions with expertise in sepsis, the complex presentation of sepsis requires multimodal approaches [29]. These multimodal approaches, beginning at the time of ED triage, should be designed to harness information technology to screen patients to improve severe sepsis recognition (the afferent arm) and to utilize structures and processes of care efficiently and effectively (the efferent arm) to guide severe sepsis management according to sepsis-care bundles espoused by guidelines (Figure) [4].

Operational processes to screen for sepsis in the ED will need to account for ED organizational flow (eg, average time from registration to triage, average time from triage to being seen by a physician, average length of stay in the ED, number of hospital beds) and hand-off practices (eg, care transition from ED team to floor or ICU team, or within ED at shift change). For ED organizations with shorter ED lengths of stay (eg, < 2 hours), screening practices at ED triage will serve as the focal point to identify cases of sepsis. Boarding, defined as caring for a patient in the ED pending transfer, is common, increasing as a result of ED closures [30,31], and associated with prolonged hospital length of stay and increased in-hospital mortality when ICU transfer is delayed [32]. Sepsis patients in particular appear to be a vulnerable group of patients. While many explanations exist to account for the relationship between delayed transfer and adverse outcomes, timely recognition and management of the septic patient could be compromised with prolonged boarding. To combat this potential effect, continual assessment during the entire ED stay may unmask an initially unclear presentation of sepsis.

One strategy to identify sepsis in ED organizations with prolonged ED lengths of stay is through the use of a track-and-trigger system, or early warning system. Traditionally, track-and-trigger systems were implemented on the hospital wards, as means to identify physiological deterioration in a timely manner to prevent clinical deterioration [33]. More recently, early warning systems have been used to identify patients with sepsis on the hospital wards and within EDs, as these systems rely on physiological parameters such as SIRS that are cardinal features of sepsis [34]. However, given the potential for alert fatigue, designing a system that operates with high accuracy is imperative.

Efforts are underway to redefine sepsis, using a simplified approach and readily available physiological variables, with the main goal of targeting those most at-risk of an adverse outcome during the hospitalization. Simultaneously, an understanding of the overt and more occult manifestations are essential to incorporate into the clinical decision-making and pattern recognition required to identify sepsis in a timely and accurate manner. In Table 2, the signs and symptoms that may serve as flags for severe sepsis are presented.

Mature early warning systems, designed to leverage the electronic medical record (EMR) by capturing vital signs, laboratory measures, (eg, elevated serum creatinine compared to a recent hospitalization) and symptoms (eg, altered mental status), are well-positioned to herald clinical deterioration (eg, cardiac arrest) with improved accuracy [35] and to be applied to sepsis specifically [34]. While sophisticated analytical strategies, such as machine learning, are being used to improve the test characteristics of these early warning systems, iterative, prospective chart review is an essential and complementary performance improvement step to refine the process. Further, chart review affords the opportunity to ensure compliance with sepsis care bundles.

Knowledge of the risk factors associated with development of sepsis is critical for the front-line emergency physician and nurse. Additionally, as many of these risk factors are associated with adverse outcomes, including unplanned ICU transfer and in-hospital mortality, which occur in as many as one out of 8 patients admitted directly to the ward, they have utility for early risk-stratification and triaging purposes in the ED. Advanced age and pre-existing comorbid conditions, particularly an oncologic diagnosis and/or chronic organ dysfunction, are major risk factors for sepsis and worse outcomes result in those who develop sepsis [2]. Further, illness severity, including an elevated serum lactate level, is associated with adverse outcomes. These factors can be incorporated into triage decisions and/or close monitoring for patients admitted to the general ward [36]. Conversely, because patients admitted to the ICU setting and subsequently stepped down through their hospitalization may experience better outcomes compared to patients admitted to the general ward who then require step-up to an ICU setting (37,38), attention to triage practices is critical.

These complementary strategies, which serve as the afferent arm of the system, summon health care providers to the bedside of a vulnerable patient. However, clinical effectiveness in the management of severe sepsis requires a robust, sophisticated, and mature efferent arm capable of delivering expert care to the now recognized septic patient.

Principles of Effective Management Post-Recognition

Risk Stratification

An elevated serum lactate level was initially described in pathological states in the mid 19th century by Johann Joseph Scherer [39] and has long been associated with increased mortality in hospitalized patients [40]. Lactate is a useful biomarker for risk stratification in a variety of patients arriving to the ED, particularly those who have been identified at high risk for sepsis. Jansen and colleagues examined the measurement of pre-hospital serum lactate at the time of paramedic on-scene assessment in a group of acutely ill patients [41]. Patients with point-of-care lactate levels of 3.5 mmol/L or greater were found to have an in-hospital mortality of 41% versus 12% for those with lactate levels less than 3.5 mmol/L. Within the population with an elevated lactate, patients with a systolic blood pressure greater than 100 mgHg experienced a mortality of nearly 30%, while it was greater than 50% in hypotensive patients with an elevated lactate, highlighting the value of both hemodynamic and serum lactate measures. Upon arrival to the ED, lactate measurements have a strong correlation with mortality. In one retrospective cohort, lactate level was linearly associated with mortality in a broad array of patients older than age 65 years [42]. An initial serum lactate level in the ED in the intermediate (2.0 – 3.9 mmol/L) or high range (≥ 4 mmol/L) has been associated with increased odds of death 2 to 5 times higher independent of organ dysfunction in severe sepsis specifically [43].

As the association between serum lactate levels and death is independent of organ dysfunction, serum lactate is a simple and reliable tool to both enhance detection and risk-stratify patients presenting to the ED with severe sepsis. Given the frequency with which hyperlactatemia is present in patients with suspected infection [43], operationalizing serum lactate measures with the initial phlebotomy draw is an important step to risk-stratify patients. This step can be coupled later with intravenous fluid resuscitation for those with marked elevations (≥ 4 mmol/L), in accord with guideline recommendations [4]. Screening of initial lactate values can be further expedited by utilizing fingerstick point-of-care lactate devices [44]. Last, while serial lactate measures can be incorporated into triage decisions, there is no clear threshold that warrants ICU admission. Rather, persistent elevations in serum lactate can be used to identify patients who require close observation regardless of their admission location.

Several scoring systems have been developed to augment sepsis risk stratification within the ED. The most prominent of these are the Predisposition Insult Response and Organ failure (PIRO), Sequential Organ Failure Assessment (SOFA), and Mortality in the Emergency Department Sepsis (MEDS) scores, and the National early warning score (NEWS) [45-48]. The MEDS score incorporates host factors including age and co-morbid illness, as well as physiologic and laboratory tests which can be obtained rapidly in an ED setting. Multiple prospective and retrospective examinations of the MEDS scoring systems have demonstrated that it performs optimally in ED patients with sepsis but not those with severe sepsis, in terms of predicting 30-day mortality [46,47]. The PIRO score more extensively incorporates predisposing co-morbidities, physiologic and laboratory parameters, and has been modified to consider presumed source of infection, leading to a stronger predictive ability for mortality in more severely ill patients. In patients presenting to the ED with severe sepsis and septic shock, a prospective observational study found the PIRO to be the best predictor of mortality, compared to SOFA and MEDS scores [45]. In a recent study by Corfield et al, sepsis patients with a higher NEWS, according to initial ED vital signs (temperature, pulse, respiratory rate, systolic blood pressure, oxyhemoglobin saturation) and consciousness level, were significantly more likely to be admitted to an ICU within 48 hours or to experience in-hospital mortality [48].

Timely and Appropriate Antibiotics

In a landmark study published by Kumar and colleagues in 2006, the relationship between timing of antibiotics and mortality was established [49]. In 2731 adult septic shock patients, mortality increased 7.6% for every hour delay in effective antimicrobial administration. A striking finding, given that the study population was limited to patients cared for in the ICU, was the fact that only 50% of patients received appropriate antibiotics within 6 hours of onset of shock and nearly one-quarter of patients did not receive antibiotics until the 15th hour. As a direct result, in-hospital mortality was observed to be 58% in this study.

Over the ensuing decade, a series of studies have demonstrated a narrowing of the quality gap in this regard, and the result has coincided with a significant improvement in survival. In 2010, Gaieski and colleagues demonstrated a significant improvement in the prompt administration of antibiotic delivery in patients presenting to an ED with severe sepsis, with the median time from shock onset (sustained hypotension or lactate ≥ 4 mmol/L) to antibiotics down to 42 minutes [50]. Importantly, consistent with the Kumar study, time to appropriate antibiotics, rather than simply initial antibiotics, remained associated with in-hospital mortality independent of initiating early goal-directed therapy. In 2011, Puskarich and colleagues revealed that time to antibiotics continued to improve and, as a result, the investigators did not identify a relationship between time from triage to antibiotics and in-hospital mortality [51]. However, when antibiotics were delayed until after shock recognition, consistent with the study by Kumar and colleagues, survival decreased. Until recently, this important observation was challenging to operationalize clinically as little was known about how to facilitate risk-stratification of those at risk to develop shock. However, Capp and colleagues recently found that deterioration to septic shock 48 hours after ED presentation occurs in approximately one out of eight patients and identified gender (female), transient hypotension, and/or hyperlactatemia upon presentation as risk factors associated with such a deterioration [52].

As an essential element of sepsis care bundles, a focus on timely use of antibiotics in patients with suspected infection, has the potential to increase the use of antibiotics in the ED in patients determined subsequently to not be infected. To combat this acknowledged downstream effect, reconsideration of the utility of empiric antibiotics 48 to 72 hours after admission is required. This step can be accomplished through the use of a sepsis care pathway and/or a formal antibiotic stewardship program.

Quantitative Resuscitation

Rivers and colleagues, in a landmark 2001 trial, examined the effectiveness of a protocolized resuscitation strategy in the most proximal phase of severe sepsis and septic shock [53]. A distinguishing characteristic between the usual care arm and the intervention in this ED-based study, in addition to whether mixed central venous oxygen saturation was measured as a resuscitation end-point, was the inclusion of an ED provider at the bedside to attend to clinical management. The intervention, aimed at achieving physiologic targets, resulted in significantly more fluid resuscitation (3.5 L vs. 5.0 L within the first 6 hours) and a significant decrease in in-hospital mortality compared to the usual care arm (46.5 vs. 30.5%). The study revolutionized the culture and practice of sepsis care, in part by shining a light on the importance of timely resuscitation at the most proximal point of contact between the patient and the healthcare system. It also highlighted the importance of integrating serum lactate measurement into the early screening and risk stratification processes for sepsis care delivery.

The 2014 randomized trial of Protocol-Based Care for Early Septic Shock (ProCESS) revisited this concept, comparing the Rivers 2001 protocol to both a current guideline-based non-invasive algorithmic protocol and what had become usual ED care in the interim [54]. The ProCESS trial, which operationalized a team of bedside providers to direct care for each of the 3 distinct arms, found no significant difference between the arms in terms of 90-day and 1-year mortality, but mortality was approximately 10% less in all arms compared with the intervention arm of the Rivers trial. Further, subjects in each of the 3 arms received in excess of 2 L intravenous fluid resuscitation pre-randomization and 4.4–5.5 L when resuscitation spanned from pre-randomization to 6 hours post-randomization. The conclusion drawn is that the commonalities between the arms—early fluid resuscitation, early antibiotics, and the option to use physiologic measures as markers of the adequacy of treatment, all guided by bedside ED providers—are the most important factors for surviving sepsis. And the result is that practitioners have refined these tools over a decade, leading to steady improvements in survival.

Consistent with the ProCESS trial, a recent Australia and New Zealand trial confirmed no significant difference in 90-day mortality between protocolized EGDT and current usual care for septic shock within an ED [55]. Consistent with ProCESS and ProMISe [56], subjects enrolled in ARISE received in excess of 2.5 L in resuscitation pre-randomization, which when paired with fluid resuscitation in the 0-6 hour post-randomization period (1.96 L in the EGDT arm and 1.71 in the usual-care arm) resulted in resuscitation in the 4.5 to 5L range during the initial resuscitation. The ARISE trial was unique in that appropriate antibiotic administration was a requirement prior to randomization, ensuring that this important driver of mortality reduction was standardized between the two arms of the trial. In summary, while the ideal fluid resuscitation amount is unknown, requires a personalized approach, and further investigation is required to effectively incorporate non-invasive measures to guide fluid responsiveness, early and aggressive resuscitation paired with early antibiotic administration are essential aspects of effective sepsis management.

The Efferent Arm: Structure And Processes To Improve Outcomes

The efferent arm of the system, beyond risk stratification, requires the implementation of optimal staffing and processes to care for the septic patient. While options will vary, preparation is a requisite, as are strategies that efficiently lead the clinician at the bedside to the use of evidence-based medicine (Table 2).

Personnel and Staffing

Quality care for the septic patient requires immediate availability of a multidisciplinary care team, including physicians and nurses with critical care experience who can be rapidly deployed to the bedside. The location of care provision may include on-going care in the initial ED room assignment or transfer to a dedicated area for the care of the critically ill patient within the ED.

To provide optimal care in the era of overcrowding and delayed transfer to an ICU, a movement towards ED intensive care units (ED-ICUs) has emerged [57]. The models of practice range from a model based upon ED intensivists, with expertise in critical care medicine, providing care within the traditional structure of an ED, to a model wherein a portion of the ED is assigned for the care of the critically ill for extended periods of time beyond the initial resuscitation. As these models mature from resuscitation bays capable of scaling up based on need to dedicated ED-ICUs, investments in shared Unit leadership (physician and nursing), staffing (physician, critical care nursing, respiratory therapy, critical care pharmacist) and processes of care (eg, multidisciplinary rounds) in line with established ICUs will be necessary.

While attractive conceptually, large-scale implementation of this movement is unlikely to occur outside of tertiary care academic medical centers. In the many EDs across the US without ED intensivists, and confronted with limited clinician resources, flexible physician and nursing staffing models will be necessary to ensure that care provisions are in accord with established guidelines. Potential solutions to provide the resources to meet the needs of these high-intensity patients include critical care consultation and a strategy traditionally applied to the ICU, telemedicine [58]. Last, given the relationship between hospital volume and mortality in severe sepsis [59,60], timely transfer to a high-volume center for specific cases may be appropriate, although the optimal timing, case selection, and impact of transfer on outcomes warrant further examination.

Clinical Decision Support Strategies

To complement the identification and risk-stratification available by screening and scoring systems, clinical decision support systems are novel tools to improve outcomes in the era of electronic medical records (EMR). Specific to sepsis care delivery, performance improvement initiatives including audit-and-feedback practice can increase severe sepsis guideline adherence, and even modest improvements in adherence appear to lead to sustained improvements that contributed to a 25% relative risk reduction in the observed mortality rate [61,62]. Clinical decision support tools can be used to link early recognition to optimal care processes, such as the Surviving Sepsis Campaign resuscitation and management bundles. The use of prompts as strategies to ensure that bundles of care are ordered and carried out is an important aspect to operationalize during the design phase [63].

Significant preparation is required to effectively carry out the clinical decision support design strategy. For example, to ensure timely antibiotic dispensing, a number of process steps will be required, including prompt notification to a central pharmacist or preferably, an ED pharmacist with access to a local pharmacy pre-stocked with commonly used antibiotics [64]. In addition, the use of an institution-specific antibiogram within the physician computer-order entry sepsis order set, that includes site-specific recommendations (eg, pulmonary, gastrointestinal source) and susceptibility patterns, is an essential aspect of optimal sepsis processes of care. Last, the antibiogram will need to be frequently updated to include season-specific (eg, oseltamivir administration for high-risk cases during influenza season) recommendations to ensure that providers are prompted with the most up-to-date clinical information.

Audit and Feedback and Continuous Performance Improvement

The multimodal approach required to translate knowledge (eg, guidelines) into sepsis care implemented at the bedside is an iterative process. An ED armed with a robust track-and-trigger system and an effective efferent arm, including sophisticated clinical decision support strategies, will require frequent auditing in the plan-do-study-act model of quality improvement to yield clinical effectiveness [61,62,65]. Auditing, paired with feedback to frontline providers, is essential to refine and improve the complex process required to provide expert care to the septic patient [29,65]. Sustained success in optimizing sepsis care delivery is the goal, yet significant work is required to determine the best strategies to achieve this endpoint.

Conclusion

Severe sepsis affects millions of individuals each year in the United States. Delays in recognition result in increased morbidity and mortality, at a tremendous cost to the patient and society. By designing strategies to identify sepsis in a timely, efficient, and effective manner, and by implementing ED structures and processes to increase adherence with sepsis-based guidelines, improved patient-centered outcomes can be realized.

 

Corresponding author: Mark E. Mikkelsen, MD, MSCE, Gates 05.042, 3400 Spruce St., Philadelphia, PA 19104, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JHM, MEM; analysis and interpretation of data, DFG; drafting of article, JHM, DFG, MEM; critical revision of the article, JHM, MEM.

Whenever I meet families who oppose vaccination, my first response is to flood them with more evidence, reciting the pro-vaccine fact sheet that every doctor knows by heart. I can’t help myself. The evidence is so self-explanatory that it should put any question to rest.

But this approach may just exacerbate the problem. In fact, studies suggest that attacking parents’ beliefs can backfire, and that “attempts to increase concerns about communicable diseases or correct false claims about vaccines may be … counterproductive.” We can inform parents that vaccines prevent thousands of deaths and millions of cases of disease while saving billions in health care costs, but this will not change the mind of someone who does not trust the data.

One major problem is that doctors and parents sometimes speak different languages. As trainees, we are raised on nomograms, algorithms, and clinical trials. When a problem presents itself, we instinctively seek out a rational, data-driven response. This is how doctors are built, but studies suggest that vaccine-hesitant parents may be built differently, driven more by fears and negative emotions than by data. Their decisions seem to be based not on a misunderstanding of the facts, but rather a mistrust of the facts.

As pediatric trainees, this is the world we are inheriting. The more successful vaccines become at preventing disease, the harder it will become to convince parents of the serious risks of nonvaccination. It is a perpetual uphill battle.

To make the future better for our patients (and to contribute to our future sanity), we need to work past frustrations and focus on developing pragmatic solutions. There is surely no easy or perfect answer, and different parents may require different approaches, but the status quo is not working. To find the solutions, we need to develop a robust evidence base to guide our good intentions. Perhaps the answer will come from tailoring communication strategies, refocusing public outreach efforts, creating legal mandates, or maybe something completely different.

And if we are successful, maybe we can close the communications gap between vaccine-resisting parents and doctors.

Dr. Sisk is a pediatrics resident at St. Louis Children’s Hospital. E-mail him at [email protected].

Whenever I meet families who oppose vaccination, my first response is to flood them with more evidence, reciting the pro-vaccine fact sheet that every doctor knows by heart. I can’t help myself. The evidence is so self-explanatory that it should put any question to rest.

But this approach may just exacerbate the problem. In fact, studies suggest that attacking parents’ beliefs can backfire, and that “attempts to increase concerns about communicable diseases or correct false claims about vaccines may be … counterproductive.” We can inform parents that vaccines prevent thousands of deaths and millions of cases of disease while saving billions in health care costs, but this will not change the mind of someone who does not trust the data.

One major problem is that doctors and parents sometimes speak different languages. As trainees, we are raised on nomograms, algorithms, and clinical trials. When a problem presents itself, we instinctively seek out a rational, data-driven response. This is how doctors are built, but studies suggest that vaccine-hesitant parents may be built differently, driven more by fears and negative emotions than by data. Their decisions seem to be based not on a misunderstanding of the facts, but rather a mistrust of the facts.

As pediatric trainees, this is the world we are inheriting. The more successful vaccines become at preventing disease, the harder it will become to convince parents of the serious risks of nonvaccination. It is a perpetual uphill battle.

To make the future better for our patients (and to contribute to our future sanity), we need to work past frustrations and focus on developing pragmatic solutions. There is surely no easy or perfect answer, and different parents may require different approaches, but the status quo is not working. To find the solutions, we need to develop a robust evidence base to guide our good intentions. Perhaps the answer will come from tailoring communication strategies, refocusing public outreach efforts, creating legal mandates, or maybe something completely different.

And if we are successful, maybe we can close the communications gap between vaccine-resisting parents and doctors.

Dr. Sisk is a pediatrics resident at St. Louis Children’s Hospital. E-mail him at [email protected].

Whenever I meet families who oppose vaccination, my first response is to flood them with more evidence, reciting the pro-vaccine fact sheet that every doctor knows by heart. I can’t help myself. The evidence is so self-explanatory that it should put any question to rest.

But this approach may just exacerbate the problem. In fact, studies suggest that attacking parents’ beliefs can backfire, and that “attempts to increase concerns about communicable diseases or correct false claims about vaccines may be … counterproductive.” We can inform parents that vaccines prevent thousands of deaths and millions of cases of disease while saving billions in health care costs, but this will not change the mind of someone who does not trust the data.

One major problem is that doctors and parents sometimes speak different languages. As trainees, we are raised on nomograms, algorithms, and clinical trials. When a problem presents itself, we instinctively seek out a rational, data-driven response. This is how doctors are built, but studies suggest that vaccine-hesitant parents may be built differently, driven more by fears and negative emotions than by data. Their decisions seem to be based not on a misunderstanding of the facts, but rather a mistrust of the facts.

As pediatric trainees, this is the world we are inheriting. The more successful vaccines become at preventing disease, the harder it will become to convince parents of the serious risks of nonvaccination. It is a perpetual uphill battle.

To make the future better for our patients (and to contribute to our future sanity), we need to work past frustrations and focus on developing pragmatic solutions. There is surely no easy or perfect answer, and different parents may require different approaches, but the status quo is not working. To find the solutions, we need to develop a robust evidence base to guide our good intentions. Perhaps the answer will come from tailoring communication strategies, refocusing public outreach efforts, creating legal mandates, or maybe something completely different.

And if we are successful, maybe we can close the communications gap between vaccine-resisting parents and doctors.

Dr. Sisk is a pediatrics resident at St. Louis Children’s Hospital. E-mail him at [email protected].